WO2002092606A1 - Fused imidazolidine derivatives, process for preparation of the same and use thereof - Google Patents

Abstract

Compounds represented by the general formula (I) and having excellent inhibitory activity against the degradation of cartilage matrix; or salts or sulfoxides of the same: (I) wherein R1 is -(S)n-R2 (wherein R2 is optionally substituted hydrocarbyl or the like; and n is an integer of 0 to 2) or the like; R5 is hydrogen, optionally substituted hydrocarbyl, or the like; symbol (II) is a group represented by the general formula (III) or the like; and symbol (IV) is a group represented by the general formula (V) or the like: (II) (III) (IV) (V) [wherein R6 is hydrogen, optionally substituted hydrocarbyl, or the like; R10 is -ZR15 (wherein Z is -SO2- or the like; and R15 is optionally substituted hydrocarbyl or the like) or the like; and R11 is hydrogen or the like].

Description

 Specification

 Condensed imidazolidine derivatives, their production methods and applications

 The present invention relates to a novel condensed imidazolidine derivative useful as a medicament such as an agent for treating a joint disease, a method for producing the same, or an agent therefor. Background art

 Osteoarthritis is a progressive disease with degeneration and destruction of articular cartilage caused by aging, obesity> mechanical stress, inflammation, etc., and mainly occurs in the knee and hip joints. In recent years, in the developed countries, the increase in the prevalence due to the increase in the elderly has become a problem, and anti-inflammatory drugs and hyaluronic acid preparations have been used as therapeutic agents mainly for the purpose of pain relief [Bad Etz Chin- (Bird, HA :), Drugs & Aging, 12, 87-95, 1998, Lund, B., Scandinavian Journal Rhematology (Scandinavian J. Rheumatol.), Vol. 27, pp. 32-37, 1998, and Ando Inoue, Diagnosis and treatment of osteoarthritis, Medical Shoin, 94-99, 1994].

Cartilage is formed from chondrocytes and a cartilage matrix produced by chondrocytes.The matrix components are proteodalican, which has hydration ability and gives flexibility and elasticity to cartilage, and type II, which forms a reticulated skeleton. It is roughly divided into collagen. Cartilage destruction in osteoarthritis can be divided into two stages: proteodalican degradation followed by type II collagen degradation [Poole, AR], Takashi Fujisawa (translation), protein nucleic acid enzymes, 40, 520—531, 1995, Takei Doi et al., The Bone, 1, 293—297, 2000]. Hymen ialdisine, a compound derived from a marine sponge, has been reported to inhibit proteoglycan degradation from articular cartilage [Alison, MB (Alison, MB), The Journal of Pharmaceutical Sciences and Ande The Journal of Pharmacology and Experimental Therapeutics, Vol. 290, pp. 587-593, 1999], and a derivative of hymenialdisine, debromohymenialdisine (DBH), Inhibition of matrix meta-oral proteinase (MMP) mRNA production in articular chondrocyte culture system [Vasios, G. Proceedings of 1999 American College of Rheumatology Announcer Meeting, poster session! (Poster Session D), No. 1123], Protective effect on articular cartilage in animal models [Huibregtse, Β ·, et al., Proceedings of 1999 American College of Rheumatology Annual Meeting ), Poster Session D, No. 1102].

 On the other hand, as a compound having a condensed imidazolidine skeleton, a patent on a bicyclic hydantoin derivative having herbicidal activity has been reported [Japanese Patent Application No. 10-501453, WO 97/47626]. There is no report.

 As a synthesis of condensed imidazolidines, the synthesis of m-imidazo [5, tric] [1,4] thiazine 1,3,5 (2H, 6H) -trione has been reported [Chem. Ber.l00 ( 2), pp. 564-577, 1967], but there is no report on the inhibitory effect of this compound on proteodarican degradation. For patients with osteoarthritis, drugs that inhibit the progression of joint destruction by suppressing cartilage matrix degradation can be curative drugs unlike symptomatic drugs such as analgesics. It has been demanded. Disclosure of the invention

 In view of this situation, the present inventors have conducted various studies and found that the general formula

[式中、 R¹は、 一 （S) _n— ; ²または一 NR³R⁴を、 nは 0ないし 2の整数を、 R²は水素原子、 置換されていてもよい炭化水素基または置換されていてもよい複 素環基を、 R³および R⁴は同一または異なって水素原子、 置換されていてもよい 炭化水素基、置換されていてもよい複素環基またはそれらが結合している窒素原子 と一緒に形成する含窒素複素環を、 R⁵は水素原子、 置換されていてもよい炭化水 素基、 シァノ基、 ァシル基、 エステル化もしくはアミド化されていてもよい力ルポ キシル基または置換されていてもよい複素環基を、

[Wherein, R ¹ represents one (S) _n —; ² or one NR ³ R ⁴ , n represents an integer of 0 to 2, R ² represents a hydrogen atom, an optionally substituted hydrocarbon group or substituted Wherein R ³ and R ⁴ are the same or different and are each a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or A nitrogen-containing heterocyclic ring formed together with a nitrogen atom, R ⁵ is a hydrogen atom, and an optionally substituted hydrocarbon An alkyl group, a cyano group, an acyl group, an esterified or amidated hydroxyl group or an optionally substituted heterocyclic group,

,9また

, 9 also

 r, R

R ⁶ represents a hydrogen atom, a hydrocarbon group which may be substituted, a cyano group, an acyl group, a propyloxyl group which may be esterified or amidated, or a heterocyclic group which may be substituted; R ⁷ is an optionally substituted hydroxyl group; R ⁸ and R ⁹ are each a hydrogen atom or an optionally substituted hydrocarbon group (R ⁵ and R ⁶ , R ⁵ and R ⁸ or R ⁸ And R ⁹ may be taken together to form an optionally substituted cyclic hydrocarbon or heterocyclic ring),

A, R ^1. Is a hydrogen atom, -ZR ¹⁵ (Z is _S0 ₂ —, SO—, _C〇NR ¹⁸ S〇 ₂ — (R ¹⁸ is ₆ alkyl), — CONR ¹⁹ — (R ¹⁹ is —6 alkyl R ¹⁵ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group) or — P (〇) R ¹⁶ R ¹⁷ (R ¹⁶ and R ¹⁷ Represents an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group or an optionally substituted amino group), and R ¹¹ represents a hydrogen atom or an optionally substituted hydrocarbon group ( R ^1Q and R ¹¹ may together form a nitrogen-containing heterocyclic ring which may be substituted), R ¹² and R ¹³ are each a hydrogen atom or an optionally substituted hydrocarbon group, or Together with the nitrogen atom to which it is attached forms a nitrogen-containing heterocycle, R ¹⁴ is a hydrogen atom, Or a hydrocarbon group or ZR ¹⁵ (Z and R ¹⁵ have the same meanings as described above). Where R ⁵ is a hydrogen atom, XY is

In the formula, R ¹⁴ represents an optionally substituted hydrocarbon group or ZR ¹⁵ (Z and R ¹⁵ have the same meanings as described above). The first synthesis of a novel condensed imidazolidine derivative, which is a compound (I) or a salt thereof, or a sulfoxide thereof represented by the formula: It has an excellent inhibitory effect on proteogliin degradation in the culture system, and has excellent properties as a pharmaceutical, such as an inhibitory effect on proteodalican release from knee cartilage in animal models. The present invention has been completed based on these findings. That is, the present invention

 (1) General formula

[Wherein, R ¹ represents one (S) _n —R ² or —NR ³ R ⁴ , n represents an integer of 0 to 2, R ² represents a hydrogen atom, or a substituted or unsubstituted hydrocarbon group. R ³ and R ⁴ may be the same or different and represent a hydrogen atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted or R ⁵ represents a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group, an acyl group, an esterified or amidated nitrogen-containing heterocyclic ring formed together with a nitrogen atom A xyl group or an optionally substituted heterocyclic group,

R ⁶ represents a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group, an acyl group, a carboxyl group which may be esterified or amidated, or a heterocyclic group which may be substituted, ⁷ is an optionally substituted hydroxyl group, R ⁸ and R ⁹ are each a hydrogen atom or an optionally substituted hydrocarbon group (R ⁵ and R ⁶ , R ⁵ and R ⁸ or R ⁸ R ⁹ may be taken together to form an optionally substituted cyclic hydrocarbon or heterocyclic ring),

The, R ¹⁰ is a hydrogen atom, _ZR ¹⁵ (Ζ one _{S0 2 -, -SO-, - CONR} 18 SO 2 - (R 18 represents a CI- ₆ alkyl), one CONR ¹⁹ - (R ¹⁹ is ( Or ₆ represents an alkyl) or —CO—, and R ¹⁵ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group) or — P (0) R ¹⁶ R ¹⁷ (R ¹⁶ and R ¹⁷ each represent an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group or an optionally substituted amino group), and R ¹¹ represents a hydrogen atom or an optionally substituted hydrocarbon group. A hydrogen group (R ¹ ° and R ¹¹ may be taken together to form a nitrogen-containing heterocyclic ring which may be substituted); R ¹² and R ¹³ each represent a hydrogen atom or a carbon atom which may be substituted; hydrogen group, or a connexion nitrogen-containing heterocyclic ring such together with the nitrogen atom to which they are attached, R ¹⁴ is a hydrogen atom, Conversion are optionally substituted hydrocarbon group or also -. Z ¹⁵ (Z and R ¹⁵ are as defined above) shows the proviso, R ⁵ is a hydrogen atom, XY is

In the formula, R ¹⁴ represents an optionally substituted hydrocarbon group or ZR ¹⁵ (Z and R ¹⁵ have the same meanings as described above). A compound (I) or a salt or a sulfoxide thereof represented by the formula:

 (2) General formula

は または Wherein R ¹ is (S) _n _R ² or _NR ³ R ⁴ , n is an integer of 0 to 2, R ² is a hydrogen atom, an optionally substituted hydrocarbon group or a substituted R ³ and R ⁴ may be the same or different and represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or a nitrogen atom to which they are bonded. And R ⁵ is a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group, an acyl group, a carboxyl group which may be esterified or amidated, or a substituted heterocyclic ring. A heterocyclic group which may be

Is or

 R z, R

R ⁶ represents a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group, an acyl group, an esterified or amidated propyloxyl group or an optionally substituted heterocyclic group. R ⁷ is an optionally substituted hydroxyl group; R ⁸ and R ⁹ are each a hydrogen atom or an optionally substituted hydrocarbon group (R ⁵ and R ⁶ , R ⁵ and R ⁸ Or R ⁸ and R ⁹ may be taken together to form an optionally substituted cyclic hydrocarbon or heterocyclic ring),

The, R ^{1 ()} is a hydrogen atom or _ZR ¹⁵ (Z - S0 ₂ - or - a CO-, R ¹⁵ is a optionally substituted hydrocarbon group or an optionally substituted heterocyclic group R ¹¹ represents a hydrogen atom or an optionally substituted hydrocarbon group, R ¹² and R ¹³ represent a hydrogen atom or an optionally substituted hydrocarbon group, respectively, or R ¹⁴ represents a hydrogen atom, an optionally substituted hydrocarbon group or one ZR ¹⁵ (Z and R ¹⁵ have the same meanings as described above) . And R ⁵ is a hydrogen atom,

In the formula, R ¹⁴ represents an optionally substituted hydrocarbon group or ZR ¹⁵ (Z and R ¹⁵ have the same meanings as described above). Or a salt thereof or a sulfoxide thereof;

(3) The above-mentioned (1), wherein R ⁵ is an optionally substituted hydrocarbon group, a cyano group, an acyl group, a carboxyl group which may be esterified or amidated, or an optionally substituted heterocyclic group. Or the compound according to (2);

(Four)

[R ⁶ is a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group, an acyl group, R ⁷ is an optionally substituted hydroxyl group or an optionally substituted heterocyclic group, R ⁷ is an optionally substituted hydroxyl group, and R ⁸ and R ⁹ are each a hydrogen atom or a substituted Represents an optionally substituted hydrocarbon group (R ⁵ and R ⁶ , R ⁵ and R ^8, or R ⁸ and R ⁹ are taken together to form an optionally substituted cyclic hydrocarbon or heterocyclic ring, (5) the compound according to the above (1) or (2),

One A

 But

[R ¹⁰ is a hydrogen atom, one ZR ¹⁵ (Z one S0 ₂ -, One SO-, One C_〇_NR ¹⁸ S_〇 ₂ one (R ¹⁸ is (: ₆ represents an alkyl), - CONR ¹⁹ - (R ¹⁹ ^ - a indicates to) or single CO- ₆ alkyl, R ¹⁵ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group) or - P (O) R ¹⁶ R ¹⁷ (R ¹⁶ and R ¹⁷ each represent an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group or an optionally substituted amino group), and R ¹¹ represents a hydrogen atom or a substituted R ^{1 Q} and R ¹¹ may be taken together to form a nitrogen-containing compound ring which may be substituted, and R ¹² and R ¹³ are each a hydrogen atom or (1) a hydrocarbon group which may be substituted, or a nitrogen-containing heterocyclic ring together with a nitrogen atom to which they are bonded]. A compound of

 (6)

One A

 But

[R ^1C1 represents a hydrogen atom or _ZR ¹⁵ (Z represents one S〇 ₂ — or —C〇 one, and R ¹⁵ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. ), R ¹¹ is a hydrogen atom or an optionally substituted hydrocarbon group, and R ¹² and R ¹³ are each a hydrogen atom or an optionally substituted hydrocarbon group, or a nitrogen atom to which they are bonded. Together with a nitrogen-containing heterocycle].

 (7) When the compound (I) has the general formula

()

 [The symbols are as defined in the above (1). ] The compound according to the above (1), which is a compound represented by the formula:

 (8) When the compound (I) has the general formula

1

 ()

 [The symbols are as defined in the above (2). ] The compound according to the above (2), which is a compound represented by the formula:

(9) R ^1Q is — S〇 ₂ R ¹⁵ (R ¹⁵ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group), and R ⁵ and R ⁶ are each substituted Or (8) a hydrocarbon group which may be substituted or an optionally substituted cyclic hydrocarbon or an optionally substituted heterocyclic ring which are formed together, and wherein R ¹¹ is a hydrogen atom. A compound as described above;

(10) The method according to the above (9), wherein R ¹ is one SR ² (R ² represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group). Compound; (11) The compound according to the above (10), wherein R ² is an optionally substituted hydrocarbon group;

(12) The compound according to the above (9) to (11), wherein R ⁵ and R ⁶ are each an optionally substituted hydrocarbon group having 1 to 6 carbon atoms;

(13) The compound according to the above (12), wherein R ⁶ is methyl or ethyl;

(14) The compound according to the above (12), wherein R ⁵ and R ⁶ together form an optionally substituted benzene ring;

( ¹⁵ ) The above-mentioned (9) to (14), wherein R ¹⁵ is an optionally substituted aryl group, an optionally substituted aralkyl group or an optionally substituted heterocyclic group. Compound;

(16) The compound according to the above ( ¹⁵ ), wherein R ¹⁵ is an optionally substituted phenyl group, an optionally substituted benzyl group or an optionally substituted phenyl group;

(17) R ¹ is one SR ² (R ² is an optionally substituted alkyl group having 1 to 8 carbon atoms, an alkenyl group optionally having 2 to 8 carbon atoms, A cycloalkyl group having 3 to 8 carbon atoms or an aralkyl group having 7 to 10 carbon atoms which may be substituted), wherein R ¹⁵ is an optionally substituted phenyl group, an optionally substituted benzyl group Or the optionally substituted phenyl group, the compound according to the above (9), wherein both R ⁵ and R ⁶ are methyl groups;

(18) The compound according to the above (17), wherein R ² is an optionally substituted alkyl group having 1 to 8 carbon atoms;

(19) The compound according to the above (18), wherein R ² is an alkyl group having 4 to 8 carbon atoms which may be substituted with a halogen atom;

(20) R ^1G is —COR ¹⁵ (R ¹⁵ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group), and R ⁵ and R ⁶ are each substituted. A hydrocarbon group which may be optionally substituted or an optionally substituted cyclic hydrocarbon or an optionally substituted heterocyclic ring which are formed together, wherein R ¹¹ is a hydrogen atom;

(21) The method according to the above (20), wherein R ¹ is one SR ² (R ² represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group). Compound; (22) The compound according to the above (21), wherein R ² is an optionally substituted hydrocarbon group;

(23) The compound according to the above (20) to (22), wherein R ⁵ and R ⁶ are each an optionally substituted hydrocarbon group having 1 to 6 carbon atoms;

(24) The compound according to the above (23), wherein R ⁶ is methyl or ethyl;

(25) The compound according to the above (23), wherein R ⁵ and R ⁶ together form an optionally substituted benzene ring;

(26) The compound according to any of the above (20) to (25), wherein R ¹⁵ is an optionally substituted aryl group, an optionally substituted aralkyl group or an optionally substituted heterocyclic group;

(27) The compound according to the above (26), wherein R ¹⁵ is an optionally substituted pyridyl group;

 (28) 4-Promote N— {8— [(5-Fluoropentyl) sulfanyl] -1-5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, l_c] [l, 4] thiazine _ 1-ylidene} benzenesulfonamide, N— {5,6-dimethyl-3-oxo-1 8 — [(4,4,4,5,5_pentafluoropentyl) sulfanyl] —2,3-dihydro-1H —Imidazo [5,1-c] [1,4] thiazine-1-1ylidene} (phenyl) methanesulfonamide, N— {5,6-dimethyl-3-oxo-8— [(4,4,4,5 , 5 pentafluorofluoropentyl) sulfanyl] ― 2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-111-ylidene} —4-methylbenzenesulfonamide, 4-bromo-N— [8_ (Isopentylsulfanyl) — 5,6-dimethyl-3, oxo-1,2,3-dihydro-1H-imidazo [5,1_c] [ 1,4] thiazine 1.-ylidene] benzenesulfonamide or a salt thereof;

 (29) a prodrug of the compound (I) according to the above (1) or a salt thereof or a sulfoxide thereof;

 (30) A pharmaceutical composition comprising the compound (I) according to the above (1) or a salt thereof, a sulfoxide thereof or a prodrug thereof;

(31) the pharmaceutical composition according to (30), which is a cartilage matrix degrading enzyme production inhibitor; (32) The pharmaceutical composition according to (30), which is a proteodalican degradation inhibitor; (33) the pharmaceutical composition according to (30), which is a osteoarthritis preventive or therapeutic agent;

 (34) The pharmaceutical composition according to the above (30), which is an agent for preventing or treating a disease caused by cartilage destruction; (35) the pharmaceutical composition according to the above (30), which is a matrix meta-oral proteinase gene expression inhibitor;

 (36) The pharmaceutical composition according to the above (30), which is a matrix meta-oral proteinase-13 gene expression inhibitor;

 (37) a proteoglitin degradation inhibitor comprising a condensed imidazolidine derivative;

 (38) a cartilage matrix degrading enzyme production inhibitor comprising a condensed imidazolidine derivative;

 (39) a prophylactic / therapeutic agent for osteoarthritis, comprising a condensed imidazolidine derivative;

 (40) an agent for preventing and treating diseases caused by cartilage destruction, characterized by containing a condensed imidazolidine derivative;

 (41) A method for preventing or treating osteoarthritis, which comprises administering to a mammal an effective amount of the compound (II) or a salt thereof or a sulfoxide or a prodrug thereof according to (1);

 (42) a method for preventing or treating a disease caused by cartilage destruction, which comprises administering an effective amount of the compound (I) or a salt thereof or a sulfoxide or a prodrug thereof according to the above (1) to a mammal;

 (43) Use of the compound (I) according to the above (1) or a salt thereof or a sulfoxide or a prodrug thereof for the manufacture of a prophylactic or therapeutic agent for osteoarthritis;

 (44) Use of the compound (I) or a salt thereof or a sulfoxide or a prodrug thereof according to the above (1) for producing an agent for preventing or treating a disease caused by cartilage destruction;

Equation (45)

 Wherein the symbol is as defined in the above (1), or a salt thereof;

[L is a leaving group, and R ⁵ and R ⁶ have the same meanings as described in the above (1)] or a salt thereof, and then subjected to a ring-forming reaction, and if desired, a hydrolysis reaction and a dehydration reaction. General formula characterized by conducting a reaction, an alkylation reaction, a substitution reaction and / or an oxidation reaction.

[The symbols are as defined in the above (1)], or a method for producing a compound thereof, a salt thereof, or a sulfoxide thereof;

Etc.

In the present specification, R ¹ represents — (S) _n —R ² or —NR ³ R ⁴ , n represents an integer of 0 to 2, R ² represents a hydrogen atom, an optionally substituted hydrocarbon group or R ³ and R ⁴ are the same or different hydrogen atoms, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted heterocyclic group, A nitrogen-containing heterocyclic ring formed together with a nitrogen atom is shown.

Examples of the “hydrocarbon group” of the optionally substituted hydrocarbon group represented by R ² include an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an aralkyl group, and a cycloalkyl group. A kill group, a cycloalkenyl group, and the like.

 Examples of the “alkyl group” as the optionally substituted hydrocarbon group include an alkyl group having 1 to 20 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl) , Pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl , 2-ethylbutyl, 1,1,2-trimethylpropyl pill, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl Heptyl, isoheptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 1-propylbutyl, 1 1,1-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3,

3-dimethylpentyl, 3,4-dimethylpentyl, 4,4-dimethylpentyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, 1,2,2-trimethylbutyl, 1,2 1,3,3-methylbutyl, 1,3,3-trimethylbutyl, 2,2,3-trimethylbutyl, 2,3,3-trimethylbutyl, 1-ethyl-1-methylbutyl, 1-ethyl-2-methylbutyl, 1- Ethyl-3-methylbutyl, 2-ethyl-1-methylbutyl, 2-ethyl-2-methylbutyl, 2-ethyl_3-methylbutyl, octyl, isooctyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 1-ethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 1-propylpentyl, 2-propylpentyl, 1,1-dimethyl Xyl, 2,2-dimethyl Hexyl, 3, hexyl 3-dimethylaminopropyl, 4,

4-dimethylhexyl, 5,5-dimethylhexyl, 3-ethyl-3-methylpentyl, 1,1-ethylethylbutyl, 2,2-di'ethylbutyl, 1,1,2,2-tetramethylbutyl, 1 1,1,3,3-tetramethylbutyle, 2,2,3,3-tetramethylbutyl, 1,1-dimethyl-2-ethylbutyl, nonyl, isononyl, 1-isobutyl-3-methylbutyl, Syl, isodecyl, pendecyl, isopendecyl, dodecyl, isododecyl, tridecyl, isotridecyl, tetradecyl, isotetradecyl, pendudecyl, isopendudecyl, hexadecyl, isohexadecyl, hepdudecyl, isohepdecyl, octyldecyl Decyl, isooctadecyl, nonadecyl, isononadecyl and the like, and preferably an alkyl group having 1 to 10 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl) , Isopentyl, 2-methylbutyl, hexyl, isohexyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, heptyl, isoheptyl, 1-methylhexyl , 1-ethylpentyl, 3-ethyl Pentyl, 1-propyl Rupuchiru, Okuchiru, Isookuchiru, 2 - propyl pentyl, Noel, Isonoeru,

1-isobutyl-3-methylbutyl, decyl, isodecyl, etc.).

 “Alkenyl group” as the optionally substituted hydrocarbon group includes alkenyl groups having 2 to 20 carbon atoms (for example, vinyl, aryl, isoprobenyl, 1-probenyl, 1-butenyl, 2-butenyl, 3 -Butenyl, 1,3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl, 2_methyl-2-propenyl 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1,3-pentenyl, 2,4-pentenyl, 1,4-pentagenenyl, 1-methyl-1-butenyl, 2-methyl 1-butenyl, 3-methyl-1-butenyl, 1_methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl 3-butenyl, 3-methyl-3-butenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexe 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1,3-hexenyl, 1,4-hexenyl, 1,5-hexenyl, 2,4-hexyl Xaxenyl, 2,5-hexagenyl, 1-methyl-1-pentenyl,

2-Methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4- Methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl 4-pentenyl, 3-methyl-4-pentenyl, 4_methyl-4-pentenyl, 1-ethyl-1-butenyl, 2-ethyl-1-butenyl, triethyl-2-butenyl, 2-ethyl-2 -Bute Nil, 1-ethyl-3-butenyl, 2-ethyl-3-butenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1,3-h Ptadenyl, 1,4-heptagenyl, 1,5-heptagenyl, 1,6-heptagenyl, 2,4-heptaphenyl, 2,5-heptagenyl, 2,6-heptagenyl, 3,5-heptagenyl , 3,6-heptagenyl, 4,6-heptagenyl, 1-methyl-1-hexenyl, 1-methyl-2-hexenyl, 1-methyl 3-hexenyl, 1-methyl-4-hexenyl, 1- Methyl-5-hexenyl, 2-methyl-1-hexenyl, 2-methyl-2-hexenyl, 2-methyl-3-hexenyl, 2-methyl-4-hexenyl, 2-methyl-5- Hexenyl, 3-methyl-

1-hexenyl, 3-methyl-2-hexenyl, 3-methyl-3-hexenyl, 3-methyl 4-hexenyl, 3-methyl-5-hexenyl, 4-methyl-1-hexenyl, 4 -Methyl-

2-hexenyl, 4-methyl-3-hexenyl, 4-methyl-4-hexenyl, 4-methyl-5-hexenyl, 5-methyl-1-hexenyl, 5-methyl-2-hexenyl , 5-Methyl-

3-hexenyl, 5-methyl-4-hexenyl, 5-methyl-5-hexenyl, 1-methyl-2,4-hexhexenyl, 2-methyl-2,4-hexenyl, 3-methyl-2 , 4-Hexenyl, 4-methyl-2, 4-hexenyl, 5-methyl-2, 4-hexenyl, 5-methyl-2,5-hexexenyl, 1-ethyl-1-pentenyl, 2-ethyl 1-pentenyl, 3-ethyl-1-pentenyl, 1-ethylile-2-pentenyl, 2-ethyl-2-pentenyl, 3-ethyl-2-pentenyl, 1-ethyl-3-pentenyl, 2-ethyl-3 -Pentenyl, 3-ethyl-3-pentenyl, 1-ethyl-4-pentenyl, 2-ethyl-4-pentenyl, 3-ethyl-4-pentenyl, 1-propyl-1-butenyl, 1-propyl-2 -Butenyl, 1-propyl-3-butenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octyl Thenyl, trimethyl-2-heptenyl, 1-methyl-3-heptenyl, 1-methyl-4-heptenyl, 1-methyl-5-heptenyl, 1-methyl-6-heptenyl, 6-methyl-2-heptenyl , 6-methyl-3-heptenyl, 6-methyl-4-heptenyl, 6-methyl-5-heptenyl, 6-methyl-6-heptenyl, 6-methyl-3,5-heptenyl, 6-methyl-2 , 5-heptadienyl, 4-ethyl-2-hexenyl, 4-ethyl-3-hexenyl, 2-nonenyl, 8-nonenyl, 7-methyl-1-octenyl, 7-methyl-2-octenyl, 7-methyl-3-octenyl, 7-methyl-4-octenyl, 7-methyl-5-octenyl, 7-methyl-6-octenyl, 7-methyl-7-octenyl, ethyl-2-heptenyl, 1-ethyl -3-heptenyl, 1-ethyl -4 -Heptenyl, Tetyl-5-heptenyl, 1-Ethyl-6-heptenyl, 5-Ethyl-2-heptenyl, 5-Ethyl-3-heptenyl, 5-Ethyl-4-heptenyl, 5-Ethyl-5 -Heptenyl, 5-ethyl-6-heptenyl, 2-decenyl, 9-decenyl, 8-methyl-2-nonenyl, 8-methyl-3-nonenyl, 8-methyl-4-nonenyl, 8-methyl-5 -Nonenyl, 8-methyl-6-nonenyl, 8-methyl-7-nonenyl, 8-methyl-8-nonenyl, 3,7-dimethyl-2,6-octagenyl, 2-p-decenyl, 10-p-decenyl, 9 -Methyl-2-decenyl, 9-methyl-8-decenyl, 9-methyl-9-decenyl, 2-dodecenyl, 1-dodecenyl, 10-methyl-2-didecenyl, 10-methyl-9-dendecenyl, 10-methyl -10-Pendecenyl, 2-tridecenyl, 12-tridecenyl, 1-methyl-2-dodecenyl, 11-methyl-10-dodecenyl , 11-methyl-1-tododecenyl, 2-tetradecenyl, 13-tetradecenyl, 12-methyl_2-tridecenyl, 12-methyl-11-tridecenyl, 12-methyl-12-tridecenyl, 2-pentenodecenyl, 14 -Pentadecenyl, 13-methyl-2-tetradecenyl, 13-methyl-12-tetradecenyl, 13-methyl-13-tetradecenyl, 3,7,1 trimethyl-2,6,10-dodecatrienyl, 2-hexadecenyl, 15-hexadecenyl, 14-methyl-2-pentadecenyl, 14-methyl-13-pentadecenyl, 14-methyl-14-pentadecenyl, 2-heptadecenyl, 16-heptadecenyl, 15-methyl-2- Hexadecenyl, 15-methyl-14-hexadecenyl, 15-methyl-15-hexadecenyl, 2-octadecenyl, 17-octadecenyl, 9,12-octadecadienyl, 9,12,15-octadecatri Henil, 9, 11, 13-octade Trienyl, 16-methyl-2-heptadecenyl, 16-methyl-15-heptadecenyl, 16-methyl-16-hepcenyldecenyl, 2-nonadecenyl, 18-nonadecenyl, 17-methyl-2-octadecenyl, 17-methyl- 16-octenyl decenyl, 17-methyl-17-octadecenyl, 2-eicosenyl, 19-eicosenyl, 5,8,11,14-icosatetraenyl, 18-methyl-2-nonadecenyl, 18-methyl-17- Nonadecenyl, 18-methyl-18-nonadecenyl, 3,7,11,15-tetramethyl-2,6,10,14-dodecatetenyl), preferably an alkenyl group having 2 to 10 carbon atoms. (E.g., Bier, aryl, isopropyl, 2-methyl-1-propenyl, 3-butenyl, 4-pentenyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 5-to- Xenyl, 4-methyl-2-pentenyl, 4-methyl-3- Tenenyl, 4-methyl-4-pentenyl, 6-heptur, 5-methyl-2-hexenyl, 5-methyl-3-hexenyl, 5-methyl-4-hexenyl, 5-methyl-5-to Xenyl, 5- Methyl-2,4-hexagenyl, 7-octenyl, 6-methyl-2-heptenyl, 6-methyl-3-heptenyl, 6-methyl-4-heptenyl, 6-methyl-5-heptenyl, 6-methyl-6 -Heptenyl, 8-nonenyl, 9-decenyl, 3,7-dimethyl-2,6-octenyl, etc.).

 Examples of the “alkynyl group” as the optionally substituted hydrocarbon group include an alkynyl group having 2 to 20 carbon atoms (eg, ethynyl, 1-propynyl, 2-propynyl,

1-butynyl, 2-butynyl, 3-butynyl, 1_methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butenyl ,.

2-Methyl-3-butynyl, 1-hexynyl, 2_hexynyl, 3-hexynyl, 4-hexynyl, 5_hexynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4_ Heptchel, 5-heptinyl, 6-heptyl, 2-octinyl, 3-octinyl, 4-octinyl, 5-octinyl, 6-octinyl, 7-octinyl, 2-noninyl, 8-noni Nyl, 2-decinyl, 9-decinyl, 2-p-decinyl, 10-p-decinyl, 2-dodecyl, 11-dodecinyl, 2-tridecinyl, 12-tridecinyl, 2-tetradecinyl, IS-tetradecinyl, 2-pentydecinyl , 14-pentadecynyl, 2_hexadecynyl, 15-hexadecynyl, 2-heptadecynyl, 16-hepdecanedecynyl, 2-octadedecynyl, 17-octanedecynyl, 2-nonadecynyl, 18-nonadecynyl, 2-eicosynyl, 19-Eico Shinil And alkenyl groups having 2 to 8 carbon atoms (e.g., ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 4-pentynyl, 2-hexynyl, 5-hexynyl, 2_heptynyl, 6-heptynyl, 2-octiel, 7-octynyl, etc.).

 Examples of the "reyl group" as the optionally substituted hydrocarbon group include an aryl group having 6 to 10 carbon atoms (eg, phenyl, 0-tolyl, m-tolyl, p-tolyl, 2-,

3- or 4-biphenyl, tri- or 2-naphthyl, anthryl, phenanthryl, etc.), preferably phenyl, p-tolyl, 1-, 3_ or 4-biphenyl, 1- or 2-naphthyl And the like.

Examples of the "aralkyl group" as the optionally substituted hydrocarbon group include an aralkyl group having 7 to 14 carbon atoms (eg, benzyl, 1-phenethyl, 2-phenethyl, 1-methyl-2-phenethyl, Methyl-1-phenethyl, 1,1-dimethyl-2-phenethyl, 1- Phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, trimethyl-2-phenylpropyl, 2_methyl-2-phenylpropyl, triphenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4_phenylbutyl, 1-phenylpentyl, 2-phenylpentyl, 3-phenylpentyl, 4-phenylpentyl, 5 phenylpentyl, 3-methyl-3-phenylbutyl, 1,1-dimethyl-3-phenylpropyl, 2,2-Dimethyl-3-phenylpropyl, 1,2-dimethyl-4-phenylbutyl, 2,2-dimethyl-4-phenylbutyl, 3,3-dimethyl-4-phenylbutyl, 4-methyl-4- Phenylpentyl, 1-methyl-5-phenylpentyl, 2-methyl-5-phenylpentyl, 3-methyl-5-phenylpentyl, 4-methyl-5-phenylpentyl, 1-naphthylmethyl, 2 -Naphthylmethyl 1-naphthylethyl, 2-naphthylethyl, 2-biphenylmethyl, 3-biphenylmethyl, 4-biphenylmethyl, 1-anthrylmethyl, 2-anthrylmethyl, 9-anthrylmethyl, phenanthrylmethyl, etc.) Preferably benzyl, 2-phenyl, 2-phenylpropyl, 3-phenylpropyl, 2-methyl-2-phenylpropyl, 4-phenylbutyl, 1-naphthylmethyl, 2-naphthylmethyl, 1-naphthylethyl, 2 -Naphthylethyl, 2-biphenylmethyl, 3-biphenylmethyl, 4-biphenylmethyl and the like.

 Examples of the "cycloalkyl group" as the optionally substituted hydrocarbon group include cycloalkyl groups having 3 to 8 carbon atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.). ). These may further be condensed with an aryl group such as a phenyl group, and examples thereof include indanyl, benzocyclohexyl, benzocycloheptyl, and benzocyclooctyl. Of these, preferred are cyclohexyl, cycloheptyl, cyclohexyl, indanyl, benzocycloheptyl and the like.

This cycloalkyl group is bridged through a linear atom chain having 1 or 2 carbon atoms to form bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [ 3.2.1 octyl, bicyclo [3.3.1] nonyl, bicyclo [3.2.23 nonyl, etc. (preferably a cyclo group having a bridge through a linear atom chain having 1 or 2 carbon atoms) Hexyl, and more preferably bicyclo [2.2.1] heptyl) may form a crosslinked cyclic hydrocarbon residue. It also forms an adamantyl group. May be formed.

 Examples of the "cycloalkenyl group" as the optionally substituted hydrocarbon group include a cycloalkenyl group having 3 to 8 carbon atoms (for example, 2-cyclopropenyl, 2-cyclobutenyl, 2-cyclopentenyl, 3-cyclopentenyl). Pentenyl, 2-cyclohexenyl, 3-cyclohexenyl, 2-cycloheptenyl, 3-cycloheptenyl, 4-cycloheptenyl; k 2-cyclooctenyl, 3-cyclooctenyl, 4-cyclooctenyl. These may further be condensed with an aryl group such as a phenyl group, for example, indenyl, benzocyclohexenyl, benzocycloheptenyl, benzocyclooctenyl and the like. Hexenyl, 2-cycloheptenyl, cyclooctyl, indenyl and the like can be mentioned.

Examples of the substituent of the “optionally substituted hydrocarbon group” for R ² include (1) a nitro group, (2) an oxo group, and (3) a halogen atom (eg, fluorine, chlorine, bromine, (4) cyano group, (5) methylene group, (6) optionally substituted lower alkyl group, (7) optionally substituted lower alkenyl group, (8) substituted (9) optionally substituted aralkyl group, (10) optionally substituted aralkyl group, (11) optionally substituted cycloalkyl group, (12) lower haloalkyl Group, (13) olepoxyl group which may be esterified or amidified, (14) thiol bamoyl group, (15) acyl group, (16) amidyl group, (17) hydroxyl group which may be substituted (18) an optionally substituted sulfanyl group, (19) a substituted An optionally substituted alkylsulfinyl group, (20) an optionally substituted arylsulfinyl group, (21) an optionally substituted alkylsulfonyl group, (22) an optionally substituted arylsulfonyl group (23) a sulfonic acid group which may be esterified or amidated, (24) an amino group which may be substituted, (25) a guanidyl group which may be substituted by a nitro group, and (26) a substituted guanidyl group. An optionally substituted heterocyclic group, (27) an alkylenedioxy group, (28) an imino group, and (29) an optionally substituted cycloalkenyl group. It may have from 6 to 6 substituents at substitutable positions.

The substituent of the "optionally substituted hydrocarbon" and the "lower alkyl group" of the "optionally substituted lower alkyl group" for R ² are, for example, methyl, ethyl, η_propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl And C1 to C4 alkyl groups.

Examples of the substituent which the “lower alkyl group” may have include, for example, (1) a nitro group, (2) an oxo group, (3) a halogen atom (eg, fluorine, chlorine, bromine, etc.), (4) ) A cyano group, (5) a methylene group, (6) a lower alkyl group (for example, having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, butyl, isoptyl, sec-butyl, tert-butyl, etc.) (7) a lower alkenyl group (for example, bier, allyl, isopropyl, 1-butenyl, 2-butenyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, An alkenyl group having 2 to 5 carbon atoms such as 1-pentenyl and 2-pentenyl); (8) a lower alkynyl group (an alkynyl group having 2 to 5 carbon atoms such as ethynyl, propargyl, 2-butenyl and 2-pentynyl), ( 9) Aryl group (for example, Phenyl, 2_, 3-or 4-tolyl, tri- or 2-naphthyl, 2- or 3- or 4-biphenyl, etc., aryl group having 6 to 12 carbon atoms), (10) aralkyl group (for example, benzyl) Aralkyl groups having 7 to 13 carbon atoms, such as, 2-phenyl, 3-phenylpropyl, 1- or 2-naphthylmethyl, 1-3- or 4-piphenylmethyl), (11) cycloalkyl groups (eg For example, a cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl), Q2) a propyloxyl group which may be esterified or amidated (eg, a carboxyl group) A C 2 -C 18 alkoxycarbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxyca Bonyl, hexyloxycarbonyl, dodecyloxycarbonyl, hexadecyloxycarbonyl, etc.), alkenyloxycarbonyl groups having 2 to 18 carbon atoms (for example, allyloxycarbonyl, octa_2, 6-genyloxycarbonyl, dodeforce-2,6,10-trienyloxycarbonyl, etc., aryloxycarbonyl group (for example, phenoxycarbonyl, 1-naphthoxycarbonyl, 2-naphthoxycarbonyl, etc.), An aralkyloxycarbonyl group (for example, benzyloxycarbonyl, phenethyloxycarbonyl, 3-phenylpropoxycarbonyl, etc.), a carbamoyl group, a lower alkyl group, a lower alkenyl group, a cycloalkyl group, an aryl group, an aralkyl group And a heterocyclic group (“R ² An “optionally substituted hydrocarbon” as a substituent of “an optionally substituted heterocyclic group”, and the like) A substituted carbamoyl group, a lower alkyl group, a lower alkenyl group, a cycloalkyl group, an aryl group, an aralkyl group, and a heterocyclic group (the “optionally substituted hydrocarbon” represented by R ² described below); N, N-disubstituted carbamoyl groups, cyclic aminocarbamoyl groups (eg, N-pyrrolidylcarbonyl, N- Imidazolyl carbonyl, N-pibelidyl carbonyl, N-piperazyl carbonyl, N-methyl- ピ '-piperazyl carbonyl, Ν-morpholyl carbonyl, etc.)), (13) an optionally substituted hydroxyl group (for example, The lower alkyl group, the lower alkenyl group, the cycloalkyl group, the aryl group, the aralkyl group, the esterified or amidated olepoxyl A hydroxyl group which may be replaced by an alkylsulfanylthio carbonyl group (for example, methylsulfanylthio carbonyl group, ethylsulfanyl thiocarboxy group, tert-butoxysulfanyl thiocarbonyloxy group, etc.), aralkyl sulfanylthio group A sulfonyl group (eg, benzylsulfanylthio group, N-imidazolylthiocarboxy group, N-morpholylthio group, etc.), (14) an optionally substituted sulfanyl group (eg, , Sulfanyl, alkylsulfanyl group (eg, methylsulfanyl, ethylsulfanyl, isopropylsulfanyl, tert-butylsulfanyl, etc.), arylsulfanyl group (eg, phenylsulfanyl, etc.), aral (15) alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, butylsulfonyl, etc.), (16) arylsulfonyl group (eg, benzenesulfonyl group) (17) an amino group which may be substituted (for example, an amino group mono- or di-substituted by an amino group, an alkyl group or an aralkyl group (for example, methylamino, ethylamino, isopropylamino, dimethylamino) , Acetylamino, ethylmethylamino, benzylamino, benzylmethylamino, etc.), acylamino (for example, formylamino, acetylamino, propionylamino, butyrylamino, isoptyrylamino, valerelli) Amino, isovaleryl Rua Mino, Pibaro Iruamino, Benzoiruamino, etc. Fuenashiruamino), alkoxycarbonyl Amino (e.g., methoxy Cal Poni Rua amino, ethoxy Cal Poni Rua amino, tert - Butoxycarponylamino, etc., aryloxylponylamino (for example, phenoxycarponylamino, naphthyloxycarponylamino, etc.), aralkyloxycarbonylamino (for example, benzyloxycarponylamino, phenethyloxycarponylamino, etc.) ), Alkylsulfonylamino (eg, methylsulfonylamino, ethylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino, etc.), arylsulfonylamino (eg, benzenesulfonylamino, naphthylsulfonylamino, etc.) (18) alkylenedioxy group (for example, methylenedioxy, ethylenedioxy, etc.), (19) imino group, etc., and one or more substituents selected from these are located at substitutable positions. do it Good.

Examples of the “lower alkenyl group” of the “optionally substituted lower alkenyl group” as the substituent of the “optionally substituted hydrocarbon” represented by R ² include, for example, vinyl and allyl. ), Isoprobenyl, 1-butenyl, 2-butenyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 1 pentenyl, 2-pentenyl and the like. Can be Examples of the substituent which the “lower alkenyl group” may have include the “optionally substituted lower” as a substituent of the “optionally substituted hydrocarbon” represented by R ² above. The same number and the same as the substituents that the “alkyl group” may have.

Examples of the “lower alkynyl group” of the “optionally substituted lower alkynyl group” as the substituent of the “optionally substituted hydrocarbon” represented by R ² include, for example, ethynyl, propargyl, 2- Examples thereof include alkynyl groups having 2 to 5 carbon atoms, such as lower alkynyl groups such as butynyl and 2-pentynyl. Examples of the substituent which the “lower alkynyl group” may have include a “optionally substituted lower alkyl group” as a substituent of the aforementioned “optionally substituted hydrocarbon” represented by R ^2. And the same number and the same as the substituents that may be possessed.

Examples of the “aryl group” of the “optionally substituted arylyl group” as the substituent of the “optionally substituted hydrocarbon” represented by R ² include, for example, phenylyl, 2_, 3-or 4 And aryl groups having 6 to 12 carbon atoms such as -tolyl, 1- or 2-naphthyl, 2-, 3- or 4-biphenyl. Examples of the substituent which the “aryl group” may have include a substituent of the “optionally substituted hydrocarbon” represented by R ² above. And the same number and the same as the substituents which the “optionally substituted lower alkyl group” may have.

Examples of the “aralkyl group” of the “optionally substituted aralkyl group” as a substituent of the “optionally substituted hydrocarbon” represented by R ² include, for example, benzyl, 2-phenethyl, 3-phenyl Examples thereof include aralkyl groups having 7 to 13 carbon atoms such as propyl, 1- or 2-naphthylmethyl, 2-, 3- or 4-biphenylmethyl. Examples of the substituent which the “aralkyl group” may have include “optionally substituted lower alkyl” as a substituent of the aforementioned “optionally substituted hydrocarbon” for R ^2. And the same number and the same as the substituents which the group may have.

Examples of the “cycloalkyl group” of the “optionally substituted cycloalkyl group” as a substituent of the “optionally substituted hydrocarbon” represented by R ² include, for example, cyclopropyl, cyclobutyl, cyclopentyl, C3-C8 cycloalkyl groups such as cyclohexyl, cycloheptyl and cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl , Bicyclo [3.3.1] Noel, picicyclo [3.2.2] Noel and adamantyl. Examples of the substituent which the “cycloalkyl group” may have include a “optionally substituted lower alkyl group” as a substituent of the “optionally substituted hydrocarbon” represented by R ² above. And the same number and the same as the substituents which may be possessed.

As the “lower haloalkyl group” as a substituent of the “optionally substituted hydrocarbon” represented by R ² , for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-Trifluoroethyl, 1,1,2,2-Tetrafluoroethyl, 1,1,2,2,2-pentafluorofluorethyl, 3-Fluoro mouth pill, 3,3-Diflu Trifluoropropyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, 4-fluorobutyl, 4,4-difluorobutyl, 4,4,4-trifluorobutyl, 3,3,4,4,4-pentyl butyl, 5-fluoropentyl, 5,5-difluoropentyl, 5,5,5-trifluoropentyl, 4,4,5,5,5-pentyl 1 such as fluoropentyl, chloromethyl, dichloromethyl, bromomethyl Lower alkyl groups substituted with stone 6 halogen group. As the “optionally esterified or amidated hapoxyl group” as a substituent of the “optionally substituted hydrocarbon” represented by R ² , an alkoxyl group, an alkoxycarbonyl group, an alkenyloxycarbonyl group And aralkyloxycarbonyl groups, alkaryloxycarbonyl groups, rubamoyl groups, N-monosubstituted carbamoyl groups, and N, N-disubstituted rubamoyl groups.

Examples of the “alkoxycarbonyl group” include, for example, those having 2 to 2 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, hexoxycarbonyl, dodecyloxycarbonyl, hexadecyoxycarbonyl and the like. 18 alkoxycarbonyl groups. The “alkoxy group” may have a substituent, and the substituent may be a “substituted hydrocarbon” represented by R ² described above. The same number and the same as the substituents which the lower alkyl group which may be substituted "may have.

Examples of the “alkenyloxycarbonyl group” include those having 2 carbon atoms such as allyloxycarbonyl, octa-2,6-genyloxycarbonyl, dodeforce-2,6,10-trienyloxycarbonyl. To 18 alkenyloxycarbonyl groups. The “alkenyloxycarbonyl group” may have a substituent, and the substituent may be a “substituted hydrocarbon” represented by R ² described above as a substituent of “optionally substituted hydrocarbon”. And the same number and the same as the substituents which the lower alkyl group which may be substituted "may have.

As the “aryloxycarbonyl group”, for example, phenoxycarbonyl, 1-naphthoxycarponyl, 21-naphthoxycarponyl and the like can be mentioned. The “aryloxycarbonyl group” may have a substituent, and the substituent may be a “substituted hydrocarbon” as a substituent of the “optionally substituted hydrocarbon” represented by R ^2. And the same number and the same as the substituents which the lower alkyl group may have.

Examples of the “aralkyloxycarbonyl group” include aralkyloxycarbonyl groups such as benzyloxycarbonyl, phenethyloxycarbonyl, and 3-phenylpropoxycarbonyl. The “aralkyloxycarbonyl group” may have a substituent, and the substituent is the “substituted or substituted” represented by R ² described above. The same number and the same as the substituents which the “optionally substituted lower alkyl group” may have as a substituent of the “optionally substituted hydrocarbon”.

Examples of the substituent of the “N-monosubstituted carpamoyl group” include lower alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.), lower alkenyl (eg, Bier, Aryl, isopropenyl, propenyl, butenyl, pentenyl, hexenyl, etc., cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), aryl (eg, phenyl) , 1-naphthyl, 2-naphthyl), aralkyl (eg, benzyl, phenethyl, etc.), heterocyclic group (for example, “substituted as a substituent of“ optionally substituted hydrocarbon ”shown by R ² described below) The same as the "heterocyclic group which may be substituted") and the like. Lower alkyl, lower alkenyl, cycloalkyl, § Li - Le, Ararukiru, heterocyclic group may have a substituent, examples of the substituent group, represented by R ² "which may be substituted As the substituent for the "good hydrocarbon", the same number and the same substituents as the substituent which the "optionally substituted lower alkyl group" may have.

 The substituent of the “N, N-disubstituent rubamoyl group” means a disubstituted group having two substituents on a nitrogen atom, and is the same as the substituent in the above “N-monosubstituent rubamoyl”. One. In some cases, two substituents may be combined with a nitrogen atom to form a cyclic amino.In such a case, examples of the cyclic amino group rubamoyl include N-pyrrolidylcarbonyl, N-imidazolylcarbonyl, and N-imidazolylcarbonyl. Piveridyl rucarbonyl, N-piperazylcarbonyl, N-methyl-Ν'-piperazylcarbonyl,

Ν-morpholylcarbonyl and the like.

As the “acyl group” as a substituent of the “optionally substituted hydrocarbon” represented by R ² , a hydrogen atom or a substituent having one of the above-mentioned monosubstituent rubamoyl groups on the nitrogen atom And carbonyl, such as a lower alkanoyl group such as formyl group, acetyl and propionyl, or an aroyl group such as benzoyl and naphthyl.

As the substituent of the `` optionally substituted hydroxyl group '' as the substituent of the `` optionally substituted hydrocarbon '' represented by R ² , an optionally substituted lower alkyl group, Lower alkenyl group which may be substituted, lower alkynyl group which may be substituted, aryl group which may be substituted, aralkyl group which may be substituted, cycloalkyl group which may be substituted, esterification Or an amidated propyloxyl group, an optionally substituted alkylsulfanylthiocarbonyl group, an optionally substituted aralkylsulfanylthiocarbonyl group, an optionally substituted alkylsulfonyl group, An arylsulfonyl group which may be substituted, an optionally substituted N-imidazolylthiol haponyl, an optionally substituted N-morpholylthio haponyl, a hydroxyl-protecting group, and the like. The “optionally substituted lower alkyl group”, the “optionally substituted lower alkenyl group”, the “optionally substituted lower alkynyl group”, the “optionally substituted aryl group”, As the “optionally substituted aralkyl group” and the “optionally substituted cycloalkyl group”, the “substituted hydrocarbon” represented by R ² may be a “substituted hydrocarbon”. Optionally substituted lower alkyl group, optionally substituted lower alkenyl group, optionally substituted lower alkynyl group, optionally substituted aryl group, and substituted And an optionally substituted aralkyl group "and a" optionally substituted cycloalkyl group ". The “esterified or amidated carboxyl group” refers to the optionally esterified or amidated lipoxyl as a substituent of the aforementioned “optionally substituted hydrocarbon” represented by R ^2. Group "from which the carboxyl group has been removed. Examples of the "optionally substituted alkylsulfanylthiocarponyl group" include methylsulfanylthiocarponyl, ethylsulfanylthiocarponyl, tert-butoxysulfanylthiocarponyl, and the like. Examples of the "good aralkylsulfanylthiocarbonyl group" include benzylsulfanylthiocarbonyloxy and the like, and the "optionally substituted alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, Examples of the "optionally substituted arylsulfonyl group" include benzenesulfonyl, p-toluenesulfonyl, m-toluenesulfonyl, o-toluenesulfonyl and the like. Said "optionally substituted alkylsulfanylthiocarbonyl group", "optionally substituted aralkylsulfanylthiocarbonyl group", and "substituted The optionally substituted alkylsulfonyl group and the optionally substituted arylsulfonyl group include, for example, the optionally substituted hydrocarbon represented by R ² above. And the same number and the same as the substituents which the “lower alkyl group which may be substituted” may have. Examples of the substituent which may be possessed by the `` optionally substituted N-imidazolylthiol compound '' and the `` optionally substituted N-morpholylthio compound '' are those represented by R ² described above. As the substituent of the "optionally substituted hydrocarbon", the same number and the same substituents as the "optionally substituted lower alkyl group" may have. Examples of the “hydroxyl protecting group” include 2-tetrahydropyranyl, trimethylsilyl, triethylsilyl, tert-butyldiphenylsilyl and the like.

Examples of the “optionally substituted sulfanyl group” as a substituent of the “optionally substituted hydrocarbon” represented by R ² include, for example, a sulfanyl group, methylsulfanyl, methysulfanyl, isopropylsulfanyl, tert- Examples thereof include an alkylsulfanyl group such as butylsulfanyl, an arylsulfanyl group such as phenylsulfanyl, and an aralkylsulfanyl group such as benzylsulfanyl. Examples of the substituent which the “optionally substituted sulfanyl group” may have include “substituted or substituted hydrocarbon” as a substituent of the aforementioned “optionally substituted hydrocarbon” for R ^2. The same number and the same as the substituents which the “lower alkyl group which may be optionally present” may have.

Examples of the “optionally substituted alkylsulfinyl group” as a substituent of the “optionally substituted hydrocarbon” represented by R ² include, for example, methylsulfinyl, ethylsulfinyl, isopropylsulfinyl and the like. Examples of the substituent which the “optionally substituted alkylsulfinyl group” may have include “substituted or substituted hydrocarbon” as a substituent of the aforementioned “optionally substituted hydrocarbon” for R ^2. The same number and the same as the substituents which the “lower alkyl group which may be optionally present” may have.

Examples of the “optionally substituted arylsulfinyl group” as a substituent of the “optionally substituted hydrocarbon” for R ² include, for example, benzenesulfinyl, toluenesulfinyl and the like. The "arylsulf optionally substituted" As has also been have substituents Iniru group ", it said; have the" optionally substituted lower alkyl group "as the substituent of the" hydrocarbon which may be substituted "represented by ² And the same number and the same as the substituents which may be included.

Examples of the “optionally substituted alkylsulfonyl group” as a substituent of the “optionally substituted hydrocarbon” represented by R ² include, for example, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, butylsulfonyl and the like. Is mentioned. Examples of the substituent which the “optionally substituted alkylsulfonyl group” may have include “substituted hydrocarbon” as a substituent of the aforementioned “optionally substituted hydrocarbon” for R ^2. The same numbers and the same as the substituents which the lower alkyl group which may be optionally possessed "may have.

Examples of the "optionally substituted arylsulfonyl group" as a substituent of the "optionally substituted hydrocarbon" represented by R ² include, for example, benzenesulfonyl, toluenesulfonyl, naphthylsulfonyl and the like. . Examples of the substituent which the “optionally substituted arylsulfonyl group” may have include a substituent of the “optionally substituted hydrocarbon” represented by R ² above. The same number and the same thing as the substituent which the "lower alkyl group which may be substituted" may have are mentioned.

Examples of the “sulfonic acid group which may be esterified or amidated” as a substituent of the “optionally substituted hydrocarbon” represented by R ² include, for example, a sulfonic acid group, methyl sulfonic acid, and sulfonic acid Ethyl, sulfonic acid amide, N-methylsulfonic acid amide and the like.

As the “optionally substituted amino group” as a substituent of the “optionally substituted hydrocarbon” for R ² , amino or di-substituted amino with an amino group, an alkyl group or an aralkyl group Groups, acylamino, alkoxyl propylonamino, aryloxycarbonylamino, aralkyloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino and the like.

 "An amino group j mono- or di-substituted with an alkyl group or an aralkyl group j includes, for example, methylamino, ethylamino, isopropylamino, dimethylamino, methylamino, ethylmethylamino, benzylamino, benzylmethylamino and the like.

\, Can be. The "amino group mono- or di-substituted by an alkyl group or an aralkyl group" May have a substituent, and the substituent may be a `` optionally substituted lower alkyl group '' as a substituent of the `` optionally substituted hydrocarbon '' represented by R ² above. And the same number and the same as the substituents that may be possessed.

"Acylamino" includes, for example, formylamino, acetylamino, propionylamino, butyrylamino, isoptyrylamino, valerylamino, isovaleramino, pivaloylamino, benzoylamino, phenacylamino and the like. The “acylamino” may have a substituent, and the substituent may be a “optionally substituted lower” as a substituent of the “optionally substituted hydrocarbon” shown in the above ² The same number and the same as the substituents that the “alkyl group” may have.

The “alkoxyl ponylamino” includes, for example, methoxycarbonylamino, ethoxycarbonylamino, tert-butoxycarponylamino and the like. The “alkoxy compound / amino” may have a substituent, and the substituent may be a substituent of the “optionally substituted hydrocarbon” represented by R ^{2 described above} . The same number and the same as those of the substituent which the “optionally substituted lower alkyl group” may have are exemplified.

The "aryloxycarbonylamino" includes, for example, phenoxycarbonylamino, naphthyloxycarbonylamino and the like. The “aryloxycarbonylamino” may have a substituent, and the substituent may be a “optionally substituted hydrocarbon” represented by R ² described above. The same number and the same as the substituents which the "lower alkyl group which may be substituted" may have.

“Aralkyloxycarbonylamino” includes, for example, benzyloxycarponylamino, phenethyloxycarbonylamino and the like. The “aralkyloxycarbonylamino” may have a substituent, and the substituent may be a “substituted hydrocarbon” as a substituent of the “optionally substituted hydrocarbon” for R ^2. The same numbers and the same as the substituents that the “lower alkyl group which may be substituted” may have.

"Alkylsulfonylamino" includes, for example, methylsulfonylamino, ethylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino and the like. Can be The “alkylsulfonylamino” may have a substituent, and the substituent may be a “substituted hydrocarbon” as a substituent of the aforementioned “optionally substituted hydrocarbon” represented by R ^2. The same number and the same as the substituents which the lower alkyl group which may be substituted "may have.

The "arylsulfonylamino" includes, for example, benzenesulfonylamino, naphthylsulfonylamino and the like. The “arylsulfonylamino” may have a substituent, and the substituent may be a “optionally substituted hydrocarbon” represented by R ² described above. The same number and the same as the substituents which the lower alkyl group which may be substituted "may have.

Examples of the “optionally substituted heterocyclic group” as a substituent of the “optionally substituted hydrocarbon” represented by R ² include, for example, an aliphatic monocyclic nitrogen-containing heterocyclic group and an aromatic monocyclic group. Examples include a cyclic nitrogen-containing heterocyclic group, a condensed nitrogen-containing heterocyclic group, an oxygen-containing monocyclic or condensed heterocyclic group, and a sulfur-containing monocyclic or condensed heterocyclic group.

"Aliphatic monocyclic nitrogen-containing heterocyclic group" refers to, for example, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidyl, piperazyl, pyrazolyl, morpholinyl, morpholinyl Oxazinyl, thiazinyl, azepinyl, diazepinyl, oxazepinyl, thiazepinyl and the like. The “aliphatic monocyclic nitrogen-containing heterocyclic group” may have a substituent, and the substituent is a substituent of the “optionally substituted hydrocarbon” represented by R ² above. And the same number and the same as the substituents which the "optionally substituted lower alkyl group" may have.

"Aromatic monocyclic nitrogen-containing heterocyclic group" means, for example, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrazinyl Is mentioned. The “aromatic monocyclic nitrogen-containing heterocyclic group” may have a substituent, and the substituent may be a “optionally substituted hydrocarbon” represented by R ² described above. As the substituent, the same number and the same as those of the "optionally substituted lower alkyl group" may be mentioned. You.

"Fused nitrogen-containing heterocyclic group" is, for example, benzopyrrolidinyl, benzimidazolidinyl, benzopyrazolidinyl, benzoxazolidinyl, benzoisoxazolidinyl, benzothiazolidinyl, benzoisothiazolidinyl Benzopiperidyl, benzopiperidyl, benzopyrazinyl, benzomorpholinyl, benzothiomorpholyl, benzoxazinyl, benzothiazinyl, benzozepinyl, benzodiazepinyl, benzoxazepinyl, benzothiazepinel, indolyl, isoindolyl, 1H-indazolyl , Benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, m-benzotriazolyl, benzoxoxadiazolyl, benzothiadiazolyl, quinolyl, iso Noryl, quinazolinyl, quinoxalinyl, naphthyridinyl, prenyl, pteridinyl, carbazolyl, carporinyl, acridinyl, phenoxazinyl, phenothiazinyl, fenazinyl, indolizinyl, piro-pyridazinyl, piro-mouth pyrimidinyl, piro-mouth pyrazinyl, piro-mouth pyrazinyl Imidazopyridazinyl, imidazopyrimidinyl, imidazopyrazinyl, imidazopyridyl, thienopyridazinyl, thienopyrimidinyl, thienopyrazinyl, thienopyridyl, thiazolopyridazinyl, thiazolopyrimidinyl, thiazolopizyl, thiazolopizyl Examples include pyridazopyridazinyl, pVdazopyrimidinyl, pyridazopyrazinyl, pyridazopyridyl, triazolopyridyl and the like. The “condensed nitrogen-containing heterocyclic group” may have a substituent, and the substituent may be a “substituted hydrocarbon” represented by R ² described above. The same number and the same as the substituents which the lower alkyl group which may be substituted "may have.

"Oxygen-containing monocyclic or fused heterocyclic group" means, for example, oxilanyl, oxenyl, oxolanyl, dioxolanyl, furyl, pyranyl, tetrahydroviranyl, dioxanyl, benzofuranyl, isobenzofuranyl, benzopyrael, isobenzopyranyl, benzol Dioxanyl, 7-oxabicyclo [2.2.1] heptyl), 9-oxabicyclo [3.3.1] nonyl, and the like. The “oxygen-containing monocyclic or condensed heterocyclic group” may have a substituent, and the substituent may be any of the above-mentioned “optionally substituted hydrocarbon” represented by R ² . As a substituent, "substituted The same numbers and the same as the substituents that the “lower alkyl group which may be substituted” may have.

The “sulfur-containing monocyclic or condensed heterocyclic group” includes, for example, phenyl, thioxolanyl, tetrahydrothiopyrael, dithianil, benzothenyl and the like. The “sulfur-containing monocyclic or condensed heterocyclic group” may have a substituent, and the substituent may be a substituent of the “optionally substituted hydrocarbon” represented by R ² described above. As the group, the same number and the same as the substituent which the "lower alkyl group which may be substituted" may have.

 As the "alkylenedioxy group" as a substituent of the "optionally substituted hydrocarbon" represented by, for example, methylenedioxy, ethylenedioxy and the like can be mentioned.

Examples of the “optionally substituted cycloalkenyl group” as a substituent of the “optionally substituted hydrocarbon” represented by R ² include a cycloalkenyl group having 3 to 8 carbon atoms (eg, 2-cyclopropenyl, 2-cyclobutenyl, 2-cyclopentenyl, 2-cyclohexenyl, 3-cyclohexenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2-cyclooctenyl, 4-cyclooctenyl and the like. Examples of the substituent which the “cycloalkenyl group” may have include a “optionally substituted lower alkyl group” as a substituent of the “optionally substituted hydrocarbon” represented by R ² above. And the same number and the same as the substituents that may be possessed.

As the "optionally substituted heterocyclic group" represented by R ^2, "may be substituted as the substituent of the" hydrocarbon which may be substituted "represented by R ² Heterocyclic group ". '

Examples of the hydrocarbon group as the “optionally substituted hydrocarbon group” represented by R ³ and R ⁴ include the hydrocarbon as the “optionally substituted hydrocarbon group” represented by the aforementioned R ² And the same. Preferable examples include an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, and the like.

3 As the substituent of the `` optionally substituted hydrocarbon group '' represented by R <sup>4</sup> , the same number as the substituent of the `` optionally substituted hydrocarbon group '' represented by the aforementioned R ² , Similar ones can be mentioned.

The `` optionally substituted heterocyclic group '' represented by R <sup>3</sup> or R <sup>4</sup> may be `` optionally substituted '' as a substituent of the `` optionally substituted hydrocarbon '' represented by R ² And the same as the “good complex ring group”.

Examples of the nitrogen-containing heterocyclic ring as “an optionally substituted nitrogen-containing heterocyclic ring represented by R ³ and R ⁴ together with the nitrogen atom to which they are bonded” include, in addition to a carbon atom, May contain 1 to 4 heteroatoms selected from atoms, sulfur atoms, nitrogen atoms, etc. 3- to 8-membered monocyclic heterocycles or condensed bicyclic or tricyclic heterocycles And fused heterocyclic groups. Among them, a preferable example is a 5- to 7-membered nitrogen-containing heterocyclic ring. Particularly preferred examples include azepier, piperidyl, piperazyl, N-methylbiperazyl, pyrrolidyl, morpholyl, and the like.

The substituent of the "R ^3, R ⁴ are both nitrogen-containing heterocyclic ring which may be substituted, such connexion represent together with the nitrogen atom to which they are attached", "is substituted represented by R ² And the same number as the substituents of the "optionally substituted hydrocarbon group".

R ¹ is preferably —SR ² (R ² represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group), and in particular, R ² is substituted. Those which are good hydrocarbon groups are preferred. In particular, in SR ² , R ² is an optionally substituted alkyl group (optionally substituted alkyl group having 1 to 8 carbon atoms) and an optionally substituted alkenyl group (optionally substituted An alkenyl group having 2 or 8 carbon atoms, an aralkyl group which may be substituted (an aralkyl group having 7 to 10 carbon atoms which may be substituted), a cycloalkyl group which may be substituted (substituted) And a cycloalkyl group having 3 to 8 carbon atoms which may be substituted. In particular, in SR ² , R ² is preferably an alkyl group having 1 to 8 carbon atoms which may be substituted, and more preferably an alkyl group having 4 to 8 carbon atoms which may be substituted by a halogen atom. Are preferred.

The hydrocarbon group as the `` optionally substituted hydrocarbon group '' represented by R <sup>5</sup> is the same as the hydrocarbon group as the `` optionally substituted hydrocarbon group '' represented by the aforementioned R ² Things. Preferably, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, an alkynyl group having 2 to 12 carbon atoms, and 6 carbon atoms And an aryl group having 7 to 10 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, and a cycloalkenyl group having 3 to 8 carbon atoms. Among them, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, and a cycloalkyl having 3 to 8 carbon atoms The group is preferably a cycloalkenyl group having 3 to 8 carbon atoms. In particular, an alkyl group having 1 to 6 carbon atoms is preferable, and methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isobenzyl, 2-methylbutyl, hexyl, isobutyl Hexyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylpentyl, and 3,3-dimethylpentyl are preferred.

As the substituent of the `` optionally substituted hydrocarbon group '' represented by R <sup>5</sup> , the same number as the substituent of the `` optionally substituted hydrocarbon group '' represented by R ² , and the same Things.

The “acyl group” represented by R ⁵ is the same as the “acyl group” as a substituent of the “optionally substituted hydrocarbon group” represented by R ² .

The “carboxyl group which may be esterified or amidated” represented by R ⁵ means “esterification or amide as a substituent of the aforementioned“ optionally substituted hydrocarbon group ”represented by R ^2. And the like. Among them, an alkoxycarbonyl group having 2 to 18 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxyl-proponyl, tert-butoxycarbonyl, hexyloxyl-proponyl, dodecyloxycarbonyl, hexadecyloxycarbonyl and the like is preferable.

The “optionally substituted heterocyclic group” represented by R ^{5 includes the same} as the “optionally substituted heterocyclic group” represented by R ² .

The hydrocarbon group as the `` optionally substituted hydrocarbon group '' represented by R <sup>6</sup> is the same as the hydrocarbon group as the `` optionally substituted hydrocarbon group '' represented by the aforementioned R ² Things. Preferable examples include an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, and an aralkyl group having 7 to 10 carbon atoms. Among them, alkyl groups having 1 to 6 carbon atoms, A phenyl group and a benzyl group are preferred. ,

As the substituent of the `` optionally substituted hydrocarbon group '' represented by R <sup>6</sup> , the same number as the substituent of the `` optionally substituted hydrocarbon group '' represented by the aforementioned R ² , the same Things.

The “acyl group” represented by R ⁶ is the same as the “acyl group” as a substituent of the aforementioned “optionally substituted hydrocarbon group” represented by R ² .

The `` optionally esterified or amidated olepoxyl group '' represented by R <sup>6</sup> means `` esterification or a hydrocarbon group which may be substituted '' represented by R ² above. And the like.

The "optionally substituted heterocyclic group" represented by R ^6, even if "substituted as the substituent of the" optionally substituted charcoal I nonhydrogen "represented by R ² And the same as the “good heterocyclic group”.

The cyclic hydrocarbon or heterocyclic ring formed by R ⁵ and R ⁶ together may contain, in addition to carbon atoms, one to three atoms selected from nitrogen, oxygen, sulfur and the like. Or an unsaturated 5- to 8-membered monocyclic carbocyclic or heterocyclic ring, or a bicyclic fused carbocyclic or heterocyclic ring containing these. For example, cycloalkyl (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.), cycloalkenyl (eg, cyclopentenyl, cyclohexenyl, cyclohexenyl, cycloheptenyl, etc.), aromatic hydrocarbon ring (eg, phenyl) , Naphthyl, etc.), oxygen-containing ring (for example, furyl, oxolanyl, tetrahydroviranyl, oxepinyl, benzofuranyl, benzopyranyl, etc.), nitrogen-containing ring (for example, pyrrolidyl, piperidyl, pyridyl, azepinyl, indolyl, quinolinyl, benzoxazepinyl, etc.) ), Sulfur-containing rings (eg, phenyl, tetrahydrothiopyranyl, benzothenyl, etc.), among which cyclohexyl, cyclopentenyl, cyclohexenyl, phenyl and the like are particularly preferred. Masui. Cyclic hydrocarbon or heterocyclic ring and R ⁵ and R ⁶ are you connexion formed such together may have a substituent, examples of the substituent group, be "substituted represented by R ² The same number and the same as the substituents of the “good hydrocarbon group”. R ⁵ is preferably an optionally substituted hydrocarbon group, a cyano group, an acyl group, an optionally esterified or amidated propyloxyl group, or an optionally substituted heterocyclic group. An optionally substituted hydrocarbon group is preferred. Among them, alkyl groups having 1 to 12 carbon atoms, alkenyl groups having 2 to 12 carbon atoms, alkynyl groups having 2 to 12 carbon atoms, aryl groups having 6 to 10 carbon atoms, and 7 carbon atoms. Preferred are an aralkyl group having 10 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, and a cycloalkenyl group having 3 to 8 carbon atoms. Among them, alkyl groups having 1 to 8 carbon atoms, alkenyl groups having 2 to 8 carbon atoms, aryl groups having 6 to 10 carbon atoms, aralkyl groups having 7 to 10 carbon atoms, cycloalkyl groups having 3 to 8 carbon atoms And a cycloalkenyl group having 3 to 8 carbon atoms is preferred. Particularly, a hydrocarbon group having 1 to 6 carbon atoms, particularly an alkyl group having 1 to 6 carbon atoms is preferable, and methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, Preferred are isopentyl, 2-methylbutyl, hexyl, isohexyl, 2-ethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl and 3,3-dimethylbutyl.

R ⁶ is preferably an optionally substituted hydrocarbon group. Of these, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, and the like are preferable. In particular, a hydrocarbon group having 1 to 6 carbon atoms, especially an alkyl group having 1 to 6 carbon atoms (methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butyl, tert-butyl, pentyl, isopentyl, 2 -Methylbutyl, hexyl, isohexyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, etc., particularly methyl and ethyl) are preferred.

Further, a compound forming a benzene ring which may be substituted together with R ⁵ and R ⁶ or a cyclohexene ring which may be substituted may also be mentioned as a preferable example.

Examples of the substituent of the `` optionally substituted hydroxyl group '' represented by R <sup>7</sup> include an optionally substituted hydrocarbon group, an optionally substituted alkylsulfonyl group, and an optionally substituted An arylsulfonyl group, an optionally substituted alkyl group, and an optionally substituted arylcarbonyl group. Among the “optionally substituted hydroxyl groups” represented by R <sup>7</sup> , a hydroxyl group is preferable. As the `` hydrocarbon group '' of the optionally substituted hydrocarbon group as a substituent of the `` optionally substituted hydroxyl group '' for R ⁷ , an alkyl group having 1 to 8 carbon atoms, an alkyl group having 2 to 2 carbon atoms An alkenyl group having 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, and the like. Of these, an alkyl group having 1 to 6 carbon atoms, a benzyl group and the like are preferable. As a substituent of the optionally substituted hydrocarbon group as a substituent of the “optionally substituted hydroxyl group”, a substituent of the “optionally substituted hydrocarbon group” represented by R ² above Similar numbers and similar ones are included.

Optionally substituted alkylsulfonyl group as the substituent of the "hydroxy group which may be substituted" represented by R ^7, examples of the optionally substituted § Li one Rusuruhoniru group, for example substituted And an optionally substituted alkylsulfonyl group, an optionally substituted benzenesulfonyl group, and the like, among which methanesulfonyl group, trifluoromethanesulfonyl group, benzenesulfonyl group, and toluenesulfonyl group are preferable. .

Examples of the optionally substituted alkylcarbonyl group and the optionally substituted arylcarbonyl group as the substituent of the `` optionally substituted hydroxyl group '' represented by R ⁷ include, for example, Examples thereof include an alkylcarbonyl group having a good carbon number of 1 to 4, an optionally substituted benzoyl group, and the like. Among them, an acetyl group, a propionyl group, a benzoyl group and the like are preferable.

An optionally substituted alkylsulfonyl group, an optionally substituted arylsulfonyl group, an optionally substituted alkylcarbonyl group as a substituent of the "optionally substituted hydroxyl group" for R ⁷ Examples of the substituent of the arylcarbonyl group which may be substituted include the same numbers and the same substituents as those of the “optionally substituted hydrocarbon group” for R ² .

Examples of the hydrocarbon group as the “optionally substituted hydrocarbon group” represented by R ⁸ and R ⁹ include the hydrocarbon as the “optionally substituted hydrocarbon group” represented by the aforementioned R ² Examples are the same as the groups. Preferable examples include an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, and an aralkyl group having 7 to 10 carbon atoms. Among them, an alkyl group having 1 to 6 carbon atoms, a phenyl group, a benzyl group and the like are preferable. The substituent of the “optionally substituted hydrocarbon group” represented by R ⁸ and R ⁹ is the same as the substituent of the “optionally substituted hydrocarbon group” represented by R ² described above. , And the like.

The cyclic hydrocarbon or heterocyclic ring formed by R ⁵ and R ⁸ together may contain 1 to 3 atoms selected from nitrogen, oxygen, sulfur, etc., in addition to carbon. Or an unsaturated 5- to 8-membered monocyclic carbocyclic or heterocyclic ring, or a bicyclic fused carbocyclic or heterocyclic ring containing these. For example, cycloalkyl (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.), cycloalkenyl (eg, cyclopentenyl, cyclohexenyl, cyclohexenyl, cycloheptenyl, etc.), aromatic hydrocarbon ring (eg, phenyl) , Naphthyl, etc.), oxygen-containing ring (for example, frill, oxorael, tetrahydropyranyl, oxepinyl, benzofuranyl, benzopyranyl, etc.), nitrogen-containing ring (for example, pyrrolidyl, piperidyl, pyridyl, azepinyl, indolyl, quinolinyl, benzoxazepiel, etc.) ), Sulfur-containing rings (eg, phenyl, tetrahydrothiopyranyl, benzothenyl, etc.), among which cyclohexenyl, phenyl and the like are particularly preferred. The cyclic hydrocarbon or heterocyclic ring formed by R ⁵ and R ⁸ together may have a substituent, and the substituent may be `` substituted or substituted '' represented by R ² above. And the same number and the same as the substituents of the "optionally substituted hydrocarbon group".

The cyclic hydrocarbon or heterocyclic ring formed by combining R ⁸ and R ⁹ may include one to three atoms selected from a nitrogen atom, an oxygen atom, a sulfur atom, and the like in addition to a carbon atom. Examples thereof include a saturated or unsaturated, 5- to 8-membered monocyclic carbocyclic or heterocyclic ring, or a bicyclic fused carbocyclic or heterocyclic ring containing these. For example, cycloalkyl (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.), cycloalkenyl (eg, cyclopentenyl, cyclohexenyl, cyclohexenyl, cycloheptenyl, etc.), aromatic hydrocarbon ring (eg, phenyl) , Naphthyl, etc.), oxygen-containing ring (for example, furyl, oxazolanyl, tetrahydropyranyl, oxepiel, benzofuranyl, benzopyranyl, etc.), nitrogen-containing ring (for example, pyrrolidyl, piperidyl, pyridyl, azepinyl, indolyl, quinolinyl, benzoxazepiel, etc.) ), Sulfur-containing rings (eg, phenyl, tetrahydrothioviranyl, benzo) Chenyl, etc.). The cyclic hydrocarbon or heterocyclic ring formed by R ⁸ and R ⁹ together may have a substituent, and the substituent may be `` optionally substituted '' represented by R ² described above. And the same number and the same as the substituents of the "hydrocarbon group".

As R ⁸ and R ⁹ , an optionally substituted hydrocarbon group is preferable. Of these, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, a phenyl group having 6 to 10 carbon atoms, and an aralkyl group having 7 to 10 carbon atoms are preferable. That is, an alkyl group having 1 to 6 carbon atoms, a phenyl group, a benzyl group and the like are preferable.

RIG represents a hydrogen atom, one ZR ¹⁵ or —P (O) R ¹⁶ R ¹⁷ .

As the hydrocarbon group of the `` optionally substituted hydrocarbon group '' represented by R <sup>15</sup> of ZR <sup>15</sup> , the `` optionally substituted hydrocarbon group '' represented by the aforementioned R ² Examples include the same as the hydrocarbon group. Preferably, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, an alkynyl group having 2 to 12 carbon atoms, an aryl group having 6 to 10 carbon atoms, and a 7 to 10 carbon atom Aralkyl groups, cycloalkyl groups having 3 or 8 carbon atoms, cycloalkenyl groups having 3 to 8 carbon atoms, and the like. Of these, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, and a cycloalkyl group having 3 to 8 carbon atoms are preferable.

^The substituent of the “optionally substituted hydrocarbon group” represented by 5 is the same as or similar to the substituent of the “optionally substituted hydrocarbon group” represented by R ² above. Is mentioned. Of these, an optionally substituted alkyl group having 1 to 4 carbon atoms, an optionally substituted alkenyl group having 2 to 4 carbon atoms, a halogen atom such as fluorine, chlorine, and bromine, and having 1 to 4 carbon atoms Examples of the substituent include a methyl group, an ethyl group, a propyl group, an isopropyl group, a Bier group, and the like. Examples include fluorine, chlorine, bromine, a methoxy group, and an ethoxy group.

- ZR ^{1 5} and R ^{1 5} in the "optionally substituted heterocyclic group" represented is as the substituent of the "optionally substituted hydrocarbon" represented by R ² ' Heterocyclic group which may be substituted "and the like. Among them, a phenyl group which may be substituted, a quinolyl group which may be substituted, and a benzoxazidi which may be substituted Azolyl group, optionally substituted pyridyl group, optionally substituted benzothiadiazolyl group, optionally substituted benzozoenyl group, optionally substituted oxazolidinyl group, optionally substituted An benzodioxanyl group, a substituted or unsubstituted dibenzofuranyl group and a morpholyl group are preferred, and particularly a optionally substituted phenyl group, an optionally substituted benzothiadiazolyl group and an optionally substituted A preferred example is a pyridyl group.

Z is ^{_{-S0 2 _, -SO-, -CON 18}} S0 2 - (R 18 is (:. ₆ alkyl), -CONR ¹⁹ - (R ¹⁹ is - ₆ alkyl) or - CO- shown R ¹⁸ and R the C Bok ₆ alkyl represented by ^{1 9,} for example, methyl, Echiru, propyl, iso-propyl, heptyl, isobutyl, sec- butyl, tert- butyl, pentyl, hexyl, and the like to.

The “optionally substituted hydrocarbon group” represented by R ¹⁶ and R ¹⁷ is the same as the hydrocarbon group represented by the aforementioned R ² ¾ “optionally substituted hydrocarbon group” And the like. Preferably, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, an alkynyl group having 2 to 12 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, Examples thereof include a 3-8 cycloalkyl group and a C3-8 cycloalkenyl group. Of these, an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, and the like are preferable. Particularly, methyl, ethyl, phenyl, benzyl and the like are preferable.

The substituent of the `` optionally substituted hydrocarbon group '' represented by R <sup>16</sup> and R <sup>17</sup> is the same as the substituent of the `` optionally substituted hydrocarbon group '' represented by R ² And the like.

Examples of the “optionally substituted hydroxyl group” represented by R ¹⁶ and R ¹⁷ include, for example, an optionally substituted hydrocarbon group.

As the `` hydrocarbon group '' of the optionally substituted hydrocarbon group as a substituent of the `` optionally substituted hydroxyl group '' represented by R ¹⁶ and R ¹⁷ , an alkyl group having 1 to 8 carbon atoms, Examples thereof include an alkenyl group having 2 to 8 carbon atoms, an aryl group having 6 to 10 carbon atoms, and an aralkyl group having 7 to 10 carbon atoms. Among them, 1 to 6 carbon atoms And an alkyl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, and the like. Particularly, methyl, ethyl, propyl, butyl, phenyl, benzyl and the like are preferable. Examples of the substituent of the optionally substituted hydrocarbon group as the substituent of the “optionally substituted hydroxyl group” include the substituent of the “optionally substituted hydrocarbon group” represented by R ² above. Similar numbers and similar ones are included.

The “optionally substituted hydroxyl group” represented by R ¹⁶ and R ¹⁷ is preferably a hydroxyl group substituted by an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, or the like.

The `` optionally substituted amino group '' represented by R <sup>16</sup> and R <sup>17 includes</sup> the `` substituted amino group '' as a substituent of the `` optionally substituted hydrocarbon '' represented by R ^{2 above.} And the like. " Preferably, methyl, ethyl, phenyl, benzyl and the like are mentioned.

R ¹⁶ and R ¹⁷ are an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, a hydroxyl group substituted with an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms. And a hydroxyl group substituted with methyl, ethyl, phenyl, benzyl, methyl, a hydroxyl group substituted with ethyl, and a hydroxyl group substituted with phenyl.

As R ^1Q , one ZR ¹⁵ (Z and R ¹⁵ are as defined above) is preferable. Among them, Z is —S〇 ₂ — or 1 CO—, and R ¹⁵ is an optionally substituted aryl group, an optionally substituted aralkyl group, and an optionally substituted heterocyclic ring. What is a group is preferable. In particular, Z is —SO ₂ — or 1 CO—, and R ¹⁵ is an optionally substituted aralkyl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 10 carbon atoms which may be substituted, Those which are heterocyclic groups which may be substituted are preferred. In particular, Z is -S〇 _2- , and R ¹⁵ may be substituted with methyl, ethyl, propyl, isopropyl, vinyl, fluorine, chlorine, bromine, methoxy, ethoxy, etc. Phenyl, benzyl, phenyl, benzothiadiazolyl, or Z is —CO—, and R ¹⁵ is methyl, ethyl, propyl, isopropyl, vinyl, fluorine, chlorine, bromine, methoxy And a pyridyl group which may be substituted with an ethoxy group or the like. R ¹¹ represents a hydrogen atom or a hydrocarbon group which may be substituted. . The hydrocarbon group of the `` optionally substituted hydrocarbon group '' represented by R <sup>11</sup> is the same as the hydrocarbon group of the `` optionally substituted hydrocarbon group '' represented by the aforementioned R ² Things. Preferable examples include an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, and an aralkyl group having 7 to 10 carbon atoms. Of these, an alkyl group having 1 to 6 carbon atoms, a benzyl group and the like are preferable, and an alkyl group having 1 to 4 carbon atoms is particularly preferable. The substituent of the `` optionally substituted hydrocarbon group '' represented by R <sup>11</sup> is the same as or similar to the substituent of the `` optionally substituted hydrocarbon group '' represented by R ² One.

R ¹¹ is preferably a hydrogen atom.

The nitrogen-containing heterocyclic ring which may be formed by combining R ^1Q and R ¹¹ is

で表される部分構造が

The partial structure represented by

(In the formula, ring B represents an optionally substituted 5- to 8-membered ring)

Means a 5- to 8-membered nitrogen-containing heterocycle represented by More specifically, the expression

[Wherein, R ¹⁷ has the same meaning as described above, and ring B ^{1 to} ring B ¹² each represent a nitrogen-containing heterocyclic ring which may further have a substituent]. In addition, the substituent which the ring B ^{1 to} ring B ¹² may have is the same as the substituent which the `` optionally substituted hydrocarbon group '' represented by R ¹⁵ may have Means things.

Examples of the nitrogen-containing heterocyclic ring which may be formed by R ^{1 Q} and R ¹¹ together include:

[In the formula, ring B ^{2 and} ring B ³ represent a nitrogen-containing heterocyclic ring which may further have a substituent.]

A 6- or 7-membered nitrogen-containing heterocyclic ring represented by

The hydrocarbon group of the “optionally substituted hydrocarbon group” represented by R ¹² and R ¹³ Examples thereof include the same hydrocarbon groups as the aforementioned “optionally substituted hydrocarbon group” for R ² . Preferably, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, an alkynyl group having 2 to 12 carbon atoms, an aryl group having 6 to 10 carbon atoms, and a 7 to 10 carbon atom An aralkyl group, a cycloalkyl group having 3 or 8 carbon atoms, a cycloalkenyl group having 3 to 8 carbon atoms, and the like. Of these, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, and an aralkyl group having 7 to 10 carbon atoms are preferable. Examples of the substituent of the “optionally substituted hydrocarbon group” represented by R ¹² and R ¹³ include the substitution of the “optionally substituted hydrocarbon group” represented by the aforementioned R ² The same number and the same as the group can be mentioned.

Examples of the nitrogen-containing heterocyclic ring which may be replaced together with R ¹² and R ¹³ together with the nitrogen atom to which they are bonded include the aforementioned `` R ³ and R ⁴ are both those wherein Nitrogen-containing heterocycles which may be substituted together with the nitrogen atom to be bonded ”. Particularly preferred examples include piperidyl, piperazyl, N-methylpiperazyl, pyrrolidyl, morpholyl and the like.

Examples of the substituent of the “nitrogen-containing heterocyclic ring which may be substituted by both R ¹² and R ¹³ forming a nitrogen atom to which they are bonded to —” are those represented by the aforementioned R ² The same number and the same as the substituents of the “optionally substituted hydrocarbon group”.

R ¹² is a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, an alkynyl group having 2 to 12 carbon atoms, an aryl group having 6 to 10 carbon atoms. Preferred are a group, an aralkyl group having 7 to 10 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, a cycloalkenyl group having 3 to 8 carbon atoms, and the like. Among them, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, and an aralkyl group having 7 to 10 carbon atoms are preferable.

R ¹³ is preferably a hydrogen atom.

As the hydrocarbon group of the “optionally substituted hydrocarbon group” represented by R ¹⁴ , the hydrocarbon group represented by the aforementioned “optionally substituted hydrocarbon group” represented by R ² And the same as the group. Preferably, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, an alkynyl group having 2 to 12 carbon atoms, not having 6 carbon atoms And an aryl group having 10 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, and a cycloalkenyl group having 3 to 8 carbon atoms. Among them, an alkyl group having 1 to 4 carbon atoms and an aralkyl group having 7 to 10 carbon atoms are preferable. The substituent of the “optionally substituted hydrocarbon group” represented by R ¹⁴ is the same as or similar to the substituent of the “optionally substituted hydrocarbon group” represented by the aforementioned R ^2. And the like. One ZR ¹⁵ represented by R ¹⁴ include the same as one ZR ¹⁵ represented by R ^1Q.

As R ¹⁴ , an optionally substituted hydrocarbon group is preferable. Among them, an alkyl group having 1 to 12 carbon atoms, an alkenyl group having 2 to 12 carbon atoms, an alkynyl group having 2 to 12 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, A cycloalkenyl group having 3 to 8 carbon atoms and the like are preferable, and an alkyl group having 1 to 6 carbon atoms and an aralkyl group having 7 to 10 carbon atoms are particularly preferable.

が好ましく、 なかでも

とりわけ

が好ましい _c

Is preferred, especially

Above all

Is preferred _c

Is preferred, especially

が好ましい。

Is preferred.

 As the compound (I),

 [Wherein the symbols have the same meanings as described above. ] Is particularly preferably used. As a specific example,

4-bromo-N_ {8— [(5-fluoropentyl) sulfanyl] —5,6-dimethyl-3-oxo-1,2,3-dihydro-1 H-imidazo [5,1-c] [1,4] thiazine-1] · 1-ylidene} benzenesulfonamide, N- {5,6-dimethyl-3—oxo-18 — [(4,4,4,5,5-pentafluoropentyl) sulfanyl] —2,3-dihydro—1H— Imidazo [5,1—c] [l, 4] thiazine—11-ylidene} (phenyl) methanesulfonamide, N— {5,6-dimethyl_3-oxo-1-8- [(4, 4, 4, 5,5-Pentafluoropentyl) sulfanyl] -2,3 -dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1 1-ylidene} 1-4 1-methylbenzenesulfonamide, 4_bromo-N- [8- (isopentylsulfanyl) -1, 6, -dimethyl-3-oxo-1,2,3-dihydro-1H-imidazo [5,11c] [l, 4] thiazine-1-ylidene] benzenesulfonamide and the like.

Hereinafter, a method for synthesizing the compound represented by the general formula (I) or a salt thereof will be described. In the general formula (I), R ¹ is-(S) _n — R ² ,

X Y

が である化合物 （I X) またはその塩の合成

Synthesis of compound (IX) or a salt thereof in which is

 (V I I)

 (I I I) (I X)

Reaction 1 2 — Amino — 3, 3 — Dichloroacrylonitrile (2-amino-3,3-dichloroacrylonitrile, hereafter sometimes abbreviated as ADAN) By reacting with an isocyanate represented by R ^1Q -NCO, a 5-dichloromethyleneimidazolidine compound represented by the general formula (II) or a salt thereof is obtained.

The isocyanate compound represented by R ^{1 G} —NC〇 is used in an amount of 0.1 to 10 equivalents, preferably 0.2 to 5 equivalents, more preferably 1 to 2 equivalents, based on the amount of the raw material. The isocyanate compound represented by R ^{1 Q-} NCO is preferably a sulfonyl isocyanate compound in which R ¹⁰ is R ¹⁵ SO ₂ , more preferably a benzene ring in which R ¹⁵ may be substituted, For example, benzenesulfonyl isocyanate, p-toluenesulfonyl isocyanate, P-fluorobenzenesulfonyl isocyanate, P-chlorobenzenesulfonyl isocyanate, and p-bromobenzenesulfonyl isocyanate are particularly preferable. These isocyanates can be prepared from the corresponding amide by a method known per se. This reaction is advantageously performed in a solvent. These reactions are usually performed in a solvent that does not affect the reaction. Solvents are not specified as long as they do not affect the reaction, but amide solvents (eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, etc.), halogenated Hydrocarbon solvents (eg, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chloroform benzene, etc.), nitrile solvents (eg, acetonitrile, etc.), ester solvents (eg, ethyl formate, Ethyl acetate, tert-butyl acetate, etc.), ketone solvents (eg, acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), ether solvents (eg, tetrahydrofuran, getyl ether, diisopropyl ether, dioxane, dimethoxy) ), Hydrocarbon solvents (eg, hexane, benzene, toluene, etc.), aromatic organic salts Base solvents (eg, pyridine, 2,4,6-trimethyl revilidine, picoline, 2,6-lutidine, 1,8-diazabicyclo [5,4,0] -7-indene), etc., or a mixture thereof Solvents. Among them, octogenated hydrocarbon solvents, ester solvents, ether solvents, hydrocarbon solvents and the like are preferable, and dichloromethane, chloroform, tetrahydrofuran, getyl ether, toluene and the like are particularly preferable. Suitable organic bases (eg, pyridine, 2, 4, 6- Aromatic bases such as trimethylpyridine, picoline, 4-dimethylaminopyridine, 2,6-lutidine, 1,8-diazabicyclo [5,4,0] -7-indenecene, and tertiary such as triethylamine and dimethylalanine Amin, etc.). The base is used in an amount of 0 to 10 equivalents, preferably 0 to 1 equivalent, the reaction temperature is — 40 ° C to 15 ° C, preferably 0 ° C to 100 ° C, and the reaction time is 2 minutes to 96 hours, preferably 5 minutes to 60 hours.

Reaction 2

Starting from a 5-dichloromethyleneimidazolidine compound represented by the general formula (II) or a salt thereof, and in the presence of a base, a mercapto compound represented by the general formula R〇C〇CH ₂ CH ₂ SH (where R is Represents an alkyl group such as methyl, ethyl, propyl, isopropyl, 2-ethylhexyl, etc.), and is reacted with an imidazolidine compound represented by the general formula (III) (R represents the above alkyl group) or Obtain the salt.

The mercapto compound represented by ROC〇CH ₂ CH ₂ SH is used in an amount of 0.5 to 20 equivalents, preferably 1 to 10 equivalents, more preferably 2 to 5 equivalents, based on the amount of the raw material. Examples of the base include alkali metal hydride or alkaline earth metal hydride (eg, sodium hydride, potassium hydride, calcium hydride, etc.), alkali metal alkoxide (eg, sodium methoxide, sodium ethoxide, Sodium tert-butoxide, etc.), inorganic bases (eg, sodium bicarbonate, sodium carbonate, sodium bicarbonate, sodium carbonate, sodium hydroxide, sodium hydroxide, sodium hydroxide), organic bases (eg, sodium tert-butoxide) Aromatic bases such as pyridine, 2,4,6-trimethylpyridine, picoline, 4-dimethylaminopyridine, 2,6-lutidine, 1,8_diazabicyclo [5,4,0] -7_indene, Tertiary amines such as triethylamine, dimethylaniline, etc.), alkali metals (eg, sodium, potassium, etc.), metal hydrogenation (Eg, lithium aluminum hydride, lithium borohydride, diisobutylaluminum hydride, etc.), alkyl lithium (eg, methyl lithium, butyl lithium, etc.), or alkali metal amide (eg, lithium diisopropylamide, lithium piste) Sodium hydride, which is preferably an alkali metal hydride, an alkali metal alkoxide, an inorganic base, an organic base, an alkyllithium, or an alkali metal amide. Particularly preferred are sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium bicarbonate, potassium carbonate, 4-dimethylaminopyridine, triethylamine, methyllithium, butyllithium, lithium diisopropylamide, lithium bistrimethylsilylamide and the like. Of these, liquid ones are also used as solvents. The base is used in an amount of 1 to 50 equivalents, preferably 2 to 10 equivalents, more preferably 2 to 5 equivalents. These reactions are usually advantageously performed in a solvent. Solvents are not specified as long as they do not affect the reaction, but amide solvents (eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, etc.), ether solvents (eg, , Tetrahydrofuran, getyl ether, dioxane, dimethoxyethane, etc.), sulfoxide solvents (eg, dimethyl sulfoxide), alcohol solvents (eg, methanol, ethanol, 2-propanol, tert-butanol, etc.), nitrile Solvent (eg, acetonitrile, etc.), ester solvent (eg, ethyl formate, ethyl acetate, tert-butyl acetate, etc.), hydrocarbon solvent (eg, hexane, benzene, toluene, etc.), halogenated carbon Hydrogen solvents (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, ), Organic base solvents (eg, pyridine, 2,4,6-trimethylpyridine, picoline, 4-dimethylaminopyridine, 2,6-lutidine, 1,8-, quasabicyclo [5,4,0] -7 Aromatic bases such as -indene, tertiary amines such as triethylamine and dimethylaniline), liquid ammonia and the like, or a mixed solvent thereof. Among them, N, N-dimethylformamide, N, N-dimethylacetamide, methanol, ethanol, 2-propanol, tert-butanol, pyridine, tetrahydrofuran, dioxane, dimethoxyethane, acetonitrile, etc. preferable. The reaction temperature is from 140 to 150 ° C., preferably from 0 ° C. to 100 ° C., and the reaction time is from 5 minutes to 96 hours, preferably from 30 minutes to 48 hours.

Reaction 3

The imidazolidine compound represented by the general formula (III) or a salt thereof is used as a raw material and reacted with a base to give an imidazolidine compound represented by the general formula (IV) (R represents the above alkyl group) or a compound thereof. Get the salt.

Examples of the base include the bases shown in the above Reaction 2, and preferable examples are For example, an alkali metal hydride, an alkali metal alkoxide, an inorganic base, an organic base, an alkyl lithium, or an alkali metal amide is preferable. And 4-dimethylaminopyridine, methyllithium, butyllithium, lithium disopropylamide, lithium pistrimethylsilylamide and the like are particularly preferred. The base is used in an amount of 1 to 50 equivalents, preferably 2 to 10 equivalents, more preferably 2 to 5 equivalents. These reactions are usually advantageously performed in a solvent. The solvent is not specified as long as it does not affect the reaction, but the solvent shown in Reaction 2 above is used, and preferably an amide solvent, an ether solvent, an alcohol solvent, a nitrile solvent, an organic base solvent Solvents, or a mixture thereof, among which N, N-dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane, methanol, ethanol, 2-propanol, tert-butanol, acetonitrile, pyridine Etc. are particularly preferred. The reaction temperature is 140 ° C. to 150 ° C., preferably 2 Ot: to 120 ° C., and the reaction time is 5 minutes to 96 hours, preferably 30 minutes to 24 hours. .

The above Reaction 2 and Reaction 3 can be advantageously performed by continuously performing the reaction without isolating and purifying the product during the reaction. By reacting the above 5-dichloromethylene imidazolidine compound represented by the general formula (II) or a salt thereof as a raw material with the above mercapto compound represented by the general formula ROCOCH ₂ CH ₂ SH in the presence of a base, the general formula An imidazolidine compound represented by (IV) or a salt thereof is obtained.

Reaction 4

 Starting from an imidazolidine compound represented by the general formula (IV) (R represents the above-mentioned alkyl group) or a salt thereof, a ketone compound having a leaving group L at the octyl position represented by the general formula (V) ( L represents a halogen atom such as chlorine, bromine or iodine or a sulfonyloxy group such as methanesulfonyloxy, P-toluenesulfonyloxy, trifluoromethanesulfonyloxy, etc.) or a salt thereof in the presence of a base By the reaction, an imidazothiazine compound represented by the general formula (VI) (R represents the above alkyl group) or a salt thereof is obtained.

In the compound represented by the general formula (V) or a salt thereof, the leaving group L is a halogen atom. Can be prepared from the corresponding ketone compound by halogenating the α-position by a method known per se. The compound represented by the general formula (V) or a salt thereof, in which the leaving group L is a sulfonyloxy group, is a compound known per se represented by the corresponding -hydroxyketone compound, for example, the method shown in Reaction 10 below. It can be prepared by sulfonylation of a hydroxyl group by the method described in the above.

In the ketone compound having a leaving group L at the α-position represented by the general formula (V) or a salt thereof, L is preferably a halogen atom such as chlorine, bromine or iodine, and more preferably chlorine or bromine. It is. The ketone compound or a salt thereof is used in an amount of 0.2 to 10 equivalents, preferably 1 to 5 equivalents, more preferably 1 to 3 equivalents, based on the raw material. Examples of the base include the bases shown in Reaction 2 above, and preferable examples thereof include, for example, alkali metal hydrides, alkali metal alkoxides, inorganic bases, organic bases, alkyllithiums, and alkali metal amides. , Sodium hydride, sodium methoxide, sodium methoxide, potassium tert-butoxide, sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, triethylamine, disopropylethylamine, pyridine, 4 -Dimethylaminopyridine, 1,8-diazabicyclo [5,4,0] -7-indene, methyllithium, butyllithium, lithium diisopropylamide, lithium pistrimethylsilylamide and the like are particularly preferred. Of these, liquid ones are also used as solvents. The base is used in an amount of 1 to 50 equivalents, preferably 2 to 10 equivalents, and more preferably 2 to 5 equivalents. These reactions are usually advantageously performed in a solvent. The solvent is not specified as long as it does not affect the reaction, but the solvent shown in Reaction 2 above is used, and preferably, an amide solvent, an ether solvent, a ketone solvent, an ester solvent, and a nitrile solvent are used. Solvents, hydrocarbon solvents, halogenated hydrocarbon solvents, organic base solvents, etc., and mixtures thereof. Among them, N, N-dimethylformamide, N, N-dimethylileacetamide, titra Hydrofuran, dioxane, dimethoxyethane, acetate, 2-butenonone, ethyl acetate, tert-butyl acetate, acetatetonitrile, toluene, dichloromethane, chloroform, 1,2-dichloroethane, pyridine and the like are particularly preferred. The reaction temperature is from 140 ° C to 150 ° C, preferably from 0 to 100 ° C, and the reaction time is from 5 minutes to 96 hours, preferably from 30 minutes to 48 hours. Reaction 5

The imidazothiazine compound represented by the general formula (VI) (R represents the above-mentioned alkyl group) or a salt thereof is subjected to a dehydration reaction in the presence of an acid, whereby the compound represented by the general formula (VII) is obtained. (Wherein R represents the above alkyl group). Preferred examples of the acid used include, for example, octaacetic acid (eg, trifluoroacetic acid), inorganic acid (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid, etc.), and organic carboxylic acids. Acids (eg, formic acid, acetic acid, citric acid, tartaric acid, oxalic acid, etc.), Lewis acids (eg, zinc monoacetic acid, boron trifluoride etherate, etc.), organic sulfonic acids (eg, methanesulfonic acid, octanesulfonic acid, Benzenesulfonic acid, P-toluenesulfonic acid, camphorsulfonic acid, etc.), among which trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, methanesulfonic acid, P-toluenesulfonic acid, camphorsulfonic acid, etc. Is particularly preferred. Of these, liquid ones are also used as solvents. The acid is used in an amount of 0.05 to 10 equivalents, preferably 0.1 to 5 equivalents, and more preferably 0.2 to 2 equivalents, based on the raw material. The reaction is advantageously carried out by coexisting a dehydrating agent to remove the usually generated water. As the dehydrating agent, molecular sieves 4A, acid anhydride (eg, acetic anhydride, propionic anhydride, benzoic anhydride, etc.) are used. For example, if the molecular weight is 4 A (1 Z 16 to 200 mesh), the amount is 5% to 10 times, preferably 10% to 5 times, or 10% by weight of the raw material. If it is an acid anhydride, it is used in an amount of 0.5 to 20 equivalents, preferably 1 to 10 equivalents, more preferably 1 to 5 equivalents, based on the raw materials. These reactions are usually advantageously performed in a solvent. The solvent is not specified as long as it does not affect the reaction, but is preferably an organic acid-based solvent (eg, formic acid, acetic acid, propionic acid, etc.), an amide-based solvent (eg, N, N-dimethylformamide, N, N —Dimethylacetamide, etc.), ether solvents (eg, tetrahydrofuran, getylether, dioxane, dimethoxyethane, etc.), sulfoxide solvents (eg, dimethylsulfoxide, etc.), alcohol solvents (eg, methanol, ethanol, propanol, Isopropanol, isobutanol, tert-butanol, etc., nitrile solvents (eg, acetonitrile, etc.), ester solvents (eg, ethyl formate, ethyl acetate, tert-butyl acetate, etc.), hydrocarbon solvents (eg, Hexane, benzene, toluene, xylenes, etc.), halogenated carbon Hydrogenated solvents (eg, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, cyclobenzene, etc.) and the like, and a mixed solvent thereof are exemplified. Among them, acetic acid, N, N-dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane, tert-butanol, acetonitrile, ethyl acetate, tert-butyl acetate, toluene, xylenes, chloroform, 1,2- Dichloroethane is preferred. The reaction temperature is −4 Ot: to 180 ° C, preferably 0 ° C to 120 ° C, and the reaction time is 5 minutes to 120 hours, preferably 10 minutes to 72 hours. .

Reaction 6

 The imidazothiazine compound represented by the general formula (VIII) is obtained by reacting the imidazothiazine compound represented by the general formula (VII) (R represents the above alkyl group) or a salt thereof with a base. A compound or a salt thereof is obtained.

 Examples of the base include the bases shown in Reaction 2 above, and preferable examples thereof include, for example, alkali metal hydrides, alkali metal alkoxides, inorganic bases, organic bases, alkyllithiums, and alkali metal amides. Preferably, sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, diisopropylethylamine, 4-dimethylaminopyridine, 1,8-diazavisic mouth [5,4,0] -7-Pendecene, methyllithium, butyllithium, lithium diisopropylamide, and lithium bistrimethylsilylamide are particularly preferred. The base is used in an amount of 1 to 20 equivalents, preferably 2 to 10 equivalents, more preferably 2 to 5 equivalents. These reactions are usually advantageously performed in a solvent. The solvent is not specified as long as it does not affect the reaction, but the solvent shown in Reaction 2 above is used, preferably an amide solvent, an ether solvent, an alcohol solvent, a nitrile solvent, an organic base. Solvent, or a mixture of these solvents. Among them, N, N-dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane, methanol, ethanol, 2-propanol, tert-butanol, Acetonitrile, pyridine and the like are particularly preferred. The reaction temperature is −40 ° C. to 15 Ot: preferably 20 ° C. to 120 °, and the reaction time is 5 minutes to 96 hours, preferably 30 minutes to 24 hours.

Reaction 7-(a) By reacting an imidazothiazine compound represented by the general formula (VIII) or a salt thereof as a raw material with a general formula R ² —L (L represents a leaving group) or a salt thereof in the presence of a base, An imidazothiazine compound represented by the general formula (IX) (n = l) or a salt thereof is obtained.

In the compound represented by the general formula R ² — L or a salt thereof, L is a halogen atom such as chlorine, bromine, iodine, etc., or methanesulfonyloxy, P-toluenesulfonyl, trifluoromethanesulfonyloxy, etc. Sulfonyloxy group and the like are preferable. General formula: ² a compound represented by one L or compound leaving group L is Nono androgenic atom of its salt corresponding alcohol Ichiru compound R ² - 0 H or a hydroxyl by a method per se publicly known salts thereof Can be prepared by halogenating Among the compounds represented by the general formula R ² —L or a salt thereof, the compound in which the leaving group L is a sulfonyloxy group can be converted from R ² —〇H to a compound represented by, for example, the method shown in Reaction 10 below. It can be prepared by sulfonylating a hydroxyl group by a known method.

The compound represented by the above general formula R ² -L or a salt thereof is used in an amount of 0.2 to 20 equivalents, preferably 1 to 10 equivalents, more preferably 1 to 5 equivalents to the starting material. Examples of the base include the bases shown in the above Reaction 2, and preferable examples thereof include, for example, hydrogenated metal alkoxides, metal alkoxides, inorganic bases, organic bases, alkyllithiums, and metal alkoxides. Amides and the like are preferable, and sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, triethylamine, disopropylethylamine, pyridine, 4-dimethylaminopyridine , 1,8-Diazavicic mouth [5,4,0] -7-indene, methyllithium, butyllithium, lithium diisopropylamide, lithium bistrimethylsilylamide and the like are particularly preferable. Of these, liquid ones are also used as solvents. The base is used in an amount of 1 to 50 equivalents, preferably 2 to 10 equivalents, and more preferably 2 to 5 equivalents. These reactions are usually advantageously performed in a solvent. The solvent is not specified as long as it does not affect the reaction, but the solvent shown in Reaction 2 above is used, preferably an amide solvent, ether solvent, ketone solvent, ester solvent, nitrile Solvents, alcohol-based solvents, hydrocarbon-based solvents, organic base-based solvents, and the like, or a mixture thereof. Among them, N, N-dimethylform Muamide, N-methylpyrrolidone, tetrahydrofuran, dioxane, dimethoxyethane, acetone, 2-butanone, ethyl acetate, tert-butyl acetate, acetonitrile, toluene, pyridine and the like are particularly preferred. The reaction temperature is −20 ° C. to 20 O, preferably 20 ° C. to 120 ° C., and the reaction time is 5 minutes to 120 hours, preferably 20 minutes to 72 hours. . Reaction 6 and reaction 7_ (a) can also be performed in a concatenated manner.

Reaction 7— (b)

By subjecting an imidazothiazine compound represented by the general formula (VIII) or a salt thereof as a raw material to a dehydration condensation reaction using a Mitsunobu reaction with an alcohol compound represented by the general formula R ² —ΔH or a salt thereof, An imidazothiazine compound represented by the general formula (IX) (n = l) or a salt thereof is obtained.

The alcohol compound represented by the general formula R ² —OH or a salt thereof is used in an amount of 0.2 to 20 equivalents, preferably 1 to 10 equivalents, and more preferably 1 to 5 equivalents to the starting material. Examples of the dehydrating condensing agent include phosphine monoazodicarboxylates and phosphine monoazodicarboxylates reported in the Mitsunobu reaction [Synthes is, p. 1, 1989] [Journal of the Society of Synthetic Organic Chemistry] 55, 631, 1997] are advantageously used as the dehydrating condensing agent. Examples of the phosphine include triaryl phosphine, triaryl phosphine such as tri-0-tolyl phosphine, and the like, or trialkyl phosphine such as trimethyl phosphine and tributyl phosphine, among which triphenyl phosphine and tributyl phosphine are preferable. . Examples of the azodicarboxylate include acetyl dicarboxylate, diisopropyl azodicarboxylate, and the like. Examples of azodicarboxylic acid amides include N, N, Ν ', Ν'-tetramethyl azodicalpoxamide, Ν, Ν, N', N'-tetraisopropyl azodicarpoxamide, 1, tri (azodicarponyl) And dipiperidine. The dehydrating condensing agent is used in an amount of 1 to 20 equivalents, preferably 2 to 10 equivalents, and more preferably 2 to 5 equivalents. It is preferable to use the same moles of phosphine and azodicarboxylic acid ester or azodicarboxylic acid amide. These reactions are usually advantageously performed in a solvent. The solvent is not specified as long as it does not affect the reaction. Preferably used are amide solvents, ether solvents, ketone solvents, ester solvents, nitrile solvents, hydrocarbon solvents, octogenated hydrocarbon solvents, organic base solvents, etc., or a mixture thereof. N, N-dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane, acetone, 2-butanone, ethyl acetate, tert-butyl acetate, acetonitrile, toluene, chloroform, 1,2-dichloroethane, pyridine, etc. Is particularly preferred. The reaction temperature is between 120 ° C and 150 ° C, preferably between 20 ° C and 120 ° C, and the reaction time is between 5 minutes and 120 hours, preferably between 20 minutes and 60 hours. is there.

Reaction 7 — (c)

A thiol compound represented by the general formula R ² —SH (where R ² represents an aryl group which may have a substituent) from an imidazothiazine compound represented by the general formula (VIII) or a salt thereof as a raw material. Alternatively, an imidazothiazine compound represented by the general formula (IX) (n = l or 2) or a salt thereof is obtained by subjecting the salt thereof to a dehydration condensation reaction applying the Mitsunobu reaction.

The thiol compound represented by the general formula R ² —SH or a salt thereof is used in an amount of 0.2 to 20 equivalents, preferably 1 to 10 equivalents, more preferably 1 to 5 equivalents, based on the amount of the raw material. As the dehydrating condensing agent, for example, the phosphine and azodicarboxylic acid ester or azodicarboxylic acid amide mentioned in the above reaction 7- (b) are advantageously used. Examples include acetyldiazolate azodicarboxylate and diisopropyl azodicarboxylate. Examples of azodicarboxylate amides include N, N, N ', N, -tetramethylazodicarpoxamide, 1,1- (azodicarpoxamide). Nyl) dipiperidine and the like are preferred. The dehydrating condensing agent is used in an amount of 1 to 20 equivalents, preferably 2 to 10 equivalents, and more preferably 2 to 5 equivalents. It is preferable that phosphine and azodicarboxylic acid ester or azodicarboxylic acid amide be used in the same mole number. These reactions are usually advantageously performed in a solvent. The solvent is not specified as long as it does not affect the reaction, but the solvent shown in Reaction 2 above is used, and preferably, an amide solvent, an ether solvent, a ketone solvent, an ester solvent, and nitrile are used. Solvent, hydrocarbon solvent, halogenated hydrocarbon solvent, organic base solvent, etc. Include mixed solvents of these, among which N, N-dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane, acetone, 2-butanone, ethyl acetate, tert-butyl acetate, acetonitrile, toluene, chloroform Mouth form, 1,2-dichloroethane, pyridine and the like are particularly preferred. The reaction temperature is -20 ° C to 120 ° C, preferably 20 ° C to 80 ° C, and the reaction time is 10 minutes to 240 hours, preferably 20 minutes to 120 hours.

In the general formula (I), R ^{1 is} -NR ³ R ⁴ ,

X Y

In the compound (XI) or a salt thereof and the general formula (I), R ^{1 is} -SR ² ,

X Y

である化合物 （X I I) またはその塩の合成

Of compound (XII) or its salt

Reaction 8

Imidazolidine compound represented by the general formula (X) (Z represents a S0 _2.) Or As a salt as a raw material, Amin or its salt with a base represented by R ³ R ⁴ NH or R ¹² R ¹³ NH To give an imidazolidine compound (Z represents S 式₂ ) represented by the general formula (XI) or (XII) or a salt thereof.

The amine represented by R ³ R ⁴ NH or R ¹² R ¹³ NH or a salt thereof is 1 to 50 Equivalents, preferably 2 to 20 equivalents, more preferably 2 to 10 equivalents are used. Of these, liquid ones are also used as solvents. These amines are also advantageously used as salts with suitable acids. Examples of the acid include octaacetic acid (eg, trifluoroacetic acid), inorganic acid (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid, etc.), and organic carboxylic acid (eg, formic acid, acetic acid) , Citric acid, tartaric acid, oxalic acid, etc.), organic sulfonic acids (eg, methanesulfonic acid, benzenesulfonic acid, P-toluenesulfonic acid, camphorsulfonic acid, etc.) are used, among which hydrochloric acid, formic acid, acetic acid , Methanesulfonic acid, P-toluenesulfonic acid and the like are particularly preferred. The acid is usually used in an equimolar amount to the amine. Examples of the base include the bases shown in the above Reaction 2, and preferable examples include, for example, hydrogenated alkali metal, alkoxide of alkali metal, inorganic base, organic base, and alkali metal amide. Sodium hydride, sodium ethoxide, potassium tert-butoxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, diisopropylpyrethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5,4,0] -7-Pendecene, lithium diisopropylamide, lithium bistrimethylsilylamide and the like are particularly preferred. The base is used in an amount of 0.1 to 20 equivalents, preferably 0.5 to 10 equivalents, and more preferably 1 to 5 equivalents. These reactions are usually advantageously carried out in a solvent. The solvent is not specified as long as it does not affect the reaction, but the solvent shown in the above Reaction 2, etc. is used, and preferably an amide solvent, an ether solvent, an alcohol solvent, a nitrile solvent, Examples include organic base solvents and the like, or a mixed solvent thereof. Among them, N, N-dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane, methanol, ethanol, 2-propanol, tert-butanol , Acetonitrile, pyridine and the like are particularly preferred. The reaction temperature is from −40 ° C. to 150 ° C., preferably from 20 ° to 120 ° C. (: the reaction time is from 5 minutes to 96 hours, preferably from 30 minutes to 24 hours.

In the general formula (I), R ¹ is one SR ² , XY is

である化合物 （X) またはその塩の合成

Of compound (X) or its salt

 (X I I I) (X)

Anti-j¾, 9-a)

Imidazothiazine compound represented by the general formula (XIII) or a salt thereof as a starting material, the general formula R ^{1 5} in the presence of a base - Z- L (Z is S 0 ₂ or C_〇, L is a leaving group represented. the compound or reacting it with a salt thereof), imidazothiazine compound represented by the general formula (X) (Z is obtained.) or a salt thereof shows a S_〇 ₂ or CO. Examples of the base include the bases shown in Reaction 2 above, and preferable examples include, for example, alkali metal hydrides, alkali metal alkoxides, inorganic bases, organic bases, alkyllithiums, and alkali metal amides. Preferably, sodium hydride, potassium tert-butoxide, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5,4,0]- 7-Pendecene, methyllithium, butyllithium, lithium disopropylamide, lithium pistrimethylsilylamide and the like are particularly preferred. Of these, liquid ones are also used as solvents. The base is used in an amount of 1 to 50 equivalents, preferably 2 to 10 equivalents, and more preferably 2 to 5 equivalents. In the compound represented by the general formula R ¹ ′ ⁵ —Z—L, L is preferably a halogen atom such as chlorine, bromine or iodine, or a cyano group or an imidazole group. The compound represented by the above general formula R ¹⁵ —Z—L is used in an amount of 0.2 to 20 equivalents, preferably 1 to 1 equivalent to the raw material. 0 equivalents, more preferably 1 to 5 equivalents are used. These reactions are usually advantageously performed in a solvent. The solvent is not specified as long as it does not affect the reaction, but the solvent shown in Reaction 2 above is used, and preferably an amide solvent, an ether solvent, a ketone solvent, an ester solvent, a nitrile solvent. , Alcohol-based solvents, hydrocarbon-based solvents, organic base-based solvents and the like, and mixtures thereof. Among them, N, N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, dioxane, dimethoxyethane, acetone, Particularly preferred are 2-butanone, ethyl acetate, tert-butyl acetate, acetonitrile, toluene, pyridine and the like. The reaction temperature is from 180 ° C. to 150 ° C., preferably from 0 to 100 ° C., and the reaction time is from 1 minute to 120 hours, preferably from 5 minutes to 48 hours.

 (X I I I) (Χ ')

Reaction 91 (b)

Starting from the imidazothiazine compound represented by the general formula (XIII) or a salt thereof, in the presence of a base, represented by the general formula R ¹⁶ R ¹⁷ P (〇) —L (L represents a leaving group). By reacting with a compound represented by the formula or a salt thereof, an imidazothiazine compound represented by the general formula (X ') or a salt thereof is obtained.

Examples of the base include the bases shown in the above-mentioned Reaction 9-1 (a), and preferable examples include, for example, alkali metal hydrides, alkali metal alkoxides, inorganic bases, organic bases, alkyllithiums, and alkalis. Metal amides and the like are preferred, and sodium hydride, potassium tert-butoxide, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazapicyclo 0]-7-Pendecene, methyllithium, butyllithium, And lithium pistrimethylsilylamide are particularly preferred. Of these, liquid ones are also used as solvents. The base is used in an amount of 1 to 50 equivalents, preferably 2 to 10 equivalents, more preferably 2 to 5 equivalents. In the compound represented by the general formula R ¹⁶ R ¹⁷ P (〇) —L, L is preferably a halogen atom such as chlorine, bromine, and iodine. The compound represented by the above general formula R ¹⁶ R ¹⁷ P (〇) 1 L is used in an amount of 0.2 to 20 equivalents, preferably 1 to 10 equivalents, more preferably 1 to 5 equivalents, based on the amount of the raw material. These reactions are advantageously carried out usually in a solvent. The solvent is not specified as long as it does not affect the reaction, but the solvent shown in the above reaction 9- (a) or the like is used, preferably an amide solvent, an ether solvent, a ketone solvent, an ester solvent, Examples include nitrile-based solvents, alcohol-based solvents, hydrocarbon-based solvents, organic base-based solvents, and the like, or a mixed solvent thereof. Dimethoxyethane, acetone, 2-butanone, ethyl acetate, tert-butyl acetate, acetonitrile, toluene, pyridine and the like are particularly preferred. The reaction temperature is -80 to 150 ° C, preferably 0 to 100 ° C, and the reaction time is 1 minute to 120 hours, preferably 5 minutes to 48 hours.

 (XIII)

 (X ")

Reaction 91 (C)

And imidazothiazine compound represented by the general formula (XIII) or a salt thereof as a starting material, the general formula R ¹⁸ _Z- NCO (Z represents S_〇 ₂ or a single bond.) Represented by the 'Isoshi Aneto acids or their By reacting with a salt, an imidazothiazine compound represented by the general formula (X ") or a salt thereof is obtained.

When Z represents a single bond, the reaction is advantageously performed in the presence of a base. As the base, The base shown in the above reaction 9-1 (a) and the like are preferable. Preferred examples include, for example, alkali metal hydride, alkali metal alkoxide, inorganic base, organic base, alkyl lithium, and alkali metal amide. Sodium hydride, potassium tert-butoxide, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabisic D [5, 4, 0]- 7-Pendecene, methyllithium, butyllithium, lithium diisopropylamide, lithium pistrimethylsilylamide and the like are particularly preferred. Of these, liquid ones are also used as solvents. The base is used in an amount of 1 to 50 equivalents, preferably 2 to 10 equivalents, more preferably 2 to 5 equivalents. The isocyanate represented by the general formula R ¹⁸ —Z-NCO is used in an amount of 0.2 to 20 equivalents, preferably 1 to 10 equivalents, more preferably 1 to 5 equivalents, based on the amount of the raw material. These reactions are usually and advantageously effected in a solvent. The solvent is not specified as long as it does not affect the reaction, but the solvent shown in the above reaction 9-1 (a) is used, and preferably an amide solvent, an ether solvent, a ketone solvent, an ester solvent, Examples include nitrile solvents, alcohol solvents, hydrocarbon solvents, organic base solvents, and mixtures thereof.N, N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, dioxane , Dimethoxyethane, acetone, 2-butanone, ethyl acetate, tert-butyl acetate, acetonitrile, toluene, pyridine and the like are particularly preferred. The reaction temperature ranges from 80 ° C to 150 ° C, preferably from 0 ° C to 100 ° C, and the reaction time ranges from 1 minute to 120 hours, preferably from 5 minutes to 48 hours.

 (XIII) (X)

Reaction 9— (d)

Starting from an imidazothiazine compound represented by the general formula (XIII) or a salt thereof, Reaction with a compound represented by the general formula R ¹⁵ —CO ₂ H or a salt thereof in the presence of a condensing agent and a base gives an imidazothiazine compound represented by the general formula (X) or a salt thereof .

トキシカルポニル _2 - エトキシ -1, 2-ジヒドロキノリン、 塩酸 1-ェチル -3- (3-ジメチルァミノプロピル） カルポジイミドなどが挙げられ、 好ましい例としては例えば、 N，N ジシクロへキ シルカルポジイミド、 シァノりん酸ジェチル、 塩酸 卜ェチル -3- (3-ジメチルアミ ノプロピル）カルポジイミドなどが特に好ましい。 縮合剤は 1ないし 5 0当量、 好 ましくは 2ないし 1 0当量、 さらに好ましくは 2ないし 5当量を用いる。塩基とし ては、 上記反応 9一 ( a ) で示した塩基などが挙げられ、 好ましい例としては例え ば、 水素化アルカリ金属、 アルカリ金属のアルコキシド、 無機塩基、 有機塩基、 7 ルキルリチウム、 またはアルカリ金属アミドなどが好ましく、 水素化ナトリウム、 カリウム ter卜ブトキシド、 炭酸ナトリウム、 炭酸カリウム、 トリェチルァミン、 ジイソプロピルェチルァミン、 ピリジン、 4-ジメチルァミノピリジン、 1, 8-ジァザ ビシクロ [5， 4， 0]- 7-ゥンデセン、 メチルリチウム、 ブチルリチウム、 リチウムジィ ソプロピルアミド、 リチウムピストリメチルシリルアミドなどが特に好ましい。 こ れらのうち液体のものは溶媒としても用いられる。塩基は 1ないし 5 0当量、好ま しくは 2ないし 1 0当量、 さらに好ましくは 2ないし 5当量を用いる。 一般式 R ^{1 5}— C〇₂Hで表される化合物は原料に対して 0 . 2ないし 2 0当量、 好ましくは 1 ないし 1 0当量、 さらに好ましくは 1ないし 5当量を用いる。 これらの反応は通常 溶媒中で有利に行われる。溶媒は反応に影響を与えないものであれば特定されない が、 上記反応 9一 ( a ) で示した溶媒などが用いられ、 好ましくはアミド系溶媒、 ェ一テル系溶媒、 ケトン系溶媒、 エステル系溶媒、 二トリル系溶媒、 アルコール系 溶媒、 炭化水素系溶媒、有機塩基系溶媒など、 あるいはこれらの混合溶媒が挙げら れ、 なかでも N, N—ジメチルホルムアミド、 N-メチルピロリドン、 テトラヒド 口フラン、 ジォキサン、 ジメトキシェタン、 アセトン、 2-ブ夕ノン、 酢酸ェチル、 酢酸 ter t-プチル、 ァセトニトリル、 トルエン、 ピリジンなどが特に好ましい。 反 応温度は— 80 °Cないし 150 °C、好ましくは 0 ないし 100 °C、反応時間は 1 分間ないし 120時間、 好ましくは 5分ないし 48時間である。 Examples of the condensing agent include N, N'-carbonyldiimidazole, benzotriazolyl-N-hydranide salt, N, N, -disocyanate.

Toxicarbonyl_2-ethoxy-1,2-dihydroquinoline, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, and the like. Preferred examples thereof include, for example, N, N dicyclohexylcarboimide, Particularly preferred are getyl cyanophosphate, and triethyl hydrochloride-3- (3-dimethylaminopropyl) carbodiimide. The condensing agent is used in an amount of 1 to 50 equivalents, preferably 2 to 10 equivalents, more preferably 2 to 5 equivalents. Examples of the base include the bases shown in the above reaction 9-1 (a). Preferred examples include alkali metal hydrides, alkali metal alkoxides, inorganic bases, organic bases, 7-alkyllithiums, and alkalis. Metal amides and the like are preferable, and sodium hydride, potassium tert-butoxide, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5,4,0 ] -7-Pendecene, methyllithium, butyllithium, lithium disopropylamide, lithium pistrimethylsilylamide and the like are particularly preferred. Of these, liquid ones are also used as solvents. The base is used in an amount of 1 to 50 equivalents, preferably 2 to 10 equivalents, and more preferably 2 to 5 equivalents. Formula R ^{1 5} -. C_〇 compound represented by the ₂ H 0 2 to 2 0 equivalents relative to the starting, preferably 1 to 1 0 equivalents, more preferably 1 to use 5 equivalents. These reactions are advantageously carried out usually in a solvent. The solvent is not specified as long as it does not affect the reaction, but the solvent shown in the above reaction 9-1 (a) is used, and preferably an amide solvent, an ether solvent, a ketone solvent, or an ester solvent Solvents, nitrile-based solvents, alcohol-based solvents, hydrocarbon-based solvents, organic base-based solvents and the like, or a mixture thereof, among which N, N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, Dioxane, dimethoxyethane, acetone, 2-butanone, ethyl acetate, tert-butyl acetate, acetonitrile, toluene, pyridine and the like are particularly preferred. Anti The reaction temperature is -80 ° C to 150 ° C, preferably 0 to 100 ° C, and the reaction time is 1 minute to 120 hours, preferably 5 minutes to 48 hours.

 In general formula (I)

X Y

Compound (XVI) or a salt thereof and

X Y

Of compound (XVI I) or its salt

 (XVI) (XVII) Reaction 10

Formula imidazothiazine compound represented by (X IV) (Z represents a S_〇 _2.) Or a salt thereof as a raw material, subjecting the hydroxyl group in the formula a conversion reaction of the leaving group L, to Accordingly, imidazothiazine compound represented by the general formula (XV) (Z represents a S_〇 _2.) or a salt thereof. ' Examples of the conversion reaction to the leaving group L ′ include a halogenation reaction with a halogenating agent and a sulfonic acid esterification reaction. Examples of the halogenating agent include hydrogen halide (eg, hydrogen iodide, hydrogen bromide, hydrogen chloride, etc.) or halogenating agent (eg, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, Organophosphorus compounds such as phosphorus halides such as phosphorus bromide, triphenylphosphine monocarbon tetrachloride, triphenylphosphine monobromine, triphenylphosphine mono-N-bromosuccinimide, triphenylphosphite methyl iodide, or thionyl chloride, oxalyl chloride , Phosgene, etc.). The halogenating agent is used in an amount of 1 to 10 equivalents, preferably 1 to 3 equivalents. Of these, liquid ones are also used as solvents. These halogenation reactions are advantageously performed in a solvent. Solvents include water, organic acid solvents (eg, formic acid, acetic acid, etc.), ketone solvents (eg, acetone, methylethyl ketone, methyl isobutyl ketone, etc.), amide solvents (eg, N, N-dimethylformamide) , Dimethylacetamide, etc.), halogenated hydrocarbon solvents (eg, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, cyclobenzene), alcohol solvents (eg, tert- Butanol), nitrile solvents (eg, acetonitrile), ester solvents (eg, ethyl formate, ethyl acetate, tert-butyl acetate, etc.), ether solvents (eg, tetrahydrofuran, getyl ether, dioxane, dimethoxy) ), Hydrocarbon solvents (eg, hexane, benzene, toluene, etc.), aromatic organic bases Medium (eg, pyridine, 2,4,6-trimethylpyridin, picoline, 2,6-lutidine, 1,8-diazabi- sic [5,4,0] -7-indene), and the like A mixed solvent is mentioned. Of these, water, acetone, N, N-dimethylformamide, dimethylacetamide, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, dioxane, pyridine and the like are preferred. These reactions may be performed in the presence of a suitable inorganic acid (eg, sulfuric acid, phosphoric acid, etc.). The reaction temperature is −20 to 150, preferably to 100 ° C., and the reaction time is 2 minutes to 48 hours, preferably 5 minutes to 10 hours.

In the sulfonic acid esterification reaction, the hydroxyl group of the raw material is converted to a sulfonyl halide (eg, methanesulfonyl chloride, benzenesulfonyl chloride, P-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride, etc.) or a sulfonic anhydride (eg, methanesulfone Acid anhydride, benzenesulfonic anhydride, P-toluenesulfonic anhydride, trifluoromethanesulfonic anhydride, etc.) in the presence of a suitable base. This is a reaction for converting to a group. The sulfonyl halide or sulfonic anhydride is used in an amount of 0.2 to 20 equivalents, preferably 1 to 10 equivalents, and more preferably 1 to 5 equivalents, based on the starting material. Examples of the base include the bases shown in the above Reaction 2, and preferable examples thereof include, for example, an alkali metal hydride, an inorganic base, an organic base, and an alkali metal amide. Particularly preferred are potassium, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5,4,0] -7-indene, lithium diisopropylamide, lithium pistrimethylsilylamide and the like. Of these, liquid ones are also used as solvents. The base is used in an amount of 1 to 20 equivalents, preferably 2 to 10 equivalents, and more preferably 2 to 5 equivalents. The sulfonyloxy group formed in the sulfonic acid esterification reaction can be converted to a halogen group by reacting with an appropriate inorganic halide (eg, sodium iodide, potassium iodide, sodium bromide, potassium bromide, etc.). It is possible. The inorganic halide is used in an amount of 1 to 50 equivalents, preferably 1 to 20 equivalents, and more preferably 1 to 10 equivalents, based on the raw material. These reactions are usually performed in a solvent that does not affect the reaction. Examples of the solvent include those used in the above-mentioned halogenation reaction except for water, and among them, acetone, methylethylketone, N, N-dimethylformamide, dimethylacetamide, dichloromethane, and chloroform And 1,2-dichloroethane, acetonitrile, ethyl acetate, tert-butyl acetate, tetrahydrofuran, getyl ethere, dioxane, dimethoxyethane, hexane, toluene, pyridine, and the like, or a mixed solvent thereof. These are particularly preferably water-free solvents. The reaction temperature is from 120 to 200, preferably from 20 ° C. to 12 Ot: and the reaction time is from 5 minutes to 120 hours, preferably from 20 minutes to 72 hours.

Reaction 1 1

The imidazothiazine compound represented by the general formula (XV) (Z represents so ₂ ) or a salt thereof is reacted with a base or an acid to obtain the compound represented by the general formula (XVI). Others imidazothiazine compound represented by (XVII) (Z represents a S_〇 _2.) Or a salt thereof.

 Examples of the base include the bases shown in Reaction 2 above, and preferable examples thereof include, for example, alkali metal hydrides, alkali metal alkoxides, inorganic bases, organic bases, and alkali metal amides. , Potassium tert-butoxide, sodium carbonate, potassium carbonate, diisopropylethylamine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5,4,0] -7-indene, lithium diisopropylamide, lithium pistrimethylsilylamide Etc. are particularly preferred. The base is used in an amount of 1 to 20 equivalents, preferably 2 to 10 equivalents, more preferably 2 to 5 equivalents. Examples of the acid include the acids shown in the above Reaction 5, among which, for example, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, methanesulfonic acid, P-toluenesulfonic acid, camphorsulfonic acid And boron trifluoride etherate complex are particularly preferred. Of these, liquid ones are also used as solvents. The acid is used in an amount of 0.05 to 10 equivalents, preferably 0.1 to 5 equivalents, and more preferably 0.2 to 2 equivalents, based on the raw material. These reactions are advantageously carried out usually in a solvent. The solvent is not specified as long as it does not affect the reaction, but the solvent shown in the above Reaction 2 or Reaction 5 is used, and preferably, an organic acid solvent, an amide solvent, an ether solvent, or an alcohol solvent Solvents, nitrile-based solvents, hydrocarbon-based solvents, halogenated hydrocarbon-based solvents, organic base-based solvents, and the like, or a mixture thereof. Among them, formic acid, acetic acid, N, N-dimethylformamide, tetrahydrofuran, Dioxane, dimethyloxetane, acetonitrile, benzene, toluene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, cyclobenzene, pyridine and the like are particularly preferred. The reaction temperature is —40 ° C. to 200 ° C., preferably 0 to 12 O, and the reaction time is 5 minutes to 120 hours, preferably 30 minutes to 48 hours.

In the general formula (I), R ¹ is — SR ² , Fifteen

X Y

 But

である化合物 （X) またはその塩および R¹がー SR²、

A compound (X) or a salt thereof, and R ^{1 is} -SR ² ,

 Fifteen

X Y »

Of compound (XX I) or its salt

Base

 Reaction 1 3

 (I V) (XV I I I)

 (X) (XX I)

Reaction 12

Under the same conditions as in Reaction 7- (a) described above, the imine represented by the general formula (IV) Dazorijin compounds (Z is S 0 _2, R indicates the alkyl group.) Or a salt thereof as raw materials, the general formula R ² shown in the presence of a base in the above reaction 7- (a) - L (L is by reacting with.) or a salt thereof represents a leaving group, the general formula (XV III) imidazolidine represented Ru compounds (Z is S_〇 _2, R is obtained.) or a salt thereof shows the alkyl group .

Reaction 1 3

Under the same conditions as described in Reaction 3 of the description, Imida Zorijin compound represented by the general formula (XV III) (Z is S_〇 _2, R represents the alkyl group.) Or a salt thereof as a starting material, the base and the reaction by, imidazolidine compound represented by the general formula (XIX) (Z is S 0 _2, R represents the alkyl group.) is obtained or a salt thereof.

Reaction 1 4.

 Under the same conditions as in Reaction 4 described above, an imidazolysine compound represented by the general formula (XIX) or a salt thereof is used as a starting material, and a ketone having a leaving group L at the α-position represented by the above general formula (V) By reacting the compound or a salt thereof in the presence of a base, an imidazothiazine compound represented by the general formula (XX) or a salt thereof is obtained.

Reaction 1 5

The imidazothiazine compound represented by the general formula (XX) (Ζ represents so ₂ ) or a salt thereof is reacted with an acid to form the compound represented by the general formula (X) or (XXI). that imidazothiazine compound (Z denotes a S_〇 _2.) or a salt thereof. Examples of the acid include the acids shown in Reaction 5 above, among which, for example, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid And boron trifluoride etherate are particularly preferred. Of these, liquid ones are also used as solvents. The acid is used in an amount of 0.05 equivalents, preferably 10 equivalents, preferably 0.1 to 5 equivalents, more preferably 0.2 to 2 equivalents, based on the raw material. These reactions are usually advantageously performed in a solvent. The solvent is not specified as long as it does not affect the reaction, but the solvents described in Reaction 5 above are used, and preferably, organic acid solvents, amide solvents, ether solvents, alcohol solvents, nitriles Solvents, hydrocarbon solvents, haptic hydrocarbon solvents, organic base solvents, etc., and mixtures thereof. Among them, formic acid, acetic acid, N, N-dimethyl Formamide, tetrahydrofuran, dioxane, dimethoxyethane, acetonitrile, benzene, toluene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, cyclobenzene, pyridine and the like are particularly preferred. The reaction temperature is between 14O: to 200 ° C, preferably not 0 to 120 ° C, and the reaction time is 5 minutes to 120 hours, preferably 30 minutes to 48 hours.

In the general formula (I), R is _SR ² ,

X Y is 0

Of compound (XXIV) or its salt

 (XX I I) (XX I V)

Reaction 16

Under the same conditions as described in Reaction 4 of the described general formula (XX II) imidazolidine compound represented by (Z is S_〇 ₂ are shown.) Or a salt thereof as a raw material, represented by the general formula (XX III) (R represents an alkyl group such as methyl, ethyl, propyl, isopropyl, 2-ethylhexyl) or a salt thereof in the presence of a base. To obtain an imidazothiazine compound represented by the general formula (XX IV) (Z represents so ₂ ) or a salt thereof.

In the general formula (I), R ¹ is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,

である化合物 （XV I ) またはその塩の合成

Of compound (XVI) or its salt

(X) (XVI) reaction 1 7

By reacting an imidazothiazine compound represented by the general formula (X) (Z represents so ₂ ) or a salt thereof with an organometallic reagent or an equivalent thereof or a metal hydride, the general formula (X XVI) (wherein R ¹ ′ represents an optionally substituted hydrocarbon or hydrogen atom, and Z represents so ₂ ) or a salt thereof.

Examples of the organometallic reagents or their equivalents include alkyl lithium (eg, methyl lithium, ethyl lithium, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, etc.), alkyl magnesium hydride (eg, Methylmagnesium bromide, ethylmagnesium bromide, n-butylmagnesium bromide, n-pentylmagnesium bromide, n-hexylmagnesium bromide, etc., alkyl zinc halides (eg, methyl zinc bromide, getyl zinc bromide, etc.) Alkyl zinc (eg, dimethyl zinc, diethyl zinc, etc.), alkyl aluminum (eg, trimethyl aluminum, etc.) are used. Alternatively, an arbitrary halide can be converted into an organolithium, an organomagnesium halide or an alkyl zinc halide by a method known per se as a raw material and used in this reaction. Examples of the metal hydride include lithium aluminum hydride, sodium borohydride, lithium borohydride, diisobutylaluminum hydride, and the like. The organic metal reagent or its equivalent or metal hydride is used in an amount of 0.5 to 20 equivalents, preferably 1 to 10 equivalents. These reactions can be advantageously performed in the presence of an appropriate organic phosphorus compound or the like. Examples of the organic phosphorus compound include triarylphosphine (eg, triffee). Nylphosphine, tri-0-tolylphosphine, etc.), trialkylphosphine (eg, trimethylphosphine, tributylphosphine, etc.), or trialkylphosphite (eg, trimethylphosphite, triethylphosphite, etc.) Among them, triphenylphosphine, tributylphosphine and the like are preferable. The organic phosphorus compound is used in an amount of 1 to 50 equivalents, preferably 1 to 10 equivalents, based on the amount of the raw material. These reactions can be performed in the presence of an appropriate inorganic salt (eg, lithium iodide, lithium bromide, lithium chloride, cerium chloride, etc.). The inorganic salt is used in an amount of 1 to 50 equivalents, preferably 1 to 10 equivalents, based on the raw material. These reactions are usually performed in a solvent that does not affect the reaction. Examples of the solvent include amide solvents (eg, N, N-dimethylformamide, N, N-dimethylacetamide, etc.), ether solvents (eg, tetrahydrofuran, getyl ether, dioxane, dimethoxetane, etc.), Hydrocarbon solvents (eg, hexane, benzene, toluene, etc.), organic base solvents (eg, pyridine, 2,4,6-trimethylpyridine, picoline, 2,6-lutidine, 1,8-diazabicyclo [5 , 4, 0] -7-dendene and the like, or a mixed solvent thereof. Among them, tetrahydrofuran, getyl ether, dimethoxyethane, N, N-dimethylformamide, N, N-dimethylacetamide and the like are preferable. It is particularly preferred that these are anhydrous solvents. Although it depends on the type of reaction, the reaction temperature is from 100 to 150, preferably from 140 to 120, and the reaction time is from 2 to 120 hours, preferably from 10 to 4 hours. 8 hours.

In the general formula (I)

Of compound (XXVI) or its salt Four

Reaction 1 8

 An imidazothiazine compound represented by the general formula (XXV) or a salt thereof is obtained by reacting an imidazothiazine compound represented by the general formula (XX) (Z represents CO) or a salt thereof with an acid. Get the salt.

 Examples of the acid include the acids shown in the above Reaction 5, among which, for example, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, methanesulfonic acid, P-toluenesulfonic acid, camphorsulfonic acid And boron trifluoride etherate complex are particularly preferred. Of these, liquid ones are also used as solvents. The acid is used in an amount of 0.05 to 10 equivalents, preferably 0.1 to 5 equivalents, more preferably 0.2 to 2 equivalents, based on the raw material. These reactions are usually advantageously performed in a solvent. The solvent is not specified as long as it does not affect the reaction, but the solvent shown in the above Reaction 2 or Reaction 5 is used, and preferably an organic acid solvent, an amide solvent, an ether solvent, or an alcohol. Solvents, nitrile-based solvents, hydrocarbon-based solvents, halogenated hydrocarbon-based solvents, and the like, and mixtures thereof. Among them, formic acid, acetic acid, N, N-dimethylformamide, tetrahydrofuran, dioxane, dimethoxy Tan, acetonitrile, benzene, toluene, xylene, dichloromethane, chloroform, 1,2-dichloroethane and cyclobenzene are particularly preferred. The reaction temperature is from −40 to 200, preferably from 0 ° C. to 120 ° C., and the reaction time is from 5 minutes to 120 hours, preferably from 30 minutes to 48 hours.

Reaction 1 9

Using an imidazothiazine compound represented by the general formula (XXV) or a salt thereof as a raw material and reacting with the general formula R ¹⁴ — L (L represents a leaving group) or a salt thereof in the presence of a base As a result, an imidazothiazine compound represented by the general formula (XXVI) or a salt thereof is obtained. Examples of the base include the bases shown in the above Reaction 2. Preferred examples are, for example, alkali metal hydrides, alkali metal alkoxides, inorganic bases, organic bases, alkyllithiums, and alkali metal amides. Preferred are sodium hydride, potassium tert-butoxide, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5,4,0] ]-7-Pendecene, methyllithium, butyllithium, lithium disopropylamide, lithium pistrimethylsilylamide and the like are particularly preferred. Of these, liquid ones are also used as solvents. The base is used in an amount of 1 to 50 equivalents, preferably 2 to 10 equivalents, and more preferably 2 to 5 equivalents. L is preferably a halogen atom such as chlorine, bromine or iodine. In R ^{1 4} is compound of represented by R ^{1 5} Z-, L is chlorine, bromine, a halogen atom such as iodine or Metansuru Honiruokishi,, p - toluenesulfonyl O carboxymethyl, such as triflate Ruo b methanesulfonyl two Ruoki Shi Sulfonyloxy groups and the like are preferred. The compound represented by the above general formula R ¹⁴ -L or a salt thereof is used in an amount of 0.2 equivalents, preferably 1 to 10 equivalents, and more preferably 1 to 5 equivalents to the raw material. . These reactions are advantageously carried out usually in a solvent. The solvent is not specified as long as it does not affect the reaction, but the solvent shown in Reaction 2 above is used, and preferably an amide solvent, an ether solvent, a ketone solvent, an ester solvent, Examples include tolyl solvents, alcohol solvents, hydrocarbon solvents, organic base solvents, and the like, and mixtures thereof, among which N, N_dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, dioxane, dimethyloxetane, Acetone, 2-butanone, ethyl acetate, tert-butyl acetate, acetonitril, toluene, pyridine and the like are particularly preferred. The reaction temperature is from 180 to 150, preferably from 0 to 100 T, and the reaction time is from 1 to 120 hours, preferably from 5 to 48 hours.

—In general formula (I), R ¹ is — SR ² ,

χ ^γ is ⁴

Of compound (XXXIII) or its salt

 (XXX I I I) Reaction 20

Using ADA as a raw material, an isocyanate represented by the general formula R ¹⁴ -NC を (R ¹⁴ represents an optionally substituted hydrocarbon group) is reacted in the presence of an acid, and then reacted with a base As a result, a 5-dichloromethyleneimidazolidine compound represented by the general formula (XXV II) or a salt thereof is obtained.

The isocyanate compound represented by R ¹⁴ -NCO is used in an amount of 0.1 to 10 equivalents, preferably 0.2 to 5 equivalents, more preferably 1 to 2 equivalents, based on the amount of the raw material. The isocyanate compound represented by R ¹⁴ -NC 0 is preferably such that R ¹⁴ is, for example, methyl Particularly preferred is isocyanate which is a group, benzyl group, n-butoxycarbonylmethyl group, ethoxycarbonylmethyl group, ethoxycarbonylethyl group and the like. Examples of the acid catalyst include Lewis acids (eg, boron trifluoride ether complex, zinc chloride, aluminum chloride, titanium tetrachloride, tin tetrachloride, etc.), organic sulfonic acids (eg, methanesulfonic acid, octanesulfonic acid, benzene) Sulfonic acid, P-toluenesulfonic acid, camphorsulfonic acid, etc., haloacetic acid (eg, trifluoroacetic acid, etc.), inorganic acid (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid, etc.) Among them, Lewis acids are preferable, and aluminum chloride is particularly preferable. The acid is used in an amount of 0.1 to 10 equivalents, preferably 0.2 to 5 equivalents, more preferably 1 to 2 equivalents, based on the amount of the raw material. This reaction is advantageously performed in a solvent. These reactions are usually performed in a solvent that does not affect the reactions. Solvents are not specified as long as they do not affect the reaction, but amide solvents (eg, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, etc.), halogenated carbon Hydrogen-based solvents (eg, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, cyclobenzene), nitrile solvents (eg, acetonitrile, etc.), ester solvents (eg, ethyl formate, ethyl acetate) , Tert-butyl acetate, etc.), ketone solvents (eg, acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), ether solvents (eg, tetrahydrofuran, getyl ether, diisopropyl ether, dioxan, dimethyloxetane, etc.) ), Hydrocarbon solvents (eg, hexane, benzene, toluene), aromatic solvents Organic base solvents (eg, pyridine, 2,4,6-trimethylpyridine, picoline, 2,6-lutidine, 1,8-diazabicyclic [5,4,0] -7-dendene, etc.) A mixed solvent is mentioned. Of these, halogenated hydrocarbon solvents, ester solvents, ether solvents, hydrocarbon solvents, and the like are preferable, and dichloromethane, chloroform, tetrahydrofuran, ethyl ether, and toluene are particularly preferable. The reaction temperature is −40 ° C. to 150 ° C., preferably O to 100 ° C., and the reaction time is 2 minutes to 96 hours, preferably 5 minutes to 60 hours.

Examples of the base to be used include the bases shown in the above Reaction 2, and preferable examples thereof include, for example, pyridine, 4-dimethylaminopyridine, 1,8-diazabicycline [5,4,0] -7-pentadecene , Triethylamine, Dimethylaniline, Sodium carbonate, Carbonated Liu And the like. The base is used in an amount of 0 to 10 equivalents, preferably 0 to 1 equivalent.The reaction temperature is 14 to 150, preferably Ot: to 100, and the reaction time is 2 to 96 hours, preferably 5 to 60 hours. is there.

Reaction 21

 A 5-dichloromethylene imidazolidine compound represented by the general formula (XXVI I) or a 5-dichloromethylene imidazolidine compound represented by the general formula (XXV III) by subjecting the compound to an acid hydrolysis reaction or Obtain the salt.

 Examples of the acid to be used include the acids shown in the above Reaction 5, etc., among them, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, Ρ-toluenesulfonic acid, camphorsulfonic acid and the like. preferable. Of these, liquid ones are also used as solvents. The acid is used in an amount of 0.1 to 20 equivalents, preferably 0.5 to 10 equivalents, more preferably 1 to 5 equivalents, based on the amount of the raw material. These reactions are advantageously carried out usually in a solvent. The solvent is not specified as long as it does not affect the reaction.Examples of the solvent include, for example, water in addition to the solvent shown in Reaction 5 above, and preferably water, formic acid, acetic acid, Ν, Ν-dimethylformamide, Examples thereof include tetrahydrofuran, dioxane, dimethoxetane, dimethyl sulfoxide, methanol, ethanol, propanol, isopropanol, isobutanol, tert-butanol, and acetonitrile, or a mixed solvent thereof. The reaction temperature is between 140 ° C. and 180 ° C., preferably Ot: 120, and the reaction time is between 10 minutes and 72 hours, preferably between 30 minutes and 48 hours.

Reaction 22

Under the same conditions as in Reaction 2 described above, a 5_dichloromethyleneimidazolidine compound represented by the general formula (XXVI II) or a salt thereof is used as a raw material, and expressed by a general formula R〇COCH ₂ CH ₂ SH in the presence of a base. (R represents an alkyl group such as methyl, ethyl, propyl, isopropyl, 2-ethylhexyl, etc.) to form an imidazolidine compound represented by the general formula (XX IX). Or to obtain its salt.

Reaction 23

The same conditions as in Reaction 4 described above (hereinafter, imidazo represented by the general formula (XX IX)) Using a lysine compound (R represents the above-mentioned alkyl group) or a salt thereof as a raw material, a ketone compound represented by the general formula (V) having a leaving group L at the cH position or a salt thereof is reacted in the presence of a base. As a result, an imidazothiazine compound represented by the general formula (XX) (R represents the above alkyl group) or a salt thereof is obtained.

Reaction 2 4

 Under the same conditions as in Reaction 5 described above, an imidazothiazine compound represented by the general formula (XXX) (R represents the above alkyl group) or a salt thereof is subjected to a dehydration reaction in the presence of an acid. As a result, an imidazothiazine compound represented by the general formula (XXXI) (R represents the above alkyl group) or a salt thereof is obtained.

Reaction 2 5

 Under the same conditions as in Reaction 6 described above, an imidazothiazine compound represented by the general formula (XX XI) (R does not have the above-mentioned alkyl group) or a salt thereof is used as a raw material and reacted with a base to give a general compound. An imidazothiazine compound represented by the formula (XXXII) or a salt thereof is obtained.

Reaction 2 6

Under the same conditions as in Reaction 7- (a) described above, an imidazothiazine compound represented by the general formula (XXXII) is used as a starting material, and in the presence of a base, a compound represented by the general formula R ² — L (L is a leaving group To obtain an imidazothiazine compound represented by the general formula (XXXIII).

 In each of the above reactions, some substituents may have functional groups that decompose and react under each reaction condition.However, their protection and deprotection after the reaction can be performed by a method known per se. it can. The conversion of various functional groups that may be present on each substituent can be performed by a method known per se.

For example, in the case where an esterified hydroxyl group is hydrolyzed into a carboxyl group, the hydrolysis is advantageously performed in the presence of, for example, an acid or a base. Examples of the acid include the acid shown in Reaction 5 above, and examples of the base include the base shown in Reaction 3 above. Among them, hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, P-toluenesulfone Acid, camphorsulfonic acid, etc., sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, carbonic acid Potassium, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5,4,0] -7-pinedecene and the like are preferable. The acid or base is used in an amount of 0.1 to 20 equivalents, preferably 1 to 5 equivalents, based on the starting material. These reactions are usually advantageously performed in a solvent that does not affect the reaction, and water, the solvent shown in the above Reaction 2, or the like is used. Among them, water, tetrahydrofuran, dioxane, dimethoxyethane, methanol, ethanol, 2-propanol, tert-butanol, acetonitrile, pyridine and the like, or a mixed solvent containing these waters are preferable. The reaction temperature is from −20 ° C. to 20 ° C., preferably from 20 ° C. to 120 ° C., and the reaction time is from 5 minutes to 120 hours, preferably from 20 minutes to 72 hours.

 For example, when a functional group such as an esterified or amidated carboxyl group, a cyano group, or a carbonyl group is reduced to be converted to a formyl group, a hydroxymethyl group, an aminomethyl group, a hydroxyl group, or the like, the starting compound is used. It is obtained by subjecting it to a reduction reaction. This reaction involves metal hydride (eg, lithium aluminum hydride, sodium aluminum hydride, lithium borohydride, sodium borohydride, sodium cyanoborohydride, etc.), aluminum hydride (eg, hydrogen Diisobutylaluminum, etc.), dipolane (eg, borane-tetrahydrofuran, polan-methanol, etc.), dialkylborane (eg, di-sec-butylbutyl, ditexylporan, 9-boravisic [3,3,1] norpolonene, etc.) The reaction is carried out by reacting with a reducing agent in an inert solvent. Examples of the inert solvent include ether solvents (eg, tetrahydrofuran, methyl ether, dioxane, dimethyloxetane, etc.), hexane, benzene, toluene and the like. The reducing agent is used in an amount of 1 to 20 equivalents, preferably 1 to 5 equivalents, and the reaction temperature is from 170 ° C to 1.50 ° C, preferably from 0 to 100 ° C. The reaction time is 10 minutes to 48 hours, preferably 1 hour to 20 hours. When the desired product is obtained in a free state by each of the above-mentioned reactions, it may be converted into a salt according to a conventional method, and when the desired product is obtained as a salt, the free form is obtained according to a conventional method Alternatively, it can be converted to another salt. The compound thus obtained or a salt thereof can be obtained by known means, for example, phase transfer, concentration, solvent extraction, fractionation,

It can be isolated and purified from the reaction solution by crystallization, recrystallization, etc. < The salt of the compound described in the present specification is preferably a pharmacologically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, or a basic salt. Or a salt with an acidic amino acid.

 Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt, ammonium salt and the like. Can be

 Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, Ν, Ν'-dibenzylethylene. And salts with diamine and the like.

 Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.

 Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, -Salts with toluenesulfonic acid and the like. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ordinine, and the like. Preferred examples of the salt with an acidic amino acid include, for example, aspartic acid, glutamic acid, and the like. Salts.

 The compound (I) of the present invention may be a hydrate or a non-hydrate. In addition, the compound (I) used in the present invention may have one asymmetric carbon in the skeleton and thus may have two kinds of optical isomers. Each of these isomers and a mixture thereof are also described in the present invention. Included in the invention. When the substituent has an asymmetric carbon atom or an unsaturated bond, a stereoisomer or a geometric isomer is similarly produced, and the isomers and mixtures thereof are also included in the present invention.

The compound of the present invention has a sulfur atom in its structure, which may be oxidized by an oxidizing agent (eg, hydrogen peroxide or m-chloroperbenzoic acid) according to a conventional method. Sulfonated compounds are also included in the present invention. The compound of the present invention may have an amide, imide, amidino, guanidino or peridode group in its structure or as a substituent, and these compounds have a resonance structure in which the double bond is isomerized. In some cases, these resonance structural compounds are also included in the present invention.

 The compound (I) of the present invention may be used as a prodrug. As such a prodrug, a compound which is converted into a compound (I) by a reaction with an enzyme or gastric acid under physiological conditions in a living body, that is, a compound which is oxidized enzymatically , A compound that undergoes reduction, hydrolysis, etc., and changes to the compound (I), and a compound, which undergoes hydrolysis, etc., due to stomach acid or the like, to change to the compound (I). Examples of the prodrug of the compound (I) include compounds in which the amino group of the compound (I) is acylated, alkylated, and phosphorylated (eg, the amino group of the compound (I) is icosanoylated, alanylated, pentylamino). Carponylated, (5-methyl-2-oxo- 1,3-dioxolen-141-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, bivaloyoxymethylated, tert-butylated compounds Compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated or borated (eg, the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloyylated, succinylated) , Fumarylation, aranylation, dimethylaminomethylcarbonylated compounds, etc.); Compounds (e.g., compound (I) is converted to ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester, Ethoxycarponyloxetyl esterification, 'phthalidyl esterification, (5-methyl-1-oxo-1,3,3-dioxolen-4-yl) methyl esterification, hexyloxyl-propyl-2-ethyl esterification, methylamide And the like); and the like. These compounds can be produced from compound I) by a method known per se. The prodrug of compound (I) is compounded under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals”, Vol. 7, Molecular Design, pp. 163 to 198. It may change to an object (I).

Compounds that inhibit cartilage matrix degradation can be used as preventive and therapeutic agents for osteoarthritis and diseases caused by cartilage destruction. Compounds that inhibit proteoglycan degradation, compounds that inhibit type I collagen degradation, and that inhibit the production of cartilage matrix-degrading enzymes such as matrix meta-oral proteinase 13 (MMP-13) and aggrecanases Compound and MMP gene expression suppression The compound having an effect is used as a prophylactic / therapeutic agent for diseases caused by osteoarthritis and cartilage destruction. Compounds that inhibit proteodalican degradation, compounds that inhibit type II collagen degradation, compounds that inhibit the production of cartilage matrix-degrading enzymes such as MMP-13 and aglycanase, and those that inhibit MMP gene expression Preferred examples of the compound having the following are condensed imidazolidine derivatives, and more specifically, the compound (I) or a salt thereof or a sulfoxide thereof.

 The compound (I) or a salt thereof or a sulfoxide thereof has excellent proteoglycan release inhibitory activity, collagen II degradation inhibitory activity, and cartilage matrix degrading enzyme production inhibitory activity such as MMP-13 and aggrecanase. The therapeutic agent for cartilage disease of the present invention containing Compound (I) or a salt thereof as an active ingredient is particularly useful for cartilage disease before the lesion reaches the bone itself, in terms of preventing deterioration of the cartilage tissue condition. Yes, it can be applied not only to treatment of osteoarthritis, rheumatoid arthritis and diseases caused by cartilage destruction, but also to prevention of these diseases.

 The compound (I) or its salt or its sulfoxide has an excellent inhibitory effect on the expression of the MMP gene (particularly the MMP-13 gene), and is useful as a safe preventive and therapeutic agent for all MMP-related diseases. is there.

 That is, compound (I) or a salt thereof or a sulfoxide thereof exhibits an inhibitory action on proteoglycan release, an inhibitory action on collagen type I degradation, and an inhibitory action on cartilage matrix degrading enzyme production such as MMP-13 and aglycanase. Substrates, specifically t, inhibit the degradation of proteodalican and type II collagen. That is, it has an effect as a proteodalican degradation inhibitor, a type I collagen degradation inhibitor, and a cartilage matrix degrading enzyme inhibitor. As a result, it has a strong inhibitory effect on cartilage destruction, so it can be used for various cartilage diseases (deformation) in mammals (eg, humans, rats, guinea pigs, mice, cats, dogs, puppies, cows, pigs, etc.). Osteoarthritis and diseases caused by cartilage destruction), for example, for the prevention and treatment of osteoarthritis involving cartilage, rheumatoid arthritis involving cartilage, or cartilage destruction in joints etc. in related diseases Can be used for

Compound (I) or its salt or its sulfoxide has an excellent MMP gene (Especially the MMP-13 gene) has an expression-suppressing effect, and in addition to all MMP-related diseases, for example, the above-mentioned joint diseases (eg, osteoarthritis, rheumatoid arthritis, etc.), osteoporosis, Cancer (eg, primary, metastatic or recurrent, breast, prostate, cancer, stomach, lung, colon (colon, rectum, anal), esophagus, duodenum, head and neck (tongue) Cancer, pharyngeal cancer, laryngeal cancer), brain tumor, schwannoma, non-small cell lung cancer, small cell lung cancer, liver cancer, kidney cancer, bile duct cancer, uterine cancer (uterine body cancer, cervical cancer), ovarian cancer, bladder Cancer, skin cancer, hemangiomas, malignant lymphomas, malignant melanomas, thyroid cancer, bone tumors, hemangiomas, angiofibromas, retinal sarcomas, penile cancers, pediatric solid carcinomas, lipopositive sarcomas, lipopositive sarcomas caused by AIDS, Maxillary sinus tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, liposarcoma, child Fibroids, osteoblastomas, osteosarcomas, chondrosarcomas, carcinomatous mesothelial tumors, tumors such as leukemia), periodontal disease, corneal ulcers, chronic ulcers, pathological bone resorption (such as Beiget's disease), Useful as a safe preventive and therapeutic agent for nephritis, angiogenesis, aneurysm, arterial sclerosis, emphysema, cirrhosis, autoimmune diseases (Crohn's disease, Si: n-Darren's disease, etc.), cancer invasion and metastasis, etc. is there.

 In the present invention, when the compound (I) or a salt thereof or a sulfoxide thereof is used as an agent for preventing or treating cartilage disease, the compound (I) or a salt thereof is mixed with a pharmaceutically acceptable carrier according to a conventional method to obtain a drug having a dosage form suitable as a medicament. Solid preparations such as tablets, capsules, granules, powders, and suppositories; or liquid preparations such as syrups, drops, solutions, suspensions, and injections, orally or parenterally It can be administered. .

Pharmaceutically acceptable carriers include various organic or inorganic carrier materials commonly used as drug substances, such as excipients, lubricants, binders, and disintegrants in solid preparations; solvents and dissolution in liquid preparations. It is formulated as an auxiliary, suspending agent, tonicity agent, buffer, soothing agent, stabilizing agent, anticoagulant, and the like. If necessary, pharmaceutical additives such as preservatives, antioxidants, coloring agents and sweeteners can also be used. Preferred examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light gay anhydride, and the like. Preferred examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Suitable examples of the binder include, for example, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, and hydroxypropylmethyl. And cellulose bilipyrrolidone. Preferable examples of the disintegrant include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethylsuniform sodium and the like. Preferred examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Preferable examples of the solubilizing agent include, for example, polyethylene glycol, propylene glycol, D-mannitol, cyclodextrins, twins, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, and carbonic acid. Sodium and sodium citrate. Preferred examples of the suspending agent include surfactants such as, for example, stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; And hydrophilic polymers such as benzyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Preferable examples of the tonicity agent include sodium chloride, glycerin, D-manniyl, glucose, sorbyl, and the like. Preferred examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Preferable examples of the soothing agent include benzyl alcohol and the like. Preferable examples of the stabilizer include polyethylene glycol, polylactic acid and the like. Preferred examples of the coagulant include dextran sulfate, heparin and the like. Preferred examples of preservatives include, for example, paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Suitable examples of the antioxidant include, for example, sulfite, ascorbic acid and the like. For administration, the compound (I) or a salt thereof or a sulfoxide thereof is dissolved in a conventional aqueous diluent and used as a solution. Diluents include glucose aqueous solution, physiological saline, Ringer's solution, and nutritional supplement solution.

Compound (I) or a salt thereof or a sulfoxide thereof was dispersed by an appropriate method. The prophylactic / therapeutic agent of the present invention can also be produced by dissolving the suspension and shaping it into microcapsules, spheres, rods, needles, pellets, films and the like. Further, the prophylactic / therapeutic agent of the present invention may be formed into a sustained-release preparation containing compound (I) or a salt thereof or a sulfoxide thereof and a biodegradable high molecular compound. The preparation of the sustained-release preparation can be in accordance with the method described in JP-A-9-1265355.

 In the above formulation, the ratio of containing compound (I) or a salt thereof or a sulfoxide thereof is about 0.1 to about 95% by weight, preferably about 1 to about 50% by weight, based on the whole preparation. . Compound (I) or a salt thereof or a sulfoxide thereof is preferably used as an oral preparation. Compound (I) or a salt thereof or a sulfoxide thereof can be directly administered to a cartilage disease-affected site when formed into a topical preparation and administered. In this case, injection is preferable. Parenteral preparations for topical administration (eg, injection preparations for intramuscular, subcutaneous, organ, joint, etc., solid preparations such as implants, granules, powders, liquid preparations such as suspensions, ointments, etc.) It can also be administered as

 For example, to prepare an injection, compound (I) or a salt thereof or a sulfoxide thereof is dispersed in a dispersant (eg, a surfactant such as Tween 80, HCO-60, carboxymethyl cellulose, sodium alginate, hyaluronic acid). , Polysorbates, etc.), preservatives (eg, methyl paraben, propyl paraben, etc.), tonicity agents (eg, sodium chloride, mannitol, sorbitol, glucose, etc.), buffering agents (eg, calcium carbonate, etc.), A practical injectable preparation can be obtained by preparing an aqueous suspension together with a pH adjuster (eg, sodium phosphate, potassium phosphate, etc.). In addition, vegetable oils such as sesame oil and corn oil, or mixtures of these with phospholipids such as lecithin, or dispersed with medium-chain fatty acid triglycerides (eg, migliol 812) are used as oily suspending agents. Make injections that can be used.

In particular, when osteoarthritis patients are to be administered directly into the joint cavity as a topical agent, a compound (e.g., a hyaluronic acid formulation for injection (eg, Kaken Pharmaceutical Co., Ltd .: Aru Note)) should be used as a dispersion medium. It can be prepared by dispersing I) or a salt thereof or a sulfoxide thereof. Hyaluronic acid used in the dispersion medium may be a non-toxic salt thereof, for example, an alkali such as sodium or potassium. Metal salts, salts of alkaline earth metals such as magnesium, calcium and the like can be mentioned, and particularly, sodium salts are preferably used. Hyaluronic acid and non-toxic salts thereof have a molecular weight of about 200,000 to 500,000 (viscosity method), preferably about 500,000 to 300,000, and more preferably about 700,000 to 250,000. Things are used.

 The final concentration of hyaluronic acid or sodium hyaluronate in this dispersant is preferably less than 1% (W / V) as a viscosity, and is preferable in terms of various operations and ease of administration, and particularly about 0.02 to 1%. It is more preferably less than about 0.1 to 1% (W / V).

 The dispersion medium may contain a pH adjuster, a local anesthetic, an antibiotic, a solubilizer, an isotonic agent, an anti-adsorption agent, glycosaminodalican, a polysaccharide, etc. by a method known per se. Good. Preferred examples thereof include mannitol, sorbitol, salt, glycine, ammonium acetate, or a water-soluble protein that can be injected into a body fluid without substantially exhibiting pharmacological activity. Examples of the glycosaminodalican include hyaluronic acid, chondroitin, chondroitin sulfate A, chondroitin sulfate C, dermatan sulfate, heparin, heparan sulfate, and keutane sulfate. Examples of the polysaccharide include an acidic polysaccharide such as arginic acid.

 The above-mentioned water-soluble protein may be any protein which is soluble in water, physiological saline or buffer, and includes, for example, human serum albumin, human serum globulin, collagen, gelatin and the like. Examples of the pH adjuster include glycine, ammonium acetate, citrate, hydrochloric acid, sodium hydroxide and the like. Examples of the local anesthetic include chlorobutanol and xylocaine hydrochloride. Examples of the antibiotic include gentamicin and the like. Examples of the solubilizer include glycerin and polyethylene glycol 400. Examples of the tonicity agent include mannitol, sorbitol, sodium chloride and the like. Examples of the above-mentioned adsorption inhibitor include polyoxyethylene sorbitol monooleate.

Further, when the water-soluble protein is contained in the dispersion medium, the content of the water-soluble protein is preferably 0.05 to 5 Omg, more preferably 0.5 to 2 Omg, per one administration of the preparation. Preferably, it is more preferably 0.75 to 1 O mg. The formulation is Acid or a salt thereof (eg, sodium phosphate, potassium phosphate, etc.).

 When phosphoric acid or a salt thereof is contained in an injection, the concentration of sodium phosphate or potassium phosphate in the injection is about 0.1 mM to 50 mM, and about lmM to 10 mM. Is preferred. 'Aseptic preparations include, but are not particularly limited to, a method of sterilizing the entire production process, a method of sterilizing with gamma rays, and a method of adding a preservative.

 Since the agent of the present invention has an excellent cartilage destruction inhibitory activity (cartilage matrix degrading enzyme production inhibitor and proteodalican degradation inhibitor), it can be used for cartilage diseases (eg, osteoarthritis, osteoarthritis of the knee, rheumatoid arthritis). And the destruction of articular cartilage (disease caused by cartilage destruction) and the like in the similar diseases. The agent of the present invention can be used together with other therapeutic agents for joint diseases. For example, when Compound (I) or its salt or its sulfoxide is used as a cartilage destruction inhibitor (a cartilage matrix degrading enzyme production inhibitor and a proteodalican degradation inhibitor), it should be used in combination with other therapeutic agents for joint diseases. Can also. Drugs to be combined include anti-inflammatory steroids (eg, prednisolone, hydrocortisone, methylprednisolone, dexamethasone, vesamethasone, etc.), non-steroidal anti-inflammatory analgesics

(Eg, indomethacin, diclofenac, loxoprofen, ibuprofen, aspirin, piroxicam, sulindac, etc.) or hyaluronic acid preparations (eg, sodium hyaluronate, etc.), COX-II inhibitors (eg, celecoxib, lefecoxib, etc.) In-polymer preparations (eg, Remicade, Enbrel, Kinneret, etc.) and the like.

The agent of the present invention is used as a safe and highly efficacious preparation suitable for prevention and treatment of cartilage disease, maintenance of cartilage tissue, and the like. For example, it is possible to efficiently exert the inhibitory effect on cartilage destruction locally, and to improve the quality of life of patients who are impaired in daily life due to fatigue due to joint cartilage or pain due to destruction. When compound (I) or a salt thereof or a sulfoxide thereof is used as a prophylactic / therapeutic agent for cartilage disease, the daily dose depends on the condition and weight of the patient, the method of administration, and the release rate from the preparation. Adult (weight 5 O kg) for administration 1 About 5 to about 2,000 mg, preferably about 30 to about 50 Omg, of the compound (I) or its salt or its sulfoxide per person, is administered in 1 to 3 divided doses.

 In the case of parenteral administration, about 1 to about 50 mg, preferably about 5 to about 300 mg of compound (I) or its salt or its sulfoxide per adult (body weight 5 Okg) per person, administered in 1 to 3 doses I do.

 When the pharmaceutical composition of the present invention is a sustained-release preparation, the dose may be determined according to the type and content of compound (I) or a salt thereof or a sulfoxide thereof, the dosage form, the duration of drug release, the animal to be administered (eg, Humans, rats, mice, cats, dogs, puppies, cattle, pigs, and other mammals) vary depending on the purpose of administration, but when applied by parenteral administration, for example, from about 0.1 to about 10 Omg of compound (I) or a salt thereof or a sulfoxide thereof may be released from the administration preparation.

The pharmaceutical composition of the present invention has low toxicity and can be used safely. For example, when the compound was orally administered to rats at a dose of 30 OmgZkg / day, no abnormal findings were observed. In particular, the following example compounds are excellent in absorbability when administered orally, and can be advantageously used for oral preparations.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto. In addition, the percentage (%) in the solution is expressed by weight Z volume percent unless otherwise specified. In addition, the mixing ratio of the solvent is indicated by the volume ratio unless otherwise specified. The 1H and 13 C nuclear magnetic resonance (NMR) spectra were obtained using DPX-300 or AC-300 spectra using tetramethylsilane as an internal standard (Bulliki, Germany), The values were measured with a Gemini 200 or Mercury 300 spectrum meter (Varian, USA) and ± 6 values are shown in ppm. During ^l H- NMR scan Bae spectrum of Example, s is singlet, d is doublet, t is triplet, Q is quartet, quint the quintet, s Ixtet the sextet, sept Represents a sevenfold line, m represents a multiple line, and b or br represents a wide line, respectively. Also, for example, dd is a double double line, ddd is a double double double line, dt is a double triple line, dq is a double quadruple line, brd Φ 畐 wide double line, and so on. They may be displayed in combination. Coupling constants are shown in Hz. In the ¹³ C-NMR spectrum, CH ₃ means methyl carbon, CH ₂ means methylene carbon, CH means methine carbon, and Q means quaternary carbon. Heavy black port Holm measurement solvent and CDC1 _3, deuterated dimethyl sulfoxide is sometimes abbreviated as DMS0_d _s. The infrared absorption spectrum (IR) was measured with SHIMADZU FTIR-8200PC. Among mass spectrometry, FAB-MS is JE0L JMS-AX505W (manufactured by JEOL, Japan), and SIMS is Hitachi D-80B GC double focusing mass spectrometer or Hitachi M-2000 mass spectrometer (Hitachi, Ltd.). Japan). The melting point (mp.) Was measured using a melting point analyzer MP-J8 manufactured by Yanako Instruments Development Laboratory. In the reference examples and examples, room temperature refers to 0 ° C. to 3 Ot :.

The following abbreviations may be used in Reference Examples and Examples.

ADAN (2-amino-3, 3-dichloroacrylonitrile) = 2-amino-3,3-dichloroacrylonitrile ''

ADDP (1, 1,-(azodicarbonyl) dipiperidine) = 1, Γ-(azodicarponyl) dipiperidine

 Boc (tert-butoxycarbonyl)-tert-butoxycarbonyl

 CSA (D_camphor-10-sul fonic acid) = D-camphor-10-sulfonic acid

DAST (diethyl aminosul fur tri f luoride) = getylamino sulfur trifluoride Deoxo-Fluor ™ (bis [(2-methoxyletyl) amino] sulfur trif luoride) = trifluoride [(2-methoxylethyl) amino] sulfur

 DEAD (diethyl azodicarboxylate) =

DHP (3, 4-dihydro-2H-pyran) = 3,4-dihydro-2H-pyran

DIAD (diisopropyl azodicarboxylate) = diisopropyl azodicarboxylate DMAP (4-N, N-dimethhy1 am i nopyr idine) = 4_N, N-dimethylaminopyridine

DMF (N, N-dimethylformamide) = Ν, Ν-dimethylformamide

DMSO (dimethylsulfoxide) = dimethylsulfoxide

HOBT (l-hydroxybenzotriazole) = 1-hydroxybenzotriazole

TFA (trifluoroacetic acid) = trifluoroacetic acid

THF (tetrahydrofuran) = tetrahydrofuran

p-TsOH (p-toluenesulfonic acid) = p-toluenesulfonic acid

WSC (l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride) = 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride

bp. (boiling point) = boiling point

quant, (quant i tat ive) = quantitative yield

Reference example 1-1

Synthesis of R ^1Q gar ZR ¹⁵ (Z is S0 _2, R ¹⁵ is p- Toruiru group) compound 'compound in the formula (II)

 ADAN (31.9 g, 0.233 mol, manufactured by Junsei Chemical Co., Ltd.) is dissolved in getyl ether (300 ml, hereinafter abbreviated as ether), and stirred at room temperature while stirring with P-toluenesulfonyl isocyanate (36.0 ml). , Purity 98%, manufactured by Tokyo Chemical Industry Co., Ltd.), and the mixture was stirred at room temperature for 14 hours. The resulting precipitate was collected by filtration, washed with diethyl ether, and dried to give a pale yellow powder of the title compound (74.3 g, 0.222 mol).

'H-NMR (300 MHz, double-mouthed form-deuterated dimethyl sulfoxide = 9: 1): δ 2.44 (3Η, s), 7.34 (2Η, d, J = 8.2 Hz), 7.90 (2H, d, J = 8.2 Hz), 8.19 (1H, brs), ca. 10.2 (1H, br). ¹³ C-NMR (75 MHz, double-mouthed form-deuterated dimethyl sulfoxide = 9: 1 in): δ 21.6 (CH3), 110.4 (Q), 111.3 (Q), 127.8 (Q), 127.9 (2CH), 129.6 (2CH), 136.2 (Q), 144.8 (Q), 147.9 (Q).

Elemental analysis: C _U H ₉ N ₃ 0 ₃ SC ₁₂ Calculated: C, 39.54; H, 2.71; N, 12.57; S, 9.60; Cl, 21.22 (%), found; C, 39.62; H, 2.48; N, 12.66; S, 9.63; C1, 21.00 (%).

Reference example 1-2

Synthesis of R ¹⁰ Gar ZR ¹⁵ (Z is S0 _2, R ¹⁵ is p- black port phenyl group) compound which is in the formula (II)

 Dissolve ADAN (11.2 g, 82.0 imol) in getyl ether (120 ml) and add benzenesulfonyl isocyanate (20 g, 85% pure, Aldrich) for about 10 minutes while stirring at room temperature. And drop it. The mixture was further stirred at room temperature for 14 hours, and the formed precipitate was collected by filtration, washed with diethyl ether, and dried to obtain a pale yellow powder of the title compound (27.3 g, 76.8 mmol).

 Ή-NMR (300 MHz, deuterated chloroform-deuterated dimethyl sulfoxide = 5: 1): δ 7.53 (2Η, ddm, J = 8.8, 4.4 Hz), 7.97 (2H, ddm, J = 8.8, 5.2 Hz), 8.36 (1H, brs), 11.01 (1H, brs).

The following is a list of compounds synthesized in the same manner as the compounds synthesized in Reference Examples 1-1 and 1-2.

〔table 1〕

 (I I) (R "> = -ZR is)

参考例ト 6 - -. ΓΠ : ί-Ι^ 式（I I) において R¹⁰が _ZR¹⁵ (∑が( 〇、 R ¹⁵がフエニル基） である化合 物の合成

Reference example 6--. ΓΠ: ί-Ι ^ Synthesis of a compound of the formula (II) wherein R ¹⁰ is _ZR ¹⁵ (∑ is (〇, R ¹⁵ is a phenyl group)

 Benzyl isocyanate (20 g) was added to a dichloromethane (400 ml) solution of ADAN (19.4 g), and aluminum chloride (18.9 g) was added in three portions. After stirring at the same temperature for 1 hour, water (150 ml) was added, and the organic solvent was distilled off. To the remaining aqueous layer were added ethyl acetate (150 ml), water (150 ml) and 0.5 M citrate (150 ml), and the mixture was stirred for 5 minutes. After the organic 'solvent was distilled off, the precipitate was collected by filtration, washed with water, and dried to obtain 58.6 g of a colorless powder.

 The obtained compound was dissolved in acetone (400 ml), carbonated lime (39.2 g) was added, and the mixture was heated under reflux for 50 minutes. After cooling to room temperature, water (400 ml) was added, and the mixture was adjusted to pH 3 with about 500 ml of IN hydrochloric acid. The precipitate was collected by filtration, washed with water (100 ml), and dried to give the title compound (31.2 g, 77%).

 -Thigh R (300 MHz, in double-mouthed holm): 57.49-7.56 (2H, m), 7.60-7.67 (1H, m), 8.05-8.10 (2H, m), 11.0 (1H, br s), 11.6 (1H, br s).

Elemental _{analysis: (^ Η 7 Ν 3 0} 2 (ΐ 2 Calculated: C; 46.50, Η; 2.48 , Ν; 14.79 (%), actual Hakachi; C; 45.99, Η; 2.43 , Ν; 14.66 ( %).

 Similarly, the compounds of Reference Examples 7 and 1-8 were synthesized.

 Reference Example 1-7

(In the formula (II), R ¹⁰ is —ZR ¹⁵ (compound in which Ζ is S〇 ₂ and R ¹⁵ is 4_phenoxyphenyl group)

-NMR (300 MHz, in double-mouthed form): <57.05 (2H, dt, J = 9.0, 2.5 Hz), 7.08 '(2H, dq, J = 8.0, 1.9 Hz), 7.24 (1H, brt, J = 7.2 Hz), 7.42 (2H, brtt, J = 8.1, 1.9 Hz), 7.61 (1H, brs), 7.90 (2H, dt, J = 9.0, 2.3 Hz), 9.74 (1H, brs). _{: C 1S H "N 3 0} 4 SC1 2 calculated: C, 46.62; H, 2.69 ; N, 10.19; S, 7.78; Cl, 17.20 (%), Found; C, 46.42; H, 2.86 ; N , 9.97; S, 7.85; C1, 17.09 (%)

(In the formula (II), R ¹⁰ is -ZR ¹⁵ (Z is S〇 ₂ , R ¹⁵ is a 4-chlorophenyl group))

 Ή-thigh (200 MHz, in heavy dimethyl sulfoxide): <57.58 (1H, m), 7.68 (2H, d, J =

4.8 Hz), 8.15 (1H, d, J = 7.0 Hz), 11.28 (1H, brs), 11.90 (1H, br).

Elemental analysis: Calculated as CiAWClg: C, 33.87; H, 1.71; N, 11.85; S, 9.04; CI, 29.99 (), observed; C, 34.09; H, 1.67; N, 11.80; S, 9.10; CI, 29.54.

(%).

Reference Example 2-1

Synthesis of a compound of the formula (III) wherein R ¹⁰ is —ZR ¹⁵ (Z is S〇 ₂ , R ¹⁵ is a p-tolyl group) and R is an ethyl group

 Ethanol (310 ml) was added to the compound synthesized in Reference Example 1-1 (30.8 g, 92.2 mmol) and potassium carbonate (29.3 g, 0.212 mol), and the mixture was stirred at room temperature while stirring with ethyl 3_mercaptopropionate (24.2 g). ml, 0.180 mol) was added dropwise over about 6 hours, and the reaction mixture was stirred at room temperature for 12 hours. 1N Hydrochloric acid (240 ml) was added to the reaction solution, and the mixture was stirred for 30 minutes. The mixture was concentrated to remove ethanol, water (300 ml) was added, the resulting precipitate was collected by filtration, washed with water, and dried to give a pale yellow powder of the title compound (29.8 g, 56.3 imnol). Obtained.

 ¾-NMR (300 MHz, in double-mouthed form): δ 1.25 (3Η, t, J = 7.1 Hz), L 27 (3H, t, J- 7.1 Hz), 2.43 (3H, s), 2.57 (2H , t, J = 7.3 Hz), 2.60 '(2H, t, J = 6.7 Hz), 3.12 (2H, t, J = 6.7 Hz), 3.20 (2H, t, J = 7.3 Hz), 4.13 (2H, q, J = 7.1 Hz), 4.19 (2H, q, J = 7.1 Hz), 7.32 (2H, brd, J = 8.3 Hz), 7.89 (2H, brd, J = 8.3 Hz), 8.30 (1H, brs) , 9.67 (1H, br).

Elemental analysis: C ₂₁ H と し て N ₃ 0 ₇ S ₃ Calculated: C, 47.62; H, 5.14; N, 7.93; S, 18.16 (%), found; C, 47.51; H, 4.84; N, 8.19; S, 18.12 (%).

Reference Example 2-2

Synthesis of Compound (III) wherein R ^1Q is a hydrogen atom and R is an ethyl group To the compound (6.96 g, purity 90%, 13.1 mmol) synthesized in Reference Example 2-1 was added ethanol (310 ml) and stirred. While adding ammonium formate (3.93 g, 59.1 mmol), the mixture was stirred at 80 for 12 hours. After the mixture was concentrated to remove ethanol, the mixture was diluted with ether (300 ml) and extracted three times with 0.3N hydrochloric acid (100 ml). The extracted aqueous layer was adjusted to pH 8 by adding sodium hydrogen carbonate, and extracted with ethyl acetate (200 ml and 150 ml). The ethyl acetate layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried over sodium sulfate, and concentrated to dryness under reduced pressure. Ether was added to the residue, and the resulting precipitate was collected by filtration, washed with ether and dried to give a pale yellow powder of the title compound (3.37 g, 9.00 mmol) was obtained.

¾-NMR (200 MHz, in double-mouthed form): <5 1.26 (3H, t, J = 7.2 Hz), 1.27 (3H, t, J = 7.2 Hz), 2.60 (2H, t, J = 7.0 Hz) ), 2.63 (2H, t, J = 7.0 Hz), 3.13 (2H, t, J = 6.9 Hz), 3.14 (2H, t, J = 7.0 Hz), 4.16 (2H, q, J = 7.1 Hz), 4.17 (2H, q, J = 7.4 Hz), 7.78 (1H, brs), 7.97 (1H, brs).

Elemental _{analysis: C 14 H 21 N 3 0} 5 S 2 Calculated: C, 44.78; H, 5.64 ; N, 11.19; S, 17.08

(%), Found; C, 44.67; H, 5.49; N, 11.39; S, 17.11 (%). 'Melting point: 150.5-152.5 ° C

Reference example 2-3

In the formula (III), R ¹⁰ is —ZR ¹⁵ (Z is S〇 ₂ , R ¹⁵ is a p-bromophenyl group),

Synthesis of compounds in which R is an ethyl group

 The compound synthesized in Reference Example 2-2 (12.8 g, 34.3 mmol) was dissolved in tetrahydrofuran (250 ml, hereinafter sometimes abbreviated as THF), and triethylamine (14.3 ml, 0.103 mol) and p_bromobenzenesulfonyl chloride were dissolved. (9.84 g, 37.7 thighs 01) was added, and the mixture was stirred at room temperature for 23 hours. During this period, N, N-dimethylaminopyridine (0.21 g, 1.72 mmol) was added 16 hours after the start of the reaction, and p-bromobenzenesulfonyl chloride (0.89 g, 3.43 mmol) was added 18 hours later. After concentration of the reaction solution, the residue was diluted with ethyl acetate (500 ml), washed with 0.3 N hydrochloric acid, 0.1 N hydrochloric acid, water, and saturated saline, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, ether and ethyl acetate were added to the residue, and the resulting precipitate was collected by filtration, washed with ether, and dried to give a yellow powder of the title compound (14.9 g, 25.1 ol). Obtained.

 'H-NMR (200 MHz, in double-mouthed form): δ 1.25 (3Η, t, J = 7.2 Hz), 1.28 (3H, t, J = 7.1 Hz), 2.59 (2H, t, J = 7.2 Hz) ), 2.61 (2H, t, J = 6.4 Hz), 3.12 (2H, t, J = 6.6 Hz), 3.23 (2H, t, J = 7.2 Hz), 4.13 (2H, q, J = 7.1 Hz), 4.20 (2H, q, J = 7.2 Hz), 7.67 (2H, dt, J = 8.8, 2.2 Hz), 7.88 (2H, dt, J = 8.8, 2.0 Hz), 8.36 (1H, brs), 9.60 (1H , br).

Elemental _{analysis: C 20 H 24 N 3 O} 7 S 3 Br Calculated: C, 40.40; H, 4.07 ; N, 7.07; S, 16.18; Br, 13.44 (%), Found; C, 40.33; H , 3.89; N, 6.99; S, 16.17; Br, 13.13 (%). Melting point: 118.0-118.5 ° C

Reference Example 2-4

Synthesis of a compound of the formula (III) wherein R ^{1 ()} is _ZR ¹⁵ (Z is S〇 ₂ , R ¹⁵ is a p-chlorophenyl group) and R is an ethyl group ′

 The title compound was obtained in the same manner as in Reference Example 2-3.

 'H-NMR (200 MHz, in double-mouthed form): (5 1.25 (3H, t, J = 7.0 Hz), 1.28 (3H, t, J = 7.1 Hz), 2.58 (2H, i, J = 7.1 Hz), 2.61 (2H, i, J = 6.6 Hz), 3.13 (2H, t, J = 6.4 Hz) ,, 3.23 (2H, t, J = 7.2 Hz), 4.13 (2H, q, J = 7.1 Hz) ), 4.20 (2H, q, J = 7.1 Hz), 7.51 (2H, d, J = 8.6 Hz), 7.96 (2H, d, J = 8.8 Hz), 8.49 (1H, brs), 9.72 (1H, br) ).

Elemental _{analysis: C 20 H 24 N 3 0} 7 S 3 C1 Calculated: C, 43.67; H, 4.40 ; N, 7.64; S, 17.49; C1, 6.45 (%), Found; C, 43.72; H , 4.39; N, 7.72; S, 17.52; C1, 16.33 (%). Melting point: 115.5-117.0

Reference example 3-1

In the formula (IV), synthesis of a compound in which R ¹⁰ is one ZR ¹⁵ (Z is S 0 ₂ , R ¹⁵ is a p-chlorophenyl group) and R is an ethyl group

Method A

 Ethanol (27 ml) was added to the compound synthesized in Reference Example 2-4 (1.35 g, 2.45 bandol) and carbonic acid rim (407 mg, 2.95 bandol), and the mixture was stirred at 80 ° C for 2 hours. After concentration of the reaction solution, the residue was diluted with ethyl acetate-THF (1: 1, 60 ml) and washed with 0.1N hydrochloric acid (60 ml). The aqueous layer was extracted with ethyl acetate (30 ml), combined with the organic layer, washed with brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, methanol was added to the residue, and the resulting precipitate was collected by filtration, washed with methanol, and dried to give a tan powder of the title compound (588 mg, 1.24 mmol). .

Method B

To the compound synthesized in Reference Example 2 (5.06 g, 14.3 麵 01) and potassium carbonate (4.54 g, 32.8 band01), add ethanol (100 ml), and stir at room temperature while stirring ethyl 3-mercaptopropionate (3.84 g). Then, the mixture was stirred at 80 ° C for 4 hours. 1N Hydrochloric acid (37 ml) was added to the reaction mixture, mixed and concentrated to dryness. (200 ml), washed with water, 10% saline and saturated saline, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, methanol was added to the residue, and the resulting precipitate was collected by filtration, washed with methanol, and dried to give a tan powder of the title compound (7.9 g, purity approximately 70%, 12.3 g). mmol).

 Ή-NMR (200 MHz, in heavy dimethyl sulfoxide): δ 1.18 (3Η, t, J = 7.1 Hz), 2.63 (2H, t, J = 6.9 Hz), 3.32 (2H, i, J = 7.1 Hz), 4.07 (2H, q, J = 7.1 Hz), 7.57 (2H, d, J = 8.4 Hz), 7.87 (2H, d, J = 8.4 Hz), 9.31 (1H, brs), ca. 10.2 (1H, br ).

Elemental analysis: Calculated as _{C 5 H 16 N 3 0 5} S 3 C1:! C, 40.04; H, 3.58; N, 9.34; S, 21.38; C1, 7.88 (%), Found; C, 40.06; H, 3.61; N, 9.42; S, 21.26; C1, 7.76 (%). Melting point: 166.3-169.8 ° C

 Reference example 3-2

In the formula (IV), synthesis of a compound in which R ^{1 ()} is — ZR ¹⁵ (Z is S〇 ₂ , R ¹⁵ is a P-tolyl group), and the length is ethyl

 To the compound synthesized in Reference Example 1-1 (45.5 g, 0.136 mol) and carbonated lime (65.8 g, 0.476 mol), N, N-dimethylformamide (450 ml, hereinafter sometimes abbreviated as DMF) was added. While stirring at room temperature, 3_ ethyl mercaptopropionate (35.9 ml,

0.272 mol) was added dropwise over about 2 hours. The reaction mixture was stirred at room temperature for 12 hours and further at 80 ° C. for 7 hours. After the reaction mixture was concentrated to dryness, 2N hydrochloric acid (340 ml) and methanol (100 ml) were added to the residue and mixed, and the resulting precipitate was collected by filtration, washed with 50% aqueous methanol and ethanol, and dried. An orange-brown powder of the title compound (55.3 g, purity about 70%, 0.090 mol) was obtained.

• Ή-NMR (300 MHz, in heavy dimethyl sulfoxide): δ 1.18 (3Η, t, J = 7.1Hz), 2.33

(3H, s), 2.63 (2H, t, J = 7.1 Hz), 3.30 (1H, s), 3.32 (2H, t, J = 7.1 Hz), 4.07 (2H, q, J = 7.1 Hz), 7.28 (2H, d, J = 8.1 Hz), 7.74 (2H, d, J = 8.1 Hz), 8.75

(1H, brd, 'J-2 Hz), 9.61 (1H, brs).

 Reference Example 3-3

Synthesis of a compound of formula (IV) wherein R ¹⁰ is —ZR ¹⁵ (Z is CO, R ¹⁵ is a phenyl group) and R is a methyl group Reference Example To a solution of the compound synthesized in Example 6 (2.85 g) and methyl 2-mercaptopropionate (2.2 ml) in DMF (50 ml) was added potassium carbonate (3.17 g) at room temperature, and the mixture was stirred for 1 hour. And stirred for 45 minutes. The precipitate was separated by filtration, the filtrate was concentrated under reduced pressure, and ethyl acetate (50 ml) was added. The pH was adjusted to 3 with 1N hydrochloric acid, and the formed precipitate was collected by filtration, washed with water (30 ml), and dried to obtain the title compound (3.27 g, 90 °).

 Ή-NMR (300 MHz, in heavy dimethyl sulfoxide): 52.77 (2H, t, J-7.0Hz), 3.52 (2H, t, J = 7.0Hz), 3.63 (3H, s), 7.61-7.68 (2H, m), 7.70-7.77 (1H, m), 7.97-8.02 (2H, m), 11.0 (1H, s), 12.1 (1H, br s), 13.6 (1H, s).

Reference Example 3-4

Synthesis of a compound of the formula (IV) wherein R ¹⁰ is —ZR ¹⁵ (Z is S〇 ₂ , R ¹⁵ is a p-bromophenyl group) and R is an ethyl group

 Synthesized according to a method similar to that of Reference Example 3-1.

¾-NM (200 MHz, in heavy dimethyl sulfoxide): δ 1.18 (3Η, t, J = 7.0 Hz), 2.63 (2H, t, J = 7.0 Hz), 3.32 (2H, t, J = 7.10 Hz), 4.06 (2H, q, J = 7.1 Hz), 7.68 (2H, d, J = 8.4 Hz), 7.79 (2H, d, J = 8.4 Hz), 8.83 (1H, brs), 9.76 (1H, brs). Reference example 4

Methanesulfonic acid indane-2-yl ester

To a solution of 2-indanol (1.00 g, 7.45 mmol) in tetrahydrofuran (20.0 ml) was added methanesulfonyl chloride (0.865 ml, 11.2 cas 01) and triethylamine (2.08 ml, 14.9 mmol) sequentially under ice cooling. . After stirring the reaction mixture at room temperature for 3 hours, IN hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (1.43 g, 90%) as colorless crystals.

Infrared absorption spectrum (IR) (in KBr): 3069, 3027, 2965, 2936, 2911, 1481 cm- ¹ .

_{'H-NMR (CDC1 3)} : δ 3.02 (3H, s), 3.25 (2H, dd, J = 16.8, 3.6 Hz), 3.38 (2H, dd, J = 17.0, 6.0 Hz), 5.48-5.59 (1H , m), 7.17-7.29 (4H, m).

Reference example 5

Methanesulfonic acid 4,4,5,5,5-pentafluoropentyl ester

Methanesulfonyl chloride (0.652 ml, 8.42 mmol) was added to a solution of 4,4,5,5,5-pentafluoroethanol (1.00 g, 5.61 ol) in tetrahydrofuran (20.0 ml). And triethylamine (1.57 ml, 11.2 mmol) were sequentially added under ice-cooling. After stirring the reaction mixture at room temperature for 3 hours, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was water washed to give after drying (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (1.42 g, 99¾) as an oil-like product.

Infrared absorption spectrum (IR) (in KBr): 3031, 2946, 912, 743 cm " ¹ .

_{Ή-NMR (CDC1 3):} . Δ 1.98-2.35 (4Η, m), 3.05 (3H, s), 4.32 (2H, t, J = 5.6 Hz) Reference Example 6

 5, 5, 6, 6, 6-Penyu Fluorohexanenitrile

To a suspension of sodium cyanide (5.03 g, 78.1 fraction) in dimethyl sulfoxide (10.0 ml) was added the methanesulfonic acid 4,4,5,5,5-pentanofluoroethyl ester obtained in Reference Example 5. (10.0 g, 39.0 tmol) in dimethyl sulfoxide (10.0 ml) was added. After stirring the reaction mixture at room temperature for 17 hours, water was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (5.25 g, 72%) as an oil.

Infrared absorption spectrum (IR) (in KBr): 2959, 2251 cm- ¹ .

 Ή-NR (CDCI3): δ 1.93-2.17 (2Η, m), 2.17-2.37 (2H, m), 2.51 (2H, t, J = 7.0

Hz).

Reference Example 7

 5,5,6,6,6-hexanoic acid

The 5,5,6,6,6-pentafluoromouth hexanenitrile (5.25 g, 28.1 mmol) obtained in Reference Example 6 was dissolved in acetic acid (50.0 ml) and concentrated hydrochloric acid (25.0 ml), and the solution was heated at 120 ° C. Stir for 4 hours. The reaction mixture was added to ice water and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (4.80 g, 83%) was obtained as an oil.

Infrared absorption spectrum (IR) (in KBr): 3700-2300, 1715 cm- ¹ .

 Ή-NMR (CDCI3): 51.86-2.04 (2H, m), 2.08-2.28 (2H, m), 2.50 (2H, t, J = 7.0 Hz).

Reference Example 8

5,5,6,6,6-pentafluorohexanol To a solution of 5,5,6,6,6-pentanofluorhexaenoic acid (4.80 g, 23.3 maraudal 01) obtained in Reference Example 7 in tetrahydrofuran (50.0 ml) was added oxalyl chloride (2.68 ml, 27.9 ) And N, N-dimethylformamide (0.100 ml) were added sequentially. After the reaction mixture was stirred at room temperature for 4 hours, the solvent was distilled off under reduced pressure. To a solution of sodium borohydride (1.76 g, 46.6 mmol) in tetrahydrofuran (25.0 ml) and 1,2-dimethoxyethane (20.0 ml) was added a solution of the residue in tetrahydrofuran (25.0 ml) under ice-cooling. After stirring the reaction mixture at room temperature for 19 hours, the reaction mixture was poured into ice water, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water, dried (MgSO _4), the solvent was evaporated reduced pressure the title compound (3.23 g, 73%) as an oil.

Infrared absorption spectrum (IR) (in KBr): 3710-3050, 2953, 2884 cm " ¹ .

_{'Η - NMR (CDC1 3)} : δ 1.36-1.80 (6Η, m), 1.92-2.22 (2H, m), 3.70 (2H, t, J = 6.2 Hz).

Reference Example 9

Methanesulfonic acid 5,5,6,6,6-Pentafluorohexyl ester

Methanesulfonyl chloride (1.95 ml, 25. 2) was added to a solution of 5,5,6,6,6-pentafluorohexanol (3.23 g, 16.8 t) obtained in Reference Example 8 in tetrahydrofuran (60.0 ml). mmol) and triethylamine (4.69 ml, 33.6 maraudal 01) were sequentially added under ice cooling. After stirring the reaction mixture at room temperature for 2 hours, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (4.13 g, 91¾) as an oil.

Infrared absorption spectrum (IR) (in KBr):. 3029, 2949, 1354, 1175, 974, 936 cm- 1 Ή-NMR (CDC1 3): δ 1.66-1.95 (4Η, m), 1.95-2.29 (2H , m), 3.03 (3H, s), 4.27 (2H, t, J = 6.2 Hz).

Reference Example 10

R ² Gabe Njiru group in formula (XVI II), the synthesis of Z is S0 _2, R ¹⁵ is p- Toruiru group, and R is an Echiru group

The compound synthesized in Reference Example 3-2 (1.09 g, 2.54 thigh 01) was dissolved in acetonitrile (30 ml), and benzyl dibromide (0.339 ml, 2.79 删 01) and triethylamine (1.06 ml, 7.61 bandol) were added. After stirring at room temperature for 2.5 hours, the mixture was further stirred at 60 ° C. for 19 hours. This During this period, DMF (6 ml), benzyl bromide (0.339 ml, 2.79 miol) and triethylamine (1.06 ml, 7.61) were added as appropriate. After concentrating the reaction solution, the residue was diluted with ethyl acetate (50 ml), washed with a 2% aqueous sodium hydrogen carbonate solution, 0.1N hydrochloric acid, water and saturated saline, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography on silica gel 60 (25 g). The fraction eluted with ethyl acetate: hexane (40:60 to 50:50) was concentrated to dryness under reduced pressure. As a result, a yellow oily substance (0.95 g, 1.83 mmol) of the title compound was obtained.

 'H-NMR (300 MHz, in double-mouthed form): δ 1.24 (3Η, t, J = 7.1 Hz), 2.43 (3H, s), 2.55 (2H, t, J = 7.3 Hz), 3.18 (2H , t, J = 7.3 Hz), 4.01 (2H, s), 4.13 (2H, q, J = 7.1 Hz), 7.32 (2H, d, J = 8.2 Hz), 7.89 (2H, d, J = 8.2 Hz) ), 7.97 (1H, brs), 9.76 (1H, br).

Reference example Π

Synthesis of Compound R ² Gabe Njiru group, Z is S0 _2, R ¹⁵ is p- Toruiru radical, R is a Echiru group in the formula (XIX)

 The compound synthesized in Reference Example 10 (1.95 g, 3.75 t1) was dissolved in THF (25 ml) and methanol (25 ml), and potassium hydroxide (0.99 g, 15.0 t) was added. Stirred for minutes. To the reaction solution, 1N hydrochloric acid (15 ml), water (25 ml) and methanol (10 ml) were added and mixed, followed by stirring at room temperature for 30 minutes. The resulting precipitate was collected by filtration, washed with aqueous methanol, and dried to give a yellow powder of the title compound (1.28 g, 3.05 mmol).

 'H-NMR (300 MHz, in double-mouthed form): <5 2.44 (3H, s), 4.53 (2H, s), 7.31 (5H, m), 7.34 (2H, d, J = 8.7 Hz), 7.78 (2H, d, J = 8.3 Hz), 8.12 (1H, brs), 9.28 (1H, brs), 12.54 (1H, brs).

Elemental _{analysis: C 18 H 17 N 3 0} 3 S 3 Calculated: C, 51.53; H, 4.08 ; N, 10.02; S, 22.93 (%), Found; C, 51.53; H, 4.08 ; N, 10.02; S, 22.93 (%).

Reference Example 12

Synthesis of a compound of the formula (XXV II) wherein R ¹⁴ is an ethoxycarbonylmethyl group

ADAN (10.8 g, 79.1 mmol) was dissolved in dichloromethane (220 ml), and isocyanate was dissolved. Ethyl acetate (10.0 g, 75.1 dust ol) was added, and the mixture was cooled to, and aluminum chloride (2 g, 75.1 ol) was added in several portions. After stirring the reaction solution at Ot for 3.5 hours, the precipitate was filtered, washed with ether, ice-cold water, and water, and dried to obtain a pale yellow powder (14.2 g, 46.6 mmol). The powder (15.1 g, 56.4 mmol) thus obtained was suspended in ethyl acetate (300 ml), 1, and lithiamine (15.6 ηιΚ 0.113 mol) was added thereto, followed by stirring at room temperature for 12 hours. The precipitate was filtered, washed with ether and dried to give an off-white powder of the title compound (12.2 g, 45.8 ol).

 ¾-NMR (300 MHz, in heavy dimethyl sulfoxide): δΐ.20 (3H, t, J = 7.1 Hz), 4.14 (2H, q, J = 7.1 Hz), 4.27 (2H, s), 8.74 (1H, brs).

Elemental _{analysis: C 8 N 3 0 3 C1} 2 Calculated: C; 36.11 H; 3.41, N; 15.79; C1, 26.65 (%), Found; C; 36.39 H; 3.41, ; 15.69; C1, 26.47 (%).

Reference Example 13-1

Synthesis of compound of formula (XXVIII) wherein R ¹⁴ is an ethoxycarbonylmethyl group

 The compound synthesized in Reference Example 12 (14.7 g, 55.1 tmol) was dissolved in ethanol (150 ml), 1N hydrochloric acid (150 ml) was added, and the reaction mixture was stirred at room temperature for 67 hours. The precipitate was filtered, washed with water to remove hydrochloric acid, and a water-containing white powder was obtained. This was suspended in ethanol (200 ml), 1N sodium hydroxide (100 ml) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated to distill off ethanol, and 1N hydrochloric acid (100 ml) was added to the remaining aqueous layer to adjust to PH2. The resulting precipitate was collected by filtration, washed with water, and dried to give the title compound as a white powder (7.18 g, 30.0 tmol).

 'H-NMR (300 MHz, double-mouthed form-deuterated dimethyl sulfoxide, in 9: 1): δ 4.23 (2Η, s), 10.87 (1H, brs).

Elemental _{analysis: C 6 H 4 N 2 0} 4 C1 2 Calculated: C, 30.15; H, 1.69 ; N, 11.72; C1, 29.67 (%), Found; C, 30.32; H, 1.86 ; N, 11.73; C1, 29.66 ().

Reference Example 13-2

Synthesis of a compound of the formula (XXVIII) wherein R ¹⁴ is a tert-butoxycarbonylmethyl group

The compound synthesized in Reference Example 13-1 (7.25 g, 30.3 mmol) was added to tert-butyl acetate (240 ml), and the mixture was dissolved with boron trifluoride etherate (3.81 ml, 30.3 Band01) and stirred at room temperature for 7 hours. The reaction solution was poured into ice-cold water (200 g), mixed and partitioned, and the aqueous layer was extracted with ethyl acetate (200 ml). The organic layers were combined, washed with an aqueous solution of sodium carbonate, water and saturated saline, dried over sodium sulfate, and concentrated to dryness under reduced pressure. Ether and diisopropyl ether were added to the residue, and the resulting precipitate was collected by filtration, washed with diisopropyl ether, and dried to give the title compound as a white powder (6.17 g, 20.9 tmol).

 Ή-NMR (300 MHz, in double-mouthed form): δ 1.48 (9Η, s), 4.22 (2H, s), 7.37 (1H, brs).

Elemental _{analysis: C 10 H I2 N 2 0} 4 C1 2 Calculated: C, 40.70; H, 4.10 ; N, 9.49; C1, 24.03 (%) Found; C, 40.70; H, 4.12 ; N, 9.23 ; C1, 23.97 (%).

Reference Example 14

Synthesis of a compound of the formula (XX IX) wherein R ¹⁴ is a tert-butoxycarbonylmethyl group and R is a methyl group

 Acetonitrile (60 ml) was added to the compound synthesized in Reference Example 13-2 (3.05 g, 10.3 mmol) and carbonated carbonate (4.29 g, 31.0 ol) and suspended, and methyl 3-mercaptopropionate (2.34 ml) was added. , 20.7 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hours, and further stirred at 8 for 40 minutes. After concentrating the reaction solution, 1N hydrochloric acid (31 ml), water (80 ml) and ethyl acetate (100 ml) were added and mixed, and the organic layer was extracted with a 2% aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, adjusted to pH 3, and extracted with ethyl acetate. The organic layer was washed with a 7% saline solution and a saturated saline solution, and then dried with sodium sulfate. The solvent was distilled off under reduced pressure, methanol was added to the residue, and the resulting precipitate was collected by filtration, washed with methanol, and dried to give the title compound as an orange oil (3.20 g, 8.50 benzyl) .

Ή-concealed (300 MHz, in double-mouthed form): δ 1.45 / 1.49 (9Η, s), 2.71 / 2.75 (2H, t, J = 6.9 / 7.0 Hz), 3.24 / 3.58 (2H, t, J = 6.9 / 7.0 Hz), 3.72 / 3.74 (3H, s), 4.14 (1 / 2H, d, J = 17.9 Hz), 4.16 (1 / 2H, d, J = 17.9 Hz), 4.23 (2 / 2H, s ), 5.28 (1 / 2H, d, J = 0.7 Hz), 6.14 (1 / 2H, brs), 7.36 (1 / 2H, brs), 7.74 (1 / 2H, brs) elemental analysis:. C ₁₄ H ₂ . N ₂ 0 ₆ S ₂ Calculated: C, 44.67; H, 5.35 ; N, 7.44; S, 17.04 (%), Found: C, 44.77; H, 5.48 ; N, 7.27; S, 16.61 (%) · Reference Example 15 "3-{[(isobutylsulfanyl) (5-{[(4-methylphenyl) sulfonyl] imino} -2-oxo-4-imidazolidinylidene) methyl] sulfanyl} ethyl propionate Reference Example 3 -The compound synthesized in (2) (8.00 g, 18.6 mol) was dissolved in THF (80.0 ml) and DF (40.0 ml), and isobutyl iodide (2.36 ml, 20.5 mmol) and triethylamine (7.79 ml, 55.9 ml) were dissolved. ) Was added and the mixture was stirred at room temperature for 17 hours.After concentration of the reaction solution, the residue was diluted with ethyl acetate, washed with water and saturated saline, and dried over sodium sulfate. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (6.05 g, 67%) as yellow crystals. Recrystallization from ethyl acetate gave yellow crystals with a melting point of 95-97 ° C.

IR (KBr) V: 3368, 3200, 3071, 2953, 2924, 2907, 2868, 1765, 1730, 1634, 1574, 1499 CDT ¹ .

E -賺_{(CDC1 3): δ 1.00 (} 6Η, d, J = 6.6 Hz), 1.25 (3H, t, J = 6.8 Hz), 1.73-1.89 (1H, m), 2.43 (3H, s), 2.56 (2H, t, J = 7.4 Hz), 2.80 (2H, d, J = 6.6 Hz), 3.16 (2H, t, J = 7.4 Hz), 4.13 (2H, q, J = 7.0 Hz), 7.32 (2H , d, J = 8.2 Hz), 7.56 (1H, bs), 7.89 (2H, d, J = 8.4 Hz), 9.65 (1H, bs).

Elemental analysis: C _2. H ₂₇ N ₃ 0 _{5 As} S ₃

Calculated value (¾): C, 49.46; H, 5.60; N, 8.65; S, 19.81.

Found (¾): C, 49.42; H, 5.45; N, 8.60; S, 19.83.

Reference Example 16

N- {5-[(Isoptylsulfanyl) (sulfanyl) methylidene] -2-oxo-4-imimi 3-{[(isobutylsulfanyl) (5-{[(4-methylphenyl) Sulfonyl] imino} -2-oxo-4-imidazolidinylidene) methyl] sulfanyl} A suspension of ethyl (1,69 ml) in ethyl (17.0 ml) and propanolate (17.0 ml) in water was added to water. Potassium oxide (689 mg, 10.4 ol) was added and stirred at room temperature for 40 minutes. 1N Hydrochloric acid (12.2 ml) was added to the reaction solution, mixed, and stirred at room temperature for 10 minutes. The precipitate formed was collected by filtration, washed with water and ethanol, dried and titled The compound was recrystallized from ethyl acetate to give yellow crystals having a melting point of 204-205 ° C.

IR (Br) V: 3300-2800, 2961, 1703, 1671, 1570, 1507 cm " ¹ .

_{Ή-NR (CDC1 3):} 51.02 (6H, d, J = 6.6 Hz), 1.90-2.04 (1H, m), 2.44 (3H, s), 3.21 (2H, d, J = 6.6 Hz), 7.34 ( 2H, d, J = 8.4 Hz), 7.78 (2H, d, J = 8.4 Hz), 8.19 (1H, bs), 9.24 (1H, bs).

Elemental analysis: as C ₁₅ H ₁₉ N ₃ 0 ₃ S ₃

Calculated (¾): C, 46.73; H, 4.97; N, 10.90; S, 24.95.

Found (¾): C, 46.58; H, 4.87; N, 10.61; S, 24.70.

Reference Example 17

 2-{[(isobutylsulfanyl) (5-{[(4-methylphenyl) sulfonyl] imino} -2oxo-4-imidazolidinylidene) methyl] sulfanyl} ethyl propionate N-synthesized in Reference Example 16 {5-[(Isoptylsulfanyl) (sulfanyl) methylidene] -2-oxo-4-imidazolidinylidene} -4-methylbenzenesulfonamide (4.33 g, 11.2 bandol) was added to THF (43.0 ml) and DMF ( 21.5 ml), and ethyl 2-bromopropionate (1.61 ml, 12.4 band01) and triethylamine (4.70 ml, 33.7 mmol) were added, followed by stirring at room temperature for 7 hours. After concentration of the reaction solution, the residue was diluted with ethyl acetate, washed with water and saturated saline, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (4.22 g, 11%) as yellow crystals. Recrystallization from ethyl acetate gave yellow crystals with a melting point of 97-99.

IR (KBr) V: 3258, 2959, 2932, 2870, 1750, 1634, 1566, 1497 cm— ¹ .

_{Ή-NM (CDC1 3):} δ 0.912 (6Η, dd, J = 6.6, 2.2 Hz), 1.23 (3H, t, J = 7.2 Hz), 1.54 (3H, d, J = 7.2 Hz), 1.64-1.80 (1H,), 2.43 (3H, s), 2.79 (2H, dd, J = 6.6, 1.0 Hz), 3.93 (1H, q, J = 7.4 Hz), 4.13 (2H, q, J = 7.0 Hz), 7.30 (2H, d, J-8.4 Hz), 7.89 (2H, d, J = 8.4 Hz), 7.91 (1H, bs), 7.67 (1H, bs).

Elemental analysis: as C _2Q H ₂₇ N ₃ 0 ₅ S ₃

Calculated (¾): C, 49.46; H, 5.60; N, 8.65; S, 19.81.

Found (¾): C, 49.25; H, 5.60; N, 8.63; S, 19.86. Reference Example 18

 Dimethyl 3-bromo-2-ketoglurate

 A solution of 2-ketoglutaric acid (25.3 g, 0.171 mol) and concentrated hydrochloric acid (14.3 ml, 0.171 mol) in methanol (200 ml) was stirred at room temperature for 24 hours. Extraction with ethyl acetate gave a pale yellow oil of crude dimethyl 2-ketoglurate (purity 72%, 30.4 g, 0.126 mol, 73%).

_{Ή-NR (300MHz, CDC1 3} ): δ 2.69 (2Η, t, J = 6.5 Hz), 3.17 (2H, t, J = 6.5 Hz), 3.70 (3H, s), 3.89 (3H, s).

 3 The above-mentioned dimethyl 2-ketoglutarate (purity 72%, 8.4 g, 34.9 ol) was added to a suspension of trimethylphenylammonium bromide (13.4 g, 34.9 mmol) in chloroform (100 ml) with stirring at room temperature. Was added dropwise over 5 minutes, and the reaction solution was stirred at room temperature for 3 hours. After concentrating the reaction solution and distilling off the chloroform form, dilute with ethyl acetate (350 ml), wash with 15% and saturated saline, dry over sodium sulfate and concentrate to obtain crude 3-bromo- A yellow oil of dimethyl 2-ketoglutarate (purity 70%, 11.8 g, 32.6 mmol, 93.5%) was obtained.

'H-NMR (200MHz, CDC1 3): 53.06 (1H, dd, J = 17.2, 5.8 Hz), 3.33 (1H, dd, J = 17.2, 9.2 Hz), 3.71 (3H, s), 3.95 (3H, s), 5.40 (1H, dd, J = 9.2, 5.8 Hz). Reference Example 19

 N-Boc-5-aminopentyl mesylate

 5-Aminopentanol (purity 95%, 4.25 g, 39.1 mmol) and ditert-butyl bicarbonate (8.81 g, 39.1 marl) were dissolved in THF-water (1: 1, 100 ml) in triethylamine (1: 1). 13.6 ml, 97.8 t ol) to give N-Boc 5-amino-pentanol (purity 87¾, 9.10 g, 39.1 fraction ol) as a colorless oil.

_{Ή-NMR (300MHz, CDC1 3} ): 61.U (9H, s), 1.4-1.6 (6H, m), 3.13 (2H, brq, J = 6.6 Hz), 3.65 (2H, brq, J = 2.4 Hz ), 4.57 (1H, m).

To a solution of the resulting 5-aminopentanol (3.92 g, 16.8 ol) and methanesulfonyl chloride (1.45 ml, 18.5 t ol) in THF (80 ml) was stirred with 0 at 0 ° C. 20.1 mmol) was added, and the reaction solution was stirred at 0 ° C for 2 hours. The reaction solution was purified by extraction with ethyl acetate and purified with N-Boc-5-amino-1-pentyl mesylate (purity 87%, 5.46 g, 16.8 mmol) of a colorless oil.

_{Ή-NMR (300MHz, CDC1 3} ): 51.44 (9H, s), 1.56 (4H, m), 1.79 (2H, brquint, J = 7.5 Hz), 3.03 (3H, s), 3.13 (2H, brq, J = 6.3 Hz), 4.23 (2H, t, J = 6.4 Hz), 4.56 (1H, m).

Reference Example 20

N-Boc-6-amino-trihexyl iodide

 In the same manner as in Reference Example 19, N-Boc-6-amino-1-hexyl mesylate (purity 80.4, 6.39 g, 40.5 thigh 01) was obtained from 6-amino-1-hexanol (5.0 g, 40.5 thigh ol). A colored oil was obtained.

'H-NMR (300MHz, CDC1 3): δ 1.34-1.50 (6Η, m), 1.44 (9H, s), 1.75 (2H, brquint, J = 6.8 Hz), 3.01 (3H, s), 3.11 (2H , brq, J = 6.4 Hz), 4.22 (2H, t, J = 6.4 Hz), 4.53 (1H, br).

 Suspension of N-Boc-6-amino-1-hexyl mesylate (purity 80.4%, 2.72 g, 7.40 t ol) and sodium iodide (2.22 g, 14.8 t ol) in acetone (60 ml) obtained above Was heated to reflux for 2 hours. The reaction solution was extracted with ethyl acetate to obtain N-Boc-6-amino-1-hexyl iodide (94%, 2.57 g, 7.40 mmol) as a brown oil. Reference Example 21

 4,4-difluoro-1-cyclohexane

 Sodium borohydride (purity 90%, 0.57 g, 13.6 band01) in a solution of cyclohexane-1,4-dionemonoethylene ketal (8.84 g, 55.5 tmol) in methanol (170 ml) at room temperature with stirring Was added and stirred for 15 minutes. Sodium borohydride (70 mg, 1.67 mmol) was added to the reaction solution, and the mixture was stirred for 20 minutes. The reaction solution was purified by extraction with ethyl acetate to obtain a light brown oil of 4-oxocyclohexanolethylene ketal (8.44 g, 53.3 mmol, 96%).

_{¾-NMR (200MHz, CDC1 3} ): 51.43 (6H, s), 1.47 (3H, s), 2.26 (1H, ddd, J = 14.4, 8.2, 4.8 Hz), 2.62 (1H, m), 3.06 (3H , s), 3.75 (3H, s), 3.79 (2H, m), 4.43 (1H, dt, J = 12.8, 8.1 Hz), 5.26 (1H, m).

The mixture was stirred at 0 ° C in a solution of 4-oxocyclohexanol ethylene ketal (4.05 g, 25.6 mmol) and methanesulfonyl chloride (3.47 g, 30.0 butyl) in THF (80 ml). While stirring, a solution of triethylamine (4.85 ml, 35.0 mmol) in THF (10 ml) was added dropwise over 30 minutes. The reaction was stirred at 0 for 90 minutes. The reaction solution was extracted with ethyl acetate to obtain a crude 4-oxocyclohexylmesylethylene ethylene ketal (purity 65%, 6.55 g, 18 ol, 70 »pale yellow oily substance).

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.66 (2Η, m), 1.84 (2H, brq, J = 6.4 Hz), 1.99 (4H, brt, J = 5.9 Hz), 3.02 (3H, s), 3.95 (4H, brt, J = 2.0 Hz), 4.85 (1H, quint, J = 5.1 Hz).

 The above obtained 4-oxocyclohexyl mesylate ethylene ketal (purity 65¾, 6.55 g, 18 liters) and p-toluenesulfonic acid hydrate (2.47 g, 13.0 liters) in acetone-water (1: 1, 130 ml) solution was stirred at room temperature for 2.5 hours and at 50 ° C for 4 hours. The reaction mixture was extracted with ethyl acetate to give 4-oxocyclohexyl mesylate (purity 90 °, 3.44 g, 16.1 mmol, 89.4%) as a yellow oil.

_{Ή-NMR (200MHz, CDC1 3} ): 62.15 (2H, m), 2.3-2.5 (4H, m), 2.62 (2H, m), 3.10 (3H, s), 5.13 (1H, tt, J = 5.4, 2.7 Hz).

 A solution of 4-oxocyclohexyl mesylate (purity 90¾, 3.4 g, 16.1 mmol) in dichloromethane (30 ml) was stirred at 0 with Deoxo-Fluor ™ (7.08 g, 32.0 mmol) in dichloromethane (3 ml). ml) solution was added dropwise over 30 minutes, and after heating, the reaction solution was stirred at room temperature for 6 hours. The reaction solution was diluted with getyl ether (30 ml), poured into ice (50 g), and extracted with getyl ether (50 ml) and diisopropyl ether (50 ml). The organic layer is washed with saturated sodium bicarbonate, water and saturated saline, dried over sodium sulfate, concentrated and concentrated to 4,4-difluorocyclohexyl mesylate (purity 92¾, 3.5 g, 15 bandol, 93%) Was obtained as a yellow oil.

_{Ή-NMR (200MHz, CDC1 3} ): (51.92-2.18 (6H, m), 2.40 (2H, m), 3.04 / 3.05 (3H, s), 4.92 / 4.98 (1H, m).

A suspension of 4,4-difluorocyclohexyl mesylate (purity 92, 3.5 g, 15 t ol) and sodium iodide (4.50 g, 30 t ol) in 2-butaneone (60 ml) was heated for 13 hours. Refluxed. The reaction solution was extracted with disopropyl ether-ethyl ether to obtain crude 4,4-difluoromethylcyclohexane (purity: 45%, 4.9 g, 9.0 mmol, 60%) as a brown oil. . ^{l H - NMR (300MHz, CDC1} 3): 51.91 (2H, m), 2.08 (4H, i), 2.14 (2H, m), 4.40 / 4.46 (1H, m).

Reference Example 22

 4,4-difluoro-methyl-cyclohexane

 Deoxo-Fluor ™ (5.06 g, 22.9 mmol) was added dropwise over 30 minutes to a solution of 4-oxocyclohexanecarbethylate (2.29 g, 13.4 mmol) in dichloromethane (20 ml) with stirring with stirring for 30 minutes. After warming, the reaction was stirred at room temperature for 6 hours. The reaction solution was poured into ice (50 g), and extracted with ethyl acetate (100 ml) and getyl ether (30 ml). The organic layer was washed with 5% aqueous sodium hydrogencarbonate solution, water and saturated saline, dried over sodium sulfate, and concentrated to give crude 4,4-difluorocyclohexanecarboxylate (2.79 g). Obtained as a yellow oil. This yellow oil was dissolved in THF (55 ml), lithium aluminum hydride (purity 80%, 636 mg, 13.4 mmol) was added in several portions with stirring at 0 ° C, and the mixture was added at 0 ° C for 30 minutes. Stirred. Unreacted lithium aluminum hydride was decomposed by slowly adding methanol to the reaction solution, and then 0.5M citric acid (28 ml) was added thereto, followed by extraction with getyl ether-diisopropyl ether (1: 1, 100 ml). The organic layer was washed, dried and concentrated to give 4,4-difluorocyclohexanemethanol (1.94 g, 12.9 mmol, 96%) as a yellow oil.

_{Ή-NMR (200MHz, CDC1 3} ): 51.34 (2H, m), 1.55 (2H, m), 1.75 (1H,), 1.80 (2H, m), 2.05-2.25 (2H, m), 3.53 (2H, m).

Triethylamine (2.15 ml, 15.5 mmol) in a solution of 4,4-difluorocyclohexanemethanol (1.94 g, 12.9 mmol) and methanesulfonyl chloride (1.64 g, 14.2 mmol) in THF (39 ml) while stirring at 0 ° C. After a THF (5 ml) solution was added dropwise over 60 minutes, the reaction solution was stirred at 0 ° C for 60 minutes. The reaction mixture was extracted with getyl ether-diisopropyl ether (1: 1, 100 ml) and the crude 4,4-difluorocyclohexylmethyl mesylate (purity 90%, 2.79 g, 11 bandol ol, 85 %) As a colorless oil. _{Ή-NR (200MHz, CDC1 3} ): (51.39 (2H, brq, J- 12.1 Hz), 1.57 (1H, m), 1.70-2.10 (2H, m), 1.85 (2H, m), 2.19 (2H, brd, J = 16 Hz), 3.02 (3H, s), 4.08 / 4.13 (2H, d, J = 6.2 Hz).

4, 4-difluorocyclohexylmethyl mesylate (Purity 90%, 2.79g, 11 ol) A suspension of sodium iodide (3.30 g, 22 imol) in acetone (60 ml) was heated under reflux for 1.5 hours, and then stirred at 50 ° C for 16 hours. The reaction mixture was extracted with ethyl acetate-hexane (1: 1) to give 4,4-difluoro-1-iodomethylcyclohexane (51% ethyl acetate solution, 5.6 g, 11 ol, quant.). Obtained as a brown oil. 'Ή-NMR (200MHz, CDC1 3): 61.35 (2H, brq, J = 10.6 Hz), 1.59 (2H, m), 1.80 (2H, m), 1.92 (2H, m), 2.23 (1H, m) , 3.13 / 3.19 (2H, d, J = 6.2 / 5.8 Hz).

Reference Example 23

Cis_4- (2-tetrahydropyranyl) oxycyclohexylmethyl iodide

 A solution of cis-4-hydroxycyclohexanecarboxylic acid (4.00 g, 27.7 mmol) and concentrated hydrochloric acid (4.62 ml, 55.5 mol / l) in ethanol (80 ml) was stirred at room temperature for 19 hours. Purification by extraction with ethyl acetate gave a colorless oily substance of cis-4-hydroxycyclohexanyl ethyl ruponate (4.72 g, 27.4 bandages 01, 98.9%).

_{¾-NMR (200MHz, CDC1 3} ): (51.26 (3H, t, J = 7.1 Hz), 1.36 (1H, brs), 1.67 (6H, m), 1.95 (2H, quint, J = 8.2 Hz), 2.38 (1H, m), 3.90 (1H, in), 4.14 (2H, q, J = 7.1 Hz).

 Ethyl cis-4-hydroxycyclohexanecarboxylate (2.65 g, 15.4 olol) and 3,4-dihydro-2H-pyran (hereinafter abbreviated as DHP, 1.72 ml, 18.5 mmol) The solution was stirred with D-camphor-10-sulfonic acid (hereinafter sometimes abbreviated as CSA, 357 mg, 1.54 mmol) at room temperature for 3 hours. Purification by extraction with ethyl acetate gave a colorless oily substance of ethyl cis-4- (2-tetrahydropyrael) oxycyclohexane hexane propionate (4.14 g, 15.4 mmol, quant.).

 Lithium aluminum hydride (purity 80%, 0.402) was added to a solution of ethyl cis-4- (2-tetrahydroviranyl) oxycyclohexanecarboxylate (4.14 g, 15.4 benzyl) in THF (80 ml) while stirring at 0 ° C. g, 8.47 mmol) was added in several portions, and the mixture was stirred for 2.5 hours with TC. The extract was purified by extraction with ethyl acetate, and cis-4- (2-tetrahydropyranyl) oxycyclohexanemethanol (purity 90%) was added. , 3.67 g, 15.4 mmol, quant.).

_{Ή - NMR (200MHz, CDC1 3} ): δ 1.40-1.75 (11H, m), 1.84 (4H, m), 3.50 (2H, m), 3.50 (2H, d, J = 6.0 Hz), 3.88 (2H, m), 3.92 (1H, m), 4.66 / 4.95 (1H, m). 3: 1 panoma mixture

 Cis-4- (2-tetrahydropyranyl) oxycyclohexanemethanol (purity 90%, 3.67 g, 15.4 mmol) and triethylamine (2.56 ml, 18.5 mmol) in THF (70 ml) were stirred at 0 with methane. A solution of sulfonyl chloride (1.87 g, 16.2 ml) in THF (5 ml) was added dropwise over 20 minutes, and the reaction solution was stirred at 0 ° C for 2.5 hours. The crude material (5.27 g) obtained by extraction with ethyl acetate was purified by silica gel (50 g) chromatography (elution solvent, ethyl acetate-hexane, 2: 8-3: 7), and cis-4- A pale yellow oil of (2-tetrahydrobilanyl) oxycyclohexylmethyl mesylate (3.76 g, 12.9 ol, 83.5%) was obtained.

_{¾- NMR (300MHz, CDC1 3)} : δ 1.41 (2Η, in), 1.50-1.62 (8H, m), 1.70 (1H, m), 1.84 (4H, m), 3.01 (3H, s), 3.49 ( 2H, dt, J = 11.7, 5.1 Hz), 3.90 (2H, m), 4.06 (2H, d, J = 6.6 Hz), 4.65 (1H, t, J = 3.8 Hz).

 A suspension of ci s-4_ (2-tetrahydroviranyl) oxycyclohexylmethyl mesylate (3.76 g, 12.9 mmol) and sodium iodide (3.85 g, 25.7 ol) in acetone (70 ml) was heated at reflux for 18 hours. did. The reaction solution was extracted with ethyl acetate and purified to give a pale yellow oil of cis-4- (2-tetrahydroviranyl) oxycyclohexylmethyl iodide (3.84 g, 11.8 mmol, 91.8%).

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.39 (2Η, brq, J = 8.4 Hz), 1.50-1.65 (8H, m), 1.69 (1H, m), 1.84 (4H, m), 3.13 (2H, d, J = 5.6 Hz), 3.48 (2H, dt, J = 11.4, 5.8 Hz), 3.84 (1H, m), 3.92 (1H, m), 4.65 (1H, brt, J = 4 Hz).

Reference Example 24

Cis-5-Acetoxycyclooctyl iodide

 A solution of cis-1,5-cyclooctanediol (2.01 g, 13.7 mmol) and p-toluenesulfonyl chloride (2.95 g, 15.0 marl) in pyridine (30 ml) was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness, extracted with ethyl acetate, and the residual oil (4.2 g) was purified by silica gel (50 g) chromatography (ethyl acetate-hexane, 2: 8-4: 6) to give cis. A colorless oil of -1,5-cyclooctanediol monotosylate (2.27 g, 7.61 mmol, 55.7%) was obtained.

_{Ή-NMR (200MHz, CDC1 3} ): 51.40 (2H, brq,; J = 8.2 Hz), 1.59 (2H, m), 1.82 (8H, m), 2.45 (3H, s), 3.75 (1H, brt, J = 8.8 Hz), 4.59 (1H, m), 7.34 (2H, d, J = 8.8 Hz), 7.79 (2H, d, J = 8.0 Hz).

 A pyridine (10 ml) solution of cis-1,5-cyclooctanediol monotosylate (0.89 g, 2.98 thigh 01) and anhydrous acetic acid (5 ml) was stirred at room temperature for 12 hours. The reaction solution was concentrated to dryness to obtain a colorless oily product of cis-5-acetoxycyclooctyl tosylate (1.1 g, quant.).

_{Ή-NMR (200MHz, CDC1 3} ): (51.44 (2H, m), 1.60-1.90 (10H, m), 2.00 (3H, s), 2.45 (3H, s), 4.61 (1H, m), 4.77 ( 1H, HI), 7.34 (2H, d, J = 8.0 Hz), 7.79 (2H, d, J = 8.4 Hz).

 A suspension of cis-5-acetoxycyclooctyl tosylate (1.1 g, 2.98 mmol) and sodium iodide (1.34 g, 8.94 mmol) in 2-butaneone (25 ml) was heated under reflux for 1.5 hours. . The reaction solution was extracted with ethyl acetate to obtain a brown oily substance of cis-5-acetoxycyclooctyl iodide (purity 60, 0.81 g, 1.6 mmol, 55%).

Reference Example 25

 (2S, 4S) -N-Boc-4-fluoro-2-fluoromethylpyrrolidine.

 A solution of Deoxd-Fluor ™ (1.20 g, 5.42 rol) in dichloromethane (10 ml) was stirred at 0 with (2S, 4R) -N-Boc-4-hydroxypyrrolidine-2-methyltosylate (1.68 g, A solution of 4.52 mol) in dichloromethane (10 ml) was added dropwise over 45 minutes, and after heating, the reaction solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice-water (about 80 g) in which sodium carbonate (1.51 g, 18.1 mol) was dissolved, and extracted with ethyl acetate-hexane (1: 1, 60 nil) and ethyl acetate (50 ml). The organic layer was washed with saturated sodium bicarbonate and saturated brine, dried over sodium sulfate, and concentrated to give a yellow oil. This was subjected to chromatography on silica gel (20 g) (ethyl acetate-hexane, 1: 9-4: 6), and the ethyl acetate-hexane (2: 8-3: 7) fraction was concentrated to dryness. Later, it was diluted with Jetil ether. The precipitate was collected by filtration, washed with getyl ether, and dried to give (2S, 4S) -N-Boc-4_fluoropyrrolidine-2-methyltosylate (1.30 g, 3.48 bandages 01, 77.0%) Obtained as a white powder.

_{Ή-NMR (200MHz, CDC1 3} ): 51.43 (9H, s), 2.00 (1H, m), 2.28 (1H, brd, J = 18.4 Hz), 2.45 (3H, s), 3.58 (1H, brd, J = 27.4 Hz), 3.87 (1H, m), 4.14 (1H, m), 4.29 (1H, m), 5.17 (1H, brd, J = 52.4 Hz), 7.35 (2H, d, J = 8.0 Hz), 7.80 (2H, d, J = 8.4 Hz).

Elemental analysis C ₁₇ H ₂₄ N0 ₅ SF Calculated: C, 54.68; H, 6.48 ; N, 3.75; S, 8.59; F, 5.09 (%), Found: C, 54.61; H, 6.60 ; N, 3.70; S, 8.66; F, 4.80 (%).

 Suspension of (2S, 4S) -N-Boc-4_fluoropyrrolidine-2-methyltosylate (1.20 g, 3.21 tall ol) and sodium iodide (1.44 g, 9.64 marl ol) in acetone (24 ml) After the solution was stirred at room temperature for 12 hours, it was heated and refluxed for 8 hours. The reaction solution was extracted with diisopropyl ether to obtain a crude substance (1.00 g) of (2S, 4S) -N_Boc-4_fluoro-2-iodomethylpiperidine as a yellow oil.

Reference Example 26

 5,5-difluorocyclooctyl tosylate

 To a solution of oxalyl chloride (1.27 ml, 14.1 ol) in dichloromethane (80 ml) was added dropwise a solution of dimethyl sulfoxide (1.36 ml, 19.0 mmol) in dichloromethane (6 ml) over 5 minutes while stirring at -78 ° C. After 10 minutes, a solution of cis_l, 5-cyclooctanediol monotosylate (2.10 g, 7.04 benzyl) in dichloromethane (30 ml) was added dropwise over 20 minutes. After stirring the reaction solution at room temperature for 2 hours, triethylamine (7.12 ml, 51.4 mmol) was added dropwise to the reaction solution. The reaction solution was heated to 0 ° C over 30 minutes and stirred for 20 minutes. The reaction solution was poured into ice water (100 g), and the upper layer was extracted with ethyl acetate (100 ml). The ethyl acetate layer was washed with saturated saline, combined with the lower layer, concentrated to distill off dichloromethane, diluted with ethyl acetate (150 ml), washed successively with 5% and saturated saline, and washed with sodium sulfate. After drying, concentration gave a yellow solid. This is pulverized in diethyl propyl ether, collected by filtration, washed with diisopropyl ether, and dried to give 5-oxocyclooctyl tosylate (1.63 g, 5.51 bandat 01, 78.3%). Obtained as a white powder.

_{Ή-NMR (200MHz, CDC1 3} ): (51.71 (2H, m), 1.82 (2H, t, J = 5.0 Hz), 1.85 (2H, t, J = 5.0 Hz), 1.91 (2H, m), 2.26 (2H, ddd, J = 13.6, 8.8, 3.6 Hz), 2.51 (2H, ddd, J = 13.2, 8.8, 3.6 Hz), 4.30 (1H, quint, J = 5.9 Hz), 7.35 (2H, d, J = 8.8 Hz), 7.76 (2H, d, J = 8.4 Hz).

Elemental analysis: C ₁₅ H ₂₀ 0 ₄ S Calculated: C, 60.79; H, 6.80 ; S, 10.82 (%), actual Found: C, 60.79; H, 6.92; S, 10.95 (%).

 To a solution of 5-oxocyclooctyl tosylate (1.26 g, 4.25 mmol) in dichloromethane (10 ml) while stirring at 0 with Deoxo-Fluor ™ (1.88 g, 8.50 mmol) in dichloromethane (5 ml) The solution was added dropwise over 30 minutes. After the temperature was raised, the reaction solution was stirred at room temperature for 6 days, and further heated under reflux for 2 days. The reaction solution was poured into ice water (about 50 g) in which sodium carbonate (2.14 g, 25.5 mmol) was dissolved, and extracted with ethyl acetate-ethyl ether α: 1.0 ml) and ethyl acetate (30 ml). The organic layer was washed with saturated sodium bicarbonate and saturated saline, dried over sodium sulfate, and concentrated to give a yellow oil. This was subjected to chromatography on silica gel (15 g) (ethyl acetate-hexane, 1: 9-4: 6), and the ethyl acetate-hexane (1: 9) fraction was concentrated to dryness to give 5,5-hexane. Difluorocyclooctyl tosylate (purity 85%, 0.48 g, 1.28 t, 30%) was obtained as a pale yellow oil.

'H-NMR (200MHz, CDC1 3): (51.58 (2H, m), 1.68-2.12 (10H, m), 2.46 (3H, s), 4.63 (1H, tt, J = 8.0, 3.8 Hz), 7.34 (2H, d, J = 8.4 Hz), 7.79 (2H, d, J- 8.4 Hz).

Reference Example 27

 3-Methyl methyl adaman-1-methyl acetate

 A solution of adamantane-1,3-dimethanol (1.53 g, 7.79 mmol) and p-toluenesulfonyl chloride (1.69 g, 8.57 mol) in pyridine (20 ml) was stirred at room temperature for 14 hours. Triethylamine (0.063 ml, 0.455 t) was added to the reaction solution, and the mixture was further stirred for 2 hours. Getyl ether was added to the gel obtained by extraction from the reaction mixture with ethyl acetate, and the precipitate was removed. The mother liquor was subjected to silica gel (25 g) chromatography (ethyl acetate-hexane, 2: 8-4: 6). Attached. The fraction of ethyl acetate-hexane (4: 6) was concentrated to dryness and dried to give 3-hydroxymethyladamantane-1-methyltosylate (1.72 g, 4.91 hexane, 63.0%) as a colorless oil. Was.

_{¾-NMR (200MHz, CDC1 3} ): δ 1.25 (3Η, m), 1.44 (8H, br), 1.60 (2H, brs), 2.08 (2H, m), 2.45 (3H, s), 3.21 (2H, d, J = 6.0 Hz), 3.60 (2H, s), 7.34 (2H, d, J = 8.4 Hz), 7.77 (2H, d, J = 8.4 Hz).

3-Hydroxymethyladamantane-1-methyltosylate (1.72 g, 4.91 mmol) And a solution of acetic anhydride (5 ml) in pyridine (10 ml) were stirred at room temperature for 12 hours. The reaction solution was concentrated to dryness to obtain a white solid of 3-acetoxymethyladamantane-methyltosylate (1.89 g, 4.91 mmol, 98.0%).

_{Ή-NMR (200MHz, CDC1 3} ): 51.27 (2H, s), 1.44 (8H, br), 1.60 (2H, brs), 2.06 (3H, s), 2.07 (2H, brs), 2.46 (3H, s ), 3.59 (2H, s), 3.67 (2H, s), 7.35 (2H, d, J = 7.6 Hz), 7.77 (2H, d, J = 8.4 Hz).

 Heat a suspension of 3-acetoxymethyladamantane-1-methyltosylate (1.51 g, 3.85 mmol) and sodium iodide (1.73 g, 11.5 tmol) in 2-butanone (40 ml) for 18 hours. Refluxed. The reaction solution was extracted with ethyl acetate to obtain a brown oil, which was then subjected to silica gel (15 g) chromatography (ethyl acetate-hexane, 0: 100-10: 90). The fraction of ethyl acetate-hexane (3:97) was concentrated to dryness and dried to give 3-odomethytyl adamantane-1-methyl acetate (768 mg, 2.21 bandages 01, 57.3%) as a colorless oil.

_{Ή-NMR (200MHz, CDC1 3} ): δΐ.31 (2Η, brs), 1.43 (4H, brd, J = 2.2 Hz), 1.49 (4H, brs), 1.58 (2H, brs), 2.07 (3H, s ), 2.07 (2H, brs), 3.05 (2H, s), 3.73 (2H, s).

Reference Example 28

 3-hydroxymethylcyclohexane-1-methyl acetate

 A solution of cyclohexane-1,3-dicarponic acid (cis / trans mixture, purity 90%, 2.6 g, 13.8 mmol) and concentrated hydrochloric acid (2.30 ml, 27.6 mmol) in methanol (50 ml) was stirred at room temperature for 13 hours. did. The reaction mixture was neutralized with sodium bicarbonate and purified by extraction with ethyl acetate.Dimethyl cyclohexane-1,3-dicarbonate (cis / trans mixture, purity 96%, 2.85 g, 13.7 mmol, 99 %) As a colorless oil.

_{lH-NMR (200MHz, CDC1 3} ): δΐ.35 (2Η, m), 1.57 (3 / 2H, m), 1.72 (3 / 2H, m), 1.92 (1H, i), 1.97 (2H, t, J = 8.6 Hz), 2.23 (1H, dm, J = 12.8 Hz), 2.33 (2H, m) 2.69 (1H, quint, J = 5.8 Hz), 3.67 (3H, s), 3.68 (3H, s).

While stirring at 0 with a solution of dimethyl cyclohexane-1,3-dicarbonate (2.85 g, 13.7 mmol) in THF (60 ml), several powders of lithium aluminum hydride (purity 80729, 729 mg, 15.4 膽 01) were added. Add 0 times. Stirred at C for 90 minutes. With ethyl acetate Extraction and concentration to dryness gave a colorless oil of cyclohexane-1,3-dimethanol (cis / trans mixture, purity 90%, 2.20 g, 13.7 mmol, quant.).

_{Ή-NMR (200MHz, CDC1 3} ): δ 0.89 / 0.66 (2Η, qd / q, J = 12.8, 4.0 / 12.1 Hz), 1.30-1.65 (7H, in), 1.74-1.91 (3H, m), 3.48 /3.55 (4H, d, J = 6.2 / 6.8 Hz) elemental analysis:. C ₁₂ H _2. 0 ₂ Calculated: C, 73.43; H, 10.27 (%), Found: C, 73.47; H, 10.56 (%).

 To a solution of cyclohexane-1,3-dimethanol (purity 90%, 2.20 g, 13.7 fraction 01) in pyridine (25 ml) was added a solution of p-toluenesulfonyl chloride (2.96 g, 15.1 ranol) in pyridine (5 ml). The mixture was added dropwise at room temperature over 6 hours, and then the reaction solution was stirred for 2 hours. Triethylamine (0.063 ml, 0.455 mol) was added to the reaction solution, and the mixture was further stirred for 2 hours. The crude substance (4.1 g) obtained by extraction with ethyl acetate from the reaction solution was purified by chromatography on silica gel (40 g) (ethyl acetate-hexane, 2: 8-4: 6) to give 3-hydroxymethyl Lecyclohexane-1-methyltosylate (cis / trans mixture, 2.44 g, 8.17 mmol, 59.7%) was obtained as a colorless oil.

_{Ή-NMR (200MHz, CDC1 3} ): (50.85 / 0.64 (2H, brq / q, J = 13.2 / 11.8 Hz), 1.24 (2H, m), 1.39 (1H, m), 1.42 (1H, t, J = 5.8 Hz), 1.62-1.82 (4H, m), 2.45 (3H, s), 3.4 / 3.47 (2H, t, J = 5.8 / 7.2 Hz), 3.83 / 3.93 (2H, d, J = 5.8 /7.0 Hz), 7.34 (2H, d, J = 8.2 Hz), 7.78 (2H, dt, J = 8.0, 1.8 Hz).

 A solution of 3-hydroxymethylcyclohexane-1-methyltosylate (1.37 g, 4.59 mol) and acetic anhydride (5 ml) in pyridine (10 ml) was stirred at room temperature for 13 hours. The reaction solution was concentrated to dryness to obtain a colorless oil of 3-acetoxymethylcyclohexane-1-methyltosylate (cis / trans mixture, 1.52 g, 4.49 mmol, 98%).

_{LH-NMR (300MHz, CDC1 3} ): δ 0.87 / 0.65 (2Η, q, J = 13.2 / 11.4 Hz), 1.27 / 1.41 (2H, t, J = 11.6 / 6.0 Hz), 1.60-1.85 (5H, m ), 1.98 (1H, m), 2.04 (3H, s), 2.45 (3H, s), 3.82 / 3.84 (2H, d / dd, J = 6.3 / 5.6, 0.9 Hz), 3.91 / 3.87 (2H, d , J = 6.6 / 3.6 Hz), 7.34 (2H, d, J = 7.8 Hz), 7.77 (2H, d, J = 8.1 Hz).

A suspension of 3-acetoxymethylcyclohexane-methyltosylate (1.52 g, 4.49 mol) and sodium iodide (2.06 g, 13.8 mmol) in acetone (30 ml) was heated under reflux for 3 hours. The reaction solution was extracted with ethyl acetate-diisopropyl ether, Concentration to dryness yielded 3-odomethylcyclohexane-1-methylacetate (cis / trans mixture, 1.24 g, 4.18 imol, 91.2%) as a colorless oil.

'H-NMR (200MHz, CDC1 3): δ 0.90 / 0.70 (2Η, tq / q, J = 3.2, 12.4 / 12.0 Hz), 1.25-1.58 (4H, m), 1.65-1.80 (2H, m), 1.85 / 1.94 (1H, m), 2.06 (3H, s), 3.11 / 3.18 (2H, d, J = 6.2 / 6.6 Hz), 3.91 / 3.99 (2H, d, J = 6.4 / 7.4 Hz).

Reference Example 29

 3-fluoromethylcyclohexane-1-methyltosylate

 The 3-hydroxymethylcyclohexane-1-methyl tosylate (cis / cis) obtained in Reference Example 28 was stirred at 0 ° C in a solution of Deoxo-Fluor ™ (952 mg, 4.30 tmol) in dichloromethane (7 ml). A solution of the trans mixture, 1.07 g, 3.59 bandol) in dichloromethane (4 ml) was added dropwise over 80 minutes, and the reaction solution was stirred at 0 ° C for 1.5 hours. The reaction solution was poured into ice water (about 50 g), and the oil obtained by extraction with ethyl acetate-diisopropyl ether (1: 1) and getyl ether was chromatographed on silica gel ao g) (ethyl acetate-hexane). 0: 100-10: 90) to give 3-fluoromethylcyclohexane-methyltosylate (cis / trans mixture, 172 mg, 0.573 bandol, 15.9%) as a colorless oil. '

_{Ή-NMR (200MHz, CDC1 3} ): ά 0.90 / 0.70 (2Η, q, J = 13.0 / 12.0 Hz), 1.20-1.45 (3H, m), 1.60-1.85 (5H, m), 2.46 (3H, s ), 3.84 (2H, d, J = 5.8 Hz), 4.20 (2H, dd, J = 47.2, 5.6 Hz), 7.35 (2H, d, J = 8.2 Hz), 7.78 (2H, d, J = 8.0 Hz) ).

Reference Example 30

Acetic acid 5-chloride-3,3-dimethylpentyl

Lithium aluminum hydride (purity 80, 2.41 g, 50.9 t) was added to a solution of 3,3-dimethyldaltaric anhydride (purity 95¾, 6.92 g, 46.2 t) in THF (140 ffll) while stirring at 0 ° C. ) Was added in several portions, and the mixture was stirred (TC for 2 hours, room temperature for 13 hours, and heated to reflux for 4.5 hours. Ethyl acetate (20 ml) was added to the reaction solution, and the mixture was stirred. The mixture was diluted with water, extracted with ethyl acetate-THF (1: 1) and concentrated to dryness to give a yellow oil, which was chromatographed on silica gel (50 g) (ethyl acetate-hexane, 4: 6 and Purification by 5: 5) gave 5-hydroxy-3,3-dimethylpentyl acetate (purity 90, 1.60 g, 8.3 mmol, 18) as a colorless oil. _{Ή-NMR (200MHz, CDC1 3} ): δθ.96 (6H, s), 1.56 (2H, t, J = 7.2 Hz), 1.60 (2H, t, J = 7.4 Hz), 2.04 (3H, s), 3.73 (2H, t, J = 7.5 Hz), 4.13 (2H, t, J = 7.5 Hz).

 A solution of 5-hydroxy-3,3-dimethylpentyl acetate (purity 90¾, 1.60 g, 8.3 i ol) and ρ-toluenesulfonyl chloride (1.79 g, 9.09 marl ol) in pyridine (20 ml) was stirred at room temperature for 19 hours. did. The crude substance obtained by extracting the reaction solution with ethyl acetate-hexane (1: 1) was purified by chromatography on silica gel (20 g) (ethyl acetate-hexane, 1: 9-1: 3) to give 5-acetate. Toxyl-3,3-dimethylpentyl silyl h (1.82 g, 5.54 mmol, 66.8%) was obtained as a colorless oil.

_{Ή-NR (200MHz, CDC1 3} ): 50.91 (6H, s), 1.53 (2H, t, J = 7.3 Hz), 1.63 (2H, t, J = 7.2 Hz), 2.02 (3H, s), 2.46 ( 3H, s), 4.05 (2H, t, J = 7.4 Hz), 4.10 (2H, t, J = 7.3 Hz), 7.35 (2H, d, J = 8.4 Hz), 7.79 (2H, d, J = 8.4) Hz).

 A suspension of 5-acetoxy-3,3-dimethylpentyl tosylate (1.82 g, 5.54 mmol) and sodium iodide (2.49 g, 16.6 mmol) in acetone (40 ml) was heated under reflux for 3 hours. . The reaction solution was extracted with ethyl acetate-hexane (1: 1) to give crude 5-chloride-3,3-dimethylpentyl acetate (purity 90%, 1.50 g, 4.75 mmol, 85.8%) as a yellow oil. I got it.

'H-NMR (300MHz, CDC1 3): 50.93 (6H, s), 1.57 (2H, t, J = 7.2 Hz), 1.94 (2H, m), 2.06 (3H, s), 3.16 (2H, m) , 4.10 (2H, t, J = 7.2 Hz).

Reference Example 31

G (2-Edoetil) 7 Damantan

 A solution of adamantane-acetic acid (10.0 g, 51.0 mmol) and concentrated hydrochloric acid (6.37 ml, 76.4 mmol) in methanol (150 ml) was stirred at room temperature for 2.5 days. The reaction solution was neutralized by adding sodium hydrogen carbonate, and purified by extraction with ethyl acetate to obtain a colorless oil of adamantan-1-methyl acetate (10.8 g, quant.).

_{Ή-NMR (200MHz, CDC1 3} ): (51.61 (6H, d, J = 2.6 Hz), 1.67 (6H, br), 1.97 (3H, br), 2.08 (2H, s), 3.65 (3H, s) .

A solution of lithium aluminum hydride (purity 80%, 1.45 g, 30.6 mmol) in a solution of adamantane-methyl acetate (10.8 g, 51.0 bandol) in THF (200 ml) was stirred at 0 ° C. The powder was added in several portions and stirred with Ot for 90 minutes. Purification by ethyl acetate extraction gave a white powder of adamantane-ethanol (9, 21 g, 51.0 mmol, quant.). Ή-NR (300MHz, CDC "): 51.10 (1H, br), 1.38 (2H, t, J = 7.5 Hz), 1.52 (6H, d, J = 2.4 Hz), 1.63 (3H, brd, J = 13.5) Hz), 1.70 (3H, brd, J = 12.3 Hz), 1.94 (3H, brs), 3.71 (2H, t, J = 7.5 Hz).

Elemental analysis C ₁₂ H ₂₀ 0 Calculated: C, 79.94; H, 11.18 (%), Found: C, 80.00; H, 11.35 (%).

 Triethylamine (3.07 ml, 22.2 mmol) was added to a solution of adamantane-1-ethanol (3.33 g, 18.5 mmol) and methanesulfonyl chloride (2.24 g, 19.4 mmol) in THF (70 ml) for 20 minutes while stirring at 0. And dropped. The reaction solution was stirred at 0 ° C for 2 hours. The reaction solution was purified by extraction with ethyl ethyl diisopropyl acetate (1: 1) to give adamantan-toethyl methanesulfonate (5.30 g, 18.5 mmol, quant.) As a pale yellow oil.

'H-NMR (200MHz, CDC1 3): (51.54 (6H, d, J = 2.6 Hz), 1.56 (2H, t, J = 7.4 Hz), 1.67 (6H, m), 1.97 (3H, m), 3.00 (3H, s), 4.30 (2H, t, J = 7.5 Hz).

 A suspension of adamantane-methaneethyl methanesulfonate (5.30 g, 18.5 mmol) and sodium iodide (5.55 g, 37.0 mmol) in acetone (100 ml) was heated under reflux for 3 hours. The reaction mixture was extracted with ethyl acetate-hexane (2: 3) to give crude 2- (ododoethyl) adamantane (purity 86%, 4.91 g, 14.6 mmol, 79.0) as a yellow solid.

Ή- thigh _{(200MHz, CDC1 3): δ} 1.50 (6Η, d, J = 2.6 Hz), 1.65 (6H, m), 1.79 (2H, m), 1.96 (3H, m), 3.17 (2H, 1) .

Reference Example 32

Adamantane methanesulfonate-1-methyl

To a solution of adamantane methanol (2.72 g, 15.8 mmol) and methanesulfonyl chloride (1.92 g, 16.6 mmol) in THF (50 ml) (while stirring with TC, was added THF of triethylamine (2.63 ml, 19.0 mmol) while stirring with TC. (5 ml) solution was added dropwise over 20 minutes The reaction solution was stirred for 40 minutes at 0 ° C. The reaction solution was purified by extraction with ethyl acetate-hexane (1: 1), and adamantan methanesulfonate 1- Methyl (purity 90¾, 4.27 g, 15.8 mmol, quant.) was obtained as a pale yellow oil.

'H-NMR (200MHz, CDC1 3): <51.57 (6H, d, J- 2.6 Hz), 1.70 (6H, brd, J = 8.4 Hz), 2.02 (3H, m), 2.99 (3H, s), 3.78 (2H, s).

 A suspension of adamantane trimethyl methanesulfonate (purity 90%, 4.27 g, 15.8 mmol) and sodium iodide (7.10 g, 47.4 mmol) in 2-butanone (85 ml) was heated under reflux for 3.5 days. The reaction mixture was extracted with ethyl acetate-hexane (2: 3), purified by silica gel (40 g) chromatography (hexane), and purified with 1-odomethyladamantane (2.20 g, 7.96 bandol, 50.4%) as a white solid.

_{^ - R (200MHz, CDC1 3} ): 51.52 (6H, d, J = 3.0 Hz), 1.62 (6H, brd, J = 2.2 Hz), 1.96 (3H, brs), 3.02 (2H, s).

Reference Example 33-1

 (2S, 4R) -N-Boc-2-hydroxymethyl-4- (2-tetrahydropyraeroxy) pyrrolidine

 A solution of (2S, 4R) -N-Boc-4-hydroxy-L-proline (5.03 g, 21.7 mmol) 'and concentrated hydrochloric acid (0.90 ml, 10.9 benzene) in methanol (100 ml) was stirred at room temperature for 15 hours. . The reaction mixture was neutralized with sodium hydrogen carbonate (0.91 g, 10.9 mmol), purified by extraction with ethyl acetate, and purified with (2S, 4R) -N-Boc-4-hydroxyproline methyl ester (3.45 g, 14.0 g). ol, 64.8%).

_{- NMR (300MHz, CDC1 3)} : 51.42 (6H, s), 1.46 (3H, s), 1.91 (1H, dd, J = 15.6, 3.3 Hz), 2.09 (1H, m), 2.31 (1H, brdd, J = 13.5, 8.1 Hz), 3.57 (1H, brd, J =

12.0 Hz), 3.64 (1H, dd, J = 11.4, 4.2 Hz), 3.74 (3H, s), 4.41 (1H, dt, J = 16.2,

8.4 Hz), 4.50 (1H, brs).

 A solution of (2S, 4R) -N-Boc-4-hydroxy-L-proline methyl ester (3.15 g, 12.8 mmol) and DHP (1.80 ml, 19.3 t) in dichloromethane (60 ml) was treated with CSA (298 mg, 1.28 mmol) at room temperature for 18 hours. .Purified by ethyl acetate extraction

(2S, 4R) -N-Boc-4-tetrahydrobilanyloxy-L-proline methyl ester

(5.00 g) of a light brown crude oil was obtained as an anomeric mixture.

_{Ή-NMR (200MHz, CDC1 3} ): δΙΛΙ (, s), 1.46 (3H, s), 1.5-1.6 (4H, m), 1.75 (2H, m), 2.08 (1H, m), 2.37 (1H, m), 3.45-3.60 (3H, m), 3.73 (3H, s), 3.84 (1H, m), 4.40 (2H, m), 4.65 / 4.96 (1H, m).

 A solution of the crude oil (5.00 g) of (2S, 4R) -N-Boc-4-tetrahydropyranyloxy-L-proline methyl ester obtained above in THF (80 ml) was stirred at room temperature at room temperature with borohydride. Add sodium (purity 90%, 538 mg, 12.8 bandages 01) powder and then 60. C., and methanol (2 ml) in THF (8 ml) was added dropwise over 70 minutes. Purification by ethyl acetate extraction gave a yellow oil (4.5 g). This was purified by silica gel (35 g) chromatography (ethyl acetate-hexane, 2: 8-4: 6) to give (2S, 4R) _N-Boc-2-hydroxymethyl-4- (2-tetrahydropyrane A colorless oil of (Roxy) pyrrolidine (3.58 g, 11.9 mmol, 92.8%) was obtained.

_{-NMR (200MHz, CDC1 3):} δΐ.47 (9Η, s), 1.54 (4H, m), 1.6-1.8 (3H, m), 2.13 (1H, m), 3.40-3.60 (3H, m), 3.69 (1H, m), 3.84 (1H, m), 4.10 (1H, m), 4.28 (1H, m), 4.66 (1H, i), .91 (1H, brdd, J = 16.6, 8.1 Hz).

Reference Example 33-2

(2S, 4R) -N-Boc_4-hydroxypyrrolidine-2-methyl iodide

 (2S, 4R) -N-Boc_2-hydroxymethyl-4- (2-tetrahydropyranyloxy) pyrrolidine (1.11 g, 15.4 mmol) and methanesulfonyl chloride (0.473 g, 4.04 mmol) in THF (15 ml) While stirring at 0 ° C, a solution of triethylamine (0.663 ml, 4.78 mmol) in THF (5 ml) was added dropwise over 30 minutes. The reaction was stirred at 0 ° C for 20 minutes. The crude substance obtained by ethyl acetate extraction was purified by silica gel (20 g) chromatography (ethyl acetate-hexane, 2: 8-3: 7), and (2S, 4R) -N-Boc-4- (2 A colorless oil of -tetrahydrobilanyloxy) pyrrolidine-2-methyl mesylate (1.35 g, 3.55 mmol, 96.9%) was obtained.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.46 (9Η, s), 1.54 (4H, i), 1.69 (1H, m), 1.77 (1H, m), 2.11 (1H, m), 2.17 (1H, ni), 3.00 (3H, s), 3.51 (2H, m), 3.85 (1H, m), 4.16 (1H, m), 4.20-4.45 (3H, m), 4.55 (1H, m), 4.61 (1H , m).

A solution of (2S, 4R) -N-Boc-4-hydroxy-L-proline methyl ester (1.78 g, 7.26261) in THF (80 ml) was stirred at room temperature while stirring with sodium borohydride (purity 90%, 305 mg, 7.26 bandol) were added, and the mixture was heated to 60 ° C., and a solution of methanol (2 ml) in THF (5 ml) was added dropwise over 90 minutes. Purified by ethyl acetate extraction, A colorless oil of (2S, 4R) -N_Boc-4-hydroxy-2-hydroxymethylpyrrolidine (1.61 g, quant.) Was obtained.

'H-NMR (200MHz, CDC1 3): 51.48 (9H, s), 1.86 (1H, brs), 2.05 (1H, in), 3.44 (1H, dd, J = 12.0, 4.0 Hz), 3.52 (1H, m), 3.59 (1H, dd, J = 7.0, 2.8 Hz), 3.72 (1H, brt, J = 8.4 Hz), 4.14 (1H, m), 4.38 (1H, brs), 5.04 (1H, m).

 A solution of (2S, 4R) -N_Boc-4-hydroxy-2-hydroxymethylpyrrolidine (1.61 g, 7.26 t) and p-toluenesulfonyl chloride (1.50 g, 7.62 t) in pyridine (16 ml) was added at room temperature to 9 ml. Stirred for hours. The crude material obtained by ethyl acetate extraction was purified by silica gel (25 g) chromatography (ethyl acetate-hexane, 2: 8-4: 6) to give (2S, 4R) -N_Boc-4- 4-hydroxypyrrolidine-2- A colorless oil of methyl tosylate (1.10 g, 2.96 mmol, '40 .8%) was obtained.

JH-N R (200MHz, CDC1 3): (51.38 (9H, s), 2.06 (2H, m), 2.44 (3H, s), 3.40 (1H, m), 3.44 (1H, m), 4.06 (1H , m), 4.11 (2H, brs), 4.45 (1H,), 7.34 (2H, d, J = 7.8 Hz), 7.76 (2H, d, J = 8.4 Hz).

 A suspension of (2S, 4R) -N_Boc-4-hydroxypyrrolidine-2-methyltosylate (1.10 g, 2.96 mmol) and sodium iodide (1.33 g, 8.88 mmol) in acetone (25 ml) was heated at reflux for 9 hours. did. The reaction solution was purified by extraction with ethyl acetate-hexane (1: 1) and purified by (2S, 4R) -N-Boc-4-hydroxypyrrolidine-2-methyl iodide (406 mg, 1.24 mmol, 41.9% ) Was obtained as a colorless oil.

 Reference example 34

 trans-2-odemethylcyclohexane-1-methylacetate

 A solution of trans-cyclohexane-1,2-dicarboxylic acid (10.1, 55.9 t) and concentrated hydrochloric acid (7.00 ml, 83.9 t) in methanol (150 ml) was stirred at room temperature for 1.5 days. The reaction mixture was neutralized with sodium hydrogen carbonate, and purified by extraction with ethyl acetate to obtain a colorless oily substance of dimethyl trans-cyclohexane-1,2-dicarboxylate (11.0 g, 54.8 mol, 98.2%). Was.

'H-NMR (200MHz, CDC1 3): 51.32 (4H, m), 1.78 (2H, m), 2.06 (2H, brd, J = 10 Hz), 2.62 (2H, m), 3.67 (6H, s) 'Dimethyl trans-cyclohexane-1,2-dicarbonate (11.0 g, 54.8 mmol) in THF (200 ml) A solution of lithium aluminum hydride (purity 80%, 2.86 g, 60.4 thigh 01) was added in several portions to the solution while stirring at 0, and the mixture was stirred at 0 ° C for 100 minutes. After extraction with ethyl acetate and concentration, diisopropyl ether and hexane were added to the residue. The precipitate was collected by filtration, washed with hexane, and dried to obtain a colorless oil of trans-cyclohexane-1,2-dimethanol (5.77 g, 40.0 mmol, 71.6 »).

_{Ή-NMR (300MHz, CDC1 3} ): 51.07 (2H, brt, J = 10.8 Hz), 1.25 (2H, m), 1.33 (2H, m), 1.63 (2H, brd, J = 13.2 Hz), 1.74 ( 2H, m), 3.56 (2H, dd, J = 11.0, 5.8 Hz), 3.63 (2H, dd, J = 10.8, 3.0 Hz).

 To a solution of trans-cyclohexane-1,2-dimethanol (2.00 g, 13.9 mmol) in THF (65 ml) was added sodium hydride (purity 60% oily, 0.556 g, 13.9 tmol) at room temperature, and the mixture was added for 60 minutes. Stirred. The resulting suspension was added dropwise to a solution of p-toluenesulfonyl chloride (2.73 g, 13.9 carbonyl) in THF (20 ml) over 30 minutes at room temperature, and the reaction solution was stirred for 1 hour. The crude oil obtained by extraction from the reaction mixture with ethyl acetate was purified by chromatography on silica gel (40 g) (ethyl acetate-hexane, 2: 8-4: 6) to give trans-2-hydroxymethylcyclohexane- Trimethyl tosylate (2.21 g, 7.41 mmol, 53.3%) was obtained as a colorless oil.

_{-NMR (300MHz, CDC1 3):} 61.18 (4H, m), 1.28 (2H, m), 1.59 (1H, m), 1.71 (4H, m), 1.74 (2H, m), 2.45 (3H, s) , 3.51 (1H, dd, J = 11.1, 4.2 Hz), 3.54 (1H, dd, J = 10.8, 4.5 Hz), 4.05 (2H, d, J = 5.1 Hz), 7.34 (2H, d, J = 8.1 Hz), 7.78 (2H, d, J = 8.1 Hz).

 A solution of trans-2-hydroxymethylcyclohexane-1-methyltosylate (2.21 g, 7.41 mmol) and acetic anhydride (6 ml) in pyridine (12 ml) was stirred at room temperature for 11 hours. The reaction solution was concentrated to dryness to give trans-2-acetoxymethylcyclohexane-methyltosylate (2.54 g, 7.4 mmol, quant.) As a colorless oil.

_{Ή-NR (200MHz, CDC1 3} ): δΐ.18 (4Η, brd, J = 6.2 Hz), 1.54 (2H, m), 1.70 (4H, m), 2.02 (3H, s), 2.45 (3H, s ), 3.91 (2H, d, J-4 Hz), 4.00 (2H, d, J = 4.2 Hz), 7.35 (2H, d, J = 8.0 Hz), 7.78 (2H, d, J = 8.4 Hz).

trans-2-Acetoxymethylcyclohexane-1-methyltosylate (2.54 g, 7.4 t ol) and sodium iodide (3.33 g, 22.2 t ol) suspended in 2-butane nonone (55 ml) The liquid was heated at reflux for 2.5 hours. The reaction mixture was extracted with ethyl acetate-hexane (1: 4), concentrated to dryness, and trans-2-iodomethylcyclohexane-1-methyl acetate (1.98 g, 6.68 mmol, 90.1) was obtained as a colorless oil. Obtained as a product.

'H-NMR (200MHz, CDC1 3): (51.02 (IH, i), 1.27 (4H, brt, J = 7.6 Hz), 1.53 (1H, m), 1.73 (4H, i), 2.07 (3H, s ), 2.45 (3H, s), 3.30 (IH, dd, J = 10.2, 5.4 Hz), 3.34 (IH, dd, J = 9.8, 3.0 Hz), 3.99 (IH, dd, J = 11.4, 4.0 Hz) , 4.06 (IH, dd, J = 11.2, 5.2 Hz).

Reference Example 35

 (2S)-N-Boc-4-Ed _L-proline methyl ester

 (2S, 4R) -N-Boc-4-hydroxy_L-proline methyl ester (3.45 g, 14.0 mmol) and methanesulfonyl chloride (1.70 g, 14.7 mmol) in THF ^ (? !!!!!) A solution of triethylamine (2.33 ml, 16.8 eol) in THF (10 ml) was added dropwise over 30 minutes, and the reaction mixture was stirred for 80 minutes with TC. To give a white powder of (2S, 4R) -N-Boc-4-mesyloxy-L-proline methyl ester (4.05 g, 12.5 t, 89.5%).

_{Ή-NMR (200MHz, CDC1 3} ): 51.43 (6H, s), 1.47 (3H, s), 2.26 (IH, ddd, J = 14.4, 8.2, 4.8 Hz), 2.62 (IH, m), 3.06 (3H , s), 3.75 (3H, s), 3.79 (2H, i), 4.43 (m, dt, J = 12.8, 8.1 Hz), 5.26 (IH, m).

 2-butanone (30 ml) of (2S, 4R) -N-BQC-4_mesyloxy-L-proline methyl ester (purity 80%, 1.45 g, 3.77 marl) and sodium iodide (1.70 g, 11.3 mmol) The suspension was heated at reflux for 38 hours. The reaction solution was purified by extraction with ethyl acetate, and a light brown oily substance of (2S) -N-Boc-4-ode-L-proline methyl ester (purity 80%, 1.29 g, 2.90 mmol, 11%) was obtained. Was.

E - Ran _{R (200MHz, CDC1 3):} 51.43 (6H, s), 1.47 (3H, s), 2.40 (1H, m), 2.57 / 2.85 (IH, m), 3.74 / 3.76 (3H, s), 3.75 (IH, m), 3.98 / 4.08 (IH, m), 4.40 (2H, brquint, J = 5.6 Hz).

Reference Example 36

 4-Eodomethylcyclohexane-1-methanol

cis-cyclohexane-1,4-dicarbonic acid (purity 90%, 9.80 g, 51.2 t ol, 8% A mixture of trans-isomer) and concentrated hydrochloric acid (6.77 ml, 81.3 mol) in methanol (150 ml) was stirred at room temperature for 1.5 days. The reaction mixture was neutralized with sodium bicarbonate, and purified by extraction with ethyl acetate-hexane (1: 1) .Dimethyl cis-cyclohexane-1,4-dichloromethane (purity 91%, 11.2 g) , quant., a mixture with 8¾ trans-isomer).

_{'Η- NMR (200MHz, CDC1 3} ): δΐ.67 (4Η, m), 1.89 (4H, m), 2.47 (2H, i), 3.68 (6H, s)..

 Lithium aluminum hydride (purity 80¾, 2.12 g) was added to a solution of dimethyl cis-cyclohexane-1,4-dicarbonate (8.19 g, 37.2 mmol) obtained above in THF (160 ml) while stirring at 0 ° C. , 44.7 mmol) was added in several portions, and the mixture was stirred at 0 ° C for 80 minutes. Extract with ethyl acetate-THF (4: 1), dry and concentrate to dryness to obtain cis-cyclohexane-1,4-dimethanol (purity 87%, 6.18 g, quant., 8% trans-isomer A colorless oil was obtained.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.35-1.60 (10Η, m), 1.70 (2H, m), 1.96 (2H, m), 3.55 (4H, d, J = 6.6 Hz).

 The cis-cyclohexane-1,4-dimethanol obtained above (purity 87%, 2.1 g, 12.9 mmol, mixture with 8% trans-isomer) and p-toluenesulfonyl chloride (2.79 g, 14.2 ol) in pyridine (30 ml) was stirred at room temperature for 15 hours. The crude oil obtained by extraction from the reaction mixture with ethyl acetate was purified by chromatography on silica gel (30 g) (ethyl acetate-hexane, 2: 8-4: 6) to give 4-hydroxymethylcyclohexane-1. -Methyl tosylate (2.40 g, 8.04 olol, 57.4 ¾, cis / trans: 92: 8 mixture) was obtained as a colorless oil.

_{Ή-NM (300MHz, CDC1 3} ): 51.20 (1H, brt, J = 5 Hz), 1.23-1.43 (5H, m), 1.50 (3H, m), 1.66 (1H, m), 1.89 (1H, m ), 2.45 (3H, s), 3.49 (2H, dd, J = 6.3, 5.1 Hz), 3.92 (2H, d, J = 6.9 Hz), 7.34 (2H, d, -J = 7.8 Hz), 7.78 ( 2H, d, J = 8.4 Hz).

4-Hydroxymethylcyclohexane-1-methyltosylate (2.40 g, 8.04 mmol, cis / trans = 92: 8 mixture) obtained above and sodium iodide (3.62 g, 24.1 mmol) in acetone (50 ml) Stir the suspension at room temperature for 15 hours, then heat for 3 hours Shed. The reaction mixture was extracted with ethyl acetate and concentrated to dryness to give 4-hydroxymethylcyclohexane-1-methanol (1.83 g, 7.20 mmol, 89.6¾, cis / trans = 92: 8 mixture) as a pale brown oil. Was.

Reference Example 37

4-Fluoro-4-methylpentyl mesylate

 Triethylamine (27.2) was added to a solution of 3_methyl-1,3_butanediol (20.66 g, purity 90%, 0.179 mol) and methanesulfonyl chloride (14.7 ml, 0.187 mol) in THF (300 ml) with stirring at 0 ° C. ml, 0.196 mol) was added dropwise over 80 minutes, and the reaction solution was stirred at 0 ° C for 1.5 hours. The reaction mixture was extracted with getyl ether-hexane (1: 1), washed with water, dried and concentrated to dryness to give 3-methyl-3-hydroxybutyl mesylate (purity 80.5%, 39.3 g, 0.174 mol). Obtained as a yellow oil.

'H-NMR (300MHz, CDC1 3): 51.30 (6H, s), 1.43 (1H, brs), 1.96 (2H, t, J = 6.9 Hz), 3.03 (3H, s), 4.43 (2H, t, J = 6.9 Hz).

 N, N-dimethylsulfoxide of 3-methyl-3-hydroxybutyl mesylate (80.5% purity, 39.3 g, 0.174 mol) and sodium cyanide (13.6 g, 0.269 mol)

(100 ml) The suspension was stirred at 50 for 27 hours. Extraction and purification with ethyl acetate gave 4-methyl-4-hydroxypareronitrile (0.174 mol, containing ethyl acetate, 44 g) as a yellow oil. '

'H-NMR (200MHz, CDC1 3): 51.28 (6H, s), 1.85 (2H, t, J = 7.9 Hz), 2.48 (2H, t, J = 6.9 Hz).

A solution of 4-methyl-4-hydroxyvaleronitrile (0.174 mol, containing ethyl acetate, 44 g) in acetic acid (200 ml) and concentrated hydrochloric acid (100 ml) was heated under reflux for 21 hours. The reaction solution was extracted and purified with ethyl acetate to obtain 4,4-dimethylbutyrolactone (purity: 72, 23 g, 0.146 mol) as a colorless oil. - Ή-NMR (200MHz, CDC1 3): (51.44 (6H, s), 2.06 (2H, t, J- 8.3 Hz), 2.63 (2H, t, J = 8.1 Hz).

4,4-Dimethylbutyrolactone (containing toluene, 9.0 g, 52 bandages) was dissolved in THF (120 ml), and lithium aluminum hydride (purity: 80, 3.04 g, 64 tonol) was added while stirring at 0 ° C. The mixture was added in portions and stirred at 0 ° C for 2 hours. Ethyl acetate -THF ' Extraction and purification yielded crude 4-methyl-1,4-pentanol (purity 80%, 5.00 g, 34 t ol) as a yellow oil.

 While stirring at 0 ° C, a solution of 4-methyl-1,4-pentanol (purity 80%, 5.00 g, 34 mmol) and methanesulfonyl chloride (3.31 il, 42.3 bandol) in THF (100 ml) was stirred. A solution of triethylamine (6.57 il, 47.4ΜΙΟ1) in THF (10 ml) was added dropwise over 20 minutes, and the reaction solution was stirred with for 1 hour. The reaction solution was extracted with ethyl acetate, washed with water, dried and concentrated to dryness to obtain crude 4-methyl-4-hydroxypentyl mesylate (8.2 g, about 40 mmol) as a brown oil.

 A solution of 4-methyl-4-hydroxypentyl mesylate (8.2 g, about 40 mmol) in dichloromethane (5 ml) was stirred with _78 at _78 while DAST (7.16 g, 40 marl) in dichloromethane (4 ml). ) The solution was added dropwise over 50 minutes, the temperature was raised to 0 ° C, and the reaction solution was stirred at room temperature for 10 minutes. The reaction solution was extracted with ethyl acetate, washed with water, dried and concentrated to dryness to obtain a crude oil. This was purified by silica gel (50 g) chromatography (ethyl acetate 1-hexane, 1: 4-1: 3), and 4-fluoro-4-methylpentyl mesylate (3.97 g, 20.0 t) was pale yellow. Obtained as an oil.

_{Ή-NMR (200MHz, CDC1 3} ): 01.34 (3H, s), 1.41 (3H, s), 1.73 (2H, m), 1.89 (2H, m), 3.02 (3H, s), 4.27 (2H, t , J = 6.3 Hz).

Reference example 38.

trans-4-methoxymethylcyclohexane methanol

 A solution of trans-cyclohexane-1,4-dicarponic acid (purity 97%, 9.62 g, 54.2 Cafe 01) and concentrated hydrochloric acid (6.77 ml, 81.3 thigh 01) in methanol (150 ml) was stirred at room temperature for 1.5 days. The reaction solution was neutralized by adding sodium hydrogen carbonate, and purified by extraction with ethyl acetate to obtain a white solid of dimethyl trans-cyclohexane-1,4-dicarbonate (purity 99%, 10.9 g, quant.). Was.

_{Ή-NMR (200MHz, CDC1 3} ): (51.45 (4H, dd, J = 11.4, 9.2 Hz), 2.05 (4H, brd, J = 7.0 Hz), 2.29 (2H, brt, J = 7 Hz), 3.67 (6H, s).

A solution of lithium aluminum hydride (purity 80%, 2.00 g, 42.2 mmol) was added to a solution of trans-cyclohexane-dimethyl 1,4-dicarboxylate (7.76 g, 38.3 mol) in THF (150 ml) while stirring at 0. The powder was added in several portions and stirred at 0 ° C for 80 minutes. Ethyl acetate -Extracted with THF (5: 1), dried and concentrated to dryness to obtain a white solid substance of trans-cyclohexane-1,4-dimethylethanol (5.48 g, 38.0 marl, 99.2%).

_{Ή- NMR (300MHz, CDC1 3)} : δ 0.98 (4Η, dd, J = 11.4, 9.2 Hz), 1.33 (2H, brs), 1.47 (2H, m), 1.85 (4H, brd, J = 6.8 Hz) , 3.47 (4H, d, J = 6.2 Hz).

 A solution of trans-cyclohexane-1,4-dimethanol (2.47 g, 17.1 mmol) and p-toluenesulfonyl chloride (3.70 g, 18.8 bandol) in pyridine (30 ml) was stirred at room temperature for 7.5 hours. The crude oil obtained by extraction with ethyl acetate from the reaction solution was purified by chromatography on silica gel (20 g) (ethyl acetate-hexane, 2: 8-4: 6) to give trans-4-hydroxymethylcyclohexane- 1-Methyl tosylate (3.00 g, 10.0 t, 58.5 5) was obtained as a colorless oil.

_{Ή-NMR (200MHz, CDC1 3} ): 50.94 (4H, dd, J = 11.2, 8.8 Hz), 1.42 (1H, m), 1.60 (1H, m), 1.79 (4H, m), 2.46 (3H, s ), 3.44 (2H, brt, J = 5.7 Hz), 3.83 (2H, d, J = 6.2 Hz), 7.33 (2H, d, J- 8.0 Hz), 7.79 (2H, d, J = 8.4 Hz),

 A suspension of trans-4-hydroxymethylcyclohexane-1-methyltosylate (1.21 g, 4.05 olol) and sodium iodide (1.82 g, 12.2 ol) in acetone (25 ml) was heated to reflux for 5 hours. . The reaction solution was extracted with ethyl acetate and concentrated to dryness to obtain trans-4-hydromethylcyclohexane-1-methanol (0.92 g, 3.62 mmol, 89.4%) as a pale yellow oil.

'H-NMR (200MHz, CDC1 3): δ 1.00 (4Η, dd, J = 11.2, 8.8 Hz), 1.28 (1H, br), 1.84 (2H, m), 1.95 (2H, m), 3.11 (2H , d, J = 6.6 Hz), 3.47 (2H, m).

Reference example 39

5-hydroxy-4,4-dimethylpentyl p-toluate

 A solution of 2,2-dimethyldartaric acid (98¾, 10.2 g, 62.3 bandol) and concentrated hydrochloric acid (7.79 ml, 93.5 mmol) in methanol (150 ml) was stirred at room temperature for 1.5 days. The reaction solution was neutralized with sodium hydrogen carbonate, and purified by extraction with ethyl acetate-hexane (2: 1). The colorless solution of dimethyl 2,2-dimethyldaltarate (9.00 g, 47.8 marl ol, 76.7%) was obtained. An oil was obtained.

_{Ή-NMR (300MHz, CDC1 3} ): 51.19 (6H, s), 1.88 (2H, m), 2.28 (2H, m), 3.66 (6H, s). A powder of lithium aluminum hydride (purity 80, 2.49 g, 52.6 bandages 01) was added to a 11 ^ (180 ml) solution of dimethyl 2,2-dimethyldaltarate (9.00 g, 47.8111101) while stirring at 0 ° C. The mixture was added in portions and stirred at 0 ° C for 2 hours. Extracted with ethyl acetate-THF (3: 1), dehydrated, dried and concentrated to dryness to give a colorless oil of 2,2-dimethylpentane-1,5-diol (purity 90%, 6.99 g, quant.). Was.

_{¾-NMR (200MHz, CDC1 3} ): δθ.89 (6Η, s), 1.33 (2H, m), 1.42 (2H, m), 3.34 (2H, s), 3.65 (2H, t, J = 6.4 Hz ).

 A solution of 2,2-dimethylpentane-1,5-diol (purity 90%, 625 g, 4.25 r. Ol) and chlorinated P-toluoyl (724 mg, 4.68 c. Ol) in pyridine (7 ml) for 3 hours at room temperature Stirred. The reaction solution was concentrated to dryness, dissolved in ethyl acetate, washed with water, dehydrated and dried, and concentrated to obtain a crude oil. This was purified by chromatography on silica gel (10 g) (ethyl acetate-hexane, 1: 9-2: 8) to give 5-hydroxy-4,4-dimethylpentyl p-toluate (490 mg, ί.96 Ol, 46.1) as a colorless oil.

_{¾- NMR (200MHz, CDC1 3)} : 50.91 (6H, s), 1.39 (2H, m), 1.73 (2H, m), 2.41 (3H, s), 3.36 (2H, s), 4.29 (2H, t , J = 6.8 Hz), 7.24 (2H, d, J = 8.0 Hz), 7.93 (2H, d, J = 8.0 Hz).

Reference example 40

 1-Methylcyclohexan-1-methanol

 A methanol (50 ml) solution of trimethylcyclohexanecarponic acid (purity 98¾, 3.05 g, 21.2 bandol) and concentrated hydrochloric acid (2.65 ml, 31.9 bandol) was stirred at room temperature for 2.5 days. The reaction mixture was neutralized with sodium hydrogen carbonate and purified by extraction with diisopropyl ether to obtain a colorless oily substance of methyl 1-methylcyclohexanecarboxylate (purity: 81.4¾, 3.00 g, 15.6 mmol, 73.8¾). Was.

_{Ή-NMR (200MHz, CDC1 3} ): 61.15 (3H, s), 1.20-1.40 (5H, m), 1.54 (3H, m), 2.01 (2H, brdd, J = 8.4, 6.2 Hz), 3.68 (3H , s).

Powder of lithium aluminum hydride (purity 80, 503 nig, 10.6 painting 01) in THF (60 ml) solution of methyl trimethylcyclohexanecarbonate (purity 81. «, 3.00 g, 15.6 mmol) at 0 ° C with stirring Was added in several portions, and the mixture was stirred at 0 ° C for 2 hours. Extract with ethyl acetate, concentrate to dryness and dry 1-methylcyclohexane-1-methanol (purity 91.8%, 1.95 g, 14.0 mmol, 89.7%).

'H-NMR (200MHz, CDC1 3): (50.91 (3H, s), 1.28 (6H, m), 1.37 (1H, br), 1.40-1.55 (4H, m), 3.35 (2H, brs).

Reference Example 41

5-fluoro-2,2-dimethylpentanoyl

 A solution of 2,2-dimethylpentane-1,5-diol (purity 90%, 5.82 g, 39.6 mmol) and 3,4-dihydro-2H-pyran (4.10 ml, 43.6 mol) in dichloromethane (100 ml) was treated with CSA. (920 mg, 3.96 mmol) and stirred at room temperature for 3.5 hours. The oil obtained by extraction with ethyl acetate-hexane (2: 1) was chromatographed on silica gel (90 g) (ethyl acetate-hexane, 15:85 and 3: 7) to give ethyl acetate-hexane. The fraction of xanthane (3: 7) is concentrated to dryness to give 4,4 dimethyl-5- (2-tetrahydropyranyloxy) pentanol and 2,2-dimethyl-5- (2-tetrahydropyranyloxy) A 1: 1 mixture of pennitol (3.00 g, 13.9 mmol) was obtained as a colorless oil.

'H-NMR (300MHz, CDC1 3): δ 0.88 / 0.89 (3Η, s), 0.91 / 0.91 (3H, s), 1.30 (2H, m), 1.50-1.62 (7H, m), 1.70 (1H, m), 1.82 (1H, m), 3.01 (1 / 2H, d, J = 9.0 Hz), 3.33 (2 / 2H, brd, J = 3.2 Hz), 3.38 (1 / 2H, dt, J = 9.6, 6.6 Hz), 3.50 (1H, m), 3.62 (2 / 2H, brd, J = 6.6 Hz), 3.73 (1 / 2H, dt, J = 9.6, 6.9 Hz), 3.85 (1H, m), 4.57 / 4.54 (1H, m).

 A solution of the above-obtained oil (3.00 g, 13.9 mmol) and p-toluenesulfonyl chloride (1.18 g, 5.96 mmol) in pyridine (30 ml) was stirred at room temperature for 3 hours. The crude oil obtained by extracting the reaction mixture with ethyl acetate-hexane (1: 1) was purified by chromatography on silica gel (40 g) (ethyl acetate-hexane, 10: 90-15: 85). There was obtained 4,4-dimethyl-5- (2-tetrahydrovinyliloxy) pentyl tosylate (purity 75%, 1.04 g, 2.11 mmol) as a colorless oil.

'H-NMR (200MHz, CDC1 3): (50.84 (3H, s), 0.86 (3H, s), 1.26 (2H, m), 1.45-1.65 (6H, m), 1.80 (2H, m), 2.45 (3H, s), 2.94 (1H, d, J = 9.2 Hz), 3.42 (1H, d, J = 9.6 Hz), 3.51 (1H, m), 3.80 (1H, m), 4.00 (2H, t, J = 6.6 Hz), 4.51 (1H, brs), 7.35 (2H, d, J = 8.0 Hz), 7.79 (2H, d, J = 8.4 Hz).

4,4-Dimethyl-5- (2-tetrahydrobiranyloxy) pentyl tosyl obtained above A solution of acetate (purity 75%, 1.04 g, 2.11 mmol), tetrabutylammonium fluoride (2.28 g, 7.03 01) and water (0.190 ml, 10.5 mmol) in acetonitrile (10 ml) was stirred at 80 for 4 hours at 80 Stirred. After the reaction solution was concentrated, it was extracted with ethyl acetate (50 ml). The organic layer was washed with water, 0.1N hydrochloric acid, water and saturated saline, dried over sodium sulfate, and concentrated to dryness to obtain a crude oil. This was subjected to silica gel (10 g) chromatography (ethyl acetate-hexane, 0: 10-2: 8), and the ethyl acetate-hexane (1:19) fraction was concentrated to dryness to give 5- Fluoro-2,2-dimethylpentyl 2-tetrahydropyranyl ether (389 mg, 1.78 mmol) was obtained as a colorless oil. '

] H-NMR (200MHz, CDC1 3): 60.91 (3Η, s), 0.92 (3H, s), 1.36 (2H, m), 1.50-1.65 (4H, m), 1.60 (1H, m), 1.70 ( 1H, m), 1.70-1.85 (2H, m), 3.00 (1H, d, J = 9.6 Hz), 3.48 (1H, d, J = 9.62 Hz), 3.51 (1H, m), 3.84 (1H, m ), 4.42 (2H, dt, J = 47.6, 6.2 Hz), 4.56 (1H, i).

 A solution of 5-fluoro-2,2-dimethylpentyl 2-tetrahydropyranyl ether (1.10 g, 5.04 mmol) and CSA (117 mg, 0.504 mol) in methanol (10 ml) was stirred at room temperature for 5 hours. The reaction mixture was concentrated, extracted with ethyl acetate and purified to obtain a 1: 1 mixture (1.40 g) of 5-fluoro-2,2-dimethylpentanol and ethyl acetate as a colorless oil.

_{Ή-NMR (200MHz, CDC1 3} ): 50.90 (6H, s), 1.35 (2H, m), 1.73 (2H, m), 3.35 (2H, brd, J = 4.8 Hz), 4.44 (2H, brdt, J = 47.2, 6.2 Hz).

Reference Example 42

 2-bromo-5,5-dimethylcyclohexane-1,3-dione

 5,5-Dimethylcyclohexane-1,3-dione (5.00 g, 35.3 mmol) was dissolved in 47% hydrobromic acid (5.34 ml) and water (25.0 ml), and potassium bromate (2.0, 12.0 mmol) was dissolved. ) In warm water (25.0 ml). The resulting precipitate was collected by filtration, washed with water, and dried to synthesize the title compound (8.46 g, ca. 100¾). Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 175-177 ° C.

IR (KBr) V: 3700-2700, 2959, 2872, 2614, 1719, 1645, 1590 cm " ¹ .

E - Awakening: _{(CDC1 3: 01.12 (6H,} s), 2.48 (4H, s), 6.58 (1H, bs).

Elemental analysis: CAABr ^ I ^ O Calculated value (¾): C, 42.80; H, 5.20.

Found (¾): C, 42.72; H, 4.84.

Reference Example 43

 2-Promo-4,4-dimethylcyclohexan-ί, 3-dione

 By the same method as in Reference Example 42, the title compound (7.53 g, 96%) was synthesized from 4,4-dimethylcyclohexane-1,3-dione (5.00 g, 35.7 recited 01). Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 147-U9 ° C.

IR (KBr) V 3700-2200, 2967, 2932, 2872, 1574 cm " ¹ .

_{Ή- NMR (CDC1 3): δ} 1.18 (6ΗΧ0.62, s), 1.32 (3HX0.38, s), 1.86 (2H, t, J = 6.6 Hz), 2.63 (2HX0.38, t, J = 6.2 Hz), 2.68 (2HX0.62, t, J = 6.2 Hz), 6.42 (1H

X0.38, bs), 6.53 (1HX0.62, bs).

Elemental analysis: as CsHuO ^ r

Calculated value (%): C, 43.86; H, 5.06.

Found (%): C, 43.68; H, 5.01.

Reference example 44

 2-bromo-5-methylcyclohexane-1,3-dione

 In the same manner as in Reference Example 42, 5-methylcyclohexane-1,3-dione (5.

The title compound (7.45 g, 94¾) was synthesized from 38.8 bandits01). Recrystallization from ethyl acetate-ethyl ether yielded dark red crystals with a melting point of 173-175 ° C.

IR (KBr): 3700-2300, 2963, 2936, 2878, 2614, 1636, 1599 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ \ Λ2 (3Η, d, zo = 6.0 Hz), 2.16-2.44 (3H , m), 2.58-2.80 (2H, m), 6.55 (1H, bs).

Elementary analysis: as C ₇ H ₉ 0 ₂ Br

Calculated value (%): C, 41.00; H, 4.42.

Found (¾): C, 41.31; H, 4.41.

Reference example 45

 3-pyridinesulfonyl chloride

Method A

^^ Dimethylformamide (10.0g, l.OOg, 6.09 thigh 01) To this suspension, thionyl chloride (0.925 ml, 12.2 mmol) was slowly added dropwise under ice-cooling. The reaction mixture was stirred at room temperature for 50 minutes and then at 80 ° C for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated saline, and then dried over sodium sulfate. The solvent was removed under reduced pressure to a total volume of 2.00 ml, and used as it was in the next reaction.

Method B

 A mixture of 3-pyridinesulfonic acid (l.OOg, 6.09 mmol) and phosphorus pentachloride (2.64 g, 12.2 g 01) was stirred at 140 ° C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated, the residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound as an oil. Used directly in the reaction.

IR (KBr) V: 3652, 3434, 3065, 1742, 1719, 1567, 1468 cm " ¹ .

_{Ή-NMR (CDC1 3):} 57.62 (1H, ddd, J = 8.0, 4.8, 0.8 Hz), 8.34 (1H, ddd, J = 8.0,

2.2, 1.4 Hz), 8.98 (1H, dd, J = 5.2, 1.4 Hz), 9.27 (1H, d, 1 = 2.2 Hz).

Reference Example 46

p-toluenesulfinic acid

 Concentrated hydrochloric acid (6.80 ml) was slowly added to a solution of p-toluenesulfinic acid sodium salt (5.00 g, 27.2 band01) in warm water (40.0 ml). After cooling the reaction mixture under ice cooling, it was left in a refrigerator for 3.5 hours. The resulting precipitate was collected by filtration and washed with ice water to give the title compound (3.12 g, 73%) as colorless crystals.

74.0-75.0X

Elemental analysis: as C ₇ H ₈ 0 ₂ S

Calculated value (%): C, 53.82; H, 5.16; S, 20.53.

Found (¾): C, 53.64; H, 5.10; S, 20.68.

Reference Example 47

 P-toluenesulfinyl chloride

To a solution of P-toluenesulfinic acid (200 rag, 1.28 mmol) obtained in Reference Example 46 in N, N_dimethylformamide (4.00 ml) was added thionyl chloride (0.194 ml, 2.56 maraudal 1). After stirring the reaction mixture at room temperature for 1 hour, the reaction mixture is stirred with ethyl acetate. Diluted, washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (181 mg, 92¾) as an oil, it was used directly in the next reaction.

Reference Example 48

 D-(+)-3-bromo-campha-1-sulfonyl chloride

To a solution of D-(+)-3-bromo-1-camphor-8-sulfonic acid ammonium (500 mg, 1.48 mmol) in N, N-dimethylformamide (5.00 ml) was added thionyl chloride (0.224 ml, 2.96 mmol). Was. After stirring 1 hour the reaction mixture at room temperature, the reaction mixture was diluted with acetic acid E chill, washed with water, dried (MgSO _4), to give the title compound as an oil-like material and the solvent was evaporated under reduced pressure, the following Used directly in the reaction.

Reference 49

 6,6,7,7,7-Pen evening Fluorohep evening night nitrile

To a suspension of sodium cyanide (1.59 g, 31.5 mmol) in dimethylsulfoxide (4.00 ml) was added the methanesulfonic acid 5,5,6,6,6-pentenefluorohexyl ester obtained in Reference Example 9. (7.10 g, 26.3 bandol) in dimethyl sulfoxide (4.00 ml) was added. After stirring the reaction mixture at room temperature for 19.5 hours, water was added thereto, and the mixture was extracted with getyl ether. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure to give the title compound as an oil, it was used directly in the next reaction.

_{Ή-NMR (CDC1 3):} . 51.68-1.83 (4H, m), 1.90-2.22 (2H, m), 2.38-2.46 (2H, m) Reference Example 50

6, 6, 7, 7, 7-pentafluoroheptanoic acid

6,6,7,7,7-Pentafluoroheptanil nitrile obtained in Reference Example 49 was dissolved in acetic acid (30.0 ml) and concentrated hydrochloric acid (15.0 ml), and the mixture was stirred at 120 for 2 hours. The reaction mixture was added to ice water and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was evaporated reduced pressure to give the title compound as an oil, was used directly in the next reaction.

IR (KBr) v: 3700-2200, 2955, 1715, 1661, 1603 cm " ¹ .

_{¾-NMR (CDC1 3):} (51.54-1.84 (4H, m), 1.92-2.24 (2H, m), 2.42 (2H, t, J = 7.0 Hz).

Reference Example 51

6,6,7,7,7-Pentafluoro mouth In a solution of 6,6,7,7,7-pentafluorofluorheptanoic acid obtained in Reference Example 50 in tetrahydrofuran (80.0 ml), oxalyl chloride (3.80 ml, 39.7 mmol) and N, N-dimethylformamide ( 0.100 ml). After stirring the reaction mixture at room temperature for 3.5 hours, the solvent was distilled off under reduced pressure. To a solution of sodium borohydride (2.50 g, 66.1 mmol) in tetrahydrofuran (40,0 ml) and 1,2-dimethoxyethane (30.0 ml) was added a solution of the residue in tetrahydrofuran (40.0 ml) under ice cooling. After stirring the reaction mixture at room temperature for 23 hours, the reaction mixture was poured into ice water, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO ₄₎ after calculating the carboxy glycol ester and the solvent was distilled off under reduced pressure the title compound (3.72 g, 69¾ (methanesulfonic acid 5, 5, 6, 6, the 6- Pentafuruo port) ) Was obtained as an oil.

IR (KBr) V: 3700-2700, 2949, 2878, 1723 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 1.34 - 1.88 (6Η, m), 1.88-2.20 (2H, m), 3.68 (2H, t, J = 6.2 Hz)..

Reference Example 52

Methanesulfonic acid 6,6,7,7,7-Penta fluorester heptyl ester

Methanesulfonyl chloride (2.09 ml, 27.1) was added to a solution of 6,6,7,7,7-pentafluorofuranol (3.72 g, 18.0 mmol) obtained in Reference Example 51 in tetrahydrofuran (80.0 ml). mmol) and triethylamine (5.03 ml, 36.1 bandol) were sequentially added under ice-cooling. After stirring the reaction mixture at room temperature for 3.5 hours, 1 hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water, dried '(MgSO _4), solvent was evaporated under reduced pressure to give the title compound (3.80 g, 74%) as an oil.

IR (KBr) V: 2948, 2878, 1734, 1674, 1356, 1194, 1177, 976, 945 cm " ^1. .-NMR (CDCI3): 51.35-1.90 (6H, m), 1.90-2.26 (2H, m ), 3.02 (3H, s), 4.25 (2H, t, J = 6.6 Hz).

Reference Example 53-1

 5,5,5-Trifluoropentane nitrile.

To a suspension of sodium cyanide (1.13 g, 18.7 dragon 01) in dimethyl sulfoxide (5.70 ml) was added 4-bromo-ί, 1,1-trifluorobutane (3.64 g, 18.7 mmol). Stir the reaction mixture at room temperature for Π hour, add water and extract with getyl ether. Issued. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure to give the title compound as an oil, it was used directly in the next reaction.

IR (KBr) V: 2944, 2251 cm " ¹ .

_{^{] H-NMR (CDC1 3)}} : (51.88-2.05 (2H, m), 2.16-2.42 (2H, m), 2.49 (2H, t, J = 7.0 Hz).

Reference Example 53-2

 5,5,5-trifluoropentanoic acid

5,5,5-Trifluoropentane nitrile obtained in Reference Example 53-1 was dissolved in acetic acid (20.0 ml) and concentrated hydrochloric acid (10.0 ml), and the mixture was stirred at 120 ° C for 2 hours. The reaction mixture was added to ice water and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure to give the title compound as an oil, it was used directly in the next reaction.

IR (KBr) V: 3600-2300, 1717 cm— ¹ .

 Ή-NMR (CDCI3): (51.82-2.00 (2H, m), 2.06-2.32 (2H, m), 2.49 (2H, t, J = 7.2 Hz).

Reference Example 53-3

 5, 5, 5-Trifluoro-1_ Pen Pennol

To a solution of 5,5,5-trifluorohexanoic acid in tetrahydrofuran (40.0 ml) obtained in Reference Example 53-2, oxalyl chloride (2.93 ml, 25.5 mmol) and dimethylformamide (100 ml) were sequentially added. . After stirring the reaction mixture at room temperature for 2 hours, the solvent was distilled off under reduced pressure. To a solution of sodium borohydride (1.93 g, 51.0 mmol) in tetrahydrofuran (20.0 ml) and 1,2-dimethoxyethane (15.0 ml) was added a solution of the residue in tetrahydrofuran (20.0 ml) under ice cooling. After stirring the reaction mixture at room temperature for 20 hours, the reaction mixture was poured into ice water, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (680 mg, 26¾ (4- bromo-1, 1, calculated from the 1-triflate Ruo Rob Tan,)) and Obtained as an oil.

IR (KBr) V: 3700-3100, 2951 cm— ¹ .

Ή-NMR (CDCI3): (51.56-1.72 (4H, m), 2.00-2.25 (2H, m), 3.69 (2H, t, J = 5.8 Hz). Reference Example 53-4

Methanesulfonic acid 5,5,5-trifluoropentyl ester

To a solution of 5,5,5-trifluoro-1-pentanol (680 mg, 4.88 ranol) obtained in Reference Example 53-3 in tetrahydrofuran (15.Oml) was added methanesulfonyl chloride (0.555 ml, 7.18 mmoi). Triethylamine (1.33 ml, 9.57 mmol) was sequentially added under ice cooling. After stirring the reaction mixture at room temperature for 2 hours, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (790 mg, 75¾) as an oil.

IR (KBr) Re:. 2949, 2888, 1360, 1337, 1258, 1175, 1146, 976, 939 cm- 1 Ή-NMR (CDC1 3): 51.62-1.96 (4H, m), 2.02-2.28 (2H, m), 3.03 (3H, s), 4.26 (2H, t, J = 6.2 Hz).

Reference Example 53-5

 6,6,6-Trifluohexanenitrile

To a suspension of sodium cyanide (950 mg, 18.8 t ol) in dimethyl sulfoxide (6.00 ml) was added the methanesulfonic acid 5,5,5-trifluoropentyl ester obtained in Reference Example 53-4 (2.76 g, 12.5 mmol). ol) in dimethylsulfoxide (4.00 ml). After stirring the reaction mixture at room temperature for 19.5 hours, water was added and extracted with getyl ether. The extract was washed with water, dried (MgSO _4), to give the title of compound as an oil and the solvent was evaporated under reduced pressure and used directly in the next reaction.

Reference example 54

 6,6,6-Trifluohexanoic acid

6,6,6-Trifluorohexanitolitol obtained in Reference Example 53-5 was dissolved in acetic acid (8.00 ml) and concentrated hydrochloric acid (16.0 ml), and the mixture was stirred at 120 ° C. for 2 hours. The reaction mixture was added to ice water and extracted with ethyl acetate. As an oil - the extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (calculated from Torifuruoropen Chiruesuteru) 1.03 g, 49% (methanesulfonic acid 5, 5, 5) Was.

IR (KBr) V: 3700-2300, 2949, 2884, 1715, 1661, 1605 cm- ¹ .

_{'H-NMR (CDC1 3)} : (51.56-1.80 (4H, m), 2.04-2.22 (2H, m), 2.41 (2H, t, J = 7.2 Hz). Reference Example 55

 6,6,6-Trifluo-1-hexanol

In a solution of 6,6,6-trifluoromethylhexanoic acid (1.03 g, 6.13 mmol) obtained in Reference Example 54 in tetrahydrofuran (10.Oml), oxalyl chloride (0.704 ml, 7.35 t01) and N, N- Dimethylformamide (0.100 ml) was added sequentially. After stirring the reaction mixture at room temperature for 1 hour, the solvent was distilled off under reduced pressure. To a solution of sodium borohydride (464 mg, 12.3 mmol) in tetrahydrofuran (5.00 ml) and 1,2-dimethoxyethane (4.00 ml) was added a solution of the residue in tetrahydrofuran (5.00 ml) under ice cooling. After stirring the reaction mixture at room temperature for 18 hours, the reaction mixture was poured into ice water, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (730 mg, 79¾) as an oil.

IR (KBr) V: 3700-3050, 2948, 2874 cm " ¹ .

_{Ή-NMR (CDC1 3):} 51.34-1.70 (6H, m), 2.00-2.22 (2H, m), 3.67 (2H, t, J = 6.2

Hz).

Reference Example 56

Methanesulfonic acid 6,6,6-trifluorohexyl ester

 To a solution of 6,6,6-trifluoro-1-hexanol (730 mg, 4.86 mmol) obtained in Reference Example 55 in tetrahydrofuran (15.0 ml) was added methanesulfonyl chloride (0.376 ml,

4.86 mmol) and triethylamine (1.02 ml, 7.29 thigh 01) were sequentially added under ice cooling. After stirring the reaction mixture at room temperature for 2 hours, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain the solvent was distilled off under reduced pressure the title compound (873 mg, 77%) as an oil.

IR (KBr) V: 2949, 2878, 1177, 1144, 974, 947 cm- ¹ .

_{Ή-NMR (CDC1 3):} (51.38-1.88 (6H, m), 2.00-2.24 (2H, m), 3.02 (3H, s), 4.24 (2H, t, J = 6.4 Hz).

Reference Example 57

 5-Fluoropentane nitrile

To a suspension of sodium cyanide (2.12 g, 41.9) in dimethyl sulfoxide (6.00 ml) was added 4-bromo_1_fluorobutane (4.42 g, 57.9 mmol) in dimethyl sulfoxide. A solution of foxide (4.00 ml) was added. After stirring the reaction mixture at room temperature for 17.5 hours, water was added and extracted with getyl ether. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure to give the title compound as an oil, it was used directly in the next reaction. Reference Example 58

5-Fluoropen Pen

 To a solution of 5-fluoropentanenitrile obtained in Reference Example 57 in dichloromethane (200 ml), diisobutylaluminum hydride 1.5 mol / 1 toluene solution (37.2 ml, 55.8 mmol) was added at -70 ° C. The reaction mixture was stirred at -70 ° C under an argon stream for 2.5 hours. A saturated aqueous solution of ammonium chloride (100 ml) was added, the reaction mixture was stirred at room temperature for 1 hour, hydrochloric acid was added, and the mixture was extracted with dichloromethane. Wash the extract with water and dry

(GS0 ₄₎ After the solvent was evaporated under reduced pressure to give the title compound as an oil, was used directly in the next reaction.

Reference example 59

 5-Fluo mouth

To a suspension of lithium aluminum hydride (1.59 g, 33.5 mmol) in getyl ether (100 ml) was added a solution of 5-fluoropentanal in dimethyl ether (50.0 ml) obtained in Reference Example 58 on ice. The reaction mixture was stirred at room temperature for 1 hour. Excess lithium aluminum hydride was decomposed with a small amount of water under ice-cooling, and the reaction mixture was filtered and washed with ethyl ether. After the filtrate dried (GS0 _4), to obtain solvent was distilled off under reduced pressure the title compound (850 mg, 29% (calculated from 4-bromo-1-Furuorobutan)) as an oil.

IR (KBr) V: 3700-3050, 2938, 2867 cm— ¹ .

_{'H-NMR (CDC1 3)} : 51.46-1.56 (2H, i), 1.58-1.84 (4H, m), 3.67 (2H, t, J = 6.3 Hz), 4.46 (2H, dt, J = 47.4, 6.0 Hz).

Reference Example 60

Methanesulfonic acid 5_fluoropentyl ester

To a solution of 5-fluoropentanol (400 mg, 3.77 thigh 01) obtained in Reference Example 59 in tetrahydrofuran (10.0 ml) was added methanesulfonyl chloride (0.350 ml, 4.52 thigh ol) and triethylamine (0.788 ml). , 5.65 mmol) were sequentially added under ice cooling. Reaction mixture After the mixture was stirred at room temperature for 45 minutes, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (690 mg, 99¾) as an oil.

IR (Br): 2946, 2919, 2874, 1352, 1175, 976, 955, 924 cm- ¹ .

Ή-NMR (CDC): δ 1.50-1.62 (3Η, m), 1.66-1.88 (3H, m), 3.02 (3H, s), 4.25 (2H, t, J-6.3 Hz), 4.47 (2H, dt) , 1 = 47.1, 6.0 Hz).

Reference Example 61

 1-bromo-5-fluoropen

Example 1

To a solution of getylaminosulfur trifluoride (67.9 g, 0.421 ol) in dichloromethane (200 ml) was added a solution of 5-bromo-toppentanol (67.0 g, 0.401 mmol) in dichloromethane (100 ml) at -70 ° C. And slowly dripped. After the reaction mixture was heated to 0 ° C. over 22 hours, saturated sodium bicarbonate was added thereto under ice-cooling, and the mixture was extracted with dichloromethane. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure, the title compound was purified Ri by distillation (34.2 g, 51¾) as an oil.

_{'H-NMR (CDC1 3)} : (51.52-1.64 (2H, m), 1.64-1.84 (2H, m), 1.92 (2H, quint, J = 7.2 Hz), 3.43 (2H, t, J = 6.9 Hz ), 4.46 (2H, dt, J = 47.4, 6.0 Hz).

Example 2

To a solution of getylaminosulfur trifluoride (50.0 g, 0.310 mmol) in dichloromethane (200 ml) was added a solution of 5-bromo-topopenol (50.0 g, 0.299 mmol) in dichloromethane (50.0 ml) at -7 (TC after heating was slowly added dropwise. the reaction mixture to room temperature for 16.5 hours Placing and gave extracted with dichloromethane by the addition of saturated sodium bicarbonate. the extract was washed with water, dried (MgSO ₄₎ after the solvent under reduced pressure The residue was purified by distillation to give the title compound (30.7 g, 61¾) as an oil.

Reference Example 62

Hexanoic acid (4-hydroxybutyl) amide

To a solution of 4-hydroxybutylamine (1.00 g, 11.0 mmol) and n-hexanoic acid (1.68 ml, 12.1 mmol) in N, N-dimethylformamide (20.0 ml) was added getyl cyanophosphate (1.96 ml, 12.1 ml). mmol) and then add triethylamine (1.69 ml, 12.1 ol). Was. After stirring the reaction mixture at room temperature for 18 hours, water was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure to give the title compound (2.24 g, ca.l00¾) as an oil, it was used directly in the next reaction.

_{Ή-NMR (CDC1 3):} 50.896 (3H, t, J = 6.6Hz), 1.16-1.44 (6H, m), 1.48-1.76 (4H, m), 2.16 (2H, t, J-7.6 Hz), 3.22-3.38 (2H, m), 3.69 (1H, bt, J = 6.0 Hz), 4.08 (2H, t, J = 6.2 Hz), 5.62 (1H, bs).

Reference Example 63

Methanesulfonic acid 4-hexanoylaminobutyl ester

In a solution of hexanoic acid (4-hydroxybutyl) amide (2.24 g, 11.0 t) obtained in Reference Example 62 in tetrahydrofuran (50.0 ml), methanesulfonyl chloride (1.02 ml, 13.2 t01) and triethylamine ( 2.30ml, 16.5case01) were sequentially added under ice-cooling. After stirring the reaction mixture at room temperature for 2.5 hours, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (2.78 g, 95¾) as an oil.

_{LH-NMR (CDC1 3):} (50.897 (3H, t, J = 7.5Hz), 1.22-1.40 (6H, m), 1.50-1.74 (4H, m), 2.16 (2H, t, J = 7.2 Hz) , 3.31 (2H, q, J = 6.0 Hz), 2.02 (3H, s), 4.27 (2H, t, J = 6.0 Hz), 5.50 (1H, bs).

Reference Example 64

Hexanoic acid [4- (2-hydroxyethyl) phenyl] amide

To a solution of 4- (2-hydroxyethyl) phenylamine (500 mg, 3.57 liters) and n-hexanoic acid (0.547 ml, 3.93 mmol) in N, N-dimethylformamide (10.0 ml) was added cyanophosphoric acid. Getyl (0.635 ml, 3.93 mmol) was added followed by triethylamine (0.548 ml, 3.93). After stirring the reaction mixture at room temperature for 18 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure to give the title compound (520 mg, 62%) as colorless crystals, it was used directly in the next reaction. IR (KBr) V: 3700-2600, 2930, 2872, 1653, 1593, 1532 cm " ¹ .

Ή-NM (CDCI3): 50.910 (3H, t, J = 7.0Hz), 1.24-1.45 (4H, m), 1.64-1.82 (4H, m), 2.35 (2H, t, J = 7.6 Hz), 2.84 (2H, t, J = 6.6 Hz), 3.84 (2H, t, J = 7.0 Hz), 7.12 (1H, bs), 7.19 (2H, d, J = 8.4 Hz), 7.46 (2H, d, J = 8.0 Hz). Reference example 65

Methanesulfonic acid 2- (4-hexanoylaminophenyl) ethyl ester

Methanesulfonyl chloride (0.205 ml, 2.65 mmol) was added to a solution of hexanoic acid [4- (2-hydroxyethyl) phenyl] amide (520 mg, 2.21 ol) in tetrahydrofuran (10.0 ml) obtained in Reference Example 64. And triethylamine (0.462 ml, 3.31 mmol) were sequentially added under ice cooling. After stirring the reaction mixture at room temperature for 2 hours, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO ₄₎ After the solvent was distilled off under reduced pressure to give the title compound (630 mg, 91¾) was synthesized. Recrystallization from ethyl acetate-getyl ether gave colorless crystals having a melting point of 88.0-90.

IR (KBr) V 3304, 2957, 2932, 2861, 1661, 1601, 1526 cm— ¹ .

_{Ή-NMR (CDC1 3):} 50.912 (3H, t, J = 7.0Hz), 1.30-1.42 (4H, m), 1.65-1.82 (2H, m), 2.35 (2H, t, J = 7.6 Hz), 2.87 (3H, s), 3.02 (2H, t, J = 6.8 Hz), 4.39 (2H, t, J = 6.6 Hz), 7.11 (IH, bs), 7.19 (2H, d, J = 8.8 Hz), 7.48 (2H, d, J = 8.4 Hz) elemental analysis:. as C ₁₅ H ₂₃ N0 ₄ S

Calculated value (¾): C, 57.48; H, 7.40; N, 4.47; S, 10.23.

Found (¾): C, 57.21; H, 7.41; N, 4.31; S, 9.85.

Reference Example 66

 4-hexanoylamino benzoic acid ethyl ester,

To a solution of 4-ethylaminobenzoic acid ethyl ester (1.00 g, 6.05 mmol) and n-hexanoic acid (0.927 ml, 6.66 mmol) in N, N-dimethylformamide (5.00 ml) was added getyl cyanophosphate (1.08 ml, 6.66). 01) Subsequently, triethylamine (0.928 ml, 6.66 mmol) was added. After stirring the reaction mixture at room temperature for 20 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (2.82 g, ca.100¾) as a yellow amorphous crystals.

IR (KBr) Seo: 3326, 2959, 2932, 2863, 1715, 1701, 1597, 1534 cm " ¹ .

'H-NMR (CDC "): (50.916 (3H, t, J = 6.9 Hz), 1.30-1.48 (4H, m), 1.39 (3H, t, J = 7.2 Hz), 1.68-1.82 (2H, m ), 2.39 (3H, t, J = 7.8Hz), 4.36 (2H, q, J = 6.9Hz), 7.31 (1H, bs), 7.61 (2H, d, J = 8.7 Hz), 8.01 (2H, d , J = 8.7 Hz). 'Example 67 Hexanoic acid (4-hydroxymethylphenyl) amide

To a solution of 4-hexanoylaminobenzoic acid ethyl ester (2.82 g, 10.7 mmol) obtained in Reference Example 66 in tetrahydrofuran (6.00 ml), lithium borohydride (389 mg, 16.1 bandol) was added. The reaction mixture was stirred at room temperature for 24 hours. Further, lithium borohydride (389 mg, 16.1 bandol) was added to the reaction mixture, and the mixture was stirred at room temperature for 17.5 hours, and then added with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (690 mg, 29%) as amorphous crystals.

IR (Br) V: 3700-2500, 2953, 2930, 2863, 1657, 1605, 1541 cm " ¹ .

_{'H-NMR (CDC1 3)} : 60.911 (3H, t, J = 6.9Hz), 1.38-1.44 (4H, m), 1.60-1.80 (2H, m), 2.35 (2H, t, J = 7.8 Hz) , 4.65 (2H, s), 7.22 (1H, bs), 7.31 (2H, d, J = 8.7 Hz), 7.50 (2H, d, J = 8.1 Hz).

Reference Example 68

Hexanoic acid (4-chloromethylphenyl) amide

To a solution of hexanoic acid (4-hydroxymethylphenyl) amide (690 mg, 3.12 mmol) obtained in Reference Example 67 in tetrahydrofuran (15.0 ml) was added methanesulfonyl chloride (0.290 ml, 3.74 alcohol) and triethyl alcohol. Min (0.652 ml, 4.68 mmol) was added sequentially under ice cooling. After stirring the reaction mixture at room temperature for 22 hours, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), and the solvent was evaporated under reduced pressure to synthesize the title compound (640 mg, 85%). Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 75.0-77.0 ° C.

IR (KBr) Re:. 3318, 3193, 3119, 3048, 2935, 2932, 2863, 1659, 1599, 1537 cm- 1 l H-NMR (CDC1 3): δ 0.911 (3Η, t, J = 6.9Hz) , 1.30-1.42 (4H, m), 1.68-1.80 (2H, m), 2.35 (2H, t, J = 7.5 Hz), 4.56 (2H, s), 7.18 (1H, bs), 7.34 (2H, d , J = 8. Hz), 7.52 (2H, d, J = 8. Hz).

Elemental analysis: as C ₁₃ H ₁₈ N0C1 -0.2H ₂₀

Calculated value (¾): C, 64.17; H, 7.62; N, 5.76.

Observed value (): C, 64.23; Η, 7.69; Ν, 5.44. Reference Example 69

 (2,2,2-Trifluoroethoxy) acetic acid ethyl ester

To a suspension of sodium hydride (1.43 g, 35.6 0101) (60 oily) in tetrahydrofuran (40.0 ml) was added 2,2,2-trifluoroethanol (3.00 g, 29.7 thigh 01) in tetrahydrofuran (10.0 g). ml), and the mixture was stirred under ice-cooling for 5 minutes. To this was added a solution of ethyl bromoacetate (3.80 ml, 32.7 mol) in tetrahydrofuran (10.0 ml), and the mixture was further stirred at room temperature for 15.5 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (4.62 g, 85%) as an oil.

IR (KBr) V: 2961, 2926, 1755 cm " ¹ .

_{Ή-NMR (CDC1 3):} (51.26 (3H, t, J-6.9 Hz), 3.79 (2H, s), 3.99 (2H, q, J = 8.7 Hz), 4.26 (2H, s).

Reference Example 70 A suspension of lithium aluminum hydride (1.79 g, 37.6 mmol) in ethyl ether (100 ml) was added to a suspension of ethyl (2,2,2-trifluoroethoxy) acetate obtained in Reference Example 69 (100 ml). A solution of 4.62 g, 25.1 mmol) in getyl ether (100 ml) was added under ice-cooling, and the reaction mixture was stirred at room temperature for 3 hours. Excess lithium aluminum hydride was decomposed with a small amount of water under ice-cooling, and the reaction mixture was filtered and washed with diethyl ether. After the filtrate dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (1.84 g, 51¾) was obtained as an oil.

_{¾-NMR (CDC1 3):} 51.95-2.06 (1H, m), 3.71-3.84 (4H, m), 3.90 (2H, q, J = 8.8 Hz).

Reference Example 71

Methanesulfonic acid 2- (2,2,2-trifluoroethoxy) ethyl ester

Methanesulfonyl chloride (1.19 ml, 15.3 mmol) was added to a solution of 2- (2,2,2-trifluoroethoxy) ethanol (1.84 g, 12.8 to 01) obtained in Reference Example 70 in tetrahydrofuran (40.0 ml). And triethylamine (2.17 ml, 19.2 thigh 01) were added sequentially under ice cooling. Stir the reaction mixture at room temperature for 2 hours, then add 1N hydrochloric acid and add ethyl acetate. Extracted. The obtained extract was washed with water, dried (MgSO _4), solvent was distilled off under reduced pressure the title of compound a (2.62 g, 92%) as an oil.

IR (KBr) V: 3029, 2924, 2853, 1354, 1279, 1173, 968, 924 cm— ¹ .

_{Ή-NMR (CDC1 3):} 53.06 (3H, s), 3.91 (2H, q, J = 12.6 Hz), 3.88-3.94 (2H, m), 4.37-4.43 (2H, m).

Reference Example 72

 1-bromo-4- (2,2,2-trifluoroethoxy) butane

To a suspension of sodium hydride (950 g, 23.8 thigh 01) (60% oil) in tetrahydrofuran (10.0 ml) was added 2,2,2-trifluoroethanol (2.00 g, 19.8 mmol) in tetrahydrofuran (20.0 t ml), and the mixture was stirred under ice-cooling for 5 minutes. To this was added a solution of 1,4-dibromobutane (1.20 ml, 9.90 thigh 01) in tetrahydrofuran (10.0, ml), and the mixture was further stirred at 80 ° C for 16 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (2.07 g, 40¾) as an oil.

_{Ή-NMR (CDC1 3):} δ 1.64-2.06 (4Η, m), 3.45 (2Η, ί, J = 6.6 Hz), 3.65 (2H, t,

J = 6.2 Hz), 3.80 (2H, q, J = 8.8 Hz).

Reference Example 73

 1-bromo-5- (2,2,2-trifluoroethoxy) pentane

To a suspension of sodium hydride (475 g, 11.9 mmol) (60 oily) in tetrahydrofuran (10.0 ml) was added 2,2,2-trifluoroethanol (1.00 g, 9.90 t01) in tetrahydrofuran (10.0 mi). ) The solution was added and stirred for 5 minutes under ice cooling. To this was added a solution of 1,5-dibromopentane (1.50 ml, 10.9 marl) in tetrahydrofuran (10.0 ml), and the mixture was further stirred at 80 ° C for 16 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title of compound a (2.23 g, 47¾) as an oil.

_{Ή-NMR (CDC1 3):} 61.38-1.73 (4H, in), 1.80-1.96 (2H, m), 3.42 (2H, t, J = 6.8 Hz), 3.61 (2H, t, J = 6.2 Hz), 3.80 (2H, q, J = 8.8 Hz).

Reference example 74

(3-Fluoropropoxy) acetic acid ethyl ester To a suspension of sodium hydride (622 g, 15.6raraol) (60% oil) in tetrahydrofuran (5.00 ml) was added a solution of ethyl gluconate (1.50 g, 13.0 mmol) in tetrahydrofuran (20.0 ml). The mixture was stirred for 5 minutes under ice cooling. To this was added a solution of tribromo-3-fluoropropane (1.87 g, 13.0 mmol) in tetrahydrofuran (5.00 ml), and the mixture was further stirred at 60 for 19 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (680 mg, 15¾) as an oil.

_{'H-NMR (CDC1 3)} : 51.29 (3H, t, J = 7.2 Hz), 2.01 (2H, dt, J = 26., l, 5.7 Hz), 3.67 (2H, t, J = 6.3 Hz), 4.09 (2H, s), 4.23 (2H, q, J = 6.9 Hz), 4.58 (2H, dt, J = 47.1, 5.7 Hz).

Reference Example 75

 (4-Fluorobutoxy) acetic acid ethyl ester

To a suspension of sodium hydride (415 g, 10.4 mmol) (60% oil) in tetrahydrofuran (5.00 ml) was added a solution of ethyl glycolate (1.00 g, 8.65 t) in tetrahydrofuran (10.0 ml), and the mixture was cooled on ice. Stir for 5 minutes below. A solution of tripromo-4-fluorobutane (0.947 ml, 8.65 mmol) in tetrahydrofuran (5.00 ml) was added thereto, and the mixture was further stirred at 60 ° C for 14.5 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (680 mg, 44¾) as an oil.

IR (KBr) v: 2963, 2909, 2876, 1755, 1206, 1140 cm " ¹ .

_{¾-NR (CDC1 3):} 51.29 (3H, t, J = 7.0 Hz), 1.70-1.95 (4H, m), 3.58 (2H, t, J = 6.2 Hz), 4.07 (2H, s), 4.22 ( 2H, q, J = 7.4 Hz), 4.49 (2H, dt, J-47.2, 5.8 Hz).

Reference Example 76

(5-Fluoropentyloxy) acetic acid ethyl ester

In the same manner as in Reference Example 74, 1-bromo-5-fluoropentane (2.41 g, 14.3 mmol) was used in place of 1-bromo-3-fluoropropane, and glycoethyl ester (3.00.g, 26.0 g) was used. mmol) to give the title compound (2.11 g, 84%) as an oil. IR (KBr) v: 2964, 2870, 1755 cm- ¹ .

_{Ή-NMR (CDC1 3):} 51.26 (3H, t, J = 6.0 Hz), 1.42-1.88 (6H, m), 3.55 (2H, t, J = 6.2 Hz), 4.07 (2H, s), 4.22 ( 2H, q, J = 7.4 Hz), 4.45 (2H, dt, J = 47.4, 6.0 Hz).

Reference Example 77

 2- (3-fluoropropoxy) ethanol

A suspension of lithium aluminum hydride (295 mg, 6.21 band01) in getyl ether (20.0 ml) was added to the (3-fluoropropoxy) acetate ethyl ester (680 mg, 4.14 mmol) obtained in Reference Example 74. )) In dimethyl ether (10.0 ml) was added under ice-cooling, and the reaction mixture was stirred at room temperature for 2 hours. Excess lithium aluminum hydride was decomposed with a small amount of water under ice cooling, and the reaction mixture was filtered and washed with getyl ether. After the filtrate dried (MgSO _4), the title compound solvent was evaporated under reduced pressure (260 mg, 36¾) was obtained as an oil.

Ή one _{NMR (CDC1 3): 51.99 (} 2H, dt, J = 26.1, 5.7 Hz), 3.54-3.59 (2H, m), 3.62 (2H, t, J = 6.0 Hz), 3.70-3.78 (2H, m ), 4.56 (2H, dt, J = 47.1, 5.7 Hz).

 2_ (4-fluorobutoxy) ethanol

In a suspension of lithium aluminum hydride (272 mg, 5.72 band01) in ethyl acetate (20.0 ml), ethyl 4- (butyrolbutoxy) acetic acid ethyl ester (680 mg, 3.82 mmol) obtained in Reference Example 75 was added. (10.0 ml) The solution was added under ice-cooling, and the reaction mixture was stirred at room temperature for 3 hours. Excess lithium aluminum hydride was decomposed with a small amount of water under ice cooling, and the reaction mixture was filtered and washed with getyl ether. After filtrate Drying (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (200 mg, 38¾) was obtained as an oil.

IR (KBr): 3700-3100, 2926, 2872, 1123, 1067 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 1.69-1.79 (4Η, m), 2.03 (1H, t, J = 5.7 Hz), 3.50-3.58 (4H, m), 3.74 (2H, dt, J = 5.1, 3.9 Hz), 4.48 (2H, dt, J = 47., 6.0 Hz).

Reference Example 79

2- (5-fluoropentyloxy) ethanol A suspension of lithium aluminum hydride (781 mg, 16.5 mmol) in getyl ether (60.0 ml) was added to the (5-fluoropentyloxy) acetate ethyl ester (2. llg, 11.0 g) obtained in Reference Example 76. (mmol) of getyl ether (20. Oral) was added under ice cooling, and the reaction mixture was stirred at room temperature for 50 minutes. Excess lithium lithium hydride was decomposed with a small amount of water under ice cooling, and the reaction mixture was filtered and washed with getyl ether. After the filtrate dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (910 mg, 55¾) as an oil.

_{¾-NMR (CDC1 3):} δ 1.44-1.86 (6Η, m), 2.02 (1H, t, J = 6.2 Hz), 3.50 (2H, t, J = 6.6 Hz), 3.48-3.56 (2H, m) , 3.68-3.78 (2H, m), 4.46 (2H, dt, 1 = 47.2, 5.8 Hz).

Reference Example 80

Methanesulfonic acid 2- (3-fluoropropoxy) ethyl ester

To a solution of 2- (3-fluoropropoxy) ethanol (260 mg, 2.13 mmol) obtained in Reference Example 77 in tetrahydrofuran (10.0 ml) was added methylsulfonyl chloride (0.198 il, 2.55 mmol) and triethyla. Min (0.445 ml, 3.19 dragon ol) was added sequentially under ice cooling. After stirring the reaction mixture at room temperature for 2.5 hours, 1N hydrochloric acid was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (320 mg, 83%) as an oil.

_{Ή-NMR (CDC1 3):} δΐ.98 (2Η, dt, J = 26.4, 6.0 Hz), 3.06 (3H, s), 3.63 (2H, t, J-6.3 Hz), 3.70-3.75 (2H, m ), 4.35-4.39 (2H, m), 4.55 (2H, dt, J = 47., 6.0 Hz).

Reference 81

2- (4-fluorobutoxy) ethyl ester of maleic sulfonic acid

In a solution of 2- (4-fluorobutoxy) ethanol (200 mg, 1.47 mmol) obtained in Reference Example 78 in tetrahydrofuran (10.0 ml), methanesulfonyl chloride (0.136 ml, 1.76 mmol) and triethylamine (0.307 ml, 2.20) were added. mmol) were sequentially added under ice cooling. After stirring the reaction mixture at room temperature for 1 hour, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (242 mg, 77¾) as an oil. IR (KBr): 2951, 2874, 1352, 1175, 974, 922 cm " ¹ .

_{Ή-NMR (CDC1 3):} ά 1.66-1.88 (4H, m), 3.06 (3H, s), 3.54 (2H, t, J = 6.3 Hz), 3.68-3.73 (2H, m), 4.34-4. 0 (2H, m), 4.45 (2H, dt, J = 47.4, 6.0 Hz). Reference example 82

Methanesulfonic acid 2- (5-fluoropentyloxy) ethyl ester

To a solution of 2- (5-fluoropentyloxy) ethanol (910 mg, 6.06 mmol) obtained in Reference Example 79 in tetrahydrofuran (30.0 ml) was added methyl sulfonyl chloride (0.563 ml, 7.27 mmol) and triethyla. Min (1.27 ml, 9.09 mmol) was added sequentially under ice cooling. After stirring the reaction mixture at room temperature for 1 hour, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (1.28 g, 93%) as an oil.

IR (KBr) V: 3027, 2944, 2968, 1354, 1177, 1130, 1019, 974, 924 cm " ^1. — NMR (CDCI3): (51.40-1.90 (6H, m), 3.06 (3H, s), 3.51 (2H, t, J-6.Hz), 3.66-3.74 (2H, m), 4.30-4.40 (2H, m), 4.45 (2H, dt, J = 47.4, 6.4 Hz) .Reference example 83

 (2-Fluoroethoxy) acetic acid ethyl ester

To a suspension of sodium hydride (2.14 g, 53.4 virgin 01) (60 oily) in tetrahydrofuran (40.0 ml), add a solution of 2-fluoroethanol (3.00 g, 44.5 thigh 01) in tetrahydrofuran (10.0 ml) And stirred under ice cooling for 5 minutes. To this was added a solution of ethyl bromoacetate (7.77 ml, 66.7 mmol) in tetrahydrofuran (10.0 ml), and the mixture was further stirred at room temperature for 45 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The obtained extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (9.25 g, 60¾) as an oil.

_{Ή-NMR (CDC1 3):} (51.31 (3H, t, J = 7.2 Hz), 3.84 (2H, s), 3.84 (2H, dt, J = 29.7, 3.9 Hz), 4.23 (2H, q, J = 7.2 Hz), 4.61 (2H, dt, J = 46.2, 4.2 Hz).

Reference Example 84

 2- (2-fluoroethoxy) ethanol

A suspension of lithium aluminum hydride (4.38 g, 92.4 thigh 01) in getyl ether (400 ml) was added to the (2-fluoroethoxy) acetic acid ethyl ester (9.25) obtained in Reference Example 83. g, 61.6) was added under ice-cooling, and the reaction mixture was stirred at room temperature for 1.5 hours. Excess lithium aluminum hydride was decomposed with a small amount of water under ice-cooling, and the reaction mixture was filtered and washed with getyl ether. After the filtrate dried (MgSO _4), to give the title compound (1.87 g, 28%) as an oil and the solvent was evaporated under reduced pressure. _{Ή-NMR (CDC1 3):} . 53.51-3.84 (6H, m), 4.59 (2H, dt, J-47.7, 4.2 Hz) Reference Example 85

Methanesulfonic acid 2_ (2-fluoroethoxy) ethyl ester

In a tetrahydrofuran (100 ml) solution of 2_ (2-fluoroethoxy) ethanol (1.87 g, 17.3 thigh 01) obtained in Reference Example 84, methanesulfonyl chloride (1.34 ml, 20.8 mmol) and triethylamine (2.89 ml, 20.8 thigh) were added. 01) was added sequentially under ice cooling. After stirring the reaction mixture at room temperature for 2.5 hours, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (2.79 g, 87¾) as an oil.

_{Ή-NMR (CDC1 3):} 53.07 (3H, s), 3.69-3.84 (4H, m), 4.38-4.42 (2H, m), 4.58 (2H, dt, J = 46.5, 5.4 Hz).

Reference Example 86

Methanesulfonic acid tetrahydropyran-4_methyl

A solution of tetrahydropyran-4,4-dicarponic acid (purity 65, 3.04 g, 11.3 ol) in acetonitrile (300 ml) was placed in an argon atmosphere in the presence of cuprous oxide (84 mg, 0.567 ol). Heated to reflux for an hour. The reaction solution was concentrated and dissolved with methanol (60 ml). Concentrated hydrochloric acid (1.88 ml, 22.6 ranol) was added and the mixture was stirred at room temperature for 25 hours. After neutralizing the reaction solution, it was saturated with sodium chloride and extracted with ethyl acetate. After dehydration and drying, the mixture was concentrated to give a brown oil (3.0 g). This was dissolved in THF (60 ml), and lithium aluminum hydride (purity 80, 0.54 g, 11.3 bandol) powder was added in several portions while stirring at 0 ° C, and the mixture was added at 0 ° C for 60 minutes. Stirred. A 0.5 M aqueous solution of cunic acid (23 ml) was added to the reaction solution, and the mixture was saturated with sodium chloride and extracted twice with THF (50 ml). The THF was distilled off, diluted with ethyl acetate (100 ml), dried and concentrated to obtain a pale yellow oil (1.68 g). This oil was dissolved in chloroform (30 ml), methanesulfonyl chloride (0.89 ml, 11.3) was added with stirring at 0 ° C, and then triethylamine (1.72 ml, 12.4 mmol) was added dropwise. The reaction solution is kept at 0 ° C for 60 Stirred for minutes. The reaction solution was concentrated, diluted with ethyl acetate (100 ml), washed with water and saturated saline, dried and concentrated. The residue was purified by silica gel (20 g) chromatography (ethyl acetate-hexane, 3: 7-4: 6), and tetrahydropyran-4-methyl methanesulfonate (0.77 g, 3.96 mmol) was added to a pale brown oil. Obtained as a product.

'H-NMR (200MHz, CDC1 3): 51.40 (2H, dq, J = 4.8, 12.0 Hz), 1.68 (2H, brdq, J = 12.4, 2.0 Hz), 2.03 (1H, m), 3.02 (3H, s), 3.40 (2H, dt, J = 2.2, 11.6 Hz), 4.00 (2H, brdd, J = 11,6, 3.9 Hz), 4.07 (2H, d, J = 6.6 Hz).

Reference Example 87

Methanesulfonic acid 2- (tetrahydropyran-4-yl) ethyl

 A toluene (5 ml) solution of ethoxycarbonylmethylphosphonate getyl (2.05 ml, 10.0 mmol) was added to a suspension of sodium hydride (oil-based 60%, 0.40 g, 10.0 tmol) in toluene (15 ml) while stirring at room temperature. The solution was added dropwise over 20 minutes and the reaction solution was stirred for 70 minutes. To this reaction solution, a solution of tetrahydropyran-4-one (0.983 ml, 10.0 mmol) in toluene (5 ml) was added dropwise over 50 minutes, and the reaction solution was stirred at room temperature for 2 hours and at 60 ° C for 2 hours. did. 1N Hydrochloric acid (10 ml) and water (40 ml) were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and concentrated to give a colorless oil (about 2 g).

 This colorless oil (about 2 g) was dissolved in methanol (40 ml), and the mixture was stirred for 4 hours at room temperature under a hydrogen atmosphere in the presence of 10% palladium on carbon (324 mg, containing 52% water). The reaction solution was filtered to remove the catalyst, and concentrated to dryness to obtain crude tetrahydropyran-4-ethyl acetate (1.7 g) as a colorless oil.

The above crude tetrahydropyran-4-ethyl acetate (1.7 g) was dissolved in THF (30 ml), and the powder of lithium aluminum hydride (purity 80%, 0.47 g, 10 mmol) was added several times while stirring at 0. The reaction mixture was stirred for 4 hours with T. To the reaction solution was added a 0.5 M aqueous solution of citric acid (20 ml), and the mixture was saturated with sodium chloride and extracted with THF and ethyl acetate. ), Dried and concentrated to give crude 2- (tetrahydropyran-4-yl) ethanol as a pale brown oil, which was dissolved in chloroform (15 ml). While stirring at ° C, methanesulfonyl chloride (0.783 ml, 10.0 mmol) was added, and then a solution of triethylamine (1.52 ml, 11.0 mmol) in chloroform (5 ml) was added. Was added dropwise over 15 minutes, and the reaction solution was stirred at 0 ° C for 65 minutes. The reaction solution was concentrated, diluted with ethyl acetate (100 ml), washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried and concentrated. The residue was purified by silica gel (20 g) chromatography (ethyl acetate-hexane, 2: 8-4: 6), and the ethyl acetate-hexane (3: 7-4: 6) fraction was concentrated to dryness. This gave 2- (tetrahydrovirane-4-yl) ethyl methanesulfonate (0.84 g, 4.03 mmol) as a pale yellow oil.

_{Ή-NMR (200MHz, CDC1 3} ): 51.33 (2H, m), 1.64 (2H, brd, J = 14.0 Hz), 1.60 (1H, m), 1.70 (2H, brdd, J = 7.0, 4.4 Hz), 3.02 (3H, s), 3.99 (2H, dt, J = 1.8, 11.9 Hz), 3.96 (2H, brdd, J = 11.6, 4.4 Hz), 4.29 (2H, t, J = 6.2 Hz).

Reference Example 88

 3-bromo-2_ (4-fluorophenyl) propene

 AIBN (120 mg, 0.175 g) was added to a suspension of 2- (4_fluorophenyl) propene (9.94 g, 71.5 mfflol) and N-bromosuccinimide (13.6 g, 75.1 mmol) in ethyl acetate (100 ml) while heating under reflux. mmol) was added 12 times every 10 minutes, and the reaction solution was further heated to reflux for 4 hours. The reaction solution was concentrated, and diluted with hexane (60 ml). The insoluble material was separated by filtration and washed with hexane-diisopropyl ether (3: 1, 60 ml). The mother liquor and the washings were combined and concentrated to dryness to give 3-bromo-2- (4-fluorophenyl) propene (purity 70%, 11.7 g, about 35 mmol) as a pale yellow oil.

_{Ή- MR (200MHz, CDC1 3)} : 54.35 (2H, d, J = 0.6 Hz), 5.47 (1H, brs), 5.50 (1H, brs), 7.06 (2H, t, J = 8.8 Hz), 7.46 ( 2H, dd, J = 9.0, 5.4 Hz).

Reference example 89

2-propylpentyl methanesulfonate

 A solution of 2-propylpentanoic acid (8.50 g, 57.8 mol) and concentrated hydrochloric acid (9.6 ml, 0.116 mmol) in methanol (140 ml) was stirred at room temperature for 20 hours. Purification by extraction with ethyl acetate gave a mixture of methyl 2-propylpentanoate and ethyl acetate (2: 1, 6.38 g, 31.8 mmol) as a colorless oil.

_{Ή-NMR (200MHz, CDC1 3} ): (50.89 (6H, t, J = 7.0 Hz), 1.31 (4H, m), 1.45 (2H, m), 1.57 (2H, m), 2.37 (1H, m) , 3.67 (3H, s).

Dissolve the oil (6.38 g) in THF (100 ml) and stir at 0 ° C Pum aluminum (purity 80%, 1.51 g, 31.8 band01) powder was added in several portions and stirred at 0 ° C for 2 hours. The reaction solution was post-treated in the same manner as in Reference Example 31 to give 2-propylphenol (purity 90%, 4.2 g, 29.0 ol) as a colorless oil.

'H-NMR (200MHz, CDC1 3): <50.91 (6H, t, J = 6.5 Hz), 1.30 (8H, m), 1.49 (1H, m), 3.54 (2H, d, J = 5.2 Hz).

 This 2-propylpentanol (purity 90%, 4.2 g, 29.0 t ol) was dissolved in chloroform (60 ml), and methanesulfonyl chloride (2.39 ml, 30.5 ol) was stirred at 0 ° C while stirring. Then, a solution of triethylamine (4.62 ml, 33.4 tmol) in chloroform (10 ml) was added dropwise over 30 minutes, and the reaction mixture was stirred for 3 hours with TC. During this time, methanesulfonyl chloride ( 0.69 ml, 8.70 mmol) and triethylamine (1.21 ml, 8.70 mmol) were added, and the reaction mixture was worked up in the same manner as in Reference Example 31 to give 2-propylpentyl methanesulfonate (5.57 g, 26.7 mmol) as a colorless product. Obtained as an oil.

_{Ή-NMR (200MHz, CDC1 3} ): 50.91 (6H, m), 1.34 (8H, m), 1.74 (1H, m), 3.00 (3H, s), 4.13 (2H, d, J = 5.0 Hz).

Reference Example 90

a ゥ 2,6-Dimethylheptan-4-yl

 Dissolve 2,6-dimethyl_4-heptanol (4.02 g, 23.7 ol) in chloroform (60 ml), add methanesulfonyl chloride (2.22 ml, 28.4 t) with stirring with, and then triethylamine ( A solution of 4.27 ml (30.8 tmol) in black form (10 ml) was added dropwise over 60 minutes, and the reaction solution was stirred at 0 ° C for 20 minutes. The reaction solution was post-treated in the same manner as in Reference Example 31 to obtain 2,6-dimethylheptane-4-yl methanesulfonate (purity 83%, 6.32 g, 23.7 mol) as a colorless oil.

_{ΐ-NMR (200MHz, CDC1 3} ): (50.94 (6H, d, J = 6.2 Hz), 1.45 (2H, m), 1.69 (4H, m), 3.00 (3H, s), 4.87 (1H, d, m).

The obtained 2,6-dimethylheptane-4-yl methanesulfonate (purity 83, 6.32 g, 23.7 tmol) and sodium iodide (7.10 g, 47.4 mmol) were suspended in 2-butane nonone (140 ml). The suspension was stirred at room temperature for 14 hours and then heated to reflux for 2 hours. Purification by extraction with ethyl acetate-hexane (1: 1) gave crude 2,6-dimethylheptane-4-yl iodide (purity 50%, 7.2 g) as a yellow oil. Reference Example 91

Mesulfone tetrahydrofuran-3-methyl

 To a solution of tetrahydrofuran-3-methanol (2.75 g, 26.7 mmol) and methanesulfonyl chloride (3.23 g, 28.0 mmol) in chloroform (30 ml), stir at 0, and triethylamine (4.06 ml, 29.3 bandol). Was added dropwise over 60 minutes, and the reaction solution was stirred at 0 ° C for 60 minutes. The reaction solution was purified by extraction with ethyl acetate to give tetrahydrofuran-3-methyl methanesulfonate (4.20 g, 23.3 mmol) as a colorless oil.

_{Ή-NMR (200MHz, CDC1 3} ): 51.66 (1H, m), 2.10 (1H, m), 2.69 (1H, brquint, J = 6.9 Hz), 3.03 (3H, s), 3.65 (1H, dd, J = 9.0, 5.2 Hz), 3.74 (1H, dd, J-8.4, 7.4 Hz), 3.84 (1H, dd, J = 9.2, 6.6 Hz), 3.87 (1H, m), 4.14 (1H, dd, J = 9.8, 8.0 Hz), 4.19 (1H, dd, J = 9.8, 7.0 Hz).

Reference Example 92

Methanesulfonic acid 2- (tetrahydrofuran-3-yl) ethyl

 A suspension of tetrahydrofuran-3-methyl methanesulfonate (3.16 g, 17.5 ol) and sodium cyanide (1.77 g, 35.1 ol) in DMSO (15 ml) obtained in Reference Example 91 at 50 ° C. for 14 hours. Stirred. The crude oil obtained by extraction with ethyl acetate was purified by chromatography on silica gel (40 g) (ethyl acetate-hexane, 3: 7-5: 5), and a mixture of tetrahydrofuran-3-acetonitrile and ethyl acetate (2 : 1, 2.83 g, 14.5 mmol) as a colorless oil.

'H-NMR (300MHz, CDC1 3): (51.73 (1H, brsixtet, J = 7.5 Hz), 2.20 (1H, m), 2.42 (1H, dd, J = 16.7, 7.7 Hz), 2.45 (1H, dd , J = 16.7, 6.6 Hz), 2.61 (1H, brseptet, J = 6.5 Hz), 3.56 (1H, dd, J = 9.0, 5.2 Hz), 3.81 (1H, q, J = 7.0 Hz), 3.92 (2H , m).

 This colorless oil (2.80 g, 14.3 ol) was dissolved in 3N sodium 7-dioxide (60 ml) and heated under reflux for 13 hours. The reaction solution was adjusted to be acidic, extracted and purified with ethyl acetate, and tetrahydrofuran-3-acetic acid (1.80 g, 13.8 mmol) was obtained as a pale brown oil.

¾ one _{NMR (300MHz, CDC1 3):} (51.60 (1H, m), 2.12 (1H, m), 2.44 (1H, dd, J = 13.0, 1.0 Hz), 2.43 (1H, d, J = 13.0 Hz) , 2.65 (1H, brseptet, J = 7.3 Hz), 3.45 (1H, dd, J = 8.8, 6.2 Hz), 3.79 (1H, q, J = 8.4 Hz), 3.90 (2H, m). Tetrahydrofuran-3-acetic acid (1.80 g, 13.8 banded 01) and concentrated hydrochloric acid (2.3ml, 27.6) A solution of imol) in ethanol (36 ml) was stirred at room temperature for 13 hours. Purification by extraction with ethyl acetate gave tetrahydrofuran-3-ethyl acetate (1.70 g, 10 Onraiol) as a pale yellow oil.

'H-NMR (200 MHz, CDCI ₃ ): 51.26 (3H, t, J = 7.1 Hz), 1.60 (1H, m), 2.13 (1H, m), 2.41 (2H, d, J = 8.0 Hz), 2.63 (1H, brsixtet, J = 7.1 Hz), 3.42 (1H, dd, J = 8.4, 6.6 Hz), 3.76 (1H, dd, J-8.4, 7.2 Hz), 3.85 (1H, m), 3.95 (1H, dd, J = 8.6, 7.0 Hz), 4.14 (2H, q, J = 7.1 Hz).

 This tetrahydrofuran-3-ethyl acetate (1.70 g, 10.0 ol) was dissolved in THF (35 ml), and lithium aluminum hydride (purity 80¾, 0.47 g, 10.0 olol) was stirred at 0 ° C to obtain a powder. The mixture was added in several portions and stirred at 0 ° C for 1 hour. The reaction solution was post-treated in the same manner as in Reference Example 31 to obtain a mixture of 2- (tetrahydrofuran-3-yl) ethanol and ethyl acetate (1.43 g, 9.55 mmol) as a brown oil.

'H-NMR (200MHz, CDC1 3): (51.56 (1H, m), 1.68 (2H, q, J = 6.7 Hz), 2.09 (1H, m), 2.31 (1H, sixtet, J = 7.4 Hz), 3.39 (1H, dd, J = 8.4, 7.4 Hz), 3.69 (2H, dd, J = 1.4, 6.6 Hz), 3.74 (1H, brt, J = 7.4 Hz), 3.86 (1H, m), 3.93 (1H , Brt, J = 8.2 Hz).

 This brown oil (1.43 g, 9.55 mmol) was dissolved in THF (20 ml), methanesulfonyl chloride (0.783 ml, 10.0 mmol) was added while stirring with Ot :, and then triethylamine (1.52 ml, 11.0 mmol). ) In THF (5 ml) was added dropwise over 60 minutes, and the reaction solution was stirred at 0 for 1.5 hours. The reaction solution was post-treated in the same manner as in Reference Example 31 to obtain an oily product, which was purified by chromatography on silica gel (10 g) (ethyl hexane acetate, 2: 8-5: 5) to give methanesulfonic acid 2- ( Tetrahydrofuran-3-yl) ethyl (1.10 g, 5.66 mmol) was obtained as a colorless oil.

_{Ή-NMR (200MHz, CDC1 3} ): 51.57 (1H, m), 1.83 (1H, dd, J = 6.2, 2.8 Hz), 1.88 (1H, dd, J = 6.6, 2.6 Hz), 2.11 (1H, m ), 2.33 (1H, brsixtet, J = 7.1 Hz), 3.03 (3H, s), 3.39 (1H, brt, J = 7.7 Hz), 3.77 (1H, brq, J = 7.9 Hz), 3.87 (1H, in ), 3.93 (1H, brt, J = 8.0 Hz), 4.26 (2H, t, J = 6.4 Hz). Reference 93

Maleic sulfonic acid (S) -2-phenylpropyl

 A solution of (S) -2-phenylpropionic acid (1.0 g, 6.66 benzyl) and concentrated hydrochloric acid (1.11 ml, 13.3 mmol) in methanol (20 ml) was stirred at room temperature for 18 hours. Purification by ethyl acetate extraction gave methyl (S) -2-phenylpropionate (1.20 g, 6.66 ol) as a colorless oil.

_{Ή-NMR (200MHz, CDC1 3} ): δΐ.50 (3Η, d, J = 7.0 Hz), 3.66 (3H, s), 3.73 (1H, q, J = 7.3 Hz), 7.30 (5H, m).

 This methyl (S) -2-phenylpropionate (1.20 g, 6.66 mmol) was dissolved in THF (25 ml), and lithium aluminum hydride (purity 80, 316 mg, 6.66 t ) Was added in several portions, and the mixture was stirred at 0 ° C for 80 minutes. The reaction solution was purified by extraction with ethyl acetate to obtain a mixture of (S) -2-phenylpropanol and ethyl acetate (3: 2, 1.24 g, 6.48 mol) as a colorless oil.

'H-NM (200MHz, CDC1 3): δ 1.28 (3H, d, J = 7.0 Hz), 2.96 (1H, sixtet, J = 7.3 Hz), 3.71 (2H, brd, J = 7.0 Hz), 7.25 ( 3H, m), 7.33 (2H, m).

 This (S) -2-phenylpropanol (1.24 g, 6.48 alcohol) was dissolved in chloroform (20 ml), methanesulfonyl chloride (0.533 ml, 6.80 mmol) was added while stirring at 0, and then triethylamine was added. A solution of (1.03 ml, 7.45 mmol) in chloroform (5 ml) was added dropwise over 30 minutes, and the reaction solution was stirred at 0 for 80 minutes. The reaction solution was purified by extraction with ethyl acetate to obtain (S) -2-phenylpropyl methanesulfonate (1.29 g, 6.02 mmol) as a colorless oil.

_{^ - MR (200MHz, CDC1 3} ): <51.37 (3H, d, J = 7.0 Hz), 2.80 (3H, s), 3.19 (1H, sixtet, J = 7.0 Hz), 4.25 (1H, dd, J = 9.8, 7.0 Hz), 4.30 (1H, dd, J = 10.0, 7.0 Hz), 7.20-7.33 (5H, m).

Reference Example 94

Methanesulfonic acid (R) _2-phenylpropyl

According to the method of Reference Example 93, (R) -2-phenylpropanol (1.30 g, 6.66 mmoK containing ethyl acetate) was obtained as a colorless oil from (R) -2-phenylpropionic acid (1.0 g, 6.66 mmol). . _{^{l HN R (200MHz, CDC1 3}} ): 51.28 (3H, d, J = 6.8 Hz), 2.96 (1H, sixtet,] = 6.8 Hz), 3.71 (2H, d, J = 7.0 Hz), 7.23 (3H, m), 7.32 (2H, d, J = 5.4 Hz).

 From this colorless oil, methanesulfonic acid (R) -2-phenylpropyl (purity 90%, 1.55 g, 6.51 mol) was obtained as a colorless oil according to the method of Reference Example 93.

_{¾-NMR (200MHz, CDC1 3} ): 51.37 (3H, d, J = 7.2 Hz), 2.81 (3H, s), 3.19 (1H, sixtet, J = 7.0 Hz), 4.25 (1H, dd, J = 9.8 , 7.0 Hz), 4.31 (1H, dd, J = 10.0, 7.0 Hz), 7.20-7.39 (5H, m).

Reference example 95.

2- (4-fluorophenyl) propyl sulfonic acid

 3-bromo-2- (4-fluorophenyl) propene (purity 70, 3.31 g, 10.7 mmol), acetic acid (0.93 ml, 16.2 ol) and potassium carbonate (2.33 g, 16.2 mmol) obtained in Reference Example 88 ) In acetonitrile (20 ml) was stirred at room temperature for 20 hours and then at 7 (6 hours at T). The reaction mixture was concentrated and diluted with ethyl acetate-hexane (1: 1, 40 ml). After removal, the residue was washed with ethyl acetate-hexane (1, 40 ml) and the mother liquor and the washings were concentrated to dryness to give 2_ (4-fluorophenyl) -2-propenyl acetate (purity 70 2.33 g, 8.4 mmol). Was obtained as a brown oil.

 This colorless oil (2.33 g, 8.4 mmol) was dissolved in ethyl acetate (75 ml), and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere in the presence of 10% palladium carbon (417 mg, containing 52% water). The reaction solution was filtered to remove the catalyst, and concentrated to dryness to obtain crude 2- (4-fluorophenyl) propyl acetate (78% purity, 2.10 g, 8.4 benzyl) as a pale yellow oil.

_{Ή-NMR (200MHz, CDC1 3} ): 51.28 (3H, d, J = 6.8 Hz), 2.01 (3H, s), 3.08 (1H, sixtet, J two 7.0 Hz), 4.10 (1H, dd, J = 10.6 , 7.0 Hz), 4.14 (1H, dd, J = 11.0, 7.4 Hz), 7.00 (2H, i, J- 8.8 Hz), 7.18 (2H, dd, J = 8.8, 5.6 Hz).

 This pale yellow oil (purity 78, 2.10 g, 8.411111101) was dissolved in methanol (401111), and the mixture was stirred with sodium hydroxide (0.71 g, 16.8 t) at room temperature for 1.5 hours. The reaction solution was neutralized, extracted with ethyl acetate, dehydrated and dried, and concentrated to dryness to obtain crude 2- (4-fluorophenyl) propanol (1.98 g) as a pale brown oil.

This oily substance α.98 g) was dissolved in chloroform (20 ml), methanesulfonyl chloride (0.72 ml, 9.22 mmol) was added while stirring at 0, and then triethylamine was added. A solution of (1.39 ml, 10.1 mmol) in chloroform (5 ml) was added dropwise over 40 minutes, and the reaction solution was stirred at 0 ° C for 60 minutes. The reaction solution was concentrated and extracted with ethyl acetate. The oil obtained was purified by chromatography on silica gel (10 g) (ethyl acetate-hexane, 1: 9-2: 8) to give methanesulfonic acid 2- (4-Fluorophenyl) propyl (1.33 g, 5.68 mmol) was obtained as a pale yellow oil.

_{¾-NMR (200MHz, CDC1 3} ): 51.35 (3H, d, J = 7.4 Hz), 2.86 (3H, s), 3.18 (1H, sixtet, J = 6.9 Hz), 4.22 (1H, dd, J = 9.6 , 7.0 Hz), 4.26 (1H, dd, J = 10.0, 7.0 Hz), 7.03 (2H, t, J = 8.6 Hz), 7.20 (2H, dd, J = 8.8, 3.0 Hz).

Reference Example 96

Methanesulfonic acid 2- (2,3,4,5,6-pentamethylphenyl) ethyl

A suspension of 2,3,4,5,6-pentamethylbenzyl chloride (4.01 g, 20.0 mmol) and sodium cyanide (2.02 g, 40.0 mmol) in DMS0 (20 ml) was stirred at room temperature for 3 days. did. The pale yellow solid obtained by extraction with ethyl acetate was pulverized in methanol to give 2,3,4,5,6-pentamethylphenylacetonitrile (1.75 g, 9.36 t ol) as a white powder. 'H-NMR (200MHz, CDC1 3): 52.24 (9H, s), 2.32 (6H, s), 3.70 (2H, s).

Dissolve the crude 2,3,4,5,6-pentamethylphenylacetonitrile (purity 90%, 2.04 g, 9.8 benzene) in acetic acid (13.6 ml) and concentrated hydrochloric acid (6.8 ml) and heat to reflux for 24 hours did. The reaction solution was cooled and diluted with water (30 ml). The precipitate was collected by filtration, washed with water, and dried to give 2,3,4,5,6-pentamethylphenylacetic acid (2.08 g, 10.1 liter) as a white powder. _{Ή-NMR (200MHz, CDC1 3} ): δ 2.23 (9Η, s), 2.24 (6H, s), 3.80 (2H, s).

 Methyl 2,3,4,5,6-pentamethylphenylacetate (2,3,4,5,6-pentamethylphenylacetate (1.55 g, 7.49 mmol) according to the esterification method of Reference Example 93 1.51 g, 6.86 t) was obtained as a white powder.

_{Ή-NMR (200MHz, CDC1 3} ): (52.23 (9H, s), 2.24 (6H, s), 3.68 (3H, s), 3.77 (2H, s).

According to the reduction method using lithium aluminum hydride of Reference Example 93 from methyl 2,3,4,5,6-pentanomethylphenylacetate (1.51 g, 6.86 mmol), 2- (2,3,4,5,6 -Phenylmethylphenyl) ethanol (1.34 g, 6.86 mmol) was obtained as a white powder. _{Ή-NMR (200MHz, CDC1 3} ): 52.23 (9H, s), 2.29 (6H, s), 3.04 (2H, t, J = 7.7 Hz), 3.75 (2H, t, J = 7.7 Hz).

 According to the method of methanesulfonic acid esterification of Reference Example 93 from 2- (2,3,4,5,6-pentanoylmethylphenyl) ethanol (1.34 g, 6.86 mmol), methanesulfonic acid 2- (2,3,4, 5,6-Pentamethylphenyl) ethyl (1.85 g, 6.84 mmol) was obtained as a white powder. .

_{Ή-NMR (200MHz, CDC1 3} ): 62.22 (6H, s), 2.23 (3H, s), 2.29 (6H, s), 2.95 (3H, s), 3.23 (2H, brdd, J = 8.4, 8.0 Hz ), 4.25 (2H, dd, J = 8.4, 8.2 Hz).

Reference Example 97

2- (2,4,6-trimethylphenyl) ethyl methanesulfonate

 According to the method of cyanation in Reference Example 96, 2,2,6-trimethylphenylacetonitrile (3.69 g, 22.0 mmol) was obtained from 2,4,6-trimethylbenzyl chloride (3.91 g, 22.0 ol) as a pale yellow powder. .

_{lH-NMR (200MHz, CDC1 3} ): 52.27 (3H, s), 2.36 (6H, s), 3.70 (2H, s), 6.90 (2H, s).

 2,4,6-Trimethylphenylacetic acid (2.80 g, 15.7 t ol) was obtained from 2,4,6-trimethylphenylacetonitrile (2.72 g, 16.2 t) according to the acid hydrolysis method of Reference Example 96 as a white powder. As obtained.

_{- NMR (200MHz, CDC1 3)} : (32.26 (3H, s), 2.29 (6H, s), 3.68 (2H, s), 6.87 (2H, brs).

 Methyl 2,4,6-trimethylphenylacetate (1.96 g, 10.2 mmol) was obtained from 2,4,6-trimethylphenylacetic acid (1.84 g, 10.3 thigh 01) according to the esterification method of Reference Example 96 as a colorless oil. As obtained.

_{Ή-NMR (200MHz, CDC1 3} ): 52.26 (3H, s), 2.29 (6H, s), 3.66 (2H, s), 3.67 (3H, s), 6.87 (2H, brs).

 Methyl 2,4,6-trimethylphenylacetate a.96 g, 10.2 mol) according to the method of reduction using lithium aluminum hydride in Reference Example 96 to give 2- (2,4,6-trimethylphenylacetate). Enyl) ethanol (purity 90%, 1.83 g, 10.0 mmol) was obtained as a white gel.

_{Ή-NMR (200MHz, CDC1 3} ):. (52.25 (3H, s), 2.32 (6H, s), 2.93 (2H, t, J = 7.5 Hz), 3.74 (2H, t, J = 7.5 Hz), 6.85 (2H, brs).

 From 2_ (2,4,6-trimethylphenyl) ethanol (purity 90 1.8, 1.83 g, 10.0 mmol), 2- (2,4,6-trimethyl methanesulfonate was obtained according to the method for methanesulfonate esterification in Reference Example 96. Phenyl) ethyl (2.46 g, 9.64 mmol) was obtained as a pale yellow oil.

_{Ή-NMR (200MHz, CDC1 3} ): 52.25 (3H, s), 2.32 (6H, s), 2.89 (3H, s), 3.11 (2H, t, J = 7.9 Hz), 4.27 (2H, t, J = 7.7 Hz), 6.86 (2H, brs).

Reference 98

I- (2-tetrahydropyranyl) ethyl ester

 A suspension of 2-tetrahydroviranylmethyl bromide (2.98 g, 16.3 thigh) and sodium cyanide (2.02 g, 40.0 mmol) in DMSO (15 ml) was stirred at room temperature for 2 days. Extraction and purification were performed with ethyl acetate, and 2-tetrahydropyranyl acetonitrile (2.81 g, 16.3 mol, containing ethyl acetate) was obtained as a yellow oil.

_{Ή-NMR (200MHz, CDC1 3} ): 51.47 (1H, brq, J = 12.4 Hz), 1.54 (3H, m), 1.73 (1H, dm, J = 9.6 Hz), 1.89 (1H, m), 2.50 ( 2H, d, J- 6.2 Hz), 3.47 (1H, tm, J = 10.6

Hz), 3.56 (1H, m), 4.01 (1H, dm, J = 11.0 Hz).

 The obtained 2-tetrahydropyranyl acetonitrile (2.81 g, 16.3 acetyl) was converted to acetic acid.

(20 ml) and concentrated hydrochloric acid (10 ml) and heated under reflux for 20 hours. The reaction solution was concentrated to dryness to obtain a mixture of a colorless oil and ammonium chloride. This was suspended in ethanol (39 ml) and stirred at room temperature for 3 days with concentrated hydrochloric acid (2.72 ml, 32.6 mol). Extraction and purification with ethyl acetate yielded 2-tetrahydropyranyl ethyl acetate (3.3 g, 13.4 mol ol, containing ethyl acetate) as a yellow oil.

'H-NMR (300MHz, CDC1 3): 51.26 (3H, t, J = 7.1 Hz), 1.45-1.58 (4H, m), 1.64 (1H, dm, J = 11.0 Hz), 1.83 (1H, m) , 2.38 (1H, dd, J = 15.0, 5.3 Hz), 2.50 (1H, dd, J = 15.0, 7.8 Hz), 3.45 (1H, brt, J = 10.8 Hz), 3.74 (1H, m), 3.96 ( 1H, brd, J = 10.3 Hz), 4.15 (2H, q, J = 7.2 Hz).

From the obtained 2-tetrahydropyranyl acetate ethyl (3.3 g, 13.4 mmol), according to the reduction method using lithium aluminum hydride of Reference Example 93, crude 2- (2-tetrahydroviranyl) ethanol (1.96 g) was used. Was obtained as a brown oil. From this oil The brown oil obtained according to the method of methanesulfonic acid esterification of Reference Example 91 was purified by chromatography on silica gel (25 g) (ethyl acetate-hexane, 3: 7-4: 6) to give methanesulfonic acid 2 -(2-Tetrahydropyranyl) ethyl (purity 95%, 2.08 g, 9.44 mmol) was obtained as a pale yellow oil.

_{Ή-NMR (200MHz, CDC1 3} ): 61.30 (1H, brq, J = 10.6 Hz), 1.54 (3H, m), 1.58 (1H, brd, J = 10 Hz), 1.86 (3H, m), 3.01 ( 3H, s), 3.40 (2H, m), 3.96 (1H, brd, J = 11 Hz), 4.31 (1H, dd, J = 10.0, 6.6 Hz), 4.38 (1H, dd, J = 10.0, 6.6 Hz) A suspension of the obtained 2- (2-tetrahydropyrael) ethyl methanesulfonate (purity: 95, 2.08 g, 9.44 acetyl) and sodium iodide (3.00 g, 20.0 liter) in acetone (40 ml) Was heated to reflux at room temperature for 2 hours. The extract was purified by extraction with ethyl acetate to obtain crude 2- (2-tetrahydropyranyl) ethyl chloride (2.60 g, 9.4 mmol, containing ethyl acetate) as a brown oil.

_{Ή-NMR (200MHz, CDC1 3} ): 1.32 (1H, brq, J = 11 Hz), 1.53 (3H, m), ca. 1.6 (1H, m), 1.84 (3H, m), 1.93 (2H, m ), 3.26 (1H, d, J = 7.8 Hz), 3.30 (1H, d, J = 7.6 Hz), 3.38 (2H, m), 3.97 (1H, dm, J = 11.0 Hz).

Reference 99

 Tert-butyl 3-bromo-2-oxobutyrate

A solution of ethyl chloroglyoxylate (13.9 g, 0.10 mol) and tert-butanol (10.3 ml, 0.11 mol) in chloroform (60 ml) was stirred at room temperature at room temperature with pyridine (8.90 ml, 0.11 mol). (10 ml) solution was added dropwise over 40 minutes and the mixture was stirred for 20 hours. After diluting the reaction mixture with a mixture of diisopropyl ether and hexane (1: 1, 300 ml), the insolubles were removed, and the supernatant was concentrated and tert-butylethyl dalioxylate (purity 79%, 21.9 g) , Containing diisopropyl ether) as a colorless oil. _{Ή-NMR (200MHz, CDC1 3} ): 1.37 (3H, t, J = 7.1 Hz), 1.56 (9H, s), 4.32 (2H, q, J = 7.1 Hz).

To a solution of the obtained tert-butylethyl glyoxylate (5.15 g, 23.3 bandol) in THF-ethyl ether (1: 2, 90 ml) was added, under an argon atmosphere, tilmagnesium bromide (1.0 M THF solution, 28.0 ml). The solution was dropped at 78 at 60 minutes. After the reaction solution was stirred at −78 for 2 hours, the temperature was raised to −60 over 30 minutes. Dilute the reaction solution with 1N hydrochloric acid (28 ml) And 4.5 ammonium chloride (120 ml) and extracted with diisopropyl ether-hexane (1: 1, 100 ml). The organic layer was washed with water and saturated saline, dried over sodium sulfate, and concentrated to obtain crude tert-butyl 2-oxobutyrate (purity 70%, 3.87 g, 17.1 mmol) as a pale yellow oil. .

_{Ή-NMR (200MHz, CDC1 3} ): άΐ.11 (3Η, t, J = 7.2 Hz), 1.55 (9H, s), 2.81 (2H, q, J = 7.3 Hz).

 To a solution of tert-butyl 2-oxobutyrate (0.98 g, 4.3 t) in chloroform (16 ml) was added, while stirring at 0 ° C, trimethylphenammonium tribromide α.66 g, 4.3 t). The reaction was stirred at 0 ° C. for 90 minutes. The reaction solution was returned to room temperature and stirred for 40 minutes. The reaction solution was extracted with diisopropyl ether to obtain crude tert-butyl 3-bromo-2-oxobutyric acid (purity: 50, 0.94 g, about 2 t ol) as a pale yellow oil.

Reference example 100

2- (4-chlorophenyl) propyl iodide

 According to the method of esterification in Reference Example 31 from methyl 2- (4-chlorophenyl) propionate (6.4 g, 33.6 mmol), methyl 2- (4-chlorophenyl) propionate (6.67 g, 33.6 mmol) was obtained. A yellow oil was obtained.

_{Ή-NMR (200MHz, CDC1 3} ): 61.49 (3H, d, J = 7.4 Hz), 3.66 (3H, s), 3.70 (1H, q, J- 7.2 Hz), 7.25 (2H, dt, J = 8.8 , 2.6 Hz), 7.28 (2H, dt, J = 8.8, 2.4 Hz).

 According to the method of reduction using lithium aluminum hydride of Reference Example 31 from methyl 2- (4-cyclobutenyl) propionate (6.67 g, 33.6 mmol), 2- (4-chlorobutenyl) propanol (5.64 g) , 33.1 thigh).

_{lH - NMR (200MHz, CDC1 3} ): 51.26 (3H, d, J = 6.8Hz), 2.94 (1H, sixtet, J = 6.8 Hz), 3.69 (2H, d, J = 7.0 Hz), 7.18 (2H, dt, J = 8.4, 2.0 Hz), 7.29 (2H, dt, J = 8.8, 2.2 Hz).

 According to the method of methanesulfonic acid esterification of Reference Example 31 from 2- (4-chlorophenyl) propanol (5.64 g, 33.1 tmol), 2- (4-chlorophenyl) propyl methanesulfonate (purity 95%) , 8.54 g, 32.6 marl ol).

_{Ή- NMR (200MHz, CDC1 3)} : 1.35 (3H, d, J = 7.2 Hz), 2.86 (3H, s), 3.18 (1H, sixtet, J = 7.0 Hz), 4.22 (1H, dd, J = 9.8 , 7.0 Hz), 4.27 (1H, dd, J = 9.8, 6.8 Hz), 7.19 (2H, dt, J = 8.4, 2.2 Hz), 7.30 (2H, dt, J = 8.8, 2.2 Hz).

 From 2- (4-chlorophenyl) propyl methanesulfonate (purity 95%, 8.54 g, 32.6 mmol) according to the method of iodinating in Reference Example 98, 2- (4-chlorophenyl) propyl pill (purity) 95, 9.04 g, 30.6 mol) of a pale oily substance was obtained.

_{Ή-NMR (200MHz, CDC1 3} ): <51.39 (3H, d, J = 6.8 Hz), 3.02 (1H, sixtet, J = 7.0 Hz), 3.30 (1H, dd, J = 9.4, 7.0 Hz), 3.35 (1H, dd, J = 9.4, 7.0 Hz), 7.14 (2H, dt, J = 8.4, 1.8 Hz), 7.29 (2H, dt, J = 8.4, 1.8 Hz).

Reference Example 101

 2,2-Difluoro mouth trifluorosulfonic acid 2-phenylethyl

 Ethyl phenyloxalylate (purity: 80 7., 7.35 g, 33.0 mmol) Diethyl trifluoride (hereinafter sometimes abbreviated as DAST, 5.91 g, 33.0 mmol) was added dropwise over 80 minutes at room temperature. The mixture was stirred at ° C for 4 hours. The reaction solution was poured into ice (200 g), mixed, and extracted with ethyl acetate (250 ml). The organic layer was washed with a 2% aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over sodium sulfate, and concentrated to give a crude oily substance of crude 2,2-difluoro-2-ethylphenyl acetate (8.6 g) as a yellow oil. I got

 The brown oily substance (8.7 g) obtained from the obtained crude 2,2-difluoro-2-ethylphenylacetate (8.6 g) according to the reduction method using lithium aluminum hydride of Reference Example 31 was treated with silica gel ( 80 g) chromatography (ethyl acetate-hexane, 3: 97-15: 85), and 2,2-difluoro-2-phenethyl alcohol (purity 78%, 4.94 g, 24.4 tmol) was purified. Obtained as an oil.

_{Ή-NR (200MHz, CDC1 3} ): 61.94 (1H, t, J- 7.0 Hz), 3.98 (2H, dt, J = 7.2, 13.5 Hz), 7.48 (5H, m).

At 0 ° C, a solution of 2,2-difluoro mouth-2-phenylethanol (0.30 g, 1.90 mmol) and trifluoromethanesulfonic anhydride (0.665 g, 2.28 benzene) in chloroform (5 ml) was added at 0 ° C. While stirring, a solution of triethylamine (0.316 ml, 2.28 alcohol) in chloroform (2 ml) was added dropwise over 50 minutes, and the reaction solution was stirred at 0 ° C for 30 minutes. The reaction mixture was diluted with ethyl acetate (30 ml) and hexane (12 ml), washed with ice water and saturated saline, dried over sodium sulfate, and concentrated to give 2,2-difluorotrifluoromethanesulfonic acid. -2-phenylethyl (0.50 g, 1.73 t) was obtained as a pale brown oil. _{¾-NMR (200MHz, CDC1 3} ): δ4.69 (2H, t, J = 12.1 Hz), 7.52 (5H, s).

Reference Example 102

 2,2-dimethylbutanol

 A solution of 2,2-dimethylbutyric acid (purity 90 °, 10.8 g, 83.7 inmol) concentrated hydrochloric acid (13.9 ml, 0.167 mol) in methanol (90 ml) was stirred at room temperature for 22 hours. The reaction solution was neutralized by adding sodium hydrogen carbonate, and purified by extraction with ethyl acetate to obtain a pale yellow oil of methyl 2,2-dimethylate.

_{Ή-NMR (200MHz, CDC1 3} ): 50.83 (3H, t, J = 7.3 Hz), 1.16 (6H, s), 1.56 (2H, q, J = 7.3 Hz), 3.66 (3H, s).

 The powder of lithium aluminum hydride (purity 80%, 3.97 g, 83.7 hi) was added to the obtained solution of methyl 2,2-dimethylbutyrate in THF (200 ml) with stirring at 0 ° C in several portions. The mixture was stirred at 0 ° C for 2 hours. Extraction with getyl ether, drying and concentration, the resulting oil was distilled under reduced pressure (95-100 mmHg) to give a colorless oil of 2,2-dimethylbutanol (5.70 g, 55.8 mmol).

_{¾-NMR (200MHz, CDC1 3} ): δ 0.84 (3Η, t, J = 7.5 'Hz), 0.86 (6H, s), 1.28 (2H, q, J = 7.5 Hz), 3.32 (2H, s).

Boiling point. 77-80

Reference Example 103

 2,2-difluoroisopene

 DAST (5.00 g, 27.9 mmol) was added dropwise to ethyl 3-methyl-2-oxobutyrate (4.15 g, 27.9 mmol) at room temperature with stirring at room temperature over 60 minutes, and the mixture was stirred at 60 ° C for 4 hours. did. The reaction solution was poured into ice (200 g), mixed, and extracted with ethyl acetate (250 ml). The organic layer was washed with 5% aqueous sodium hydrogencarbonate, water and saturated saline, dried over sodium sulfate, and concentrated to give a crude oily substance of crude ethyl 2,2-difluoro-3-methylbutyrate (5.0 g) as a yellow oil. I got

The brown oil obtained from the crude 2,2-difluoro-3-methylbutyrate (5.0 g) according to the reduction method using lithium aluminum hydride of Reference Example 31 was converted to a silica gel (35 g). Purified by chromatography (getyl ether-hexane, 0: 10-2: 8), 2,2-difluoroisopentanol (purity 20 純度, 0.34 g, 0.55 ml) Ethyl ether) as an oil.

'H-NMR (200MHz, CDC1 3): (51.05 (6H, d, J = 6.8 Hz), 2.25 (1H, septet, J = 7.1 Hz), 3.80 (2H, dt, J = 7.0, 13.4 Hz).

Reference Example 104

 2,2-difluoroisopentyl trifluoromethanesulfonate

 Clonal form of 2,2-difluoroisopentanol (purity 80%, 1.51 g, 9.73 tmol) and trifluoromethanesulfonic anhydride (2.22 ml, 13.3 l) obtained in the same manner as in Reference Example 103. (25 ml) 0 in solution. While stirring with C, a solution of triethylamine (2.00 ml, 14.5 tmol) in chloroform (5 ml) was added dropwise over 30 minutes, and the reaction solution was stirred at 0 ° C for 45 minutes. The reaction solution was diluted with diisopropyl ether (160 ml), washed with ice water and saturated saline, dried and concentrated. The residue was purified by chromatography on silica gel (20 g) (ethyl acetate-hexane, 1: 19-2: 18), concentrated to dryness, and 2,2-difluoroisopentyl trifluoromethanesulfonate (purity 60¾, 1.24 g, 3.4 mmol) as a yellow powder.

'H-NMR (300MHz, CDC1 3): 61.09 (6H, d, J = 6.9 Hz), 2.25 (1H, t of septet, J = 14.4, 7.2 Hz), 4.57 (2H, t, J = 11.7 Hz) .

Example 1-1

R ⁵ is n in formula (VI) - pentyl group, R ⁶ is a methyl group, R ¹⁰ gar ZR ¹⁵ (Z is S0 _2, R ¹⁵ is p - Toruiru group) Synthesis of Compound R is Echiru group

The compound synthesized in Reference Example 3-2 (20.0 g, 46.5 mmol) was dissolved in THF (200 ml) and DMF (100 ml), and 3-bromo-2-octanone (17.6 ml, purity 51%, 51.2 mmol) was dissolved. And triethylamine (19.4 ml, 0.140 mol) were added, and the mixture was stirred at room temperature for 2 hours. After the reaction mixture was concentrated to dryness, the residue was diluted with ethyl acetate (700 ml), washed with water, 3% aqueous sodium hydrogen carbonate, water, 0.1N hydrochloric acid, water and saturated saline, and dried over sodium sulfate. . The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography on silica gel 60 (200 g, Kieselgel 60, 70-230 mesh, Art. 7734, manufactured by A Merck, Germany) to give ethyl acetate: The eluted fraction of hexane (30:70 to 40:60) was concentrated to dryness under reduced pressure to obtain a pale yellow powder (19.6 g, 35.3 mmol) of the title compound as a mixture of four isomers. ¾-NMR (300 MHz, in double-mouthed form): δ 0.89 / 0.90 (3Η, t, J = 6.5 Hz), 1.27 (3H, t, J = 7.1 Hz), 1.27 (6H, m), 1.57 ( 1H, m), 1.71 / 1.80 (3H, s), 2.10 (1H, m), 2.42 (3H, s), 2.69 (2H, t, J = 7.5 Hz), 3.25 (1H, m), 3.26 / 3.27 (2H, t, J = 7.5 Hz), 4.16 (2H, q, J = 7.1 Hz), 5.57 / 5.73 (1H, brs), 7.30 (2H, d, J = 8.2 Hz), 7.87 / 7.89 (2H, . d, J = 8.2 Hz) , 9.72 (1H, brs), elemental _{analysis: C 24 H 33 N 3 0} 6 S 3 · 0.4H 2 0 calculated: C, 51.21; H, 6.05 ; N, 7.46 S, 17.09 (%), found; C, 51.20; H, 5.90; N, 6.92; S, 16.99 (%).

Example 1-2

In the formula (VI), R ⁵ is an n-hexyl group, R ⁶ is a hydrogen atom, R ¹ . Synthesis of compounds with ZR ¹⁵ (Z is S〇 ₂ , R ¹⁵ is p-tolyl group) and R is ethyl group

 The compound synthesized in Reference Example 3-2 (0.49 g, 1.14 alcohol) was dissolved in THF (8 ml) and DMF (4 ml), and 2-bromooctanal (0.21 ml, purity 94%, 1.14 t ol) was dissolved. ) And triethylamine (0.47 ml, 3.42 imol) were added, and the mixture was stirred at room temperature for 90 minutes. After concentrating the reaction solution, the residue was diluted with ethyl acetate (35 ml), washed with 0.1N hydrochloric acid, water and saturated saline, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography on silica gel 60 (10 g). The fraction eluted with ethyl acetate: hexane (30:70 to 40:60) was concentrated to dryness under reduced pressure. A pale yellow powder (0.48, 0.86 tmol) of the title compound was obtained as a mixture of four isomers.

'H-NMR (300 MHz, in double-mouthed form): δ 0.87 / 0.88 (3H, t, J = 6.8 Hz), 1.25 / 1.26 (3H, t, J = 7.2 Hz), 1.28 (4H, brs) , 1.32 (2H, m), 1.45 (1H, m), 1.48 (2H, brquint, J = 5.7 Hz), 1.74 / 1.85 (1H, m), 2.41 (3H, s), 2.69 (2H, t, J = 7.5 Hz), 3.23 (1H, m), 3.25 / 3.27 (2H, t, J = 7.5 Hz), 4.15 (2H, q, J = 7.2 Hz), 4.55 / 4.78 (1H, m), 5.80 / 5.86 (1H, d / brs, J = 1.9 Hz), 7.28 / 7.29 (2H, d, J = 7.9 Hz), 7.88 / 7.89 (2H, d, J = 7.9 Hz), 10.03 (1H, brs).

Elemental _{analysis: C 24 H 33 N 3 0} 6 S 3 Calculated: C, 51.87; H, 5.99 ;, 7.56; S, 17.31 (%), Found; C, 51.58; H, 6.03 ; N, 7.59 S, 17.48 (%).

Example ί-3

Formula (VI) in R ⁵ is ethoxy Cal Poni Le group, R ⁶ is a methyl group, the synthesis of ^{R 1 (^ S-ZR 15} (Z is S0 _2, R ¹⁵ is P- Toruiru group), and R is an Echiru group The compound synthesized in Reference Example 3-2 (0.51 g, 1.19 mmol) was dissolved in THF (8 ml) and DMF (4 ml), and ethyl 2-chloroacetoacetate (0.18 ml, 1.31 ol) and triethylamine (0.49 g) were dissolved. ml, 3.56 mmol) and stirred at room temperature for 2 hours. After concentrating the reaction solution, the residue was diluted with ethyl acetate (35 ml), washed with 0.1N hydrochloric acid, water and saturated saline, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography on silica gel 60 (10 g). The fraction eluted with ethyl acetate: hexane (40:60 to 50:50) was concentrated to dryness under reduced pressure. Then, a pale yellow powder (0.52 g, 0.93 mol) of the title compound was obtained as a mixture of four isomers.

Ή-NMR (300 MHz, in double-mouthed form): δ 1.25 (6Η, t, J = 7.2 Hz), 1.81 / 2.01 (3H, s), 2.42 (3H, s), 2.64 (2H, m), 3.21 (2H, m), 3.79 / 3.92 (1H, s), 4.15 (2H, q, J = 7.2 Hz), 4.19 (2H, q, J = 7.2 Hz), 6.02 / 4.98 (1H, br), 7.31 (2H, d, J = 8.3 Hz), 7.87 (2H, d, J = 8.3 Hz), 9.77 (1H, brs).

Elemental analysis: Calculated as _{C 22 H 27 N 3 0 8} S 3: C, 47.38; H, 4.88; N, 7.53; S, 17.25 (%), Found; C, 47.18; H, 5.08 ; N, 7.55; S, 17.28 (%).

Example 4

R ⁵ is n- butyl group in the formula (VI), the synthesis of R ⁶ is a methyl group, R ^1Q gar ZR ¹⁵ is S0 _2, R ¹⁵ is p- Toruiru group), and R is an Echiru group

 The compound synthesized in Reference Example 3-2 (697 mg, 1.62 bandol) was dissolved in THF (12 ml) and DMF (8 ml), and 3-bromo-2-hepnonone (1.01 ml, purity 77%, 1.64 mmol) and triethylamine (0.675 ml, 4.87 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was treated in the same manner as in Example 1, to give a pale yellow powder of the title compound (0.65 g, 1.20 mmol) as a mixture of four isomers.

Ή-NMR (300 MHz, in double-hole form): δ 0.93 / 0.91 (3Η, t, J = 6.9 Hz), 1.27 (3H, t, J = 7.1 Hz), 1.32 (2H, m), 1.36 ( 2H, m), 1.55 (1H, m), 1.72 / 1.80 (3H, s), 2.10 (1H, m), 2.41 (3H, s), 2.69 (2H, t, J = 7.4 Hz), 3.24 (1H , m), 3.27 (2H, t, J = 7.4 Hz), 4.16 (2H, q, J = 7.1 Hz), 5.61 / 5.77 (1H, br), 7.29 (2H, brd, J = 8.3 Hz), 7.87 /7.89 (2H, d, J = 8.3 Hz), 9.83 (1H, br)., Elemental analysis: C ₂₃ H ₃₁ N ₃ 0 ₆ S ₃ · 0.2H ₂ 0 Calculated: C, 50.66; H, 5.80; N, 7.71; S, 17.64 (%), found; C, 50.60; H, 5.59; N, 7.72; S, 17.88 (%). The following is a list of compounds synthesized in Examples 1_1 to 1-4 and compounds synthesized in the same manner.

(Table 2)

Replacement paper rules (Table 3)

Difference paper (Rule 26) (Table 4)

Replacement form (rules) (Table 5)

Swallowing saliva (Rule 26) (Table 6)

差替え用紙 (m ) 以下に実施例 1- 5〜1- 52で合成した化合物のデータを示す。

Replacement paper (m) The data of the compounds synthesized in Examples 1-5 to 1-52 are shown below.

Example 1-5

_{Ή-NMR (300MHz, CDC1 3} ): δ 1.25 (3Η, t, J = 7.2 Hz), 2.44 (3H, s), 2.68 (2H, t, J = 7.2 Hz), 3.17 (1H, d, J = 13.2 Hz), 3.25 (2H, dt, J = 5.8, 7.2 Hz), 3.43 (1H, d, J = 13.2 Hz), 4.14 (2H, q, J = 7.2 Hz), 5.61 (1H, s), 7.28 (2H, d, J = 8.3 Hz), 7.28 (2H, m), 7.40 (3H, m), 7.90 (2H, d, J = 8.3 Hz), 9.70 (1H, brs). Elemental analysis: C ₂₄ H ₂₅ N ₃ 0 ₆ S ₃ calculated: C, 52.63; H, 4.60 ; N, 7.67; S, 17.56

(%), Found: C, 52.39; H, 4.61; N, 7.74; S, 17.59 (%).

Example 1-6

_{Ή-NMR (300MHz, CDC1 3} ): δ 2.44 (3Η, s), 2.69 (2H, t, J = 7.2 Hz), 3.17 (1H, d, J = 13.2 Hz), 3.25 (2H, dt, J = 5.7, 7.2 Hz), 3.42 (1H, d, J = 13.2 Hz), 3.68 (3H, s), 5.61 (1H, s), 7.33 (2H, d, J = 8.3 Hz), 7.33 (2H, m) , 7.40 (3H, m), 7.91 (2H, d, J = 8.3 Hz), 9.71 (1H, brs).

Elemental _{analysis: C 23 H 23 N 3 0} 6 S 3 Calculated: C, 51.77; H, 4.34 ; N, 7.87; S, 18.03

(%), Found: C, 51.86; H, 4.54; N, 7.95; S, 18.08 (%).

Example 1-7 '' H-NMR (300MHz , CDC1 3): δ 1.24 (3Η, t, J = 7.1 Hz), 2.44 (3H, s), 2.69 (2H, t, J = 7.4 Hz), 3.20 (1H, d, J = 13.2 Hz), 3.26 (2H, dt, J = 5.4, 7.4 Hz), 3.44 (1H, d, J = 13.2 Hz), 4.14 (2H, q, J = 7.1 Hz), 5.66 (1H, s), 7.33 (2H, d, J = 8.2 Hz), 7.36-44 (5H, m), 7.58 (2H, d, J- 8.9 Hz), 7.61 (2H, d, J = 8.9 Hz) , 7.91 (2H, d, J = 8.2 Hz), 9.74 (1H, brs).

Elemental _{analysis: C 30 H 29 N 3 0} 6 S 3 Calculated:. C, 57.77; H, 4.69; N, 6.74; S, 15.42 (%) Found: C, 57.49; H, 4.80 ; N, 6.74; S, 15.44 ().

Example 1-8

 4-isomer mixture

Ή-NMR (300 MHz, in double-mouthed form): 51.24 (3H, t, J = 7.1 Hz), 2.45 (3H, s), 2.67 / 2.71 (2H, t, J = 7.3 Hz), 3.26 (2H , m), 4.14 (2H, q, J- 7.1 Hz), 4.36 / 4.72 (1H, s), 5.93 / 6.08 (1H, s), 6.77 / 6.93 (2H, brd, J = 7.5 Hz), 7.12- 7.40 (10H, m), 7.92 (2H, brd, J = 8.1 Hz), 9.67 / 9.72 (1H, brs). Elemental _{analysis: C 30 H 29 N 3 0} 6 S 3 Calculated: C, 57.77; H, 4.69 ; N, 6.74; S, 15.42

(%), Found; C, 57.52; H, 4.80; N, 6.78; S, 15.43 (%).

Example 1-9

Isomer mixture Main / By-product

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.88 (3Η, brt, J = 7 Hz), 1.27 (3H, t, J = 7.1 Hz), 1.29 (9H, m), 1.32 (6H, m), 1.56 (1H, i), 1.71 / 1.80 (3H, s), 2.42 (3H, s), 2.69 (2H, t, J = 7.2 Hz), 3.25 (1H, m), 3.26 / 3.27 (2H, t, J = 7.6 Hz), 4.17 (2H, q, J = 7.1 Hz), 5.57 / 5.73 (1H, brs), 7.30 / 7.31 (2H, d, J = 8.2 Hz), 7.87 / 7.89 (2H, d, J = 8.2 Hz), 9.70 (1H, brs).

Elemental analysis: C ₂₆ H ₃₇ N ₃ 0 ₆ S ₃ * H ₂ 0 Calculated: C, 51.89; H, 6.53;, 6.98; S, 15.98 (%), Found: C, 51.93; H, 6.31 ; N, 6.94; S, 16.21 {%).

Example 1-10

Isomer mixture Main / By-product

E - thigh _{(300MHz, CDC1 3): δ} 0.86 / 0.87 (3Η, brt, J = 7 Hz), 1.24 / 1.26 (3H, t, J = 7.1 Hz), 1.24 (8H, br), 1.28 (2H, ), 1.41 (1H, m), 2.17 (1H, m), 2.43 (3H, s), 2.65 / 2.71 (2H, t, J = 7.5 Hz), 3.17 / 3.53 (1H, dd, J = 12.1 / 11.3 , 2.3, 2.6 Hz), 3.29 (2H, m), 4.13 / 4.16 (2H, q, J = 7.1 Hz), 5.59 / 6.11 (1H, brs), 7.26 (1H, m), 7.34 (6H, m) , 7.89 / 7.92 (2H, d, J = 8.3 Hz), 9.75 (1H, brs).

Elemental _{analysis: C 31 H 39 N 3 0} 6 S 3 Calculated: C, 57.65; H, 6.09 ; N, 6.51; S, 14.89 (%), Found: C, 57.41; H, 6.00 ; N, 6.57; S, 15.08 (%).

Example 11

_{Ή-NMR (300MHz, CDC1 3} ): δ 1.26 (3Η, t, J = 7.2 Hz), 1.28 (3H, t, J = 7.1 Hz), 2.42 (3H, s), 2.70 (2H, t, J = 7.5 Hz), 3.11 (1H, d, J = 13.2 Hz), 3.21 (2H, s), 3.27 (2H, t, J = 7.5 Hz), 3.53 (1H, d, J = 13.2 Hz), 4.16 (2H , q, J = 7.2 Hz), 4.20 (2H, dq, J = 1.5, 7.2 Hz), 5.96 (1H, br), 7.30 (2H, d, J = 8.3 Hz), 7.86 (2H, d, J = 8.3 Hz), 9.71 (1H, brs).

Elemental _{analysis: C 22 H 27 N 3 0} 8 S 3 Calculated: C, 47.38; H, 4.88 ; N, 7.53; S, 17.25

(%), Found: C, 47.14; H, 5.01;, 7.48; S, 17.11 (%).

Example 12 Isomer mixture Main / By-product

'H-NMR (300MHz, CDC1 3): δ 0.86 / 0.87 (3Η, brt, J = 6.8 / 6.6 Hz), 1.26 / 1.24 (3H, t, J = 7.2 Hz), 1.27 (4H, brs), 1.30 (2H, i), 1.40 (IH, m), 2.17 (1H, m), 2.43 (3H, s), 2.65 / 2.71 (2H, t, J = 7.3 / 7.2 Hz), 3.17 / 3.53 (1H, dd , J = 10.9 / 11.3, 2.6 / 3.0 Hz), 3.29 / 3.22 (2H, q / m, J- 6.9 Hz), 4.13 / 4.16 (2H, q, J = 7.2 Hz), 5.59 / 6.10 (IH, s ), 7.27 (IH, m), 7.29-7.39 (4H, m), 7.35 / 7.34 (2H, d, J = 7.9 Hz), 7.89 / 7.92 (2H, d, J = 7.9 Hz), 9.74 (IH, m br).

Elemental analysis: Calculated as _{C 29 H 35 N 3 0 6} S 3: C, 56.38; H, 5.71;, 6.80; S, 15.57 (%), Found: C, 56.12; H, 5.85 ; N, 6.81 ; S, 15.51 (%).

Example 1-13

Isomer mixture Main / By-product

_{Ή-NMR (300MHz, CDC1 3} ): <5 1.24 (3H, t, J = 7.2 Hz), 2.13 / 2.15 (3H, s), 2.42 (3H, s), 2.66 (2H, t, J = 7.5 Hz ), 3.11 (IH, d, J = 13.2 Hz), 3.23 (2H, dt, J = 2.6, 7.5 Hz), 3.32 (IH, d, J = 13.2 Hz), 4.13 / 4.12 (2H, q, J = 7.2 Hz), 5.86 (1H, brs), 7.21 (2H, d, J = 8.3 Hz), 7.30 (2H, d, J = 8.3 Hz), 7.49 (2H, d, J = 8.3 Hz), 7.89 (2H , d, J = 8.3 Hz), 8.00 (IH, brs), 9.86 (IH, brs).

Elemental _{analysis: C 26 H 28 N 4 0} 7 S 3 Calculated: C, 51.64; H, 4.67 ; N, 9.26; S, 15.91

(%), Found: C, 51.23; H, 4.72; N, 9.33; S, 15.68 (%).

Examples 1-14

Isomer mixture

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.88 (3Η, t, J = 6.8 Hz), 0.91 (3H, t, J = 6.8 Hz), 1.26 / 1.27 (3H, t, J- 7.2 Hz), 1.28 -1.43 (8H, m), 1.55 (2H, m), 2.00 (2H, m), 2.24 / 1.89 (2H, m), 2.42 (3H, s), 2.69 (2H, t, J = 7.5 Hz), 3.08 / 3.27 (2H, dd / m, J = 10.1, 2.3 Hz), 3.26 (2H, dt, J = 6.4, 7.5 Hz), 4.16 / 4.17 (2H, q, J = 7.2 Hz), 5.80 / 6.07 ( IH, brs / br), 7.31 / 7.30 (2H, d, J = 8.3 Hz), 7.89 / 7.88 (2H, d, J = 8.3 Hz), 9.69 (1H, brs).

Example 1-15

1: 1 isomer mixture

_{Ή-NMR (300MHz, CDC1 3} ): 6 0.87 / 0.88 (3H, t, J = 6.7 Hz), 1.25 (3H, t, J- 7.2 Hz), 1.25 (12H, brs), 1.48 (2H, m), 2.41 (3H, s), 2.69 (2H, t, J = 7.5 Hz), 3.23 (IH, m), 3.27 / 3.25 (2H, t , J = 7.5 Hz), 4.15 (2H, q, J = 7.2 Hz), 4.6 / 4.8 (IH, br), 5.80 / 5.87 (IH, d, J = 2.6 / 1.1 Hz), 7.29 / 7.28 (2H, d, J = 8.3 Hz), 7.89 / 7.88 (2H, d, J = 8.3 Hz), 10.05 (IH, brs).

Elemental analysis: C ₂₆ H ₃₇ N ₃ 0 ₆ S ₃ · 0.5 H ₂ 0 Calculated: C, 52.68; H, 6.46; N, 7.09; S, 16.22 (), Found: C, 52.63; H, 6.31;, 7.12; S, 16.56 (%).

Example 1-16

Isomer mixture Main / By-product

_{Ή-NMR (300MHz, CDC1 3} ): δ 1.23 / 1.24 (3Η, t, J = 7.2 Hz), 2.41 (3H, s), 2.69 (2H, t, J- 7.5 Hz), 3.28 (2H, t, J = 7.5 Hz), 4.13 (2H, q, J = 7.2 Hz), 4.38 / 4.54 (IH, d, J = 1.1 / 2.6 Hz), 4.93 / 4.57 (IH, br), 6.05 (IH, brs / brd , J = 2.6 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.30 (IH, m), 7.37 (2H, m), 7.50 / 7.15 (2H, m), 7.87 / 7.88 (2H, d, J = 8.3 Hz), 9.95 (IH, br).

Elemental analysis: C ₂₄ H ₂₅ N ₃ 0 ₆ S ₃ · 0 3Η ₂計算 Calculated: C, 52.12; Η, 4.67; Ν, 7.60; S, 17.39 (%), found: C, 52.17; Η, 4.77; Ν, 7.66; S, 17.54 (%).

Example 1-17

_{^ -NMR (300MHz, CDC1 3)} : δ 1.26 (3Η, t, J = 7.2 Hz), 1.32 (3H, t, J = 7.1 Hz), 2.43 (3H, s), 2.71 (2H, dd, J = 7.5, 7.2 Hz), 3.08 (IH, d, J = 12.8 Hz), 3.28 (2H, dt, J = 3.0, 7.5 Hz), 3.31 (IH, d, J = 12.8 Hz), 4.16 (2H, q, J = 7.2 Hz), 4.38 (2H, dq, J = 1.1, 7.2 Hz), 5.24 (1H, br), 7.31 (2H, d, J = 8.3 Hz), 7.87 (2H, d, J = 8.3 Hz) , 9.73 (IH, brs).

Elemental analysis: C ₂₁ H ₂₅ N ₃ 0 ₈ S ₃ Calculated: C, 46.40; H, 4.64;, 7.73; S, 17.70

(%), Found: C, 46.49; H, 4.63; N, 7.77; S, 17.74 (%).

Example 18

Isomer mixture Main / By-product

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.89 / 0.88 (3Η, t, J = 6.8 Hz), 1.26 (11H, m), 1.50 (IH, in), 1.60 / 1.67 (3H, s), 2.41 ( 3H, s), 3.17 / 2.90 (1H, brdd, J = 9.9 / 10.2, 2.4 / 2.5 Hz), 4.16 / 4.15 (IH, d, J = 12.8 / 13.2 Hz), 4.26 / 4.25 (IH, d, J = 12.8 / 13.2 Hz), 5.49 / 5.69 (IH, br), 7.28 (7H, m), 7.86 / 7.88 (2H, d, J-8.3 Hz), 9.73 (IH, br).

Elemental _{analysis: C 28 H 25 N 3 0} 4 S 3 · 0.5H 2 0 Calculated: C, 57.70; H, 6.23 ; N, 7.21; S, 16.50 (%), Found: C, 57.78; H , 6.26; N, 7.37; S, 16.60 (%).

Example 1-19

Isomer mixture Main / By-product

_{¾-NMR (300MHz, CDC1 3} ): δ 0.87 / 0.88 (3Η, brt, J = 6.8 Hz), 1.25 (1 H, m), 1.45 (9H, s), 1.72 (IH, m), 1.84 (IH , m), 2.40 / 2.41 (3H, s), 3.19 / 3.28 (IH, brddd / m, J = 7.9, 6.8, 1.2 Hz), 3.67 (IH, d, J = 15.8 Hz), 3.72 (IH, dd , J = 15.8, 2.3 Hz), 4.30 / 4.53 (IH, brd / br, J = 5.3 Hz), 5.78 / 5.84 (IH, brd, J = 1.9 / 3.5 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.88 / 7.90 (2H , d, J = 8.3 Hz), 9.96 (IH, br) elemental _{analysis:. C 27 H 3g N 3} 0 6 S 3 · 0.5H 2 0 calculated: C, 53.44 H, 6.48; N, 6.92; S, 15.85 (%), found: C, 53.40; H, 6.41 ;, 7.07; S, 16.58 (%).

Example 1-20

1: 1 isomer mixture

_{¾-NMR (300MHz, CDC1 3} ): δ 0.88 / 0.91 (3H, t, J = 7.2 / 7.3 Hz), 1.25 / 1.25 (3H, t, J = 7.2 Hz), 1.25 (2H, m), 1.34 ( 2H, m), 1.47 (IH, m), 1.75 / 1.86 (IH, m), 2.41 (3H, s), 2.69 (2H, t, J = 7.2 Hz), 3.23 (1H, m), 3.27 (2H , m), 4.14 (2H, q, J = 7.2 Hz), 4.67 / 4.91 (IH, m), 5.81 / 5.87 (IH, brs / brd, J = 4.2 Hz), 7.27 / 7.29 (2H, d, J = 8.3 Hz), 7.87 / 7.89 (2H, d, J = 8.3 Hz), 10.05 (1H, br).

 1: 1 isomer mixture

^{L H-NMR (300MHz, CDC1} 3); δ 0.88 (3H, t, J = 6.9 Hz), 1.25 (3H, t, J = 7.1 Hz), 1.25 (20H, brs), 1.48 (IH, m), 1.74 / 1.85 (IH, m), 2.41 / 2.41 (3H, s), 2.69 (2H, t, J = 7.3 Hz), 3.23 (IH, m), 3.27 (2H, m), 4.15 (2H, q, J = 7.1 Hz), 4.9 / 4.74 (IH, brd / brs, J = 5.0 Hz), 5.80 / 5.86 (IH, brs / brd, J = 3.7 Hz), 7.28 / 7.29 (2H, d, J- 8.0 Hz), 7.87 / 7.89 (2H, d, J = 8.0 Hz), 10.02 (1H, br).

Isomer mixture Main / By-product

_{Ή-NMR (300MHz, CDC1 3} ); δ 1.27 (3Η, t, J = 7.1 Hz), 1.72 (IH, m), 1.79 / 1.81 (3H, s), 2.42 (3H, s), 2.46 (1H, m), 2.56 (2H, i), 2.68 (2H, t, J = 7.3 Hz), 3.11 (1H, dd, J = 10.8, 3.3 Hz), 3.25 (2H, t, J = 7.3 Hz), 3.70 / 3.68 (3H, s), 4.16 (2H, q, J = 7.1 Hz), 5.42 / 5.83 (1H, br), 7.30 (2H, d , J = 8.2 Hz), 7.86 / 7.88 (2H, d, J = 8.2 Hz), 9.74 (1H, br).

Elemental _{analysis: C 23 H 29 N 3 0} 8 S 3 Calculated: C, 48.32; H, 5.11 ; N, 7.35; S, 16.83 (%), Found: C, 48.13; H, 4.94 ; N, 7.40; S, 17.06 (%).

Example 1-23

Isomer mixture

'H-NMR (300MHz, CDC1 3); δ 1.26 (3Η, t, J = 7.1 Hz), 1.88 (3H, s), 2.42 (3H, s), 2.69 (2H, t, J = 7.4 Hz), 3.03 (1H, d, J = 13.3 Hz), 3.16 (1H, d, J = 13.3

Hz), 3.26 (2H, t, J- 7.4 Hz), 4.16 (2H, q, J = 7.1 Hz), 5.32 (1H, br), 7.30

(2H, d, J = 8.2 Hz), 7.87 (2H, d, J = 8.2 Hz), 9.76 (1H, br).

Elemental _{analysis: C 19 H 23 N 3 0} 6 S 3 Calculated: C, 46.99; H, 4.77 ; N, 8.65; S, 19.81 (%), Found: C, 46.71; H, 4.80 ; N, 8.61; S, 19.88 (%).

Example 1-24

Isomer mixture Main / By-product

_{¾- MR (300MHz, CDC1 3)} ; δ 1.26 (3Η, t, J = 7.1 Hz), 1.42 (1H, m), 1.72 (1H, m), 1.72 / 1.80 (3H, s), 1.93 (1H, m), 2.15 (1H, m), 2.36 (2H, m), 2.42 (3H, s), 2.68 (2H, t, J = 7.3 Hz), 3.27 (2H, dt, J = 1.2, 7.3 Hz), 3.68 / 3.66 (3H, s), 4.16 (2H, q, J = 7.0 Hz), 5.59 / 5.80 (1H, br), 7.30 (2H, brd, J = 8.2 Hz), 7.87 / 7.88 (2H, d, J = 8.2 Hz), 9.79 (1H, br).

Elemental analysis: C ₂₄ H ₃₁ N ₃ 0 ₈ S ₃ · 0.6 H ₂ 0 Calculated: C, 48.32; H, 5.44; N, 7.04; S, 16.12 (%), found: C, 48.00; H , 5.01; N, 7.00; S, 16.71 (%).

Example 25

Data for one isomer of the isomer mixture

_{Ή-NMR (300MHz, CDC1 3} ): δ 1.25 (3Η, t, J = 7.2 Hz), 1.60 (1H, m), 1.90 (1H, m), 2.41 (3H, s), 2.50 (2H, brt, J = 7.5 Hz), 2.68 (2H, brdt, J = 1.5, 7.2 Hz), 3.26 (2H, dt, J = 3.4, 7.2 Hz), 3.47 (1H, m), 3.67 (3H, s), 4.14 ( 2H, q, J = 7.2 Hz), 4.82 (1H, br), 5.84 (1H, brs), 7.29 (2H, d, J = 8.3 Hz), 7.88 (2H, d, J = 8.3 Hz), 10.04 (1H, br).

Elemental _{analysis: C 22 H 27 N 3 0} 8 S 3 Calculated: C, 47.38; H, 4.88 ; N, 7.53; S, 17.25

(%), Found: C, 47.11; H, 4.99; N, 7.52; S, 17.25.

Example 1-26

Isomer mixture Main / By-product

] H-NMR (300MHz, CDCi ₃ ): δ 1.24 / 1.25 (3H, t, J = 7.2 Hz), 2.39 / 2.41 (3H, s), 2.65 / 2, 66 (2H, brt, J = 7.5 Hz) , 2.69 / 3.02 (IH, dd, J = 13.9 / 14.0, 8.3 / 7.2 Hz), 2.80 / 3.13 (IH, dd, J = 13.9 / 14.0, 6.8 / 6.8 Hz), 3.20 / 3.23 (2H, t, J = 7.5 Hz), 3.48 / 3.58 (IH, dt, J = 1.5 / 2.6, 7.7 / 7.9 Hz), 4.13 (2H, q, J- 7.2 Hz), 4.70 / 4.75 (IH, br), 5.72 / 5.80 ( IH, brs / d, J = 2.3 Hz), 7.10 / 7.21 (2H, d, J = 7.2 / 7.0 Hz), 7.27 (3H, m), 7.29 (2H, d, J = 8.3 Hz), 7.85 / 7.90 (2H, d, J = 8.3 Hz), 10.00 (IH, br).

Elemental analysis: C ₂₅ H ₂₇ N ₃ 0 ₆ S ₃ · 0.4H ₂ 0 Calculated: C, 52.78; H, 4.93; N, 7.39; S, 16.91 (%). Observed: C, 52.56; H , 4.89; N, 7.52; S, 17.41 (%).

Example 1-27

'H-NMR (300MHz, CDC1 3): δ 1.25 (3Η, t, J = 7.1 Hz), 2.40 (3H, s), 2.70 (2H, t, J = 7.3 Hz), 3.03 (IH, dd, J = 13.1, 1.4 Hz), 3.23 (IH, dd, J = 13.1, 2.3 Hz), 3.27 (2H, q, J = 7.3 Hz), 4.14 (2H, q, J = 7.1 Hz), 4.83 (IH, br ), 6.10 (IH, brs), 7.28 (2H, d, J = 8.2 Hz), 7.87 (2H, d, J = 8.2 Hz), 10.03 (IH, br). Elemental analysis: C ₁₈ H ₂₁ N ₃ 0 ₆ S ₃ calculated: C, 45.85; H, 4.49 ; N, 8.91; S, 20.40 (%)ゝFound: C, 45.76; H, 4.60 ; N, 8.81; S, 20.52 (%).

Example 1-28

1: 1 isomer mixture

_{Ή-NMR (300MHz, CDC1 3} ): δ 1.26 (3Η, t, J = 7.2 Hz), 1.71 / 1.95 (IH, m), 2.15 / 2.29 (IH, m), 2.43 / 2.42 (3H, s), 2.71 / 2.67 (2H, t, J = 7.2 Hz), 3.25 (2H, m), 3.33 (IH, m), 3.66 / 3.67 (IH, brd, J = 7.2 / 6.8 Hz), 3.88 (2H, m) , 4.15 / 4.14 (2H, q, J = 7.2 Hz), 5.81 / 6.04 (IH, dd, J = 7.2 / 6.8, 3.0 / 1.5 Hz), 7.31 / 7.29 (2H, d, J = 8.3 Hz), 7.74 (2H, m), 7.85 (4H, m), 9.68 (IH, brs).

Elemental _{analysis: C 28 H 28 N 4 0} 8 S 3 Calculated: C, 52.16; H, 4.38 ; N, 8.69; S, 14.92 (%), Measured: C, 52.01; H, 4.27;, 8.69; S, 14.98 (%). Examples 1-29

'H-NMR (300MHz, CDC1 3): δ 0.87 (3H, brt, J = 6.8 Hz), 1.26 (6H, br), 1.44 (2H, brquint, J = 7.1 Hz), 2.04 (2H, brt, J = 7.1 Hz), 2.41 (3H, s), 4.22 (2H, s), 6.47 (1H, brt, J = 0.5 Hz), 7.25 (2H, d, J = 8.3 Hz), 7.32 (5H, s), 7.80 (2H, d, J = 8.3 Hz), 9, 73 (1H, brs).

Elemental _{analysis: C 26 H 31 N 3 0} 4 S 3 · 0.2H 2 O Calculated: C, 56.84; H, 5.76 ; N, 7.65; S, 17.51 (%), Found: C, 56.78; H , 5.66; N, 7.61; S, 17.83 (%)

Example 1-30

Isomer mixture Main / By-product

'H-NMR (300MHz, CDC1 3): δ 0.89 / 0.88 (3Η, t, J = 6.7 Hz), 1.27 (3H, t, J = 7.1 Hz), 1.29 (6H, m), 1.32 (2H, m ), 1.55 (1H, m), 1.71 / 1.80 (3H, s), 2.10 (1H, m), 2.42 (3H, s), 2.69 (2H, t, J = 7.5 Hz), 3.25 (1H, m) , 3.26 / 3.27 (2H, t, J = 7.6 / 7.5 Hz), 4.16 (2H, q, J = 7.1 Hz), 5.58 / 5.75 (1H, br), 7.29 (2H, brd, J = 8.2 Hz), 7.87 / 7.89 (2H, d, J = 8.2 Hz), 9.76 (1H, br).

Elemental analysis: C ₂₅ H ₃₅ N ₃ 0 ₆ S ₃ · 0.5 H ₂ 0 Calculated: C, 51.88; H, 6.27; N, 7.26; S, 16.62 (%), Found: C, 51.86; H , 5.97; N, 7.24; S, 16.38 (%).

Example 1-31

Isomer mixture Main / By-product

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.87 / 0.88 (3Η, ί, J = 6.8 Hz), 1.25 (3H, t, J = 7.2 Hz), 1.28 (2H, m), 1.31 (2H, m) , 1.35 (1H, m), 1.48 (2H, m), 1.74 / 1.85 (1H, m), 2.40 / 2.41 (3H, s), 2.69 (2H, t, J = 7.4 Hz), 3.20 / 3.31 (1H , m), 3.25 / 3.27 (2H, brt, J = 7.4 Hz), 4.14 / 4.15 (2H, q, J = 7.2 Hz), 4.69 / 4.91 (1H, brd / br, J = 5.3 Hz), 5.80 / 5.86 (1H, brd, J = 2.3 / 3.1 Hz), 7.28 / 7.29 (2H, brd, J = 8.2 Hz), 7.87 / 7.89 (2H, d, J = 8.2 Hz), 10.06 (1H, br).

Elemental _{analysis: C 23 H 31 N 3 0} 6 S 3 Calculated: C, 51.00; H, 5.77 ; N, 7.76; S, 17.76

(%), Found: C, 50.70; H, 5.54; N, 7.87; S, 17.53 (%).

Example 1-32

Isomer mixture Main / By-product '(in' ΗΖ) '(in' ΜΙ) SS — ΟΓΙ '( ^m ¾S) 60-09: ( ^ε 10α3) 丽-

 "(in Έ ΓΟΙ-ΟΖ'β '(in' ΗΖ) Γ8-6Ζ '¾S) Z9'L-9fL' (ω ¾ΐ) Ζ8-9- Ζ9 '(ιπ Έΐ) S H0' ¾S) 8Γδ-29 "S '(m Ή8) OS—SO' (in ΈΖ) S8 ー OS '(ω' ΗΟΙ) 01 'Ζ-ΟΟ' (ω Ήε) 26'0-28" 05 ： 13 (13) 丽-E ^

 9S-T drawing

• () 9 · 9 '13 · '8.ί' S -ΌΓ8 'Ν: ¾: 60 ·,' 3: Thigh traction (%) Ζ8'9 '13: 030381 'S: 80 · 8 'Ν: 9Ζ' Η: 88 · ^ '3: Kake + Emma 13 ^s S ⁹ o ¥ ¾ ^6, 3: Army ί ^ 挲

'(s-rq ¾t) ΟΑ'6' ( ^Ζ Η Γ8 = Γ 'Ρ' ΕΖ)

98 '(ΖΗ 6ΖΗ = r' ρ 'κ) τε'Α' (jq 'HI)' s 'l' 1 \ = ί 'Ρ Ήΐ) 91' ^£ (ΖΗ ΟΖ

1ί = ί 'Μ) l \' f '(ΖΗ 0Ί' Γ2ΐ = ί 'ΡΡ' Ηΐ) 96 "S '(ΖΗ 9" 8ΐ = f' Ρ Ήΐ) 09 "8

'(ΖΗ 9'Ζ'ί = 1 ΊΡ 'ΗΖ) ΙΙ'Ζ' (ΖΗ 0Ί '9 · = ί' ΡΡ ¾ΐ) 80 * 8 '(ΖΗ S'Z = f Ί' ΗΖ) Wl '(S' Η2) '(ZH 0 * Α = ί' Η2) 8Γΐ 9: ( ^ε 1303 'ZHWOOS) flat-

(S Jq 'Ηΐ) 9 90' (in QI ¾ΐ) 689-9 '5' (ιπ '0 0' '(s' Η8) Zf '(ω ¾8) fS-irg' (ZH9-Z = f

'1 ⁽ ) U'Z' (in 'Η8ΐ) 96Ί-0 Ϊ' (ω ¾S) S6 Ό P: md) ¾WN-H, tS-ΐ

• (%) Si '91 'S: 6n' N: S0'9 'H: 8S' 3: Door} Thigh pull, (%) • 91 'S -nl' Μ: 91'9 'Η: I9'8S '3: One hook θ ¥ ¾ ⁸ : ΟΤ

 SC-I MSi

0¾S ·0 · ^SS⁹0¾⁹¾^SZ3 ：華 挲 • (%) 81 '91 'S-fL' N: i0'9 Ή: 6Ϊ · 3 '3: Thigh traction, (%) 2Χ * 9ΐ' S: ΐΓ 'Ν

0¾S · 0 · ^S S ⁹ 0¾ ⁹ ¾ ^SZ 3 ： Hana

 • (q ¾ΐ) 20 * 01 '(ΖΗ VI = f' Ρ 'Ζ) 68 Ί / 1 Ί' (ΖΗ Ζ "Ζ = ί 'P-iq ΈΖ) QZ'WL' (ΖΗ Ί = ί q 'HI ) 98 * 9/08 "9 '(ZH f S

= r 'jq / p-iq Ήΐ) ε8 / 09' '(ΖΗ Ι-= r' f> sr / 'q

'ΗΖ) LZ'WZ' (ω ¾l) Og-g / ZZ'S '(ΖΗ Γ 丄 = ί' 1 ¾) 69 '(s' Η8) / 0 Z '(∞ ¾Ι) 8 Hi' («ι) 8f "ΐ '(' HI) S8't '(sjq ¾8) 6Π' (ΖΗ t -i = Γ 'ϊ' Η8) 9Ζ" ΐ / 92ΐ ΐ '(ΓΑ ΓΑ / 8'9 = f Ί ¾S) 88 · 0 / Α8 · 0 Q: ( ⁸ 1303 'lia 0S) recitation-

0t9 爾 Odf / ェ :) d 909Z60 / Z0 OAV 3.21-3.30 (2H, m), 3.70 (3H, s), 5.48-5.80 (1H, m), 7.46-7.61 (3H, m), 7.96-8.03 (2H, m), 9.70 (1H, br s) .

Example 1-38

_{Ή-NMR (300MHz, CDC1 3} ): δ 1.25 (3H, t, J = 7.2 Hz), 2.44 (3H, s), 2.68 (2H, t, J = 7.2 Hz), 3.15 (1H, d, J = 13.6 Hz), 3.24 (1H, dt, J = 6.8, 6.8 Hz), 3.27 (1H, quint, J = 7.2 Hz), 3.42 (1H, d, J = 13.2 Hz), 4.14 (2H, q, J = 7.2 Hz), 5.60 (1H, s), 6.99 (2H, d, J 8.7 Hz), 7.04 (2H, brd, J = 8.3 Hz), 7.15 (1H, t, J = 7.5 Hz), 7.27 (2H, m), 7.32 (2H, d, J = 7.9 Hz), 7.36 (2H, brt, J = 7.5 Hz), 7.89 (2H, d, J = 8.3 Hz), 9.68 (1H, brs).

Elemental analysis: C _3. H ₂₉ N ₃ 0 ₇ S ₃ Calculated: C, 56.32; H, 4.57; N, 6.57; S, 15.04 (%), Found: C, 56.33; H, 4.56; N, 6.30; S, 14.86 ( %).

Example 1-39

 1: 1 isomer mixture main / by-product

Ή— NMR (300MHz, DMS0-d ₆ ): δ 2.35 / 2.38 (3Η, s), 3.60 (1H, brd, J = 12.1 Hz), 3.99 (1H, d, J = 12.1 Hz), 7.03 (2H, brd, J = 8.7 Hz), 7.06 (2H, brd, J = 9.0 Hz), 7.18 (1H, t, J = 7.3 Hz), 7, 35 / 7.39 (2H, d, J = 8.0 Hz), 7.42 ( 2H, brt, J = 7.8 Hz), 7.72 (2H, brd, J = 7.7 Hz), 7.81 / 7.86 (2H, d, J = 8.3 / 7.5 Hz), 10.59 / 10.74 (1H, br / s), 11.24 /11.40 (1H, s / br).

Elemental analysis: C ₂₅ H ₂₁ N ₃ 0 ₅ S ₃ · 0.3 H ₂ 0 Calculated: C, 55.09; H, 3.99; N, 7.71; S, 17.65 (%), found: C, 55.16; H , 4.03; N, 7.65; S, 17.42 ().

Example 1-40

Isomer mixture

 'H-NMR (300 MHz, in double-mouthed form): <50.88 / 0.89 (3H, t, J = 6.8Hz), 1.26 (3H, t, J = 7.2Hz), 1.29 (6H, m), 1.33 (2H, m), 1.75 (1H, m), 1.84 (1H, m), 2.70 / 2.70 (2H, t, J2 7.2 Hz), 3.27 (3H, m), 4.15 (2H, q, J = 7.2 Hz), 5.74 / 5.81 (1H, m), 7.02 / 7.04 (2H, d, J = 9.0 Hz), 7.07 (2H, d, J = 8 Hz), 7.21 (1H, brt, J = 7.9 Hz), 7.41 (2H, brt, J- 7.7 Hz), 7.92 / 7.93 (2H, dt, J = 8.7, 1.9 Hz), 9.65 (1H, br).

Elemental _{analysis: C 29 H 35 N 3 0} 7 S 3 Calculated: C, 54.96; H, 5.57 ; N, 6.63; S, 15.18 C, 54.87; H, 5.20;, 6.72; S, 15.20 (%). Examples 1-41

_{'Η - NMR (CDC1 3,} 300 MHz): δ 2.01 (3H, s), 2.42 (3H, s), 3.18 (3H, s), 3.68 (3H, s), 3.71 (IH, s), 4.13 ( 2H, d, J = 12.5 Hz), 4.25 (2H, d, J = 12.5 Hz) 7.27 (5H, m), 7.28 (2H, d, J = 8.3 Hz), 7.87 (2H, d, J = 8.3 Hz) .), 9.62 (IH, brs ) elemental _{analysis: C 24 H 25 N 3 0} 6 S 3 calculated: C, 52.63; H, 4.60 ; N, 7.67; S, 17.56

(%), Found: C, 52.53; H, 4.61;, 7.65; S, 17.45 (%).

Example 42

_{Ή-NR (CDC1 3, 300} MHz): δ 1.03 (6Η, d, J = 6.7 Hz): 1.85 (3H, s), 1.90 (IH, sept, J = 6.8 Hz), 2.42 (3H, s), 2.88 (2H, d, J = 6.8 Hz), 3.00 (IH, d, J = 13.3 Hz), 3.15 (IH, d, J = 13.4 Hz), 5.26 (1H, s), 7.30 (2H, d, J = 8.3 Hz), 7.89 (2H, d, J = 8.3 Hz), 9.61 (IH, brs).

Elemental _{analysis: C 18 H 23 N 3 0} 4 Calculated _{S 3: C, 48.96; H} , 5.25; N, 9.52; S, 21.78 (%), Found: C, 49.00; H, 5.23 ; N, 9.55; S, 21.92 (%).

Example 43

Isomer mixture Main / By-product

_{Ή-NMR (CDC1 3, 300} MHz): δ 1.28 / 1.32 (3Η, t, J = 7.2 Hz), 1.83 / 2.02 (3H, s), 2.72 / 2.74 (2H, t, J = 7.5 Hz), 3.13 /3.14 (3H, s), 3.29 (2H, m), 3.72 / 3.72 (3H, s), 3.82 / 3.95 (IH, s), 4.22 / 4.27 (2H, q, J = 7.2 Hz), 4.88 / 6.01 (IH, brs / s), 9.55 (IH, brs).

Elemental analysis: Calculated as _{C 15 H 2i N 3 0 8} S 3: C, 38.53; H, 4.53; N, 8.99; S, 20.58

(%), Found: C, 38.57; H, 4.52; N, 9.10; S, 20.40 (%).

Example 1-44

Recrystallization from ethyl acetate gave pale yellow crystals with a melting point of 140-142.

Infrared absorption spectrum (IR) (in KBr) v 3700-3100, 2961, 2934, 2872, 1730, 1624, 1557 cm-

_{Ή-NR (CDC1 3):} δ 0.974 (3Η, t, J = 7.2 Hz), 1.27 (3H, t, J = 7.0Hz), 1.20-1.58 (3H, m), 1.71 (3HX0.87, s) , 1.80 (3HX0.13, s), 2.00-2.18 (IH, m), 2.42 (3H, s), 2.69 (2H, t, J = 7.6 Hz), 3.20-3.34 (1H, m), 3.27 (2H , I, J = 7.0 Hz), 4.17 (2H, q, J = 7.4 Hz), 5.52 (1HX0.87, bs), 5.70 (1HX0.13, bs), 7.30 (2H, d, J = 7.8 Hz), 7.87 (2H, d, J = 8.4 Hz), 9.61 (1H, bs).

Elementary analysis: as _{C 22 H 29 N 3 0 6} S 3

Calculated value (%): C, 50.07; H, 5.54; N, 7.96; S, 18.23.

Obtained value (%): C, 50.07; H, 5.53; N, 7.93; S, 18.11.

Example 1-45

Recrystallization from ethyl acetate gave pale yellow crystals having a melting point of 143-145.

Infrared absorption spectrum (IR) (in KBr): 3700-2800, 2957, 1732, 1622, 1557 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 0.934 (3Η, d, J = 6.2 Hz), 0.990 (3H, d, J = 6.4 Hz), 1.27 (3H, t, J-7.0 Hz), 1.37 (1H, t , J = 10.6 Hz), 1.76 (3HX0.90, s), 1.81 (3HX

X0.10, s), 1.75-1.95 (2H, m), 2.42 (3H, s), 2.70 (2H, t, J = 7.6 Hz), 3.26

(2H, t, J = 7.4 Hz), 3.30 (1H, t, J = 11.4 Hz), 4.17 (2H, q, J = 7.0 Hz), 5.54 (1H

X0.81, bs), 5.64 (1HX0.19, bs), 7.30 (2H, d, J = 8.0 Hz), 7.87 (2H, d, J = 8.6

Hz), 9.61 (1H, bs).

Elementary analysis: as _{C 23 H 31 N 3 0 6} S 3

Calculated (¾): C, 51.00; H, 5.77; N, 7.76; S, 17.76.

Found (¾): C, 51.04; H, 5.65; N, 7.89; S, 17.70.

Example 1-46

 3: 1 isomer mixture main / by-product

'H-NMR (200MHz, CDC1 3): δ 1.00 / 1.04 (3Η, t, J = 7.4 Hz), 1.27 (3H, t, J = 7.1

Hz), 1.43 / 1.41 (3H, d, J = 7.0 / 6.8 Hz), 2.07 (2H, brq, J = 7.4 Hz), 2.43 (3H, s), 2.68 / 3.69 (2H, t, J = 7.4 / 7.8 Hz), 3.24 (2H, m), 3.32 / 3.48 (1H, q, J = 6.8 / 7.0

Hz), 4.16 (2H, q, J = 7.1 Hz), 5.65 / 5.95 (1H, s / br), 7.31 (2H, d, J = 8.4 Hz),

7.88 / 7.87 (2H, d, J-8.4 Hz), 9.63 (1H, brs).

Elemental _{analysis: C 21 H 27 N 3 0} 6 S 3 · 0.25H 2 O Calculated: C, 48.68; H, 5.35 ;, 8.11; S,

18.57 (%), Found: C, 48.63; H, 5.41;, 8.08; S, 18.66 (%).

Example 1-47

Infrared absorption spectrum (IR) (in KBr) v: 3700-2800, 3061, 3031, 2984, 2938, 1732, 1626, 1557, 1495 cm- ¹ . ¾-NMR (CDCI3): 51.25 (3HX0.58, t, J = 7.0 Hz), 1.26 (3HX0.42, t, J = 7.0 Hz), 1.84 (3H, s), 2.41 (3HX0.58, s) , 2.44 (3HX0.42, s), 2.56 (2HX0.58, t, J = 7.2 Hz), 2.63 (2HX0.42, t, J = 7.4 Hz), 3.12 (2H, t, J = 7.2 Hz), 3.16-3.32 (1H, m), 3.45-3.72 (2H, m), 4.13 (2HX0.58, q, J = 7.4 Hz), 4.14 (2HX0.42, q, J = 7.2 Hz), 5.59 (1HX0. 58, bs), 5.95 (1HX0.42, bs), 7.12-7.38 (7H, m), 7.85 (2HX0.58, d, J = 8.Hz), 7.90 (2HX0.42, d, J = 8.4 Hz ), 9.63 (1H, bs) Elementary analysis:. as _{C 26 H 29 N 3 0 6} S 3

Calculated value (¾): C, 54.24; H, 5.08; N, 7.30; S, 16.71.

Found (%): C, 54.18; H, 5.30; N, 7.13; S, 16.71.

Example 1-48

 8-[(3-ethoxy-3-oxopropyl) sulfanyl] -5-hydroxy-6-methyl [(4_methylphenyl) sulfonyl] imino} -3-oxo-2,3,5,6-tetrahydro-1H-imidazo [5, 1-c] [1, 4] tert-butyl thiazine-5-carboxylate

 The compound synthesized in Reference Example 3-2 (purity 80%, 1.07 g, 2.0 ol), tert-butyl 3-bromo-2-oxobutyrate (0.94 g, about 2 mmol) obtained in Reference Example 99, and triethylamine ( A suspension of 0.83 ml (6.0 mmol) in DMF-THF (1: 4, 20 ml) was stirred at room temperature for 1 hour. Then, the compound synthesized in Reference Example 3-2 (purity 80%, 0.55 g, 1.0 mmol) was added to the reaction solution twice every hour. The reaction was stirred at room temperature for 3 hours. The reaction solution was concentrated and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and concentrated. The residue was purified by silica gel (15 g) chromatography (ethyl acetate-hexane, 2: 8-5: 5) to give the title compound (0.97 g, 1.66 mmol) as a yellow oil.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.26 (3Η, t, J = 7.1 Hz), 1.29 (3H, d, J = 7.0 Hz), 1.54 (9H, s), 2.43 (3H, s), 2.71 (2H, t, J = 7.5 Hz), 3.26 (2H, t, J = 7.4 Hz), 3.53 (1H, q, J = 7.0 Hz), 4.16 (2H, q, J = 7.1 Hz), 4.96 (1H , s), 7.31 (2H, d, J = 8.0 Hz), 7.87 (2H, d, J = 8.4 Hz), 9.61 (1H, brs).

Elemental _{analysis: C M H 31 N 3 0} 8 S 3 Calculated: C, 49.21; H, 5.33 ; N, 7.17; S, 16.42

(%), Found: C, 49.13; H, 5.44; N, 6.94; S, 16.21 (%) ·

Example 1-49 ' 3-[(5_ (1-bromoethyl) -5-hydroxy-6-methyl-tri {[(4-methylphenyl) sulfonyl] iminoto 3_oxo-2,3,5,6-tetrahydro-1H-imidazo [5 , 1-c] [1,] thiazin-8-yl) sulfanyl] ethyl propionate

 The compound synthesized in Reference Example 3-2 (purity 80¾, 5.08 g, 9.46 maraudal 01) and 2,4-dibutene-3- (pentamerone) (2.90 g, 11.8 mmol) in DMF-THF (1: 9, To the suspension (100 ml), triethylamine (3.93 ml, 28.4 mmol) was added dropwise at room temperature over 30 minutes, and the mixture was stirred for 30 minutes. The reaction solution was concentrated, diluted with ethyl acetate (200 ml), washed with aqueous sodium hydrogen carbonate, 0.1 hydrochloric acid, water and saturated saline, dried over sodium sulfate, and concentrated. The residue was purified by silica gel (50 g) chromatography (ethyl acetate-hexane, 2: 8-4: 6) and crystallized from getyl ether to give the title compound (1.81 g, 3.05 mmol) as a yellow powder. .

One _{NMR (200MHz, CDC1 3):} δ 1.27 (3Η, t, J = 7.2 Hz), 1.41 (3H, d, J = 6.6 Hz), 1.76 (3H, d, J = 7.0 Hz), 2.44 (3H, s), 2.70 (2H, t, J = 7.3 Hz), 3.27 (2H, dt, J = 3.2, 7.2 Hz), 4.00 (1H, q, J = 6.9 Hz), 4.17 (2H, q, J = 7.2 Hz), 4.46 (1H, q, J = 6.9 Hz), 6.63 (1H, s), 7.33 (2H, d, J = 8.4 Hz), 7.89 (2H, d, J = 8.0 Hz), 9.73 (1H, br).

Elemental _{analysis: C 21 H 26 N 3 0} 6 S 3 Br Calculated: C, 42.75; H, 4.42 ; N, 7.09; S, 16.23: Br, 13.48 (), Found: C, 42.55; H, 4.19; N, 7.16; S, 15.89: Br, 13.03 (%).

mp. 95.0-99.0 ° C

Example 1-50

 3-[(5-hydroxy-6-methyl_1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-5-propionyl-2,3,5,6-tetrahydro-1H-imidazo [5, 1-c] [1,4] thiazine-8-yl) sulfanyl] ethyl propionate

A brown oil (8.6 g) containing 2-bromo-3,4-hexadione (8. OMIOI) obtained in the same manner as in Example 2-48 and the compound synthesized in Reference Example 3-2 (purity: 80% , 12.9 g, 24.0 mmol) in DMF-THF (1: 4, 250 ml) was added at room temperature over 10 minutes with triethylamine (10.0 ml, 72.0 mmol) and the mixture was stirred for 1.5 hours. The reaction solution was worked up in the same manner as in Example 2-48 to obtain a brown oil. This brown oil is washed with silica gel (120 g). Purification by oral chromatography (ethyl acetate-hexane, 15: 85-40: 60), and the yellow-brown fraction of ethyl acetate-hexane (30: 70-35: 65) was crystallized from getyl ether to give the title. The compound (3.19 g, 5.89 mmol) was obtained as a yellow powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.18 (3Η, d, J = 7.0 Hz), 1.23 (3H, t, J = 7.1 Hz), 1.27 (3H, t, J = 7.1 Hz), 2.43 (3H , s), 2.43 (IH, m), 2.71 (2H, t, J = 7.2 Hz), 2.72 (1H, m), 3.27 (2H, dt, J = 1.4, 7.0 Hz), 3.56 (IH, q, J = 6.8 Hz), 4.16 (2H, q, J = 7.1 Hz), 5.19 (IH, s), 7.31 (2H, d, J = 8.2 Hz), 7.86 (2H, d, J = 8.4 Hz), 9.65 (1H, br).

Elemental _{analysis: C 22 H 27 N 3 0} 7 S 3 Calculated: C, 48.78; H, 5.02 ; N, 7.76; S, 17.76 (), Found: C, 48.69; H, 4.97 ; N, 7.82 ; S, 17.53 (%).

mp.158.5-159.0 ° C

Examples 1-51,

Isomer mixture Main / By-product

'H-NM (300MHz, CDC1 3): δ 1.26 (3Η, t, J = 7.1 Hz), 1.54, 1.75, 1.90, 2.17, 2.85 (8H, m), 2.42 (3H, s), 2.69 (2H, t, J = 7.4 Hz), 3.25 (2H, t, J = 7.4 Hz),

3.30 / 3.22 (IH, m), 4.16 (2H, q, J = 7.1 Hz), 4.78 / 3.62 (IH, br), 7.29 (2H, brd,

J = 8.3 Hz), 7.87 / 7.86 (2H, d, J = 8.3 Hz), 9.71 (IH, br).

Elemental _{analysis: C 22 H 27 N 3 0} 6 S 3 Calculated:. C, 50.27; H, 5.18; N, 7.99; S, 18.30 (%), Found: C, 50.07; H, 5.16 ; N , 7.97; S, 18.40 (%).

Example G 52

8-[(3-Ethoxy-3-oxop-mouth pill) sulfanyl] -5-Hydroxy-6- (2-methoxy-2- oxoethyl) _1- {[(4-Methylphenyl) sulfonyl] imino} -3- Methyl oxo-2,3,5,6-tetrahydro-1H-imidazo [5,1-c] [1,4] thiazine-5-methylcarboxylate Compound synthesized in Reference Example 3-2 (purity 90%, 9.63 g, 20.2 mmol) and triethylamine (8.40 ml, 60.5 tmol) in THF-DMF (9: 1, 160 ml) while stirring at room temperature while stirring at room temperature. A solution of dimethyl ketoglutarate (purity 70%, 7.29 g, 20.l mmol) in THF-DMF (9: 1, 20 ml) was added dropwise over 20 minutes, and the reaction solution was stirred at room temperature for 4 minutes. The reaction solution was concentrated, diluted with ethyl acetate (300 ml), and washed with water, sodium hydrogencarbonate and saturated saline. Wash solution with ethyl acetate (200 ml) Extracted. The organic layer was dried over sodium sulfate and concentrated to dryness to obtain an orange solid. This was ground in getyl ether, collected by filtration, washed with getyl ether, and dried to give the title compound (6.22 g, 10.3 mmol) as an orange powder.

_{Ή-NMR (300MHz, CDC1 3} ): d 1.20 (3H, t, J- 7.2 Hz), 2.33 (3H, s), 2.49 (1H, dd, J = 17.7, 9.9 Hz), 2.58 (2H, t, J = 7.2 Hz), 2.75 (1H, dd, J = 17.7, 3.6 Hz), 3.11 (2H, m), 3.67 (6H, s), 3.83 (1H, dd, J = 9.9, 3.6 Hz), 4.08 ( 2H, q, J = 7.1 Hz), 7.14 (2H, d, J = 7.8 Hz), 7.86 (2H, d, J = 8.4 Hz), 9.81 (1H, br).

Elemental analysis: C ₂₃ H ₂₇ N ₃ 0 ₁₀ S ₃ · 2Η ₂₀ Calculated: C, 43.32; Η, 4.90; Ν, 6.59; S, 15.09 (%), found: C, 43.33; H, 4.30; N, 6.76; S, 14.94

(%).

Example 2-1

R ⁵ is n- pentyl group in the formula (VII), R ⁶ is a methyl group, R ^{1 Q} is - ZR ¹⁵ (sigma is 30 _2, R ¹⁵ is P- Toruiru group) of the compound R is an Echiru group Synthesis

 The compound synthesized in Example 1-1 (19.6 g, 35.3 mmol) was dissolved in toluene (600 ml) and acetic anhydride (4.08 ml), and D-methyl-10-sulfonic acid (8.20 g, 35.3 mmol) was dissolved. Was added and heated under reflux for 1 hour. After the reaction solution was concentrated to dryness, the residue was diluted with ethyl acetate (700 ml), washed with a 2% aqueous sodium hydrogen carbonate solution, water, 0.1N hydrochloric acid, water and saturated saline, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, methanol was added to the residue, and the resulting precipitate was collected by filtration, washed with methanol, and dried to obtain a red-purple powder of the title compound (U.2 g, 20.2 mmol). .

Ή-NMR (300 MHz, in double-mouthed form): δ 0.90 (3Η, t, J = 6.9 Hz), 1.7 (3H, t, J = 7.1 Hz), 1.32 (2H, m), 1.34 ( 2H, m), 1.47 (2H, brquint, J = 7.1 Hz), 2.11 (2H, brt, J = 7.4 Hz), 2.26 (3H, s), 2.41 (3H, s), 2.70 (2H, t, J = 7.4 Hz), 3.21 (2H, t, J = 7.4 Hz), 4.17 (2H, q, J = 7.1 Hz), 7.28 (2H, d, J = 8.2 Hz), 7.84 (2H, d, J = 8.2) Hz), 9.5 (1H, br). '

Elemental _{analysis: C 24 H 31 N 3 0} 5 S 3 Calculated: C, 53.61; H, 5.81 ; N, 7.81; S, 17.89 (), Found: C, 53.77; H, 5.80 ; N, 7.78 ; S, 17.92 (%). Example 2-2 '

Formula (VII) in R ⁵ is hexyl group n-, R ⁶ is a hydrogen atom, R ^{1 Q} is - compound ZR ¹⁵ (Z is S_〇 _2, R ¹⁵ is p- Toruiru group), R is Echiru group Synthesis of things

 The compound synthesized in Example 1-2 (325 mg, 0.584 mmol) was dissolved in toluene (11 ml), D-camphor-10-sulfonic acid (136 mg, 0.584 mmol) was added, and the mixture was heated under reflux for 2 hours. . The reaction solution was diluted with ethyl acetate (20 ml), washed with water, a 2% aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over sodium sulfate, and concentrated to dryness under reduced pressure. The residue is dissolved in methanol, and reversed-phase preparative HPLC (Carrier: 0DS, YMC-Pack, S-363--15, inner diameter 30 mm x length 250 mm, manufactured by YMC Corp., mobile phase : Apply 0.05% (v / v)% trifluoroacetic acid Z 75 (v / v)% acetonitrile water), collect the fractions with elution volume of 720-900 ml, concentrate and concentrate the remaining aqueous layer with ethyl acetate (45 ml). ). The organic layer was washed with 0.05N hydrochloric acid, water and saturated saline, dried over sodium sulfate, and concentrated to dryness under reduced pressure. Ether was added to the residue, and the resulting precipitate was collected by filtration, washed with ether, and dried to give a red powder of the title compound (103 mg, 0.192 mmol).

 Ή-NMR (300 MHz, in double-mouthed form): <5 0.89 (3H, t, J = 6.8 Hz), 1.27 (3H, t, J = 7.2 Hz), 1.29 (4H, brs), 1.32 (2H , m), 1.46 (2H, brquint, J = 5.7 Hz), 2.07 (2H, brt, J = 7.5 Hz), 2.42 (3H, s), 2.70 (2H, t, J = 7.5 Hz), 3.23 (2H , t, J = 7.5 Hz), 4.17 (2H, q, J = 7.2 Hz), 6.50 (1H, s), 7.29 (2H, d, J = 8.3 Hz), 7.84 (2H, d, J = 8.3 Hz) ), 9.79 (1H, br),

Elemental _{analysis: C 24 H 31 N 3 0} 5 S 3 Calculated: (:, 53.61; H, 5.81; N, 7.81; S, 17.89 (%), Found: C, 53.58; H, 5.87 ; N , 7.89; S, 18.13 (%). Examples 2-3 R ⁵ is ethoxy Cal Poni Le group in the formula (VII), R ⁶ is a methyl group, the synthesis of R ¹⁰ Gar ZR ¹⁵ (Z is S 0 _2, R ¹⁵ is P- Toruiru group), R is Ru Echiru group Der compound

 The compound (236 mg, 0.424 mmol) synthesized in Example 1-3 was dissolved in toluene (8 ml), D-camphor-10-sulfonic acid (98 mg, 0.424 mmol) was added, and the mixture was heated under reflux for 2 hours. . The reaction solution was diluted with ethyl acetate (15 mU, washed with 2% aqueous sodium hydrogen carbonate, Q.1N hydrochloric acid, water and saturated saline, dried over sodium sulfate, concentrated to dryness under reduced pressure, and ether was added to the residue. The resulting precipitate was collected by filtration, washed with ether, and dried to give a red powder of the title compound (174 mg, 0.323 mmol).

 -Dragon R (300 MHz, double-holed): <5 1.27 (3H, t, J = 7.2 Hz), 1.32 (3H, t, J = 7.2 Hz), 2.42 (3H, s), 2.75 (3H , s), 2.71 (2H, t, J = 7.2 Hz), 3.26 (2H, t, J = 7.2 Hz), 4.17 (2H, q, J = 7.2 Hz), 4.26 (2H, q, J = 7.2 Hz) ), 7.30 (2H, d, J = 8.3 Hz), 7.83 (2H, d, J = 8.3 Hz), 9.78 (1H, brs).

Elemental analysis: Calculated as _{C 22 H 25 N 3 0 7} S 3: C, 48.97; H, 4.67; N, 7.79; S, 17.83 {%), Found; 48.78; H, 4.59; N , 7.80; S, 17.91 (%). Example 2-4

Formula (VII) in R ⁵ is n- butyl group, R ⁶ is a methyl ^{group, R 1 (^ S- ZR 1} 5 (Z is S_〇 _2, R ¹⁵ is p- Toruiru group), R is a Echiru group Synthesis of compound

The compound (415 mg, 0.766 mmol) synthesized in Example 4 was dissolved in toluene (14 ml), D-camphor-10-sulfonic acid (178 mg, 0.766 mmol) was added, and the mixture was heated under reflux for 1 hour. The reaction solution was diluted with ethyl acetate (30 ml), washed with a 2% aqueous sodium hydrogen carbonate solution, hydrochloric acid, water and saturated saline, dried over sodium sulfate, and concentrated to dryness under reduced pressure. The residue was dissolved in methanol and subjected to reversed-phase preparative HPLC (Carrier: 0DS, YMC-Pack, S-363-15, 30 mm ID x 250 mm length, mobile phase: 0.05 (v / v) trifluoroacetic acid / ( v / v acetonitrile water), collect fractions with an elution volume of 640-780 ml, concentrate, The layer was extracted with ethyl acetate (20ml). The organic layer was washed with 0.05M hydrochloric acid and saturated sodium chloride solution, dried over sodium sulfate, and concentrated to dryness under reduced pressure. Ether was added to the residue, and the resulting precipitate was collected by filtration, washed with ether, and dried to give a red powder of the title compound (155 mg, 0.296 mmol).

Ή-NMR (300 MHz, in double-mouthed form): δ 0.92 (3Η, t, J = 7.1 Hz), 1.26 (3H, t, J = 7.1 Hz), 1.34 (2H, m), 1.44 (2H, m), 2.12 (2H, brdd, J = 7.9, 7.0 Hz), 2.26 (3H, s), 2.40 (3H, s), 2.70 (2H, t, J = 7.4 Hz), 3.21 (2H, t, J = 7.4 Hz), 4.16 (2H, q, J = 7.1 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.82 (1H, br).

Elemental _{analysis: C 23 H 29 N 3 0} 5 S 3 Calculated: C, 52.75; H, 5.58 ; N, 8.02; S, 18.37 (%), Found; C, 52.77; H, 5.38 ; N, 8.21; S, 18.28 (%). Example 2-5

Both methyl groups R ⁵ and R ⁶ in formula (VII), R ^{1 Q} Gar ZR ^{1 5} (Z is S_〇 _2, R ¹⁵ is p- Toruiru group), if the compound R is an Echiru group formed

 The compound synthesized in Reference Example 3-2 (40 g, about 50% purity, about 43 mmol) was dissolved in THF (600 ml), and 3-chloro-2-butanone (9.1 ml, 86 mmol) and triethylamine ( 35.8 ml, 0.258 mol) was added, and the mixture was stirred at room temperature for 1.5 hours, and then heated and refluxed for 8 hours. After concentration of the reaction solution, the residue was diluted with ethyl acetate (600 ml), washed with 2% aqueous sodium hydrogen carbonate, water, 0.1N hydrochloric acid, water and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure to dryness Solidification afforded a brown oil (29 g) containing the title compound.

The above brown oil was dissolved in toluene (580 ml) and acetic anhydride (11.4 ml), and P-toluenesulfonic acid monohydrate (8.98 g, 47 mmol) was added. The mixture was heated and stirred at 100 for 2 hours. did. After concentration of the reaction solution, the residue was diluted with ethyl acetate (700 ml), washed four times with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and methanol was added to the residue. The resulting precipitate was collected by filtration, washed with methanol, and dried to obtain a red-purple powder of the title compound (9.68 g, 20.1 mmol). Ή-NMR (300 MHz, in double-mouthed form): δ 1.27 (3Η, t, J = 7.2 Hz), 1.79 (3H, brq, J = 0.8 Hz), 2.26 (3H, brq, J = 0.8 Hz) , 2.42 (3H, s), 2.70 (2H, t, J = 7.5 Hz), 3.20 (2H, t, J = 7.5 Hz), 4.17 (2H, q, J = 7.2 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.84 ( 2H, d, J = 8.3 Hz), 9.61 (1H, br) elemental analysis:. C _2. H ₂₃ N ₃ 0 ₅ S ₃ Calculated: C, 49.88; H, 4.81 ; N, 8.72; S, 19.97 (%), Found; C, 49.78; H, 5.03 ; N, 8.68; S, 20.00 ( %). Examples 2-6

Case of compounds wherein R ⁵ Echiru group, R ⁶ is a methyl group, R ^{1 (gar} ZR ^{1 5} (sigma is 3_Rei _2, R ¹⁵ is p- Toruiru group), R is Echiru group in the formula (VII) Success

 The compound synthesized in Reference Example 3-2 (8.70 g, 20.3 mmol) was dissolved in THF (100 ml) and DMF (40 ml), and 3-bromo-2-pentanone (5.7 g, purity 60%, approx. mmol) and triethylamine (8.4 ml, 61 mmol) were added, and the mixture was stirred at room temperature for 7.5 hours. During this time, 2, 4-, and 6 hours after the start of the reaction, 3-promo-2-pennone (1.4 g, purity 50%, about 4 mfflol) was added. After concentrating the reaction mixture, the residue was diluted with ethyl acetate (300 ml), washed with water, 2% aqueous sodium hydrogen carbonate, water, 0.1N hydrochloric acid, water and saturated saline, and then washed with sodium sulfate. It was dried and concentrated to dryness under reduced pressure to give a brown oil (8.6 g) containing the title compound.

 The above brown oil was dissolved in toluene (250 ml) and acetic anhydride (5.86 ml), p-toluenesulfonic acid monohydrate (3.12 g, 16.2 mmol) was added, and the mixture was heated at 100 ° C for 2 hours. Stirred. After concentration of the reaction solution, the residue was diluted with ethyl acetate (300 ml), washed three times with water and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, methanol was added to the residue, and the resulting precipitate was collected by filtration, washed with methanol, and dried to give the title compound as a red powder (4.71 g, 9.50 mmol).

'Η-Awake R (300 MHz, in the double-mouthed form): δ 1.09 (3Η, t, J = 7.4 Hz), 1.27 (3H, t, J = 7. Hz), 2.14 (2H, q, J = 7.0 Hz), 2.26 (3H, s), 2.42 (3H, s), 2.70 (2H, t, J = 7.6 Hz), 3.22 (2H, t, J = 7.8 Hz), 4.17 (2H, q, J = 7.4 Hz), 7.29 (2H, d, J = 8.2 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.63 (1H, br).

Elemental analysis: C ₂₁ H ₂₅ N ₃ 0 ₅ S ₃ Calculated: C, 50.89; H, 5.08; N, 8.48; S, 19.41 (%), found; C, 50.76; H, 4.84; N, 8.46; S, 19.37 (). Examples 2-7

Formula (VII) in which R ⁵ and R ⁶ are both methyl, R ^{1 Q} is - ZR ^{1 5} (Σ is 3_Rei _2, R ¹⁵ is p- black port phenyl group), the compound wherein R is an Echiru group Synthesis

 The compound synthesized in Reference Example 3-1 (7.9 g, purity of about 70%, 12.3 mmol) was dissolved in THF (130 ml), and 3-chloro-2-butanone (1.66 ml, 15.7 mmol) and triethylamine ( 5.93 ml, 42.8 mmol) was added and the mixture was refluxed for 7 hours. Further, 3-chloro-2-butanone (0.45 ml, 4.28 mmol) and triethylamine (1.97 ml, 14.3 mmol) were added, and the mixture was further refluxed for 5 hours. After concentration of the reaction solution, the residue was diluted with ethyl acetate (200 ml), washed with water and saturated saline, dried over sodium sulfate, and concentrated to dryness under reduced pressure to give a brown oil (7.7 g). Obtained.

 The above brown oil was dissolved in toluene (140 ml) and acetic anhydride .12 ml, 42.8 mmol), and P-toluenesulfonic acid monohydrate (2.17 g, 11.4 mmol) was added, followed by stirring at room temperature for 63 hours. did. The reaction solution was diluted with ethyl acetate (200 ml), washed three times with water and saturated saline, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, methanol was added to the residue, and the resulting precipitate was collected by filtration, washed with methanol, and dried to give the title compound as a gray-red powder (3.67 g, 7.31 mmol).

Ή-NR (300 MHz, in the double-mouthed form): δ 1.27 (3Η, t, J- 7.1 Hz), 1.80 (3H, brq, J = 1.0 Hz), 2.27 (3H, q, J = 1.2 Hz) ), 2.70 (2H, t, J = 7.4 Hz), 3.22 (2H, t, J = 7.4 Hz), 4.17 (2H, q, J =-7.0 Hz), 7.47 (2H, dt, J = 8.8, 1.8 . Hz), 7.90 (2H, dt, J = 8.8, 2.2 Hz), 9.60 (1H, brs) elemental analysis: calculated _{C 19 H 2Q N 3 0 5} S 3 C1: C, 45.46; H, 4.02 N, 8.37; S, 19.16; Cl, 7.06 () Found; C, 45.54; H, 3.97; N, 8.38; S, 19.07; CI, 6.82 (%).

Example 2-8

Formula (VII) in which R ⁵ and R ⁶ are both methyl, R ^{1 ()} is - ZR ^{1 5} (2 is 3_Rei _2, R ¹⁵ is P- Buromofueniru group) Synthesis of Compound R is Echiru group

 The compound synthesized in Reference Example 3-4 (5.36 g, purity about 96%, 10.5 mmol) was dissolved in THF (110 ml), and 3-chloro-2--2-butanone (1,22 ml, 11.6 mmol) was dissolved. ) And triethylamine (4.40 ml, 31.5 mmol) were added, and the mixture was refluxed for 20 hours. The reaction solution was diluted with ethyl acetate (300 ml), washed with water, 2% aqueous sodium hydrogen carbonate solution and saturated saline, dried over sodium sulfate, and concentrated to dryness under reduced pressure to give a brown oil (5.87 g). Obtained.

 The above brown oil was dissolved in toluene (120 ml) and acetic anhydride (3.03 ml, 31.5 mmol), and p-toluenesulfonic acid monohydrate (1.60 g, 8.40 mmol) was added. Stir for 2 hours. The reaction solution was concentrated under reduced pressure, methanol was added to the residue, the resulting precipitate was collected by filtration, washed with methanol, and dried to give the title compound as an off-white powder (3.46 g, 6.33 mmol).

^ -R (300 MHz, in double-hole form): δ 1.27 (3Η, t, J = 6.9 Hz), 1.80 (3H, brq, J = 1.2 Hz), 2.27 (3H, q, J = 0.9 Hz) , 2.71 (2H, t, J = 7.4 Hz), 3.22 (2H, t, J = 7.5 Hz), 4.17 (2H, q, J = 7.2 Hz), 7.64 (2H, dt, J = 8.7, 2.1 Hz) , 7.83 (2H, dt, J = 8.7, 2.1 Hz), 9.60 (1H, brs) elemental analysis:. C ₁₉ H _2. Calculated for N ₃ 0 ₅ S ₃ Br: C, 41.76; H, 3.69;, 7.69; S, 17.60; Br, 14.62 (), found; C, 41.80; H, 3.71; N, 7.72; S, 17.61. Br, 14.42 (%). Melting point: 165.0-167.0. C.

The following is a list of compounds synthesized in Examples 2-1 to 2-8 and compounds synthesized in the same manner. (Table 7)

Replacement paper (M 26) (Table 8)

Replacement paper »2β) (Table 9)

For replacement 弒 (M026) (Table 10) '

Replacement paper (Table 11) '

Replacement bridal (Μ2 ^ (Table 12) '

^^; ^ m) (Table 13) '

Replacement form (Rule 26) The following shows the results of the compounds synthesized in Examples 2-9 to 2-78.

Example 2-9

- negation _{R (300MHz, CDC1 3):} δ 1.27 (3Η, t, J = 7.1 Hz), 2.43 (3H, s),

2.73 (2H, t, J = 7.4 Hz), 3.24 (2H, t, J = 7.4 Hz), 4.17 (2H, q, J = 7.1 Hz), 4.98 (1H, s), 7.20 (2H, dd, J = 8.3, 1.5 Hz), 7.32 (2H, d, J = 8.3 Hz), 7.37 (3H, m), 7.87 (2H, d, J = 8.3 Hz), 9.69 (1H, brs).

Elemental _{analysis: C 24 H 23 N 3 0} 5 S 3 Calculated: C, 54.42; H, 4.38 ; N, 7.93; S, 18.16 (%), Found: C, 54.23; H, 4.46 ; N, 8.00; S, 18.45 (%). Example 2-10

_{Ή-NMR (300MHz, CDC1 3} ): δ 2.43 (3Η, s), 2.74 (2H, t, J- 7.4 Hz),

3.24 (2H, t, J = 7.4 Hz), 3.72 (3H, s), 4.98 (1H, s), 7.20 (2H, dd, J-7.9, 1.8 Hz), 7.32 (2H, d, J = 8.2 Hz) ), 7.36 (3H, m), 7.87 (2H, d, J = 8.2 Hz), 9.68 (1H, brs).

Elemental analysis: C ₂₃ H _{2 I} N ₃ 0 ₅ S ₃ Calculated: C, 53.58; H, 4.10; N, 8.15; S, 18.66 (), found: C, 53.66; H, 4.08; N, 8.14 ; S, 18.65 (%). Examples 2-11

'H-NMR (300MHz, CDC1 3): δ 1.28 (3Η, t, J = 7.1 Hz), 2.43 (3H, s), 2.73 (2H, t, J = 7.4 Hz), 3.25 (2H, t, J = 7.4 Hz), 4.18 (2H, q, J = 7.1 Hz), 5.04 (1H, s), 7.27 (2H, d, J = 8.2 Hz), 7.32 (2H, d, J = 8.3 Hz), 7.36 ( 1H, t, J = 7.2 Hz), 7.44 (2H, t, J = 7.8 Hz), 7.58 (2H, d, J = 8.2 Hz), 7.58 (2H, m), 7.88 (2H, d, J = 8.3) Hz), 9.73 (1H, brs).

Elemental analysis: C _3. H ₂₇ N ₃ 0 ₅ S ₃ Calculated: C, 59.48; H, 4.49; N, 6.94; S, 15.88 (), Found: 59.41; H, 4.31;, 6.68; S, 15.94 (). 2-12

_{Ή-NMR (300MHz, CDC1 3} ): δ 1.25 (3Η, t, J = 7.1 Hz), 2.44 (3H, s), 2.71 (2H, t, J = 7.3 Hz), 3.24 (2H, t, J = 7.3 Hz), 4.15 (2H, q, J = 7.1 Hz), 7.03 (2H, m), 7.05 (2H, dd, J = 7.5, 1.4 Hz), 7.17 (5H, m), 7.30 (1H, m) , 7.32 (2H, d, J = 8.2 Hz), 7.87 (2H, d, J = 8.2 Hz), 9.63 (1H, brs). Elemental analysis: C _3. Calculated for H ₂₇ N ₃ 0 ₅ S ₃ : 59.48; H, 4.49; N, 6.94; S,

15.88 (%), Found: (:, 59.47; H, 4.0; N, 7.03; S, 15.90 (%).

_{Ή-NMR (300MHz, CDC1 3} ): 6 0.89 (3H, t, J = 6,9 Hz), 1.27 (3H, t, J = 7.1 Hz), 1.29 (6H, brs), 1.31 (2H, br) , 1.6 (2H, brquint, J = 7.2 Hz), 2.11 (2H, dd, J = 7.9, 7.2 Hz), 2.26 (3H, s), 2.41 (3H, s), 2.70 (2H, t, J = 7.4 Hz), 3.22 (2H, t, J = 7.4 Hz), 4.17 (2H, q, J = 7.1 Hz), 7.28 (2H, d, J = 8.2 Hz), 7.85 (2H, d, J = 8.2 Hz), 9.73 (1H, brs).

Elemental analysis: C ₂₆ H ₃₅ N ₃ 0 ₅ S ₃ Calculated: C, 55.20; H, 6.24; N, 7.43; S, 17.00 (%), found: C, 55.09; H, 6.13; N, 7.43; S, 17.29 (%). Example 2-14

_{^ -NMR (300MHz, CDC1 3)} : <5 0.85 (3H, t, J = 6.8 Hz), 1.13 (6H, br), 1.17 (2H, m), 1.28 (3H, t, J = 7.2 Hz), 1.37 (2H, brquint, J = 7.2 Hz), 1.94 (2H, dd, J = 8.3, 7.Hz), 2.42 (3H, s), 2.74 (2H, t, J = 7.5 Hz), 3.28 (2H, t, J = 7.5 Hz), 4.18 (2H, q, J = 7.2 Hz), 7.17 (2H, dd, J = 6.8, 3.1 Hz), 7.30 (2H, d, J = 8.3 Hz), 7.39 (3H, m), 7.85 (2H, d, J = 8.3 Hz), 9.52 (1H, brs).

Elemental analysis: C ₃₁ H ₃₇ N ₃ 0 ₅ S ₃ Calculated: C, 58.47; H, 6.01;, 6.60; S, 15.10 (%), found: C, 58.53; H, 5.86; N, 6.53 S, 15.30 (). Examples 2-15

Ή-NMR (300 MHz, DMS0-'d ₆ ): 6 0.80 (3H, t, J = 7.2 Hz), 1.05-1.20 (8H, m), 1.34 (2H, brquint, J = 6.6 Hz), 1.95 (2H , Dd, J = 7.5, 7.2 Hz), 2.39 (3H, s), 2.66 (2H, t, J = 7.1 Hz), 3.20 (2H, t, J = 7.1 Hz), 7.28 (2H, m), 7.35 (3H, m), 7.39 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 11.62 (1H, br), 12.62 (1H, br).

Elemental _{analysis: C 29 H 33 N 3 0} 5 S 3 Calculated: C, 58.07; H, 5.55 ; N, 7.01; S,

16.04 (%;), Found: 58.02; H, 5.58; N, 7.02; S, 16.22 (). Examples 2-16

_{lH- NMR (300MHz, CDC1 3)} : δ 0.81 (3Η, t, J = 6.8 Hz), 1.15 (2H, m), 1.15 (2H, m), 1.28 (3H, t, J- 7.2 Hz), 1.37 (2H, brquint, J = 7.4 Hz), 1.94 (2H, dd, J = 7.9, 7.5 Hz), 2.42 (3H, s ), 2.74 (2H, t, J = 7.2 Hz), 3.28 (2H, t, J = 7.2 Hz), 4.18 (2H, q, J = 7.2 Hz), 7.17 (2H, m), 7.30 (2H, d , J = 8.3 Hz), 7.39 (3H, m), 7.85 (2H, d, J = 8.3 Hz), 9.50 (1H, brs).

Elemental _{analysis: C 29 H 33 N 3 0} 5 S 3 Calculated: C, 58.07; H, 5.55 ; N, 7.01; S, 16.04 (%), Found: C, 57.79; H, 5.39 ; N, 6.85; S, 16.09 (%). Example 2-17

 Ή-NMR (300 MHz, CDC: δ 1.27 (3Η, t, J = 7.2 Hz), 2.15 (3H, s), 2.3 (3H, s), 2.72 (2H, t, J = 7.5 Hz), 3.24 (2H, t, J = 7.5 Hz), 4.17 (2H, q, J = 7.2 Hz), 4.96 (1H, s), 7.14 (2H, d, J = 8.3 Hz), 7.32 (2H, d, J = 8.3 Hz), 7.47 (2H, d, J = 8.3 Hz), 7.91 (2H, d, J = 8.3 Hz), 7.33 (1H, brs), 9.68 (1H, brs).

Elemental _{analysis: C 26 H 26 N 4 0} 6 S 3 Calculated: C, 53.23; H, 4.47 ; N, 9.55; S, 16.40 (), Found: C, 52.96; H, 4.25 ; N, 9.55 S, 16.11 (%). Example 2-18

_{Έ- NMR (300MHz, CDC1 3)} : δ 0.73 (3H, t, J = 7.2 Hz), 1.18 (2H, m), 1.24 (3H, t, J = 7.2 Hz), 1.33 (2H, m), 2.43 (3H, s), 2.59 (2H, brt, J = 7.2 Hz), 2.68 (2H, t, J = 7.5 Hz), 3.18 (2H, t, J = 7.5 Hz), 4.14 (2H, q, J = 7.2 Hz), 7.28 (2H, m), 7.31 (2H, d, J = 8.3 Hz), 7.40 (2H, m), 7.0 (1H, m), 7.87 (2H, d, J = 8.3 Hz) , 9.67 (1H, br).

Elemental analysis: C ₂₈ H ₃₁ N ₃ 0 ₅ S ₃ Calculated: C, 57.41; H, 5.33; N, 7.17

(%) Found: C, 57.67; H, 5.24;, 7.18 (%).

Example 2-19

^{] H-NMR (300MHz, CDC1} 3): δ 0.89 (3H, brt, J = 6.4 Hz), 0.93 (3H, t, J = 7.2 Hz), 1.27 (3H, t, J = 7.2 Hz), 1.32 ( 6H, m), 1.40 (4H, m), 2.15 (2H, dd, J = 8.7, 6.8 Hz), 2.42 (3H, s), 2.70 (2H, t, J = 7.5 Hz), 2.72 (2H, brt , J- 7.5 Hz), 3.22 (2H, t, J = 7.5 Hz), 4.17 (2H, q, J = 7.2 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.84 (2H, d, J = 8.3 Hz), 9.61 (1H, br). Example 2-20

_{Ή-NR (300MHz, CDC1 3} ): δ 0.88 (3H, t, J = 6.7 Hz), 1.27 (3H, t, J = 7.2 Hz), 1.27 (8H, brs), 1.30 (2H, m), 1 6 (2H, brquint, J = 7.5 Hz), 2.06 (2H, brt, J = 7.2 Hz), 2.41 (3H, s), 2.70 (2H, t, J = 7.5 Hz), 3.23 (2H, t, J = 7.5 Hz), 4.17 (2H, q, J = 7.2 Hz), 6.50 (1H, brt, J = 1.0 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.84 (2H, d, J = . 8.3 Hz), 9.81 (1H , br) elemental analysis: calculated _{C 26 H 35 N 3 0 5} S 3: C, 54.33; H, 6.31;, 7.31; S, 16.73 (), Found: C , 54.43; H, 6.15; N, 7.37; S, 17.19 (). Examples 2-21

_{Ή-NMR (300MHz, CDC1 3} ): δ 1.27 (3H, t, J = 7.2 Hz), 2.43 (3H, s), 2.74 (2H, t, J = 7.5 Hz), 3.30 (2H, t, J = 7.5 Hz), 4.17 (2H, q, J = 7.2 Hz), 6.93 (1H, s), 7.31 (2H, d, J = 8.3 Hz), 7.38 (5H, s), 7.86 (2H, d, J = 8.3 Hz), 9.82 (1H, br).

Elemental _{analysis: C 24 H 23 N 3 0} 5 S 3 Calculated: C, 54.42; H, 4.38 ; N, 7.93; S, 18.16 (%), Found: C, 54.22; H, 4.34 ; N, 7.97; S, 18.29 (%). Examples 2-22

 8-[(3-Ethoxy-3-oxopropyl) sulfanyl] -1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydrogen-1H-imidazo c] [1,4] thiazine-5-ethyl carboxylate

 Of the compound obtained in Reference Example 3-2 (purity 80%, 10.1 g, 18.8 mmol), ethyl 3-bromo-2-oxopropionate (3.66 g, 18.8 mmol) and triethylamine (7.81 ml, 56.3 mmo 1) The suspension of DMF-THF (1: 4, 200 ml) was stirred at room temperature for 50 minutes. The reaction solution was concentrated and extracted with ethyl acetate. The organic layer was washed with a 5% aqueous solution of sodium hydrogen carbonate and saturated saline, dried over sodium sulfate, and concentrated to obtain a brown solid (11 g).

A suspension of the obtained brown solid (11 g), acetic anhydride (5.42 ml, 56.3 mmol) and p-TsOH hydrate (3.58 g, 18.8 tmol) in toluene (200 ml) was stirred at 80 for 3 hours. did. The reaction solution was concentrated and extracted with ethyl acetate. The organic layer is washed with a 5% aqueous sodium hydrogen carbonate solution and saturated saline, and then dried over sodium sulfate. And concentrated. Methanol was added to the residue, and the precipitate was collected by filtration, washed with methanol, and dried to give the title compound (4.86 g, 9.23 mmol) as a red-purple powder.

_{Ή-NR (300MHz, CDC1 3} ): δ 1.27 (3Η, t, J = 7.2 Hz), 1.32 (3H, t, J = 7.1 Hz), 2.43 (3H, s), 2.69 (2H, t, J = 7.5 Hz), 3.21 (2H, t, J = 7.5 Hz), 4.16 (2H, q, J = 7.2 Hz), 4.31 (2H, q, J- 7.2 Hz), 5.89 (1H, s), 7.31 (2H , d, J = 8.3 Hz) , 7.84 (2H, d, J = 8.3 Hz), 9.72 (1H, brs) elemental analysis: calculated _{C 21 H 23 N 3 0 7} S 3: C, 47.99;. H, 4.41; N, 7.99; S, 18.30 (%), Found: C, 47.87; H, 4.47; N, 8.01; S, 18.10 (%). Mp.130.0-131.5

Example 2-23

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.92 (3H, t, J = 7.2 Hz), 1.27 (3H, t, J = 7.1 Hz), 1.36 (2H, quint, J = 7. Hz), 1.45 ( 2H, quint, J = 7.2 Hz), 2.07 (2H, brt, J = 7.0 Hz), 2.41 (3H, s), 2.70 (2H, t, J = 7.3 Hz), 3.23 (2H, t, J = 7.3) Hz), 4.17 (2H, q, J = 7.1 Hz), 6.51 (1H, s), 7.29 (2H, d, J = 8.3 Hz), 7.84 (2H, d, J = 8.3 Hz), 9.80 (1H, br).

Elemental _{analysis: C 22 H 27 N 3 0} 5 S 3 · H 2 0 Calculated: C, 50.08; H, 5.54 ; N, 7.96; S, 18.22 (%), Found: 9.66; H, 5.22; N, 7.70; S, 18.08 (). Examples 2-24

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.88 (3Η, t, J- 6.9 Hz), 1.26 (16H, brs), 1.27 (3H, t, J = 7.1 Hz), 1. 6 (2H, brquint, J = 6.8 Hz), 2.07 (2H, brt, J2 7.2 Hz), 2.2 (3H, s), 2.70 (2H, t, J = 7.4 Hz), 3.23 (2H, t, J = 7.4 Hz) , 4.17 (2H, q, J = 7.1 Hz), 6.50 (1H, brt, J = 1 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.84 (2H, d, J = 8.3 Hz), 9.79 (1H, br).

Elemental analysis: C _3. H ₄₃ N ₃ 0 ₅ S ₃ · 0.4H ₂ 0 Calculated: C, 57.28; H, 6.89; N, 6.68; S, 15.29 (%), Found: C, 57.28; H, 7.00; N, 6.64 ; S, 15.20

(%).

Example 2-25

_{Ή-NMR (300MHz, CDC1 3} ): δ 1.26 (3H, t, J = 7.2 Hz), 2.27 (3H, d, J = 1.1 Hz), 2.42 (3H, s), 2.69 (2H, t, J = 7.5 Hz), 3.18 (2H, t, J = 7.5 Hz), 4.16 (2H, q, J = 7.2 Hz), 4.63 (1H , q, J = 1.1 Hz), 7.29 (2H, d, J = 8.2 Hz), 7.84 (2H, d, J = 8.2 Hz), 9.71 (1H, br).

Elemental analysis: C ₁₉ H ₂₁ N ₃ 0 ₅ S ₃ Calculated: C, 48.81; H, 4.53; N, 8.99; S, 20.57 (), found: C, 48.52; H, 4.51; N, 9.00 ; S, 20.69 (%). Example 2-26

_{Ή-NMR (300MHz, CDC1 3} ): δ 1.27 (3Η, t, J- 7.2 Hz), 1.80 (2H, quint, J = 7.2 Hz), 2.19 (2H, brdd, J = 7.9, 7.5 Hz), 2.27 (3H, s), 2.36 (2H, t, J = 7.2 Hz), 2.41 (3H, s), 2.69 (2H, t, J = 7.5 Hz), 3.21 (2H, t, J = 7.5 Hz), 3.68 (3H, s), 4.16 (2H, q, J = 7.2 Hz), 7.28 (2H, brd, J = 8.3 Hz), 7.84 (2H, d, J = 8.3 Hz), 9.76 (1H, br).

Elemental _{analysis: C 24 H 29 N 3 0} 7 S 3 Calculated: C, 50.78; H, 5.15 ; N, 7.40; S, 16.94 (%), Found: C, 50.75; H, 5.21 ;, 7.45 ; S, 17.01 (%). Example 2-27

_{Ή-NMR (300MHz, CDC1 3} ): δ 1.26 (3H, t, J = 7.1 Hz), 2.41 (2H, m), 2.41 (3H, s), 2.51 (2H, brt, J = 6.4 Hz), 2.70 (2H, t, J = 7.4 Hz), 3.22 (2H, t, J = 7.4 Hz), 3.70 (3H, s), 4.17 (2H, q, J = 7.1 Hz), 6.57 (1H, brs), 7.28 (2H, d, J = 8.3 Hz), 7.84 (2H, d, J = 8.3 Hz), 9.89 (1H, br) elemental _{analysis:. C 22 H 25 N 3} 0 7 S 3 calculated: C, 48.97; H, 4.67; N, 7.79; S, 17.83 (%), Found: C, 48.67; H, 4.60; N, 7.59; S, 17.94 (%). Example 2-28

_{Ή-NMR (300MHz, CDC1 3} ): δ 1.26 (3Η, t, J = 7.1 Hz), 2.41 (2H, m), 2.41 (3H, s), 2.56 (2H, brt, J = 6.6 Hz), 2.70 (2H, t, J = 7.4 Hz), 3.22 (2H, t, J = 7.4 Hz), 4.17 (2H, q, J = 7.1 Hz), 6.61 (1H, brs), 7.29 (2H, d,] = 8.3 Hz), 7.84 (2H, d, J = 8.3 Hz), 9.96 (1H, br).

Elemental analysis: C ₂₁ H ₂₃ N ₃ 0 ₇ S ₃ Calculated: C, 47.99; H, 4.41; N, 7.99; S, 18.30 (%), found: C, 47.83; H, 4.33; N, 8.01; S, 18.55 (%). Example 2-29

_{Ή-NMR (300MHz, CDC1 3} ): δ 1.24 (3Η, t, J = 7.1 Hz), 2.40 (3H, s), 2.62 (2H, brt, J = 7.3 Hz), 3.15 (2H, t, J = 7.3 Hz), 3.36 (2H, brs), 4.14 (2H, q, J = 7.1 Hz), 6.58 (1H, brt, J = 1 Hz), 7.20 (2H, bfd, J = 7.5 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.30 (1H, m), 7.32 (2H, brt, J = 7.3 Hz), 7.83 ( 2H, d, J = 8.3 Hz), 9.82 (1H, br).

Elemental analysis: C ₂₅ H ₂₅ N ₃ 0 ₅ S ₃ Calculated: C, 55.23; H, 4.63;, 7.73; S, 17.69 (%), found: C, 55.04; H, 4.73; N, 7.66 ; S, 17.82 (%). Example 2-30

_{Ή-NMR (300MHz, CDC1 3} ): 6 1.26 (3H, t, J = 7.1 Hz), 2.42 (3H, s), 2.70 (2H, t, J = 7.4 Hz), 3.20 (2H, t, J = 7.4 Hz), 4.16 (2H, q, J = 7.1 Hz), 5.02 (1H, t, J = 8.0 Hz), 6.66 (1H, d, J = 8.0 Hz), 7.29 (2H, d, J = 8.3 Hz) ), 7.83 (2H, d, J = 8.3 Hz), 9.82 (1H, br).

Elemental _{analysis: C 18 H 19 N 3 0} 3 S 3 Calculated: C, 47.67; H, 4.22 ; N, 9.26; S, 21.21 (%), Found: C, 47.48; H, 4.16 ; N, 9.13; S, 21.42 (%). Examples 2-31

Ή-NMR (300 MHz, DMS0-d ₆ ): δ 1.18 (3Η, t, J = 7.1 Hz), 2.39 (3H, s), 2.50 (2H, t, J = 6.4 Hz), 2.63 (2H, t, J = 7.0 Hz), 3.09 (2H, t, J = 7.0 Hz), 3.73 (2H, brt, J = 6.4 Hz), 4.08 (2H, q, J- 7.1 Hz), 6.71 (1H, brs), 7.37 . (2H, d, J = 8.2 Hz), 7.80-7.90 (6H, m), 11.80 (1H, br) elemental _{analysis: C 28 H 26 N 4 0} 7 S 3 calculated: 53.66; H, 4.18 N, 8.94; S, 15.35 (%), Found: 53.48; H, 4.21; N, 8.77; S, 15.34 (). Examples 2-32

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.90 (3Η, t, J = 6.8 Hz), 1.27 (3H, t, J = 7.1 Hz), 1.29 (2H, brs), 1.31 (2H, m), 1.47 (2H, brquint, J = 7.4 Hz), 2.07 (2H, brt, J = 7.5 Hz), 2.42 (3H, s), 2.70 (2H, t, J = 7.4 Hz), 3.23 (2H, t, J = 7.4 Hz), 4.17 (2H, q, J = 7.1 Hz), 6.50 (1H, brt, J = 0.5 Hz), 7.29 (2H, d, 8.3 Hz), 7.83 (2H, d, J = 8.3 Hz), 9.70 (1H, br). Elemental analysis: C ₂₃ H ₂₉ N ₃ 0 ₅ S ₃ · 0.3H ₂ 0 Calculated: C, 52.21; H, 5.64; N, 7.94; S, 18.18 (%), found Values: C, 52.28; H, 5.53; N, 7.98; S, 18.12 (%). Example 2-33

_{Ή-NR (300MHz, CDC1 3} ): δ 0.89 (3H, brt, J = 6.9 Hz), 1.27 (3H, t, J = 7.2 Hz), 1.28 (8H, brs), 1.46 (2H, brquint, J = 6.8 Hz), 2.06 (2H, brt, J = 7.3 Hz), 2.41 (3H, s), 2.70 (2H, t, J = 7.4 Hz), 3.23 (2H, t, J = 7.4 Hz), 4.17 (2H , q, J = 7.1 Hz), 6.50 (1H, brs), 7.29 (2H, d, J = 8.3 Hz), 7.83 (2H, d, J = 8.3 Hz), 9.79 (1H, brs).

Elemental _{analysis: C 25 H 33 N 3 0} 5 S 3 Calculated: C, 54.42; H, 6.03 ; N, 7.62; S, 17.43 (%), Found: 54.14; H, 5.78; N , 7. 4; S, 17.30 (%). Example 2-34

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.89 (3Η, t, J = 6.8 Hz), 1.26 (3H, t, J = 7.1 Hz), 1. 9 (6H, m), 1. 4 (2H, brqiunt, J = 7.2 Hz), 2.11 (2H, brdd, J-7.9, 7.2 Hz), 2.26 (3H, s), 2.40 (3H, s), 2.70 (2H, t, J = 7.4 Hz), 3.21 ( 2H, t, J = 7.4 Hz), 4.16 (2H, q, J = 7.1 Hz), 7.27 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.84 (1H, br).

Elemental analysis: Calculated as _{C 25 H 33 N 3 0 5} S 3: C, 54.42; H, 6.03; N, 7.62; S, 17.43 (%), Found: C, 54.27; H, 5.96 ; N, 7.76; S, 17.33 (%). Examples 2-35

_{Ή-NMR (300MHz, CDC1 3} ): δ 1.26 (3Η, t, J = 7.2 Hz), 2.42 (3H, s), 2.68 (2H, t, J = 7.1 Hz), 3.26 (2H, t, J = 7.1 Hz), 3.81 (2H, s), 4.16 (2H, q, J = 7.2 Hz), 6.90 (1H, s), 7.31 (2H, d, J = 8.3 Hz), 7.87 (2H, d, J = 8.3 Hz), 9.76 (1H, brs).

Elemental analysis: C ₁₉ H _2. Calculated for N ₃ 0 ₅ S ₃ C1: C, 45.46; H, 4.02; N, 8.37; S, 19.16 (%), found: C, 45.76; H, 3.90; N, 8.28; S, 19.12 (% Example 2-36

_{Ή-NMR (300MHz, CDC1 3} ): δ 1. 7 (3H, t, J = 7.2 Hz), 2.43 (3H, s), 2.72 (2H, t, J = 7.3 Hz), 3.24 (2H, t, J = 7.4 Hz), 4.17 (2H, q, J = 7.2 Hz), 4.95 (1H, s), 6.94 (2H, dt, J = 8.7, 2.3 Hz), 7.05 (2H, dq, J = 8.3, 1.1 Hz), 7.09 (2H, d, J = 8.7 Hz), 7.10 (1H, tq, J = 6.0, 0.7 Hz), 7.31 (2H, d, J = 8.3 Hz), 7.36 (2H, brt, J = 8.3) Hz), 7.86 (2H, d, J = 8.3 Hz), 9.68 (1H, brs).

Elemental analysis: C _3. Calcd _{H 27 N 3 0 6 S 3} : C, 57.95; H, 4.38;, 6.76; S, 15. 7 (%), Found: C, 58.22; H, 4.34 ; N, 6.58; S, 15.37 Example 2-37

'Η- 丽 R (300 MHz, in double-mouthed form): δ 2.27 (3Η, d, J = 1.2 Hz), 2.42 (3H, s), 2.71 (2H, t, J = 7.5 Hz), 3.18 ( 2H, t, J = 7.6 Hz), 3.71 (3H, s), 4.63 (1H, q, J = 1.3 Hz), 7.30 (2H, d, J = 8.2 Hz), 7.84 (2H, d, 8.3 Hz) , 9.67 (1H, brs) elemental analysis: calculated _{C 18 H 19 N 3 0 5} S 3:. C, 47.67; H, 4.22; N, 9.26; S, 21.21 (%), Found; C, 47.38; H, 4.26; N, 9.09; S, 21.35 ().

Example -38

_{Ή-NMR (CDC1 3, 300} MHz): δ 1.79 (3H, s), 2.26 (3H, d, J = 0.8 Hz), 2.42 (3H, s), 2.71 (2H, t, J = 7.5 Hz), 3.21 (2H, t, J = 7.6 Hz), 3.72 (3H, s), 7.29 (2H, d, J = 8.2 Hz), 7.84 (2H, d, J = 8.3 Hz), 9.63 (1H, brs).

Elemental analysis: Calculated as _{C 19 H 21 N 3 0 5} S 3: C, 48.80; H, 4.53; N, 8.99; S, 20.57 (%), Found: C, 48.55; H, 4. 7; N, 9.09; S, 20.64 (%). Example 2-39

_{Ή-NMR (CDC1 3, 300} MHz): δ 1.27 (3Η, ί, J = 7.2 Hz), 2.41 (3H, s), 2.63 (3H, s), 2.72 (2H, t, J = 7.5 Hz), 3.29 (2H, t, J = 7.5 Hz), 4.17 (2H, q, J-7.2 Hz), 7.30 (2H, d, J = 8.3 Hz), 7.84 (2H, d, J = 8.3 Hz), 9.80 ( 1H, br).

Elemental analysis: Calculated for C ₂₁ H ₂₃ N ₃ 0 ₆ S ₃ : C, 49.49; H, 4.55; N, 8.25; S, 18.88 (%), found: C, 49.17; H, 4.50; N, 8.26; S, 18.78 (%). Examples 2-40

_{Ή-NMR (CDC1 3, 200} MHz): δ 1.10 (6Η, d, J = 7.0 Hz), 1.27 (3H, t, J = 7.0 Hz), 2.28 (3H, s), 2.42 (3H, s), 2.71 (2H, t, J = 7.2 Hz), 2.96 (1H, quint, J = 6.6 Hz), 3.25 (2H, t, J = 7.2 Hz), 4.17 (2H, q, J = 7.4 Hz), 7.29 ( 2H, d, J = 7.8 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.64 (1H, br). Elemental _{analysis: C 22 H 27 N 3 0} 5 S 3 Calculated: C, 51.84; H, 5.34 ; N, 8.24; S, 18.87 (%), Found: 51.62; H, 5.44; N , 8.26; S, 18.99 (%). Example -41

Recrystallization from ethyl acetate gave dark red crystals with a melting point of 138-140 ° C.

Infrared absorption spectrum (IR) (in KBr): 3280, 2961, 2930, 2872, 1732, 1657, 1559 cm " ¹ .

^ -NMR (CDClg): δ 0.950 (3Η, t, J = 7.0 Hz), 1.27 (3H, t, J = 7.0 Hz), 1.44-1.60 (2H, m), 2.11 (2H, t, J = 7.2 Hz), 2.26 (3H, s), 2.42 (3H, s), 2.69 (2H, t, J = 7.6 Hz), 3.21 (2H, t, J = 7.8 Hz), 4.17 (2H, q, J = 7.2 Hz), 7.29 (2H, d , J = 8.4 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.62 (1H, bs) Elementary analysis:. as _{C 22 H 27 N 3 0 5} S 3

Calculated)): C, 51.84; H, 5.34; N, 8.24; S, 18.87.

Found (¾): C, 51.70; H, 5.21; N, 8.12; S, 18.72.

Example 2-42

Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 139-140 ° C.

Infrared absorption spectrum (IR) (in KBr): 3248, 2957, 2934, 2870, 1732, 1657, 1615, 1564, 1495 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 0.946 (6H, d, J = 6.4 Hz), 1.27 (3H, t, J = 7.4 Hz), 1.71-1.90 (1H, m), 2.03 (2H, d, J = 7.0 Hz), 2.27 (3H, s), 2.42 (3H, s), 2.69 (2H, t, J = 7.4 Hz), 3.21 (2H, t, J = 7.8 Hz), 4.17 (2H, q, J = 7.0 Hz), 7.29 (2H, d, J = 9.2 Hz), 7.84 (2H, d, J = 8.0 Hz), 9.63 (1H, bs). Elemental analysis: C ₂₃ H ₂₉ N ₃ 0 ₅ S ₃

Calculated value (: C, 52.75; H, 5.58; N, 8.02; S, 18.37., Measured value): C, 52.75; H, 5.55; N, 7.87; S, 18.36.

Example 2-43

_{- NMR (200MHz, CDC1 3)} : δ 1.08 (3Η, t, J- 7.3 Hz), 1.27 (3H, t, J = 7.2 Hz), 1.82 (3H, s), 2. 2 (3H, s), 2.70 (2H, t, J = 7.3 Hz), 2.78 (2H, q, J = 7.3 Hz), 3.21 (2H, t, J = 7.5 Hz), 4.17 (2H, q, J = 7.2 Hz), 7.29 (2H, d, 8.4 Hz), 7.84 (2H, dt, J = 8.4, 1.8 Hz), 9.63 (1H, brs). Elemental analysis: C ₂₁ H ₂₅ N ₃ 0 ₅ S ₃ Calculated: C , 50.89; H, 5.08; N, 8.48; S, 19.1 (%), found: C, 50.62; H, 5.08; N, 8.46; S, 19.40 (%). Melting point. 148.5-150.0 ° C

Example 2-44

The crystal was recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 1-143 ° C.

Infrared absorption spectrum (IR) (in KBr) Re: 3243, 3063, 3029, 2980, 1732, 1657, 1620, 1564, 1495 cm- ¹ .

_{Ή-NMR (CDC1 3):} δ 1.25 (3Η, t, J = 7.0 Hz), 2.37 (3H, s), 2.42 (3H, s), 2.58 (2H, t, J = 7.8 Hz), 3.12 (2H , t, J = 7.4 Hz), 3.50 (2H, s), 4.13 (2H, q, J = 7.2 Hz), 7.14-7.4 (7H, m), 7.84 (2H, d, J-8.4 Hz) , 9.67 (1H, bs).

Elemental analysis: as C ₂₆ H ₂₇ N ₃ O ₅ S ₃ '0.3H ₂ O

Calculated value (%): C, 55.46; H, 4.94; N, 7.6; S, 17.08.

Found (%): C, 55.54; H, 5.07; N, 7.39; S, 17.23.

Example 2-45

 8-[(3-Ethoxy-3-oxopropyl) sulfanyl] -6-methyl-1-{[(4-methylphenyl) sulfonyl] iminoto 3-oxo-2,3-dihydro-1H-imidazo [5, 1-c] [1,4] thiazine-5-carboxylate

 To a solution of the crude ethyl 2-oxobutyric acid (7.8 g, 35.7 mmol) in chloroform (100 ml) was added trimethylphenylammonium tribromide (13.7 g, 35.7 mmol) while stirring at 0 ° C. . The reaction solution was returned to room temperature over 20 minutes and stirred at room temperature for 70 minutes. The reaction solution was extracted with diisopropyl ether to obtain crude ethyl 3-bromo-2-oxobutyrate (purity 60¾, 6.5 g, about 18.7 fflfflol) as a yellow oil. .

^{J H-NMR (200MHz, CDC1} 3): δ 1.40 (3Η, t, J = 7.1 Hz), 1.82 (3H, d, J two 6.8 Hz), 4.39 (2H, q, J = 7.1 Hz), 5.18 ( 1H, q, J = 6.8 Hz).

Compound synthesized in Reference Example 3-2 (purity 80, 10.0 g, 18.6 mmol), A suspension of ethyl 3-bromo-2_oxobutyrate (6.5 g, 18.6 benzyl) and triethylamine (7.75 ml, 55.9 mmol) in DMF-THF (1: 4, 200 ml) was stirred at room temperature for 1.5 hours. did. Then, the compound synthesized in Reference Example 3-2 (purity 80%, 1.0 g, 1.86 mmol) was added to the reaction solution three times every 20 minutes. The reaction solution was stirred at room temperature for 1.5 hours. The reaction solution was concentrated and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium hydrogencarbonate and saturated saline, dried over sodium sulfate, and concentrated to obtain a brown solid (10.1 g).

'Eta -丽_{R (200MHz, CDC1 3):} δ 1.27 (3Η, t, J = 7.2 Hz), 1.29 (3H, d, J two 6.6 Hz), 1.34 (3H, t, J = 7.1 Hz), 2 .3 (3H, s), 2.71 (2H, t, J = 7.4 Hz), 3.26 (2H, t, J = 7.4 Hz), 3.57 (1H, q, J = 6.8 Hz), 4.16 (2H, q, J = 7.1 Hz), 4.40 (2H, q, J = 7.2 Hz), 4.93 (1H, brs), 7.31 (2H, d, J = 8.0 Hz), 7.86 (2H, d, J = 8.4 Hz), 9.64 (1H, brs).

The resulting brown solid (10.1 g), acetic anhydride (5,05 ml, 52.5 t) and p-toluenesulfonic acid hydrate (hereinafter sometimes abbreviated as P-TsOH hydrate, 3.33 g, 17.5 g) mmol) in toluene (200 ml) was stirred at 80 ^ for 2.5 hours. The reaction solution was concentrated and extracted with ethyl acetate. The organic layer was washed with a sodium hydrogencarbonate aqueous solution and saturated saline, dried over sodium sulfate, and concentrated. Methanol was added to the residue, and the precipitate was collected by filtration, washed with methanol, and dried to give the title compound (5.68 g, 10.5 mmol) as a red-purple powder. _{Ή-NMR (200MHz, CDC1 3} ): 6 1. 7 (3H, t, J = 7.2 Hz), 1.33 (3H, t, 7.1 Hz), 1.93 (3H, s), 2.43 (3H, s), 2.70 (2H, t, J = 7.3 Hz), 3.23 (2H, t, J = 7.3 Hz), 4.17 (2H, q, J = 7.2 Hz), 4.33 (2H, q, J = 7.1 Hz), 7.31 (2H , d, J = 8.4 Hz) , 7.84 (2H, d, J = 8.4 Hz), 9.71 (1H, brs) elemental analysis: calculated _{C 22 H 25 N 3 0 7} S 3: C, 48.96;. H, 4.67; N, 7.79; S, 17.83 (%), Found: C, 48.86; H, 4.52; N, 7.58; S, 17.80 (%). Melting point.

Example 2-46

8-[(3-Ethoxy-3-oxopropyl) sulfanyl] -6-methyl-tri {[(4-methylphenyl) sulfonyl] imino} -3- 3-oxo-2,3-dihydro-1H-imida Zo [5, 1-c] [1,4] thiazine-5-carboxylic acid

 Suspension of the compound obtained in Examples 1-48 (0.38 g, 0.649 mmol), acetic anhydride (0.187 ml, 1.95 mmol) and p-TsOH hydrate (123 mg, 0.649 mmol) in toluene (7.6 ml) Was stirred at 80 ° C for 40 minutes. The reaction solution was concentrated and extracted with ethyl acetate. The organic layer was washed with a 5% aqueous sodium hydrogen carbonate solution and saturated saline, dried over sodium sulfate, and concentrated. Ethyl acetate and getyl ether were added to the residue, and the precipitate was collected by filtration, washed with getyl ether, and dried to give the title compound (274 mg, 0.536 mmol) as a red powder.

! H-wake R (200MHz, CDC1 ₃ ) ': δ 1.27 (3Η, t, J = 7.1 Hz), 2.00 (3H, brs), 2.41 (3H, s), 2.70 (2H, t, J = 7.3 Hz) ), 3.23 (2H, t, J = 7.3 Hz), 4.17 (2H, q, J = 7.1 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.86 (2H, d, J = 8.4 Hz), 10.24 (1H, br).

Elemental analysis: C _2. H ₂₁ N ₃ 0 ₇ S ₃ Calculated: C, 46.95; H, 4.14; N, 8.21; S, 18.80 (%), found: C, 46.91; H, 4.21; N, 8.07; S, 18.72 ( %) Melting point. 176.5-178.0 ° C

Example 2-47

3-{[6-Methyl (4-methylphenyl) sulfonyl] imino} -5- (4-morphoylcarbonyl) -3-oxo-1,3-dihydro-1H-imidazo [ 5, 1-c] [1,4] thiazin-8-yl] sulfanyl} ethyl propionate The compound obtained in Example 2-46 (1.60 g, 3.1 mmol) and H0BT (0.442 g, 3.1 mmol) WSC (0.71 g, 3.7 mmol) was added to a THF (32 ml) solution at room temperature, and the mixture was stirred at room temperature for 30 hours. The reaction solution was concentrated, diluted with ethyl acetate, washed with dilute hydrochloric acid, a 2% aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over sodium sulfate, and concentrated. Getyl ether was added to the residue, and the precipitate was collected by filtration to obtain a H0BT ester (1.53 g, 2.43 tmol) of the compound obtained in Example 2-46 as a red-orange powder. Morpholine (0.648 ml, 7.29 mmol) was added to a solution of this red-orange powder (1.53 g, 2.43 mmol) in THF (30 ml) at room temperature, and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction solution, dilute with ethyl acetate, wash with dilute hydrochloric acid, 2% aqueous sodium hydrogen carbonate solution, water and saturated saline, Dried over sodium sulfate and concentrated. Ethyl acetate was added to the residue, and the precipitate was collected by filtration, washed with ethyl acetate and getyl ether, and dried to give the title compound (1.32 g, 2.27 mmol) as a purple-red powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.27 (3Η, t, J = 7.2 Hz), 1.80 (3H, s), 2.43 (3H, s), 2.70 (2H, t, J- 7.3 Hz), 3.22 (2H, t, J = 7.3 Hz), 3.49 (2H, m), 3.64 (4H, m), 3.80 (2H, m), 4.17 (2H, q, J = 7.2 Hz), 7.31 (2H, d, J = 8.6 Hz), 7.82 (2H, d, J = 8.4 Hz), 9.62 (1H, brs).

Elemental _{analysis: C 24 H 28 N 4 0} 7 S 3 Calculated: C, 49.64; H, 4.86 ; N, 9.65; S, 16.57 (%), Found: C, 49.50; H, 4.91 ; N, 9.74; S, 16.24 (%). Melting point. 180.0-181.0 ° C

Example 2-48

 3-[[6-Methyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-5-propionyl_2,3-dihydrido-1H-imidazo [5,1-c] [1,4 ] Thiazine-8-yl) sulfanyl] ethyl propionate

To a suspension of trimethylphenylammonium tribromide (28.8 g, 75.0 mmol) in chloroform (100 ml) was added 3,4-hexadione (10 ml, 82.2 mmol) with stirring at room temperature, and the mixture was cooled to room temperature. For 75 minutes. After concentrating the reaction mixture, it was extracted with ethyl acetate-hexane-ethyl ether (1: 1: 1, 150 ml), and a brown oil (13.4) containing 2-bromo-3,4-hexadione (8.9 mmol) was obtained. g) was obtained. The above brown solution was added to a suspension of the compound synthesized in Reference Example 3-2 (purity 80%, 12.5 g, 23.3 mmol) and triethylamine (9.68 ml, 69.8 mmol) in DMF-THF (1: 3, 200 ml) at room temperature. A solution of the oil (13.4 g) in THF (50 ml) was added and the mixture was stirred for 3.5 hours. The reaction solution was concentrated and extracted with ethyl acetate (300 ml). The organic layer was washed with a 4% aqueous sodium hydrogen carbonate solution and saturated saline, dried over sodium sulfate, and concentrated to give a brown oil. A suspension of the obtained brown oil, anhydrous acetic acid (6.72 ml, 69.8 mmol) 1 and p-TsOH hydrate (4.43 g, 23.3 mmol) in toluene (250 ml) was stirred at 80 ° C for 2 hours. The reaction solution was concentrated and mixed with ethyl acetate (300 ml) and water (150 ml). The precipitate was collected by filtration, washed with water and ethyl acetate, and dried to obtain a reddish purple powder (4.5 g). Mother liquor and The organic layer was washed with an aqueous solution of sodium bicarbonate, 0.2N hydrochloric acid, water and saturated saline, dried and concentrated, and the residue was mixed with methanol at 50 ° C. The precipitate was collected by filtration, combined with the reddish purple powder (4.5 g), and mixed with THF (200 ml) at 50 ° C. The THF soluble matter was concentrated and suspended in ethyl acetate (100 ml). The precipitate was collected by filtration, washed with ethyl acetate, and dried to give the title compound (3.22 g, 6.15 minol) as a red-purple powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.17 (3Η, t, J = 7.2 Hz), 1.27 (3H, t, J = 7.2 Hz), 1.76 (3H, s), 2.43 (3H, s), 2.58 (2H, q, J = 7.2 Hz), 2.70 (2H, t, J = 7.5 Hz), 3.23 (2H, t, J = 7.3 Hz), 4.17 (2H, q, J = 7.2 Hz), 7.31 (2H , d, J = 8.0 Hz) , 7.84 (2H, d, J = 8.4 Hz), 9.74 (1H, brs) elemental analysis: calculated _{C 22 H 25 N 3 0 6} S 3: C, 50.46;. H, 4.81; N, 8.02

(%), Found: C, 50.56; H, 4.52; N, 8.04 ().

Melting point. 206.5-209.0 ° C

Example 2-49

_{'H-NMR (CDC1 3,} 200 MHz): δ 1.26 (3Η, t, J = 7.2 Hz), 1.79 (3H, s), 2.26 (3H, s), 2.42 (3H, s), 2.70 (2H, t, J = 7.4 Hz), 3.21 (2H, t, J = 7.4 Hz), 4.16 (2H, q, J = 7.2 Hz), 7.36 (1H, brd, J = 2.0 Hz), 7.38 (1H, brs) , 7.77 (2H, m), 9.63 (1H, brs).

Elemental analysis: C _2. Calculated as _{H 23 N 3 0 5 S 3} : 9.88; H, 4.81;, 8.72; S, 19.97 (%), Found: C, 50.11; H, 4.89 ; N, 8.67; S, 19.91 (%). Example 2-50

_{Ή-NMR (CDC1 3, 200} MHz): δ 1.26 (3Η, t, J = 7.2 Hz), 1.32 (3H, t, J = 7.1 Hz), 2.43 (3H, s), 2.72 (2H, t, J = 7.4 Hz), 2.76 (3H, s), 3.27 (2H, t, J = 7.4 Hz), 4.16 (2H, q, J = 7.2 Hz), 4.27 (2H, q, J = 7.4 Hz), 7.38 ( 2H, m), 7.76 (2H, m), 9.79 (1H, brs).

Elemental _{analysis: C 22 H 25 N 3 0} 7 S 3 Calculated: C, 48.96; H, 4.67 ; N, 7.79; S, 17.83 (%), Found: C, 48.89; H, 4.56 ; N, 7.72; S, 17.83 (%). Examples 2-51

_{Ή-NMR (CDC1 3):} δ 0.89 (3H, t, J = 7.0Hz), 1.24-1.37 (6H, m), 1.39-1.52 (2H, m), 2.07 (2H, t, J = 7.0Hz), 2.72 (2H, t, J = 7.3Hz), 2.77 (3H, s), 3.25 (2H, t, J = 7.3Hz ), 3.71 (3H, s), 6.50 (1H, s), 7.25-7.34 (2H, m), 7.45 (1H, ddd, J = 7.5, 7.5, 1.2Hz), 8.01 (1H, dd, J = 7.5) , 1.5Hz), 9.75 (1H, brs).

Elemental analysis: Calculated as _{C 23 H 29 N 3 0 5} S 3: C; 52.75, H; 5.58, N; 8.02 (), Found: C; 52.63, H; 5.59 , N; 8.08 (%).

Example 2-52

_{Ή-NMR (CDC1 3, 200} MHz): δ 1.26 (3H, t, J = 7.2 Hz), 1.79 (3H, s), 2.26 (3H, s), 2.69 (2H, t, J- 7.3 Hz), 2.77 (3H, s), 3.22 (2H, t, J = 7.5 Hz), 4.16 (2H, q, J = 7.0 Hz), 4.26 (2H, q, J = 7.4 Hz), 7.31 (2H, m), 7.43 (1H, tm, J = 7 Hz), 8.01 (1H, dm, J = 7.6 Hz), 9.66 (1H, brs).

Elemental analysis: C _2. H ₂₃ N ₃ 0 ₅ S ₃ Calculated: C, 49.88; H, 4.81; N, 8.72; S, 19.97 (%), Found: C, 49.74; H, 4.61; N, 8.86; S, 19.99 ( %). Example 2-53

 Ή-NMR (200 MHz, in double-mouthed form): δ 1.26 (3Η, t, J = 7.0 Hz), 1.32 (3H, t, J = 7.0 Hz), 2.71 (2H, t, J = 7.2 Hz) , 2.75 (3H, s), 2.76 (3H, s), 3.28 (2H, t, J = 7.2 Hz), 4.17 (2H, q, J = 7.2 Hz), 4.26 (2H, q, J = 7.4 Hz) , 7.31 (2H, m), 7.46 (1H, brt, J = 5.4 Hz), 8.01 (1H, dm, J = 8.4 Hz), 9.82 (1H, brs).

Elemental _{analysis: C 22 H 25 N 3 0} 7 S 3 Calculated: C, 48.96; H, 4.67 ; N, 7.79; S, 7.83 (%), Found; C, 48.89; H, 4.82 ; N, 7.95; S, 17.85 (%). Example 2-54

_{Ή-NMR (CDC1 3):} δ 0.89 (3Η, t, J = 6.9Hz), 1.23-1.37 (6H, m), 1.41-1.52 (2H, m), 2.01 (2H, t, J = 7.6Hz) , 2.72 (2H, t, J = 7.4Hz), 3.24 (2H, t, J = 7.4Hz), 3.71 (3H, s), 6.51 (1H, br s), 7.52-7.61 (3H, m), 7.94 -7.99 (2H, m), 9.73 (1H, br s).

Elemental analysis: Calculated as _{C 22 H 27 N 3 0 5} S 3: C; 51.85, H; 5.34, N; 8.24 (%), Found: C; 51.77, H; 5.37 , N; 8.19 (). Example 2-55

'.Eta. Yuzuru _{R (CDC1 3, 200 MHz)} : δ 1.27 (3H, t, J = 7.4 Hz), 1.32 (3H, t, J = 7.2 Hz), 2.72 (2H, t, J = 7.0 Hz), 2.76 (3H, s), 3.27 (2H, t, J = 7.4 Hz), 4.17 (2H, q, J = 7.0 Hz), 4.27 (2H, q, J = 7.0 Hz), 7.53 (3H, m), 7.96 (2H, dm, J = 8 Hz), 9.80 (1H, brs).

Elemental analysis: Calculated for C ₂₁ H ₂₃ N ₃ 0 ₇ S ₃ : C, 47.99; H, 4.41; N, 7.99; S,

18.30 (%), Found: C, 47.89; H, 4.32; N, 7.90; S, 18.45 (%).

lH- negation _{R (CDC 1 3, 200 MHz} ): δ 1.27 (3H, t, J = 7.1 Hz), 1.79 (3H, brq, J = 0.8 Hz), 2.27 (2H, brq, J = 0.6 Hz), 2.70 (2H, t, J = 7.4 Hz), 3.21 (2H, t, J = 7.4 Hz), 4.16 (2H, q, J = 7.2 Hz), 7.52 (3H, m), 7.96 (2H, dm, J = 7.6 Hz), 9.64 (1H, brs).

Elemental analysis: Calculated as _{C 19 H 21 N 3 0 5} S 3: C, 48.80; H, 4.53; N, 8.99; S, 20.57 (%), Found: C, 48.67; H, 4. 9; N, 8.86; S, 20.60 (%). Example 2-57

_{Ή-NMR (CDC1 3, 200} MHz): δ 1.09 (3Η, t, J = 7.5 Hz), 1.27 (3H, t, J = 7.2 Hz), 2.24 (2H, q, J = 7.6 Hz), 2.27 ( 3H, s), 2.70 '(2H, t, J = 7.4 Hz), 3.23 (2H, t, J = 7.4 Hz), 4.17 (2H, q, J = 7.2 Hz), 7.52 (3H, m), 7.96 (2H, m), 9.65 (1H, brs).

Elemental analysis: C _2. H ₂₃ N ₃ 0 ₅ S ₃ Calculated: 49.88; H, 4.81; N , 8.72; S,

19.97 (%), found: C, 49.73; H, 4.53; N, 8.67; S, 20.01 (%). Example 2-58

^L H-NMR (200 MHz, in double-mouthed form): δ 0.89 (3Η, t, J = 7.2 Hz), 1.26 (3H, t, J = 7.2 Hz), 1.30 (4H, m), 1.33 (2H , m), 1.7 (2H, brquint, J- 7.0 Hz), 2.07 (2H, t, J = 7.5 Hz), 2.71 (2H, t, J = 7.4 Hz), 3.24 (2H, t, J = 7.4 Hz), 4.16 (2H, q, J = 7.I Hz), 6.50 (1H, s), 7.02 (2H, dt, J = 8.7, 2.3 Hz), 7.07 (2H, brd, J = 8.0 Hz) , 7.21 (1H, brt, J = 7.5 Hz), 7.40 (2H, tt, J = 7.9, 2.3 Hz), 7.89 (2H, dt, J = 9.0, 2.3 Hz), 9.70 (1H, brs). Elemental _{analysis: C 29 H 33 N 3 0} 6 S 3 Calculated: C, 56.56; H, 5.40 ; N, 6.82

{%), Found; C, 56.41; H, 5.33; N, 6.81 (%).

Example 2-59

_{Ή-NMR (CDC1 3, 200} MHz): δ 1.26 (3Η, t, J = 7.4 Hz), 1.33 (3H, t, J = 7.4 Hz), 2.72 (2H, t, J = 7.6 Hz), 2.76 ( 3H, s), 3.27 (2H, t, J = 7.2 Hz), 4.16 (2H, q, J = 7.4 Hz), 4.27 (2H, q, J = 7.0 Hz), 7.03 (2H, d, J = 8.8 Hz), 7.07 (2H, d, J = 7.4 Hz), 7.26 (1H, m), 7.41 (2H, d, J = 8.0 Hz), 7.89 (2H, d, J = 8.8 Hz), 9.77 (1H, brs).

Elemental analysis: Calculated as _{C 27 H 27 N 3 0 8} S 3: C, 52.50; H, 4.41;, 6.80; S, 15.57 (%), Found: 52.72; H, 4.27; N , 6.80; S , 15.59 (%). Examples 2-60

_{'H-NMR (CDC1 3,} 200 MHz): δ 1. 6 (3Η, i, J = 7.4 Hz), 1.80 (3H, brq, J two 0.8 Hz), 2.27 (3H, brq, J = 1.0 Hz) , 2.70 (2H, t, J = 7.4 Hz), 3.21 (2H, t, J = 7.4 Hz), 4.15 (2H, q, J = 7.0 Hz), 7.02 (2H, d, J = 8.8 Hz), 7.06 (2H, d, J = 8.0 Hz), 7.21 (1H, t, J = 7.4 Hz), 7.41 (2H, t, J = 8.2 Hz), 7.90 (2H, d, J = 8.8 Hz), 9.61 (1H , Brs).

Elemental _{analysis: C 25 H 25 N 3 0} 6 S 3 Calculated: C, 53.65; H, 4.50 ; N, 7.51; S, 17.19 (%), Found: C, 53.57; H, 4.26 ; N, 7.76; S, 17.15 (%). Example 2-61

_{^ -NMR (CDC 1 3, 200} MHz): δ 1.24 (3Η, t, 1 = 7.1 Hz), 1.80 (3H, brs), 2.29 (3H, brs), 2.67 (2H, t, J = 7.3 Hz) , 3.19 (2H, t, J = 7.3 Hz), 4.14 (2H, q, J = 7.0 Hz), 7.42 (1H, i), 7.9 (2H, m), 8.18 (1H, d, J = 8.0 Hz), 9.75 (1H, brs).

Elemental analysis: Calculated as _{C 20 H 23 N 3 0 5} S 3 C1: C, 45.46; H, 4.02; N, 8.37; S, 19.16; CI, 7.06 (%), Found: C, 45.36; H , 3.99; N, 8.12; S, 19.14; CI, 7.09 (%).

Example 2-62

_{Ή-NMR (CDC1 3, 200} MHz): δ 1.27 (3H, t, J = 6.8 Hz), 1.33 (3H, t, J = 7.0 Hz), 2.72 (2H, t, J = 7.4 Hz), 2.77 ( 3H, s), 3.28 (2H, t, J = 7.4 Hz), 4.17 (2H, q, J = 7.0 Hz), 4.27 (2H, q, J = 7.0 Hz), 7.48 (2H, d, J = 8.8 Hz), 7.90 (2H, d, J = 8.8 Hz) ), 9.78 (1H, brs).

Elemental analysis: C ₂₁ H ₂₂ N ₃ 0 ₇ S ₃ C1 Calculated: C, 45.03; H, 3.96; N, 7.50; S, 17.18; C1, 6.33 (%), found: C, 44.77; H , 3.89; N, 7.52; S, 17.39; C1, 6.24 ().

Example 2-63

_{Ή-NMR (CDC1 3, 200} MHz): δ 1.27 (3Η, t, J = 7.2 Hz), 1.33 (3H, t, J = 7.2 Hz), 2.72 (2H, t, J = 7.4 Hz), 2.76 ( 3H, s), 3.28 (2H, t, J = 7.2 Hz), 4.17 (2H, q, J = 7.4 Hz), 4.27 (2H, q, J = 7.4 Hz), 7.18 (2H, t, J = 8.6) Hz), 7.97 (2H, dd, J = 8.8, 5.0 Hz), 9.77 (1H, brs). Elemental analysis: Calculated as C _2i H ₂₂ N ₃ 0 ₇ S ₃ F: C, 46.40 ;. H, 4.08; N, 7.73; S, 17.70; F, 3.49 (%), Found: C, 46.50; H, 4.29; N, 7.64; S, 17.76; F, 3.50 (%).

Example 2-64 '

Ή-NMR (CDCl 3, 200 MHz): 6 1.27 (3H, t, J = 7.1 Hz), 1.80 (3H, brs), 2.28 (3H, brs), 2.70 (2H, t, J = 7.2 Hz), 3.22 (2H, t, J = 7.2 Hz), 4.17 (2H, q, J = 7.4 Hz), 7.17 (2H, t, J = 8.4 Hz), 7.98 (2H, dd, J = 8.4, 5.2 Hz), 9.62 (1H, brs).

Elemental analysis: C _2. H ₂₂ N ₃ 0 ₅ S ₃ F · Calculated as 0.3H ₂ 0: C, 46.48; H, 4.23; N, 8.56; S, 19.59; F, 3.87 (%), found: C, 46.42; H, 4.20; N, 8.68; S, 19.72; F, 3.96 (%).

Example 2-65

_{lH-NMR (CDC1 3, 300} MHz): δ 1.34 (3H, t, J = 7.2 Hz), 2.76 (3H, s), 2.77 (2H, t, J = 7.2 Hz), 3.10 (3H, s), 3.31 (2H, t, J = 7.2 Hz), 3.74 (3H, s), 4.28 (2H, q, J- 7.2 Hz), 9.61 (1H, br).

Elemental analysis: C ₁₅ H ₁₉ N ₃ 0 ₇ S ₃ Calculated: 0.08; H, 4.26; N, 9.35; S, 21.0 (%), found: C, 39.85; H, 4.23; N, 9.20; S, 21.36 (). Example 2-66

_{Ή-NMR (CDC 1 3,} 300 MHz): δ 1.29 (3Η, t, J = 7.2 Hz), 1.34 (3H, t, J = 7.2 Hz), 2.75 (2H, t, J = 7.5 Hz), 2.76 (3H, s), 3.10 (3H, s), 3.31 (2H, t, J = 7.2 Hz), 4.19 (2H, q, J = 7.2 Hz), 4.28 (2H, q, J = 7.2 Hz), 9.58 (1H, br).

Elemental analysis: C ₁₆ H ₂₁ N ₃ 0 ₇ S ₃ Calculated: C, 41.46; H, 4.57; N, 9.06; S, 20.75 (%), found: C, 41.75; H, 4.77; N, 8.87; S, 20.65 (%). Example 2-67

 3-[(3-{[(4-methylphenyl) sulfonyl] imino} -toxo-2,3-dihydrone-1H-imidazo [5, .1-c] [1,4] benzothiazine-4-yl ) Sulfanyl] p Ethyl pionate

 The compound synthesized in Reference Example 3-2 (5.70 g, 13.3 mmol) was dissolved in THF (50.0 ml) and DMF (25.0 ml), and 2,6-dibumocyclohexanone (4.25 g, 16.6 mmol) and triethylamine were dissolved. (5.55 ml, 39.8 mmol) and the mixture was stirred at room temperature for 6.5 hours. After concentration of the reaction solution, the residue was diluted with ethyl acetate, washed with water and saturated saline, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain an oily substance of the title compound as a mixture of four isomers. This product was used for the next reaction without further purification.

The above oil was dissolved in toluene (50.0 ml) and acetic anhydride (3.76 ml, 39.8 mmol), and P-toluenesulfonic acid monohydrate (2.13 g, 10.6 mmol) was added. The mixture was heated and stirred at 100 for 45 minutes. . After concentrating the reaction solution, the residue was diluted with ethyl acetate, washed with water three times with a saturated saline solution, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (890 mg, 13¾). Recrystallization from ethyl acetate-getyl ether gave orange crystals with mp 163-165. Infrared absorption spectrum (IR) (in KBr): 3252, 2980, 2926, 1738, 1632, 1586, 1557, 1485 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 1.28 (3Η, t, J = 7.0 Hz), 2. 3 (3H, s), 2.74 (2H, t, J = 7.2 Hz), 3.29 (2H, t, J = 7.8 Hz), 4.18 (2H, q, J = 7.0 Hz), 6.96 (1H, dd, J = 7.6, 1.4 Hz), 7.08 (1H, dt, J = 6.2, 1.6 Hz), 7.22 (1H, dt, J = 8.4, 1.8 Hz), 7.51 (2H, d, J = 8.4 Hz), 7.86 (2H, d, J = 8.0 Hz), 8.45 (1H, dd, J = 8.4, 1.0 Hz), 9.79 (1H, bs). Elemental analysis: as C ₂₂ H _2l N ₃ 0 ₃ S ₃

Calculated value (%): C, 52.47; H, 4.20; N, 8.34; S, 19.10.

Observed value (%): C, 52.33; H, 4.31;, 8.9; S, 19.03.

Example 2-68

 3- [1, 6_dioxo-3-{[(4-methylphenyl) sulfonyl] iminot 2, 3, 6, 7, 8, 9-hexahydro-1H-imidazo [5, 1-c ] [1,4] benzothiazin-4-yl) sulfanyl] ethyl propionate

 The compound synthesized in Reference Example 3-2 (10.0 g, 23.2 mmol) was dissolved in THF (100 ml) and DMF (50.0 ml), and 2_bromo-1,3-cyclohexanedione (4.44 g, 23.2 mmol) was dissolved. And triethylamine (9.74 ml, 69.8 mmol) were added, and the mixture was stirred at room temperature for 5 hours. After concentration of the reaction solution, the residue was diluted with ethyl acetate, washed with water and saturated saline, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as an oil (10.8 g, 86%) as a mixture of four isomers. This product was used for the next reaction without further purification.

 The above oil (10.8 g, 20.0 mmol) was dissolved in toluene (170 ml) and acetic anhydride (5.66 ml, 60.0 mmol), and p-toluenesulfonic acid monohydrate (3.21 g, 16.0 mmol) was added. The mixture was heated and stirred at 100 ° C for 15 minutes. After concentrating the reaction solution, the residue was diluted with ethyl acetate, washed three times with water and a saturated saline solution, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (6.77 g, 65%). Recrystallization from ethyl acetate gave dark red crystals with a melting point of 176-178 ° C.

Infrared absorption spectrum (IR) (in KBr): 3619, 3235, 2980, 2957, 1738, 1626, 1595, 1557, 1495 cnf ¹ .

_{Ή-NMR (CDC1 3):} δ 1.27 (3Η, i, J = 7.0 Hz), 1.97-2.14 (2H, m), 2.43 (3H, s), 2.51 (2H, t, J = 7.0 Hz), 2.72 (2H, t, J = 7.0 Hz), 3.21 (2H, t, J = 6.2 Hz), 3.30 (2H, t, J = 7.2 Hz), 4.16 (2H, q, J = 7.4 Hz), 7.30 (2H , d, J = 8.4 Hz), 7.83 (2H, d, J = 8. Hz), 9.89 (1H, bs).

Elementary analysis: as _{C 22 H 23 N 3 0 6} S 3 Calculated value (¾): C, 50.66; H, 4.44;, 8.06; S, 18.44.

Obtained): C, 50.44; H, 4.32; Pi, 7.91; S, 18.27.

Example 2-69

 3-[(3-Methylphenyl) sulfonyl] imino} -1, 6-dioxo-2,3,7,8-tetrahydro-1H, 6H-cyclohexyl [b] imidazo [1,5-d] [1,4] thiazine-4-yl) sulfanyl] ethyl propionate

In formula (VII), the synthesis of cyclopentenone ring, R ^1Q is _ZR ¹⁵ (Z is S0 _2, R ¹⁵ is p- Toruiru group), and R is a Echiru group R ⁶ is condensed

 The compound synthesized in Reference Example 3-2 (5.00 g, 11.6 mmol) was dissolved in THF (50.0 ml) and DMF (50.0 ml), and 2-bromo-1,3-cyclopentanedione (2.47 g, .0 mmol) and triethylamine (4.87 ml, 34.9 mmol), and the mixture was stirred at room temperature for 20 hours. After concentration of the reaction solution, the residue was diluted with ethyl acetate, washed with water and saturated saline, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain an oily substance of the title compound as a mixture of four isomers. This product was used for the next reaction without further purification.

 The above oil was dissolved in toluene (50.0 ml) and acetic anhydride (3.29 ml, 34.9 mmol), P-toluenesulfonic acid monohydrate (1.86 g, 9.31 mmol) was added, and the mixture was heated and stirred with lOOt for 4 hours. . After concentration of the reaction solution, the residue was diluted with ethyl acetate, washed three times with water and saturated saline, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.57 g, 27%). Recrystallization from ethyl acetate gave dark red crystals with mp 207-208.

Infrared absorption spectrum (IR) (in KBr): 3202, 2980, 2926, 1769, 1748, 1698, 1626, 1605, 1541, 1530 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 1.26 (3Η, t, J = 7.0 Hz), 2.43 (3H, s), 2.54-2.62 (2H, m), 2.71 (2H, t, J = 7.4Hz), 3.20 -3.28 (2H, m), 3.26 (2H, t, J = 7.2 Hz), 4.16 (2H, q, J = 7.2 Hz), 7.31 (2H, d, J = 8.4 Hz), 7.84 (2H, d, J = 8. Hz), 9.91 (1H, bs).

Elemental analysis: as C ₂₁ H ₂₁ N ₃ 0 ₆ S ₃

Calculated value (%): C, 49.69; H, 4.17; N, 8.28; S, 18.95. Found (%): C, 49.69; H, 4.19; N, 7.90; S, 18.57.

Example 2-70

-Lease R (300MHz, CDC1 ₃ ).: Δ 1.27 (3Η, t, J = 7.1 Hz), 1.71 (4H, m), 1.98 (2H, m), 2.42 (3H, s), 2.70 (2H, t , J = 7.5 Hz), 2.75 (2H, m), 3.20 (2H, t, J = 7.4 Hz), 4.17 (2H, q, J = 7.1 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.83 (2H, d, J = 8.3 Hz), 9.60 (1H, br).

Example 2-71

 Ή-NMR (DMSO): δ 1.80-1.92 (2H, m), 2.31-2.38 (2H, m), 2.58 (3H, s), 2.70 (2H, t, J = 7.0Hz), 3.08 (2H, t) , J = 6.1Hz), 3.60 (2H, t, J = 7.0Hz), 3.63 (3H, s), 7.33-7.43 (3H, m), 7.91-7.96 (1H, m).

 Ή-NM (DMSO): 61.73-1.79 (2H, m), 1.84-1.94 (2H, m), 2.32-2.40 (2H, m), 3.19 (2H, t, J = 6.1Hz), 3.60 (2H, m t, J = 6.4Hz), 7.40-7.49 (2H, m), 7.56-7.64 (1H, m), 8.11 (1H, br d, J = 8.0Hz).

Example 2-73

 Ή-NMR (DMSO): δ 1.85-1.96 (2H, m), 2.35-2.43 (2H, m), 2.38 (3H, s), 2.72 (2H, t, J-7.0Hz), 3.09 (2H, t) , J = 5.9Hz), 3.20 (2H, t, J = 7.0Hz), 3.63 (3H, s), 7.35 (2H, d, J = 8.1Hz), 7.81 (2H, d, J = 8.1Hz). Example 2-74

_{Ή-NMR (300MHz, CDC1 3} ): δ 1.26 (3H, t, J = 7.1 Hz), 1.68 (2H, m);

1.84 (1H, m), 2.28 (1H, m), 2.32 (2H, m), 2.2 (3H, s), 2.68 (2H, t _;

J = 7.4 Hz), 3.23 (2H, dt, J = 5.0, 7.0 Hz), 3.71 (1H, brt, J = 6.5 Hz) _;

4.16 (2H, q, J = 7.1 Hz), 6.36 (1H, brt, J- 4.2 Hz), 7.30 (2H, d, J ^:

8.3 Hz), 7.87 (2H, d, J = 8.3 Hz), 9.70 (1H, br).

Elemental _{analysis: C 22 H 25 N 3 0} 5 S 3 Calculated: C, 52.05; H, 4.96 ; N, 8.28; S,

18.95 (%). Found: 52.01; H, 4.71; N, 8.34; S, 18.71 (%).

8-[(3-ethoxy-3-oxopropyl) sulfanyl] -6- (2-methoxy-2-oxoethyl) -1-{[(4-methylphenyl) sulfonyl] iminoto 3-oxo -Methyl 2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-5-carboxylate Dissolve the compound synthesized in Example 52 (8.40 g, 14.011111101) in toluene (1601111) Then, the mixture was stirred at 80 ° C for 1 hour in the presence of acetic anhydride (4.05 ml, 42.1 Miol) and P-toluenesulfonic acid hydrate (2.67 g, 14.0 jnmol). The reaction mixture was concentrated, diluted with ethyl acetate (300 ml), washed with water and saturated saline, dried over sodium sulfate, and concentrated to obtain a red oil. This was purified by chromatography on silica gel (80 g) (ethyl acetate-hexane, 3: 7-5: 5 and ethyl acetate-toluene, 5: 5) to give the title compound (5.16 g, 8.84 dragonol) as an orange powder As obtained.

_{Ή-NMR (300MHz, CDC1 3} ): δ 1.27 (3Η, t, J = 7.2 Hz), 2.43 (3H, s), 2.69 (2H, t, J = 7.2 Hz), 3.23 (2H, t, J = 7.5 Hz), 3.34 (2H, s), 3.75 (3H, s), 3.85 (3H, s), 4.16 (2H, q, J = 7.0 Hz), 7.31 (2H, d, J = 8.1 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.76 (1H, br).

Elemental _{analysis: C 23 H 25 N 3 0} 9 S 3 Calculated: C, 47.33; H, 4.32 ; N, 7.20; S, 16.48 (%), Found: 47.28; H, 4.11; N , 7.11; S, 16.45 (%). Example 2-76

 3-[(8,8-dimethyl-1,6-dioxo-3-{[(4-methylphenyl) sulfonyl] imino} -2,3,6,7,8,9-hexahydrid-1-imidazo [ 5, 1-c] [1,4] benzothi 7zin-4-yl) sulfanyl] ethyl ester propionate

The compound synthesized in Reference Example 3-2 (8.00 g, 18.6 mmol) was dissolved in THF (80.0 ml) and DMF (80.0 ml), and the 2-bromo-5,5-dimethylcyclo obtained in Reference Example 42 was dissolved. Xan-1,3-dione (4.90 g, 22.3 mmol) and triethylamine (7.79 ml, 55.9 mmol) were added, and the mixture was stirred at room temperature for 20.5 hours. After concentration of the reaction solution, the residue was diluted with ethyl acetate, washed with water and saturated saline, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was dissolved in toluene (80.0 ml) and acetic anhydride (5.27 ml, 55.9 mmol), p-toluenesulfonic acid monohydrate (2.98 g, 14.9 mmol) was added, and the mixture was heated and stirred at 100 ° C for 1 hour. After concentration of the reaction solution, the residue was diluted with ethyl acetate, washed three times with water and saturated saline, and dried over sodium sulfate. Solvent under reduced pressure The title compound (3.13 g, 31¾) was obtained. Recrystallization from ethyl acetate gave dark red crystals with a melting point of 227-229 ° C.

IR (KBr): 3221, 2963 , 1757, 1738, 1655, 1626, 1557 cm '1.

_{! H-NMR (CDC1 3)} : 61.12 (6H, s), 1.27 (3H, t, J = 7.2 Hz), 2.36 (2H, s), 2. 3 (3H, s), 2.73 (2H, t, J = 7.2 Hz), 3.08 (2H, s), 3.30 (2H, t, J = 7.2 Hz), 4.17 (2H, q, J = 7.2 Hz), 7.30 (2H, d, J = 8.1 Hz), 7.83 (2H, d, J = 8.7 Hz), 9.86 (1H, bs).

Elementary analysis: as _{C 24 H 27 N 3 0 6} S 3

Calculated values): C, 52.44; H, 4.95; N, 7.64; S, 17.50.

Found): C, 52.72; H, 4.94; N, 7.34; S, 17.11.

Example 2-77

 3-[(9,9-dimethyl-1,6-dioxo-3-{[(4-methylphenyl) sulfonyl] iminoto 2,3,6,7,8,9-hexahydro-1H-imidazo [5, 1-c] [1,4] Benzothiazin-4-yl) sulfanyl] ethyl propionate

 In the same manner as in Example 2-76, 2-bromo-4,4-dimethylcycloalkyl obtained in Reference Example 43 was used instead of 2-bromo-5,5-dimethylcyclohexane-1,3-dione. The title compound (4.92 g, 48¾) was synthesized from the compound (8.00 g, 18.6 mmol) synthesized in Reference Example 2-2 using hexane-1,3-dione (4.90 g, 22.3 mmol). Recrystallization from ethyl acetate gave dark red crystals with a melting point of 202-204.

IR (KBr) V: 3227, 2976, 2932, 2870, 1759, 1738, 1626, 1593, 1557 cm ^-1 .

 ^ -NMR (CDCI3): 51.15 (6H, s), 1.26 (3H, t, J = 7. Hz), 1.86 (2H, t, J = 6.2 Hz), 2.42 (3H, s), 2.72 (2H, s) t, J = 7.4 Hz), 3.22 (2H, t, J = 6.4 Hz), 3.30 (2H, t, J = 7.2 Hz), 4.16 (2H, q, J = 6.8 Hz), 7.30 (2H, d, J = 8.0 Hz), 7.83 (2H, d, J = 8.0 Hz), 9.86 (1H, bs).

Elemental analysis: C ₂₄ H ₂₇ N ₃ 0 ₆ S ₃

Calculated value (¾): C, 52.44; H, 4.95; N, 7.64; S, 17.50.

Found (¾): C, 52.32; H, 4.68; N, 7.45; S, 17.43. Example 2-78

 3-[(1,6-dioxo-8-methyl-3-{[(4-methylphenyl) sulfonyl] imi--1,3,6,7,8,9-hexahydro-1H-imidazo [5, 1-c] [1,4] benzothiazin-4-yl) sulfanyl] ethyl propionate

 In the same manner as in Example 2-76, 2-bromo-5-methylcyclohexane-1,3-dione was replaced with 2-bromo-5-methylcyclohexane obtained in Reference Example 44. Using 1,3-dione (6.87 g, 33.5 mmol), the title compound (10.4 g, 69%) was synthesized from the compound (12.0 g, 27.9 mmol) synthesized in Reference Example 2-2. Recrystallization from ethyl acetate gave dark red crystals with a melting point of 202-204 ° C.

IR (KBr) V: 3250, 2959, 2928, 2907, 2874, 2255, 1742, 1651, 1622, 1595, 1557 cm- ¹ .

Ή-NMR (CDC1 ₃ ): (51.14 (3H, d, J = 6.3 Hz), 1.26 (3H, t, J = 7.2 Hz), 2.12-2.30 (2H, m), 2.43 (3H, s), 2.56 (1H, t, J = 10.5 Hz), 2.62 (1H, d, J = 5.1 Hz), 2.72 (2H, t, J = 6.9 Hz), 3.29 (2H, t, J = 7.2 Hz), 3.58 (1H , Dd, J = 19.5, 3.9 Hz), 4.16 (2H, q, J = 7.2 Hz), 7.30 (2H, d, J = 8.1 Hz), 7.83 (2H, d, J = 8.4 Hz), 9.87 (1H , bs).

Elementary analysis: as _{C 23 H 25 N 3 0 6} S 3

Calculated value (%): C, 51.57; H, 4.70; N, 7.84; S, 17.96.

Found (%): C, 51.42 .; H, 4.60; N, 7.70; S, 17.99.

Example 3-1

R ⁵ is n- pentyl group in formula (VIII), R ⁶ is a methyl group, R ^{1 0} is - Synthesis Example of ZR ^{1 5} (Z is S 0 _2, R ^{1 5} is P- Toruiru group) compound is The compound synthesized in 2-1 (3.37 g, 6.27 mmol) was dissolved in THF (40 ml) and methanol (40 ml), and hydroxylated water (2.07 g, 31.3 mmol) was added. Stirred for minutes. The reaction mixture was mixed with 1N hydrochloric acid (32 ml) and stirred at room temperature for 30 minutes. The resulting precipitate was collected by filtration, washed with 50% methanol water, and dried to give the title compound as an orange powder (2.67 g, 6.10 mmol). 'Η-wake R (300 MHz, in double-mouthed form): δ 0.88 (3Η, t, J = 6.8 Hz), 1.29 (4H, m), 1.46 (2H, brquint, J = 7.2 Hz), 2.14 ( 2H, t, J = 7.5 Hz), 2.26 (3H, s), 2.42 (3H, s), 7.20 (2H, dm, J = 7.2 Hz), 7.83 (2H, d, J = 8.3 Hz), 9.36 ( 1H, br), 12.65 (1H, brs).

Elemental analysis: C ₁₉ H ₂₃ N ₃ 0 ₃ S ₃ Calculated: C, 52.15; H, 5.30;, 9.60; S, 21.98 (%), found; C, 52.21; H, 5.03;, 9.59; S, 21.84 (%). Example 3-2

Cyclohexyl group in formula (VIII) R ⁵ is n-, R ⁶ is a hydrogen atom, R ^{1 Q} is - ZR ^{1 5} (2 is 3_Rei _2, R ^{1 5} is p - Toruiru group) Synthesis embodiment, compound The compound synthesized in Example 2-2 (1.44 g, purity 93%, 2.49 mmol) was dissolved in THF (15 ml) and methanol (15 ml), and potassium hydroxide (0.67 g, 10.1 bandol) was added thereto. Stirred for 40 minutes. The reaction mixture was mixed with 1N hydrochloric acid (10 ml) and stirred at room temperature for 30 minutes. The resulting precipitate was collected by filtration, washed with aqueous methanol, and dried to give the title compound as an orange powder (1.00 g, 2.29 mmol).

 Ή-NMR (300 MHz, in double-mouthed form): δ 0.87 (3Η, brt, J = 6.9 Hz), 1.27 (4H, brs), 1.30 (2H, i), 1.49 (2H, brquint, J = 7.3) Hz), 2.19 (2H, brt, J = 7.0 Hz), 2.45 (3H, s), 6.95 (IE, brt, J = 0.5 Hz), 7.36 (2H, brd, J = 8.4 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.50 (1H, br), 12.03 (1H, brs).

Elemental _{analysis: C 19 H 23 N 3 0} 3 S 3 Calculated: C, 52.15; H, 5.30 ;, 9.60; S, 21.98 (), Found; C, 52.14; H, 5.13 ; N, 9.52; S, 21.81 (%). Example 3-3 ′

In the formula (VIII), R ⁵ is an ethoxycarbonyl group, R ⁶ is a methyl group, and R ¹ . Synthesis of a compound of the formula ZR ¹⁵ (Z is S〇 ₂ and R ¹⁵ is a p-tolyl group)

The compound synthesized in Example 2-3 (1.02 g, 1.89 mmol) was dissolved in THF (10 ml) and ethanol (10 ml), and sodium ethylate (257 mg, 3.78 mmol) was added. Stirred for 0 minutes. 1N hydrochloric acid (4.5 ml) And water (5.5 ml) were added and mixed, followed by stirring at room temperature for 10 minutes. The resulting precipitate was collected by filtration, washed with aqueous methanol, and dried to give the title compound as an orange powder (0.82 g, 1.86 mmol).

 'Η-丽 R (300 MHz, in heavy distyrsulfoxide): δ 1.20 (3Η, t, J = 7.0 Hz), 2.39 (3H, s), 2.72 (3H, s), 4.13 (2H, q, J = 7.0 Hz), 7.42 (2H, d, J = 8.3 Hz), 7.88 (2H, d, J = 8.3 Hz).

Elemental _{analysis: C 17 H 17 N 3 0} 5 S 3 Calculated: C, 46.45; H, 3.90 ; N, 9.56; S, 21.89 (), Found; C, 46.72; H, 3.93 ; N, 9.32 ; S, 20, 98 (%). Example 3-4

Both methyl groups R ⁵ and R ⁶ in formula ^(VIII), R ¹ () is - Synthesis of ZR ^{1 5} ifiS O _2, compound R ¹⁵ is P- Toruiru group)

 The compound synthesized in Example 2-5 (5.00 g, 10.4 mmol) was dissolved in THF (50 ml) and methanol (50 ml), and a hydroxylic power (2.74 g, 41.5 mmol) was added. Stirred for minutes. The reaction mixture was mixed with 1N hydrochloric acid (42 ml) and stirred at room temperature for 30 minutes. The resulting precipitate was collected by filtration, washed with 50% methanol water, and dried to give a red powder of the title compound (3.47 g, 9.10 mmol).

lH-NMR (300 MHz, double-mouthed form-deuterated dimethyl sulfoxide == 9: in 0.1): <5 1.81 (3H, s), 2.42 (3H, d, J = 0.5 Hz), 2.45 (3H, s ), 7.35 (2H, d, J = 8.1 Hz), 7.88 (2H, d, J = 8.3 Hz), 12.82 (2H, br) elemental analysis:. calculated _{C 15 H 15 N 3 0 3} S 3 : C, 47.22; H, 3.96;, 11.01; S, 25.22 (%), measured value; C, 47.20; Η, .3.90; Ν, 10.73; S, 25.19 (%).

In the formula (VIII), R ⁵ is an ethyl group, R ⁶ is a methyl group, and R ¹ . Synthesis of a compound of the formula ZR ^lb (Z is S〇 ₂ , R ¹⁵ is P-tolyl group)

The compound (4.15 g, 8.37 mmol) synthesized in Example 2-6 was dissolved in THF (50 ml) and methanol (50 ml), and hydroxylated water (2.21 g, 33.5 mmol) was added. Stirred for minutes. 1N Hydrochloric acid (34 ml) and water (16 ml) were added to the reaction solution, mixed, and stirred at room temperature for 30 minutes. The resulting precipitate The crystals were collected by filtration, washed with aqueous methanol, and dried to give the title compound as an orange powder (2.86 g, 7.23 mmol).

lH-band R (200 MHz, in double-mouthed form): δ 1.08 (3Η, t, J = 7.2 Hz), 2.18 (2H, q, J = 7.6 Hz), 2.45 (6H, s), 7.36 (2H , d, J = 8.3 Hz), 7.86 (2H, d, J = 8.3 Hz).

Elemental analysis: Calculated for C ₁₆ H ₁₇ N ₃ 0 ₃ S ₃ : C, 48.59; H, 4.33;, 10.62; S, 24.32 (%), found; C, 48.46; H, 4.29;, 10.58; S, 24.33 (%). Example 3-6

Formula (VIII) in which R ⁵ and R ⁶ are both methyl, ^ is - R ¹⁵ synthesized in (2 30 _2, R ¹⁵ is P- black port Hue group) Synthesis Example of compounds wherein 2-7 The obtained compound (3.28 g, 6.53 mmol) was dissolved in THF (35 ml) and methanol (35 ml). Hydroxidizing rim (1.73 g, 26.1 mmol) was added, and the mixture was stirred at room temperature for 40 minutes. did. The reaction mixture was mixed with 1N hydrochloric acid (26 ml) and stirred at room temperature for 30 minutes. The resulting precipitate was collected by filtration, washed with methanol water, and dried to give the title compound as an orange powder (2.56 g, 6.37 mmol).

 'H-NMR (200 MHz, in heavy dimethyl sulfoxide): 1.76 (3H, brs), 2.32 (3H, brs), 7.69 (2H, dt, J = 8.4, 1.8 Hz), 7.99 (2H, dt, J = (8.8, 1.8 Hz).

Elemental _{analysis: C 14 H 12 N 3 0} 3 S 3 C1 Calculated: C, 41.84; H, 3.01 ; N, 10.46; S, 23.93; C1, 8.82 (%), Found; C, 41.96; H , 2.97; N, 10.40; S, 23.69; C1, 8.59 ().

Melting point: 241.5-244.0 ° C.

Example 3-7

R ⁵ and R ⁶ are both methyl groups In the formula (VIII), the at scale ^{1 ()} gar 2 R ¹⁵ Synthesis Example 2-8 (2 3_Rei _2, R ¹⁵ is p_ Buromofueniru group) compound Dissolve the synthesized compound (3.04 g, 5.56 mmol) in THF (30 ml) and methanol (30 ml), add lithium hydroxide (10 g, 16.7 ol) and stir at room temperature for 80 minutes. did. 1N hydrochloric acid (16.7 ml) and Water (13 ml) was added and mixed, and the mixture was stirred at room temperature for 30 minutes. The resulting precipitate was collected by filtration, washed with aqueous methanol, and dried to give the title compound as an orange powder (2.42 g, 5.42 mmol).

-丽 R (200 MHz, in heavy dimethyl sulfoxide): δ 1.75 (3Η, brs), 2.31 (3H, brs), 7.84 (2H, d, J = 8.8 Hz), 7.91 (2H, dt, J = 8.8 Hz) .) elemental _{analysis: C 14 H l2 N 3 0} 3 S 3 Br calculated: C, 37.67; H, 2.71 ;, 9.41; S, 21.55; Br, 17.90 (%), Found; C, 37.86; H, 2.67; N, 9.17; S, 21.50; Br, 17.63 (%).

Melting point: 242.5-247.5 ° C.

The following is a list of compounds synthesized in Examples 3-1 to 3-7 and compounds synthesized in the same manner.

(Table 14)

For replacement 綁 (jM Q) (Table 15)

Replacement Form (Rule 26) (Table 16) '

涎 Feeding saliva (Rule 26)

aim t9 Odf / e :) d 909Z60 / Z0 OAV The data of the compounds synthesized in Examples 3-8 to 3-45 are shown below.

Example 3-8

_{Ή-NMR (CDC1 3):} δ 0.87 (3Η, t, J = 6.8Hz), 1.23-1.33 (6H, m), 1.40-1.60 (2H, ηι), 2.19 (2H, br t, J = 7.3Hz ), 6.96 (1H, br s), 7.54-7.62 (2H, m), 7.64-7.72 (2H, m), 7.88-7.93 (2H, m), 12.1 (1H, br.s).

Elemental _{analysis: C 18 H 21 N 3 0} 3 S 2 Calculated: C; 51.04, H; 5.00 , N; 9.92

(%), Found C; 51.50, H; 4.87, N; 9.82 (%) '.

Example 3-9

-麵 R (CDC1 ₃ -DMS0- d ₆ 2: 1, 200 MHz): δ 1.80 (3Η, d, J = 1.0 Hz), 2.39 (3H, d, J = 0.8 Hz), 7.58-74 (3H, . m), 8.02 (2H, dm, J = 7 Hz) elemental _{analysis: C 14 H 13 N 3 0} 3 S 3 calculated: C, 45.76; H, 3.57 ; N, 11.44; S, 26.18 (% ), Found: C, 45.61; H, 3.56; N, 11.37; S, 26.21 (%). Examples 3-10

_{lH-NMR (CDC1 3, 200} MHz): δ 1.08 (3Η, t, J = 7.4 Hz), 2.18 (2H, q, J = 7.2 Hz), 2.45 (3H, s), 7.59 (3H, m), . 7.91 (2H, brd, J = 7.0 Hz) elemental _{analysis: C 15 H 15 N 3 0} 3 S 3 calculated: C, 47.22; H, 3.96 ; N, 11.01; S, 25.22 (%), measured Values: C, 47.25; H, 3.94; N, 11.30; S, 25.24 (%). Examples 3-11

_{Ή-NMR (CDCl 3 -DMS0-} d 6 9: 1, 200 MHz): δ 1.30 (3Η, t, J = 7.4 Hz), 2.90 (3H, s), 4.23 (2H, q, J = 6.8 Hz) , 7.60 (2H, m), 7.68 (1H, brt, J = 7.2 Hz), 8.05 (2H, d, J = 7.2 Hz).

Elemental _{analysis: C 16 H 15 N 3 0} 5 S 3 Calculated: 45.16; H, 3.55; N , 9.88 (%), Found: C, 45.26; H, 3.67 ; N, 9.54 ().

Example 3-12

Ή-NMR (CDCl _r DMS0-d ₆ = 9: 1, 300 MHz): δ 2.43 (3Η, d, J = 1.1 Hz), 2.45 (3H, s), 5.01 (1H, q, J = 1.5 Hz) , 7.36 (2H, d, J = 8.3 Hz), 7.88 (2H, d, J = 8.3 Hz), 12.78, (1H, br).

Elemental analysis: Calculated as _{C 14 H 13 N 3 0 3} S 3: C, 45.76; H, 3.57;, 11.44; S, 26.18 (%), Found: C, 45.82; H, 3.64; N, 11.48; S, 26.06 ().

Recrystallization from ethyl acetate gave orange crystals with a melting point of 225-227 ° C.

Infrared absorption spectrum (IR) (in KBr): 3320-2700, 2969, 2930, 2868, 1713, 1634, 1580, 1514 cm—

_{Ή-NMR (CDC1 3):} δ 0.930 (3Η, t, J = 7.4 Hz), 1.38-1.60 (2H, m), 2.14 (2H, t, J = 8.2 Hz), 2.46 (6H, s), 7.36 (2H, d, 7 = 8.0 Hz), 7.79 (2H, d, J = 8.4 Hz), 9.38 (1H, bs).

Elementary analysis: as _{C 17 H 19 N 3 0 3} S 3

Calculated values (: C, 49.86; H, 4.68; N, 10.26; S, 23.49.

Found (¾): C, 49.71; H, 4.57; N, 10.10; S, 23. 6.

Example 3-14

] H - Hokusatsu _{R (CDC1 3, 200 MHz)} : δ 1.10 (6H, d, J = 7.0 Hz), 2.45 (3H, s), 2.48 (3H, s), 3.00 (1H, quint, J = 7.0 Hz ), 7.36 (2H, d, J = 8.0 Hz), 7.79 (2H, d, J = 8.4 Hz), 9.5 (1H, br).

Elemental _{analysis: C 17 H ig N 3 0} 3 S 3 Calculated: C, 49.86; H, 4.68 ; N, 10.26; S, 23.49 (%) Found: C, 49.80; H, 4.54 ; N, 10.21 S, 23.54 (%). Examples 3 to 15

Recrystallization from ethyl acetate-methanol afforded orange crystals with a melting point of 192-194 ° C.

Infrared absorption spectrum (IR) (in KBr) Re: 3320-2600, 2953, 2928, 2865, 1715, 1638, 1582, 1518 cm- ¹ .

'.Eta. Awakening: _{(CDC1 3): δ 0.901 (} 3Η, t, J = 7.0 Hz), 1.24-1.50 (4H, m), 2.15 (2H, d, J = 8.0 Hz), 2.45 (6H, s), 7.36 (2H, d, J = 8.0 Hz), 7.78 (2H, d, J = 8. Hz), 9.32 (1H, bs).

Elemental analysis: as C ₁₈ H ₂₁ N ₃ 0 ₃ S ₃

Calculated)): C, 51.04; H, 5.00; N, 9.92; S, 22.71.

Found (¾): C, 50.98; H, 4.86; N, 9.86; S, 22.77.

Example 3-16 Recrystallization from ethyl acetate-diisopropyl ether gave orange crystals with a melting point of 231-233.

Infrared absorption spectrum (IR) (in KBr) Re: 3500-2400, 2951, 1705, 1634, 1574, 1508 cm—

_{Ή-NMR (CDC1 3):} δ 0.925 (6Η, d, J = 6.6 Hz), 1.68-1.90 (1H, m), 2.05

(2H, d, J = 7.4 Hz), 2.6 (6H, s), 7.36 (2H, d, J = 8.0 Hz), 7.80 (2H, d, J = 8. Hz), 9.46 (1H, bs ).

Elementary analysis: as _{C l8 H 2l N 3 0 3} S 3 '0.7H 2 0

Calculated values (: C, 49.57; H, 5.18; N, 9.63; S, 22.05.

Found (¾): C, 49.67; H, 4.90; N, 9.37; S, 21.70.

Example 3-17

The crystals were recrystallized from ethanol-ethyl ether to obtain orange crystals having a melting point of 211-213.

Infrared absorption spectrum (IR) (in KBr): 3400-2700, 2949, 2926, 2860, 1715, 1645, 1595, 1578, 1514 cm— ¹ .

_{Ή-NMR (CDC1 3):} δ 0.875 (3Η, t, J = 6.8 Hz), 1.20-1.52 (8H, m), 2.15 (2H, t, J-8.2 Hz), 2.45 (6H, s), 7.36 (2H, d, J-8.4 Hz), 7.80 (2H, d, J = 8.4 Hz), 9.38 (1H, bs).

Elemental analysis: as C ₂₀ H ₂₅ N ₃ O ₃ S ₃

Calculated values): C, 53.19; H, 5.58; N, 9.30; S, 21.30.

Obtained): C, 52.99; H, 5.67; N, 9.22; S, 21.22.

Example 3-18

Ή-NMR (CDC1 ₃ -DMS0-d ₆ = 19: 1, 300 MHz): δ 2.36 (3Η, s), 2.46 (3H, s), 2.74 (3H, s), 7.37 (2H, d, J = . 8.3 Hz), 7.90 (2H , d, J = 8.3 Hz) elemental _{analysis: C 16 H 15 N 3 0} 4 S 3 calculated: C, 46.93; H, 3.69 ; N, 10.26; S, 23.49 ( %) Found: 46.75; H, 3.83; N, 10.00; S, 23.50 (%). Examples 3-19

The crystal was recrystallized from ethanol-ethyl ether to give an orange crystal having a melting point of 216-218. ' Infrared absorption spectrum (IR) (in KBr): 3400-2500, 1715, 1634, 1580, 1518, 1495 cm—

_{Ή-NMR (CDC1 3):} δ 2.45 (3Η, s), 2.54 (3H, s), 3.52 (2H, s), 7.14-7.32 (5Η, m), 7.36 (2Η, d, J = 7.6 Hz) , 7.78 (2H, d, J = 8.Hz), 9.34 (1H, bs).

Elemental analysis: C ₂₁ H ₁₉ N ₃ 0 ₃ S ₃ '0.2H ₂ 0

Calculated values): C, 54.69; H, 4.24; N, 9.11; S, 20.86.

Obtained): C, 54.66; H, 4.05; N, 8.99; S, 21.09.

Example 3-20

1-{[(4-Methylphenyl) sulfonyl] imino} -3-oxo-8-sulfanyl-2,3-dihydro 1H-imidazo [5, 1-c] [1,4] thiazine-5-carboxylic acid Le

 To a suspension of the compound (998 mg, 1.90 mmol) obtained in Example 2-22 in THF-ethanol (1: 1, 0 ml) was added sodium ethoxide (271 mg, 3.99 mmol) with stirring at room temperature. The reaction solution was stirred at room temperature for 7 hours. During this time, sodium methoxide (65 mg, 0.95 mmol) was added to the reaction solution three times every 1.5 hours. 1N hydrochloric acid (6.8 ml) and water (10 ml) were added to the reaction solution, and the mixture was stirred and mixed for 30 minutes. The precipitate was collected by filtration, washed with methanol / water (1: 1), and dried to give the title compound (700 mg, 1.65 mmol) as an orange powder.

_{Ή-NR (200MHz, CDC1 3} ): δ 1.33 (3H, t, J = 7.2 Hz), 2.47 (3H, s), 4.35 (1H, q, J = 7.2 Hz), 6.14 (1H, s), 7.39 (2H, d, J = 8.2 Hz), 7.82 (2H, d, J = 8.4 Hz), 9.71 (1H, brs).

Elemental _{analysis: C 16 H 15 N 3 0} 5 S 3 Calculated: C, 45.16; H, 3.55 ; N, 9.88; S, 22.61 (%), Found ^: C, 45.40; H, 3.56; N, 9.87; S, 22.49 (%). Mp. 209.5-210.5

Example 3-21

6-Methyl [(4-methylphenyl) sulfonyl] imino} -3_oxo-8-sulfanyl-2,3-dihydrido-1H-imidazo [5,1-c] [1,4] thiazine-5-force Lutyl acid ester A suspension of the compound obtained in Example 2-45 (0.29 g, 0.52 mmol) in THF-ethanol (1: 1, 6 ml) was stirred at room temperature with stirring at room temperature for 20% sodium ethoxide (ethanol solution, 0.45 g). ml, 1.14 mmol), and the reaction solution was stirred at room temperature for 30 minutes. 1N Hydrochloric acid (1.2 ml) and water (2 ml) were added to the reaction solution, and the mixture was stirred and mixed for 60 minutes. The precipitate was collected by filtration, washed with methanol / water (1: 1), and dried to give the title compound (101 mg, 0.230 ol) as an orange powder.

Ή-NMR (200MHz, CDCi ₃ ): <5 1.35 (3H, t, J = 7.2 Hz), 1.92 (3H, s), 2.46 (3H, s), 4.39 (2H, q, J = 7.2 Hz), 7.37 (2H, d, J = 8.0 Hz), 7.79 (2H, d, J = 8.4 Hz), 12.17 (1H, brs).

Elemental _{analysis: C 17 H 17 N 3 0} 5 S 3 Calculated: C, 46.45; H, 3.90 ; N, 9.56; S, 21.89 (%), Found: C, 46.42; H, 3.99 ; N, 9.39; S, 21.83 (%). Melting point. 224.5-226. O:

Example 3-22

 4-methyl-N- (6-methyl-3-oxo-5-propionyl-8-sulfanyl-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-trilidene) benzenesul Honamide

 To a suspension of the compound obtained in Example 2-48 (3.03 g, 5.79 tmol) in THF-methanol (1: 1, 60 ml) was added potassium hydroxide (1.15 g, 17.4 inmol) while stirring at room temperature. The reaction was stirred at room temperature for 30 minutes. 1N Hydrochloric acid (17.4 ml) and water (13 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol / water (1: 1), and dried to give the title compound (2.24 g, 5.28 mmol) as a red powder.

'Eta - negation _{R (200MHz, CDC1 3):} δ 1.15 (3Η, t, J = 7.2 Hz), 1.78 (3H, s), 2.46 (3H, s), 2.64 (2H, q, J = 7.6 Hz) , 7.37 (2H, d, J = 8.4 Hz), 7.89 (2H, d, J = 8.4 Hz).

Elemental analysis: Calculated as _{C 17 H 17 N 3 0 4} S 3: C, 48.21; H, 4.05; N, 9.92 (%), Found: C, 48.51; H, 4.09 ; N, 9.87 (%) .

Example 3-23

4-Methyl-N- [6-methyl-5- (4-morpholinylcarbonyl) -3-oxo-8-s Ruphanyl-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene] benzenesulfonamide

 To a suspension of the compound obtained in Example 2-47 (1.00 g, 1.72 mmol) in THF-methanol (1: 1, 20 ml) was added lithium hydroxide (0.34 g, 5.17 mmol) with stirring at room temperature. The reaction was stirred at room temperature for 30 minutes. IN hydrochloric acid (5.2 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 60 minutes. The precipitate was collected by filtration, washed with methanol / water (1: 1) and getyl ether, and dried to give the title compound (637 mg, 1.33 mmol) as a red powder.

顏_{R (200MHz, CDC1 3):} δ 1.87 (3H, s), 2.47 (3H, s), 3.46 (2H, brt, J = 4.6 Hz), 3.60-3.90 (6H, m), 7.38 (2H, d , J = 8.0 Hz), 7.79 (2H, d, J = 8.4 Hz), 12.26 (1H, brs).

Elemental analysis: C ₁₉ H _2. N ₄ 0 ₅ S ₃ Calculated: C, 47.48; H, 4.19 ; N, 11.66; S, 20.02 (%), Found: C, 47.23; H, 4.21 ; N, 11.58; S, 19.62 (%) Example 3-24

_{Ή-NMR (300MHz, CDC1 3} ): δ 2. 6 (3Η, s), 5.31 (1Η, s), 6.95 (2H, d, J = 8.7 Hz), 7.06 (2H, brd, J = 7.5 Hz) , 7.14 (1H, brt, J = 7.3 Hz), 7.20 (2H, d, J = 8.7 Hz), 7.36 (2H, brt, J = 8.3 Hz), 7.38 (2H, d, J = 8.3 Hz), 7.79 (2H, d, J = 8.3 Hz), 9.34 (1H, br), 12.62 (1H, s).

Elemental _{analysis: C 25 H l9 N 3 0} 4 S 3 Calculated: C, 57.56; H, 3.67 ; N, 8.06; S, 18.44 (%), Found: C, 57.62; H, 3.77 ; N, 7.82; S, 18.43 (). Examples 3-25

Ή-NMR (CDCl ₃ -DMS0-d ₆ = 9: 1, 00 MHz): δ 1.81 (3Η, s), 2.44 (3H, s), 7.46 (2H, brs), 7.80 (2H, brs).

Elemental analysis: _{Calculated for} C ₁₅ H ₁₅ N ₃ 0 ₃ S ₃ : C, 47.22; H, 3.96;, 11.01; S, 25.22 (%), found: C, 47.02; H, 4.18; N, 10.92; S, 25.22 (%). Example 3-26

'Η-Ran R (DMS0-d ₆ , 200 MHz): δ 1.21 (3H, ί, J = 6.9 Hz), 2.0 (3H, s), 2.73 (3H, s), 4.13 (2H, q, J = 7.0 Hz), 7.50 (2H, brd, J = 4.4 Hz), 7.83 (2H, brs). Elemental analysis: Calculated as _{C 17 H 17 N 3 0 5} S 3: C, 46.45; H, 3.90; N, 9.56; S, 21.89 (%), Found: C, 46. 7; H, 4.12; N, 9.47; S, 21.76 (%). Example 3-27

NMR-NMR (CDC1 ₃ -MS0- d ₆ = 9: 1, 200 MHz): δ 1.81 (3H, s), 2.41 (3H, brq, J = 0.8 Hz), 2.71 (3H, s), 7.37 (2H , πι), 7.55 (1H, tm, J = 8.1 Hz), 8.16 (1H, dm, J = 8.6 Hz).

Elemental _{analysis: C 15 H 15 N 3 0} 3 S 3 Calculated: C, 47.22; H, 3.96 ; N, 11.01; S, 25.22 (%), Found: C, 47.41; H, 3.80 ; N, 11.01; S, 25.07 (%). Example 3-28

Ή-NMR (Akira _{0- d 6, 200 MHz):} δ 1.20 (3Η, i, J = 7.0 Hz), 2.64 (3H, s), 2.68 (3H, s), 4.12 (2H, q, 7.2 Hz) , 7.39 (2H, t, J = 8 Hz), 7.52 (1H, brd, J = 8 Hz), 8.06 (1H, brd, J = 8 Hz), 9.42 (1H, brs). Elemental analysis: C _n Calculated for H ₁₇ N ₃ 0 ₅ S ₃ : C, 46.45; H, 3.90; N, 9.56

(), Found: C, 46.74; H, 3.73; N, 9.59 (%).

Example 3-29

 Ή-NMR (200 MHz, in double-mouthed form): δ 0.89 (3Η, t, J = 7.2 Hz), 1.26 (3H, t, J = 7.2 Hz), 1.30 (4H, m), 1.33 (2H, m), 1.47 (2H, brquint, J = 7.0 Hz), 2.07 (2H, t, J = 7.5 Hz), 2.71 (2H, t, J = 7.4 Hz), 3.24 (2H, t, J = 7.4 Hz) , 4.16 (2H, q, J = 7.2 Hz), 6.50 (1H, s), 7.02 (2H, dt, J = 8, 7, 2.3 Hz), 7.07 (2H, brd, J = 8.0 Hz), 7.21 ( 1H, brt, J = 7.5 Hz), 7.40 (2H, tt, J = 7.9, 2.3 Hz), 7.89 (2H, dt, J = 9.0, 2.3 Hz), 9.70 (1H, brs).

Elemental analysis: Calculated as _{C 24 H 25 N 3 0 4} .S 3: 55.90; H, 4.89; N, 8.15; S, 18.65 (%) Found; C, 55.67; H, 4.64 ; N, 8.03; S, 18.52 (%). Example 3-30

- noodles _{R (CDC1 3, 200 MHz)} : δ 1.84 (3Η, s), 2.46 (3H, brs), 7.06 (2H, d, J = 9.2 Hz), 7.08 (2H, d, J = 7 Hz), 7.27 (1H, t, J = 8 Hz), 7.3 (2H, t, J = 7.9 Hz), 7.83 (2H, d, J = 8.8 Hz).

Elemental analysis: C _2. H ₁₇ N ₃ 0 ₄ S ₃ Calculated: C, 52.27; H, 3.73 ; N, 9.14; S, 20.93 (%), Found: C, 52.33; H, 3.96;, 9.29; S, 20.73 (%). Examples 3-31

_{Ή-NMR (CDC1 3, 200} MHz): δ 1.31 (3H, t, J = 7.0 Hz), 2.93 (3H, s),

4.25 (2H, q, J = 7.2 Hz), 7.06 (2H, d, J = 9.2 Hz), 7.08 (2H, d, J = 8 Hz), 7.27 (1H, t, J = 8 Hz), 7.43 ( 2H, d, J = 8.0 Hz), 7.84 (2H, d, J = 8.8 Hz).

Elemental analysis: C ₂₂ H ₁₉ N ₃ 0 Calculated _{6 S 3: C, 51.05;} H, 3.70; N, 8.12; S, 18.59 (%), Found: 51.12; H, 3.64; N , 8.13; S, 18.51 (). Example 3-32

_{Ή-NMR (DMSO- d 6,} 200 MHz): δ 1.74 (3H, s), 2.29 (3H, s), 7.60 (1H, m), 7.68 (2H, m), 1H, d, J = 7.0 Hz ).

Example 3-33

-Banded R (CDCl ₃ -DMS0-d ₆ 3: 1, 200 MHz): d 1.30 (3H, t, J = 7.0 Hz), 2.88 (3H, s), 4.22 (2H, q, J = 7.0 Hz) , 7.60 (2H, d, J = 8.8 Hz), 8.03 (2H, d, J = 8.8 Hz).

Elemental _{analysis: C 16 H 14 N 3 0} 5 S 3 C1 Calculated: C, 41.78; H, 3.07 ; N, 9.14;

5, 20.91; C1, 7.71 (%), found: C, 41.68; H, 2.96; N, 9.13; S, 20.90; C1, 7.54 ().

Example 3-34

-NMR (DMS0-d ₆ , 200 MHz): δ 1.21 (3Η, t, J = 7.2 Hz), 2.73 (3H, s), 4.14 (2H, q, J = 7.2 Hz), 7.45 (2H, t, J = 8.8 Hz), 8.08 (2H, dd, J = 8.8, 5.4 Hz).

Elemental _{analysis: C 16 H u N 3 0} 5 S 3 F Calculated: C, 43.33; H, 3.18 ;, 9.47; S, 21.69; F, 4.28 (%), Found: C, 43.20; H, 3.44; N, 9.32; S, 21.33; F, 4.29 (%).

Example 3-35

Ή-NMR (DMS0-d ₆ , 200 MHz): δ 1.74 (3H, brs), 2.31 (3H, brs), 7.46

(2H, t, J = 8.7 Hz), 8.06 (2H, dd, J = 9.2, 5.2 Hz).

Elemental _{analysis: C 14 H 12 N 3 0} 3 S 3 F Calculated: C, 43.62; H, 3.14 ; N, 10.90; F, 4.93 (%), Found: C, 43.38; H, 3.34; N, 10.88; F, 4.93 (%).

Ή-NMR (DMS0-d ₆ , 300 MHz): δ 1.23 (3H, t, J = 7.2 Hz), 2.80 (3H, s), 3.45 (3H, s), 4.17 (2H, q, J = 7.2 Hz) ).

Elemental analysis: Calculated as _{C u H i3 N 3 0 5} S 3:. C, 36.35; H, 3.61; N, 11.56; S, 26.47 (%), Found: 36.45; H, 3.75;, 11.33; S, 26.26 (%). Example 3-37

 N- (4-sulfanyl-1-oxo_1,2-dihydro-3H-imidazo [5,1-c] [1,4] benzothiazine-3-ylidene) -4-methylbenzenesulfonamide

 To a suspension of the compound synthesized in Example 2-67 (252 mg, 0.501 mmol) in THF (2.50 ml) and ethanol (2.50 ml) was added potassium hydroxide (99.1 mg, 1.50 mmol), and the mixture was stirred at room temperature for 30 minutes. Stirred for minutes. 1N Hydrochloric acid (2.00 ml) was added to the reaction solution, mixed, and stirred at room temperature for 1 hour. The resulting precipitate was collected by filtration, washed with water and ethanol, and dried to give the title compound as yellow crystals (183 mg, 9U). This product was used for the next reaction without further purification.

IR (KBr) V: 3300-2400, 2996, 1715, 1588, 1574, 1524 cm " ¹ .

Ή-NR (DMS0-d ₆ ): δ 2.51 (3Η, s), 7.04-7.14 (2Η, m), 7.16-7.28 (1Η, m), 7.44 (2H, d, J = 8.4 Hz), 7.94 ( 2H, d, J = 8.4 Hz), 8.29 (1H, bs), 8.69 (1H, d, J = 8.4 Hz).

Example 3-38

 N- (1,6-dioxo-4-sulfanyl-1,2,6,7,8,9-hexahydro-3H-imidazo [5,1-c] [1,4] benzothiazine-3-ylidene ) -4-Methylbenzenesulfonamide

To a suspension of the compound synthesized in Example 2-68 (2.43 g, 4.66 mmol) in THF (24.0 ml) and ethanol (24.0 ml) was added potassium hydroxide (980 mg, 14.0 mmol), and the mixture was stirred at room temperature for 1 hour. Stirred for hours. The reaction mixture was mixed with 1N hydrochloric acid (16.8 ml) and stirred at room temperature for 1 hour. The resulting precipitate was collected by filtration, washed with water and ethanol, and dried to give the title compound as orange crystals (1.57 g, 80 °). Recrystallization from ethyl acetate gave orange crystals with a melting point of 246-248 ° C. Infrared absorption spectrum (IR) (in KBr): 3700-2300, 1721, 1661, 1584, 1501 cm—

Ή-NMR (CDC1 ₃ side SO-d ₆ ): δ 1.98-2.16 (2Η, m), 2.34-2.62 (2Η, m), 2.45 (3Η, s), 3.37 (2Η, t, J = 5.8 Hz) , 7.36 (2H, d, J = 8.0 Hz), 7.89 (2H, d, J = 8.0 Hz).

Elementary analysis: as _{C 17 H 15 N 3 0 4} S 3 '0.4H 2 0

Calculated value (¾): C, 47.63; H, 3.71; N, 9.80.

Found (¾): C, 47.95; H, 3.66; N, 9.72.

Example 3-39

 -(l, 6-Dioxo-4-sulfanyl-1,2,7,8-tetrahydro-3H, 6H-cyclopent [b] imidazo [1,5-d] [1,4] thiazine-3- (Ylidene) -4-methylbenzenesulfonamide

 To a suspension of the compound (800 mg, 1.63 mmol) synthesized in Example 2-69 in THF (8.00 ml) and ethanol (8.00 ml) was added potassium hydroxide (322 mg, 4.88 imol), and the mixture was added at room temperature for 20 minutes. Stirred for minutes. 1N Hydrochloric acid (6.51 ml) was added to the reaction solution, mixed, and stirred at room temperature for 1 hour. The resulting precipitate was collected by filtration, washed with water and ethanol, and dried to give the title compound as orange crystals (540 mg, 85%). This product was used for the next reaction without further purification.

Infrared absorption spectrum (IR) (in KBr): 3700-2300, 1732, 1696, 1686, 1607, 1582, 1495 cm- ¹ .

Ή-NMR (CDCl ₃ + DMSO-d ₆ ): δ 2.41 (3Η, s), 2.48-2.60 (2H, m), 3.10-3.24 (2Η, m), 7.41 (2H, d, J = 8.2 Hz) , 7.91 (2H, d, J = 8.0 Hz).

Example 3-40

 5-C2-Toxy-2-oxoethyl) -tri {[(4-methylphenyl) sulfonyl] imino} -3--3-oxo-8-sulfanyl-2,3-dihydro-1H-imidazo [5, 1-c] [1,4] thiazine _6-ethyl rubonate

A solution of sulfuryl chloride (7.44 g, 54.3 mmol) in dichloromethane (5 ml) was added dropwise over 60 minutes to a solution of getyl 3-ketoglurate (11.0 g, 54.3 mmol) in dichloromethane (50 ml) with stirring at room temperature. At room temperature Stir for 1.5 hours. The reaction solution was poured into a mixture of ice (50 g) and a saturated aqueous solution of sodium hydrogen carbonate (50 ml), stirred vigorously, and the aqueous layer was extracted with dichloromethane (80 ml). The organic layer was washed with a 15% saline solution, dried over sodium sulfate, and concentrated to dryness to give crude 2_ clomouth-3-ethyl ketoglutarate (purity 50%, 13.4 g, 28 mmol, 52%) colorless. Obtained as an oil.

_{Ή-NR (300MHz, CDC1 3} , main peak): 53.72 (1H, d, J = 16.5 Hz), 3.82 (1H, d, J = 16.5 Hz), 5.03 (1H, s).

 A suspension of the compound synthesized in Reference Example 3-2 (purity 90%, 8.07 g, 16.9 mmol) and triethylamine (7.03 ml, 50.7 mmol) in THF-DMF (9: 1, 120 ml) was stirred at room temperature. A solution of 2-ethyl-3-ethyl ketoglutarate (purity 50¾, 8.00 g, 16.9 mmol) in THF-DMF (9: 1, 20 ml) was added dropwise over 30 minutes, and the reaction solution was allowed to stand at room temperature for 3 hours Stirred. The reaction solution was concentrated, diluted with ethyl acetate (300 ml), and washed with water, an aqueous solution of sodium hydrogen carbonate, and saturated saline. The washing solution was extracted with ethyl acetate (200 ml). The organic layer was dried over sodium sulfate and concentrated to dryness to give a brown oil (12.6 g).

The resulting brown oil was dissolved in toluene (200 ml) and stirred at 80 ° C for 2 hours in the presence of acetic anhydride (4.88 ml, 50.7 mmol) and p-toluenesulfonic acid hydrate (3.21 g, 16.9 mmol). did. The reaction solution was concentrated, diluted with ethyl acetate (300 ml), washed with water and saturated saline, dried over sodium sulfate, and concentrated to obtain a red oil. This was purified by chromatography on silica gel (100 g) (ethyl acetate-hexane, 3: 7-4: 6), and getyl ether was added to the obtained orange oil (3.85 g). The precipitate was collected by filtration, washed with getyl ether, and dried to obtain the following compound (3.35 g, 5.48 mmol, 32.4%) as an orange powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.21 (3H, t, J = 7.0 Hz), 1.26 (3H, t, J = 7.2 Hz), 1.31 (3H, t, J = 7.2 Hz), 2.43 (3H , s), 2.69 (2H, dt, J = 2.6, 7.2 Hz), 3.24 (2H, m), 4.15 (2H, q, J = 7.2 Hz), 4.21 (2H, q, J = 7.2 Hz), 4.15 (2H, q, J- 7.0 Hz), 6.62 (1H, s), 6.64 (1H, s), 7.31 (2H, d, J = 8.0 Hz), 7.87 (2H, d, J = 8.4 Hz), 9.81 (1H, br).

Elemental analysis: Calculated as _{C 25 H 29 N 3 0 9} S 3: 9.09; H, 4.78; N, 6.87; S, 15.73.

Found: C, 49.08; H, 4.51; N, 6.99; S, 15.71.

 To a solution of the compound obtained above (3.39 g, 5.54 mol) in THF-ethanol (1: 1, 70 ml) was added 20% sodium ethoxide (ethanol solution, 5.00 ml, 12.7 mmol) with stirring at room temperature. The reaction was stirred for 1 hour. 1N Hydrochloric acid (13.8 ml) and water (75 ml) were added to the reaction solution. The precipitate was collected by filtration, washed with methanol-water (1: 1), and dried to give the title compound (2.18 g, 4.26 mmol, 76.8) as an orange powder.

_{lH-NMR (200MHz, CDC1 3} ): δ 1.28 (3H, t, J = 7.1 Hz), 1.30 (3H, t, J = 7.2 Hz), 2.47 (3H, s), 4.20 (2H, q, J = 7.0 Hz), 4.24 (2H, q, J = 7.0 Hz), 4.65 (2H _; s), 6.64 (1H, s), 7.39 (2H, d, J = 8.2 Hz), 7.78 (2H, d, J = 8.4 Hz).

Elemental analysis: C _2. H ₂₁ N ₃ 0 ₇ S ₃ Calculated: 46.95; H, 4.14; N, 8.21; S, 18.80 (), Found: C, 47.08; H, 4.04; N, 8.07; S, 18.74 (%). mp. 199.0-200.5 ° C

Example 3-41

6- (2-Methoxy-2-oxoethyl) -tri {[(4-methylphenyl) sulfonyl] Imino} -3-oxo-8-sulfanyl-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-5-carboxylate

 To a solution of the compound synthesized in Example 2-75 (3.74 g, 6.41 mmol) in THF-methanol (1: 1, 70 ml) was added 28% sodium methoxide (ethanol solution, 2.84 g, 14.7 ml) while stirring at room temperature. mmol) and the reaction was stirred for 45 minutes. 1N Hydrochloric acid (14.7 ml) was added to the reaction solution, and the precipitate was collected by filtration, washed with methanol-water (1: 1), and dried to give the title compound (1.13 g, 2.34 mmol) as an orange powder. Was. The mother liquor was concentrated, adjusted to be acidic, extracted with ethyl acetate (100 ml), and the obtained organic layer was washed with acidified 7 and 15% saline, then with saturated brine, and dried over sodium sulfate. The residue was concentrated to dryness to give the crude title compound (2.28 g, a mixture of isomers) as an orange-brown powder.

_{Ή-NMR (300MHz, CDC1 3} ): 62.47 (3H, s), 3.27 (2H, s), 3.72 (3H, s), 3.90 (3H, s), 7.38 (2H, d, J = 8.1 Hz), 7.81 (2H, d, J = 8.4 Hz), 12.11 (1H, br).

Elemental _{analysis: C 18 H 17 N 3 0} 7 S 3 Calculated: C, 44.71; H, 3.54 ; N, 8.69; S, 19.89 (%), Found: C, 44.65; H, 3.50 ; N, 8.40; S, 19.86 (%) .mp. 211.0-214.0 ° C

Example 3-42

 N- (8,8-Dimethyl-1,6-dioxo-4-sulfanyl-1,2,6,7,8,9-hexahydro-3H-imidazo [5,1-c] [1,4] Benzothiazine_4-ylidene) -4-methylbenzenesulfonamide

3-[(8,8-Dimethyl-1,6-dioxo-3-{[(4-methylphenyl) sulfonyl] imino} -2,3,6,7,8,9 synthesized in Example 2-76 -Hexahydrid-1H-imidazo [5,1-c] [1,4] benzothiazin-4-yl) sulfanyl] ethyl propionate (3.00 g, 5.46 mmol) in THF (30.0 ml) and ethanol ( Potassium hydroxide (1.08 g, 16.4 mmol) was added to the suspension, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was mixed with 1N hydrochloric acid (21.8ιηυ) and stirred at room temperature. The resulting precipitate was collected by filtration, washed with water and ethanol, dried and dried to give orange crystals of the title compound (2.30 g, 94¾) was obtained again from ethyl acetate. Crystallization yielded orange crystals with a melting point of 255-257 ° C.

IR (KBr) V:. 3350-2500 , 2967, 2878, 2242, 1717, 1655, 1584, 1505 cm "1 L H-NMR (CDC1 3): δ 1.13 (6Η, s), 2.37 (2H, s) , 2.46 (3H, s), 3.25 (2H, s), 7.39 (2H, d, J = 8.4 Hz), 7.80 (2H, d, J = 8.7 Hz), 9.50 (1H, bs). as _{C 19 H 19 N 3 0 4} S 3

Calculated (): C, 50.76; H, 4.26; N, 9.35; S, 21.40.

Obtained): C, 50.84; H, 4.55; N, 9.21; S, 20.49.

Example 3-43

 N- (9,9-dimethyl-1,6-dioxo-4-sulfanyl-1,2,6,7,8,9-hexahydro-3H-imidazo [5,1-c] [1,4] Benzothiazine-4-ylidene) -4-methylbenzenesulfonamide

 3-[(9,9-dimethyl-1,6-dioxo-3-{[((4-methylphenyl) sulfonyl] imino) synthesized in Example 2-77 in the same manner as in Example 3-42. }-2, 3, 6, 7, 8, 9-Hexahydro-1H-imidazo [5,1-c] [1,4] benzothiazin-4-yl) sulfanyl] ethyl ester propionate (4.80 g, 8.73 mmol) to give the title compound (4.02 g, ca. 100%). Recrystallization from ethyl acetate gave dark red crystals with a melting point of 256-258.

 IR (KBr) V: 3350-2500, 2973, 2922, 2868, 2255, 1717, 1651, 1586, 1505 cm—

_{Ή-NMR (CDC1 3):} 51.15 (6H, s), 1.90 (2H, t, J = 6.0 Hz), 2.46 (3H, s), 3.38 (2H, t, J-6.3 Hz), 7.38 (2H, d, J = 8.4 Hz), 7.79 (2H, d, J = 8.4 Hz), 9.49 (1H, bs).

Elementary analysis: as _{C 19 H 19 N 3 0 4} S 3 · 0 · 5H 2 0

Calculated (%): C, 49.76; H, 4.40; N, 9.16; S, 20.98.

Obtained): C, 49.84; H, 4.14; N, 9.09; S, 20.78.

Example 3-44

N- (1,6-Dioxo-8-methyl-4-sulfanyl-1,2,6,7,8,9-hexahydride-3H-imidazo [5, 1-c] [1,4] benzothiazine- 4-ylidene) -4-methylbenzenesulfonamide In the same manner as in Example 3-42, 3-[(1,6-dioxo-8-methyl-3-{[((4-methylphenyl)) synthesized in Example 2-78. Sulfonyl] imino 2,3,6,7,8,9-hexahydro-1H-imidazo [5,1-c] [1,4] benzothiazin-4-yl) sulfanyl] ethyl ethyl propionate ( The title compound (8.49 g, ca. 100%) was synthesized from 10.2 g, 19.0 bandages. Recrystallization from ethyl acetate gave dark red crystals with a melting point of 259-261 ° C.

IR (KBr) V 3700-2700, 2955, 2926, 2851, 1717, 1663, 1584, 1493 cm " ¹ .

'.Eta. Ran _{R (CDC1 3): (51.16} (3H, d, J = 6.0 Hz), 2.13-2.33 (2H, m), 2.46 (3H, s), 2.59 (1H, d, J = 13.2 Hz) , 2.71 (1H, dd, J = 18.9, 9.9 Hz), 3.76 (1H, dd, J = 19.2, 3.0 Hz), 7.88 (2H, d, J = 8.7 Hz), 8.29 (2H, d, J-8.1 Hz), 9.41 (1H, bs).

Example 3-45

 N- (4-sulfanyl-2,3-dihydro-3H-imidazo [5,1-c] [1,4] benzothiazine-4-ylidene) -4-methylbenzenesulfonamide

 By the same method as in Example 3-42, 3-[(3-{[(4-methylphenyl) sulfonyl] imino} -toxo-2,3-dihydro-1H-imi synthesized in Example 2-67. The title compound (183 mg, 91%) was synthesized from ethyl ethyl dazo [5,1-c] [1,4] benzothiazine-4-yl) sulfanyl] propionate (252 mg, 0.501 bandol).

 IR (KBr) V: 3300-2400, 2996, 1715, 1558, 1574, 1524 cm—

_{Ή-NR (CDC1 3):} δ 2.51 (3Η, s), 7.04-7.14 (2H, m), 7.16-7.28 (2Η, in), 7.44 (2Η, d, J = 8.4 Hz), 7.94 (2H, d, J = 8.Hz), 9.29 (1H, bs), 8.69 (1H, d, J = 8.4 Hz).

Example 4-1

In the formula (IX), R ^{2 is a} benzyl group, R ⁵ is an n-hexyl group, R ⁶ is a hydrogen atom, R ^{1 Q} is —ZR ¹⁵ (Z is S〇 ₂ , R ¹⁵ is a p-tolyl group), Synthesis of compounds where n is 1

Compound (150 mg, purity 95.3%, 0.266 mmol) synthesized in Example 2-2 The residue was dissolved in THF (2 ml) and methanol (2 ml), potassium hydroxide (86 mg, 1.30 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Benzyl bromide (0.035 ml, 0.292 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. 1N Hydrochloric acid (1.03 ml) was added to the reaction solution, mixed, and stirred at room temperature for 30 minutes. The resulting precipitate was collected by filtration, washed with aqueous methanol, and dried to give the title compound as an orange powder (110 mg, 0.208 mmol).

lH-Maraudal R (300 MHz, in double-mouthed form): δ 0.89 (3Η, t, J = 6.9 Hz), 1.28 (4H, m), 1.30 (2H, m), 1.54 (2H, brquint, J = 6.8 Hz), 2.41 (3H, s), 2.90 (1H, dt, J = 13.1, 1.6 Hz), 3.12 (1H, dt, J = 13.1, 2.7 Hz), 3.53 (1H, dt, J = 9. 6.8 Hz), 3.60 (1H, dt, J-9.4, 6.8 Hz), 4.22 (1H, d, J = 12.6 Hz), 4.25 (1H, d, J = 12.6 Hz), 5.71 (1H, brdd, J = 2.7,

I.6 Hz), 7.26 (2H, d, J-8.2 Hz), 7.32 (5H, s), 7.87 (2H, d, J = 8.2 Hz), 9.73 (1H, brs).

Elemental _{analysis: C 26 H 29 N 3 0} 3 S 3 Calculated: C, 59.18; H, 5.54 ; N, 7.96; S, 18.23 (%), Found; C, 59.07; H, 5.50 ; N, 7.94; S, 18.52 (%). Example 4-2

In the formula (IX), R ² is an isobutyl group, R ⁵ is an n-pentyl group, R ⁶ is a methyl group, and R ¹ . Synthesis of Gar ZR ^{1 5} (Z is SO _2, R ¹⁵ is P- Bok Ruiru group), compounds wherein n is 1

 The compound synthesized in Example 3-1 (5.22 g, 11.9 mmol) and potassium carbonate (2.47 g, 17.9 mmol) were mixed with DMF (87 ml), and the mixture was stirred at 80 for 5 minutes. Isobutyl iodide (1.51 ml, 13.1 mmol) was added to the reaction solution, and the mixture was further stirred for 2 hours. The reaction mixture was mixed with 1N hydrochloric acid (30 ml) and stirred at room temperature for 30 minutes. The resulting precipitate was collected by filtration, washed with 50% aqueous methanol and then with methanol, and dried to give a purple powder of the title compound (5.54 g,

II.2 mmol).

Ή-NMR (300 MHz, in double-mouthed form): δ 0.90 (3Η, t, J = 6.8 Hz), 1.02 (6H, d, J = 6.8 Hz), 1.31 (4H, m), 1.7 ( 2H, brquint, J = 7.5 Hz), 1.90 (1H, septet, J = 6.8 Hz), 2.11 (2H, brdd, J = 7.9, 7.2 Hz), 2.26 (3H, s), 2.41 (3H, s), 2.82 (2H, t, J = 7.1 Hz), 7.27 (2H, d, J = 8.3 Hz), 7.86 (2H, d, J = 8.3 Hz), 9.62 (1H, brs).

Elemental _{analysis: C 23 H 31 N 3 0} 3 S 3 Calculated: C, 55.95; H, 6.33 ; N, 8.51; S, 19.48 (%), Found; C, 55.96; H, 6.06 ; N, 8.75; S, 19.56 (%). Melting point: 123.5-124. Ot:

Example 4-3

R ² is 4_ pyridylmethyl group in formula (IX), hexyl radical R ⁵ is the n-, R ⁶ is a hydrogen atom, R ^{1 0} Gar _{^{ZR 1 5 i / LifiS O 2}} , R 15 is p - Toruiru group ), Synthesis of compounds where n is 1

The compound synthesized in Example 3-2 (99 mg, 0.226 mmol), picolyl chloride hydrochloride (57 mg, 0.339 mmol) and potassium carbonate (63 mg, 0.452 ol) were mixed with DMF (1.5 ml). The mixture was stirred at room temperature for 80 minutes and further at 80 ° C for 2.5 hours. 1N Hydrochloric acid (0.68 ml) and 50% aqueous methanol (2 ml) were added to the reaction solution, mixed, and stirred at room temperature for 30 minutes. It was filtered off and the resulting precipitate was washed with main evening Knoll water, purple powder (82 mg, 0.155 mmol) in dried title compound was obtained _b

 Ή-NR (300 MHz, in double-hole form): d 0.89 (3H, t, J = 6.6 Hz), 1.27 (6H, br), 1.1 (2H, brquint, J = 6.6 Hz), 2.02 ( 2H, t, J = 7.2 Hz), 2.43 (3H, s), 4.15 (2H, s), 6.52 (1H, brs), 7.26 (2H, d, J = 5.7 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.82, (2H, d, J = 8.3 Hz), 8.57 (2H, d, J = 5.7 Hz).

Elemental analysis: Calculated for C ₂₅ H ₂₈ N ₄ 0 ₃ S ₃ : C, 56.79; H, 5.34; N, 10.60; S, 18.19 (%) found; C, 56.59; H, 5.23; N, 10.52 ; S, 18.08 (%). Examples 4-4

R ² is 2-phenethyl in formula (IX), R ⁵ is ethoxy Cal Poni Le group, R ⁶ is a methyl group, R ^{1 ()} gar ZR ^{1 5} (Z is S_〇 _2, R ^{1 5} is p- Toruiru group ), Synthesis of compounds where n is 1

The compound synthesized in Example 3-3 (520 mg, 1.18 mmol), 2-phenyl bromide (202 ml, 1.42 mmol) and potassium carbonate (245 mg, 1.77 mmol) were added. It was mixed with DMF (8 ml) and stirred at 80 ° C for 2 hours and 20 minutes. The reaction mixture was concentrated, diluted with ethyl acetate (50 ml), washed with 0.1N hydrochloric acid, water and saturated saline, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and methanol was added to the residue. The resulting precipitate was collected by filtration, washed with methanol, and dried to obtain a dark red powder of the title compound (609 mg, 1.12 mmol). .

lH-NMR (300 MHz, in double-mouthed form): δ 1.34 (3Η, t, J = 7.1 Hz), 2.43 (3H, s), 2.76 (3H, s), 2.99 (2H, brdd, J = 8.5) , 7.2 Hz), 3.23 (2H, brdd, J = 8.5, 7.0 Hz), 4.26 (2H, q, J = 7.1 Hz), 7.21 (2H, brd, = 7.8 Hz), 7.29 (5H, m), 7.83 . (2H, brd, J = 8.3 Hz), 9.80 (1H, brs) elemental _{analysis: C 25 H 25 N 3 0} 5 S 3 calculated: C, 55.23; H, 4.63 ; N, 7.73; S, 17.69 (%)>Found; C, 55.10; H, 4.51; N, 7.63; S, 17.55 (%).

R ² is an isobutyl group in the formula (IX), R ⁵ and R ⁶ are both methyl, R ^{1 ()} gar ZR ¹⁵ (Z is S_〇 _2, R ¹⁵ is p - Toruiru group), n is 1 der Compound synthesis

 The compound synthesized in Example 3-4 (1.98 g, 5.19 mmol) and lithium carbonate (1.08 g, 7.79 mmol) were mixed with DMF (35 ml), and the mixture was stirred at 8 Ot: for 5 minutes. Isobutyl (0.72 ml, 6.23 mmol) was added to the reaction solution, and the mixture was further stirred for 70 minutes. 1N Hydrochloric acid (10.5 ml) and water (10 ml) were added to the reaction solution, mixed, and stirred at room temperature for 60 minutes. The resulting precipitate was collected by filtration, washed with aqueous methanol, and dried to give a purple powder of the title compound (1.96 g, 4.48 mmol).

 Ή-NMR (200 MHz, in double-mouthed form): δ 1.02 (6Η, d, J = 6.6 Hz), 1.78 (3H, brq, J = 1.2 Hz), 1.90 (1H, sept, J = 6.7 Hz) , 2.26 (3H, brq, J = 1.2 Hz), 2.41 (3H, s), 2.81 (2H, d, J = 7.0 Hz), 7.27 (2H, d, J = 8.0 Hz), 7.86 (2H, d, J- 8. Hz), 9.65 (1H, brs).

Elemental _{analysis: C 19 H 23 N 3 0} 3 S 3 Calculated: C, 52.15; H, 5.30 ; N, 9.60; S, 21.98 (%), measured value; 51.97; H, 5.13; N , 9.69; S, 21.92 (). Examples 4-6 Wherein in (IX) R ² is 2-phenethyl, R ⁵ and R ⁶ are both methylation group, R ^{1 Q} Gar ZR ^{1 5} (Z is S_〇 _2, R ^{1 5} is p- Toruiru group), n Of compounds with

 The compound synthesized in Example 3-4 (1.73 g, 4.53 mmol) and lithium carbonate (0.94 g, 6.80 mmol) were mixed with DMF (35 ml), and the mixture was stirred at 80 for 5 minutes. 2-Phenethyl iodide (1.22 g, 4.99 mmol) was added to the reaction solution, and the mixture was further stirred for 60 minutes. 1N Hydrochloric acid (9.1 ml) and water (10 ml) were added to the reaction solution, mixed, and stirred at room temperature for 30 minutes. The resulting precipitate was collected by filtration, washed with aqueous methanol, and dried to give a purple powder of the title compound (2.17 g, 4.47 mmol).

 'Η-Marauder R (200 MHz, in double-mouthed form): δ 1.79 (3Η, brq, J = 1.2 Hz), 2.26 (3H, brq, J = 1.2 Hz), 2.42 (3H, s), 2.97 ( 2H, brdd, J = 9.2, 5.8 Hz), 3.17 (2H, dd, J = 9.0, 5.4 Hz), 7.16-7.34 (7H, m), 7.83 (2H, d, J = 8.6 Hz), 9.66 (1H , brs).

Elemental analysis: Calculated as _{C 23 H 23 N 3 0 3} S 3: C, 56.88; H, 4.77; N, 8.65; S, 19.81 (%)ゝFound; C, 56.75; H, 4.65 ; N, 8.71; S, 19.58 (%). Examples 4-7

R ² is an isobutyl group in the formula (IX), R ⁵ is Echiru group, R ⁶ is a methyl group, 1 ^ ° gar ^{21 1 5, τΐ ^ Ο>} R 15 is ρ- Toruiru group), eta 1 der Compound synthesis

 The compound synthesized in Example 3-5 (313 mg, 0.791 mmol) and potassium carbonate (164 mg, 1.19 mmol) were mixed with DMF (5 ml), and the mixture was stirred at 80 ° C for 5 minutes. Isobutyl iodide (O.lO mI, 0.870 mmol) was added to the reaction solution, and the mixture was further stirred for 105 minutes. 1N Hydrochloric acid (1.6 ml) and water (1.0 ml) were added to the reaction solution, mixed, and stirred at room temperature for 60 minutes. The resulting precipitate was collected by filtration, washed with methanol and water, and dried to give a red powder of the title compound (274 mg, 0.608 mmol).

-NMR (200 MHz, in double chromate form): δ 1.03 (6Η, d, J = 7.8 Hz), 1.08 (3H, ί, J = 7.8 Hz), 1.91 (1H, sepi, J = 7.0 Hz) , 2.14 (2H, q, J = 7.4 Hz), 2.26 (3H, s), 2.1 (3H, s), 2.83 (2H, d, J = 6.8 Hz), 7.28 (2H, d, J = 8.2 Hz), 7.86 (2H, d, J = 7.8 Hz), 9.65 (1H, brs).

Elemental _{analysis: C 2Q H 25 N 3 0} 3 S 3 Calculated: C, 53.19; H, 5.58 ;, 9.30; S, 21.30 (%), Found; C, 53.11; H, 5.55 ; N, 9.43 ; S, 21.15 (%). Example 4-8

Wherein R ² in (IX) is 2 - phenylpropyl group, R ⁵ is and R ⁶ Gato Moni ^{methyl, R 1 (^ S- ZR 15} (Σ are 30 _2, R ¹⁵ is P- Toruiru group) Synthesis of compounds in which n is 1

 The compound synthesized in Example 3-4 (2.48 g, 6.49 mmol) and lithium carbonate (1.35 g, 9.74 mmol) were mixed with DMF (40 ml), and the mixture was stirred at 80 ° C for 5 minutes. 2-Phenylpropyl iodide (1.24 ml, 7.14 ramol) was added to the reaction solution, and the mixture was further stirred for 60 minutes. 1N Hydrochloric acid (13 ml). Water (5 ml) and methanol (5 ml) were added to the reaction solution, mixed, and stirred at room temperature for 30 minutes. The resulting precipitate was collected by filtration, washed with aqueous methanol, and dried to give a red-purple powder of the title compound (3.05 g, 6.10 imol).

NMR-NMR (200 MHz, in double-mouthed form): δ 1.38 (3Η, d, J = 6.6 Hz), 1.78 (3H, q, J = 0.8 Hz), 2.25 (3H, q, J = 1.2 Hz) , 2.42 (3H, s), 3.03 (1H, dd, J = 13.0, 7.0 Hz), 3.10 (1H, dd, J = 15.0, 8.0 Hz), 3.22 (1H, sept, J = 5.8 Hz), 7.26 ( . 7H, m), 7.79 ( 2H, d, J = 8.4 Hz), 9.60 (1H, brs) elemental analysis: calculated _{C 24 H 25 N 3 0 3} S 3: C, 57.69; H, 5.04; N, 8.41; S, 19.25 (%), found; C, 57.54; H, 4.77; N, 8.31; S, 19.08 (%). Melting point: 184.0-186. O:

Example 4-9,

R ² is an isopentyl group in formula (IX), R ⁵ is and R ⁶ are both methylation group, R ^{1 ()} is - ZR ¹⁵ (Z is S_〇 _2, R ¹⁵ is P - Toruiru group), n is 1 Of compounds that are

The compound synthesized in Example 3-4 (5.06 g, 13.3 mmol) and lithium carbonate (2.38 g, 17.2 mmol) were mixed with DMF (63 ml), and the mixture was stirred at 60 ° C for 5 minutes. Isopentyl iodide (1.93 ml, 14.6 mmol) was added to the reaction mixture. Stir for 3.5 hours. During this period, isopentyl iodide (0.20 ml, 1.66 mmol) was added 1 and 2 hours after the start of the reaction. The reaction mixture was mixed with 1N hydrochloric acid (21.2 ml) and stirred at room temperature for 30 minutes. The resulting precipitate was suspended in 50% aqueous methanol (20 ml), collected by filtration, washed with aqueous methanol and methanol, and dried to give a red-purple powder of the title compound (1.96 g, 4.48 band01). Obtained.

Ή-NR (200 MHz, in double-hole form): δ 0.93 (6Η, d, J = 6.2 Hz), 1.57 (2H, quint, J = 6.9 Hz), 1.69 (2H, septet, J = 6.5 Hz) , 1.79 (3H, brs), 2.26 (3H, q, J = 0.6 Hz), 2.42 (3H, s), 2.94 (2H, d, J- 7.5 Hz), 7.28 (2H, d, J = 8.0 Hz) , 7.85 (2H, d, J = 8.0 Hz), 9.63 (1H, brs) elemental analysis:. C _2. Calculated for H ₂₅ N ₃ 0 ₃ S ₃ : C, 53.19; H, 5.58; N, 9.30; S, 21.30 (%), found; 53.17; H, 5.87; N, 9.24; S, 21.50 (%) Melting point: 175.0-175.5 ° C

Example 4-10

In the formula (IX), R ² is a 2_ (4-methoxyphenyl) ethyl group, R ⁵ and R ⁶ are both methyl groups, R ¹⁰ is —ZR ¹⁵ (Z is SO ₂ , R ¹⁵ is p-toluyl Group), synthesis of a compound in which n is 1

 The compound synthesized in Example 3-4 (240 mg, 0.629 mmol) and potassium carbonate (130 mg, 0.944 mmol) were mixed with DMF (4.0 ml), and methanesulfonate 2- (4-methoxyphenyl) was mixed. After adding ethyl (0.19 g, purity 91%, 0.755 mmol), the mixture was stirred at 80 ° C for 50 minutes. To the reaction solution, 1N hydrochloric acid (1.3 ml), water (2 ml) and methanol (2 ml) were added and mixed, followed by stirring at room temperature for 30 minutes. The resulting precipitate was collected by filtration, washed with aqueous methanol and methanol, and dried to give a purple-red powder of the title compound (267 mg, 0.518 mmol).

Ή-NMR (200 MHz, in double-mouthed form): δ 1.78 (3Η, q, J = 0.8 Hz), 2.26 (3H, q, J = 1.2 Hz), 2.42 (3H, s), 2.90 (2H, dd, J = 8.4, 6.6 Hz), 3.15 (2H, dd, J = 8, 6.6 Hz), 3.80 (3H, s), 6.84 (2H, dt, J = 8.6, 2.5 Hz), 7.11 (2H, d, J = 8.4 Hz), 7.27 (2H, d, J = 8.0 Hz), 7.83 (2H, d, J = 8.0 Hz), 9.63 (1H, brs). Elemental analysis: Calculated as _{C 24 H 25 N 3 0 4} S 3: C, 55.90; H, 4.89; N, 8.15; S, 18.65 (%) Found; C, 55.64; H, 5.16 ; N, 8.22 ; S, 18.52 (%). Melting point: 174.5-175.5 ° C.

Example 4-11

R ² is 2 in formula (IX), 2 - dimethyl butyl group, R ⁵ is and R ⁶ Gato Moni methyl, R ¹⁰ Gar ZR ^{1 5} (Z is S 0 _2, R ^{1 5} is p- Toruiru Group), synthesis of a compound in which n is 1

 Compound (327 mg, 0.857 imol) synthesized in Example 3-4, 2,2-dimethylbutanol (114 mg, 1.11 mmol) obtained in Reference Example 102, and triphenylphosphine (324 mg, 1.20 mmol) were converted into THF ( 6.5 ml), and getyl azodicarbonate (0.199 ml, 1.20 mmol) was added dropwise, followed by stirring for 2 hours. The mixture was further stirred at 50 ° C for 26 hours. The reaction solution was diluted with ethyl acetate (30 ml), washed with a 2% aqueous sodium hydrogen carbonate solution and a saturated saline solution, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, methanol was added to the residue, and the generated precipitate was collected by filtration, washed with methanol, and dried to give a purple powder of the title compound (241 mg, 0.518 mmol).

 ^ -NMR (200 MHz, in double-mouthed form): 0.85 (3H, t, J = 7.5 Hz), 0.97 (6H, s), 1.36 (2H, q, J = 7.5 Hz), 1.79 (3H, q , J = 0.8 Hz), 2.26 (3H, q, J = 0.8 Hz), 2.41 (3H, s), 2.88 (2H, s), 7.27 (2H, d, J = 8.2 Hz), 7.87 (2H, d , J = 8.0 Hz), 9.60 (1H, brs).

Elemental analysis: Calculated for C ₂₁ HN ₃ 0 ₃ S ₃ : C, 54.17; H, 5.84; N, 9.02; S, 20.66 (%), found; 54.26; H, 5.89; N, 9.12; S, 20.61 (%). Melting point: 177.5-178. C

Example 4-Π

Wherein R ² is 4-Echirufueniru group in (IX), a methyl group R ⁵ is and R ⁶ Gatomo, R ^{1 G} Gar ZR ^{1 5} (Z is S_〇 _2, R ^{1 5} is P- Toruiru group), Synthesis of compounds where n is 1

The compound synthesized in Example 3-4 (n2 mg, 0.582 mmol), 4-ethylthiophenol (91.2 mg, 0.640 mmol) and triphenylphosphine (236 mg, 0.873 mmol) was mixed with THF (4.5 ml), and azodiphenol getyl sulfonate (0.145 ml, 0.873 mmol) was added dropwise, followed by stirring for 22 hours. The mixture was further stirred at 50 for 18 hours. To the reaction solution were added dropwise triphenylphosphine (157 mg, 0.582 mmol) and getyl azodisulfonic acid (0.097 ml, 0.582 mmol), and the mixture was further stirred at 50 ° C for 3 days. Dilute the reaction with ethyl acetate (30 ml)

The extract was washed with a 2% aqueous sodium hydrogen carbonate solution, 0.1 hydrochloric acid and saturated saline, and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was silica gel

60 (10 g) of column chromatography. Ethyl acetate: The fraction eluted with hexane (30: 70) was concentrated to dryness under reduced pressure, methanol was added to the residue, the resulting precipitate was collected by filtration, washed with methanol, and dried to give the title compound To give a purple powder (36 mg, 0.074 mmol).

^L H-NMR (200 MHz, in double-mouthed form): δ 1.26 (3Η, t, J = 7.5 Hz), 1.60 (3H, q, J = 0.9 Hz), 2.23 (3H, q, J = 1.2 Hz) ), 2.43 (3H, s), 2.70 (2H, q, J = 7.5 Hz), 7.22 (2H, d, J-7.8 Hz), 7.30 (2H, d, J = 7.8 Hz), 7.45 (2H, d , J = 8.1 Hz), 7.89 (2H, d, J = 8.1 Hz), 9.63 (1H, brs) elemental analysis: calculated _{C 23 H 23 N 3 0 3} S 3:. C, 56.88; H, 4.77; N, 8.65; S, 19.81 (%) ゝ Found; C, 56.82; H, 4.52; N, 8.42; S, 19.84 (%). Melting point: 183.0-184.5

Example 4-13

In the formula (IX), R ² is a 4-methoxyphenyl group, R ⁵ and R ⁶ are both a methyl group, R ¹ . Is— ZR ¹⁵ (Z is S 0 ₂ , R ¹⁵ is a P-tolyl group) and n is 2

The compound synthesized in Example 3-4 (257 mg, 0.674 mmol), 4-methoxybenzene (0.131 ml, 1.01 mmol) and triphenylphosphine (729 mg, 2.69 mmol) were mixed with THF (5 ml). While stirring at 60 ° C, a solution of diisopropyl azodisulfonic acid (0.547 ml, 2.69 mmol) in THF (1.5 ml) was added dropwise over 2.5 hours, and the mixture was further stirred at 60 ° C for 1 hour. The reaction solution was diluted with ethyl acetate (30 ml), washed with a 2% aqueous sodium hydrogen carbonate solution, 0.1N hydrochloric acid, water and saturated saline, and dried over sodium sulfate. solvent After distilling off under reduced pressure, methanol was added to the residue. The resulting precipitate was collected by filtration, washed with methanol, and dried to obtain a red-purple powder of the title compound (169 mg, 0.325 mmol).

 'Η-employed R (200 MHz, in double-mouthed form): δ 1.81 (3Η, q, J = 1.2 Hz), 2.26 (3H, q, J = 0.8 Hz), 2.43 (3H, s), 3.82 ( 3H, s), 6.86 (2H, dt, J = 8.8, 2.0 Hz), 7.28 (2H, d, J = 8.2 Hz), 7.50 (2H, dt, J = 8.8, 2.0 Hz), 7.82 (2H, d ,) = 8.2 Hz), 9.56 (1H, brs).

Elemental _{analysis: C 22 H 21 N 3 0} 4 S 4 Calculated: C, 50.85; H, 4.07 ; N, 8.09; S, 24.68 (%), Found; C, 50.87; H, 4.03 ; N, 8.01; S, 24.15 (%). Melting point: 197.0-198.5Ό

Example 4-14

 N- [8- (isobutylsulfanyl) -5-methyl-3-oxo-6-propyl-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene ] -4-Methylbenzenesulfonamide

N- (5-methyl-3-oxo-6-propyl-8-sulfanyl-2,3-dihydrido-1H-imidazo obtained in Example 3-13 [5, tric] [1, 4 ] Thiazine-trilidene) -4-methylbenzenesulfonamide (l.OOg, 2.44 mmol) and potassium carbonate (506 mg, 3.66 mmol) in N, N-dimethylformamide (15.0 ml) To the suspension was added a solution of isobutyl iodide (0,309 ml, 2.69 mmol) in N, N-dimethylformamide (1.00 ml). After the reaction mixture was heated at 80 ° C for 40 minutes, 1N hydrochloric acid was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (852 mg, 75%) as a dark red crystals. Recrystallization from ethyl acetate-ethyl ether afforded dark red crystals, mp 144-146.

Infrared absorption spectrum (IR) (in KBr) Re: 3218, 2961, 2930, 2872, 1732, 1659, 1615, 1557, 1507, 1495 cm ' ¹

_{- NMR (CDC1 3): δ} 0.950 (3Η, t, J = 7.2 Hz), 1.02 (6H, d, J = 6.6 Hz), 1.40-1.61 (2H, m), 1.82-1.98 (1H, m), 2.10 (2H, t, J = 7.2 Hz), 2.26 (3H, s), 2.41 (3H, s), 2.82 (2H, t, J = 7.0 Hz), 7.28 (2H, d, J = 6.6 Hz), 7.86 (2H, d, J = 8.4 Hz), 9.61 (IH, bs).

Elemental analysis: as C ₂₁ H ₂₇ N ₃ 0 ₃ S ₃

Calculated value (%): C, 54.17; H, 5.84; N, 9.02; S, 20.66.

Obtained value (: C, 54.02; H, 5.84; N, 9.05; S, 20.41.

Example 4-15

 N- [6-butyl-8- (isoptylsulfanyl) -5-methyl-3-oxo-2,3-dihydro-1H-imidazo [5, lc] [1,4] thiazine Ylidene] -4-methylbenzene benzenesulfonamide

 According to a method similar to that of Example 4-14, N- (6-butyl-5-methyl-3-oxo-8-sulfanyl-2,3-dihydrochloride-1H- obtained in Example 3-15 was obtained. Imidazo

[5, 1-c] [1,4] thiazine-1-ylidene) -4_methylbenzenesulfonamide (1.00 g, 2.36 mmol) was used to synthesize the title compound (620 mg, 55%). Recrystallization from ethyl acetate-diisopropyl ether gave dark red crystals with a melting point of 116-U7 ° C. ■ Infrared absorption spectrum (IR) (in r) Re: 3214, 2957, 2930, 2870, 1732,

1657, 1617, 1563, 1557, 1507, 1495 cm- ¹ .

_{^ - MR (CDC1 3):} δ 0.929 (3Η, t, J = 6.6 Hz), 1.03 (6H, d, J = 6.6 Hz), 1.26-1.51 (4H, m), 1.80-1.98 (IH, m) , 2.12 (2H, t, J = 8.0 Hz), 2.26 (3H, s), 2.1 (3H, s), 2.82 (2H, t, J = 7.0 Hz), 7.28 (2H, d, J = 7.0) Hz), 7.86 (2H, d, J = 8. Hz), 9.60 (IH, bs).

Elementary analysis: as _{C 22 H 29 N 3 0 3} S 3

Calculated values): C, 55.09; H, 6.09; N, 8.76; S, 20.05.

Obtained): C, 54.99; H, 6.04; N, 8.76; S, 19.98.

Example 4-16

N- [6-isobutyl 8- (isobutylsulfanyl) -5-methyl-3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-trilidene ] -4-Methyl N- (6-isobutyl 5-methyl-3-oxo-8-sulfanyl-2,3-dihydro obtained in Example 3-16 by the same method as in Example 4-14. -1H-imidazo [5, 1-c] [1,4] thiazine-triylidene) -4-methylbenzenesulfonamide (1.00 g, 2.36 mmol) was used to synthesize the title compound (924 mg, 82%). Recrystallization from ethyl acetate-diisopropyl ether gave dark red crystals with a melting point of 150-152 ^.

Infrared absorption spectrum (IR) (in KBr): 3372, 3248, 2959, 2930, 2870, 1740, 1655, 1618, 1563, 1495 cm

_{Ή-NMR (CDC1 3):} δ 0.946 (6Η, d, J-6.6 Hz), 1.02 (6H, d, J = 7.0 Hz), 1.74-1.98 (2H, m), 2.03 (2H, d, J = 7.4 Hz), 2.26 (3H, s), 2.1 (3H, s), 2.82 (2H, t, J = 7.0 Hz), 7.28 (2H, d, J = 7.0 Hz), 7.86 (2H, d, J-8.2 Hz), 9.62 (1H, bs).

Elementary analysis: as _{C 22 H 29 N 3 0 3} S 3

Calculated values): C, 55.09; H, 6.09; N, 8.76; S, 20.05.

Obtained): C, 55.10; H, 6.07; N, 8.09; S, 20.07.

Example 4-17

N_ {5,6-dimethyl-8-[(2,2-diphenylethyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine- 1-Yylidene) -4-methyl Example 3-4 in the same manner as in Example 4-14, except that 2,2-diphenylethyl methanesulfonate (261 mg, 0.944 mmol) was used instead of isobutyl iodide. N- (5,6-Dimethyl-3-oxo-8-sulfanyl-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-triylidene) obtained in Step 4 The title compound (690 mg, 38%) was synthesized from methylbenzenesulfonamide (300 mg, 0.786 mmol). Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 192-194 ^.

Infrared absorption spectrum (IR) (in KBr) Re: 3231, 3061, 3029, 2924, 1732, 1665, 1615, 1563, 1495 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 1.77 (. 3Η, d, J = l Hz), 2.24 (. 3H, d, J = l Hz), 2.41 (3H, s), 3.63 (2H, d, J = 8.0 Hz), 4.25 (1H, t, 7.6 Hz), 7.12-7.38 (12H, m), 7.67 (2H, d, J = 8.4 Hz), 9.52 (1H, bs). Elemental analysis: C ₂₉ H ₂₇ N ₃ 0 ₃ S ₃

Calculated)): C, 62.01; H, 4.84; N, 7.48; S, 17.12.

Found (%): C, 61.69; H, 4.71; N, 7.34; S, 16.91.

Example 4-18

N- {5,6-dimethyl-8 _ [(3,3-diphenylpropyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5, 1-c] [1,4] Thiazine-1-ylidene) -4-me A method similar to that of Example 4-14, except that methanesulfonic acid 3,3-diphenylpropyl ester (268 mg, 0.944 mmol) was used instead of isobutyl iodide. N- (5,6-Dimethyl-3-oxo-8-sulfanyl-2,3-dihydrogen-1H-imidazo [5,1-c] [1,4] thiazine obtained in Example 3-4 -Trilidene)-The title compound (284 mg, 63¾) was synthesized from 4-methylbenzenesulfonamide (300 mg, 0.786 mmol). The crystal was recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 146-148 ° C.

Infrared absorption spectrum (IR) (in KBr) Re: 3225, 3061, 3027, 2924, 1736, 1665, 1611, 1561, 1493 cm " ¹ .

_{Ή-NMR (CDC1 3):} . Δ 1.73 (3Η, s), 2.24 (3H, s), 2.34-2 8 (2H, m), 2.41 (3H, s), 2.85 (2H, t, J = 7.0 Hz), 4.01 (1H, t, J = 7.0 Hz), 7.25-7.38 (12H, m), 7.86 (2H, d, J = 8.0 Hz), 9.60 (1H, bs).

Elemental analysis: C _3. H ₂₉ N ₃ 0 ₃ S ₃ '0.2 As H ₂ 0

Calculated)): C, 62.19; H, 5.11; N, 7.25; S, 16.60.

Found (%): C, 62.02; H, 5.02; N, 7.25; S, 16.55.

Example 4-19

 N- {5,6-dimethyl-8-[(4-phenylbutyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene 4-Methylbenzenesulfonamide

According to a method similar to that of Example 4-14, 4-phenylbutyl methanesulfonate (197 mg, 0.865 mmol) was used in place of isobutyl iodide to obtain N- (5,6) obtained in Example 3-4. -Dimethyl-3-oxo-8-sulfanyl -I, 3-Dihydrido-IH-imidazo [5,1-c] [1,4] thiazine-trilidene) -4-methylbenzenesulfonamide (300 mg, 0.786 mmol) from the title compound (283 mg, 70¾) was synthesized. Recrystallization from ethyl acetate gave dark red crystals with a melting point of 158-159 ° C.

Infrared absorption spectrum (IR) (in KBr) Re: 3196, 3063, 3027, 2930, 1725, 1663, 1613, 1557, 1497 cm " ¹ .

_{• H-NMR (CDC1 3)} : δ 1.65-1.82 (4Η, m), 1.77 (3H, s), 2.26 (3H, s), 2.40 (3H, s), 2.59-2.70 (2H, m), 2.88 -3.02 (2H, m), 7.12-7.34 (7H, m), 7.84 (2H, d, J = 8.0 Hz), 9.60 (1H, bs).

Elemental analysis: as C ₂₅ H ₂₇ N ₃ 0 ₃ S ₃

Calculated values): C, 58.45; H, 5.30; N, 8.18; S, 18.73.

Found (%): C, 58.05; H, 5.34; N, 8.08; S, 18.42.

Example 4-20

 N- {5,6-dimethyl-8- (hexylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5, 1-c] [1,4] thiazine-1-ylidene} -4 -Methylbenzenesulfonamide

 The N- (5,6- Dimethyl-3-oxo-8-sulfanyl-2,3-dihydro-1H-imidazo [5, 1-c] [1,4] thiazine-1-ylidene) -4-methylbenzenesulfonamide (300 mg, 0.786) mmol) to give the title compound (296 mg, 81¾). Recrystallization from ethyl acetate gave dark red crystals with a melting point of 157-158.

Infrared absorption spectrum (IR) (in KBr): 3227, 2955, 2928, 2859, 1748, 1719, 1661, 1613, 1559, 1497 cm " ¹ .

 Ή-NMR (CDCI3): δ 0.899 (3Η, t, J = 6.6 Hz), 1.4-1.48 (6H, m), 1.58-1.75 (2H, m), 1.79 (3H, d, J = l. 2 Hz), 2.26 (3H, d, J = 1.0 Hz), 2.2 (3H, s), 2.93 (2H, t, J = 7.6 Hz), 7.28 (2H, d, J = 7.6 Hz) , 7.86 (2H, d, J = 8.4 Hz), 9.61 (1H, bs).

Elemental analysis: as C ₂₁ H ₂₇ N ₃ 0 ₃ S ₃ Calculated value (%): C, 54.17; H, 5.84; N, 9.02; S, 20.66.

Found (%): C, 54.14; H, 5.69; N, 9.00; S, 20.66.

Example 4-21

 N- {8- (decylsulfanyl) -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene} -4- Methylbenzene sulfonamide

 In the same manner as in Example 4-14, using 1-bromodecane (0.183 ml, 0.865 miol) in place of isobutyl iodide, the N- (5,6-dimethyl- From 3-oxo-8-sulfanyl-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-triylidene) -4_methylbenzenesulfonamide (300 mg, 0.786 mmol) The title compound (78.4 mg, 19%) was synthesized. Recrystallization from ethyl acetate gave dark red crystals with a melting point of 121-123 ° C.

Infrared absorption spectrum (IR) (in KBr): 3229, 2924, 2853, 1748, 1717, 1661, 1611, 1557 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 0.888 (3Η, i, J = 6.6 Hz), 1.14-1.48 (1 H, m), 1.61-1.72 (2H, m), 1.79 (3H, s), 2.27 (3H , S), 2.42 (3H, s), 2.93 (2H, t, J = 7.2 Hz), 7.28 (2H, d, J = 8.0 Hz), 7.86 (2H, d, J = 8.6 Hz), 9.61 (1H , Bs).

Elemental analysis: as C ₂₅ H ₃₅ N ₃ 0 ₃ S ₃

Calculated)): C, 57.55; H, 6.76; N, 8.05; S, 18.4.

Found): C, 57.24; H, 6.76; N, 8.18; S, 18.20.

Example 4-22

 -{5,6-Dimethyl-8-{[2- (1-naphthyl) ethyl] sulfanyl} -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine -1 -ylidene) -4-methylbenzenesulfonamide

According to a method similar to that of Example 4-14, 2- (1-naphthyl) ethyl methanesulfonate (206 mg, 0.865 mmol) was used instead of isoptyl iodide, to obtain N obtained in Example 3-4. -(5,6-Dimethyl-3-oxo-8-sulfanyl-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene)-4- The title compound (254 mg, 61%) was synthesized from mid (300 mg, 0.786 bandol). Recrystallization from ethyl acetate gave dark red crystals with a melting point of 203-204.

Infrared absorption spectrum (IR) (in KBr) Re: 3220, 3052, 2928, 1721, 1663, 1601, 1557 cm " ¹ .

_{'H-NMR (CDC1 3)} : δ 1.74 (3Η, d, J = l.0 Hz), 2.25 (3H, d, J = l.0 Hz),

2.43 (3H, s), 3.24-3.37 (2H, m), 3.38-3.50 (2H, m), 7.20-7.60 (6H, m), 7.74-7.92 (4H, m), 7.96-8.04 (1H, m ), 9.62 (1H, bs).

Elementary analysis: as _{C 27 H 25 N 3 0 3} S 3

Calculated value (%): C, 58.57; H, 4.91; N, 7.59; S, 17.37.

Found): C, 58.21; H, 4.78; N, 7.59; S, 17.60.

Example 4-23

 N- {5,6-dimethyl-8-{[2_ (2-naphthyl) ethyl] sulfanyl} -3-oxo_2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine -Trilydene) -4-methyl The procedure of Example 4-14 was repeated, except that 2- (2-naphthyl) ethyl methanesulfonate (206 mg, 0.865 mmol) was used instead of isobutyl iodide. N- (5,6-Dimethyl-3-oxo-8-sulfanyl-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-1-ylidene obtained in 3-4 The title compound (253 mg, 60¾) was synthesized from) -4-methylbenzenesulfonamide (300 mg, 0.786 mmol). Recrystallization from ethyl acetate gave dark red crystals with a melting point of 189-191.

Infrared absorption spectrum (IR) (in KBr): 3220, 3052, 2921, 1723, 1667, 1601, 1553 cm " ¹ .

Ή-NMR (CDCI3): δ 1.77 (3Η, s), 2.22 (3H, s), 2.37 (3H, s),

3.08-3.22 (2H, m), 3.22-3.37 (2H, m), 7.13 (2H, d, J-7.8 Hz), 7.22-7.36 (2H, m), 7.42-7.52 (2H, m), 7.66 ( 1H, s), 7.73-7.88 (4H, m), 9.58 (1H, bs).

Elemental analysis: C ₂₇ H ₂₅ N ₃ 0 ₃ S ₃ '0.8H ₂ 0 Calculated value (%): C, 58.95; H, 4.87; N, 7.64; S, 17.49.

Found): C, 58.93; H, 4.83; N, 7.32; S, 17.18.

Example 4-24

 N-[5,6-Dimethyl-3-oxo-8- (pentylsulfanyl)-2,3-dihydrido-1H-imidazo [5, 1-c] [1,4] thiazine-triylidene] -4- Methylbenzenesulfonamide

 N- (5) obtained in Example 3-4 was obtained in the same manner as in Example 4-1'4, except that n-amyl bromide (0.0907 ml, 0.721 mmol) was used instead of isobutyl iodide. , 6-Dimethyl-3-oxo-8-sulfanyl-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazin-1-ylidene) -4-methylbenzenesulfonamide ( The title compound (232 mg, 78%) was synthesized from 250 mg (0.655 mmol). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 151-153 ° C.

Infrared absorption spectrum (IR) (in KBr) Re: 3250, 2957, 2926, 2863, 1748, 1717, 1661, 1611, 1557 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 0.910 (3Η, t, J = 7.0 Hz), 1.24-1.44 (4H, m), 1.64-1.76 (2H, ι), 1.79 (3H, d, J = 0.8 Hz) , 2.26 (3H, d, J = 1.0 Hz), 2.2 (3H, s), 2.93 (2H, t, J = 7.4 Hz), 7.28 (2H, d, J = 8.0 Hz), 7.85 ( 2H, d, J = 8.2 Hz), 9.60 (1H, bs).

Example 4-25

 N- [5,6-Dimethyl-3-oxo-8- (heptylsulfanyl) -2,3-dihydrido-1H-imidazo [5,1-C] [1,4] thiazine-1-ylidene] -4-methylbenzenesulfonamide

In the same manner as in Example 4-14, 1-bromoheptane (0.113 ml, 0.721 mmol) was used in place of isobutyl iodide, and the N- (5,6-dimethyl- 3-oxo-8-sulfanyl-2,3-dihydro-1H-imidazo [5, 1-c] [1,4] thiazine-1-ylidene) -4-methylbenzenesulfonamide (250 mg, The title compound (257 mg, 82¾) was synthesized from 0.655 t-ol). Recrystallization from ethyl acetate-getyl ether, dark red with melting point 156-158 Crystals were obtained.

Infrared absorption spectrum (IR) (in KBr): 3233, 2955, 2928, 2857, 1748, 1717, 1663, 1613, 1557 cm- ¹ .

_{Ή-NMR (CDC1 3):} δ 0.897 (3Η, t, J = 6.8 Hz), 1.22-1.49 (8H, m), 1.62-1.74 (2H, m), 1.79 (3H, s), 2.26 (3H, s), 2.42 (3H, s), 2.93 (2H, t, J = 7.4 Hz), 7.28 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.2 Hz), 9.60 (1H, bs).

Elementary analysis: as _{C 22 H 29 N 3 0 3} S 3

 Calculated value (%): C, 55.09; H, 6.09; N, 8.76; S, 20.05.

 Obtained value): C, 54.91; H, 6.22; N, 8.68; S, 20.04.

 Example -26

 N- [5,6-dimethyl-8- (2-indanylsulfanyl) -3-oxo-2,3-dihydrone-1H-imidazo [5,1-c] [1,4] thiazine- Trilidene] -4-methylbenzene sulfonamide

N- (5,6-Dimethyl-3-oxo-8-sulfanyl-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1- obtained in Example 3- Reference Example 4 was prepared by adding a suspension of (ylidene) -4-methylbenzenesulfonamide (250 mg, 0.655 mmol) and potassium carbonate (136 ig, 0.983 mmol) in N, N-dimethylformamide (4.00 ml). A solution of N, N-dimethylformamide (1.00 ml) of indan-2-yl methanesulfonate (153 mg, 0.721 mmol) obtained in the above was added. After heating the reaction mixture at 80 ° C. for 1 hour, 1N hydrochloric acid was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure to give the title compound (129 mg, 40¾) as a dark red crystals. Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 210-212 ° C.

Infrared absorption spectrum (IR) (in KBr) Re: 3229, 1732, 1665, 1609, 1547 • cm- ¹ .

_{Ή-NMR (CDC1 3):} δ 1.81 (3Η, d, J = l.0 Hz), 2.28 (3H, d, J = l.2 Hz), 2.39 (3H, s), 3.06 (2H, dd, J = 16.0, 6.0 Hz), 3.48 (2H, dd, J = 16.6, 7.8 Hz), 4.13-4.28 (1H, m), 7.16-7.32 (, 6H, m), 7.78 (2H, d, J = 8.6 Hz), 9.60 (1H, bs).

Example 4-27

 N- (8-{[3,5-bis (trifluoromethyl) benzyl] sulfanyl} _5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1, 4] Thiazine-1-In the same manner as in Example 4-14, except that isobutyl iodide was replaced with 3,5-bis (trifluoromethyl) benzyl methanesulfonate (253 mg, 0.786 bandol). N- (5,6-Dimethyl-3-oxo-8-sulfanyl-2,3-dihydrido-1H-imidazo obtained in Example 3-4 [5,1-c] [1,4] thiazine The title compound (291 mg, 73%) was synthesized from 4-tribenzene) -4-methylbenzenesulfonamide (250 mg, 0.655 bandol) and recrystallized from ethyl acetate-ethyl ether to obtain a melting point of 211-213. Of dark red crystals were obtained.

Infrared absorption spectrum (IR) (in KBr): 3260, 3206, 3061, 2930, 1732, 1665, 1624, 1564, 1497 cm- ¹ .

^-MR (CDC1 ₃ ): δ 1.76 (3Η, d, J = l.2 Hz), 2.24 (3H, d, J = l.2 Hz), 2.2 (3H, s), 4.26 (2H, s), 7.27 (2H, d, J = 8.4 Hz), 7.79 (2H, s), 7.81 (2H, d, J = 8.2 Hz), 7.82 (1H, s), 9.62 (1H, bs).

Elemental analysis: C ₂₄ H ₁₉ N ₃ 0 ₃ S ₃ F ₆

Calculated value (%): C, 47.4; H, 3.15; N, 6.92; S, 15.83.

Found (¾): C, 47.55; H, 2.96; N, 6.96; S, 16.07.

Example 4-28

 N- [8-({2- [3,5-Bis (trifluoromethyl) phenyl] ethyl] sulfanyl) -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [ 5, 1-c] [1,4] thiazine-triylidene] -4-methylbenzenesulfonamide

In the same manner as in Example 4-U, 2- [3,5-bis (trifluoromethyl) phenyl] ethyl methanesulfonate (242 mg, 0.721 mmol) was used instead of isobutyl iodide. N- (5,6-Dimethyl-3-oxo-8-sulfanyl-2,3-dihydro-1H-imidazo obtained in Example 3-4 [5,1-c] [1 , 4] thiazine-triylidene) -4-methylbenzenesulfonamide The title compound (169 mg, 42 mmol) was synthesized from (250 fflg, 0.655 mmol). Recrystallization from ethyl acetate-getyl ether gave a dark red crystal with a melting point of 198-200 ° C. .

Infrared absorption spectrum (IR) (in KBr): 3221, 1721, 1665, 1609, 1564 cm

_{Ή-NR (CDC1 3):} δ 1.78 (3Η, s), 2.26 (3H, s), 2. 2 (3H, s), 3.05-3.16 (2H, m), 3.16-3.27 (2H, m), 7.28 (2H, d, J = 8.0 Hz), 7.65 (2H, s), 7.79 (1H, s), 7.82 (2H, d, J = 8.4 Hz), 9.62 (1H, bs). Elemental analysis: C ₂₅ H ₂₁ N ₃ 0 _{3 As} S ₃ F ₆

Calculated value (%): C, 48.30; H, 3.40; N, 6.76; S, 15.47.

Found (¾): C, 48.10; H, 3.35; N, 6.63; S, 15.89.

Example -29

 [(5,6-Dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} _3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine- 8-yl) sulfanyl] acetic acid methyl ester

 In the same manner as in Example 4-14, using methyl bromoacetate (0.0858 ml, 0.577 mmol) in place of isobutyl iodide, the N- (5,6-dimethyl-3) obtained in Example 3-4 was used. -Oxo-8-sulfanyl-2,3-dihydro-1H-imidazo [5, 1-c] [1,4] thiazine-triylidene) -4-methylbenzenesulfonamide

(200 mg, 0.524 mmol) to give the title compound (155 mg, 65¾). Recrystallization from ethyl acetate-getyl ether yielded dark red crystals with a melting point of 192_194 ° C.

Infrared absorption spectrum (IR) (in KBr) L: 3177, 2957, 1757, 1740, 1663, 1632, 1570 cm ' ¹ .

_{Ή-NMR (CDC1 3):} δ 1.78 (3Η, d, J = l.0 Hz), 2.25 (3H, d, J = l.2 Hz), 2.42 (3H, s), 3.73 (2H, s) , 3.78 (3H, s), 7.30 (2H, d, J-8.0 Hz), 7.85 (2H, d, J = 8. Hz), 9.60 (1H, bs).

Elementary analysis: as _{C 18 H 19 N 3 0 5} S 3

Calculated value (%): C, 47.67; H, 4.22; N, 9.26; S, 21.21. Found): C, 47.31; H, 4.02; N, 8.91; S, 20.87.

Example 4-30

 [(5,6-Dimethyl-1-{[(4-methylphenyl) sulfonyl] imino 3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine- 8-yl) sulfanyl] acetic acid

[(5,6-Dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo obtained in Example 4-29 [5,1- c] To a solution of [1,4] thiazin-8-yl) sulfanyl] acetic acid methyl ester (155 mg, 0.342 mmol) in methanol (5.00 ml) and tetrahydrofuran (5.00 ml) was added a 1N aqueous sodium hydroxide solution (1.03 ml). ) Was added. After stirring the reaction mixture at room temperature for 30 minutes, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was water washed, dried (MgSO _4), and the solvent was evaporated under reduced pressure to give the title compound (136iag, 91%) as a dark red crystals. Recrystallization from methanol-getyl ether gave dark red crystals with a melting point of 198-200 ° C.

Infrared absorption spectrum (IR) (in KBr) Re: 3700-2750, 1732, 1661, 1620, 1559 cm " ¹ .

Ή-NMR (CDCl ₃ + D SO-d ₆ ): δ 1.78 (3Η, s), 2.24 (3H, s), 2.42 (3H, s), 3.74 (2H, s), 7.30 (2H, d, J = 8.0 Hz), 7.86 (2H, d, J = 8.4 Hz), 10.18 (1H, bs).

Elementary analysis: as _{C 17 H 17 N 3 0 5} S 3

Calculated (¾): C, 44.63; H, 4.19; N, 9.18; S, 21.02.

Found (¾): C, 44.73; H, 4.1.2; N, 9.14; S, 20.74.

Example 4-31

N- [5,6-Dimethyl-8-[(5,5,5-trifluoropentyl) sulfanyl] -3-oxo--2,3-dihydrido-1H-imidazo [5,1-c] [ 1,4] Thiazine trilide In the same manner as in Example 4-14, using methanesulfonic acid 5,5,5-trifluoropentyl ester (790 mg, 3.59 mmol) instead of isoptyl iodide. The N- (5,6-dimethyl-3-oxo-8-sulfone obtained in Example 3-4 Title compound from phenyl-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-trilidene) -4-methylbenzenesulfonamide (1.14 g, 2.99 mmol) Was synthesized (1.26 g, 84%). Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 177-179 ° C.

Infrared absorption spectrum (IR) (in KBr) Re: 3245, 3069, 2946, 2878, 1748, 1732, 1663, 1622, 1557, 1497 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 1.61-1.83 (4Η, m), 1.79 (3H, d, J = l.2 Hz), 2.02-2.20 (2H, m), 2.27 (3H, d, J = 0.6 Hz), 2.42 (3H, s), 2.95 (2H, t, J = 6.9 Hz), 7.29 (2H, dt, J = 8.7, 0.6 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.63 ( 1H, bs).

Elemental analysis: as C ₂₀ H ₂₂ N ₃ 0 ₃ S ₃ F ₃

Calculated value (%): C, 47.51; H, 4.39; N, 8.31; S, 19.03.

Actual values («: C, 47.3; H, 4.30; N, 8.41; S, 19.10.

Example 4-32

N- [5,6-dimethyl-8-[(2,2,3,3-tetrafluoropropyl) sulfanyl] -3_oxo-2,3-dihydro-1H-imidazo [5,1-c [1,4] Thiazine-trily In the same manner as in Example 4-14, 3-ode-1,1,2,2-tetrafluoropropane (76.1 mg) was used instead of isobutyl iodide. , 0.315 mmol) to obtain N_ (5,6-dimethyl-3-oxo-8-sulfanyl-2,3-dihydro-1H-imidazo [5,1-c] obtained in Example 3-4. The title compound (51.6 mg, 40%) was synthesized from 1,4] thiazine-triylidene) -4-methylbenzenesulfonamide (100 mg, 0.262 mmol). Recrystallization from ethyl acetate-diisopropyl ether gave dark red crystals having a melting point of 182-184 ° C.

Infrared absorption spectrum (IR) (in KBr) Re: 3221, 2990, 2930, 1748, 1667, 1626, 168 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 1.80 (3Η, d, J = 1.2 Hz), 2.25 (3H, d, J = l.2 Hz), 2.43 (3H, s), 3.49 (2H, t, J = 15.6 Hz), 5.84 (1H, tt, J = 53.4, 2.7 Hz), 7.31 (2H, d, J = 7.8 Hz), 7.85 (2H, d, J = 8. Hz), 9.63 (1H, bs). Elementary analysis: as _{C 18 H 17 N 3 0 3} S 3 F 4

Calculated value (%): C, 43.63; H, 3.46; N, 8.48; S, 19.41.

Found (%): C, 43.56; H, 3.39; N, 8.33; S, 19.22.

Example 4-33

N- [5,6-Dimethyl-8-[(4-fluorobutyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-triylidene] -4-methylbenzenesulfonamide

 According to a method similar to that of Example 4-14, 1-bromo-4-fluorobutane (149 mg, 0.944 mmol) was used in place of isoptyl iodide, and N- (5,5) obtained in Example 3-4 was used. 6-Dimethyl-3-oxo-8-sulfanyl-2,3-dihydric port-1H-imidazo [5, 1-c] [1, 4] thiazine-1-ylidene) -4-methylbenzenesulfonamide (300 mg) , 0.786 mmol) to give the title compound (211 mg, 59%). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with melting point 156-158.

Infrared absorption spectrum (IR) (in KBr): 3227, 3067, 2965, 2922, 1748, 1725, 1663, 1615, 1563 cm " ¹ .

_{lH - NMR (CDC1 3):} δ 1.70-1.90 (4Η,), 1. 9 (3Η, d, J = l.2 Hz), 2.26 (3H, d, J = 0.9 Hz), 2. 2 (3H , s)., 2.99 (2H, t, J = 7.2 Hz), 4.47 (2H, dt, J = 47.1, 5.7 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.84 (2H, d, J = 8.7 Hz), 9.62 (1H, bs).

Elemental analysis: as C ₁₉ H ₂₂ N ₃ 0 ₃ S ₃ F

Calculated value (: C, 50.09; H, 4.87; N, 9.22; S, 21.11.

Obtained value): C, 49.89; Η, 4.77; Ν, 9.21; S, 21.24.

Example 4-34

N- {5,6-dimethyl-3-oxo-8-[(4,4,5,5,5-pentafluoropentyl) sulfanyl] -2,3-dihydro-1H-imidazo [5,1 -c] [1,4] thiazine-trily N- (5,6-dimethyl-3-oxo-8-sulfanyl-2,3-dihydro-1H-imidazo obtained in Example 3- [5, 1-c] [1,4] thiazine-1-ylidene) -4-methyl Methanesulfonic acid obtained in Reference Example 5 was added to a suspension of benzenesulfonic acid amide (29.8 g, 78.1 mmol) and potassium carbonate (16.2 g, 0.117 mol) in N, N-dimethylformamide (400 ml). A solution of 4,4,5,5,5-pentafluoropentyl ester (24.0 g, 93.7 mmol) in N, N-dimethylformamide (100 ml) was added. After heating the reaction mixture at 80 ° C. for 2 hours, 1N hydrochloric acid was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (41.5 g, 98%) as a dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 190-192 ° C.

Infrared absorption spectrum (IR) (in KBr): 3208, 2934, 1753, 1663, 1624, 1566, 1497 cm " ¹ .

_{iH-NMR (CDC1 3):} δ 1.79 (3Η, d, J = l.0 Hz), 1.90-2.22 (4H, m), 2.27 (3H, d, J = l.2 Hz), 2.42 (3H, s), 3.01 (2H, t, J = 6.8 Hz), 7.29 (2H, d, J = 8.0 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.62 (1H, bs).

Elemental analysis: C _2. H _2. N ₃ 0 ₃ S ₃ F ₅

Calculated value (¾): C, 44.35; H, 3.72; N, 7.76; S, 17.76.

Found): C, 44.32; H, 3.69; N, 7.4; S, 17.67.

Example 4-35

N- {5,6-dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -2,3-dihydro-1H-imidazo [5, 1-c] [1,4] thiazine-trily N- (5,6-dimethyl-3-oxo-8-sulfanyl-2,3-dihydro-1H-imidazo obtained in Example 3-4 [ 5, 1-c] [1,4] thiazine-1-ylidene) -4-methylbenzenesulfonamide (2.00 g, 5.24 mmol) and potassium carbonate (1.09 g, 7.86 mmol) in N, N-dimethylformamide Of methanesulfonic acid 5,5,6,6,6-pentafluorohexyl ester (1.70 g, 6.29 mmol) obtained in Reference Example 9 in N, N-dimethyl suspension (30.0 ml). A solution of formamide (10.0 ml) was added. After heating the reaction mixture at 80 for 1 hour, 1N hydrochloric acid was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO ₄₎ after reduction the solvent Evaporation under pressure gave the title compound (2.38 g, 82 °) as dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 173-175 ° C.

Infrared absorption spectrum (IR) (in KBr): 3202, 3054, 2924, 2855, 1732, 1717, 1661, 1615, 1559, 1497 cm ' ¹ .

_{Ή-NMR (CDC1 3):} δ 1.64-1.84 (4Η, m), 1.79 (3H, d, J = 0.6 Hz), 1.90-2.20 (2H, m), 2.27 (3H, s), 2. 2 ( 3H, s), 2.97 (2H, t, J = 7.2 Hz), 7.29 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.6 Hz), 9.63 (1H, bs). Elemental analysis Value: as C ₂₁ H ₂₂ N ₃ 0 ₃ S ₃ F ₅

Calculated value (%): C, 45.40; H, 3.99; N, 7.56; S, 17.31.

Observed (): C, 45.30; Η, 3.87; Ν, 7.42; S, 17.29.

Example 4-36

Ethyl 6-[(5,6-dimethyl-1-{[(4-methylphenyl) sulfonyl] iminot 3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] Thiazine-8-yl) sulfanyl] hexanoate

 In the same manner as in Example 4-14, using ethyl 6-bromohexanoate (527 ml, 2.88 mmol) instead of isobutyl iodide, the N- (5,6- Dimethyl-3-oxo-8-sulfanyl-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene) -4-methylbenzenesulfonamide (1.00 g, 2.62 mmol) to give the title compound (1.19 g, 87¾). Recrystallization from ethyl acetate-jetil ether gave dark red crystals with a melting point of 122-124.

Infrared absorption spectrum (IR) (in KBr) Re: 3304, 3137, 2980, 2934, 1744, 1728, 1661, 1615, 1557, 1497 cm " ¹ .

Ή-NMR (CDCI3): δ 1.26 (3H, t, J = 7.0 Hz), 1.34-1.52 (2H, in), 1.52-1.76 (4H, m), 1.73 (3H, s), 2.27 (3H, s ), 2.31 (2H, t, J = 7.0 Hz), 2.42 (3H, s), 2.93 (2H, t, J = 7.2 Hz), 4.13 (2H, q, J = 7.0 Hz), 7.29 (2H, d , J = 8.4 Hz), 7.85 (2H, d, J = 8. Hz), 9.61 (1H, bs). Elemental analysis: As C ₂₃ H ₂₉ N ₃ 0 ₅ S ₃ Calculated values): C, 52.75; H, 5.58; N, 8.02; S, 18.37.

Found,%): C, 52.66; H, 5.32; N, 7.95; S, 18.28.

Example 4-37

 6 _ [(5,6-Dimethyl-1- (4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine- 8-yl) sulfanyl] hexanoic acid

Ethyl 6-[(5,6-Dimethyl-1-{[(4 methylphenyl) sulfonyl] imino obtained in Example 4-36 3-oxo-2,3-dihydrogen port-1H Midazo [5,1-c] [1,4] thiazine-8-yl) sulfanyl] hexanoate (1.00 g, 1.91 imol) was dissolved in a mixture of tetrahydrofuran (10.0 ml) and ethanol (10.0 ml), A 1N aqueous sodium hydroxide solution (5.73 ml) was added and the mixture was stirred for 2.5 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain the solvent was distilled off under reduced pressure the title compound (822 mg, 87¾). Recrystallization from methanol-getyl ether gave dark red crystals with a melting point of 153-155 ° C.

Infrared absorption spectrum (IR) (in Br): 3700-2760, 2934, 2861, 1728, 1661, 1615, 1557, 1495 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 1.38-1.82 (6Η, m), 1.79 (3H, d, J = 1.2 Hz), 2.26 (3H, d, J = l.2 Hz), 2.38 (2H, t, J = 7.2 Hz), 2.42 (3H, s), 2.95 (2H, t, J = 7.0 Hz), 7.31 (2H, d, J = 8.0 Hz), 7.86 (2H, d, J = 8.4 Hz), 9.65 (1H, bs).

Elemental analysis: as C ₂₁ H ₂₅ N ₃ 0 ₅ S ₃

(Calculated,%): C, 50.89; H, 5.08; N, 8.8; S, 19.41.

Found): C, 50.82; H, 5.14; N, 8.22; S, 19.32.

Example 4-38

 N- [8-[(5-chloropentyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1- Ylidene] -4-methylbenzenesulfonamide

In the same manner as in Example 4-14, 1-butyl was used in place of isobutyl iodide. N- (5,6-Dimethyl-3-oxo_8-sulfanyl-2,3-dihydro-1H obtained in Example 3-4 was obtained using lomo-5-chloromouth pentane (0.380 ml, 2.88 mmol). The title compound (1.18 g, 92¾) was synthesized from -imidazo [5,1-c] [1,4] thiazine-1-ylidene) -4-methylbenzenesulfonamide (1.00 g, 2.62 mmol). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 167-169 °.

Infrared absorption spectrum (IR) (in KBr): 3250, 3065, 2928, 2867, 1746, 1728, 1661, 1615, 1557, 1497 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 1.50-1.88 (6Η, m), 1.79 (3H, s), 2.26 (3H, s), 2. 2 (3H, s), 2.95 (2H, t, J = 7.4 Hz), 3.54 (2H, t, J = 6.6 Hz), 7.31 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.0 Hz), 9.62 (1H, bs).

Elemental analysis: C _2. H ₂₄ N ₃ 0 ₅ S ₃

Calculated value (%): C, 49.42; H, 4.98; N, 8.64; S, 19.79.

Found (%): C, 49.07; H, 4.95; N, 8.46; S, 19.68.

Example 4-39

 N- [5,6-dimethyl-8 _ [(2,2,3,3,3-pentafluorofluoropropyl) sulfanyl] —3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-yl In the same manner as in Example 4-14, 1-iodo-2,2,3,3,3-pentafluoropropane (instead of isobutyl iodide) Using 0.238 ml, 1.26 mmol) of-(5,6-dimethyl-3-oxo-8-sulfanyl-2,3-dihydro-1H-imidazo obtained in Example 3-4 [5,1- c] The title compound (56.5 mg, 11%) was synthesized from [1,4] thiazine-1-ylidene) -4-methylbutylsulfonamide (400 mg, 1.05 mmol). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 176-178 ° C.

Infrared absorption spectrum (IR) (in KBr) d: 3240, 2990, 2936, 1748, 1667, 1626, 1574, 1495 cm— ¹ .

Ή-NMR (CDCI3): δ 1.81 (3Η, d, J = 1.2 Hz), 2.25 (3H, d, J = 1.2 Hz), 2.43 (3H, s), 3.53 (2H, t, J) = 16.2 Hz), 7.30 (2H, d, J = 8.0 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.63 (1H, bs).

Example 4-40

 N- [5, 6-dimethyl-8-[(3-fluoro-3_methylbutyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5, 1-c] [1, 4] Thiazine-triylidene]-4-In the same manner as in Example 4-14, using methanesulfonic acid 3-fluoro-3-methylbutane ester (380 mg, 2.06 nimol) instead of isobutyl iodide. N- (5,6-Dimethyl-3-oxo-8-sulfanyl_2,3-dihydrogen-1H-imidazo obtained in 3-4 [5,1-c] [1,4] thiazine The title compound (111 mg, 23¾) was synthesized from (ylidene) -4-methylbenzenesulfonamide (393 mg, 1.03 mmol). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 173-175t :.

Infrared absorption spectrum (IR) (in KBr): 3241, 2976, 2934, 1752, 1717, 1659, 1613, 1561, 1497 cm- ¹ .

_{Ή-NMR (CDC1 3) δ} 1.39 (6Η, d, J = 21.2 Hz), 1.79 (3H, s), 1.87-2.08 (2H, m), 2.26 (3H, s), 2.42 (3H, s), 3.04 (2H, t, J = 8.2 Hz), 7.29 (2H, d, J = 8.0 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.62 (1H, bs).

Elemental analysis: C _2. H ₂₄ N ₃ 0 _{3 As} S ₃ F

Calculated value (%): C, 51.15; H, 5.15; N, 8.95; S, 20.48.

Found (%): C, 51.40; H, 5.02; N, 8.98; S, 20.34.

Example 4-41

N- [5,6-dimethyl-8-[(4,4,4-trifluorobutyl) sulfanyl] -3-year-old oxo-2,3-dihydro-1H-imidazo [5,1-c] [1 , 4] Thiazine-triylidene]-4-In the same manner as in Example 4-14, 4-bromo-1,1,1-trifluorotrifluorobutane (123 mg, 0.629 mmol) was used instead of isobutyl iodide. The N- (5,6-dimethyl-3-oxo-8-sulfanyl-2,3-dihydro-1H-imidazo [5, 1-c] [1, 4] Thiazine-triylidene) _4_Methylbenzenesulfonamide (200 _mg , 0.524 mmol) from the title compound (172 mg, 67¾) Was synthesized. Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 178-180 ° C.

Infrared absorption spectrum (IR) (in KBr) Re: 3225, 2932, 1755, 1725, 1663, 1624, 1566 cm " ¹ .

Awakening: _{R (CDC1 3): δ 1.79} (3H, d, J = l.2 Hz), 1.90-2.02 (2H, m), 2.11-2.26 (2H, m), 2.27 (3H, d, J = 0.9 Hz ), 2.42 (3H, s), 3.00 (2H, t, J = 7.5 Hz), 7.29 (2H, d, J = 7.8 Hz), 7.84 (2H, d, J = 8.1 Hz), 9.62 (1H, bs ).

Elemental analysis: C ₁₉ H _2. As _{N 3 0 3 S 3 F 3} .

Calculated)): C, 46.42; H, 4.10; N, 8.55; S, 19.57.

Found (): C, 46.56; H, 4.31; N, 8.70; S, 19.41.

Example 4-42

N- [1,6-Dioxo-4- (isopentylsulfanyl) -1, 2,6,1,8,9-hexahydro-3H-imidazo [5,1-c] [1, 4] Benzothiazine-3-ylidene] -4-methyl N- (1,6-dioxo-4-sulfanyl-1,2,6,7,8,9-hexahydro obtained in Example 3-38 -3H-imidazo [5, 1-c] [1, 4] benzothiazine-3-ylidene) -4-methylbenzenesulfonamide (2.00 g, 4.74 mmol) and carbon dioxide (984 mg, 7.12 mmol) N, To a suspension of N-dimethylformamide (40.0 ml) was added a solution of isoamyl iodide (0.691 ml, 5.22 mmol) in Ν, Ν-dimethylformamide (1.00 ml). After stirring the reaction mixture at room temperature for 19 hours, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was water washed, dried (MgSO _4), and the solvent was evaporated under reduced pressure to give the title compound (2.19 g, 94%) as a dark red crystals. Recrystallization from ethyl acetate-methanol-tetrahydrofuran yielded dark red crystals with a melting point of 234-236 ° C.

Infrared absorption spectrum (IR) (in KBr) Re: 3183, 2957, 2928, 1872, 1742, 1653, 1611, 1586, 1549, 1495 cm " ¹ .

_{Ή-NMR (CDC1 3):} (5 0.934 (6H, d, J = 6.2 Hz), 1.50-1.63 (2H, m), 1.63-1.78 (1H, m), 1.96-2.12 (2H, m), 2.43 (3H, s), 2.50 (2H, t, J = 7.0 Hz), 3.04 (2H, t, J = 7.6 Hz), 3.21 (2H, t, J = 6.2 Hz), 7.29 (2H, d, J = 8.8 Hz), 7.84 (2H, d, J = 8.4 Hz) , 9.85 (1H, bs).

Elementary analysis: as _{C 22 H 25 N 3 0 4} S 3

Calculated value (%): C, 53.74; H, 5.13; N, 8.55; S, 19: 57.

Found): C, 53.68; H, 5.08; N, 8.27; S, 19.31.

Example 4-43

N- [6-Hydroxy-4- (isopentyls phenyl) -toxo-1,2,6,7,8,9-hexahydro-3H-imidazo [5,1-c] [1,4] benzothiazine A suspension of lithium aluminum hydride (281 mg, 5.92 mmol) in tetrahydrofuran (10.0 ml) was added to the N_ [l, 6-dioxo obtained in Example 4-42. (Isopentylsulfanyl) -1,2,6,7,8,9-hexahydro-3H-imidazo [5, tric] [1,4] benzothiazine-3-ylidene] -4-methyl A solution of benzenesulfonamide (1.94 g, 3.95 marudium oU in tetrahydrofuran (90.0 ml) was added under ice cooling. The reaction mixture was stirred at room temperature for 5 minutes, and excess lithium aluminum hydride was decomposed with water and 1N hydrochloric acid was added. was extracted with acetic acid Echiru added. the extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. the residue was silica gel force ram chromatograph The title compound (1.18 g, 61¾) was obtained as dark red crystals by elution with n-hexane-ethyl acetate (10: 1, v / v). Recrystallization from tyl ether gave dark red crystals with a melting point of 162-164 ° C.

Infrared absorption spectrum (IR) (in KBr) Re: 3700-3000, 2955, 2870, 1732, 1655, 1615, 1557, 1495 cm- ¹ .

_{Ή-NR (CDC1 3):} δ 0.928 (6H, d, J = 6.2 Hz), 1.44-2.02 (7H, m), 2.42 (3H, s), 2.48-2.66 (1H, m), 2.90-3.12 ( 1H, m), 2.98 (2H, t, J = 8.0 Hz), 4.04-4.16 (1H, 1), 7.29 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8. Hz) , 9.66 (1H, bs).

Elementary analysis: as _{C 22 H 27 N 3 0 4} S 3 · 0.3H 2 0

Calculated value (%): C, 52.95; H, 5.57; N, 8.42. Found (¾): C, 52.95; H, 5.47; N, 8.19.

Example 4-44

 N- [4- (Isopentylsulfanyl) -toxo-1,2-dihydrido-3H-imidazo [5,1-c] [1,4] benzothiazine-3-ylidene] -4-methylbenzenesulfo Medium

N- [6-hydroxy-4- (isopentylsulfanyl) -toxo-1,2,6,7,8,9-hexahydro-3H-imidazo obtained in Example 4-43 [ 5, 1-c] [1,4] Benzothiazine-3-ylidene] -4-methylbenzenesulfonamide (980 rag, 1.99 iiol) and p-toluenesulfonic acid monohydrate (318 mg, 1.59 mmol) Acetic anhydride (0.562 ml, 5.96 mmol) was added to a toluene (20.0 ml) solution of. After stirring the reaction mixture at 100 ° C for 10 minutes, the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound ({8 mg, 15}) as orange crystals. Recrystallization from ethyl acetate-methanol-tetrahydrofuran gave orange crystals having a melting point of 207-209 ° C. Infrared absorption spectrum (IR) (in KBr): 3250, 1744, 1626, 1586, 1557, 1485 cm— ¹ .

_{Ή-NMR (CDC1 3):} δ 0.952 (6Η, d, J = 6.2 Hz), 1.54-1.80 (3H, 1), 2.42 (3H, s), 3.02 (2H, d, J = 7.6 Hz), 6.95 (1H, dd, J = 7.6, 1.4 Hz), 7.07

(1H, dt, J = 7.2, 1.0 Hz), 7.21 (1H, ddd, J = 8.4, 4.2, 1.8 Hz), 7.30

(2H, d, J = 8.0 Hz), 7.87 (2H, d, J = 8. Hz), 8.46 (1H, dd, J = 8., 1.0

Hz), 9.80 (1H, bs).

Elementary analysis: as _{C 22 H 23 N 3 0 3} S 3

Calculated value (%): C, 55.79; H, 4.89; N, 8.87; S, 20.31.

Found (¾): C, 55.89; H, 4.65; N, 8.85; S, 20.27.

Example 4-45

N- [4- (Isopentylsulfanyl) -1-oxo-1,2,7,8-tetrahydro-3H-imidazo [5,1-c] [1,4] benzothiazine-3-ylidene]- 4-methylben Zensulfonamide

N_ [6-hydroxy-4- (isopentylsulfanyl) -toxo-1,2,6,7,8,9-hexahydro-3H-imidazo obtained in Example 4-43 [5 C, [1,4] benzothiazine-3-ylidene] -4-methylbenzenesulfonamide (200 nig, 0.405 mmol) and p-toluenesulfonic acid monohydrate (64.9 mg, 0.324 mmol) in toluene ( Acetic anhydride (0.115 ml, 1.22 mmol) was added to the 4.00 ml) solution. After stirring the reaction mixture at room temperature for 15 minutes, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (108mg, 57¾) as orange crystals. Recrystallization from ethyl acetate-ethyl ether gave an orange crystal with a melting point of 154-156. Infrared absorption spectrum (IR) (in KBr): 3230, 2957, 2934, 2870, 1732, 1622, 1584, 1553 cm " ¹ .

_{Ή-NMR (CDC1 3):} (50.926 (6H, d, J = 6.2 Hz), 1.46-1.78 (3H, 1), 2.27-2.38 (4Η, m), 2.42 (3Η, s), 2.96 (2Η, t, J = 8.0 Hz), 6.12 (1H, t, J = 4.0 Hz), 6.94 (1H, t, J = 5.0 Hz), 7.29 (1H, d, J = 8.0 Hz), 7.87 (2H, d, J = 8.6 Hz), 9.68 (1H, bs).

Example 4-46

 N- [1,6-dioxo-4- (isobutylsulfanyl) -1,2,6,7,8,9-hexahydrid-3H-imidazo [5,1-c] [1 , 4] Benzothiazine-3-ylidene] -4-methylbenzenesulfonamide

In the same manner as in Example 4-42, using isobutyl sulphide (0.546 ml, 4.74 mmol) in place of isisoamyl iodide, the N- (1,6-dioxo-4) obtained in Example 3-38 was obtained. -Sulfanyl-1,2,6,7,8,9_Hexahydro-3H-imidazo [5, 1-c] [1,4] benzothiazine-3-ylidene) -4-methylbenzenesulfonamide ( The title compound (1.82 g, 80%) was synthesized from 2.00 g, 4.74 mmol). Recrystallization from ethyl acetate gave dark red crystals with a melting point of 223-225 ° C. Infrared absorption spectrum (IR) (in KBr) Re: 3218, 2961, 2928, 2872, 1759, 1653, 1624, 1595, 1549, 1495 cm " ¹ .

Ή-NMR (CDCI3): δ 1.04 (6Η, d, J = 7.0 Hz), 1.86-2.16 (3H, m), 2.42 (3H, s), 2.50 (2H, t, J = 5. Hz), 2.92 (2H, d, J = 6.6 Hz), 3.21 (2H, t, J = 6.2 Hz), 7.29 (2H, d, J = 8.0 Hz); 7.85 (2H, d, J = 8.0 Hz), 9.84 (1H, bs).

Elementary analysis: as _{C 21 H 23 N 3 0 4} S 3

Calculated value (%): C, 52.81; H, 4.85; N, 8.80; S, 20.14.

Found (): C, 52.54; H, 4.59; N, 8.73; S, 19.96.

Example 4-47

 N_ [6-Hydroxy-4- (isobutylsulfanyl) -toxo-1,2,6,7,8,9-hexahydro-3H-imidazo [5,1-c] [1,4] benzothiazine -3-ylide N- [l, 6-dioxo-4- (isobutylsulfanyl) -l, 2,6, obtained in Example 4-46 in the same manner as in Example 4-43. 7,8,9_Hexahydro-3H-imidazo [5,1-c] [1,4] benzothiazine-3-yVden] -4-methylbenzenesulfonamide (1.82 g, 3.81 mmol) from the title compound (690 mg, 38%) was synthesized. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 143-145 ° C.

Infrared absorption spectrum (IR) (in Br) Re: 3600-3000, 2959, 2872, 1742, 1653, 1617, 1557 cm—

-丽_{R (CDC1 3): δ 1.03} (6Η, d, J = 7.0 Hz), 1.65-2.08 (5H, m), 2.42 (3H, s), 2.46-2.66 (1H, m), 2.86 (2H, d, J = 6.6 Hz), 2.80-3.08 (1H, m), 4.04-4.1.5 (1H, m), 7.28 (2H, d, J = 8.4 Hz), 7.86 (2H, d, J = 8.4)

Hz), 9.65 (1H, bs).

Elementary analysis: as _{C 21 H 25 N 3 0 4} S 3 · 0.2H 2 0

Calculated (): C, 52.20; H, 5.30;, 8.70; S, 19.91.

Observed): C, 52.25; H, 5.14; N, 8.65; S, 19.58.

Example 4-48

N- [4- (Isobutylsulfanyl) -toxo_1,2-dihydro-3H-imidazo [5,1-c] [1,4] benzothiazine-3-ylidene] -4-methylbenzenesulfonamide In the same manner as in Example 4-44, the N_ [6-hydroxy-4- (isobutylsulfanyl) -toxo-1,2,6,7 obtained in Example 4-47 was obtained. , 8,9-Hexahydro-3H-imidazo [5,1-c] [1,4] benzothiazine-3-ylidene] -4-methylbenzenesulfonamide (150 mg, 0.313 mmol) from the title compound (43.1 mg, 30%). Recrystallization from ethyl acetate-getyl ether gave orange crystals with a melting point of 233-235 ° C.

Infrared absorption spectrum (IR) (in KBr) Re: 3237, 2961, 1744, 1628, 1586; 1555, 1485 cm " ¹ .

 Ή-NMR (CDC "): δ 1.05 (6Η, d, J = 6.6 Hz), 1.88-2.08 (1H, m), 2.42 (3H, s), 2.89 (2H, d, J = 7.0 Hz), 6.95 (1H, d, J = 8.2 Hz), 7.06 (1H, t, J = 6.2 Hz), 7.21 (1H, t, J-7.0 Hz), 7.29 (2H, d, 8.4 Hz), 7.88 (2H, d , J = 8.4 Hz), 8.6 (1H, d, J = 6.8 Hz), 9.79 (1H, bs).

Example 4-49

 N- [l, 6-Dioxo-4- (pentylsulfanyl) -1,2,6,7,8,9-hexahydride-3H-imidazo [5,1-c] [1,4] benzothiazine-3 -Ylidene]-4_methylbenzenesulfonamide

 Obtained in Example 3-38 by a method similar to that in Example 4-42, except that iodopentane (0.911 ml, 6.99 mmol) was used instead of isoamyl iodide.

N- (l, 6-Dioxo-4-sulfanyl-1,2,6,7,8,9-hexahydro-3H-imidazo [5,1-c] [1,4] benzothiazine-3-ylidene ) The title compound (2.72 g, 87%) was synthesized from -4-methylbenzenesulfonamide (2.68 g, 6.36 mmol). Recrystallization from ethasol-jetilether gave dark red crystals with a melting point of 218-220.

Infrared absorption spectrum (IR) (in KBr) Re:. 3187, 2955, 2928, 2870, 2857, 1738, 1651, 1609 cm -1 Ή-NMR (CDC1 3): δ 0.908 (3Η, t, J = 6.6 Hz), 1.24-1.46 (4H, m), 1.60-1.78 (2H, m), 1.96-2.12 (2H, m), 2.42 (3H, s), 2.51 (2H, t, 7.2 Hz), 3.03 (2H , t, J-7.6 Hz), 3.21 (2H, t, J = 6.0 Hz), 7.30 (2H, d, J = 8.0 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.86 (1H, bs Example 4-50 N_ [6-hydroxy-1-oxo-4- (pentylsulfanyl) -1,2,6,7,8,9-hexahydro-3H-imidazo [5,1-c] [1,4] benzothiazine-3 -Ylidene]-4-In the same manner as in Example 4-43, N- [l, 6-dioxo-4- (pentylsulfanyl) -1,2,2 obtained in Example 4-49. 6, 7, 8, 9-Hexahydro-3H-imidazo [5,1-c] [1, 4] benzothiazine-3-ylidene] -4-methylbenzenesulfonamide (1.82 g, 3.81 mmol) The title compound (690 mg, 38%) was synthesized. Recrystallization from ethyl acetate-getyl ether gave dark red crystals, mp 143-145 ^.

Infrared absorption spectrum (IR) (in KBr) Re: 3600-3000, 2959, 2872, 1742, 1653, 1617, 1557 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 1.03 (6Η, d, J = 7.0 Hz), 1.65-2.08 (5H, m), 2.42 (3H, s), 2.46-2.66 (1H, m), 2.86 (2H, d, J = 6.6 Hz), 2.80-3.08 (1H, m), 4.04-4.15 (1H, m), 7.28 (2H, d, J = 8.4 Hz), 7.86 (2H, d, J = 8.4 Hz), 9.65 (1H, bs).

Elementary analysis: as _{C 21 H 25 N 3 0 4} S 3 '0.2H 2 0

Calculated (¾): C, 52.20; H, 5.30;, 8.70; S, 19.91.

Obtained): C, 52.25; H, 5.14; N, 8.65; S, 19.58.

Example 4-51

N- [Toxo-4- (pentylsulfanyl) -1,2-dihydro-3H-imidazo [5,1-c] [1,4] benzothiazine-3-ylidene] -4-methylbenzenesulfonamide

 N_ [6-hydroxy-1-oxo-4- (pentylsulfanyl) -1, 2, 6, 7, 8, 9- obtained in Example 4-50 by the same method as in Example 4-44. Hexahydrid-3H-imidazo [5,1-c] [1,4] benzothiazine-3-ylidene] -4-methylbenzenebenzenesulfonamide (200 mg, 0.405 bandol) to give the title compound (53.8 mg, 28% ) Was synthesized. Recrystallization from ethyl acetate gave orange crystals with a melting point of 176-178 ° C.

Infrared absorption spectrum (IR) (in KBr) So: 3225, 2957, 2930, 2859, 1744, 1626, 1586, 1557 cm " ¹ .

 Ή-NR (CDClg): δ 0.923 (3H, t, J = 6.6 Hz), 1.32-1.48 (4H, m), 1.64-1.82 (2H, m), 2.42 (3H, s), 3.01 (2H, d , J = 7.6 Hz), 6.95 (1H, d, J = 7.4 Hz), 7.07 (1H, t, J = 7.4 Hz), 7.14-7.26 (1H, i), 7.30 (2H, d, J = 8.0 Hz) ), 7.88 (2H, d, J = 8.2 Hz), 8.46 (1H, d, J = 8.0 Hz), 9.78 (1H, bs).

Elemental analysis: 'Calculated _{C 22 H 23 N 3 0 3} S 3 · 0.5C 4 H 8 0 2): C, 55.68; H, 5.26; N, 8.12; S, 18.58.

Found (%): C, 55.55; H, 5.23; N, 7.88; S, 18.62.

Example 4-52

 N- [4- (cyclohexylheptylsulfanyl) -1,6-dioxo-1,2,6,7,8,9-hexahydro-3H-imidazo [5,1-c] [1,4] [Benzothiazine-3-ylidene] -4-me obtained in the same manner as in Example 4-42 except that cycloheptyl iodide (0.877 ml, 3.64 mmol) was used instead of isoamyl iodide. The N- (1,6-dioxo-4-sulfanyl-1,2,6,7,8,9-hexahydro-3H-imidazo [5,1-c] [1,4] benzothiazine-3- The title compound (1.12 g, 71%) was synthesized from (ylidene) -4-methylbenzene sulfonamide (1.28 g, 3.04 mmol). Recrystallization from ethyl acetate-methanol-tetrahydrofuran gave dark red crystals of melting point 229-23C.

Infrared absorption spectrum (IR) (in KBr) d: 3191, 2930, 2853, 1746, 1645, 1609, 1541 cm— ¹ .

_{Ή-NMR (CDC1 3):} δ 1.42-1.90 (10H, m), 1.96-2.16 (4H, m), 2.43 (3H, s), 2.51 (2H, t, J = 7.4 Hz), 3.21 (2H, t, J = 6.2 Hz), 3.60-3.80 (1H, m), 7.30 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J-8.4 Hz), 9.86 (1H, bs). Elemental analysis value: as _{C 22 H 25 N 3 0 4} S 3

Calculated)): C, 53.74; H, 5.13; N, 8.55; S, 19.57.

Found (%): C, 53.68; H, 5.08; N, 8.27; S, 19.31.

Example 4-53 N- [4- (cyclohexylsulfanyl) -6-hydroxy-1-oxo-1,2,2,6,7,8,9-hexahydro-3H-imidazo [5,1-c] [ 1,4] Benzothiazine-3-ylidene] -4-methylbenzenesulfonamide

 In the same manner as in Example 4-43, N- [4- (cyclohexylsulfanyl) -1,6-dioxo-1,2,6,7,8, 9-Hexahydro-3H-imidazo [5,1-c] [1,4] benzothiazine-3-ylidene] -4-methylbenzenesulfonamide (1.56 g, 3.01 mmol) from the title compound (657 mg, 42¾) Was synthesized. Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 156-158 ° C.

Infrared absorption spectrum (IR) (in KBr): 3700-3000, 2932, 2855, 1740, 1657, 1615, 1557 cm " ¹ .

- thigh _{R (CDC1 3): δ 1.} 4-2.16 (16H, m), 2.42 (3H, s), 2.46-2.66 (1Η, m), 2.90-3.10 (1H, m), 3.52-3.70 (1H , m), 4.04-4.18 (1H, m), 7.28 (2H, d, J = 8.0 Hz), 7.86 (2H, d, J = 8.4 Hz), 9.66 (1H, bs).

Elementary analysis: as _{C 24 H 2g N 3 0 4} S 3

Calculated values): C, 55.47; H, 5.62; N, 8.09; S, 18.51.

Found (%): C, 55.33; H, 5.66; N, 7.82; S, 18.28.

Example 4-54

 N- [4- (Cyctoheptylsulfanyl) -toxo-1,2-dihydro-3H-imidazo [5,1-c] [1,4] benzothiazine-3-ylidene] -4-methylbenzene Sulfonamide

 In the same manner as in Example 4-44, N- [4- (cyclohexylsulfanyl) _6-hydroxy-1-oxo-1,2,6,7,8, obtained in Example 4-53. 9-Hexahydrid-3H-imidazo [5,1-c] [1,4] benzothiazine-3-ylidene] -4-methylbenzenesulfonamide (456 mg, 0.879 mmol) from the title compound (51.8 mg , 12%). The crystals were recrystallized from ethyl acetate-ethyl ether to give orange crystals having a melting point of 218-.

Infrared absorption spectrum (IR) (in KBr): 3239, 2928, 2855, 1746, 1626, 1588, 1557, 1483 cm " ¹ . Ή-NMR (CDCI3): δ 1.40-2.20 (12H, m), 2.42 (3Η, s), 3.48-3.68 (1Η, m), 6.95 (1H, dd, J = 8.0, 1.4 Hz), 7.06 (1H , dt, J = 7.4, 1.Hz), 7.20 (1H, dt, 8.0, 1.4 Hz), 7.30 (2H, d, 8.0 Hz), 7.88 (2H, d, J = 8.0 Hz), 8.5 ( 1H, dd, J = 8., 1.0 Hz), 9.79 (1H, bs).

Example 4-55

N- {1,6-dioxo-4-[(4,4,5,5,5-pentafluorofluorpentyl) sulfanyl]-1,2,6,7,8,9-hexahydro-3H-imidazo [ 5, tric] [1,4] benzothia In the same manner as in Example 4-42, methanesulfonic acid 4,4,5,5,5_pentafluoropentyl ester (201 mg) was used instead of isoamyl iodide. , 0.783 mmol) using the N- (1,6-dioxo-4-sulfanyl-1,2,6,7,8,9-hexahydro-3H-imidazo obtained in Example 3-38 [ The title compound (65.4 mg, 16%) was synthesized from 5,1-c] [1,4] benzothiazine-3-ylidene) -4-methylbenzenesulfonamide (300 mg, 0.712 mmol). Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 205-207 ° C. Infrared absorption spectrum (IR) (in KBr): 3200, 3061, 2959, 1744, 1653, 1613, 1553 cm- ¹ .

 Ή-NMR (CDCI3): δ 1.95-2.24 (6Η, m), 2.43 (3H, s), 2.51 (2H, t, J = 7.2 Hz), 3.10 (2H, t, J = 6.9 Hz), 3.21 ( 2H, t, J = 6.3 Hz), 7.30 (2H, d, J = 8.4 Hz), 7.83 (2H, d, J = 8.4 Hz), 9.87 (1H, bs).

Elemental analysis: C ₂₂ H _2. N ₃ 0 ₄ S ₃ F ₅

Calculated values): C, 45.3; H, 3.47; N, 7.22; S, 16.54.

Found (¾): C, 45.24; H, 3.22; N, 7.32; S, 16.45.

Example -56

N- {1,6-Dioxo-4-[(3,3-dimethylbutyl) sulfanyl]-1,2,6,7,8,9-hexahydro -3H-imidazo [5, 1-c] [1, 4] benzothiazin-3-ylidene} -4-methylbenzenesulfonamide

In the same manner as in Example 4-42, methanesulfonic acid 3,3-dimethylbutyl ester (70.6 mg, 0.391 ramol) was used in place of isoamyl iodide. And N- (1,6-dioxo-4-sulfanyl-1,2,6,7,8,9-hexahydro-3H-imidazo obtained in Example 3-38 [5,1-c] [ The title compound (8.8 mg, 4.9%) was synthesized from 1,4] benzothiazine-3-ylidene) -4-methylbenzenesulfonamide (150 mg, 0.356 mniol). Recrystallization from ethyl acetate-jetil ether gave dark red crystals with a melting point of 223-225 ° C.

Infrared absorption spectrum (IR) (in KBr): 3187, 3073, 2957, 2868, 1742, 1651, 1609, 1584, 1547 cm- ¹ .

_{lH-NMR (CDC1 3):} δ 0.949 (9H, s), 1.50-1.64 (2H, m), 1.96-2.12 (2H, m), 2. 3 (3H, s), 2.51 (2H, t, J = 6.2 Hz), 3.00 (2H, t, J = 9.2 Hz), 3.21 (2H, t, J = 6.2 Hz), 7.30 (2H, d, J = 8.0 Hz), 7.84 (2H, d, J = 8.4) Hz), 9.88 (1H, bs).

Example 4-57

 N- {1-oxo-4-[(4,4,5,5,5-pentafluoropentyl) sulfanyl] -1,2-dihydro-3H-imidazo [5,1-c] [1, 4;] Benzothiazine-3-ylide In the same manner as in Example 4-42, methanesulfonic acid 4,4,5,5,5-pentafluoropentyl ester (76.2 mg, 0.297 mmol) was used instead of isoamyl iodide. ) To give N- (toxo-4-sulfanyl-1,2-dihydro-3H-'midazo [5,1-c] [1,4] benzothiazine- obtained in Example 3-37- The title compound (100 mg, 72 mg) was synthesized from 3-ylidene) -4-methylbenzenesulfonamide (100 mg, 0.248 mmol). Recrystallization from ethyl acetate-getyl ether yielded dark red crystals with a melting point of 210-212 ^ :.

Infrared absorption spectrum (IR) (in KBr) Re: 3170, 3071, 1742, 1630, 1590, 1559, 1485 cm— ¹ .

 Ή-NMR (CDCI3): δ 2.09-2.34 (4Η, m), 2.43 (3Η, s), 3.09 (2H, t, J = 6.6 Hz), 6.95 (1H, dd, J = 7.6, 1.4 Hz), 7.09 (1H, dt, J = 7.2, 0.8 Hz), 7.15-7.38 (3H, m), 7.86 (2H, d, J = 8.4 Hz), 8.45 (1H, dd, J = 7.8, 0.8 Hz), 9.81 (1H, bs).

Elementary analysis: as _{C 22 H 18 N 3 0 3} S 3 F 5 Calculated value (%): C, 46.88; H, 3.22; N, 7.46; S, 17.07.

Found): C, 46.92; H, 3.39; N, 7.33; S, 17.20.

Example 4-58

 NU-oxo-4-[(4,4,4-trifluoro-3-trifluoromethylbutyl) sulfanyl] -1,2-dihydro-3H-imidazo [5, 1-c] [1,4] benzothiazine Example 4 In the same manner as in Example 4-42, 4,4,4-trifluoro-3-trifluoromethylbutyl methanesulfonate (81.5 mg, 0.297 muiol) was used instead of isoamyl iodide. N-U-oxo-4-sulfanyl_1,2-dihydropene-3H-imidazo [5,1-c] [1,4] benzothiazin-3-ylidene) -4-methyl obtained in 3-37 The title compound (76.1 mg, 53%) was synthesized from benzenesulfonamide (100 mg, 0.248 mmol). Acetic acid:!; Recrystallization from chill-ethyl ether gave dark red crystals with a melting point of 207-209 ° C.

Infrared absorption spectrum (IR) (in KBr): 3247, 1750, 1732, 1647, 1590, 1559, 1487 cm " ¹ .

_{• H-NMR (CDC1 3)} : <5 2.17-2.35 (2H, m), 2.43 (3H, s), 2.95-3.22 (1H, m), 3.16 (2H, t, J = 7.6 Hz), 6.95 ( 1H, dd, J = 7.8, 1.6 Hz), 7.10 (1H, dt, J = 7.4, 1.4 Hz), 7.16-7.38 (3H, m), 7.86 (2H, d, J = 8.0 Hz), 8.45 (1H , dd, J = 8.8, 1.4 Hz), 9.78 (1H, bs).

Elementary analysis: as _{C 22 H 17 N 3 0 3} S 3 F 6

Calculated value (%): C, 45.43; H, 2.95; N, 7.23; S, 16.54.

Found (¾): C, 45.80; H, 3.22; N, 7.26; S, 16.73.

Example 4-59

 N- {4-[(3,3-Dimethylbutyl) sulfanyl] -toxo-1,2-dihydrido-3H-imidazo [5,1-c] [1,4] benzothiazine-3-ylidene}- 4-methylbenzenesulfonamide

In the same manner as in Example 4-42, methanesulfonic acid 3,3-dimethylbutyl ester (536 mg, 2.97 mmol) was used in place of isosamil iodide to obtain the N-( Toloxo-4-sulfanyl-1,2-dihydric mouth The title compound (27.21 ^, 2.2%) was synthesized from _3H-imidazo [5,1-c] [1,4] benzothiazine-3-ylidene) -4-methylbenzenesulfonamide (1.00 g, 2.4811111101). Recrystallization from ethyl acetate-n-hexane gave dark red crystals with a melting point of 205-207.

Infrared absorption spectrum (IR) (in KBr): 3250, 2957, 2905; 1740, 1626, 1586, 1557, 1485 cm- ¹ .

_{Ή-NMR (CDC1 3):} . Δ 0.965 (9H, s), 1.52-1.66 (2Η, m), 2.43 (3Η, s), 2.93-3.04 (2Η, m), 6.96 (1Η, dd J = 7.8 , 1.8 Hz), 7.07 (1H, dt, J = 8.8, 1.4 Hz), 7.22 (1H, dt, J = 8.4, 1.8 Hz), 7.30 (2H, d, J = 8.0 Hz), 7.87 (2H, d , J = 8.0 Hz), 8.46 (1H, dt, J = 8.4, 1.0 Hz), 9.81 (1H, bs). Elemental analysis: As C ₂₃ H ₂₅ N ₃ 0 ₃ S ₃

Calculated value (%): C, 56.65; H, 5.17; N, 8.62; S, 19.73.

Obtained): C, 56.59; H, 5.23; N, 8.26; S, 19.47.

Example 4-60

N- [1,6-Dioxo-4- (isopentylsulfanyl)-1,2,7,8-tetrahydro-3H, 6H-cyclopentene [b] Imidazo [1,5-d] [1,4 ] Thiazine-3-ylide N- (l, 6-dioxo_4_sulfanyl- 1,2,7,8-tetrahydro-3H obtained in Example 3-39 by a method similar to that in Example 4-42. [B] Imidazo [1,5-d] [1,4] thiazine-3-ylidene) -4-methylbenzenesulfonamide (540 mg, 1.38 mraol) from the title compound (527 mg, 80% ) Was synthesized. Recrystallization from ethyl acetate gave dark red crystals of melting point 229-23C. Infrared absorption spectrum (IR) (in KBr) Re: 3175, 2955, 2932, 2874, 1773, 1748, 1696, 1622, 1603, 1530 cm " ¹ .

Ή-NMR (CDCI3): δ 0.928 (6Η, d, J = 6.2 Hz), 1.50-1.64 (2H, m), 1.64-1.77 (1H, m), 2.43 (3H, s), 2.52-2.62 (2H , m), 3.00 (2H, t, J = 7.6 Hz), 3.20-3.28 (2H, m), 7.31 (2H, d, J = 7.6 Hz), 7.85 (2H, d, J = 8. Hz), 9.91 (1H, bs).

Example 4-61 (a)-[6-Hydroxy_4- (bisopentylsulfanyl) -toxo-1,2,7,8-tetrahydro-3H, 6H-cyclopentyl [b] imidazo [l, 5-d] [1 , 4] Thiazine-3-ylidene] -4-methylbenzenesulfonamide

(b) N- [l, 6-dioxo-1,2,6,7,8,8a-hexahydro-4- (isopentylsulfanyl) -3H, 5aH-cyclopentyl [b] imidazo [1,5-d ] A suspension of [1,4] thiazine-3- lithium aluminum hydride (264 mg, 5.56 mmol) in tetrahydrofuran (10.0 ml) was added to the suspension of N- [1,6] obtained in Example 4-60. -Dioxo-4-(isopentylsulfanyl) -1,2,7,8-tetrahydro-3H, 6H-cyclopenta [b] imidazo [1,5-d] [1,4] thiazine-3-ylidene ] _4-Methylbenzenesulfonamide (1.57 g, 3.29 mmol) in tetrahydrofuran (90.0 ml) was added under ice cooling. After stirring the reaction mixture at room temperature for 5 minutes, excess lithium aluminum hydride was decomposed with water, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (a) (24.0 mg, 1.5¾) as dark red crystals. The title compound (b) (429 mg, 27%) was obtained as yellow crystals.

 The title compound (a) was recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 156-158 ° C.

Infrared absorption spectrum (IR) (in KBr) Re: 3700-2800, 3449, 2957, 2932, 2870, 1744, 1671, 1611, 1549, 1497 cm—

_{Ή-NMR (CDC1 3):} δ 0.927 (6Η, d, J = 6.6 Hz), 1.50-1.77 (3H, m), 1.77-1.95 (1H, m), 2.42 (3H, s), 2.38-2.56 ( 1H, m), 2.80-3.02 (1H, m), 2.97 (2H, t, J = 7.2 Hz), 3.07-3.26 (1H, m), 4.62-4.76 (1H, m), 7.29 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J-8.4 Hz), 9.70 (1H, bs). Elemental analysis: C ₂₁ H ₂₃ N ₃ 0 ₄ S ₃ '0.4H ₂ 0

Calculated value (%): C, 51.81; Η, 5.34; Ν, 8.63; S, 19.76.

Found): C, 51.72;;, 5.19; Ν, 8.63; S, 19.68.

Title compound (b): Recrystallized from ethyl acetate-getyl ether and melted Yellow crystals at points 172-174 ° C were obtained.

Infrared absorption spectrum (IR) (in KBr) V: 3266, 2959, 2928, 2870, 1746, 1626, 1568 cm " ¹ .

'Eta -丽_{R (CDC1 3): (5} 0.906 (6H, d, J = 6.2 Hz), 1. 8-1.75 (3H, m), 2.05-2.30 (1H, m), 2.42 (3H, s) , 2.30-2.62 (2H, m), 2.62-2.80 (1H, m), 3.00 (2H, t, J = 7.2 Hz), 3.70 (1H, d, J = 5.4 Hz), 4.90 (1H, dt, J = 9.6, 5.8 Hz), 7.31 (2H, d, J = 8.2 Hz), 7.88 (2H, d, J = 8.4 Hz), 9.67 (1H, bs).

Elementary analysis: as _{C 21 H 23 N 3 0 4} S 3

Calculated value (%): C, 52.59; H, 5.25; N, 8.76; S, 20.06.

Obtained): C, 52.63; H, 5.38; N, 8.63; S, 20.03.

Example 4-62

R ² is an isopentyl group ,, R ⁵ and R ⁶ are both methylation group in formula ^{(IX), R 1 (^} f- ZR 15 (2 is 0 _2, R ¹⁵ is p- black port phenyl group), n is Synthesis of compound 1

 The compound synthesized in Example 3-6 (301 mg, 0.749 mmol) and potassium carbonate (155 mg, 1.12 mmol) were mixed with DMF (5 ml), and the mixture was stirred at 60 ° C for 5 minutes. Isopentyl iodide (0.109 ml, 0.824 mmol) was added to the reaction solution, and the mixture was stirred for about 3 hours. 1N Hydrochloric acid (1.5 ml) and 50% aqueous methanol (10 ml) were added to the reaction solution, mixed, and stirred at room temperature for 30 minutes. The resulting precipitate was collected by filtration, washed with aqueous methanol, and dried to give a purple-brown powder of the title compound (318 mg, 0.674 mmol).

 Marauder R (200 MHz, in double-mouthed holm): δ 0.93 (6Η, d, J- 6.2 Hz), 1.56 (2H, q, J = 7.0 Hz), 1.67 (1H, sept, J = 6.6 Hz), 1.80 (3H, brs), 2.28 (3H, brs), 2.95 (2H, t, 7.6 Hz), 7.6 (2H, d, J = 8.4 Hz), 7.91 (2H, d, J = 8 Hz) , 9.65 (1H, brs).

Elemental analysis: Calculated as _{C 19 H 22 N 3 0 3} S 3 C1: C, 48.34; H, 4.70; N, 8.90; S, 20.38; Cl, 7.51 (%), Found; C, 48.38; H , 4.56; N, 8.82; S, 20.35; C1 ,, 7.44 (). Melting point: 177.5-178.0 ° C

The following is a list of compounds synthesized in Examples 4_1 to 4-62 and compounds synthesized in the same manner.

(Table 18)

Replacement form (Rule 26) (Table 19) '

Replacement paper (M 26) [Table 20] '

Replacement paper () (Table 21)

Replacement ^ ¾ 26) (Table 22)

For replacement 弒 (m) (Table 23)

Acet for replacement (Rule 26) (Table 24) '

Acetate for replacement (fine ΰ2δ) (Table 25) '

Azeze for Acet (Rule 26) (Table 26)

ぇ ぇ ϋ Kin (β ²⁶ ^ (Table 27)

Replacement form (Rule 26) (Table 28)

Replacement form (Rule 26) (Table 29) '

For replacement (Rule 26) (Table 30)

(Replacement paper) (Table 31)

For replacement (Rule 2 (Table 3 2)

Shuffle paper wm) (Table 33)

差 (Table 34)

Replacement paper (»J26) (Table 35) '

Hairpin paper (Rule 26) (Table 36)

差替え用弒（規則 26) 〔表 3 7〕'

For replacement (Rule 26) (Table 37) '

Replacement form (Rule 26) (Table 38)

Lid replacement paper (ffi-rule 26) (Table 39) '

差替え用觝 〔表 40〕'

Replacement (Table 40) '

Replacement # & (Table 41)

(Rule) (Table 4 2)

Replacement killing (¾ i) 26 (Table 43) '

Replacement i¾II "J26) (Table 4 4) '

Replacement british (S126) (Table 45) '

For replacement 弒 (Thin U26) (Table 46)

Replacement paper (S¾26) (Table 47)

(Replacement paper m) (Table 48)

Acet for replacement (|| (| 26 :) (Table 49) '

辇 Goze ぇ paper (a rule 2β) [Table 50] '

Mm26) (Table 51)

For replacement 弒 (M J26) (Table 52)

Acet for replacement (S-law) (Table 53)

弒 m for replacement (Table 54) '

For replacement (rule) (Table 55)

For replacement 弒 (¾IJ26) (Table 56)

For Goze (MM2Q) (Table 5 7) '

Replacement paper (Rule 26) (Table 58)

(Replacement bri mu) (Table 59) '

Difference paper (! Rule 26) (Table 60) '

鍫替example corner鉞(Rule ² 6 (Table 6 1) '

For hairpins (i | iJ2s; (Table 62)

Replacement paper (Table 6-3)

Replacement 弒 (MM26) (Table 6 4) '

蘧 for 弒 (Rule 2 (Table 65)

For replacement 鬼 (Kiyoshi 26: (Table 66)

以下に実施例 4-63〜4-580で合成した化合物のデータを示す。

The data of the compounds synthesized in Examples 4-63 to 4-580 are shown below.

Example 4-63

_{Ή-NMR (CDC1 3, 200} MHz): δ 1.75 (3Η, d, J = 1.0 Hz), 2.15 (2H, quint, J = 7.0 Hz), 2.25 (3H, d, J- 1.2 Hz), 2.38 ( 3H, s), 3.08 (2H, t, J = 7.0 Hz), 3.13 (2H, t, J = 7.0 Hz), 7.25 (2H, d, J = 8.4 Hz), 7.49 (2H, tm, J = 7.8) Hz), 7.59 (1H, tm, J-7 Hz), 7.84 (2H, d, J = 8.4 Hz), 7.97 (2H, dm, J = 8 Hz), 9.64 (1H, brs).

Elemental _{analysis: C 25 H 25 N 3 0} 4 S 3 Calculated: C, 56.90; H, 4.78 ; N, 7.96; S, 18.23 (%), Found: C, 56.68; H, 4.90 ; N, 7.95; S, 18.02 (%).

Example 4-64

_{lE-MR (CDC1 3, 200} MHz): δ 1.43 (4Η, m), 1.5-1.75 (4H, m), 1.79 (3H, q, J = 1.2 Hz), 2.26 (3H, q, J = 1.2 Hz ), 2.42 (3H, s), 2.94 (2H, i, J = 7.0 Hz), 3.66 (2H, t, J = 6.3 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.85 (2H, d , J = 8.0 Hz), 9.64 (1H, brs).

Elemental analysis: Calculated as _{C 2 H 27 N 3 0 4} S 3:! C, 52.37; H, 5.65; N, 8.72; S, 19.97 (%), Found: C, 52.18; H, 5.62 ; N , 8.83; S, 20.05 (%).

Example 4-65

_{'H-NMR (CDC1 3,} 200 MHz): δ 1.77 (3H, q, J = 1.2 Hz), 2.25 (3H, q, J = 1.2 Hz), 2.41 (3H, s), 4.19 (2H, s) , 7.24 (2H, d, J = 8.0 Hz), 7.32 (5H, s), 7.81 (2H, d, J = 8.0 Hz), 9.63 (1H, brs).

Elemental _{analysis: C 22 H 21 N 3 0} 3 S 3 Calculated: C, 56.03; H, 4.49 ; N, 8.91; S, 20.40

(%), Found: C, 55.90; H, 4.50; N, 8.82; S, 20.19 (%).

Example 4-66

_{'H-NMR (CDC1 3,} 200 MHz): δ 1.75 (3Η, q, J = 1.0 Hz), 2.00 (2H, quint, J = 7.4 Hz), 2.25 (3H, q, J = 0.6 Hz), 2.39 (3H, s), 2.71 (2H, t, J = 7.4 Hz), 2.92 (2H, t, J = 7.3 Hz), 7.16 (2H, d, J = 8 Hz), 7.27 (5H, m), 7.85 (2H, d, J = 8.2 Hz), 9.64 (1H, brs).

Elemental _{analysis: C 24 H 25 N 3 0} 3 S 3 Calculated: C, 57.69; H, 5.04 ; N, 8.41; S, 19.25 (%), Found: C, 57.63; H, 5.31 ; N, 8.11; S, 19.09 (%). Example 4-67

_{Ή-NR (CDC1 3, 200} MHz): δ 1.79 (3Η, brs), 2.25 (3Η, brs), 2.43 (3H, s), 2.73 (1H, d, J = 3.6Hz), 3.19 (1H, dd , J-13.6, 8.4 Hz), 3.32 (1H, dd, J = 13.9, 4.0 Hz), 4.90 (1H, ddd, J = 8.8, 4.0, 3.6 Hz), 7.29 (2H, d, J = 8.4 Hz) , 7.36 (5H, s), 7.84 (2H, d, J = 8.4 Hz), 9.67 (1H, brs).

Elemental _{analysis: C 23 H 23 N 3 0} 4 S 3 * H 2 0 Calculated: C, 53.16; H, 4.85 ; M, 8.09; S, 18.51

(%), Found: C, 53.02; H, 4.79; N, 8.18; S, 18.53 (%).

Example 4-68

 N- {8-[(Cyclohexylmethyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-1-ylidene }-4-Methylbenzenesulfonamide

 The compound synthesized in Example 3-4 (3.28 g, 8.60 mmol) and potassium carbonate (1.78 g, 12.9 mmol) were mixed with DMF (50 ml), and cyclohexylmethyl iodide (2.30 g, 9.46 mmol) was added. And stirred at 60 ° C. for 80 minutes. IN hydrochloric acid (17.2 ml) was added to the reaction solution, mixed, and stirred at room temperature for 30 minutes. The resulting precipitate was suspended in 50% aqueous methanol (20 ml), collected by filtration, washed with aqueous methanol and methanol, and dried to give a red-purple powder of the title compound (4.24 g, 8.60 mmol).

Ή-NMR (CDC1 ₃₎ 200 MHz): 6 0.97 (2H, brt, J = 11.5 Hz), 1.22 (3H, m), 1.60 (1H, m), 1.70 (3H, brs), 1.79 (3H, brq , J- 0.8 Hz), 1.87 (2H, m), 2.26 (3H, q, J = 0.8 Hz), 2.41 (3H, s), 2.81 (2H, t, J = 7.0 Hz), 7.27 (2H, d , J = 8.0 Hz), 7.86 (2H, d, J = 8.4 Hz), 9.61 (1H, brs).

Elemental _{analysis: C 22 H 27 N 3 0} 3 S 3 Calculated: C, 55.32; H, 5.70 ; N, 8.80; S, 20.14

(%), Found: C, 55.21; H, 5.71;, 8.71; S, 20.10 (%).

Melting point: 188.0-190.0 ° C

Example 4-69

_{'H-NMR (CDC1 3,} 200 MHz): d 0.30 (2H, brq, J = 5.6 Hz), 0.66 (2H, brq, J = 6.6 Hz), 1.04 (1H, m), 1.77 (3H, s) , 2.26 (3H, s), 2.42 (3H, s), 2.90 (2H, d, J = 7.4 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.87 (2H, d, J = 8.0 Hz) , 9.64 (1H, brs) elemental _{analysis: C 19 H 21 N 3 0} 3 S 3 calculated:. C, 52.39; H, 4.86; N, 9.65; S, 22.08 (%), Found: C, 52.72; H, 4.86;, 9.56; S, 21.91 (%).

_{Ή-NMR (CDC1 3, 200} MHz): δ 1.60 (4H, m), 1.78 (3H, q, J = 1.2 Hz), 1.84 (2H, m), 2.12 (1H, quint, J = 7.3 Hz), 2.26 (3H, q, J = 1.2 Hz), 2.41 (3H, s), 2.94 (2H, t, J = 7.0 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.86 (2H, d, J = 8.4 Hz), 9.61 (1H, brs).

Elemental analysis: Calculated as C 2 ₁₅ N ₃ 0 ₃ S ₃ : C, 54.40; H, 5.43; N, 9.06; S, 20.75

(%), Found: C, 54.23; H, 5.48; N, 8.95; S, 20.56 (%).

Example 4-71

- thigh _{(CDC1 3, 200 MHz):} δ 1.79 (3H, brs), 2.26 (3H, brs), 2.43 (3H, s), 2.93 (2H, brdd, J = 8.0, 7.0 Hz), 3.15 (2H, dd, J = 8.0, 6.6 Hz), 6.98 (2H, t, J = 8.8 Hz), 7.15 (2H, dd, J- 8.0, 5.4 Hz), 7.27 (2H, d, J = 8.0 Hz), 7.82 ( 2H, d, J = 8.0 Hz), 9.63 (1H, brs).

Elemental analysis: Calculated as C ₂₃ H ₂₂ N ₃ 0 ₃ S ₃ F: C, 54.85; H, 4.40;, 8.34; S, 19.10; F, 3.77 (%), found: C, 54.72; H, 4.30; N, 8.49; S, 18.92; F, 3.94 (%).

_{Ή-NMR (CDC1 3, 200} MHz): δ 1.67-1.94 (4H, i), 1.78 (3H, q, J = 0.8 Hz), 2.15 (2H, m), 2.26 (3H, q, J = 0.8 Hz ), 2.41 (3H, s), 2.56 (1H, quint, J = 7.7 Hz), 3.02 (2H, d, J = 7.8 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.85 (2H, d , J = 8.4 Hz), 9.62 (1H, brs).

Elemental _{analysis: C 2D H 23 N 3 0} 3 S 3 Calculated: C, 53.43; H, 5.16 ; N, 9.35; S, 21.40

(%), Found: C, 53.25; H, 5.31;, 9.31; S, 21.32 (%).

Example 4-73

_{Ή-NMR (CDC1 3, 200} MHz): 6 0.94 (3H, t, J = 7.2 Hz), 1.43 (2H, sixtet, J = 7.2 Hz), 1.59 (2H, sixtet, J = 7.0 Hz), 1.79 ( 3H, q, J = 1.2 Hz), 2.26 (3H, q, J = 1.2 Hz), 2.42 (3H, s), 2.94 (2H, d, J = 7.3 Hz), 7.28 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.64 (1H, brs).

Elemental analysis: C ₁₉ H ₂₃ N ₃ 0 ₃ S ₃ Calculated: C, 52.15; H, 5.30; N, 9.60; S, 21.98 (%), found: C, 52.22; H, 5.14; N, 9.58; S, 21.82 (%) Example 4-74

 Ή-NMR (200 MHz, in double-hole form): δ 1.36 (3Η, t, J- 7.6 Hz), 1.78 (3H, brs), 2.27 (3H, brs), 2.42 (3H, s), 2.98 ( 2H, q, J = 7.5 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.63 (1H, brs).

Example 4-75

¾-NMR (CDCI3 + TFA, 200 MHz): δ 1.76 (3H, brs), 2.26 (3H, brs), 2.41 (3H, s), 4.51 (2H, s), 7.29 (2H, d, J = 8.0 Hz), 7.53 (2H, brt, J = 7.6 Hz), 7.67 (1H, brt, J = 7.6 Hz), 7.88 (2H, d, J = 8.4 Hz), 7.96 (2H, dm, J = 7.8 Hz) . elemental analysis: calculated _{C 23 H 21 N 3 0 4} S 3: C, 55.29; H, 4.24; N, 8.41; S, 19.25 (%), Found: C, 55.37; H, 4.21 ;, 8.26; S, 19.07 (%).

Example 4-76

 'H-NMR (CDC ", 200 MHz): δ 1.75 (3Η, brq. J = 1.0 Hz), 2.24 (3H, brq. J- 1.0 Hz), 2.39 (3H, s), 2.72 (1H, brd, J = 6.0 Hz), 3.23 (2H, dd, J = 9.2, 7.0 Hz), 3.80 (3H, s), 4.02 (2H, d, J = 4.8 Hz), 4..17 (1H, m), 6.47 (1H, brs), 6.49 (1H, dm, J = 7.6 Hz), 6.55 (1H, dd, J = 9, 2 Hz), 7.20 (1H, t, J = 8.0 Hz), 7.25 (2H, d, J = 8.0 Hz), 7.83 (2H, d, J = 8.0 Hz), 9.64 (1H, brs).

Elemental _{analysis: C 25 H 27 N 3 0} 6 S 3 Calculated: C, 53.46; H, 4.85 ; N, 7.48; S, 17.13

(%), Found: C, 53.41; H, 4.91; N, 7.28; S, 17.02 (%).

Example 4-77

¾- thigh _{(CDC1 3, 200 MHz):} δ 1.79 (3Η, brs), 2.27 (3H, brs), 2.42 (3H, s), 2.42 (2H, brq, J = 7.1 Hz), 3.00 (2H, t , J- 7.5 Hz), 5.07 (1H, brs), 5.14 (1H, brd, J = 8.0 Hz), 5.79 (1H, ddt, J = 17.0, 10.4, 6.6 Hz), 7.28 (2H, d, J- 8.4 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.63 (1H, brs).

Elemental _{analysis: C 19 H 2i N 3 0} 3 S 3 Calculated: C, 52.39; H, 4.86 ; N, 9.65; S, 22.08 (%) Found: C, 52.58; H, 4.83 ; N, 9.75 ; S, 22.11 (%).

Example 4-78

_{Ή-NMR (CDC1 3, 200} MHz): δ 1.80 (3Η, brs), 2.26 (3H, brs), 2.43 (3H, s), 2.75 (2H, t, J- 7.3 Hz), 3.20 (2H, t , J = 7.3 Hz), 7.31 (2H, d, J = 8.4 Hz), 7.84 (2H, d, J = 8.0 Hz), 9.64 (1H, brs). Elemental analysis: Calculated as _{C 18 H 18 N 4 0 3} S 3: C, 49.75; H, 4.18; N, 12.89; S, 22.14 (%), Found: C, 49.73; H, 4.00 ; N, 13.06; S, 22.14 (%).

Example 4-79

_{'H-NMR (CDC1 3,} 200 MHz): δ 1.78 (3Η, s), 2.25 (3H, s), 2.41 (3H, s), 3.59 (2H, brs), 4.99 (1H, brs), 5.04 ( 1H, brs), 7.28 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.0 Hz), 9.65 (1H, brs).

Elemental analysis: Calculated _{C ig H 21 N 3 0 3} S 3: C, 52.39; H, 4.86;, 9.65; S, 22.08

(%), Found: C, 52.24; H, 4.88;, 9.71; S, 22.19 (%).

Example 4-80

_{Ή-NM (CDC1 3, 200} MHz): δ 1.77 (3H, brq, J = 1.0 Hz), 2.25 (3H, brq, J = 1.2 Hz), 2.39 (3H, s), 4.05 (2H, s), 5.43 (1H, brs), 5.57 (1H, brs), 7.19 (2H, d, J = 8.0 Hz), 7.36 (5H, m), 7.76 (2H, d, J = 8.4 Hz), 9.60 (1H, brs .) elemental _{analysis: C 24 H 23 N 3 0} 3 S 3 calculated: C, 57.92; H, 4.66 ; N, 8.44; S, 19.33

(%), Found: C, 57.58; H, 4.61; N, 8.42; S, 19.37 (%).

Example 4-81

_{^ -NMR (200MHz, CDC1 3)} : δ 0.98 (4Η,, brd, J = 13.2 Hz), 1.73 (3H, q, J = 0.8 Hz), 2.22 (3H, q, J = 0.8 Hz), 2.43 ( 3H, s), 3.26 (2H, s), 7.26 (7H, m), 7.82 (2H, d, J = 8.4 Hz), 9.56 (1H, brs).

Elemental analysis: Calculated for C ₂₅ H ₂₅ N ₃ 0 ₃ S ₃ : C, 58.68; H, 4.92; N, 8.21; S, 18.80

(), Found: C, 58.74; H, 5.01; N, 7.97; S, 18.54 (%).

141.5-142.5 ° C

Example 4-82

 N- (5,6-dimethyl-3-oxo-8-{[3- (4-pyridinyl) propyl] sulfanyl} -2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine -Trilidene) -4-methylbenzenesulfonamide

(Method 1) Compound obtained in Example 3-4 (300 mg, 0.786 marl ol), 3- (4-pyridyl) -1-propanol (132 mg, 0.944 sol ol), CSA (228 rag, 0.983ιηπιο1) DEAD (0.182 ml, 1.10 mL) was added dropwise to a suspension of THF and 6.0 ml of triphenylphosphine (298 mg, 1.10 mmol) with stirring at room temperature, and the reaction solution was allowed to stand at room temperature for 7.5 hours. 60 at ° C Stirred for hours. During this time, triphenylphosphine (213 mg, 0.786 mmol) and DEAD (0.130 ml, 0.786 mmol) were added to the reaction solution. The mixture was diluted with ethyl acetate (30 ml), washed with a 2% aqueous sodium carbonate solution, a 2% aqueous sodium hydrogen carbonate solution and saturated saline, dried and concentrated. The residue was crystallized from methanol to give the title compound (a25 mg, 0.250 mmol) as a purple powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.76 (3Η, brq, J = 0.8 Hz), 2.02 (2H, quint, J = 7.3 Hz), 2.26 (3H, brq, J = 0.8 Hz), 2.40 (3H , s), 2.73 (2H, t, J = 7.5 Hz), 2.92 (2H, t, J = 7.1 Hz), 7.10 (2H, d, J = 5.8 Hz), 7.28 (2H, d, J = 8.6 Hz) ), 7.85 (2H, d, J = 8.6 Hz), 8.52 (2H, dt, J = 6.2, 1.8 Hz).

Elemental analysis: C ₂₃ H ₂₄ N ₄ 0 ₃ S ₃ Calculated: C, 55.18; H, 4.83; N, 11.19; S, 19.21 (), found: C, 55.15; H, 4.89; N, 11.12 ; S, 19.09 (%).

 (Method) To a solution of 3- (4-pyridyl) -topropanol (3.47 g, 24.8 tmol) in chloroform (60 ml) at room temperature while stirring -TsCl (4.87 g, 24.8 mmol) was divided into several portions. The reaction was stirred at room temperature for 4 hours. Triethylamine (1.03 ml, 7.43 ol) was added to the reaction solution, and the reaction solution was stirred at room temperature for 1 hour. The reaction was concentrated and diluted with ethyl acetate, THF and acetonitrile. After removing the precipitate, the mother liquor was diluted by adding ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried and concentrated. The residue was chromatographed on silica gel (50 g) (ethyl acetate-hexane, 1: 1, 3: 1 and 4: 1). The fractions of ethyl acetate-hexane ('3: 1 and 4: 1) were concentrated to dryness to give 3- (4-viridyl) -1-propyl P-tosylate (purity 8 3.53 g, 10.2 mmol) as pale yellow. Obtained as a powder.

_{'HN R (300MHz, CDC1 3} ): δ 1.99 (2H, m), 2.47 (3H, s), 2.67 (2H, t, J = 7.7 Hz), 4.03 (2H, t, J = 7.1 Hz), 7.01 (2H, d, J = 6.2 Hz), 7.36 (2H, d, J = 8.0 Hz), 7.79 (2H, d, J = 8.4 Hz), 8.46 (2H, dt, J = 6.2, 1.8 Hz).

While stirring a suspension of the compound obtained in Example 3-4 (260 mg, 0.682 mmol) and potassium carbonate (141 mg, 1.02 mmol) in DMF (4.0 ml), the above p-tosylate 3- (4- Pyridyl) -propyl (purity 84%, 308 mg, 0.886 mmol) was added, and the reaction mixture was stirred at 40 ° C for 12 hours and further at 80 at 2.5 hours. Ethyl acetate-THF (2: 1, 0 ml) was added to the reaction mixture, and the mixture was washed with an aqueous sodium hydrogen carbonate solution and saturated saline. Acetic acid Extracted with chill (50 ml). The organic layers were combined, dried and concentrated, and the residue was diluted with methanol. The precipitate was collected by filtration, washed with methanol, and dried to give the title compound (216 mg, 0.431 mol) as a dark purple powder.

Elemental _{analysis: C 23 H 24 N 4 0} 3 S 3 Calculated: C, 55.18; H, 4.83 ; N, 11.19; S, 19.21 ») · Found: C, 55.10; H, 4.71 ; N, 11.01; S, 19.13 (%).

Melting point.185.0- 186.0 ° C

Example 4-83

_{¾-NMR (200MHz, CDC1 3} ): δ 1.76 (3Η, q, J = 1.2 Hz), 2.01 (2H, quint, J = 7.5 Hz), 2.26 (3H, q, J = 1.0 Hz), 2.40 (3H , s), 2.73 (2H, t, J = 7.5 Hz), 2.93 (2H, t, J = 7.3 Hz), 7.23 (1H, m), 7.28 (2H, d, J = 8.4 Hz), 7.49 (1H , brd, J = 8.4 Hz), 7.85 (2H, d, J = 8.4 Hz), 8.47 (2H, m).

Elemental _{analysis: C 23 H 24 N 4 0} 3 S 3 Calculated: C, 55.18; H, 4.83 ; N, 11.19; S, 19.21

(%), Found: C, 55.16; H, 4.85; N, 11.06; S, 18.99 (%).

Melting point.191.5-193.0 ° C

Example 4-84

 N- {5,6-dimethyl-8-[(4-methylpentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-1-ylidene }-4-methylbenzenesulfonamide.

 The compound synthesized in Example 3-4 (2.50 g, 6.56 amino acid) and potassium carbonate (1.36 g, 9.84 mmol) were mixed with DMF (40 ml), and the mixture was stirred at 80 ° C for 5 minutes. Isohexyl iodide (1.53 ml, 7.21 mmol) was added to the reaction solution, and the mixture was stirred for 50 minutes. 1N Hydrochloric acid (13.1 ml) was added to the reaction solution, mixed, and stirred at room temperature for 30 minutes. The resulting precipitate was suspended in 50% aqueous methanol (20 ml), collected by filtration, washed with methanol water and methanol, and dried to obtain a red-purple powder of the title compound (2.94 g, 6.31 tmol). Was.

_{Ή-NMR (200MHz, CDC1 3} ): δ 0.89 (6Η, d, J = 6.6 Hz), 1.27 (2H, dt, J = 9.2, 6.2 Hz), 1.56 (1H, quint, J = 6.6 Hz), 1.67 (2H, m), 1.79 (3H, q, J = 0.6 Hz), 2.26 (3H, q, J = 1.0 Hz), 2.41 (3H, s), 2.91 (2H, t, J = 7.5 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.86 (2H, d, J = 8.4 Hz), 9.62 (1H, brs).

Elemental analysis: Calculated for C ₂₁ H ₂₇ N ₃ 0 ₃ S ₃ : C, 54.17; H, 5.84; N, 9.02; S, 20.66 (%), Found: C, 54.25; H, 5.71; N, 8.90; S, 20.43 (). Melting point. 166.0-168.5:

Example 4-85

'H-NMR (200MHz, CDC1 3): δ 1.27 (2H, m), 1.4-1.7 (10H, m), 1.79 (3H, brs), 1.8 (3H, m), 2.27 (3H, brs), 2.42 (3H, s), 2.73 (2H, d, J = 6.2 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.86 (2H, d, J = 8.2 Hz), 9.63 (1H, brs).

Elemental _{analysis: C 23 H 29 N 3 0} 3 S 3 Calculated: C, 56.18; H, 5.94 ; N, 8.55; S, 19.56

(%), Found: C, 55.96; H, 5.83; N, 8.51; S, 19.54 (%).

Melting point.179.5-180.0

Example 4-86

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.74 (3Η, brs), 2.24 (3H, brs), 2.43 (3H, s), 4.13 (2H, s), 7.28 (2H, d, J = 8.4 Hz) , 7.28 (2H, d, J = 6.4 Hz), 7.83 (2H, d, J = 8.4 Hz), 8.58 (2H, d, J = 6.4 Hz).

Elemental analysis: C ₂₁ H _2. Calculated for N ₄ 0 ₃ S ₃ : C, 53.37; H, 4.27; N, 11.85; S, 20.35 (%), found: C, 53.16; H, 4.22; N, 11.81; S, 20.29 (%) .

Melting point.189.4- 189.7 ° C

Example 4-87

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.80 (3Η, q, J = 1.2 Hz), 2.26 (3H, q, J = 1.2 Hz), 2.43 (3H, s), 3.07 (1H, brdd, J = 7.2, 2.Hz), 3.11 (1H, brd, J- 7.2 Hz), 3.19 (1H, dd, J = 6.2, 1.4 Hz), 3.22 (1H, dd, J = 6.2, 2.6 Hz), 7.28 ( 2H, d, J = 8.2 Hz), 7.36 (2H, d, J = 8.8 Hz), 7.81 (2H, d, J = 8.3 Hz), 8.16 (2H, d, J = 8.4 Hz), 9.65 (1H, brs).

Elemental _{analysis: C 23 2 N 4 0 5} S 3 Calculated: C, 52.06; H, 4.18 ; N, 10.56; S, 18.13 (%), Found: C, 51.88; H, 4.24 ; N, 10.53 ; S, 17.87 (%).

Melting point. 192.0-192.4. C

Example 4-88

_{Ή-NMR (200MHz, CDC1 3} ): δ 0.88 (6Η, d, J = 6.6 Hz), 1.20 (2H, brquint, J = 6.8 Hz), 1.39 (2H, m), 1.50 (1H, sept, J = 7.2 Hz), 1.60 (2H, quint, J = 10.6 Hz), 1.79 (3H, q, J = 1.2 Hz), 2.26 (3H, q, J = 0.8 Hz), 2.41 (3H, s), 2.93 (2H , t, J = 7.4 Hz), 7.28 ( 2H, d, J- 8.4 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.63 (1H, brs) Elemental _{analysis:. C 22 H 29 N 3} 0 3 S Calculated as ₃ : C, 55.09; H, 6.09; N, 8.76; S, 20.05

(%), Found: C, 55.00; H, 6.10; N, 8.76; S, 20.11 (%).

Melting point.150.5-150.7 ° C

Example 4-89

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.79 (3H, brs), 2.26 (3H, brs), 2.42 (3H, s), 3.02 (2H, dd, J- 7.9, 7.1 Hz), 3.20 (2H, dd, J = 8.0, 7.0 Hz), 3.92 (3H, s), 7.27 (4H, brs), 7.81 (2H, d, J- 8.0 Hz), 7.98 (2H, d, J = 7.9 Hz), 9.62 ( 1H, brs). Elemental analysis: C ₂₅ H ₂₅ N ₃ 0 ₅ S ₃ Calculated: C, 55.23; H, 4.63; N, 7.73; S, 17.69 (%), found: C, 55.08; H , 4.79; N, 7.69; S, 17.47 (%).

Melting point.191.0-191.5 ° C

Example 4-90

_{Ή-NR (200MHz, CDC1 3} ): δ 1.78 (3Η, brs), 2.26 (3H, brs), 2.42 (3H, s), 2.94 (2H, dd, J = 7.8, 7.1 Hz), 3.16 (2H, dd, J- 7.9, 7.4 Hz), 7.12. (2H, d, J = 8.3 Hz), 7.26 (2H, d, J 8.3 Hz), 7.26 (2H, d, J = 8.2 Hz), 7.81 (2H , d, J = 8.2 Hz), 9.63 (1H, brs).

Elemental analysis: Calculated as _{C 23 H 22 N 3 0 3} S 3 C1: C, 53.12; H, 4.26;, 8.08; S, 18.50; CI, 6.82 (%), Found: C, 52.83; H, 4.55; N, 8.21; S, 18.29; CI, 6.82 (%). Melting point. 189.0-190.5 ° C

Example 4-91

Ή-NMR (200 MHz, CDCl ₃ -DMSO-d ₆ 4: 1): δ 1.80 (3H, s), 2.25 (3H, s), 2.43 (3H, s), 3.03 (2H, dd, J = 7.8, 7.2 Hz), 3.22 (2H, dd, J = 7.7, 7.2 Hz), 7.27 (2H, d, J = 7.8 Hz), 7.28 (2H, d, J = 7.7 Hz), 7.82 (2H, d, J = 8.1 Hz), 7.96 (2H, d, J = 7.9 Hz), 10.84 (1H, br).

Elemental _{analysis: C 24 H 23 N 3 0} 5 S 3 Calculated: C, 54.42; H, 4.38 ; N, 7.93; S, 18.16 (%), Found: C, 54.65; H, 4.42 ; N, 7.71; S, 18.03 ().

Melting point.236.0-236.5 ° C

Example 4-92

_{Ή-NMR (200MHz, CDC1 3} ): <3 1.78 (3H, brq, J = 0.8 Hz), 2.26 (3H, brq, J = 1.2 Hz), 2.34 (3H, s), 2.43 (3H, s), 2.93 (2H, dd, J- 8.2, 6.8 Hz), 3.15 (2H, dd, J = 8.8, 6.2 Hz), 7.09 (2H, d , J = 8.8 Hz), 7.11 (2H, d, J = 8.8 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.83 (2H, d, J = 8.4 Hz), 9.64 (1H, brs).

Elemental _{analysis: C 24 H 25 N 3 0} 3 S 3 Calculated: C, 57.69; H, 5.04 ; N, 8.41; S, 19.25 (%), Found: C, 57.54; H, 4.93 ; N, 8.32; S, 19.09 (%).

Melting point.179.0-180.0 ° C

Example 4-93

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.79 (3Η, brq, J = 0.8 Hz), 2.26 (3H, brq, J- 1.2 Hz), 2.42 (3H, s), 3.03 (2H, dd, J = 7.2, 6.6 Hz), 3.19 (2H, dd, J = 7.0, 6.6 Hz), 7.27 (2H, d, J = 8.0 Hz), 7.31 (2H, d, J = 8.8 Hz), 7.56 (2H, d, J = 8.6 Hz), 7.82 (2H, d, J = 8.4 Hz), 9.65 (1H, brs).

Elemental analysis: Calculated for C ₂₄ H ₂₂ N ₃ 0 ₃ S ₃ F ₃ : C, 52.07; H, 4.01;, 7.59; S, 17.38; F, 10.29 (%), found: C, 51.79; H , 4.05; N, 7.39; S, 17.35; F, 10.56 (%). Melting point. 193.0-194.0 ° C

Example 4-94

 N- {8-[(cyclooctylmethyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1 -Yylidene}-4-methylbenzenesulfonamide

 DMF (1.05 g, 7.27 mmol) of the compound obtained in Example 3-4 (1.85 g, 4.85 t ol), eodomethyl cyclooctane (purity 90%, 1.63 g, 5.82 ol) and potassium carbonate (1.01 g, 7.27 mmol) 30 ml) was stirred at room temperature for 12 hours. The reaction mixture was diluted with 1N hydrochloric acid (9.7 ml), diluted with water (10 ml) and methanol (10 ml), and stirred at room temperature for 60 minutes. The precipitate was collected by filtration, washed with methanol (1: 1) and methanol, and dried to give the title compound (2.27 g, 4.49 fraction, 92.5%) as a red-purple powder.

_{Ή-NMR (300MHz, CDC1 3} ): δ 1.38 (2Η, m), 1.52 (6H, m), 1.60-1.80 (7H, m), 1.78 (3H, q, J = 0.9 Hz), 2.26 (3H, q, J = 1.2 Hz), 2.41 (3H, s), 2.81 (2H, d, J = 6.6 Hz), 7.26 (2H, d, J = 8.4 Hz), 7.85 (2H, d, J = 8 ^ Hz) .), 9.58 (1H, brs ) elemental analysis: calculated _{C 24 H 31 N 3 0 3} S 3: C, 57.00; H, 6.18; N, 8.31; S, 19.02 (%), Found: C , 56.89; H, 6.26; N, 8.17; S, 18.88 (%) Melting point.176.0- 178.0 ° C

Example 4-95 '

Mp 168- 170T: EtOAc- Et ₂ 0. The infrared absorption spectrum (IR) (in KBr) Seo:. 3247, 2975, 2930, 2868, 1748, 1721, 1663, 1613, 1557 cnf 1 MMR (CDC1 3): δ 1.21 (3H, t, J-7.0 Hz), 1.79 (3H, s), 2.26 (3H, d, J = 1.2 Hz), 2.42 (3H, s), 3.15 (2H, t, J = 6.6 Hz) , 3.52 (2H, q, J = 7.0 Hz), 3.64 (2H, q, J = 6.6 Hz), 7.28 (2H, d, J-8.4 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.62 (1H, bs).

Elemental _{analysis: C I9 H 23 N 3 0} 4 S 3 Calculated: C, 50.31; H, 5.11 ; N, 9.26; S, 21.21 (), Found: C, 50.19; H, 4.95 ; N, 9.23 ; S, 21.23 (%).

Example 4-96

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.78 (3Η, q, J = 1.2 Hz), 2.27 (3H, q, J = 1.2 Hz), 2.42 (3H, s), 2.46 (3H, s), 7.29 (2H, d, J = 8.4 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.63 (1H, br).

Elemental analysis: Calculated as _{C 16 H 17 N 3 0 3} S 3: C, 48.59; H, 4.33;, 10.62; S, 24.32 (%), Found: C, 48.50; H, 4.30 ; N, 10.52 ; S, 24.24 (%).

Melting point.218.0-218.5

Example 4-97

_{Ή-NMR (300MHz, CDC1 3} ): δ 1.12 (2H, m), 1.56 (4H, m), 1.67 (2H, brq, J = 7.8

Hz), 1.79 (3H, brq, J = 0.9 Hz), 1.79 (2H, m), 1.84 (1H, quint, J = 7.0 Hz), 2.26 (3H, brq, J = 0.9 Hz), 2.41 (3H, s), 2.94 (2H, t, J = 7.6 Hz), 7.27 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.61 (1H, brs).

Elemental _{analysis: C 22 H 27 N 3 0} 3 S 3 Calculated: C, 55.32; H, 5.70 ; N, 8.80; S, 20.14 (%), Found: C, 55.21; H, 5.77 ; N, 8.85; S, 20.25 (%).

Melting point: 166.0-166.5:

Example 4-98

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.06 (2Η, m), 1.42 (2H, m), 1.50-1.80 (9H, m), 1.78 (3H, brs), 2.26 (3H, brs), 2.41 ( 3H, s), 2.93 (2H, t, J-7.5 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.63 (1H, brs).

Elemental _{analysis: C 23 H 29 N 3 0} 3 S 3 Calculated: C, 56.18; H, 5.94 ; N, 8.55; S, 19.56 (%), Found: C, 56.24; H, 5.93; N, 8.71; S, 19.61 (%). Melting point. 180.0-181.0 ° C

Example 4-99

The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals. Mp:. 112- 114 ° C Infrared absorption spectrum (IR) (in KBr) V:. 3210, 2934 , 2880, 1732, 1615, 1557 cm "1 Ή-NMR (CDC1 3): δ 1.50-1.82 (6Η , m), 1.78 (3H, d, J = 0.8 Hz), 2.26 (3H, s), 2.32 (2H, t, J = 7.0 Hz), 2.42 (3H, s), 2.95 (2H, t, J = 8.4 Hz), 2.95 (3H, s), 3.01 (3H, s), 7.31 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.0 Hz), 9.61 (1H, bs). Analytical value: C ₂₃ , Calculated as N ₄ 0 ₄ S ₃ '0.20: C, 52.49; H, 5.82; N, 10.64; S, 18.27 (%), found: C, 52.41; H, 5.71; N , 10.67; S, 18.34 ().

Example 4-100

The crystals were recrystallized from ethyl acetate-getyl ether to obtain dark red crystals. Mp:. 99.0-10rC infrared absorption spectrum (IR) (in KBr) Seo:. 3129, 2926, 2861, 1736, 1686, 1659, 1593, 1545, 1508 cm "1 Ή-NMR (CDC1 3): δ 1.34 -1.50 (2Η, m), 1.62-1.86 (4H, m), 1.78 (3H, s), 2.26 (3H, s), 2.42 (3H, s), 2.91 (2H, t, J = 7.6 Hz), 7.07 (1H, s), 7.31 (2H, d, J = 8.0 Hz), 7.47 (1H, s), 7.84 (2H, d, J = 8.2 Hz), 9.63 (1H, bs).

Elemental analysis: C ₂₃ H ₂₇ N ₅ 0 ₃ S ₃ · 0.8 H ₂ 0 Calculated: C, 51.92; H, 5.42; N, 13.16; S, 18.08 (%), found: C, 52.06; H , 5.36; N, 12.70; S, 18.09 ().

Example 4-101

Recrystallization from ethyl acetate-methanol-tetrahydrofuran yielded dark red crystals. :.. Mp 174 - 176 ° C Infrared absorption spectrum (IR) (in KBr) v: 3300, 3061, 2938, 2863, 2247, 1732, 1663, 1615, 1557, 1495cm- 1 Ή-NMR (CDC1 3) : <5 1.50-1.82 (6H, m), 1.79 (3H, s), 2.27 (3H, s), 2.37 (2H, t, J = 6.6 Hz), 2.42 (3H, s), 2.95 (2H, t) , J = 7.4 Hz), 7.29 (2H, d, J = 8.0 Hz), 7.84 (2H, d, J = 8.0 Hz), 9.62 (1H, bs).

N- {5,6-dimethyl_3-oxo-8-[(tetrahydrid-2-furanylmethyl) sulfanyl] -2,3-dihydro-1H-imidazo [5,1-c] [1,] thiazine-1 -Ylidene}-4-methylbenzenesulfonamide Tedrahydrofurfuryl iodide (0.120 mg) was added to a suspension of the compound obtained in Example 3-4 (281 mg, 0.737 bandol) and potassium carbonate (153 mg, 1.10 bandol) in DMF (4.5 ml) while stirring at 80. ml, 0.958imnol), and the reaction solution was stirred for 2.5 hours. Hydrochloric acid (1.47 ml) was added to the reaction solution, which was diluted with methanol-water (8: 3, 11 ml) and stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol / water (1: 1 and 2: 1), and dried to give the title compound (205 mg, 0.440 mmol) as a gray-red powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.73 (1Η, m), 1.78 (3H, brs), 1.91 (2H, quint, J = 7.0 Hz), 2.07 (1H, m), 2.26 (3H, brs) , 2.42 (3H, s), 3.03 (1H, dd, J = 13.6, 6.2 Hz), 3.16 (1H, dd, J = 13.2, 5.4 Hz), 3.79 (1H, dt, J = 15.0, 9.0 Hz), 3.86 (1H, dt, J = 15.0, 7.0 Hz), 4.11 (1H, quint, J = 6.0 Hz), 7.28 (2H, d, J = 8.2 Hz), 7.85 (2H, d, J = 8.2 Hz), 9.64 (1H, brs).

Elemental analysis: C _2. H ₂₃ N ₃ 0 ₄ S ₃ Calculated: C, 51.59; H, 4.98 ; N, 9.02; S, 20.66

(%), Found: C, 51.34; H, 4.90; N, 8.96; S, 20.71 (%).

147.5- 148.0 ° C

Example 4-103

 N- [8- (cycloheptylsulfanyl) -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [l, 4] thiazine-triylidene] -4 -Methylbenzenesulfonamide A suspension of the compound obtained in Example 3-4 (260 mg, 0.682 mol) and potassium carbonate (HI mg, 1.02 mmol) in DMF (4.3 ml) was stirred at 80 ° C while stirring. Cycloheptyl iodide (0.197 ml, 0.818 bandol) was added, and the reaction solution was stirred for 2.5 hours. 1N Hydrochloric acid (1.36 ml) was added to the reaction solution, diluted with methanol / water (5: 3.8 ml) and stirred at room temperature for 30 minutes. The precipitate is collected by filtration, washed with methanol-water (1: 1), water, methanol-water (1: 1) and getyl ether, and dried to give the title compound (214 mg, 0.448 mmol) as a gray-red color Obtained as a powder.

_{Ή-NMR (200MHz, CDC1 3} ): 6 1.55 (6H, brs), 1.70 (4H, brs), 1.78 (3H, q, J = 0.8 Hz), 2.06 (2H, m), 2.26 (3H, q, J = 0.8 Hz), 2.42 (3H, s), 3.52 (1H, sept, J = 4.4 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.86 (2H, d, J = 8.4 Hz), 9.64 . (1H, brs) elemental analysis: calculated _{C 22 H 27 N 3 0 4} S 3: C, 55.32; H, 5.70; N, 8.80; S, 20.14 (%), Found: C, 55.32; H, 5.79; N, 8.82; S, 20.03 (%) Melting point.167.5-168.5 ° C

Example 4-104

 N- (8-{[2- (1,3-Dioxolan-2-yl) ethyl] sulfael) -5,6-dimethyl-3-year-old oxo-2,3_dihydro-1H-imidazo [5,1 -c] [1,4] thiazine-1-ylidene) -4-methylbenzenesulfonamide

 A suspension of the compound obtained in Example 3-4 (262 mg, 0.687 mol) and potassium carbonate (142 mg, 1.03 mmol) in DMF (4.4 ml) was stirred at 80 with 2- (2-bromoethyl). -1,3-Doxolan (0.109 ml, 0.893 mmol) was added, and the reaction solution was stirred for 100 minutes. The reaction mixture was diluted with 1N hydrochloric acid (1.37 ml), diluted with methanol / water (1: 2, 3 ml), and stirred at room temperature for 30 minutes. The precipitate is collected by filtration, washed with methanol-water (1: 1), water, methanol-water (1: 1) and getyl ether, and dried to give the title compound (234 mg, 0.486 mfflol) as a gray-red powder Obtained.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.79 (3Η, s), 2.03 (2H, dt, J = 4.4, 7.7 Hz), 2.26 (3H, brs), 2.42 (3H, s), 3.05 (2H, t, J = 7.7 Hz), 3.88 (2H, m), 3.97 (2H, m), 4.96 (1H, t, J = 4.2 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.63 (1H, brs).

Elemental analysis: C _2. H ₂₃ N ₃ 0 ₅ S ₃ Calculated: C, 49.88; H, 4.81 ; N, 8.72; S, 19.97

(%), Found: G, 49.53; H, 4.74; N, 8.56; S, 19.81 (%).

Melting point.185.0-188.0 ° C

Example 4-105

N- (8-{[2- (1,3-Dioxane_2-yl) ethyl] sulfanyl} -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, 1-c] [1,4] thiazine-1-ylidene) -4-methylbenzenesulfonamide, the compound obtained in Example 3-4 (234 mg, 0.613 mmol) and potassium carbonate (127 mg, 0.920 bandol) 2- (2-Promoethyl) -1,3-dioxane (0.103 ml, 0.736 mmol) was added to a suspension of DMF (4.0 ml) with stirring at 80, and the reaction solution was stirred for 2 hours. The reaction mixture was diluted with 1N hydrochloric acid (1.23 ml), diluted with methanol-water (1: 2, 3 ml), and stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol-water (1: 1), water, methanol (1: 1) and water, dried and dried to give the title compound (248 mg, 0.500 Ol) was obtained as a gray-red powder.

_{Ή-NR (200MHz, CDC1 3} ): <5 1.36 (1H, brd, J = 13.4 Hz), 1.78 (3H, s), 1.95 (2H, dt, J = 5.0, 7.0 Hz), 2.07 (1H, m ), 2.26 (3H, brq, J = 1.2 Hz), 2.42 (3H, s), 3.04 (2H, t, J = 7.5 Hz), 3.75 (2H, dt, J = 2.2, 11.2 Hz), 4.09 (2H , dd, J = 11.0, 4.8 Hz), 4.63 (1H, t, J = 4.8 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.63 (1H , brs).

Elemental analysis: C _2l H ₂₅ N ₃ 0 ₅ S ₃ · 0.30 Calculated: C, 50.34; Η, 5.15; Ν, 8.39; S, 19.20 (%), found: C, 50.60; Η, 5.13 ; Ν, 8.42; S, 18.86 (%).

Melting point.196.5-199.0 ° C

Example 4-106

iert-butyl 3 _ [(5,6-dimethyl-tri {[(4_methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,] Thiazine-8-yl) sulfanyl] propyl

 To a suspension of the compound (263 mg, 0.689 mmol) obtained in Example 3-4 and potassium carbonate (143 mg, 1.03 mmol) in DMF (4.0 ml) was added 1-amino-amine while stirring at 80 ° C. N-Boc-Tamino-3-bromopropane (purity 88%, 0.22 ml, 0.758 bandol) prepared from 3-bromopropane hydrobromide, ditert-butyl bicarbonate and triethylamine was added, and the reaction solution was added. Was stirred for 1.5 hours. 1N Hydrochloric acid (1.38 ml) was added to the reaction solution, diluted with methanol / water (1: 1, 4 ml), and stirred at room temperature for 30 minutes. The precipitate is collected by filtration, washed with methanol-water (1: 1), water, methanol-aqueous solution (1: 1) and methanol, and dried to give the title compound (323 mg, 0.600 bandol ol) as a gray-red powder As obtained.

_{Ή-NMR (200MHz, CDC1 3} ) δ 1.45 (9Η, s), 1.78 (3H, brs), 1.86 (2H, quint, J = 7.3 Hz), 2.26 (3H, brs), 2.42 (3H, s), 2.96 (2H, t, J = 7.3 Hz), 3.20 (2H, q, J = 6.5 Hz), 4.64 (1H, m), 7.29 (2H, d, J = 8.4 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.66 (1H, brs).

Elemental analysis: C ₂₃ H _3. Calculated as N ₄ 0 ₅ S ₃ · 0.20: C, 50.94; Η, 5.65; Ν, 10.33; S, 17.74 (%), found: C, 51.22; Η, 5.66; Ν, 10.39; S, 17.43 (%).

Melting point.166.0-168.0 ° C

Example 4-107 The crystals were recrystallized from ethyl acetate-getyl ether to obtain dark red crystals. Melting point: 204-206:. Infrared absorption spectrum (IR) (in KBr) V: 3167, 2922, 1734, 1663, 1618, 1561 cm " ^1. Ή-NMR (CDC"): δ 1.78 (3H, d, J = 0.6 Hz), 2.26 (3H, d, J = l.2 Hz), 2.43 (3H, s), 2.66-2.82 (3H, m), 3.04-3.24 (4H, m), 7.22-7.45 (4H , m), 7.28 (2H, d, J = 8.0 Hz), 7.87 (2H, d, J = 8.Hz), 9.61 (1H, bs).

Elemental analysis: C ₂₅ H ₂₅ N ₃ 0 ₃ S ₃ · 0.5 H ₂ 0 Calculated: C, 57.67; H, 5.03; N, 8.07; S, 18.48 (%), found: C, 57.52; H , 5.02; N, 8.24; S, 18.76 (%).

Example 4-108

The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals. Melting point 200-202 ° C. Infrared absorption spectrum (IR) (in KBr): 3231, 2976, 2932, 1761, 1694, 1622, 1559 cm " ¹ .

_{¾-NMR (CDC1 3):} δ 1.02-1.28 (2Η, m), 1.46 (9H, s), 1.50-1.86 (3H, m), 1.79 (3H, s), 2.26 (3H, s), 2.42 ( 3H, s), 2.67 (2H, t, J = 11.4 Hz), 2.84 (2H, d, J = 7.0 Hz), 3.98-4.20 (2H, m), 7.28 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.Hz), 9.62 (1H, bs).

Elemental analysis: C ₂₆ H ₃₄ N ₄ 0 ₅ S ₃ '0.20 Calculated: C, 53.62; H, 5.95; N, 9.62; S, 16.51 (%)> Found: C, 53.53; H, 6.08 ; N, 9.48; S, 16.31 ().

Example 4-109

 Recrystallization from ethyl acetate-methanol gave colorless crystals. Melting point 210-212 ° C. Infrared absorption spectrum (IR) (in KBr): 3700-2200, 3376, 3247, 2978, 2930, 2556, 2461, 2433, 1740, 1717, 1659, 1613, 1557 cm—

'H-NMR (DMS0-d ₆ ): δ 1.82 (3Η, s), 2.18 (3H, s), 2.40 (3H, s), 2.80 (6H, s), 3.12-3.48 (4H, m), 7.38 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.4 Hz).

Elemental _{analysis: C ig H 24 N 4 0} 3 S s'HCl'0.4H 2 0 Calculated: C, 45.98; H, 5.24 ; N, 11.29; S, 19.38 (%), Found: C, 46.13 ; H, 5.07; N, 11.07; S, 19.02 (%).

Example 4-110

Recrystallization from ethyl acetate-methanol gave colorless crystals. Melting point 206-208 ° C. Infrared absorption spectrum (IR) (in KBr) V: 3700-2200, 3248, 2949, 2647, 2469, 1728, 1661, 1611, 1557 cm— ¹ . Ή-NMR (DMS0-d ₆ ): δ 1.80 (3H, s), 1.93-2.08 (2H, HI), 2.18 (3H, s), 2.39 (3H, s), 2.76 (6H, s), 2.97- 3.18 (4H, m), 7.38 (2H, d, J = 8.0 Hz), 7.86 (2H, d, J = 8.4 Hz).

Example 4-111

The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals. Melting point: 173-175 ° C. Infrared absorption spectrum (IR) (in Br) V: 3221, 2934, 2249, 1732, 1663, 1615, 1563, 1495 cm- ¹ .

_{Ή-NMR (CDC1 3):} δ 1.79 (3Η, d, J = 1.2 Hz), 1.96-2.12 (2H, m), 2.26 (3H, d, J = 1.2 Hz), 2.43 (3H, s), 2.48 (2H, t, J-7.2 Hz), 3.06 (2H, t, J = 7.0 Hz), 7.31 (2H, d, J = 8.4 Hz), 7.84 (2H, d, J = 8.Hz), 9.64 ( 1H, bs).

Elemental analysis: C _19. Calculated for N ₄ 0 ₃ S ₃ : C, 50.87; H, 4.49; N, 12.49; S, 21.44

(%), Found: C, 50:95; H, 4.46; N, 12.18; S, 21.15 ().

Example 4-112

The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals.

166-168 ° C.

Infrared absorption spectrum aR) (in KBr): 3291, 2928, 2245, 1748, 1717, 1661, 1611, 1555, 1497 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 1.72-1.92 (4Η, ι), 1.79 (3H, d, J = 0.8 Hz), 2.26 (3H, s), 2.39 (2H, t, J-6.6 Hz), 2.43 (3H, s), 2.97 (2H, t, J = 6.8 Hz), 7.30 (2H, d, J = 8.2 Hz), 7.84 (2H, d, J = 8.6 Hz), 9.63 (1H, bs).

Elemental analysis: C _2. Calculated as _{H 22 N 4 0 3 S 3} : C, 51.93; H, 4.79; N, 12.11 (%), actual Hakachi: C, 51.87; H, 4.61 ;, 12.10 () ·

Example 4-113

 N- [5,6-Dimethyl-3-oxo-8- (vinylsulfanyl) -2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene]-4- Methylbenzenesulfonamide

Carbon dioxide was added to a suspension of the compound obtained in Example 3-4 (503 g, 1.3 1.3ol) and 1,2-dibromoethane (0.121 ml, 1.38 olol) in DMF (10 ml) while stirring at 80 ° C. Potassium (146 mg, 1.06 marl) was added and the reaction was stirred for 80 minutes. Hydrochloric acid (0.79 ml) was added to the reaction solution, diluted with methanol / water (1: 1, 10 ml), and stirred at room temperature for 30 minutes. Was. The precipitate was collected by filtration, washed with methanol-water (1: 1), water and methanol, and suspended in THF. The insoluble material was collected by filtration, and washed with THF-methanol (1: 1) and methanol. The mother liquor and the washings were combined, extracted with ethyl acetate, washed with 0.1N hydrochloric acid, water and saturated saline, dried over sodium sulfate, and concentrated to give the title compound (49 mg, 0.120 t ol) as a red-purple powder As obtained.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.77 (3Η, q, J = 0.6 Hz), 2.26 (3H, q, J = 1.2 Hz), 2.43 (3H, s), 5.75 (1H, d, J = 9.4 Hz), 5.79 (1H, d, J = 16.6 Hz), 6.61 (1H, dd, J = 16.6, 9.2 Hz), 7.30 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.63 (1H, br).

Elemental analysis: C ₁₇ H ₁₇ N ₃ 0 ₃ S ₃ · 0.25 0 Calculated: C, 49.56; H, 4.28; N, 10.20; S, 23.35 (), found: C, 49.48; H, 4.23; N, 10.09; S, 22.98 (%).

Melting point.212.5-213.5 ° C

Example 4-114

tert-butyl 2-[(5,6-dimethyl-tolu [[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo [5, l_c] [1,4] thiazine -8-yl) sulfanyl] ethyl carbamate

 To a suspension of the compound obtained in Example 3-4 (310 mg, 0.813 ol) and potassium carbonate (169 mg, 1.22 ol) in DMF (5.0 ml) was added triamino- N-Boc-triamino_3_chloroethane (purity 86%, 0.25 ml, 1.22 ml) prepared from 2-chloro mouth ethane hydrochloride, ditert-butyl bicarbonate and triethylamine was added, and the reaction solution was stirred for 1.5 hours. did. N-Boc-Tamino-3-chloroethane (purity 86%, 0.08 ml, 0.07 mmol) was added to the reaction solution, and the reaction solution was stirred for 0.5 hour. 1N Hydrochloric acid (1.63 ml) was added to the reaction solution, diluted with methanol / water (3: 2.5 ml), and stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol / water (1: 1), water, methanol / water (1: 1) and methanol, and dried to give the title compound (237 mg, 0.452 mraol) as a gray-red powder .

_{Ή-NM (200MHz, CDC1 3} ): δ 1.45 (9H, s), 1.78 (3H, brs), 2.26 (3H, brs), 2.42 (3H, s), 3.09 (2H, t, J = 6.4 Hz) , 3.39 (2H, q, J = 6.2 Hz), 4.93 (1H, m), 7.30 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.66 (1H, brs) .

Elemental _{analysis: C 22 H 28 N 4 0} 5 S 3 Calculated: C, 50.36; H, 5.38 ; N, 10.68; S, 18.33 (%), Found: C, 50.18; H, 5.32; N, 10.70; S, 18.05 (%). Melting point. 200.0-201.0 ° C

Example 4-115

 N- (5,6-dimethyl-3-oxo-8-{[2- (tetrahydro-2-yl) ethyl] sulfanylyl} -2,3-dihydro-1H-imidazo [5,1-c] [ 1,4] thiazine-1-ylidene) -4-methylbenzenesulfonamide

 11? Of tetrahydrofuran-2-ethyl acetate (4.82 g, 29.9 bandages 01) (96 ml) The powder of lithium aluminum hydride (purity 80 1.06 g, 22.4 thigh 01) was added in several portions to the solution while stirring at 0 ° C, and the mixture was stirred at 0 ° C for 80 minutes. A 0.5 M aqueous solution of citrate (451111) was added to the reaction solution, and extracted three times with 1 ^ (2001111). << 1 was distilled off, diluted with chloroform (100 ml), dried and concentrated to obtain a pale yellow oil. This oil was dissolved in chloroform (60 ml), methanesulfonyl chloride (2.81 ml, 35.9 t01) was added while stirring at 0, and then triethylamine (5.38 ml, 38.8 mmol) in chloroform (10 ml). ) The solution was added dropwise over 40 minutes and the reaction was stirred at 0 for 40 minutes. The reaction mixture is concentrated, diluted with ethyl acetate (100 ml), washed with water, aqueous sodium bicarbonate solution and saturated brine, dried and concentrated to give 2- (tetrahydrofuran-2-yl) ethyl methanesulfonate (Purity 90%, 4.58 g, 21.2 mmol) was obtained as a pale brown oil.

_{Ή-NMR (200MHz, CDC1 3} ): (51.70-2.20 (6H, m), 3.02 (3H, s), 3.74 (2H, dt, J = 14.0, 7.0 Hz), 3.85 (1H, dt, J = 14.0 , 6.8 Hz), 3.95 (1H, m), 4.07 (2H, dd, J = 7.1, 5.7 Hz).

 The above methanesulfonic acid 2 was added to a suspension of the compound obtained in Example 3-4 (264 mg, 0.692 mol) and potassium carbonate (143 mg, 1.04 mmol) in DMF (4.4 ml) while stirring at 80 ° C. -(Tetrahydrofuran-2-yl) ethyl (161 mg, 0.830 mmol) was added, and the reaction solution was stirred for 2 hours. Further, 2- (tetrahydrofuran-2-yl) ethyl methanesulfonate (30 mg, 0.140 mmol) was added to the reaction solution, and the reaction solution was stirred for 1 hour. 1N Hydrochloric acid (1.38 ml) was added to the reaction solution, diluted with methanol-water (1: 1, 6 ml), and stirred at room temperature for 30 minutes. The precipitate was separated from the mother liquor and crystallized from methanol to give the title compound (181 mg, 0.377 ol) as a dark purple powder.

_{¾ - NMR (200MHz, CDC1 3} ) 'δ 1.78 (3Η, brs), 1.84 (2H, q, J = 6.6 Hz), 1.90 (2H, quint, J = 7.2 Hz), 1.93 (2H, m), 2.26 (3H, q, J = 1.2 Hz), 2.42 (3H, s), 3.05 (2H, m), 3.75 (1H, t, J = 6.6 Hz), 3.84 (1H, t, J = 6.6 Hz), 3.89 (1H, m), 7.28 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.0 Hz), 9.63 (1H, brs).

Elemental analysis: Calculated as _{C 21 5 N 3 0 4 S} 3: C, 52.59; H, 5.25; N, 8.76; S, 20.06 (%), Found: C, 52.22; H, 5.23 ; N, 8.77 ; S, 20.11 (%).

Melting point.159.0-160.0 ° C

Example 4-116

Recrystallization from ethanol gave orange crystals.

Melting point: 196-198 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3700-2300, 2953, 2795, 2726, 1730, 1717, 1663, 1607, 1557, 1495 cm ¹ .

'Η-new (CDCl ₃ + DMS0-d ₆ ): δ 1.64-1.84 (3Η, m), 1.79 (3H, s), 1.90-2.08 (2H, m), 2.26 (3H, s), 2.44 (3H , s), 2.64-2.96 (2H, m), 2.90 (2H, d, J = 5.8 Hz), 3.32-3.50 (2H, m), 7.30 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.0 Hz), 9.62 (1H, bs).

Example 4-117

 N- {5,6-dimethyl-3-oxo-8-[(tetrahydric-2H-pyran-4-ylmethyl) sulfanyl] -2,3-dihydro-1H-imidazo [5,1-c] [1 , 4] Thiazine-1-yldent 4-methyl The compound obtained in Example 3-4 (305 ig, 0.799 mmol) and potassium carbonate (166 mg,

To a suspension of I.20 miiiol) in DMF (5.0 ml) was added, while stirring at 80, the tetrahydropyran-4-methyl methanesulfonate (288 mg, 1.04 mmol) obtained in Reference Example 86, and the reaction mixture was stirred for 2.5 hours. Stirred for hours. 1N Hydrochloric acid (1.60 and water (40 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml) .The organic layer was washed with water and saturated saline, dried and concentrated. The collected substance was collected, washed with methanol and dried to obtain the title compound (124 mg, 0.259 mol) as a red powder.

 Ή-NMR (200MHz, CDC): 6 1.32 (2H, dq, J = 11.6, 4.0 Hz), 1.74 (2H, brd, J =

II.6 Hz), 1.79 (3H, brs), 2.26 (3H, brs), 2.42 (3H, s), 2.86 (2H, d, J = 6.6 Hz), 2.98 (1H, m), 3.36 (2H, td, J = 11.6, 0.8 Hz), 3.97 (2H, dd, J = 11.8, 4.0 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.65 (1H, brs). Elemental analysis: C _ZI H ₂₅ N ₃ 0 ₄ S ₃ · 0.2 Calculated as ¾0: C, 52.20; H, 5.30; N, 8.70; S, 19.91 (%), Found: C, 52.21; H, 5.34; N, 8.68; S, 20.05 (%).

Example 4-118

N- {8-[(3-Aminopropyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydrido-1H-imidazo [5,1-c] [1,4] thiazine-triylidene } -4-Methylbenzenesulfonamide trifluoroacetate

 The compound (327 mg, 0.607 bandol) obtained in Example 4-106 was dissolved in TFA (0.5 ml) and left at room temperature for 60 minutes. The reaction solution was diluted with toluene (10 ml) and concentrated to dryness. Ethyl acetate was added to the residue to obtain a red suspension. The precipitate was collected by filtration, washed with ethyl acetate, and dried to give the title compound (334 rag, 0.604 mmol) as a red-purple powder.

Ή-NMR (200 MHz, in double-mouthed form): δ 1.80 (3Η, q, J-0.6 Hz), 2.04 (2H, quint, J = 6.9 Hz), 2.25 (3H, brs), 2.43 (3H, s), 2.97 (2H, t, J = 5.6 Hz), 3.06 (2H, t, J = 7.1 Hz), 7.32 (2H, d, J = 8.0 Hz), 7.87 (2H, d, J = 8.4 Hz) , 8.33 (3H, brs).

Elemental analysis: C _2. Calculated as _{H 23 N 3 0 5 S 3} F 3; C, 43.47; H, 4.20; N, 10.14; S, 17.41

(%), Found; C, 43.32; H, 4.21 ;, 9.84; S, 17.26 (%).

Example 4-119

 N- {8-[(4-Hydroxybutyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3_dihydrone-1H-imidazo [5,1-c] [1,4] thiazine-1 -Ylidene} _4-methylbenzenesulfonamide

A suspension of the compound obtained in Example 3- (1.26 g, 3.31 mmol) and carbonated rim (686 mg, 4.97 mmol) in DMF (20 ml) was stirred at 80 ° C with 4-bromo- 1-Pynool (608 mg, 3.97 minol) was added, and the reaction solution was stirred for 6 hours. During this time, 4-promo-1-butanol (506 ig, 3.31 tmol) was added to the reaction solution twice every two hours. To the reaction solution were added 1N hydrochloric acid (3.4 ml), water (6.4 ml) and methanol / water (1: 1, 10 ml), and the mixture was stirred at room temperature for 60 minutes. The precipitate is collected by filtration, washed with methanol-water (1: 1), water, methanol-water (1: 1) and methanol, suspended in THF and ethyl acetate, and heated to 60 ° C to make it insoluble Things were removed. After concentrating the soluble matter and diluting with methanol, the precipitate was collected by filtration and meta The residue was washed with ethanol and dried to give the title compound (277 mg, 0.611 mmol) as a red-orange powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.72 (4Η, m), 1.78 (3H, q, J = 1.2 Hz), 2.26 (3H, q, J = 0.8 Hz), 2.42 (3H, s), 2.99 (2H, t, J = 7.1 Hz), 3.68 (2H, t, J = 5.9 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.64 (1H , brs).

Elemental _{analysis: C 19 H 23 N 3 0} 4 S 3 · 0.25H 2 0 Calculated: C, 49.81; H, 5.17 ; N, 9.17; S, 21.00 (%), Found: C, 49.85; H , 5.09; N, 9.13; S, 21.13 (%).

Melting point.120.5-124.0 ° C

Example 4-120

N- (5,6-dimethyl-3-oxo-8-{[4- (tetrahydro-2H-pyran-2_yloxy) butyl] sulfanyl}}-2,3-dihydro-1H-imidazo [5,1- c] [1,4] thiazine-1-ylidene) -4-methylbenzenesulfonamide

 To a suspension of the compound obtained in Example 3-4 (280 mg, 0.734 mmol) and potassium carbonate (152 mg, 1.10 mmol) in DMF (4.5 ml) was added 4-bromo-1 while stirring at 80 ° C. 4-Bromo-1-butyl 2-tetrahydrobiranyl ether (0.30 ml) prepared from -butanol, 3,4-dihydro-2H-pyran and CSA was added, and the reaction solution was stirred for 70 minutes. 1N Hydrochloric acid (3.4 ml) and water (30 ml) were added to the reaction solution, and the mixture was extracted with ethyl acetate (40. ml). The organic layer was washed with water and saturated saline, dried and concentrated. Ethyl acetate and getyl ether were added to the residue, and the precipitate was collected, washed with getyl ether, and dried to give the title compound (161 g, 0.299 mmoU 3-1 anomeric mixture) as a red powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.55 (4Η, ra), 1.74 (4H, m), 1.79 (3H, brs), 2.26 (3H, q,] = 1.2 Hz), 2.42 (3H, s) , 2.99 (2H, t, J = 7.1 Hz), 3.47 (2H, m), 3.78 (2H, m), 4.23 (1 / 4H, m, hyanoomer), 4.57 (3 / 4H, brt, J = 3.4 Hz, β-anomer), 7.29 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.0 Hz), 9.64 (1H, brs). Melting point. 105.0- 108. (T

Example 4-121

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.78 ( '3Η, s), 2.06 (3H, s), 2.26 (3H, s), 2.41 (3H, s), 2.97 (2H, m), 3.43 (m ), 3.78 (m), 4.08 (m), 5,01 (brs), 5.56 (brs), 7.29 (2H, i), 7.84 (2H, m), 9.64 (1H, br). Elemental _{analysis: C 19 H 23 N 3 0} 4 S 3 · 0.25H 2 O Calculated: C, 49.81; H, 5.17 ; N, 9.17; S, 21.00 (), Found: C, 49.85; H, 5.09; N, 9.13; S, 21.13 (%).

Melting point.120.5-124.0 ° C

Example 4-122

N_ {8-[(4-Culobutyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydrido-1H-imidazo [5, tric] [1,4] thiazine-1- Silent 4-methylbenzenesulfonami F

 To a suspension of the compound (498 mg, 1.30 bandol) obtained in Example 3-4 and potassium carbonate (180 mg, 1.30 irnnol) in DMF (8 ml) was stirred at 80 ° C at 80 ° C while tribromo-4-. Chlorobutane (0.182 ml, 1.57 ol) was added and the reaction solution was stirred for 1 hour. 1N Hydrochloric acid (1.3 ml) and methanol-water (1: 1, 10 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol-water (1: 1), water, methanol-water (1: 1) and methanol, and suspended in ethyl acetate to remove insolubles. The soluble matter was concentrated, diluted with methanol, and the precipitate was collected by filtration, washed with methanol, and dried to obtain the title compound (307 mg, 0.650 mmol) as a gray purple powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.79 (3Η, brs), 1.87 (4H, m), 2.26 (3H, q, J = 1.2 Hz), 2.42 (3H, s), 2.97 (2H, brt, J = 7.0 Hz), 3.55 (2H, brt, J = 5.8 Hz), 7.29 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J- 8.0 Hz), 9.63 (1H, brs).

Elemental _{analysis: C 19 H 22 N 3 0} 3 S 3 C1 · 0.2Η 2 0 Calculated: C, 47.98; Η, 4.75 ; Ν, 8.83; S, 20.22; Cl, 7.45 (%), Found: C, 47.99; H, 4.66; N, 8.69; S, 20.36; C1, 7.10 (%).

Example 4-123

 N-{8_ [(4-odobutyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1- Ylidene}-4-Methylbenzenesulfone S

A solution of the compound obtained in Example 4-122 (0.73 g, 1.55 mol) and sodium iodide (464 mg, 3.09 mmol) in 2-butanone (20 ml) was stirred at 80 for 3 hours. Ethyl acetate (60 ml) was added to the reaction mixture, mixed, washed with water and saturated saline, dried and concentrated, and methanol was added to the residue. The precipitate is collected by filtration, washed with methanol, dried and crude The title compound (purity 89, 712 g, 1.12 mmol) was obtained as a red-purple powder.

¾ one _{NMR (200MHz, CDC1 3):} δ 1.79 (3Η, q, J = 1.2 Hz), 1.87 (4H,), 2.26 (3H, q, J = 0.8 Hz), 2.42 (3H, s), 2.95 ( 2H, brt, J = 7.2 Hz), 3.18 (2H, brt, J = 6.4 Hz), 7.30 (2H, d, J = 8.8 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.63 (1H, brs). Example 4-124

 N- (5,6-Dimethyl-3-oxo-8-{[2- (1H-pyrrole-tolyl) ethyl] sulfanyl} -2,3-dihydro-1H-imidazo [5, tric] [ [1,4] thiazine-1-ylidene) -4-methylbenzenesulfonamide

 A suspension of the compound obtained in Example 3-4 (276 mg, 0.723 mmol) and potassium carbonate (150 mg, 1.09 tmol) in DMF (4.5 ml) was stirred at 60 ° C at 60 ° C to give 2-bromoethyl. ) Pyrrol (151 mg, 0.868 mmol) was added, and the reaction solution was stirred at 60 ° C for 3 hours. During this time, 1- (2-bromoethyl) pyrrole (30 mg, 0.174 mmol) was added to the reaction solution. Monohydrochloric acid (1.5 ml) and methanol-water (1: 1, 3 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol / water α: 1 and 2: 1), and dried to give the title compound (247 mg, 0.520 bandol) as a purple powder. '

'H-NMR (200MHz, CDC1 3): δ 1.79 (3Η, q, J = 1.0 Hz), 2.26 (3H, q, J = 1.0 Hz), 2.43 (3H, s), 3.26 (2H, t, J = 7.2 Hz), 4.14 (2H, i, J = 7.1 Hz), 6.15 (2H, t, J = 2.1 Hz), 6.63 (2H, t, J = 2.0 Hz), 7.29 (2H, d, J = 8.0 Hz), 7.83 (2H, d, J2 8.0 Hz), 9.64 (1H, brs).

Elemental analysis: Calculated for C ₂₁ H ₂₂ N ₄ 0 ₃ S ₃ : C, 53.14 ;. H, 4.67; N, 11.80; S, 20.27 (%), found: C, 53.06; H, 4.65; N , 11.56; S, 20.29 (%).

Melting point.168.0-169.5 ° C

Example 4-125

 N- (5,6-dimethyl-3-oxo-8-{[3_ (1H-pyrrole-tolyl) propyl] sulfanyl} -2,3-dihydro-1H-imidazo [5,1-c] [ 1,4] thiazine-triylidene)-4_methylbenzenesulfonamide

To a suspension of the compound obtained in Example 3-4 (261 mg, 0.684 thigh) and potassium carbonate (142 mg, 1.03 mmol) in DMF (4.0 ml) was stirred at 60 ° C while adding tri (3-bromopropyl). ) Pyrrol (154 mg, 0.821 ol) was added, and the reaction solution was stirred at 60 for 3.5 hours. During this time 1- (3-Bromopropyl) pyrrole (27 rag, 0.144 mmol) was added to the reaction solution. 1N Hydrochloric acid (1.4 ml) and methanol-water (1: 1, 3 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol / water (1: 1 and 2: 1), and then crystallized from methanol to give the title compound (283 mg, 0.579 bandol) as a purple powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.76 (3Η, q, J = 0.8 Hz), 2.11 (3H, quint, J = 6.7 Hz), 2.25 (3H, q, J = 0.6 Hz), 2.41 (3H , s), 2.83 (2H, t, J = 7.1 Hz), 3.97 (2H, t, J = 6.4 Hz), 6.15 (2H, t, J = 2.0 Hz), 6.60 (2H, t, J = 2.0 Hz) ), 7.29 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.0 Hz), 9.65 (1H, brs).

Elemental _{analysis: C 22 H 24 N 4 0} 3 S 3 Calculated: C, 54.07; H, 4.95 ; N, 11.47; S, 19.69

(), Found: C, 54.01; H, 4.94; N, 11.09; S, 19.64 (%).

Melting point.194.5-195.0 ° C

Example 4-126

 N- {8-[(2-cyclohexylethyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine- 1-ylidene 4-methylbenzenesulfonamide

 A suspension of the compound obtained in Example 3-4 (275 mg, 0.721 mmol) and potassium carbonate (149 mg, 1.08 dragonol) in DMF (4.5 ml) was stirred at room temperature with stirring at room temperature for 2-cyclohexylethyl bromide. (155 mg, 0.792 mmol) was added, and the reaction solution was stirred at 80 for 1.5 hours. 1N Hydrochloric acid (1.44 ml) and methanol / water (1: 1, 5 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol-water (1: 1) and methanol, and dried to give the title compound (225 mg, 0.458 mol) as a purple-brown powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 0.93 (2Η, brq, J = 10.6 Hz), 1.18 (2H, brd, J = 8.4 Hz), 1.27 (3H, m), 1.56 (2H, q, J = 8.0 Hz), 1.71 (4H, brd, J = 9.8 Hz), 1.78 (3H, brs), 2.26 (3H, brs), 2.42 (3H, s), 2.95 (2H, t, J = 7.7 Hz), 7.28 (2H, d, J = 8.6 Hz), 7.85 (2H, d, J = 8.6 Hz), 9.63 (1H, brs).

Elemental _{analysis: C 23 H 29 N 3 0} 3 S 3 Calculated: C, 56.18; H, 5.94 ; N, 8.55; S, 19.56

(%), Found: C, 56.14; H, 5.90; N, 8.45; S, 19.70 (%).

Melting point. 166.2-167.2 ° C

Example 4-127 N- (5,6-dimethyl-3-oxo-8-{[(3-tetrahydrofuranyl) methyl] sulfanyl 2,3-dihydro_m-imidazo [5,1-c] [1,4] thiazine- Trilidene) -4-methylbenzenesulfonamide

 A suspension of the compound obtained in Example 3-4 (300 mg, 0.786 mmol) and potassium carbonate (163 mg, 1.18 mmol) in DMF (5 ml) was obtained in Reference Example 91 while stirring at 80 ° C. Tetrahydrofuran-3-methyl methanesulfonate (170 mg, 0.944 mmol) was added, and the reaction solution was stirred at 80 ° C for 4.5 hours. During this time, sodium iodide (118 mg, 0.786 ol) and tetrahydrofuran-3-methyl methanesulfonate (34 mg, 0.157 ol) were added twice to the reaction mixture. 1N Hydrochloric acid (1.60 ml) and water (3 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol / water (1: 1) and methanol, and dried to give the title compound (224 rag, 0.481 mmol) as a purple powder.

! H-NMR (200MHz, CDC1 3): d 1.66 (1H, m), 1.79 (3H, q, J = 1.0 Hz), 2.14 (1H, ddt, J = 13.0, 7.6, 5.6 Hz), 2.26 (3H , q, J- 1.0 Hz), 2.42 (3H, s), 2.52 (1H, brquint, J = 6.9 Hz), 2.99 (2H, d, J = 7.2 Hz), 3.53 (1H, dd, J = 8.8, 5.6 Hz), 3.77 (1H, brq, J = 7.8 Hz), 3.86 (1H, dd, J = 8.8, 6.8 Hz), 3.89 (1H, dt, J = 5.5, 8.6 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.85 ( 2H, d, J = 8.4 Hz), 9.65 (1H, brs) elemental analysis:. C _2. H ₂₃ N ₃ 0 ₄ S ₃ Calculated: C, 51.59; H, 4.98 ; N, 9.02; S, 20.66

(%), Found: C, 51.37; H, 5.17;, 9.04; S, 20.69 (%).

Melting point. 199.0- 201. O:

Example 4-128

N- {5,6-dimethyl-3-oxo-8-[(2-tetrahydro-2H-pyran_4-ylethyl) sulfanyl] -2,3-dihydro-1H-imidazo [5,1-c] [1 , 4] Thiazin-1-ylidene} -4-mer The compound obtained in Example 3-4 (284 mg, 0.744 mmol), 2- (tetrahydropyran-4-yl) methanesulfonate obtained in Reference Example 87 A suspension of ethyl ester (186 mg, 0.893 mmol) and potassium carbonate (154 mg, 1.128 mmol) in DMF (4.5 ml) was stirred at 80 ° C for 3 hours. During this time, 2- (tetrahydrobilan-4-yl) ethyl methyl sulfonate (31 mg, 0.148 bunol) was added twice to the reaction solution. IN hydrochloric acid (2.0 ml) and methanol-water (1: 1, 5 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The precipitate is collected by filtration, and methanol-water (1: 1) and After washing with methanol and drying, the title compound (226 Dig, 0.458 benzyl) was obtained as a gray-red powder.

'H-NMR (200MHz, CDC1 3): δ 1.32 (2Η, m), 1.61 (5H, m), 1.79 (3H, q, J = 1.2 Hz), 2.27 (3H, q, J = 0.6 Hz), 2.42 (3H, s), 2.96 (2H, t, J = 7.3 Hz), 3.36 (1H, dt, J = 1.8, 11.7 Hz), 3.97 (2H, brdd, J = 11.4, 4.0 Hz), 7.29 (2H , d, J = 8.0 Hz), 7.85 (2H, d, J = 8.0 Hz), 9.67 (1H, brs).

Elemental _{analysis: C 22 H 27 N 3 0} 4 S 3 Calculated: C, 53.53; H, 5.51 ; N, 8.51; S, 19.49

(%), Found: C, 53.16; H, 5.63; N, 8.40; S, 19.47 (%).

Melting point. 166.0- 167. (TC

Example 4-129

 N- [5,6-Dimethyl-3-oxo-8- (tetrahydro-2H-pyran-4-ylsulfanyl) -2,3-dihydrido-1H-imidazo [5, tric] [1,4] Thizine-tolylidene] -4-methylbenzenesulfonamide

 Compound (337 mg, 0.883 mmol) obtained in Example 3-4, sodium iodide (265 mg, 1.77 mmol) and potassium tert-butoxide (175 mg, 1.33 mol) of N-methylpyrrolidone (5.0 ml) While stirring the suspension at room temperature, 4-chlorotetrahydropyran (0.12 ml, 1.06 mmol) was added. The reaction solution was stirred at 100 ° C for 1.5 hours and at 140 ° C for 3 hours. 1N Hydrochloric acid (1.77 ml) and water (35 ml) were added to the reaction solution, and the mixture was extracted with ethyl acetate-diisopropyl ether (30: 5, 35 ml). The organic layer was washed with water and saturated saline, dried and concentrated. The residue was subjected to silica gel (10 g) chromatography (ethyl acetate-hexane, 3: 7-5: 5), and the ethyl acetate-hexane (35: 65-50: 50) fraction was concentrated. The title compound (19 mg, 0.041 tmol) was obtained as red-purple powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.75 (2Η, brq, J = 12 Hz), 1.79 (3H, q, J = 1.0 Hz), 2.00 (2H, brq, J = 12 Hz), 2.26 (3H , q, J = 0.8 Hz), 2.43 (3H, s), 3.47 (2H, dt, J = 2.2, 11.2 Hz), 3.53 (1H, m), 3.95 (2H, dt, J = 11.4, 7.6 Hz) , 7.30 (2H, d, J = 8.2 Hz), 7.86 (2H, d, J = 8.2 Hz), 9.66 (1H, brs).

Elemental analysis: C _2. H ₂₃ N ₃ 0 ₄ S ₃ Calculated: C, 51.59; H, 4.98 ; N, 9.02; S, 20.66 (%), Found: C, 51.29; H, 4.98 ; N, 8.98; S, 20.79 ( %) · Melting point.195.5-201.0 ° C

Example 4-130

 N- (8-{[2- (4-fluorophenyl) -2-propenyl) sulfanylto 5,6_dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, tric] [ 1,4] thiazine-1-ylidene) -4-methylbenzenesulfonamide

 Reference Example 88 was added to a suspension of the compound (329 mg, 0.862 mmol) obtained in Example 3-4 and 1: 1 ^ (6.6 ml) of triethylamine (0.330 ml, 2.16 thigh 01) at room temperature while stirring. The 3-bromo-2- (4-fluorophenyl) propene (purity 70%, 342 mg, 1.03 tmol) obtained in Step 1 was added. During this time, 3-bromo-2_ (4-fluorophenyl) propene (purity 70%, 165 mg, 0.52 mmol) was added to the reaction solution. The reaction was stirred at room temperature for 7.5 hours. 1N Hydrochloric acid (1.3 ml) and methanol-water (1: 1, 6 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol-one water (1: 1) and methanol, and dried to give the title compound (288 mg, 0.559 bandol) as a red-purple powder.

_{^ -NMR (200MHz, CDC1 3)} : δ 1.77 (3Η, brs), 2.25 (3H, brs), 2.40 (3H, s), 4.02 (2H, s), 5.41 (1H, brs), 5.51 (1H, brs), 7.03 (2H, t, J = 8.6 Hz), 7.19 (2H, d, J = 8.4 Hz), 7.37 (2H, dd, J = 8.8, 5.4 Hz), 7.75 (2H, d, J = 8.0 Hz), 9.59 (1H, brs).

Elemental analysis: C ₂₄ H ₂₂ N ₃ 0 ₃ S ₃ F Calculated: C, 55.90; H, 4.30;, 8.15; S, 18.66; F, 3.68 (%), found: C, 55.51; H, 4.15; N, 7.96; S, 19.02; F, 3.52 (%). Melting point. 154.5-156.

Example 4-131

 N- {5,6-dimethyl-3-oxo_8-[(1-propylbutyl) sulfanyl] -2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene } -4-Methylbenzenesulfonamide

A suspension of the compound obtained in Example 3-4 (310 mg, 0.813 bandol) and potassium carbonate (168 mg, 1.22 mmol) in DMF (5 ml) was stirred at 80 ° C while stirring at a temperature of 80 ° C. 83¾, 0.104 ml, 0.49 marl ol) were added twice every 30 minutes. 4-Heptoheptane (purity 83%, 0.20 ml, 0.094 ol) was further added, and the reaction solution was stirred for 30 minutes. 1N Hydrochloric acid (1.63 ml) and methanol-water (2: 1, 4 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 14 hours. The precipitate was collected by filtration, washed with methanol / water (1: 1) 'and methanol, and dried to give the title compound (128 mg, 0.267 ol) as a purple powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 0.92 (6Η, ί, J = 7.2 Hz), 1.42 (4H, brq, J = 7.4 Hz), 1.62 (4H, dt, J = 8.4, 3.8 Hz), 1.79 (3H, q, J = 1.2 Hz), 2.26 (3H, q, J = 1.2 Hz), 2.41 (3H, s), 3.39 (1H, quint, J = 6.4 Hz), 7.27 (2H, d, J = 8.0 Hz), 7.86 (2H, d, = 8.4 Hz), 9.63 (1H, brs).

Elemental _{analysis: C 22 H 29 N 3 0} 3 S 3 Calculated: C, 55.09; H, 6.09 ; N, 8.76; S, 20.05

(%), Found: C, 55.16; H, 6.06; N, 8.73; S, 20.08 (%).

Melting point.128.5-129.5 ° C

Example 4-132

 N- {5,6-dimethyl-8-[(trimethylhexyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-1-ylidene } -4-Methylbenzenesulfonamide

To a suspension of the compound obtained in Example 3-4 (267 mg, 0.697 mmol) and potassium carbonate (45 mg, 1.05 marl) in DMF (4 ml) was stirred at 80 at 80 ° C. while stirring at 2-hydroxyheptane (purity 87¾). , 109 mg, 0.42 mol) was added twice every 90 minutes, and the reaction solution was stirred for 3 hours. 1N Hydrochloric acid (1.4 ml) and methanol / water (2: 1, 5 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol / water (2: 1 and 1: 1) and methanol, and dried to give the title compound (195 mg, 0.407 mmol) as a purple powder. _{Ή-NMR (200MHz, CDC1 3} ): δ 0.90 (3Η, t, J = 6.6 Hz), 1.25-1.42 (6H, m), 1.37 (3H, d, J = 6.6 Hz), 1.63 (2H, quint, J = 7.2 Hz), 1.79 (3H, q, J = 0.8 Hz), 2.26 (3H, q, J = 1.2 Hz), 2.41 (3H ₅ s), 3.45 (1H, q, J = 6.6 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.86 (2H, d, J = 8.4 Hz), 9.64 (1H, brs).

Elemental _{analysis: C 22 H 29 N 3 0} 3 S 3 Calculated: C, 55.09; H, 6.09 ; N, 8.76; S, 20.05 (%), Found: C, 54.96; H, 5.82 ; N, 8.55; S, 20.14 (%).

140.5-141.5 ° C

Example 4-133

N- {8-[(1-Ethylpentyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, lc] [1,4] thiazine-1-ylidene}- Four-' Mid

A suspension of the compound obtained in Example 3-4 (285 mg, 0.747 mol) and potassium carbonate (155 mg, 1.12 mmol) in DMF (4.5 ml) was stirred at 80 ° C at 80 ° C with stirring for 3-heptoheptane (pure). 90%, 113 mg, 0.45 dragonol) was added twice every 30 minutes, and the reaction solution was stirred for 2 hours. 1N Hydrochloric acid (1.5 ml) and methanol-water (2: 1, 5 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol-water (2: 1 and 1: 1) and methanol, and dried to give the title compound (190 mg, 0.382 雇 ol) as a purple powder, Ή-NMR ( _{200MHz, CDC1 3): 6 0.90} (3H, t, J = 7.0 Hz), 0.97 (3H, t, J = 7.5 Hz), 1.35 (4H, m), 1.68 (4H, m), 1.79 (3H, q , J = 1.0 Hz), 2.26 (3H, q, J = 1.2 Hz), 2.41 (3H, s), 3.32 (1H, quint, J = 6.4 Hz), 7.27 (2H, d, J = 7.8 Hz), 7.86 (2H, d, J = 8.0 Hz), 9.64 (1H, brs).

Elemental _{analysis: C 22 H 29 N 3 0} 3 S 3 Calculated: C, 55.09; H, 6.09 ; N, 8.76; S, 20.05

(%), Found: C, 55.02; H, 5.88; N, 8.55; S, 20.19 (%).

Melting point.0.0-140.5 ° C

Example 4-134

 N- {5,6-dimethyl-3-oxo-8-[(2-propylbenzyl) sulfanyl] -2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-1 -Ilident 4-methylbenzenesulfonamide

 A suspension of the compound obtained in Example 3-4 (287 mg, 0.752 mmol) and potassium carbonate (156 mg, 1.13 mmol) in DMF (4.5 ml) was obtained in Reference Example 89 with stirring at 80 ° C. 2-Propylpentyl methanesulfonate (63 mg, 0.301 mmol) was added 7 times every 30 minutes, and the mixture was stirred at 80 ° C for 5 hours. During this time, potassium carbonate (120 mg, 0.868 alcohol) was added. 1N Hydrochloric acid (3.2 ml) and water (10 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration and crystallized from THF-ethyl acetate-methanol to give the title compound (182 mg, 0.369 '-mol) as a dark red powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 0.89 (6Η, brt, J = 7.0 Hz), 1.33 (8H, i), 1.69 (1H, m), 1.78 (3H, q, J = 1.2 Hz), 2.26 (3H, q, J = 0.8 Hz), 2.41 (3H, s), 2.91 (2H, d, J = 6.6 Hz), 7.27 (2H, d, J = 7.6 Hz), 7.86 (2H, dt, J = 8.6, 2.0 Hz), 9.60 (1H, brs). Elemental analysis: Calculated as _{C 23 H 31 N 3 0 3} S 3: C, 55.95; H, 6.33; N, 8.51; S, 19.48

(%), Found: C, 55.97; H, 6.25; N, 8.55; S, 19.58 (%).

134.5-144.0 ° C

Example 4-135

N- {8-[(1-Isobutyl-3-methylbutyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine -Tolylidene} -4-methylbenzenesulfonamide ''

 A suspension of the compound obtained in Example 3-4 (298 mg, 0.781 mmol) and potassium carbonate (162 mg, 1.17 ramol) in DMF (5.0 ml) was obtained in Reference Example 90 while stirring at 80 ° C at 80 ° C. 2,6-Dimethylheptyl iodide (120 mg, 0.312 mmol) was added 7 times every 30 minutes, and the mixture was stirred at 80 for 5.5 hours. During this time, potassium carbonate (120 mg, 0.868 mmol) was added. 1N hydrochloric acid (3.3 ml) and 0.05N hydrochloric acid (20 ml) were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium carbonate solution, 2% aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over sodium sulfate, and concentrated. The residue was purified by silica gel (10 g) chromatography (ethyl acetate-hexane, 2: 8) and crystallized from getyl ether-diisopropyl ether to give the title compound (57 mg, 0.112 mol) in dark red purple Obtained as a powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 0.91 (6Η, d, J = 6.6 Hz), 0.92 (6H, d, J = 6.6 Hz), 1.38 (1H, t, J = 6.4 Hz), 1.50 (3H , t, J = 7.0 Hz), 1.74 (2H, m), 1.80 (3H, brs), 2.27 (3H, brs), 2.42 (3H, s), 3.46 (1H, t, J = 7.3 Hz), 7.27 (2H, d, J = 8.2 Hz), 7.86 (2H, d, J = 8.2 Hz), 9.63 (1H, brs).

Elemental analysis: Calculated as _{C 24 H 33 N 3 0 3} S 3: C, 56.77; H, 6.55;, 8.28; S, 18.95

(%) Found: C, 56.69; H, 6.70; N, 8.20; S, 18.92 ().

Example 4-136

N- {5,6-dimethyl-3-oxo-8-[(2-tetrahydrido-3-furerethyl) sulfanyl] -2,3-dihydro-1H-imidazo [5,1-c] [1,4 ] Thiazine-1-ylidene} -4-Methylbenzenesulfonamide

The methane obtained in Reference Example 92 was stirred in a suspension of the compound obtained in Example 3-4 (299 mg, 0.784 mmol) and potassium carbonate mg, 1.18 ol) in DMF (5 ml) at 80 ° C. 2- (Tetrahydrofuran-3-yl) ethyl sulphonate (183 mg, 0.940 mmol) was added, and the reaction solution was stirred at 80 ° C for 2 hours. During this time, sodium iodide (118 mg, 0.786 mmol) and 2- (tetrahydrofuran-3-yl) ethyl (30 mg, 0.154 mmol) were added to the reaction solution five times every hour. To the reaction solution, 1N hydrochloric acid (1.57 ml), water (5 ml) and methanol (1 ml) were added and mixed. The precipitate was separated from the mother liquor, dissolved in THF and acetonitrile, concentrated, and diluted with methanol. The precipitate was collected by filtration, washed with methanol, and dried to give the title compound (152 mg, 0.317 mmol) as a red-brown powder.

_{lH-NMR (200MHz, CDC1 3} ): δ 1.53 (IH, dq, J = 11.6, 7.2 Hz), 1.76 (1H, m), 1.79 (3H, q, J = 1.0 Hz), 2.07 (IH, m) , 2.26 (3H, q, J = 1.2 Hz), 2.27 (IH, m), 2.42

(3H, s), 2.94 (2H, dt, J = 1.8, 7.6 Hz), 3.38 (IH, dd, J = 8.4, 6.6 Hz), 3.74

(IH, dd, J = 8.6, 7.2 Hz), 3.85 (IH, dt, J = 2.2, 7.0 Hz), 3.89 (IH, dd, J = 8.4,

7.0 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.65 (IH, brs) Elemental analysis:. As _{C 22 H 27 N 3 0 4} S 3 Calculated: C, 52.59; H, 5.25; N, 8.76; S, 20.06 (%), Found: C, 52.50; H, 5.23; N, 8.73; S, 19.93 (%).

139.0-140.0 ° C

Example 4-137

 N- (5,6-Dimethyl-3-oxo-8-{[2- (trifluoromethyl) benzyl] sulfanyl 2,3-dihydro-1H-imidazo [5, lc] [1,4] thiazine- 1-ylidene) -4-methylbenzenesulfonamide

 2-Trifluoromethylbenzyl bromide was added to a suspension of the compound obtained in Example 3-4 (275 mg, 0.721 alcohol) and potassium carbonate (149 mg, 1.08 iol) in DMF (4.5 ml) with stirring at room temperature. (193 mg, 0.793 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. 1N Hydrochloric acid (1.44 ml) and water (5 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol / water (1: 1) and methanol, and dried to give the title compound (369 mg, 0.663 mmol) as a red-purple powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.77 (3Η, q, J = 0.6 Hz), 2.26 (3H, q, J = 0.6 Hz), 2.41 (3H, s), 4.36 (2H, s), 7.24 (2H, brt, J = 8.4 Hz), 7.44 (IH, brt, J = 7.1 Hz), 7.57 (2H, brt, J = 7.1 Hz), 7.69 (IH, brd, J = 7.8 Hz), 7.80 (2H , d, J = 8.4 Hz), 9.63 (1H, brs).

Elemental analysis: C ₂₃ H _2. Calculated for N ₃ 0 ₃ S ₃ F ₃ : C, 51.19; H, 3.74; N, 7.79; S, 17.83; F, 10.56. (%), Found: C, 51.02; H, 3.45; N, 7.86 ; S, 17.93; F, 10.48 (%). Melting point. 206.5-207.5 ° C

Example 4-138

 N- [8- (Cyclohexylsulfanyl) -5,6-dimethyl-3-oxo_2,3-dihydro-1H-imidazo [5, lc] [1,4] thiazine-triylidene] -4-methyl Benzenesulfonamide A suspension of the compound obtained in Example 3-4 (277 mg, 0.726 bandol) and potassium carbonate (151 mg, 1.09 iranol) in DMF (4.5 ml) was stirred at 80 ° C while stirring at 80 ° C. Xanthane (0.105 ml, 0.799 ol) was added, and the reaction solution was stirred at 80 ° C for 8 hours. During this time, cyclohexane (0.105 ml, 0.799 rafflol) was added to the reaction solution three times every two hours, and potassium carbonate (50 mg, 0.363 mmol) was added. To the reaction solution were added 1N hydrochloric acid (1.45 ml) and methanol-luu water (2: 1, 10 ml) and mixed for 17 hours. The precipitate was separated from the mother liquor, dissolved in THF and methanol, concentrated, and diluted with methanol. The precipitate was collected by filtration, washed with methanol, and dried to give the title compound (180 mg, 0.388 mmol) as a gray-red powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.30 (1Η, m), 1.41 (2H, brq, J = 9.7 Hz), 1.60 (1H, m), 1.79 (3H, q, J = 0.8 Hz), 1.79 (2H, m), 2.02 (2H, m), 2.26 (3H, q, J = 1.0 Hz), 2.42 (3H, s), 3.36 (1H, m), 7.28 (2H, d, J = 8.0 Hz) , 7.86 (2H, d, J = 8.0 Hz), 9.63 (1H, brs).

Elemental _{analysis: C 21 H 25 N 3 0} 3 S 3 Calculated: C, 54.40; H, 5.43 ; N, 9.06; S, 20.75

(%), Found: C, 54.19; H, 5.38; N, 8.90; S, 20.37 (%).

Melting point.190.0-191.5 ° C

Example 4-139

N- (5,6-dimethyl-3-oxo-8-{[((2S) -2-phenylpropyl] sulfanyl chloride 2,3-dihydrido-1H-imidazo [5,1-c] [1,4] ] Thiazine-1 ylidene) -4-methylbenzenesulfonamide

A suspension of the compound obtained in Example 3-4 (1.57 _g , 4.11 alcohol) and potassium carbonate (852 mg, 6.17 mmol) in DMF (20 ml) was obtained in Reference Example 93 while stirring at 80 ° C at 80 ° C. Methanesul A solution of (S) -2-phenylpropyl phonate (0.90 g, 4.20 mmol) in DMF (5 ml) was added dropwise over 1 hour, and the reaction solution was stirred at 80 ° C for 8 hours. During this time, (S) -2-phenylpropyl methanesulfonate (0.18 g, 0.82 mmol.) Was added to the reaction solution. IN hydrochloric acid (8.2 ml) and methanol / water (1: 2, 15 ml) were added to the reaction solution, and the mixture was stirred and mixed for 1 hour. The precipitate was collected by filtration, washed with methanol / water (1: 1) and methanol, and dried to give the title compound (0.57 g, 3.17 mmol) as a purple powder.

'H-NMR (200MHz, CDC1 3): δ 1.38 (3Η, d, J = 6.6 Hz), 1.78 (3H, q, J = 1.0 Hz), 2.25 (3H, q, J = 1.2 Hz), 2.42 ( 3H, s), 3.03 (1H, m), 3.09 (1H, m), 3.22 (1H, quint, J = 5.7 Hz), 7.17-7.37 (7H, m), 7.79 (2H, d, J = 8.0 Hz .), 9.60 (1H, brs ) elemental analysis: calculated _{C 24 H 25 N 3 0 3} S 3: C, 57.69; H, 5.04; N, 8.41; S, 19.25 (%), Found: C , 57.36; H, 5.13; N, 8.33; S, 19.27 (%).

Melting point. 161.5-162. Ot:

Example 4-140

 N- (5,6-Dimethyl-3-oxo-8-{[(2R) -2-phenylpyropenpyr] sulfanyl} -2,3-Dihydro-1H-imidazo [5,1-c] [1 , 4] thiazine-triylidene) -4-methylbenzenesulfonamide

 A suspension of the compound obtained in Example 3-4 (1.58 g, 4.13 marl ol) and potassium carbonate (857 mg, 6.20 marl ol) in DMF (20 ml) was obtained in Reference Example 94 while stirring at 80 at 80 ° C. A solution of 00-2-phenylphenyl methanesulfonate (1.02 g, 4.28 benzyl) in DMF (5 ml) was added dropwise over 1 hour, and the reaction solution was stirred at 80 ° C for 6 hours. During this time, 00-2-phenylpropyl methanesulfonate (0.14 g, 0.60 mmol) was added to the reaction solution. To the reaction solution were added IN hydrochloric acid (8.3 ml) and methanolic water (1: 2, 15 ml), and the mixture was stirred and mixed for 1 hour. The precipitate was collected by filtration, washed with methanol / water (1: 1) and methanol, and dried to give the title compound (1.56 g, 3.12 benzyl) as a purple powder.

_{Ή-NR (200MHz, CDC1 3} ): δ 1.38 (3Η, d, J = 6.2 Hz), 1.78 (3H, brs), 2.25 (3H, q, J = 0.8 Hz), 2.42 (3H, s), 3.03 (1H, m), 3.09 (1H, m), 3.22 (1H, quini, J = 5.6 Hz), 7.17-7.36 (7H, m), 7.79 (2H, d, J = 8.0 Hz), 9.60 (1H, brs).

Elemental _{analysis: C 24 ¾ 5 N s 0} 3 S 3 Calculated: C, 57.69; H, 5.04 ; N, 8.41; S, 19.25 (%), Found: C, 57.55; H, 5.12 ; N, 8.38; S, 19.08 (%) Melting point. 162.0-163. Ot:

Example 4-141

 N- (8-{[2- (4-fluorophenyl) propyl] sulfanyl} -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,] thiazine-toylidene) -4-methylbenzene benzenesulfonamide

Of the compound obtained in Example 3-4 (295 mg, 0.773 mmol) and potassium carbonate (160 mg, 1.16 thigh ol) obtained in the stirring Reference Example 95 in suspension in 80 ^D C of DMF (5.0 ml) of 2- (4-Fluorophenyl) propyl methanesulfonate (181 mg, 0.773 tmol) was added, and the reaction solution was stirred at 80 ° C for 7 hours. During this period, 2- (4-fluorophenyl) propyl methanesulfonate (36 mg, 0.15 mmol) was added to the reaction solution. To the reaction solution were added 1N hydrochloric acid (1.55 ml) and methanolic water (1: 1, 4 ml), and the mixture was stirred and mixed for 1 hour. The precipitate was separated from the mother liquor, dissolved in THF and methanol, concentrated, and then diluted with methanol. The precipitate was collected by filtration, washed with methanol, and dried to give the title compound (235 mg, 0.455 mmol) as a purple powder.

_{Ή-NR (200MHz, CDC1 3} ): δ 1.36 (3H, d, J = 6.6 Hz), 1.78 (3H, brs), 2.25 (3H, brs), 2.43 (3H, s), 3.03 (1H, m) , 3.12 (2H, m), 6.99 (2H, t, J = 8.6 Hz), 7.15 (2H, dd, J = 8.8, 5.6 Hz), 7.25 (2H, d, J = 8.4 Hz), 7.78 (2H, d, J = 8.4 Hz), 9.61 (1H, brs).

Elemental _{analysis: C 24 H 24 N 3 0} 3 S 3 F Calculated: C, 55.68; H, 4.67 ; N, 8.12; S, 18.58; F, 3.67 (%), Found: C, 55.33; H , 4.67; N, 7.98; S, 18.56; F, 3.49 (%).

Example 4-142

 N- {5,6-dimethyl-3-oxo-8-[(2,3,4,5,6-pentamethylbenzyl) sulfanyl]-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-1-ylidene} -4-methylbenzenesulfonamide,

To a suspension of the compound obtained in Example 3-4 (268 mg, 0.702 mmol) and potassium carbonate (146 mg, 1.05 mmol) in DMF (4.5 ml) was added 2,3,4 chloride with stirring at 80 ° C. 2,5,6-Pentamethylbenzyl and 2,3,4,5,6-pentamethylbenzyl iodide prepared from sodium iodide (176 mg, 0.773 mL) were added, and the reaction mixture was heated to 80 ° C. And stir for 2.5 hours Was. During this time, the same iodide (18 mg, 0.08 ol) was added to the reaction mixture. 1N Hydrochloric acid (1.4 ml) and methanol / water (1: 1, 4 mD) were added to the reaction solution, and the mixture was stirred for 30 minutes, and the precipitate was collected by filtration, washed with methanol / water (1: 1) and methanol, and dried. Thus, the title compound (360 ig, 0.665 mol) was obtained as a red-purple powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.82 (3Η, q, J = 1.0 Hz), 2.24 (9H, s), 2.26 (3H, brs), 2.28 (6H, s), 2.40 (3H, s) , 4.29 (2H, s), 7.19 (2H, d, J = 8.0 Hz), 7.76 (2H, d, J = 8.0 Hz), 9.65 (1H, brs).

Elemental analysis: C ₂₇ H ₃₁ N ₃ 0 ₃ S ₃ .5 · 5H ₂ 0 Calculated: C, 58.88; H, 5.86; N, 7.63; S, 17.47 (%), found: C, 58.93; H, 5.69; N, 7.65; S, 17.32 ().

Melting point.213.0-215.0 ° C

Example 4-143

The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals.

Melting point: 175-177 ° C.

Infrared absorption spectrum (IR) (in KBr) V 3272, 2946, 2907, 2868, 1748, 1715, 1659, 1613, 1557 cm- ¹ .

 Ή-NMR (CDC "): δ 0.936 (9Η, s), 1.50-1.62 (2H, m), 1.79 (3H, d, J = 1.2 Hz), 2.27 (3H, d, J = 0.6 Hz), 2.42 (3H, s), 2.85-2.96 (2H, m), 7.29 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.62 (1H, bs).

Elemental analysis: Calculated for C ₂₁ H ₂₇ N ₃ 0 ₃ S ₃ : C, 54.17; H, 5.84; N, 9.02; S, 20.66 (%), found: C, 53.81; H, 5.72; N, 8.94; S, 20.42 (%).

Example 4-144

 N- {8-[(mesitylmethyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene}- 4-methylbenzenesulfonamide

To a suspension of the compound (287 mg, 0.752 mmol) obtained in Example 3-4 and potassium carbonate (156 mg, 1.13 mmol) in DMF (4.5 ml) was added 6 (2, 4, 6 -Trimethylpentyl (147 mg, 0.828 mmol) was added, and the reaction solution was stirred for 13 hours at 60 ° C. To the reaction solution was added 1N hydrochloric acid (1.5 ml), methanol / water (3: 2, 5 ml). The precipitate was collected by filtration, washed with methanol / water (1: 1) and methanol, dried, and dried. The title compound (381 mg, 0.741 mmol) was obtained as a purplish red powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.82 (3Η, q, J = 1.0 Hz), 2.28 (3H, q, J = 1.2 Hz), 2.29 (3H, s), 2.33 (6H, s), 2.40 (3H, s), 4.22 (2H, s), 6.88 (2H, brs), 7.20 (2H, d, J = 7.6 Hz), 7.75 (2H, d, J = 8.0 Hz), 9.62 (1H, brs) .

Melting point. 200.5-202.5 ° C

Example 4-145

 N- (5,6-dimethyl-3-oxo-8-{[2- (2,3,4,5,6-pentamethylphenyl) ethyl] sulfanyl} -2,3-dihydro-1H -Imidazo [5,1-c] [1,4] thiazine-1-ylidene) -4- The compound obtained in Example 3-4 (280 mg, 0.734 imnol) and potassium carbonate (152 rag, 1.10 mol) To a suspension of DMF (4.5 ml) in 2- (2,3,4,5,6-pentanomethylphenyl) ethyl methanesulfonate (238 mg, 0.881 The reaction mixture was stirred at 60 ° C. for 20 hours, IN hydrochloric acid (1.47 ml) and water (20 ml) were added to the reaction mixture, and the mixture was extracted with ethyl acetate.The organic layer was extracted with a 2% aqueous sodium hydrogen carbonate solution. After washing with water and saturated saline, drying over sodium sulfate, concentrating and adding methanol to the residue, the precipitate was collected by filtration, washed with methanol, and dried to give the title compound (52 mg, 0.094 ol) as a red-purple powder.

Ή-NMR (200 MHz, CDCI ₃ ): δ 1.77 (3Η, brs), 2.23 (6H, s), 2.24 (3H, s), 2.26 (9H, s), 2.43 (3H, s), 3.03 (4H, s) s), 7.30 (2H, d, J = 8.6 Hz), 7.87 (2H, d, J = 8.6 Hz), 9.66 (1H, brs).

Elemental _{analysis: C 28 H 33 N 3 0} 3 S 3 Calculated: C, 60.51; H, 5.98 ; N, 7.56; S, 17.31

(%), Found: C, 60.48; H, 6.01;, 7.34; S, 17.01 () ·

Melting point.200.7-202.3 ° C

Example 4-146

N- {8-[(2-mesitylmethyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, tric] [4] thiazine-trilidene} -4- Methylbenzene sulfone

To a suspension of the compound (291 mg, 0.763 mmol) obtained in Example 3-4 and potassium carbonate (158 mg, 1.14 mmol) in DMF (4.5 ml) was added the meta 2- (2,4,6-Trimethylphenyl) ethyl sulfonic acid (232 mg, 0.915) was added, and the reaction solution was stirred at 60 ° C for 24 hours. During this time, 2- (2,4,6-trimethylphenyl) ethyl methanesulfonate (97 mg, 0.38 ol) was added to the reaction mixture. The reaction mixture was mixed with 1N hydrochloric acid (1.53 ml) and methanol / water (2: 5.7 ml). The precipitate was separated from the mother liquor, dissolved in THF and methanol, concentrated, and then diluted with methanol. The precipitate was collected by filtration, washed with methanol, and dried to give the title compound (84 mg, 0.159 mmol) as a red-purple powder.

_{lH-NMR (200MHz, CDC1 3} ): δ 1.77 (3Η, brs), 2.26 (6H, s), 2.30 (6H, s), 2.43 (3H, s), 2.98 (4H, m), 6.86 (2H, brs), 7.30 (2H, d, J = 8.4 Hz), 7.86 (2H, d, J = 8.4 Hz), 9.67 (1H, brs).

Elemental _{analysis: C 26 H 29 N 3 0} 3 S 3 Calculated: C, 59.17; H, 5.54 ; N, 7.96; S, 18.23

(%), Found: C, 58.90; H, 5.61;, 7.83; S, 17.96 (%).

Melting point.193.0-195.5 ° C

Example 4-147

N- {5,6-Dimethyl-3-oxo-8-[(tetrahydro-2H-pyran-2-ylmethyl) sulfanyl] -2,3-dihydro-1H-imidazo [5,1-c] [1, 4] thiazin-1-ylidene} -4-methyl compound obtained in Example 3-4 (243 ig, 0.637 benzene), sodium iodide (19 mg, 0.127 mmol) and potassium carbonate (132 mg, 0.955 benzene) ) Was added to a suspension of DMF (4.0 ml) with stirring at 60 ° C, and the reaction mixture was stirred at 60 for 20 hours. The reaction mixture was mixed with 1N hydrochloric acid (1.27 ml) and water (5 ml). The precipitate was separated from the mother liquor, dissolved in THF, concentrated, and diluted with methanol. The precipitate was collected by filtration, washed with methanol, and dried to give the title compound (207 mg, 0.432 ol) as a red-purple powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.30 (2Η, brq, J = 13.0 Hz), 1.53 (2H, m), 1.73 (2H, brd, J = 13.0 Hz), 1.79 (3H, brs), 2.26 (3H, brs), 2.41 (3H, s), 2.99 (1H, dd, J = 13.0, 5.2 Hz), 3.06 (1H, dd, J = 13.2, 6.8 Hz), 3.44 (2H, m), 3.99 ( 1H, brd, J = 11.4 Hz), 7.28 (2H, d, J = 8.0 Hz), 7.86 (2H, d, J = 8.0 Hz), 9.63 (1H, brs). Elemental analysis: C ₂₁ H ₂₅ N ₃ 0 ₄ S ₃ calculated: C, 52.59; H, 5.25 ; N, 8.76; S, 20.06 (%), Found: C, 52.68; H, 5.32;, 8.64; S, 19.68 (%). Melting point. 187.0-189.0 ° C

Example 4-148

N- {5,6-dimethyl-3-oxo-8-[(2-tetrahydrido-2H-pyran-2-ylethyl) sulfanyl] -2,3-dihydro-1H-imidazo [5, tric] [ 1,4] Thiazine-1-yrident 4-me A suspension of the compound obtained in Example 3-4 (289 mg, 0.758 mmol) and potassium carbonate (157 mg, 1.14 mmol) in DMF (4.8 ml). While stirring at 60 ° C, 2- (2-tetrahydropyrael) ethyl iodide (251 mg, 0.909 mmol) obtained in Reference Example 98 was added, and the reaction solution was stirred at 60 ° C for 1.5 hours. IN hydrochloric acid (1.5 ml) and methanol / water (1: 1, 10 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol-water (2: 1 and 1: 1), and dried to give the title compound (336 mg, 0.681 benzyl) as a purple powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.28 (1Η, brq, J = 10.8 Hz), 1.52 (3H, br), ca. 1.6 (1H, m) ,. 1.78 (2H, brq, J = 1.2 Hz ), 1.79 (3H, m), 2.26 (3H, q, J = 1.2 Hz), 2.42 (3H, s), 3.02 (1H, ddd, J = 13.0, 8.8, 7.5 Hz), 3.08 (1H, ddd, J = 12.8, 8.4, 6.0 Hz), 3.32 (1H, dm, J = 8 Hz), 3.39 (1H, dm, J = 8 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.63 (1H, brs).

Elemental _{analysis: C 22 H 21 N 3 0} 4 S 3 - 0.25 O Calculated: C, 53.04; H, 5.56 ; N, 8.43; S, 19.31 (%), Found: C, 53.05; H, 5.59 ; N, 8.46; S, 19.24 (%).

Melting point.169.5-171.0 ° C

Example 4-149

 2-[(5,6-Dimethyl-toluene [[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo [5, c] [1,4] thiazine-8- Yl) sulfanyl] ethyl heptanoate

To a suspension of the compound obtained in Example 3-4 (349 mg, 0.915 mmol) and triethylamine (0.380 ml, 2.74 mmol) in THF (7.0 ml) was added ethyl 2-bromoheptanoate (0.201 ml, 1.01 mol). Added at room temperature. The mixture was stirred at room temperature for 1 hour and then heated to reflux for 24 hours. During this period, 1 ml of ethyl 2-bromoheptanoic acid (0.055 ml, 0.275 mmol) was added to the reaction mixture. Added twice. The reaction solution was concentrated and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and concentrated. The residue was subjected to chromatography on silica gel (10 g) (ethyl acetate-hexane, 1: 4-1: 3). The fraction of ethyl acetate-hexane (1: 3) was concentrated and crystallized from getyl ether to obtain the title compound (142 mg, 0.264 tmol) as a purple powder.

_{¾-NMR (200MHz, CDC1 3} ): δ 0.89 (3Η, brt, J = 6.2 Hz), 1.28 (3H, t, J = 7.1 Hz), ca. 1.31 (4H, brs), 1.38 (2H, m) , 1.78 (2H, brq, J = 1.0 Hz), 1.88 (2H, m), 2.24 (3H, q, J = 0.6 Hz), 2.42 (3H, s), 3.99 (1H, t, J = 7. l Hz), 4.21 (2H, dq, J = 0.8, 7.1 Hz), 7.28 (2H, d, J = 8.0 Hz), 7.86 (2H, dt, J = 8.0, 1.4 Hz), 9.65 (1H, brs).

Elemental _{analysis: C 24 H 31 N 3 0} 5 S 3 Calculated: (:, 53.61; H, 5.81; N, 7.81; S, 17.89

(%), Found: C, 53.81; H, 5.81; N, 8.07; S, 17.82 (%).

Melting point.82.5-87.5 ° C

Example 4-150

The crystals were recrystallized from ethyl acetate-getyl ether to obtain dark red crystals.

137-139 ° C.

Infrared absorption spectrum (IR) (in KBr): 3254, 2924, 1748, 1719, 1663, 1609, 1557, 1497 cm " ¹ .

 Ή-NMR (CDC "): δ 1.70-1.86 (2Η, m), 1.78 (3H, d, J = 0.8 Hz), 2.10-2.24 (2H, m), 2.26 (3H, d, J = 0.8 Hz) , 2.42 (3H, s), 2.94 (2H, d, J = 7.8 Hz), 5.01 (1H, s), 5.04-5.11 (1H, m), 5.64-5.87 (1H, m), 7.28 (2H, d , J = 8.0 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.62 (1H, bs).

Elemental analysis: C _2. H ₂₃ N ₃ 0 ₃ S ₃ Calculated: C, 53.43; H, 5.16; N, 9.35; S, 21.40 (%), Found: C, 53.43; H, 5.16; N, 9.33; S, 21.26 ( %) ·

Example 4-151

The crystals were recrystallized from ethyl acetate-getyl ether to obtain dark red crystals.

Melting point 184-186.

Infrared absorption spectrum (IR) (in KBr) V: 3285, 2946, 1753, 1717 cm " ¹ .

_{Ή-NR (CDC1 3):} δ 1.79 (3Η, d, J = 1.2 Hz), 2.14-2.30 (2H, m), 2.27 (3H, d, J = 1.2 Hz), 2.42 (3H, s), 2.95-3.14 (1H, m), 3.08 (2H, t, J = 7.8Hz), 7.30 (2H, d, J = 8.0 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.62 (1H, bs).

Elemental analysis: C _{2. H ig N 3 0 3 S 3} F 6 Calculated: C, 42.93; H, 3.42 ; N, 7.51; S, 17.19

(%), Found: C, 43.17; H, 3.52; N, 7.49; S, 17.38 (%).

Example 4-152

Recrystallization from ethyl acetate-diisopropyl ether gave dark red crystals.

Mp 195-197 ° C.

Infrared absorption spectrum (IR) (in KBr) So: 3250, 2924, 1732, 1667, 1615, 1557, 1495 cm ^-1 .

_{Ή-NMR (CDC1 3):} δ 1.6-1.78 (2Η, m), 1.82 (3H, d, J = 1.2 Hz), 2.12-2.42 (2H, m), 2.87 (3H, d, J = 0.8 Hz) , 2.35 (3H, s), 2.69-2.98 (4H, m), 3.64-3.80 (1H, 1), 7.06-7.18 (4H, in), 7.21 (2H, d, J = 8.0 Hz), 7.82 (2H , D, J = 8.4 Hz), 9.62 (1H, bs).

Elemental analysis: C ₂₆ H _Z7 N ₃ 0 ₃ S ₃ · 0.3 H ₂ 0 Calculated: C, 58.79; H, 5.24; N, 7.91; S, 18.11 (%), found: C, 58.71; H , 5.37; N, 7.92; S, 17.81 (%).

Example 4-153

 N- {5,6-dimethyl-8-[(2-methylbutyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5, 1-c] [1,4] thiazine-1-ylidene } -4-Methylbenzenesulfonamide

 To a suspension of the compound obtained in Example 3-4 (256 mg, 0.671 mmol) and potassium carbonate (139 mg, 1.01 mmol) in DMF (4.0 ml) was stirred at 80 ° C at 80 ° C for 1-do-2- Methyl butane (155 mg, 0.738 tmol) was added and the mixture was stirred for 50 minutes. 1N Hydrochloric acid (1.34 ml) and methanol-water (1: 1, 4 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 60 minutes. The precipitate was collected by filtration, washed with methanol / water (1: 1) and methanol, and dried to give the title compound (275 mg, 0.609 bandol) as a red powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 0.91 (3Η, t, J = 7.4 Hz), 1.00 (3H, d, J = 6.6 Hz), 1.25 (1H, dt, J = 13.6, 7.4 Hz), 1.48 (1H, sixtet, J = 6.6 Hz), 1.68 (1H, m), 1.78 (3H, s), 2.26 (3¾s), 2.43 (3H, s), 2.75 (1H, dd, J = 12.6, 7.4 Hz ), 2.94 (1H, dd, J = 12.4, 6.2 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.86 (2H, d, J = 8.4 Hz), 9.62 (1H, brs).

Elemental analysis: C _2. H ₂₅ N ₃ 0 ₃ S ₃ Calculated: C, 53.19; H, 5.58 ; N, 9.30; S, 21.30

(%), Found: C, 53.02; H, 5.60; N, 9.40; S, 21.20 (%).

Melting point 165.0-166.2 ° C

Example 4-154

 N- (8-{[2- (4-Mouth-phenyl) propyl] sulfanyl} -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1 , 4] Thiazine-1-ylidene) -4-methylbenzenesulfonamide

 In Reference Example 100, a suspension of the compound (1.59 g, 4.1711111101) obtained in Example 3-4 in DMF (20 ml) of potassium carbonate (8651 ^, 6.26 mmol) was stirred at 60 ° C. The obtained 2- (4-chlorophenyl) propyl iodide (purity 9 1.35 g, 4.59 benzyl) was added in two portions at 30 minute intervals, and the reaction solution was stirred for 1 hour. 1N Hydrochloric acid (8.4 ml) was added to the reaction solution, and the mixture was diluted with methanolic water (1: 1, 20 ml) and stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol / water (1: 1) and methanol, and dried to give the title compound (2.08 g, 3.89 mmol) as a red-purple powder.

'H-NMR (200MHz, CDC1 3): δ 1.36 (3Η, d, J = 6.6 Hz), 1.78 (3H, q, J = 0.8 Hz), 2.25 (3H, q, J = 0.8 Hz), 2.43 ( 3H, s), 3.03 (1H, m), 3.12 (2H, m), 7.14 (2H, brd, J = 8.8 Hz), 7.26 (4H, m), 7.77 (2H, d, J = 8.6 Hz), . 9.62 (1H, brs) elemental _{analysis: C 24 H 24 N 3 0} 3 S 3 C1 · 0.5H 2 0 calculated: C, 53.08; H, 4.64 ; N, 7.74; S, 17.71: CI, 6.53 (), Found: C, 53.27; H, 4.60; N, 7.85; S, 17.44: Cl, 6.83 ().

Example 4-155

 N— [8 — ({[1— (4-chlorophenyl) cyclopropyl] methyl} sulfanyl) -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1- c] [1,4] thiazine-trilidene] -4-methylbenzenesulfonamide

 According to the esterification method of Reference Example 31, methyl 4- (4-chlorophenyl) cyclopropanecarboxylate (7.07 g, 35.6 mmol) was obtained according to the esterification method of Reference Example 31 (purity about 80%, 7.3 g) of a pale yellow oil was obtained.

_{Ή-NMR (200MHz, CDC1 3} ): 51.16 (2H, q, J = 3.5 Hz), 1.61 (2H, q, J = 3.7 Hz), 3.63 (3H, s), 7.28 (4H, s).

 Methyl 1- (4-chlorophenyl) cyclopropanecarboxylate (purity: about 80%, 7.3 g) was prepared according to the method of reduction using lithium aluminum hydride in Reference Example 31 to give 1_ (4-chlorophenyl) cyclopropanemethanol. A colorless oil (purity 93%, 5.6 g, 29 fflmol) was obtained.

_{Ή-NMR (200MHz, CDC1 3} ): (50.86 (4H, s), 3.65 (2H, s), 7.29 (4H, s).

 Triethylamine (0.209 ml) was added to a solution of 2- (4-chlorophenyl) propanol (0.24 g, 1.30 benzyl) and methanesulfonyl chloride (0.108 ml, 1.38 ml) in THF (2.0 ml) while stirring at 0 ° C. , 1.51 ol) in THF (0.4 ml) was added dropwise over 5 minutes, and the reaction solution was stirred at 0 ° C for 25 minutes. This reaction solution was added to a suspension of the compound obtained in Example 3-4 (300 mg, 0.786 mol) and potassium carbonate (163 ig, 1.18 mmol) in DMF (3.5 ml) while stirring at 60 ° C. The mixture was stirred at 80 for 16 hours. 1N Hydrochloric acid (2.4 ml) was added to the reaction solution, diluted with methanol / water (1: 1, 10 ml), and stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol-water (α: ι), and then crystallized from methanol. The resulting dark purple powder (212 mg) was recrystallized from THF and ethyl acetate, and further from ethyl acetate and methanol to give the title compound (134 mg, 0.245 ol) as dark purple powder.

_{¾-NMR (200MHz, CDC1 3} ): δ 0.97 (4Η, brd, J = 3.6 Hz), 1.73 (3H, brq, J = 1.2 Hz), 2.23 (3H, brq, J = 1.2 Hz), 2.44 (3H , s), 3.21 (2H, s), 7.23 (4H, m), 7.26 (2H, d, J = 8.4 Hz), 7.79 (2H, dt, J = 8.4, 1.8 Hz), 9.60 (1H, brs) .

Elemental _{analysis: C 25 H 24 N 3 0} 3 S 3 C1 Calculated: C, 54.98; H, 4.43 ; N, 7.69; S, 17.61

(%), Found: C, 54.76; H, 4.44; N, 7.83; S, 17.57 (%).

Example 4-156

 N- {8-[(2,2-difluoro-2-phenylethyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1 , 4] Thiazine-1-ylidene} -4-Methylbenzenezensulfonamide

To a suspension of the compound (283 mg, 0.742 mmol) obtained in Example 3-4 and potassium carbonate (154 mg, 1.11 ranol) in DMF (4.5 nil) was stirred at 60 at 60.degree. 2,2-difluoro-2-phenylethyl methanesulfonate (237 mg, 0.816 mmol) and the mixture was stirred at 60 ° C. for 4 hours. 1N Hydrochloric acid (1.50 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes, diluted with methanol / water (1: 1, 5 ml), and stirred for 30 minutes. The precipitate was collected by filtration, washed with methanol-water (1: 1) and methanol, and dried to give the title compound (302 mg, 0.580 eol) as a dark purple powder.

'H-NMR (200MHz, CDC1 3): δ 1.77 (3Η, brs), 2.21 (3H, brs), 2.43 (3H, s), 3.61 (2H, t, J- 13.7 Hz), 7.30 (2H, d , J = 8.0 Hz), 7.41 (5H, m), 7.85 (2H, d, J = 8.0 Hz), 9.62 (1H, brs).

Elemental _{analysis: C 23 H 21 N 3 0} 3 S 3 F 2 Calculated: C, 52.96; H, 4.06 ; N, 8.06; S, 18.44; F, 7.28 (%), Found: C, 52.93; H, 4.11; N, 8.05; S, 18.50; F, 7.33 (%). Mp.180.0-181.5 ° C

Example 4-157

Recrystallization from ethyl acetate-getyl ether gave dark red crystals.

Melting point 167-169 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3243, 2928, 2868, 1748, 1721, 1661, 1611, 1557, 1497 cm- ¹ .

_{Ή-NMR (CDC1 3):} (5 1.61-1.84 (4H, in), 1.78 (3H, d, J = 0.8 Hz), 2.26 (3H, d, J = 0.8 Hz), 2.42 (3H, s), 2.97 (2H, t, J = 6.4 Hz), 3.33 (3H, s), 3.39 (2H, i, J-5.8 Hz), 7.29 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.62 (1H , bs) elemental _{analysis: C 2 () H 25 N} 3 0 4 S 3 '0.3H 2 0 calculated:. C, 50.78; H, 5.45; N, 8.88; S , 20.34 (%), Found: C, 50.85; H, 5.31; N, 8.99; S, 20.04 () ·

Example 4-158

N- {5,6-dimethyl-8 _ [(2-methyl-2-phenylpyrpyr) sulfanyl] -3-oxo-2,3_dihydro-1H-imidazo [5,1-c] [1,4] Thiazine-1-ylidene 4-methylbenzenesulfonamide

A solution of 2-phenyl-2-methylpropyl (8.1 g, 48 mmol), potassium hydroxide (12.7 g, 0.192 mol), and acetic acid (5.51 ml, 96 t ol) in DMS0 (40 ml) at 120 for 24 hours. Stirred. The reaction solution was mixed with diisopropyl ether (150 ml) and water (100 ml), and the organic layer was washed with dilute hydrochloric acid, water and saturated saline, dried over sodium sulfate, and concentrated to obtain a pale brown oil. . The oil was chromatographed on silica gel (50 g). Purification with ethyl acetate (5: 95-25: 75) gave 2-phenyl-2-methylpropanol (1.29 g, 8.59 mmol) as a colorless oil.

_{] HN R (200MHz, CDC1 3} ): (51.20 (1H, br), 1.35 (6H, s), 3.63 (2H, brs), 7.27 (1H, m), 7.34 (1H, m), 7.38 (3H, m).

 The compound (335 mg, 0.878 mmol) obtained in Example 3-4, 2-phenyl-2-methylpropanol (176 mg, 1.17 mmol) and triphenylphosphine (332 mg, 1.23 mmol) in THF (7 ml) were used. ) Was added dropwise to the suspension at room temperature with stirring at room temperature, and the reaction solution was stirred at room temperature for 15 hours, and then at 6 (TC for 7 hours). The reaction mixture was diluted with ethyl acetate, washed with sodium bicarbonate, 0.1 hydrochloric acid, water and saturated saline, dried over sodium sulfate and concentrated, and the residue was crystallized from methanol to give the title compound (253 mg, 0.493 mmol) as a dark purple powder.

_{^ - R (200MHz, CDC1 3} ): δ 1.44 (6Η, s), 1.76 (3H, q, J = 1.2 Hz), 2.22 (3H, q, J = 1.2 Hz), 2.42 (3H, s), 3.24 (2H, s), 7.24 (2H, d, J = 8 Hz), 7.29 (3H, m), 7.30 (2H, d, J = 8.4 Hz), 7.76 (2H, d, J = 8.4 Hz), 9.55 . (1H, brs) elemental _{analysis: C 25 H 27 N 3 0} 3 S 3 calculated: C, 58.45; H, 5.30 ; N, 8.18; S, 18.73

(%), Found: C, 58.23; H, 5.19; N, 8.28; S, 18.68 (%).

mp. 183.5-185.2 ° C

Example 4-159

N- (5,6-Dimethyl-3-oxo-8-{[2- (3-Chenyl) ethyl] sulfanyl} -2,3-dihydrido-1H-imidazo [5,1-c] [1, 4] Thiazine-1-ylidene) -4-methylbenzenesulfonamide

 (Method 1) To a solution of 2- (3-thenyl) ethanol (0.21 g, 1.61 mmol) and methanesulfonyl chloride (0.138 ml, 1.77) in THF (4.2 ml) while stirring at 0 ° C was added triethylamine (0.1 ml). (0.267 ml, 1.93 mmol) was added, and the reaction solution was stirred at 0 ° C for 60 minutes. The reaction solution was extracted with ethyl acetate, washed with water, dried and concentrated to dryness to obtain crude 2- (3-thenyl) ethyl methanesulfonate (purity 60%, 104 mg, 0.30 mmol) as a colorless oil. .

'H-NMR (200MHz, CDC1 3): 52.90 (3H, s), 3.10 (2H, t, J = 6.8 Hz), 4.42 (2H, t, J = 6.8 Hz), 6.99 (1H, dd, J = 4.8, 1.3 Hz), 7.10 (1H, m), 7.31 (1H, dd, J2 5.0, 2.9 Hz).

 The above methanesulfonic acid 2 was added to a suspension of the compound obtained in Example 3-4 (110 mg, 0.288 mol) and potassium carbonate (60 mg, 0.433 mmol) in DMF (2.0 ml) while stirring at 80 ° C. -A solution of (3-Chenyl) ethyl (purity 60, 102 mg, 0.297 t) in DMF (1.0 ml) was added and the mixture was stirred at 80 ° C for 1 hour and then at 60 ° C for 12 hours. 1N Hydrochloric acid (0.58 ml) and water (20 ml) were added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with 0.1N hydrochloric acid, water and saturated saline, dried over sodium sulfate, and concentrated. The residue was crystallized from methanol to give the title compound (62 mg, 0.126 ol) as a purple powder.

_{¾- NMR (200MHz, CDC1 3)} : δ 1.79 (3Η, q, J = 0.8 Hz), 2.26 (3H, q, J = 0.8 Hz), 2.43 (3H, s), 3.00 (2H, brt, J = 7.7 Hz), 3.18 (2H, brt, J = 7.4 Hz), 6.95 (1H, dd, J = 4.8, 1.6 Hz), 7.01 (1H, m), 7.27 (2H, m), 7.28 (2H, d, J = 8.4 Hz), 7.83 (2H, d, J-8.4 Hz), 9.63 (1H, brs).

Elemental analysis: C ₂₁ H ₂₁ N ₃ 0 ₃ S ₄ · 0.2H ₂ 0 Calculated: C, 50.93; H, 4.35; N, 8.48; S, 25.90 (%), Observed: C, 50.74; H , 4.29; N, 8.81; S, 25.86 (%)

mp. 182.0- 183.0

 (Method 2) THF (179 mg, 0.661 mmol) of the compound (240 mg, 0.629 mmol), 2- (3-thenyl) ethanol (82 mg, 0.629 mmol) and triphenylphosphine (179 mg, 0.661 mmol) obtained in Example 3-4 was used. DEAD (0.109 ml, 0.661 t) was added dropwise to the 5 ml) suspension while stirring at room temperature, and the reaction solution was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate, washed with 2% sodium hydrogen carbonate, 0.1 hydrochloric acid, water and saturated saline, dried over sodium sulfate, and concentrated. The residue was crystallized from ethyl acetate and again from THF to give the title compound (166 mg, 0.338 mmol) as a purple powder.

Example 4-160

 N- (5,6-Dimethyl-3-oxo-8-{[2- (2-Chenyl) ethyl] sulfanyl} -2,3-dihydrogen-1H-imidazo [5, lc] [1, ] Thiazine-1-ylidene) -4-methylbenzenesulfonamide

2- (2-Chenyl) ethanol (5.78 g, 44.2 olol) Triethylamine (7.04 ml, 50.8 t) was added to THF (90 ml) solution of the compound (3.63 ml, 46.t) at 40 ° C with stirring at 0 ° C for 40 minutes, and the reaction solution was added at 0 ° C. Stirred for 60 minutes. The reaction mixture was extracted with ethyl acetate-hexane (1: 1), washed with water, dried and concentrated to dryness. 2- (2-Chenyl) ethyl methanesulfonate (purity 94%, 9.7 g, 44.2 t ol) Was obtained as a colorless oil.

_{Ή-NMR (200MHz, CDC1 3} ): 52.93 (3H, s), 3.28 (2H, dt, J = 0.6, 6.6 Hz), 4.42 (2H, t, J = 6.6 Hz), 6.91 (1H, m), 6.96 (1H, dd, J = 5.2, 3.4 Hz), 7.20 (1H, dd, J = 5.0, 1.0 Hz).

 The above methanesulfonic acid 2 was added to a suspension of the compound obtained in Example 3-4 (403 mg, 1.06 mmol) and potassium carbonate (219 mg, 1.58 toluene) in DMF (6.0 ml) while stirring at 80 ° C. A solution of-(2-Chenyl) ethyl (purity 94%, 278 mg, 1.27 mmol) in DMF (1.0 ml) was added, and the mixture was stirred at 80 for 4 hours. To the reaction solution were added 1N hydrochloric acid (2.1 ml) and methanolic water (1: 1, 10 ml), and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol (1: 1) and methanol, and dried to give the title compound (430 mg, 0.875 mmol) as a purple powder.

'H-NMR (200MHz, CDC1 3): 6 1.79 (3H, q, J = 0.8 Hz), 2.27 (3H, q, J = 0.6 Hz), 2.43 (3H, s), 3.20 (4H, s), 6.85 (1H, dd, J = 3.6, 1.0 Hz), 6.94 (1H, dd, J = 5.1, 3.3 Hz), 7.18 (1H, dd, J = 5.1, 1.0 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.64 (1H, brs).

Elemental analysis: Calculated for C ₂₁ H ₂₁ N ₃ 0 ₃ S ₄ : C, 51.30; H, 4.31;, 8.55; S, 26.09 (%), found: C, 51.25; H, 4.34; N, 8.77 ; S, 25.88 (%).

mp.172.0-173.5 ° C

Example 4-161

Recrystallization from ethyl acetate-diisopropyl ether gave dark red crystals.

Melting point 118-120 ° C.

Infrared absorption spectrum (IR) (in KBr): 3250, 2936, 2863, 1728, 1661, 1615, 1557, 1495 cnr ¹ .

_{'H-NMR (CDC1 3)} : δ 1.37-1.77 (6Η, m), 1.78 (3H, d, J = 0.8 Hz), 2.26 (3H, s), 2.42 (3H, d, J = 0.8 Hz), 2.94 (2H, t, J = 7.8 Hz), 3.34 (3H, s), 3.37 (2H, t, J = 5.8 Hz), 7.29 ( 2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.61 (1H, bs) Elemental _{analysis:. C 21 H 27 N 3} 0 4 S Calculated as ₃ : C, 52.37; H, 5.65; N, 8.72; S, 19.97 (%), Found: C, 52.03; H, 5.69; N, 8.98; S, 20.15 (%).

Example 4-162

The crystals were recrystallized from ethyl acetate-ethyl ether to obtain red crystals.

190-192 ° C.

Infrared absorption spectrum (IR) (in KBr) V 3243, 2973, 2932, 2826, 1748, 1732, 1717, 1661 cnr ¹ .

_{Ή-NMR (CDC1 3):} δ 1.19 (6Η, s), 1.79 (3H, s), 1.75-1.88 (2H, m), 2.26 (3H, s), 2.42 (3H, s), 2.98 (2H, t, J = 8.4 Hz), 3.18 (3H, s), 7.29 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.6 Hz), 9.60 (1H, bs).

Elemental _{analysis: C 21 H 27 N 3 0} 4 S 3 Calculated: C, 52.37; H, 5.65 ; N, 8.72; S, 19.97

(%), Found: C, 52.03; H, 5.65; N, 8.79; S, 19.65 (%).

Example 4-163

The crystals were recrystallized from ethyl acetate-ethyl ether to obtain red crystals.

Melting point: 162-164 ° C.

Infrared absorption spectrum (IR) (in KBr) Re: 3700-3100, 2696, 1732, 1663, 1613, 1557 cm " ^1. ¾-R (CDCI ₃ ): δ 1.27 (6Η, s), 1.79 (3H , s), 1.82 (2H, t, J = 8.8 Hz), 2.26 (3H, s), 2.42 (3H, s), 3.06 (2H, t, J = 8.8 Hz), 7.29 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.2 Hz), 9.63 (1H, bs).

Elemental _{analysis: C 20 H 25 N 3 0} 4 S 3 · 0.3H 2 0 Calculated: C, 50.78; H, 5.45 ; N, 8.88; S, 20.34 (%), Found: C, 50.87; H , 5.44; N, 8.50; S, 19.97 (%).

Example 4-164

N- [8- (Cyclooctylsulfanyl) -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene] _4 -Methylbenzenesulfonamide A suspension of the compound obtained in Example 3-4 (1.85 g, 4.85 mmol) and potassium carbonate (2.82 g, 20.4 thigh 01) in DMF (80 ml) was stirred at 60 ° C. Meanwhile, a solution of o-cyclocyclotanne (purity 75%, 4.34 g, 13.6 mmol) in DMF (10 ml) was added dropwise over 2 hours. The reaction solution was stirred at 60 ° C for 4 hours. During the reaction, eodocyclooctane (purity 75%, 0.43 g, 1.36 iMiol) was added three times. IN hydrochloric acid (30 ml) was added to the reaction solution, diluted with water (50 ml), and stirred at room temperature for 60 minutes. The precipitate was collected by filtration, washed with methanol / water (1: 1) and methanol, and dried to give crude compound 4-164 (purity 80%, 5.45 g, 8.87 mmol) as a magenta powder . This powder (1.40 g) was crystallized from THF-ethyl acetate to give the title compound (837 nig, 1.70 ol) as a purple-red powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.50-1.80 (10H, m), 1.79 (3H, brs), 1.98 (4H, m), 2.26 (3H, brs), 2.42 (3H, s), 3.59 ( 1H, m), 7.28 (2H, d, J = 8.0 Hz), 7.86 (2H, d, J = 8.0 Hz), 9.62 (1H, brs).

Elemental _{analysis: C 23 H 29 N 3 0} 3 S 3 Calculated: C, 56.18; H, 5.94 ; N, 8.55; S, 19.56 (), Found: C, 55.81; H, 6.04 ; N, 8.54 ; S, 19.66 (%).

nip.166.5-169.0 ° C

Example 4-165

The crystals were recrystallized from ethyl acetate-ethyl ether to obtain red crystals.

Mp 195-197 ° C.

Infrared absorption spectrum (IR) (in KBr) Re:. 3220, 2959, 1740, 1661, 1622, 1564 cm "1 Ή-NMR (CDC1 3): δ 1.03 (9Η, s), 1.79 (3H, s) , 2.26 (3H, s), 2.41 (3H, s), 2.89 (2H, s), 7.27 (2H, d, J = 8.0 Hz), 7.87 (2H, d, J = 8.4 Hz), 9.58 (1H, bs). Example 4-166

 N- {5,6-dimethyl-8-[(4-methylphenyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-triylidene} -4-methylbenzenesulfone

A suspension of the compound obtained in Example 3-4 (259 mg, 0.679 ol), p-toluenethiol (103 mg, 0.815 ol) and triphenylphosphine (275 mg, 1.02 ol) in THF (5 ml) was used. Diisopropyl azodicarboxylate (hereinafter sometimes referred to as DIAD, 0.20.7 ml, 1.02 mmol) was added dropwise to the suspension while stirring at room temperature, and the reaction solution was stirred at room temperature for 3 days and further at 60 ° C for 2 days. . During this time, triphenylphosphine (184 mg, 0.679 t ol) and DIAD (0.138 ml, 0.679 t ol) were added to the reaction solution. The reaction solution was diluted with ethyl acetate, washed with sodium bicarbonate, 0.1N hydrochloric acid, water and saturated saline, dried over sodium sulfate, and concentrated. The residue was chromatographed on silica gel (10 g) (vinegar Purification with ethyl acetate-hexane (2: 8-3: 7), and the red fraction of ethyl acetate-hexane (3: 7) was crystallized from methanol to give the title compound (112 mg, 0.237 mol) as a purple-red powder. I got it.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.60 (3Η, brs), 2.23 (3H, brs), 2.41 (3H, s), 2.43 (3H, s), 7.20 (2H, brd, J- 8.0 Hz) , 7.31 (2H, d, J = 8.4 Hz), 7.42 (2H, d, J = 8.0 Hz), 7.89 (2H, d, J = 8.4 Hz), 9.64 (1H, brs).

Elemental _{analysis: C 22 H 21 N 3 0} 3 S 3 Calculated: C, 56.03; H, 4.49 ; N, 8.91; S, 20.40

(%), Found: C, 55.97; H, 4.45; N, 8.76; S, 20.22 ().

mp. 190.5-191.51:

Example 4-167

 N- {8-[(2,2-difluoro-3-methylbutyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4 ] Thiazine-1-ylidene} -4-Methylbenzenesulfonamide

 (Method 1) Compound (195 mg, 0.511 alcohol) obtained in Example 3-, 2,2-difluoroisopentanol (purity 20%, 0.34 g, 0.55 mmol) obtained in Reference Example 101 and trifluorophenol Nilphosphine (553 mg, 2.04 bandit 01): [11? A 1 ^ (1 ml) solution of DIAD (0.415 ml, 2.04 thigh 01) was added dropwise to the (4 ml) suspension with stirring at 60 over 3 hours, and the reaction solution was stirred for 3 hours. The reaction solution was diluted with ethyl acetate, washed with 2% sodium hydrogencarbonate, 0.1N hydrochloric acid, water and saturated saline, dried over sodium sulfate, and concentrated. The residue was purified by chromatography on silica gel (10 g) (ethyl acetate-hexane, 15: 85-30: 70), and the red fraction of ethyl acetate-hexane (20: 80-25: 75) was crystallized from methanol. The title compound (22 rag, 0.045 ol) was obtained as a deep purple powder.

_{Ή- NMR (200MHz, CDC1 3)} : δ 1.03 (6H, d, J = 7.0 Hz), 1.80 (3H, brs), 2.19 (1H, tq, J = 14.8, 7.0 Hz), 2.25 (3H, brs) , 2.42 (2H, s), 3.37 (2H, t, J = 14.8 Hz), 7.29 (2H, d, J = 8.0 Hz), 7.86 (2H, d, J = 8.0 Hz), 9.63 (1H, brs) .

Elemental analysis: C _2. Calculated as H ₂₃ N ₃ 0 ₃ S ₃ F ₂ : C, 49.26; H, 4.75; N, 8.62; S, 19.73 (%), found: C, 49.59; H, 4.71;, 8.61; S, 19.93 (%).

(Method 2) A suspension of the compound (591 mg, 1.55 mmol) obtained in Example 3-4 and DMF (10 ml) of carbonated carbonate (321 mg, 2.32 2.301) was stirred at 60 with reference to Example 102 2,2-Difluoroisopentyl trifluoromethanesulfonate (purity 60%, 187 mg, 0.517IMO1) was added three times every hour, and the reaction solution was further stirred for 4 hours. 1N Hydrochloric acid (3.1 ml) was added to the reaction solution, diluted with methanol / water (1: 1, 5 ml), and stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol / water (1: 1) and methanol, and dried to give the title compound (487 mg, 0.999 bandol) as a purple powder.

Immediately. 168.5-169.5t

Example 4-168

 N- (5,6-dimethyl_3-oxo-8-{[2- (4-pyridinyl) ethyl] sulfanyl} _2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine -1-ylidene) -4-methylbenzenesulfonamide

 The compound (276 mg, 0.723 mmol) obtained in Example 3-4, 2- (4-pyridyl) ethanol hydrochloride (173 mg, 1.09 mmol) and triphenylphosphine (783 mg, 2.89 mmol) in THF (5 A suspension of DIAD (0.587 ml, 2.89 fold) in THF (1 mi) was added dropwise to the suspension of the resulting mixture at 60 ° C. over 40 minutes, and the reaction solution was stirred for 2 hours. The reaction solution was diluted with ethyl acetate (20 ml), and the precipitate was collected by filtration, washed with ethyl acetate and getyl ether, and suspended in methanol and THF. The suspension was concentrated and diluted with acetonitrile. The insolubles were collected by filtration, washed with acetonitrile, and dried to obtain the title compound (47 mg, 0.097 mmol) as a gray-purple powder.

_{Ή - NMR (200MHz, CDC1 3} + TFA): δ 1.82 (3H, br), 2.27 (3H, brs), 2.43 (3H, s), 3.30 (4H, s), 7.30 (2H, d, J = 8.0 Hz), 7.81 (2H, d, J = 8.0 Hz), 7.84 (2H, d, J = 5.2 Hz), 8.91 (2H, d, 'J = 6.2 Hz), 9.96 (1H, br).

Elemental analysis: C ₂₂ H ₂₂ N ₄ 0 ₃ S ₃ · Η ₂₀ Calculated: C, 52.36; Η, 4.79; Ν, 11.10 (), found: C, 52.60; H, 4.91;, 11.02 ( %).

Example 4-169

The crystals were recrystallized from ethyl acetate-getyl ether to obtain red crystals.

157-159 ° C.

Infrared absorption spectrum (IR) (in KBr) V:. 3241, 1746 , 1725, 1663, 1618, 1561 cm one _{^{1 'H-NMR (CDC1 3}} ): δ 1.75 (3H, s), 1.79 (3H, d , J-0.8 Hz), 2.27 (3H, d, J = 0.8 Hz), 2.37 (2H, t, J = 7.8 Hz), 2.42 (3H, s), 3.05 (2H, t, J = 8.4 Hz), 4.76 (IH, s), 4.83 (1H, s), 7.28 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.0 Hz), 9.60 (1H, bs).

Elemental analysis: C _2. H ₂₃ N ₃ 0 ₃ S ₃ Calculated: C, 53.43; H, 5.16; N, 9.35; S, 21.40 (%); Found: C, 53.40; H, 5.26; N, 9.06; S, 21.06 ( %).

Example 4-170

 N_ (5,6-Dimethyl-3_oxo-8-{[4- (trifluoromethyl) phenyl] sulfanyl 2,3-dihydro-1H-imidazo [5,1-c] [1,4] Thiazine-1-ylidene) -4-methylbenzenesulfonamide

 Of the compound (259 ing, 0 · 679-1) obtained in Example 3-4, 4-trifluoromethylbenzenthiol (234 mg, 1.31 ol) and triphenylphosphine (734 mg, 2.72 ol) To a suspension of THF (5 ml) was added DEAD (0.450 ml, 2.72 mmol) while stirring at room temperature, and the reaction solution was stirred for 6 days. The reaction solution was diluted with ethyl acetate, washed with a 2% aqueous sodium hydrogen carbonate solution, 0.1N hydrochloric acid, water and saturated saline, dried over sodium sulfate, and concentrated. The residue was chromatographed on silica gel (10 g) (ethyl acetate-hexane, 1: 9-5: 5). The obtained crude fraction was again subjected to chromatography on silica gel (10 g) (ethyl acetate-hexane, 1: 9-3: 7), and a red fraction of ethyl acetate-hexane (25:75) was obtained. Crystallization from methanol gave the title compound (115 mg, 0.219 tmol) as a red-orange powder.

_{Ή- NMR (200MHz, CDC1 3)} : δ 1.61 (3Η, brs), 2.24 (3H, brs), 2.43 (3H, s), 7.31 (2H, d, J = 8.2 Hz), 7.65 (2H, d, J = 8.4 Hz), 7.67 (2H, d, J = 8.8 Hz), 7.88 (2H, d, J = 8.2 Hz), 9.66 (1H, brs).

Elemental _{analysis: C 22 H 18 N 3 0} 3 Calculated _{S 3 F 3: C, 50.27} ; H, 3.45; N, 7.99; S, 18.30; F, 10.84 (%), Found: C, 50.24; H, 3.15; N, 8.12; S, 18.39; F, 10.89 (%). Immediate. 197.0-199.0 ° C

Example 4-171

 N- {8-[(4-Fluorophenyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, ic] [1,4] thiazine-1-ylidene } -4-Methylbenzenesulfonamide

Compound obtained in Example 3-4 (219 mg, 0.574 tmol), 4-fluorobenzenethiol (115 mg, 0.861 mmol) and triphenylphosphine (621 mg, 2.30 brutally 01)! 1? DEAD (0.381 ml, 2.30 mmol) was added dropwise to the suspension (4.5 ml) with stirring at room temperature, and the reaction solution was stirred at room temperature for 5 days and 6 (TC for 2 days. The reaction solution was diluted with ethyl acetate. The residue was washed with 2% aqueous sodium hydrogen carbonate solution, 0.1N hydrochloric acid, water and saturated saline, dried over sodium sulfate and concentrated, and the residue was chromatographed on silica gel (10 g) (ethyl acetate hexane, 1 g). : 9-3: 7), and the red fraction of ethyl acetate-hexane (25: 75-30: 70) was crystallized from methanol to give the title compound (82 mg, 0.172 mol) as a red-purple powder. Was.

'H-NMR (200MHz, CDC1 3): δ 1.60 (3Η, brq, J = 1.0 Hz), 2.24 (3H, brq, J = 1.0 Hz), 2.43 (3H, s), 7.09 (2H, tt, J = 8.6, 2.2 Hz), 7.31 (2H, d, J = 8.2 Hz),

7.54 (2H, ddd, J = 8.6, 5.5, 2.2 Hz), 7.89 (2H, d, J = 8.0 Hz), 9.64 (1H, brs). Elemental analysis: C _2I H ₁₈ N ₃ 0 ₃ S ₃ F Calculated as: C, 53.03; H, 3.81; N, 8.84; S, 20.23;

F, 3.99 (%), Found: C, 52.98; H, 3.77; N, 9.04; S, 20.55; F, 3.80 (%). Mp. 195.0-196. Ot:

Example 4-172

 N- {8-[(4-bromophenyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-1-ylidene} -4-methylbenzenesulfonami H

 The compound (208 mg, 0.545 mmol) obtained in Example 3-4, 4-bromobenzenethiol (159 mg, 0.818 mol) and triphenylphosphine (590 mg, 2.18 mmol) in THF (4.5 ml) were added. After DEAD (0.361 ml, 2.18 mmol) was added dropwise to the suspension while stirring at room temperature, the reaction solution was stirred at room temperature for 6 days and at 60 ° C for 20 hours. The reaction mixture was diluted with ethyl acetate, washed with 2% aqueous sodium hydrogen carbonate solution, (UN hydrochloric acid, water and saturated saline, dried over sodium sulfate, and concentrated. The residue was chromatographed on silica gel (10 g). Ethyl acetate-hexane ('1: 9-3: 7), and the red fraction of ethyl acetate-hexane (25:75) was crystallized from methanol to give the title compound (59 mg, 0.110 mg 01). Was obtained as a red-purple powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.62 (3Η, brs), 2.24 (3H, brq, J = 1.0 Hz), 2.43 (3H, s), 7.31 (2H, d, J = 8.0 Hz), 7.41 (2H, dt, J = 8.4, 1.8 Hz), 7.52 (2H, dt, J = 8.4, 1.8 Hz), 7.88 (2H, d, J = 8.0 Hz), 9.65 (1H, brs). 'Elemental analysis: C ₂₁ H ₁₈ N ₃ 0 ₃ S ₃ Br Calculated: C, 47.01; H , 3.38; N, 7.83; S, 17.93

(%), Found: C, 47.14; H, 3.14; N, 8.01; S, 17.76 ().

mp. 193.5-195.0 ° C

Example 4-173

 N- {8-[(4-tert-butylphenyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-1 -Ylidene} -4-methylbenzenesulfonamide

 (Method 1) THF of the compound obtained in Example 3- (203 mg, 0.532 leak 1), 4-tert-butyl benzene thiol (135 mg, 0.798 ol) and triphenylphosphine (576 mg, 2.13 ol) DEAD (0.353 ml, 2.13 mmol) was added dropwise to the suspension (4.5 ml) while stirring at room temperature, and the reaction solution was stirred at room temperature for 5 days and at 60 ° C for 28 hours. The reaction solution was diluted with ethyl acetate, washed with a 2% aqueous sodium hydrogen carbonate solution, 0.1N hydrochloric acid, water and saturated saline, dried over sodium sulfate, and concentrated. The residue was chromatographed on silica gel (10 g) (ethyl acetate-hexane, 10: 90-25: 75), and the red-orange fraction of ethyl acetate-hexane (15: 85-20: 80) was crystallized from methanol. To give the title compound (17 mg, 0.033 mmol) as a purplish red powder.

'H-NMR (200MHz, CDC1 3): δ 1.34 (9Η, s), 1.61 (3H, q, J = 0.8 Hz), 2.24 (3H, brq, J = 0.8 Hz), 2.42 (3H, s), 7.30 (2H, d, J = 8.4 Hz), 7.40 (2H, d, J = 8.8 Hz), 7.45 (2H, d, J = 8.8 Hz), 7.89 (2H, d, J = 8.4 Hz), 9.63 ( 1H, brs). Elemental analysis: Calculated as C ₂₅ H ₂₇ N ₃ 0 ₃ S ₃ · 0.30: C, 57.84; H, 5.36; N, 8.09; S, 18.53 (%), found: C, 57.86; H, 5.30; N, 8.01; S, 18.17 ().

mp. 194.0-197.0 ° C

(Method 2) THF (131 mg, 0.600 mmol) of the compound obtained in Example 3-4 (229 mg, 0.600 mmol), 4-tert-butylbenzenthiol (152 mg, 0.900 mL) and triptylphosphine (131 mg, 0.600 mmol) To this suspension, 1,1 '-(azodicarbonyl) dipiperidine (hereinafter abbreviated as ADDP, 170 mg, 0.660 mL) was added with stirring at room temperature. The mixture was stirred at 60 ° C for 4 days. During this time, tributylphosphine (131 mg, 0.600 thigh 0) and ADDP (170 mg, 0.660 thigh ol) were added twice each to the reaction solution. The reaction solution was post-treated in the same manner to obtain a compound (40 mg, 0.078 tmol) as a red-purple powder. Example 4-174

The crystals were recrystallized from ethyl acetate-getyl ether to obtain red crystals.

Melting point: 184-186T.

Infrared absorption spectrum (IR) (in KBr) V: 3243, 2969, 2922, 1746, 1721, 1661, 1615, 1559 cm " ¹ .

_{iH-NMR (CDC1 3):} 6 1.69 (3H, s), 1.76 (3H, s), 1.78 (3H, d, J = 0.8 Hz), 2.26 (3H, d, J-1.2 Hz), 2.42 (3H , s), 3.61 (3H, d, J = 7.6 Hz), 5.23 (1H, t, J = 7.6 Hz), 7.28 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.4 Hz) ), 9.61 (1H, bs).

Example 4-175.

 N- {8-[(4-Couguchiphenyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydrido-1H-imidazo [5, tric] [1,4] thiazine- Triylidene}-4-methylbenzenesulfone

 1 ^ (3.3 ml) of the compound obtained in Example 3-4 (198 mg, 0.519 violated ol), 4-chloro benzenethiol (113 mg, 0.779 benzene) and triphenylphosphine (561 mg, 2.08 thigh 01) ) Was added dropwise to the suspension with stirring at room temperature, and the reaction solution was stirred at room temperature for 24 hours. DEAD (0.172 ml, 1.04 tmol) was added to the reaction solution, and the mixture was stirred at room temperature for 3 days. This reaction mixture was diluted with ethyl acetate together with the reaction mixture similarly obtained from the compound (200 mg, 0.524 mmol) obtained in Example 3-4, and 2% aqueous sodium hydrogen carbonate, 0.1N hydrochloric acid, After washing with water and saturated saline, it was dried over sodium sulfate and concentrated. The residue was subjected to silica gel (10 g) chromatography (ethyl acetate-hexane, 1: 9-3: 7), and the red-orange fraction of ethyl acetate-hexane (25: 75-30: 70) was crystallized from methanol. To give the title compound (69 mg, 0.140 t ol) as a purple powder.

_{^ -NMR (200MHz, CDC1 3)} : <5 1.61 (3H, q, J = 0.8 Hz), 2.23 (3H, q, J- 0.6 Hz), 2.43 (3H, s), 7.31 (2H, d, J = 8.2 Hz), 7.37 (2H, dt, J = 8.8, 2.2 Hz), 7.47 (2H, dt, J = 8.8, 2.2 Hz), 7.88 (2H, d, J = 8.6 Hz), 9.65 (1H, brs ).

Elemental analysis: Calculated for C ₂₁ H ₁₈ N ₃ 0 ₃ S ₃ C1: C, 51.26; H, 3.69; N, 8.54; S, 19.55; C1, 7.21 (%), found: C, 51.27; H , 3.54; N, 8.77; S, 19.52; C1, 7.05 (%) mp. 201.5-204.

Example 4-176

 Ν- {8-[(1,1-Dimethylbutyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine- 1-ylidene}-4-methylbenzenesulfonamide

 A solution of the compound obtained in Example 3-4 (163 mg, 0.427 mmol) and 2-methyl-topentene (0.54 ml, 4.27 mmol) in dichloromethane (3.3 ml) was mixed with a boron trifluoride ether complex (0.11 ml, 0.854 mmol) at room temperature for 23 hours. The reaction mixture was concentrated, diluted with ethyl acetate, washed with dilute hydrochloric acid, aqueous sodium hydrogen carbonate, water and saturated saline, dried over sodium sulfate, and concentrated. The residue was subjected to chromatography on silica gel (7 g) (ethyl acetate-hexane, 1: 9-3: 7). The fraction of ethyl acetate-hexane (2: 8-3: 7) was concentrated to dryness and crystallized from methanol to give the title compound (48 mg, 0.103 mol) as a dark red powder.

'H-NMR (200MHz, CDC1 3): δ 0.88 (3Η, t, J = 7.2 Hz), 1.36 (2H, m), 1.41 (6H, s), 1.60 (2H, m), 1.75 (3H, q , J = 1.2 Hz), 2.22 (3H, q, J = 1.0 Hz), 2.42 (3H, s), 7.29 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.0 Hz), 9.69 (1H, brs). Elemental analysis: Calculated for C ₂₁ H ₂₇ N ₃ 0 ₃ S ₃ : C, 54.17; H, 5.84; N, 9.02 (%), found: C, 54.06; H, 5.73 ; N, 9.09 (%).

Immediately. 169.0- 170.5

Example 4-177

 N- {5,6-dimethyl-8-[(3-methyl-2-oxobutyl) sulfanyl] -3-oxo-2,3-dihydrido-1H-imidazo [5,1-c] [1,4] Thiazine-triylidene} -4-methylbenzenesulfonamide

To a solution of 3-methyl-2-butanone (8.50 g, 95.7 mmol) in anhydrous methanol (60 ml) was added bromine (5.5 ml, 0.106 mol) at -7 ° C over 30 seconds, and the mixture was mixed. The mixture was stirred at 0 ° C for 30 minutes and further at 10 for 1 hour. Water (30 ml) was added to the reaction solution, and the mixture was further stirred at room temperature for 16 hours. Water (90 ml) was added to the reaction solution, and the mixture was extracted twice with dimethyl ether (80 ml) and dimethyl ether monohexane (1: 1, 80 nil). The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, water and saturated saline, dried over sodium sulfate, and concentrated. Was. The residual oil was distilled under reduced pressure (14 g Hg) to give 1-bromo-3-methyl-2-butanone (purity 90 °, 12.4 g, 67.6 mmol) as a colorless oil.

^{! H-NMR (200MHz, CDC1} 3): (51.17 (6H, d, J = 7.0 Hz), 2.99 (1H, septet, J = 7.0 Hz), 3.99 (2H, s).

Boiling point.58-63 ° C (14 mmHg)

 To a solution of the compound obtained in Example 3-4 (172 mg, 0.451 mmol) and tribromo-3-methyl-2-butanone (91 mg, 0.496 ol) in THF (3.4 ml) at room temperature was added triethylamine (RT). 0.125 ml, 0.902 tmol) was added, and the reaction solution was stirred for 2.5 hours. 1N Hydrochloric acid (0.91 ml) was added to the reaction solution, stirred for 10 minutes, and diluted with methanol / water (1: 1, 5 ml). The precipitate was washed with methanol-water (1: 1) and methanol, and dried to give the title compound (192 mg, 0.412 fflnol) as a red-brown powder.

_{Ή- NMR (200MHz, CDC1 3)} : δ 1.15 (6Η, d, J = 6.6 Hz), 1.75 (3H, q, J = 1.2 Hz), 2.24 (3H, q, J = 0.8 Hz), 2.42 (3H , s), 2.82 (1H, septet, J = 6.8 Hz), 3.90 (2H, s), 7.29 (2H, d, J = 8.4 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.64 (1H , brs). Elemental analysis: Calculated for C ₁₉ H ₁₇ N ₃ 0 ₃ S ₃ : C, 51.59; H, 4.98; N, 9.02; S, 20.66 (%), found: C, 51.40; H, 4.94; N, 9.13; S, 20.61 ().

Melting point.205.0-206.5 ° C

Example 4-178

The crystals were recrystallized from ethyl acetate-disopropyl ether to obtain red crystals.

Melting point: 186-188 ° C.

Infrared absorption spectrum (IR) (in KBr): 3281, 2976, 2928, 1750, 1717, 1661, 1615, 1563, 1497 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 1.61 (6Η, s), 1.80 (3H, d, J = 1.0 Hz), 2.01-2.13 (2H, m), 2.27 (3H, d, J = 1.0 Hz), 2.42 (3H, s), 3.07-3.19 (2H, m), 7.30 (2H, d, J = 8.0 Hz), 7.84 (2H, d, J = 8.2 Hz), 9.62 (1H, bs).

Example 4-179

Ή one _{NMR (300MHz, CDC1 3):} δ 0.91 (3H, t, J = 7.2 Hz), 1.33 (2H, m), 1.42 (2H, m), 2.05 (2H, brdd, J = 7.2, 6.8 Hz) , 2.42 (3H, s), 4.16 (2H, s), 6.47 (1H, brt, J = 0.5 Hz), 7.22 (1H, q, J = 7.6 Hz), 7.26 (1H, brd, J = 7.6 Hz) , 7.28 (2H, brd, J = 8.3 Hz), 7.45 (1H, dt, J = 7.7, 1.6 Hz), 7.47 (1H, brs), 7.81 (2H, d, J = 8.3 Hz), 9.71 (1H, brs).

Elemental _{analysis: C 24 H 24 N 3 0} 3 S 3 Br'0.6H 2 0 Calculated: C, 48.91; H, 4.31 ; N, 7.13 (%), Found: C, 48.61; H, 4.08 ; 7.42 (%).

Example 4-180

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.90 (3H, t, J = 7.2 Hz), 1.32 (2H, brquint, J = 7.4 Hz), 1.42 (2H, m), 2.05 (2H, brdd, J = 7.1, 6.7 Hz), 2.41 (3H, s), 3.93 (3H, s), 4.25 (2H, s), 6.47 (1H, brt, J = 0.5 Hz), 7.26 (2H, d, J = 8.3 Hz) , 7.42 (1H, t, J = 7.7 Hz), 7.53 (1H, dt, J = 7.7, 1.1 Hz), 7.80 (2H, d, J = 8.3 Hz), 7.99 (1H, brdt, J = 7.7, 1.1 Hz), 8.02 (1H, brt, J = 1 Hz), 9.74 (1H, brs). Elemental analysis: Calculated as C ₂₆ H ₂₇ N ₃ 0 ₅ S ₃ : C, 55.99; H, 4.88; N, 7.53; S, 17.25

(%), Found: C, 55.83; H, 4.66; N, 7.57; S, 17.26 (%).

Example 4-181

'H-NMR (300MHz, CDC1 3): δ 0.92 (3H, t, J = 7.2 Hz), 1.36 (2H, brquint, J = 7.4 Hz), 1.46 (2H, m), 2.08 (2H, dd, J -7.1, 6.8 Hz), 2.36 (3H, s), 2.40 (3H, s), 4.23 (2H, s), 6.49 (1H, brt, = 0.5 Hz), 7.15-7.28 (6H, m), 7.77 ( 2H, d, J = 8.3 Hz), 9.71 (1H, br).

Elemental _{analysis: C 25 H 27 N 3 0} 3 S 3 Calculated: C, 58.45; H, 5.30 ; N, 8.18; S, 18.73 (%), Found: C, 58.35; H, 5.31 ; N, 8.14; S, 18.57 (%).

Example 4-182

'H-NMR (300MHz, CDC1 3): δ 0.92 (3H, t, J = 7.2 Hz), 1.34 (2H, m), 1.44 (2H, m), 2.06 (2H, brdd, J = 7.0, 6.8 Hz ), 2.41 (3H, s), 4.15 (2H, s), 5.99 (2H, s), 6.48 (1H, brt, J = 0.5 Hz), 6.76 (1H, s), 6.78 (2H, brd, J = 8 Hz), 7.27 (2H, d, J = 8.3 Hz), 7.81 (2H, d, J = 8.3 Hz), 9.71 (1H, brs).

Elemental analysis: Calculated as _{C 25 H 25 N 3 0 5} S 3: C, 55.23; H, 4.63; N, 7.73; S, 17.69 (%), Found: C, 55.11; H, 4.59 ; N, 7.69; S, 17.79 ().

Example 4-183

_{Ή- MR (300MHz, CDC1 3)} : δ 0.91 (3Η, t, J = 7.2 Hz), 1.33 (2H, m), 1.43 (2H, m), 2.05 (2H, brdd, J = 7.1, 6.8 Hz) , 2.41 (3H, s), 3.67 (2H, s), 4.20 (2H, s), 6.47 (1H, brt, J = 0.5 Hz), 7.27 (4H, m), 7.27 (2H, d, J = 8.3 Hz), 7.80 (2H, brd, J = 8.3 Hz), 9.74 (1H, brs).

Example 4-184

Ή one _{NMR (300MHz, CDC1 3):} δ 0.91 (3H, t, J = 7.2 Hz), 1.34 (2H, brquint, J = 7.3 Hz), 1.44 (2H, m), 2.05 (2H, brdd, J = 7.2, 6.9 Hz), 2.41 (3H, s), 3.63 (2H, s), 3.71 (3H, s), 4.20 (2H, s), 6.48 (1H, brs), 7.27 (6H, m), 7.80 ( 2H, brd, J = 8.2 Hz), 9.73 (1H, brs).

Example 4-185

_{¾-NMR (300MHz, CDC1 3} ): δ 0.91 (3H, t, J- 7.1 Hz), 1.32 (2H, m), 1.39 (2H, m), 2.03 (2H, brdd, J = 7.1, 6.6 Hz) , 2.43 (3H, s), 4.22 (2H, s), 6.45 (1H, brt, J = 0.5 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.45 (2H, d, J = 8.3 Hz) , 7.62 (2H, d, J- 8.3 Hz), 7.81 (2H, d, J = 8.3 Hz), 9.60 (1H, br).

Elemental _{analysis: C 25 H 24 N 4 0} 3 S 3 Calculated: C, 57.23; H, 4.61 ; N, 10.68; S, 18.33 (%), Found: C, 56.85; H, 4.60 ; N, 10.59; S, 18.29 (%).

Example 4-186

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.90 (3Η, t, J = 7.1 Hz), 1.32 (2H, m), 1.40 (3H, t, J = 7.1 Hz), 1.41 (2H, m), 2.04 (2H, brdd, J = 7.3, 6.6 Hz), 2.42 (3H, s), 4.24 (2H, s), 4.39 (2H, q, J = 7.1 Hz), 6.46 (1H, brs), 7.27 (2H, d, J = 8.2 Hz), 7.39 (2H, d, J = 7.1 Hz), 7.81 (2H, d, J = 8.2 Hz), 8.00 (2H, d, J = 8.2 Hz), 9.73 (1H, brs) .

Elemental _{analysis: C 27 H 2g N 3 0} 5 S 3 Calculated: C, 56.72; H, 5.11 ; N, 7.35; S, 16.83

(%), Found: C, 56.54; H, 4.98; N, 7.22; S, 16.95 (%).

Example 4-187

ΉIchiran R (300MHz, DMS0-d ₆ ): δ 0.85 (3H, t, J- 7.1 Hz), 1.26 (2H, m), 1.32 (2H, m), 2.11 (2H, brdd, J = 7.0, 6.6 Hz), 2.37 (3H, s), 4.38 (2H, s), 6.60 (1H, brs), 7.33 (2H, d, J = 8.2 Hz), 7.48 (2H, d, J = 7.1 Hz), 7.80 (2H, d, J = 8.2 Hz), 7.90 (2H, d, J = 8.2 Hz), 11.80 (1H, br), 12.95 (1H, brs).

Elemental _{analysis: C 25 H 25 N 3 0} 5 S 3 Calculated: C, 55.23; H, 4.63 ; N, 7.73; S, 17.69 Found: C, 55.12; H, 4.65 ; N, 7.68; S, 17.58 (%). Example 4-188

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.91 (3H, t, J = 7.2 Hz), 1.34 (2H, m), 1.44 (2H, m), 2.06 (2H, brt, J = 7.0 Hz), 2.41 (3H, s), 3.82 (3H, s), 4.18 (2H, s), 6.48 (1H, brt, J = 1 Hz), 6.86 (2H, dt, J = 8.6, 1.8 Hz), 7.23 (2H, d, J = 8.6 Hz), 7.25 (2H, d, J = 7.3 Hz), 7.80 (2H, d, J = 8.2 Hz), 9.72 (1H, brs).

Elemental analysis: Calculated as _{C 25 H 27 N 3 0 4} S 3: C, 56.69; H, 5.14;, 7.92; S, 18.16

Found: C, 56.53; H, 5.14; N, 7.93; S, 18.25 (%).

Example 4-189

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.91 (3H, t, J = 7.2 Hz), 1.33 (2H, m), 1.43 (2H, m), 2.05 (2H, brdd, J = 7.1, 6.8 Hz) , 2.41 (3H, s), 4.22 (2H, s), 6.47 (1H, brt, J = 0.5 Hz), 7.10 (1H, d, J = 16.5 Hz), 7.11 (1H, d, J = 16.5 Hz) , 7.26 (2H, brd, J = 8.3 Hz), 7.28 (1H, m), 7.31 (2H, d, J = 8.1 Hz), 7.37 (2H, brt, J = 7.7 Hz), 7.47 (2H, d, J- 8.2 Hz), 7.52 (2H, brd, J = 7.3 Hz), 7.81 (2H, d, J = 8.2 Hz), 9.72 (1H, br).

Elemental _{analysis: C 32 H 3l N 3 0} 3 S 3 Calculated: C, 63.87; H, 5.19 ; N, 6.98; S, 15.98 (%), Found: C, 63.77; H, 5.07 ; N, 6.83; S, 15.77 (%).

Example 4-190

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.91 (3Η, ί, J = 7.2 Hz), 1.34 (2H, m), 1.44 (2H, m), 2.05 (2H, brt, J = 7 Hz), 2.40 (3H, s), 4.18 (2H, s), 5.07 (2H, s), 6.47 (1H, brt, J = 0.5 Hz), 6.93 (2H, dt, J = 8.6, 1.7 Hz), 7.23 (2H, s) d, J = 8.6 Hz), 7.25 (2H, brd, J = 8.3 Hz), 7.36 (1H, m), 7.41 (2H, d, J = 7.6 Hz), 7.43 (2H, brt, .J = 7.6 Hz) ), 7.80 (2H, d, J- 8.3 Hz), 9.70 (1H, brs).

Elemental _{analysis: C 31 H 31 N 3 0} 4 S 3 Calculated: C, 61.46; H, 5.16 ;, 6.94; S, 15.88 (%), Found: C, 61.13; H, 5.07 ; N, 6.96 ; S, 15.90 (%).

Example 4-191

Ή one _{NMR (300MHz, CDC1 3):} δ 0.92 (3H, t, J = 7.2 Hz), 0.97 (2H, brddt, J = 12.6, 2.5, 12.1 Hz), 1.19 (1H, m), 1.22 (1H, m), 1.35 (2H, m), 1.45 (2H, m), 1.57 (1H, m), 1.69 (1H, m), 1.74 (2H, dquint, J = 12, 3.0 Hz), 1.85 (2H, brd , J = 12.6 Hz), 2.07 (2H, brt, J = 7.1 Hz), 2.42 (3H, s), 2.84 (2H, d, J = 6.8 Hz), 6.50 (1H, brt, J = 0.5 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.69 (1H, brs).

Elemental _{analysis: C 24 H 31 N 3 0} 3 S 3 Calculated: C, 57.00; H, 6.18 ; N, 8.31; S, 19.02 (%), Found: C, 56.76; H, 6.16 ; N, 8.35; S, 19.09 ().

Example 4-192

'H-NMR (300MHz, CDC1 3): δ 0.92 (3H, t, J = 7.2 Hz), 1.35 (2H, m), 1.46 (2H, m), 2.07 (2H, t, J = 7.2 Hz), 2.42 (3H, s), 2.96 (2H, dd, J = 8.4, 7.2 Hz), 3.20 (2H, dd, J-8.4, 7.2 Hz), 6.50 (1H, s), 7.19 (2H, brd, J = 7.2 Hz), 7.27 (5H, m), 7.83 (2H, d, J = 8.2 Hz), 9.78 (1H, br).

Example 4-193

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.92 (3H, ί, J = 7.0 Hz), 1.35 (2H, m), 1.42 (2H, m), 2.02 (2H, quint, J = 7.3 Hz), 2.04 (2H, bri, J = 6.8 Hz), 2.40 (3H, s), 2.72 (2H, brt, J = 7.3 Hz), 2.95 (2H, dd, J = 7.6, 7.2 Hz), 6.49 (1H, brs) , 7.15 (2Η, 'brd, J = 7.0 Hz), 7.24 (1H, m), 7.27 (2H, d, J = 8.2 Hz), 7.29 (2H, brt, J = 7.0 Hz), 7.84 (2H, d , J = 8.2 Hz), 9.71 (1H, br).

Elemental _{analysis: C 26 H 2 0 3 S} 3 Calculated: C, 59.18; H, 5.54 ; N, 7.96; S, 18.23

(%), Found: C, 58.92; H, 5.53; N, 7.95: S, 18.37 (%).

Example 4-194

_{¾-NMR (300MHz, CDC1 3} ): δ 0.91 (3Η, t, J = 7.2 Hz), 1.34 (2H, quint, J = 7.3 Hz), 1.44 (2H, brquint, J = 7.4 Hz), 2.05 (2H , brt, J = 7.1 Hz), 2.41 (3H, s), 4.22 (2H, s), 6.47 (1H, brt, J = 1 Hz), 7.25 (2H, d, J = 8.3 Hz), 7.32 (5H , s), 7.80 (2H, d, J = 8.3 Hz), 9.72 (1H, br).

Elemental _{analysis: C 24 H 25 N 3 0} 3 S 3 · 0.5H 2 O Calculated:. C, 56.67; H, 5.15; N, 8.26; S, 18.91 () Found: C, 56.71; H, 5.12; N, 8.36; S, 19.12 (%).

Example 4-195

_{Ή-NMR (300MHz, CDC1 3} ): <5 0.91 (3H, t, J = 7.2 Hz), 1.34 (2H, m), 1.44 (2H, m), 2.06 (2H, brt, J = 6.9 Hz), 2.40 (3H, s), 4.63 (2H, s), 5.04 (2H, s), 6.49 (1H, brt, J = 0.5 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.33 (5H, m ), 7.86 (2H, brd, J = 8.3 Hz), 9.83 (1H, brs). Elemental analysis: Calculated as _{C 25 H 27 N 3 0 4} S 3: C, 56.69; H, 5.14; N, 7.93; S, 18.16

(%), Found: C, 56.49; H, 5.06; N, 7.91; S, 18.23 (%).

Example 4-196

'H-NMR (300MHz, CDC1 3) δ 0.92 (3Η, t, J = 7,1 Hz), 1.33 (2H, m), 1.41 (2H, m), 2.09 (2H, brdd, J = 8.0, 6.8 Hz), 2.24 (3H, s), 2.40 (3H, s), 4.20 (2H, s), 7.24 (2H, d, J = 8.3 Hz), 7.32 (5H, s), 7.81 (2H, d, J = 8.3 Hz), 9.62 (1H, br).

Elemental analysis: C ₂₅ H ₂₇ N ₃ 0 ₃ S ₃ · 0.6H ₂ 0 Calculated: C, 57.25; H, 5.42; N, 8.01; S, 18.34 (%), Observed: C, 57.35; H , 5.12; N, 7.89; S, 18.13 (%)

Example 4-197

Melting point 159-161 ° C

Infrared absorption spectrum (IR) (in KBr) V: 3202, 2926, 2853, 1732, 1657, 1615, 1559, 1497 cm—

_{'H-NMR (CDC1 3)} : δ 0.929 (3Η, t, J = 6.8 Hz), 0.86-1.92 (15H, m), 2.12 (2H, t, J = 6.6 Hz), 2.26 (3H, s), 2.41 (3H, s), 2.82 (2H, d, J = 7.0 Hz), 7.27 (2H, d, J = 8.0 Hz), 7.86 (2H, d, J-8.Hz), 9.61 (1H, bs) .

Elemental _{analysis: C 25 H 33 N 3 0} 3 S 3 Calculated: C, 57.77; H, 6.40 ; N, 8.08; S, 18.51 (%), Found: C, 57.66; H, 6.36 ; N, 7.90; S, 18.58 (%).

Example 4-198

138-140 ° C

Infrared absorption spectrum (IR) (in KBr): 3199, 2957, 2930, 2870, 1732, 1659, 1615,

1559, 1495 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 0.927 (3Η, t, J = 7.0 Hz), 1.20-1.50 (4H, m), 1.37 (3H, t, J = 7.2 Hz), 2.11 (2H, t, J = 6.8 Hz), 2.26 (3H, s), 2.42 (3H, s), 2.99 (2H, q, J = 7.6 Hz), 7.31 (2H, d, J = 8.0 Hz), 7.86 (2H, d, J = 8. Hz), 9.63 (1H, bs) elemental analysis:. C _2. Calculated for H ₂₅ N ₃ 0 ₃ S ₃ : C, 53.19; H, 5.58; N, 9.30; S, 21.30 (%) Found: C, 53.28; H, 5.52; N, 9.50; S, 21.47 (% ).

Example 4-199

With melting point 139-141 Infrared absorption spectrum (IR) (in KBr) V: 3202, 2957, 1932, 1870, 1740, 1657, 1617, 1563, 1497 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 0.930 (3Η, t, J = 6.6 Hz), 0.932 (6H, d, J = 6.2Hz), 1.24-1.74 (7H, m), 2.12 (2H, t,] = 7.2 Hz), 2.26 (3H, s), 2.42 (3H, s), 2.95 (2H, t, J = 7.6 Hz), 7.28 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = . 8.4 Hz), 9.62 (1H , bs) elemental _{analysis: C 23 H 31 N 3 0} 3 S 3 calculated: C, 55.95; H, 6.33 ; N, 8.51; S, 19.48

(%), Found: C, 55.89; H, 6.33; N, 8.68; S, 19.57 (%).

Example 4-200

 Melting point 170-172

Infrared absorption spectrum (IR) (in KBr) V: 3180, 2955, 2928, 2867, 1728, 1655, 1609, 1561 cm " ¹ .

_{¾-NMR (CDC1 3):} δ 0.912 (3Η, t, J = 7.0Hz), 0.927 (3H, t, J = 7.0Hz), 1.24-1.52 (8H, m), 1.60-1.78 (2H, m) , 2.11 (3H, t, J = 7.8 Hz), 2.26 (3H, s), 2.41 (3H, s), 2.94 (2H, t, J = 7.8 Hz), 7.30 (2H, d, J = 8.0 Hz) , 7.85 (2H, d, J = 8.4 Hz), 9.61 (1H, bs).

Elemental analysis: Calculated as _{C 23 H 31 N 3 0 3} S 3: C, 55.95; H, 6.33; N, 8.51; S, 19.48

(%;), Found: C, 55.73; H, 6.37; N, 8.22; S, 19.45 (%).

Example 4-201

Recrystallization from ethyl acetate-methyl-tetrahydrofuran gave dark red crystals. 155-157 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3229, 2957, 2932, 2861, 1732, 1657, 1617, 1559, 1508 cm- ¹ .

 One MR (CDCI3): δ 0.925 (3Η, t, J = 7.0 Hz), 1.24-1.52 (4H, m), 2.12 (2H, t, J-8.0 Hz), 2.26 (3H, s), 2.43 (3H , s), 2.94 (2H, t, J = 7.6 Hz), 3.17 (2H, t, J = 8.6 Hz), 6.99 (2H, t, J = 8 Hz), 7.09-7.20 (2H, m), 7.28 (2H, d, J = 8.0 Hz), 7.82 (2H, d, J = 8.4 Hz), 9.63 (1H, bs).

Elemental _{analysis: C 26 H 28 N 3 0} 3 S 3 F Calculated: C, 57.22; H, 5.17 ; N, 7.70; S, 17.63

(%), Found: C, 57.24; H, 5.31 ;, 7.65; S, 17.55 (%).

Example 4-202 Recrystallization from ethyl acetate-tetrahydrofuran gave dark red crystals.

167-168 ° C.

Infrared absorption spectrum (IR) (in KBr): 3220, 2955, 2936, 2863, 1732, 1659, 1615, 1557 cm " ¹ .

_{'H-NMR (CDC1 3)} : δ 0.930 (3Η, t, J = 6.6 Hz), 1.20-1.90 (10H, m), 2.03-2.18 (2H, m), 2.26 (3H, s), 2.42 (3H , s), 2.96 (2H, t, J-7.4 Hz), 3.54 (2H, t, J = 6.2 Hz), 7.29 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.0 Hz) ), 9.63 (1H, bs) elemental analysis:. C _23. Calculated for N ₃ 0 ₃ S ₃ CI: C, 52.30; H, 5.73; N, 7.96; S, 18.21

(%), Found: C, 52.24; H, 5.54; N, 8.05; S, 17.97 (%).

Example 4-203

Recrystallization from ethyl acetate-diisopropyl ether gave dark red crystals.

Melting point: 154-156 ^

Infrared absorption spectrum (IR) (in KBr) V: 3214, 2957, 2863, 1732, 1661, 1617, 1559 cm—

 Ή-NMR (CDC "): δ 0.927 (3Η, t, J = 7.0Hz), 1.24-1.51 (4H, m), 1.92-2.22 (6H, m), 2.26 (3H, s), 2.42 (3H, s), 3.02 (2H, t, J = 7.0 Hz), 7.29 (2H, d, J = 8.0 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.62 (1H, bs).

Elemental _{analysis: C 23 H 26 N 3 0} 3 S 3 F 5 Calculated: C, 47.33; H, 4.49 ; N, 7.20; S, 16.48 (%), Found: C, 47.51; H, 4.25 ; N, 7.30; S, 16.46 (%).

Example 4-204

Recrystallization from isopropyl ether-n-hexane gave dark red crystals.

Melting point 111-113 ^.

Infrared absorption spectrum (IR) (in KBr) V: 3235, 2961, 1934, 2865, 1742, 1728, 1659, 1615, 1564, 1555 cnf ¹ .

 Ή-NMR (CDCI3): δ 0.925 (3Η, t, J = 6.6 Hz), 1.24-1.55 (4H, m), 2.12 (3H, t, J = 7.8 Hz), 2.18-2.34 (2H, m), 2.26 (3H, s), 2.42 (3H, s), 2.95-3.16 (3H, m), 7.30 (2H, d, J = 8.0 Hz), 7.84 (2H, d, J = 8.Hz), 9.66 ( 1H, bs).

Example 4-205

Recrystallization from ethyl acetate-getyl ether gave dark red crystals. Melting point: 162-164 ° C.

Infrared absorption spectrum (IR) (in KBr) ν 3230, 2957, 2934, 2870, 1732, 1659, 1615, 1559 cm- ¹ .

_{¾-NMR (CDC1 3):} a 0.930 (3H, t, J = 6.6 Hz), 0.943 (9H, s), 1.24-1.64 (6H, m), 2.12 (. 2H, t, J = 7 Hz), 2.26 (3H, s), 2.42 (3H, s), 2.85-2.97 (2H, m), 7.29 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.63 (1H , Bs).

Elemental analysis: Calculated as _{C 24 H 33 N 3 0 3} S 3: C, 56.77; H, 6.55; N, 8.28; S, 18.95

(%), Found: C, 56.40; H, 6.62; N, 8.02; S, 18.71 (%).

Example 4-206

 Ή-NM (300MHz, CDC: δ 0.90 (3Η, t, J = 6.9 Hz), 1.29 (2H, m), 1.31 (2H, m), 1.45 (2H, brquint, J = 7.3 Hz), 2.04 (2H , brt, J = 7.1 Hz), 2.41 (3H, s), 4.22 (2H, s), 6.47 (1H, brt, J = 0.5 Hz), 7.25 (2H, d, J = 8.3 Hz), 7.32 (5H , s), 7.80 (2H, d, J = 8.3 Hz), 9.74 (1H, br).

Elemental analysis: Calculated as _{C 25 H 27 N 3 0 3} S 3: C, 58.45; H, 5.30; N, 8.18; S, 18.73

(%), Found: C, 58.39; H, 5.23; N, 8.07; S, 18.86 (%).

Example 4-207

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.91 (3Η, i, J = 6.8 Hz), 1.32 (4H, m), 1.48 (2H, brquint, J = 7.2 Hz), 2.12 (2H, t, J = 7.7 Hz), 2.27 (3H, s), 2.35 (3H, s), 4.67 (2H, s), 7.06 (2H, d, J = 7.9 Hz), 7.43 (1H, dd, J = 7.9, 7.2 Hz) , 7.53 (2H, ffl), 7.54 (1H, dd, J = 6.4, 3.4 Hz), 7.68 (2H, d, J = 8.33 Hz), 7.85 (1H, brd, J- 8.3 Hz), 7.91 (1H, dt, J = 9.4, 3.4 Hz), 8.01 (1H, dt, J = 9.8, 3.4 Hz), 9.59 (1H, brs).

Elemental analysis: C _3. Calculated for H ₃₁ N ₃ 0 ₃ S ₃ : C, 62.36; H, 5.41; N, 7.27; S, 16.65

Found: C, 62.44; H, 5.52; N, 7.26; S, 16.82 (%).

Example 4-208

_{¾-NR (300MHz, CDC1 3} ): δ 0.90 (3H, t, J = 6.8 Hz), 1.30 (4H, m), 1.44 (2H, brquint, J = 7.3 Hz), 2.10 (2H, t, J = 7.7 Hz), 2.25 (3H, s), 2.41 (3H, s), 4.32 (2H, s), 7.18 (1H, dt, J = 1.5, 7.5 Hz), 7.25 (2H, d, J = 8.3 Hz) , 7.30 (1H, dt, J = ll, 7.5 Hz), 7.43 (1H, dd, J = 7.5, 1.5 Hz), 7.58 (1H, dd, J = 7.9, 1.1 Hz), 7.82 (2H, d, J = 8.3 Hz), 9.62 (1H, brs).

Elemental _{analysis: C 26 H 28 N 3 0} 3 S 3 Br Calculated: C, 51.48; H, 4.65 ; N, 6.93; S, 15.86; Br, 13.17 (), Found: C, 51.48; H, 4.62; N, 6.95; S, 15.83; Br, 13.20 (%).

Example 4-209

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.90 (3Η, t, J = 6.6 Hz), 1.30 (4H, m), 1.44 (2H, brquint, J = 7.3 Hz), 2.10 (2H, t, J = 7.5 Hz), 2.25 (3H, s), 2.41 (3H, s), 4.31 (2H, s), 7.26 (4H, m), 7.41 (2H, m), 7.82 (2H, d, J = 8.7 Hz) , 9.60 (1H, brs). Elemental analysis: Calculated for C ₂₆ H ₂₈ N ₃ 0 ₃ S ₃ C1: C, 55.55; H, 5.02; N, 7.47; S, 17.11; C1, 6.31 (%), Found: C, 55.48; H, 4.95; N, 7.51; S, 17.23; C1, 6.28 (%).

One _{NMR (300MHz, CDC1 3):} δ 0.90 (3Η, t, J = 6.8 Hz), 1.30 (4H, m), 1.43 (2H, brquint, J = 7.3 Hz), 2.09 (2H, t, J = 7.5 Hz), 2.24 (3H, s), 2.41 (3H, s), 4.23 (2H, s), 7.07 (1H, dt, J-1.0, 8.7 Hz), 7.12 (1H, dt, J = ll, 7.5 Hz ), 7.25 (2H, d, J 8.3 Hz), 7.30 (1H, m), 7.37 (1H, dt, J = 1.5, 7.5 Hz), 7.81 (2H, d, J = 8.3 Hz), 9.62 (1H , brs).

Elemental analysis: C ₂₆ ¾ ₈ N ₃ 0 ₃ S ₃ F Calculated: C, 57.22; H, 5.17; N, 7.70; S, 17.63; F, 3.48 (%), found: C, 57.28; H , 5.15; N, 7.74; S, 17.71; F, 3.33 (%).

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.90 (3H, t, J = 6.8 Hz), 1.31 (4H, m), 1.45 (2H, brquint, J = 7.3 Hz), 2.10 (2H, t, J = 7.5 Hz), 2.25 (3H, s), 2.41 (3H, s), 4.30 (2H, s), 7.01 (1H, dt, J = 1.5, 7.5 Hz), 7.25 (2H, d, J = 8.3 Hz) , 7.33 (1H, dt, J = 1.1, 7.5 Hz), 7.43 (1H, dd, J = 7.9, 1.5 Hz), 7.82 (2H, d, J = 8.3 Hz), 7.86 (1H, dd, J = 7.9) , 1.5 Hz), 9.6,0 (1H, brs).

Elemental _{analysis: C 26 H 28 N 3 0} 3 S 3 I Calculated: C, 47.78; H, 4.32 ; N, 6.43; S, 14.72; I, 19.42 (%), Found: C, 47.79; H , 4.29; N, 6.40; S, 14.88; I, 19.45 (%).

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.91 (3H, t, J = 6.6 Hz), 1.32 (4H, m), 1.47 (2H, brquint, J = 7.3 Hz), 2.12 (2H, t, J = 7.5 Hz), 2.26 (3H, s), 2.36 (3H, s), 2.40 (3H, s), 4.20 (2H ₅ s), 7.15-7.28 (6H, m), 7.78 (2H, d, J = 8.3 Hz), 9.62 (1H, brs).

Elemental _{analysis: C 27 H 31 N 3 0} 3 S 3 Calculated: C, 59.86; H, 5.77 ; N, 7.76; S, 17.76 (%), Found: C, 59.81; H, 5.72 ; N, 7.85; S, 17.67 (%).

Example 4-213

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.88 (3H, t, J = 6.8 Hz), 1.27 (4H, m), 1.41 (2H, brquint, J = 7.3 Hz), 2.08 (2H, t, J = 7.5 Hz), 2.23 (3H, s), 2.38 (3H, s), 4.36 (2H, s), 7.21 (2H, d, J = 7.9 Hz), 7.42 (1H, dd, J = 8.3, 1.9 Hz) , 7.50 (2H, m), 7.77-7.84 (6H, m), 9.62 (1H, brs).

Elemental analysis: C _3. Calculated for H ₃₁ N ₃ 0 ₃ S ₃ : C, 62.36; H, 5.41; N, 7.27; S, 16.65 (%), found: C, 62.00; H, 5.35; N, 7.32; S, 16.40 ( %).

Example 4-214

_{Ή-NMR (300MHz, CDC1 3} ): 6 0.89 (3H, t, J = 7.0 Hz), 1.27 (4H, m), 1.37 (2H, brquint, J = 7.5 Hz), 2.01 (2H, brt, J- 7.5 Hz), 2.22 (3H, s), 2.41 (3H, s), 4.14 (2H, s), 7.25 (2H, d, J = 8.3 Hz), 7.26-7.41 (8H, m), 7.81 (2H, d, J = 8.3 Hz), 9.59 (1H, brs).

Elemental _{analysis: C 32 H 33 N 3 0} 3 S 3 · 0.3H 2 0 Calculated: C, 63.09; H, 5.56 ; N, 6.90; S, 15.79 (), Found: C, 62.97; H, 5.34; N, 6.95; S, 15.60 (%).

Example 4-215

_{Ή-NR (300MHz, CDC1 3} ): δ 0.90 (3Η, t, J = 7.0 Hz), 1.30 (4H, m), 1.43 (2H, brquint, J = 7.3 Hz), 2.08 (2H, t, J = 7.5 Hz), 2.24 (3H, s), 2.42 (3H, s), 4.15 (2H, s), 7.22 (1H, m), 7.27 (2H, d, J = 8.3 Hz), 7.27 (2H, m) , 7.31 (2H, brd, J = 8 Hz), 7.82 (2H, d, J = 8.3 Hz), 9.62 (1H, brs).

Elemental _{analysis: C 26 8 N 3 0 3} S 3 C1 Calculated: C, C, 55.55; H , 5.02; N, 7.47; S, 17.11; CI, 6.31 (%), Found: C, 55.37; H, 4.91; N, 7.52; S, 17.30; CI, 6.31 (%).

_{lH- NMR (300MHz, CDC1 3)} : δ 0.90 (3H, t, J = 6.6 Hz), 1.31 (4H, m), 1.46 (2H, brquint, J = 7.2 Hz), 2.11 (2H, brt, J = 7.5 Hz), 2.24 (3H, s), 2.38 (3H, s), 4.24 (2H, s), 7.25 (2H, d, J = 8.3 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.33 (2H, d, J = 8.3 Hz), 7.36 (1H, dd, J = 7.2, 0.8 Hz), 7.45 (1H, dt, J = 1.5, 7.5 Hz), 7.58 (1H, dt, J = 1.5, 7.5 Hz), 7.81 ( 2H, d, J = 7.9 Hz), 7.95 (1H, dd, J = 7.5, 1.1 Hz), 9.64 (1H, brs).

Elemental _{analysis: C 33 H 29 N 3 0} 5 S 3 · 0.9H 2 0 Calculated: C, 60.05; H, 4.70 ; N, 6.37 (%), Found: C, 60.11; H, 4.99 ; N , 6.51 (%).

Example 4-217

_{Ή-NMR (300MHz, CDC1 3} ): δ .0.91 (3Η, t, J = 6.8 Hz), 1.24 (9H, s), 1.32 (4H, m), 1.47 (2H, brquint, J = 7.3 Hz), 2.11 (2H, t, J = 7.5 Hz), 2.26 (3H, s), 2.40 (3H, s), 4.26 (2H, s), 7.25 (2H, d, J = 7.9 Hz), 7.28 (2H, d , J- 8.3 Hz), 7.30 (1H, m), 7.34 (1H, m), 7.35 (2H, d, J = 8.3 Hz), 7.41 (1H, dt, J = 1.5, 7.5 Hz), 7.50 (1H , Dt, J = 1.5, 7.5 Hz), 7.80 (2H, d, J = 7.9 Hz), 9.65 (1H, brs). Elemental analysis: Calculated as C ₃₇ H ₃₇ N ₃ 0 ₅ S ₃ · 0.3¾0 : C, 63.00; H, 5.37; N, 5.96; S, 13.64 (%), found: C, 63.05; H, 5.43; N, 6.07; S, 13.67 (%).

Example 4-218

'H-NMR (300MHz, CDC1 3): <5 0.90 (3H, t, J = 6.8 Hz), 1.30 (4H, m), 1.44 (2H, brquint, J = 7.3 Hz), 2.09 (2H, t, J = 7.5 Hz), 2.24 (3H, s), 2.31 (3H, s), 2.41 (3H, s), 4.18 (2H, s), 7.06 (2H, d, J = 8.7 Hz), 7.25 (2H, d, J = 8.3 Hz), 7.33 (2H, d,] = 8.3 Hz), 7.81 (2H, d, J- 8.3 Hz), 9.63 (1H, brs).

Elemental analysis: C ₂₈ H ₃₁ N ₃ 0 ₅ S ₃ Calculated: C, 57.41; H, 5.33; N, 7.17; S, 16.42 (%), found: C, 57.27; H, 5.03; N, 7.09; S, 16.49 (%).

Example 4-219

_{Ή-NMR (300MHz, CDC1 3} ): <5 0.90 (3H, t, J = 6.8 Hz), 1.29 (4H, m), 1.42 (2H, brquint, J = 7.3 Hz), 2.08 (2H, t, J = 7.5 Hz), 2.24 (3H, s), 2.42 (3H, s), 4.15 (2H, s), 7.26 (4H, m), 7.29 (2H, m), 7.81 (2H, d, J = 8.3 Hz ), 9.62 (1H, brs) elemental _{analysis: C Z6 H 28 N 3 0} 3 S 3 C1 calculated:. C, 55.55; H, 5.02; N, 7.47; S, 17.11; Cl, 6.31 (%) , Found: C, 55.47; H, 4.94; N, 7.49; S, 17.22; C1, 6.52 (%) · Example 4-220

Ή-NM (300MHz, CDC: <5 0.89 (3H, t, J = 6.8 Hz), 1.30 (4H, m), 1.44 (2H, brquint, J = 7.2 Hz), 2.10 (2H, t, J = 7.5 Hz), 2.25 (3H, s), 2.39 (3H, s), 4.24 (2H, s), 7.24 (2H, d, J = 8.3 Hz), 7.36 (1H, t, J = 7.2 Hz), 7.39 (2H, d, J = 8.3 Hz), 7.45 (2H, i, J- 7.4 Hz), 7.56 (2H, d, J = 8.7 Hz), 7.58 (2H, dm, J = 8 Hz), 7.82 (2H, d, J = 8.3 Hz), 9.65 (1H, brs).

Elemental _{analysis: C 32 H 33 N 3 0} 3 S 3 Calculated: C, 63.65; H, 5.51 ; N, 6.96; S, 15.93 (%), Found: C, 63.91; H, 5.39 ; N, 6.67; S, 15.78 (%)

Example 4-221

_{Ή-NMR (300MHz, CDC1 3} ): d 0.91 (3H, t, J = 6.8 Hz), 1.32 (4H, m), 1.33 (9H, s), 1.45 (2H, brquint, J = 7.3 Hz), 2.10 (2H, brt, J = 7.5 Hz), 2.25 (3H, s), 2.41 (3H, s), 4.18 (2H, s), 7.25 (4H, d, J = 8.3 Hz), 7.35 (2H, d, J = 8.3 Hz), 7.81 (2H, d, J = 8.3 Hz), 9.61 (1H, brs).

Elemental analysis: C _3. H ₃₇ N ₃ 0 ₃ S ₃ Calculated: C, 61.72; H, 6.39 ; N, 7.20; S, 16.48

(%), Found: C, 61.55; H, 6.34; N, 7.23; S, 16.55 (%).

Example 4-222

'H-NMR (300MHz, CDC1 3): δ 0.84 (3Η, t, J = 6.8 Hz), 1.21 (4H, m), 1.32 (2H, brquint, J = 7.3 Hz), 1.99 (2H, t, J = 7.5 Hz), 2.17 (3H, s), 2.42 (3H, s), 4.53 (2H, s), 7.29 (2H, m), 7.30 (2H, d, J = 8.3 Hz), 7.64 (2H, dt) , J = 9.4, 3.Hz), 7.83 (2H, d, J = 8.3 Hz).

Elemental _{analysis: C 27 H 29 N 5 0} 3 S 3 · 0.2H 2 0 Calculated: C, 56.76; H, 5.19 ; N, 12.26; S, 16.84 (%), Found: C, 56.71; H , 5.33; N, 12.35; S, 17.03 (%).

Example 4-223

'H-NMR (300MHz, CDC1 3): δ 0.90 (3H, t, J = 6.8 Hz), 1.32 (4H, m), 1.47 (2H, brquint, J = 7.0 Hz), 1.61 (3H, s), 1.69 (3H, s), 1.69 (3H, s)., 2.06 (4H, m), 2.10 (2H, brt, J = 7.3 Hz), 2.26 (3H, s), 2.41 (3H, s), 3.63 ( 2H, d, J = 7.6 Hz), 5.07 (1H, brt, J = 6 Hz), 5.24 (1H, brt, J = 7.6 Hz), 7.27 (2H, d, J = 8.3 Hz), 7.84 (2H, d, J = 8.3 Hz), 9.62 (1H, brs).

Elemental analysis: C ₂₉ H ₂₉ N ₃ 0 ₃ S ₃ · 0.2H ₂ 0 Calculated: C, 60.32; H, 6.88; N, 7.28; S, 16.66 (%), Observed: C, 60.25; H , 6.54; N, 7.27; S, 16.61 (%).

Example 4-224

_{Ή-NMR (300MHz, CDC1 3} ): <5 0.88 (6H, d, J = 6.4 Hz), 0.90 (3H, t, J = 6.8 Hz), 1.20 (2H, quint, J = 7.3 Hz), 1.31 (4H, m), 1.37 (2H, m), 1.45 (2H, brquint, J = 7.2 Hz), 1.54 (1H, quint, J = 6.4 Hz), 1.66 (2H, quint, J = 7.5 Hz), 2.11 (2H, t, J = 7.5 Hz), 2.26 (3H, s), 2.41 (3H, s), 2.94 (2H, t, J = 7.4 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.64 (1H, brs).

Elemental analysis: Calculated as _{C 26 7 N 3 0 3 S} 3: C, 58.28; H, 6.96;, 7.84; S, 17.95 (%), Found: C, 58.26; H, 6.85 ;, 7.82; S , 18.19 (%).

Example 4-225

'H-NMR (300MHz, CDC1 3): δ 0.88 (6H, d, J = 6.4 Hz), 0.90 (3H, t, J = 6.8 Hz), 1.18 (2H, brt, J = 7.2 Hz), 1.31 ( 8H, m), 1.38 (2H, m), 1.47 (2H, m), 1.53 (1H, quint, J = 6.4 Hz), 1.68 (2H, quint, J = 7.3 Hz), 2.11 (2H, t, J = 7.5 Hz), 2.26 (3H, s), 2.42 (3H, s), 2.94 (2H, t, J = 7.5 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J (8.3 Hz), 9.63 (1H, brs).

Elemental analysis: Calculated as _{C 27 H 3g N 3 0 3} S 3: C, 58.98; H, 7.15; N, 7.64; S, 17.50 (%), Found: C, 59.03; H, 7.05 ; N, 7.52; S, 17.67 (%).

Example 4-226

'H-NMR (300MHz, CDC1 3): δ 0.90 (6Η, brt, J = 6.4 Hz), 1.31 (8H, m), 1.40 (2H, m), 1.46 (2H, brquint, J = 7.4 Hz), 1.67 (2H, quint, J = 7.3 Hz), 2.11 (2H, t, J = 7.5 Hz), 2.26 (3H, s), 2.41 (3H, s), 2.94 (2H, t, J = 7.3 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.63 (1H, brs). 'Elemental analysis: Calculated as C ₂₅ H ₃₅ N ₃ 0 ₃ S ₃ : C, 57.55; H, 6.76; N, 8.05; S, 18.44 (%), found: C, 57.35; H, 6.53; N, 8.11; S, 18.41 ().

Example 4-227

_{Ή- R (300MHz, CDC1 3)} : δ 0.90 (3Η, t, J = 6.6 Hz), 0.90 (3H, t, J- 6.6 Hz), 1.30 (12H, m), 1.47 (2H, brquint, J = 7.2 Hz), 1.68 (2H, quint, J = 7.5 Hz), 2.11 (2H, t, J = 7.5 Hz), 2.26 (3H, s), 2.41 (3H, s), 2.93 (2H, t, J = 7.3 Hz), 7.28 (2H, d: J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.63 (1H, brs).

Elemental _{analysis: C 26 H 37 N 3 0} 3 S 3 Calculated: C, 58.28; H, 6.96 ; N, 7.84; S, 17.95

(%), Found: C, 58.21; H, 6.84;, 7.89; S, 17.73 (%).

Example 4-228 _{Ή-NMR (300MHz, CDC1 3} ): δ 0.89 (3H, t, J = 6.8 Hz), 0.90 (3H, i, J = 6.8 Hz), 1.29 (14H, m), 1.47 (2H, brquint, J = 7.2 Hz), 1.67 (2H, quint, J- 7.5 Hz), 2.11 (2H, t, J = 7.5 Hz), 2.26 (3H, s), 2.41 (3H, s), 2.93 (2H, t, J = 7.5 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.63 (1H, brs).

Elemental analysis: C „H _3g Calculated as N ₃ 0 ₃ S ₃ : C, 58.98; H, 7.15; N, 7.64; S, 17.50 (%), found: C, 58.86; H, 7.18; N, 7.64; S, 17.31 ().

Example 4-229

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.90 (3H, t, J = 6.8 Hz), 1.31 (4H, m), 1.47 (2H, brquint, J = 7.3 Hz), 2.11 (2H, t, J = 7.5 Hz), 2.26 (3H, s), 2.42 (3H, s), 2.97 (2H, dd, J = 8.7, 7.2 Hz), 3.17 (2H, dd, J = 8.7, 7.5 Hz), 7.20 (2H, dm, J = 7.2 Hz), 7.26-7.35 (5H, m), 7.83 (2H, d, J = 8.3 Hz), 9.63 (1H, brs).

Elemental _{analysis: C 27 H 31 N 3 0} 3 S 3 Calculated: C, 59.86; H, 5.77 ; N, 7.76; S, 17.76

(%), Found: C, 59.51; H, 5.77; N, 7.85; S, 17.77 (%).

Example 4-230

_{¾-NMR (300MHz, CDC1 3} ): δ 0.90 (3H, t, J = 6.8 Hz), 1.31 (4H, m), 1.44 (2H, brquint, J = 7.2 Hz), 2.01 (2H, quint, J = 7.5 Hz), 2.08 (2H, t, J = 7.5 Hz), 2.25 (3H, s), 2.39 (3H, s), 2.72 (2H, t, J = 7.3 Hz), 2.92 (2H, t, J = 7.3 Hz), 7.15 (2H, d, J = 7.5 Hz), 7.21 (1H, tt, J = 7.2, 2.6 Hz), 7.28 (4H, m), 7.85 (2H, d, J = 8.3 Hz), 9.62 (1H, brs).

Elemental _{analysis: C 28 H 33 N 3 0} 3 S 3 Calculated: C, 60.51; H, 5.98 ; N, 7.56; S, 17.31 (%), Found: C, 60.46; H, 5.86 ; N, 7.64; S, 17.57 (%)

Example 4-231

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.88 (3Η, t, J = 6.7 Hz), 1.24 (4H, m), 1.26 (2H, brquint, J = 6.8 Hz), 1.97 (2H, t, J = 7.2 Hz), 2.17 (3H, s), 2.42 (3H, s), 5.86 (1H, s), 7.24 (2H, d, J = 8.3 Hz), 7.32 (10H, m), 7.84 (2H, d, J- 8.3 Hz), 9.61 (1H, brs).

Elemental _{analysis: C 32 H 33 N 3 0} 3 S 3 Calculated: C, 63.65; H, 5.51 ; N, 6.96; S, 15.93

(%), Found: C, 63.64; H, 5.48; N, 6.93; S, 15.96 (%).

Example 4-232 'H-NMR (300MHz, CDC1 3): δ 0.89 (3H, t, J- 6.6 Hz), 1.30 (4H, m), 1.46 (2H, brquint, J = 7.3 Hz), 2.11 (2H, t, J = 7.7 Hz), 2.25 (3H, s), 2.39 (3H, s), 3.80 (2H, dd, J = 7.2, 1.1 Hz), 6.18 (1H, dt, J = 15.5, 7.2 Hz), 6.61 (1H , d, J = 15.8 Hz), 7.26 (2H, d, J = 8.3 Hz), 7.28 (1H, m), 7.34 (4H, m), 7.84 (2H, d, J = 8.3 Hz), 9.65 (1H , brs).

Elemental _{analysis: C 28 H 31 N 3 0} 3 S 3 Calculated: C, 60.73; H, 5.64 ; N, 7.59; S, 17.37 (%), Found: C, 60.71; H, 5.46 ; N, 7.77; S, 17.23 (%).

Example 4-233

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.90 (3Η, t, J = 6.9 Hz), 1.30 (4H, m), 1.44 (2H, quint, J = 7.3 Hz), 2.09 (2H, dd, J = 7.8, 7.3 Hz), 2.24 (3H, s), 2.42 (3H, s), 4.20 (2H, s), 7.25 (2H, d, J = 8.3 Hz), 7.32 (5H, s), 7.81 (2H, s) d, J2 8.3 Hz), 9.59 (1H, brs).

Elemental _{analysis: C 26 H 29 N 3 0} 3 S 3 · 0.2H 2 O Calculated: C, 58.77; H, 5.58 ; N, 7.91; S, 18.11 (%), Found: C, 58.75; H , 5.19; N, 8.03; S, 18.47 (%).

Example 4-234

'H-NMR (300MHz, CDC1 3): <5 0.91 (3H, t, J = 6.8 Hz), 1.32 (4H, m), 1.50 (2H, brquint, J = 7.3 Hz), 2.13 (2H, t, J = 7.7 Hz), 2.25 (3H, s), 2.41 (3H, s), 3.25 (2H, dd, J = 7.2, 6.8 Hz), 3.99 (2H, dd, J = 7.2, 6.8 Hz), 7.26 ( 2H, d, J = 8.3 Hz), 7.75 (2H, dd, J = 5.3, 3.0 Hz), 7.81 (2H, d, J = 8.3 Hz), 7.86 (2H, dd, J = 5.3, 3.0 Hz), 9.60 (1H, brs).

Elemental analysis: C ₂₉ H _3. N ₄ 0 ₅ S ₃ Calculated: C, 57.03; H, 4.95 ; N, 9.17; S, 15.75 (%), Found: C, 56.76; H, 4.81 ;, 9.31; S, 15.94 (%).

Example 4-235

■ H-NMR (300MHz, CDC1 3): δ 0.89 (3Η, t, J = 6.8 Hz), 1.28 (4H, i), 1.41 (2H, brquint, J = 7.4 Hz), 2.04 (2H, t, J = 7.5 Hz), 2.07 (2H, quint, J = 6.8 Hz), 2.24 (3H, s), 2.39 (3H, s), 2.97 (2H, dd, 1 = 7.9, 7.5 Hz), 3.77 (2H, t , J = 6.8 Hz), 7.28 (2H, brd, J-8 Hz), 7.74 (2H, dd, J = 5.7, 3.0 Hz), 7.84 (2H, d, J = 8 Hz), 7.86 (2H, dd , J = 5.3, 3.4 Hz), 9.61 (1H, brs).

Elemental analysis: C _3. H ₃₂ N ₄ 0 ₅ S ₃ Calculated: C, 57.37; H, 5.16 ; N, 8.97; S, 15.40 (%), Found: C, 57.63; H, 5.14;, 9.06; S, 15.44 (%).

Example 4-236

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.89 (3H, t, J = 6.8 Hz), 1.28 (4H, m), 1.39 (2H, brquint, J = 7.3 Hz), 2.06 (2H, t, J = 7.5 Hz), 2.23 (3H, s), 2.43 (3H, s), 4.14 (2H, s), 7.26 (2H, m), 7.28 (2H, d, J = 8.3 Hz), 7.82 (2H, d, J = 8.3 Hz), 8.57 (2H, d, J = 6.0 Hz), 9.62 (1H, brs).

Elemental analysis: Calculated for C ₂₅ H ₂₈ N ₄ 0 ₃ S ₃ : C, 56.79; H, 5.34; N, 10.60; S, 18.19

(%), Found: C, 56.51; H> 5.52; N, 10.63; S, 18.36 (%).

Example 4-237

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.85 (3H, t, J = 6.8 Hz), 1.22 (4Η, 'm), 1.35 (2H, brquint, J = 7.2 Hz), 2.04 (2H, t, J = 7.5 Hz), 2.22 (3H, s), 2.39 (3H, s), 4.52 (2H, s), 7.23 (2H, d, J = 8.3 Hz), 7.53 (1H, d, J = 8.7 Hz), 7.57 (1H, dt, J = 1.0, 7.2 Hz), 7.74 (1H, ddd, J = 8.3, 7.2, 1.5 Hz), 7.83 (1H, brd, J = 8.3 Hz), 7.83 (2H, d, J = 8.3 Hz), 8.05 (1H, brd, J = 8.3 Hz), 8.15 (1H, d, J = 8.3 Hz), 9.65 (1H, brs).

Elemental analysis: C ₂₉ H _3. N ₄ 0 ₃ S ₃ · 0.5H ₂ 0 Calculated: C, 59.26; H, 5.32; N, 9.53; S, 16.36 (%), Found: C, 59.28; H, 5.30; N, 9.59; S , 16.49 (%).

Example 4-238

_{Ή-NMR (300MHz, CDC1 3} ): 6 0.90 (3H, t, J = 6.8 Hz), 1.31 (4H, m), 1.47 (2H, brquint, J = 7.3 Hz), 1.62 (3H, s), 1.71 (3H, s), 2.11 (2H, t, J = 7.5 Hz), 2.26 (3H, s), 2.36 (2H, q, J-7.5 Hz), 2.41 (3H, s), 2.93 (2H, t, J = 7.5 Hz), 5.11 (1H, tt, J = 7.2, 1.2 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.63 (1H, .brs ).

Elemental _{analysis: C 25 H 33 N 3 0} 3 S 3 Calculated: C, 57.77; H, 6.40 ;, 8.08; S, 18.51 (%), Found: C, 57.65; H, 6.29 ; N, 8.15 ; S, 18.70 (%)

Example -239

'H-NMR (300MHz, CDC1 3): δ 0.91 (3H, t, J = 6.6 Hz), 1.31 (4H, m), 1.47 (2H, brquint, J = 7.3 Hz), 1.69 (3H, s), 1.76 (3H, s), 2.10 (2H, t, J = 7.5 Hz), 2.26 (3H, s), 2.41 (3H, s), 3.61 (2H, d, J = 7.5 Hz), 5.23 (1H, tt , J = 7.7, 1.5 Hz), 7.27 (2H, d, J = 8.3 Hz), 7.84 (2H, d, J = 8.3 Hz), 9.63 (1H, brs).

Elemental analysis: Calculated as _{C 24 H 31 N 3 0 3} S 3: C, 57.00; H, 6.18; N, 8.31; S, 19.02

(%), Found: C, 57.06; H, 6.02; N, 8.27; S, 18.72 (%).

Example 4-240

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.89 (3H, t, J = 7.5 Hz), 0.90 (6H, t, J = 6.8 Hz), 1.30 (10H, m), 1.40 (2H, quint, J = 7.2 Hz), 1.47 (2H, brquint, J = 7.2 Hz),

1.61 (1H, quint, J = 6.0 Hz), 2.11 (2H, t, J = 7.7 Hz), 2.26 (3H, s), 2.41 (3H, s), 2.91 (2H, t, J = 6.4 Hz), 7.26 (2H, d, J = 8.3 Hz), 7.86 (2H, d, J = 8.3 Hz), 9.63 (1H, brs).

Elemental analysis: Calculated as _{C 27 H 39 N 3 0 3} S 3: C, 58.98; H, 7.15; N, 7.64; S, 17.50

(%), Found: C, 59.06; H, 7.04; N> 7.75; S, 17.54 (%).

Example 4-241

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.91 (3H, t, J = 6.8 Hz), 1.21 (2H, m), 1.31 (4H, m), 1.47 (2H, brquint, J = 7.3 Hz), 1.57 (1H, q, J = 7.9 Hz), 1.67 (1H, m), 1.71 (4H, brd, J = 10.6 Hz), 2.11 (2H, t, J = 7.5 Hz), 2.26 (3H, s), 2.41 (3H, s), 2.96 (2H, t, J = 7.9 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz),

9.62 (1H, brs).

Example 4-242

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.88 (2H, brq, J = 12 Hz), 0.91 (3H, t, J = 6.6 Hz), 1.18 (2H, m), 1.26 (4H, m), 1.31 (4H, m), 1.47 (2H, brquint, J = 7.3 Hz), 1.68 (7H, m), 2.11 (2H, t, J = 7.5 Hz), 2.26 (3H, s), 2.41 (3H, s) , 2.91 (2H, t, J = 7.5 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.63 (1H, brs). Elemental analysis: C ₂₈ H ₃₉ N ₃ 0 ₃ S ₃ calculated: C, 59.86; H, 7.00 ; N, 7.48; S, 17.12

(%), Found: C, 60.00; H, 6.99; N, 7.48; S, 17.02 (%).

Example 4-243

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.91 (3Η, t, J = 6.6 Hz), 0.98 (2H, brq, J- 11.7 Hz), 1.20 (2H, brt, J = 10.2 Hz), 1.32 (4H , m), 1.47 (2H, brquint, J = 7.3 Hz), 1.67 (1H, m), 1.73 (2H, brd, J = 13.9 Hz), 1.85 (2H, brd, J = 12.0 Hz), 2.11 (2H , t, J = 7.5 Hz), 2.26 (3H, s), 2.41 (3H, s), 2.82 (2H, t, J = 6.8 Hz), 7.27 (2H, s) d, J = 8.3 Hz), 7.86 (2H, d, J = 8.3 Hz), 9.61 (1H, brs).

Elemental _{analysis: C 26 H 35 N 3 0} 3 S 3 Calculated: C, 58.50; H, 6.61 ;, 7.87; S, 18.02 (%), Found: C, 58.27; H, 6.80 ; N, 7.93 ; S, 18.05 ().

Example 4-244

 Ή-NMR (300MHz, CDC: δ 0.91 (3Η, t, J = 6.8 Hz), 1.12 (2H, m), 1.32 (4H, m), 1.47 (2H, brquint, J = 7.5 Hz), 1.50-1.65 (4H, m), 1.68 (2H, q, J = 7.9 Hz), 1.79 (2H, m), 1.87 (2H, quint, J = 7.5 Hz), 2.11 (2H, t, J = 7.5 Hz), 2.26 (3H, s), 2.41 (3H, s), 2.95 (2H, d, J = 7.7 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.63 (1H, brs).

Elemental _{analysis: C M H 35 N 3 0} 3 S 3 Calculated: C, 58.50; H, 6.61 ; N, 7.87; S, 18.02

(%), Found: C, 58.48; H, 6.47; N, 7.84; S, 18.05 (%).

Example 4-245

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.90 (3H, t, J = 6.8 Hz), 1.08 (2H, in), 1.31 (6H, m), 1.43 (2H, m), 1.45-1.55 (4H, m), 1.59 (2H, m), 1.68 (2H, q, J = 7.8 Hz), 1.75 (2H, m), 2.11 (2H, t, J = 7.5 Hz), 2.26 (3H, s), 2.41 ( 3H, s), 2.93 (2H, d, J = 7.3 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.63 (1H, brs).

Elemental analysis: Calculated as _{C 27 H 37 N 3 0 3} S 3: C, 59.20; H, 6.81;, 7.67; S, 17.56

(), Found: C, 59.07; H, 6.81; N, 7.62; S, 17.61 (%).

Example 4-246

_{Ή- NMR (300MHz, CDC1 3)} : 6 0.90 (3H, t, J = 6.8 Hz), 1.26 (2H, m), 1.31 (4H, m), 1.46 (2H, brquint, J = 7.3 Hz), 1.61 (4H, m), 1.86 (2H, m), 2.10 (2H, t, J = 7.9 Hz), 2.12 (1H, quint, J = 7.5 Hz), 2.26 (3H, s), 2.41 (3H, s) , 2.95 (2H, d, J = 7.7 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.63 (1H, brs).

Elemental analysis: Calculated as _{C 25 H 33 N 3 0 3} S 3: C, 57.77; H, 6.40; N, 8.08; S, 18.51

(%), Found: C, 57.59; H, 6.47; N, 8.08; S, 18.46 (%).

Example 4-247

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.32 (2H, brq, J = 5.7 Hz), 0.67 (2H, brq, J = 6.8 Hz), 0.90 (3H, t, J = 6.8 Hz), 1.07 (1H, m), 1.31 (4H, m), 1.46 (2H, brquint, J = 7.4 Hz), 2.10 (2H, t, J = 7.7 Hz), 2.26 (3H, s), 2.42 (3H, s), 2.91 (2H, t, J = 7.2 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.87 (2H, d, J = 8.3) Hz), 9.64 (1H, brs).

Elemental _{analysis: C 23 H 29 N 3 0} 3 S 3 Calculated ': C, 56.18; H, 5.94; N, 8.55; S, 19.56 (%), Found: C, 56.39; H, 5.91 ; N , 8.50; S, 19.56 (%).

Example 4-248

_{Ή-NR (300MHz, CDC1 3} ): δ 0.91 (3Η, t, J = 6.8 Hz), 1.32 (4H, m), 1.48 (2H, m), 1.50 (2H, brquini, J = 7.5 Hz), 1.70 (2H, quint, J = 7.4 Hz), 2.07 (2H, m), 2.11 (2H, t, J = 7.2 Hz), 2.26 (3H, s), 2.41 (3H, s), 2.95 (2H, t, J = 7.3 Hz), 4.99 (1H, brd, J = 10.2 Hz), 5.03 (1H, dq, J = 17.0, 1.9 Hz), 5.78 (1H, ddt, J- 17.0, 10.2, 6.8 Hz), 7.28 ( 2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.63 (1H, brs).

Elemental _{analysis: C 25 H 33 N 3 0} 3 S 3 Calculated: C, 57.77; H, 6.40 ; N, 8.08; S, 18.51 (%), Found: C, 57.72; H, 6.36 ; N, 8.12; S, 18.59 (%)

Example 4-249

Ή-NMR '(300 MHz, CDCI ₃ ): δ 0.90 (3Η, t, J = 6.8 Hz), 1.32 (4H, m), 1.36 (4H, m), 1.42 (2H, m), 1.47 (2H, brquint , J = 7.7 Hz), 1.68 (2H, quint, J = 7.3 Hz), 2.05 (2H, brq, J = 6.8 Hz), 2.11 (2H, t, J = 7.5 Hz), 2.26 (3H, s), 2.41 (3H, s), 2.93 (2H, t, J = 7.3 Hz), 4.96 (1H, brd, J = 10.2 Hz), 5.01 (1H, dq, J = 17.0, 1.5 Hz), 5.80 (1H, ddt , J = 17.0, 10.2, 6.8 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.64 (1H, brs).

Elemental analysis: Calculated as _{C 27 H 37 N 3 0 3} S 3: C, 59.20; H, 6.81;, 7.67; S, 17.56 (%), Found: C, 59.28; H, 6.51 ; N, 7.74 ; S, 17.70 (%).

Example 4-250

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.90 (3H, t, J = 6.8 Hz), 1.31 (4H, m), 1.46 (2H, brquint, J = 7.3 Hz), 2.10 (2H, t, J = 7.5 Hz), 2.25 (3H, s), 2.41 (3H, s), 3.62 (2H, d, J = 6.8 Hz), 5.25 (1H, dd, J = 10.2, 1.1 Hz), 5.32 (1H, dq, J = 17.0, 1.1 Hz), 5.85 (1H, ddt, J = 17.0, 10.2, 6.8 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.84 (2H, d, J = 8.3 Hz), 9.64 (1H, brs).

Elemental _{analysis: C 22 H 27 N 3 0} 3 S 3 Calculated: C, 55.32; H, 5.70 ; N, 8.80; S, 20.14

(%), Found: C, 55.08; H, 5.62; N, 9.01; S, 20.16 ().

Example 4-251

'Eta - organs _{(300MHz, CDC1 3): δ} 0.90 (3Η, t, J = 6.6 Hz), 1.32 (4H, m), 1.46 (6H, m), 1.70 (2H, quint, J = 6.9 Hz), 1.78 (2H, quint, J = 7.0 Hz), 2.11 (2H, t, J = 7.5 Hz), 2.26 (3H, s), 2.42 (3H, s), 2.95 (2H, t, J = 7.5 Hz), 3.54 (2H, t, J = 6.6 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.63 (1H, brs).

Elemental _{analysis: C 25 H 34 N 3 0} 3 S 3 C1 · 0.4H 2 0 Calculated: C, 53.30; H, 6.23 ; N, 7.46; S, 17.07; Cl, 6.29 (%), Found: C, 53.32; H, 6.06; N, 7.53; S, 17.08; C1, 6.46 (%).

Example 4-252

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.91 (3H, t, J = 6.6 Hz), 1.32 (6H, m), 1.50 (4H, m), 1.70 (4H, m), 2.05 (2H, m) , 2.12 (2H, t, J = 7.4 Hz), 2.25 (3H, s), 2.42 (3H, s), 3.53 (1H, septet, J = 4.5 Hz), 7.28 (2H, d, J = 8.3 Hz) , 7.86 (2H, d, J- 8.3 Hz), 9.63 (1H, brs).

Elemental analysis: Calculated for C ₂₆ H ₃₅ N ₃ 0 ₃ S ₃ : C, 58.50; H, 6.61; N, 7.87; S, 18.02 (%), found: C, 58.43; H, 6.57; N, 7.89; S, 17.86 (%).

Example 4-253

_{Ή-NR (300MHz, CDC1 3} ): 6 0.90 (3H, t, J = 6.8 Hz), 1.32 (4H, m), 1.47 (2H, brquint, J = 7.5 Hz), 1.62 (1H, in), 1.82 (1H, m), 1.89 (1H, m), 2.00 (1H, m), 2.05 (2H, m), 2.12 (2H, t, J = 7.5 Hz), 2.25 (3H, s), 2.41 (3H, m s), 4.13 (1H, m), 5.68 (1H, dm, J = 9.8 Hz), 5.94 (1H, dm, J = 9.8 Hz), 7.27 (2H, d, J = 7.9 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.64 (1H, brs).

Elemental analysis: Calculated as _{C 25 H 31 N 3 0 3} S 3: C, 58.00; H, 6.04; N, 8.12; S, 18.58

(%) Found: C, 57.94; H, 5.94; N, 8.23; S, 18.3 (%.

Example 4-254

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.91 (3Η, t, J = 6.6 Hz), 1.30 (2H, m), 1.31 (6H, m), 1.43 (2H, m), 1.46 (2H, brd,} = 9.0 Hz), 1.77 (2H, brd, J = 8.7 Hz), 2.02 (2H, brd, J = 11.3 Hz), 2.11 (2H, t, J = 7.7 Hz), 2.25 (3H, s), 2.41 (3H, s), 3.37 (IH, m), 7.28 (2H, d, J = 8.3 Hz), 7.86 (2H, d, J = 8.3) Hz), 9.63 (IH, brs). Elemental analysis: Calculated as C ₂₅ ¾ ₃ N ₃ 0 ₃ S ₃ · 0.1H ₂₀ : C, 57.57; H, 6.42; N, 8.06; S, 18.44 (% ), Found: C, 57.25; H, 6.27; N, 8.09; S, 18.43 (%).

Example 4-255

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.90 (3H, t, J = 6.8 Hz), 1.28 (3H, t, J = 7.2 Hz), 1.30 (4H, m), 1.46 (2H, brquint, J = 7.5 Hz), 2.00 (2H, quint, J = 7.4 Hz), 2.11 (2H, t, J = 7.5 Hz), 2.26 (3H, s), 2.42 (3H, s), 2.43 (2H, t, J = 7.0 Hz), 3.01 (2H, t, J = 7.2 Hz), 4.15 (2H, Q, J = 7.2 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz) ), 9.63 (IH, brs).

Elemental _{analysis: C 25 N 3 0 5 S} 3 Calculated: C, 54.42; H, 6.03 ; N, 7.62; S, 17.43

Found: C, 54.32; H, 5.91; N, 7.70; S, 17.59 (%).

Example 4 ^ 256

Ή one _{NMR (300MHz, CDC1 3):} δ 0.91 (3H, t, J = 6.8 Hz), 1.26 (3H, t, J = 7.0 Hz), 1.32 (4H, m), 1.47 (2H, brquint, J = 7.3 Hz), 1.73 (4H, in), 2.11 (2H, t, J = 7.5 Hz), 2.26 (3H, s), 2.33 (2H, t, J = 6.8 Hz), 2.42 (3H, s), 2.95 (2H, brt, J = 7.0 Hz), 4.14 (2H, q, J- 7.2 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.64 (IH , brs).

Elemental analysis: C ₂₆と し て₅ N ₃ 0 ₅ S ₃ Calculated: C, 55.20; H, 6.24; N, 7.43; S, 17.00 (%), found: C, 55.10; H, 6.43; N, 7.51; S, 16.94 ().

Example 4-257

_{Ή-NM (300MHz, CDC1 3} ): δ 0.89 (3H, t, J = 6.8 Hz), 0.90 (3H, t, J = 6.6 Hz), 1.28 (3H, t, J = 7.0 Hz), 1.29 (12H , m), 1.46 (2H, brquint, J = 7.3 Hz), 1.80 (IH, brquint, J = 7.0 Hz), 1.90 (IH, quint, J = 7.7 Hz), 2.10 (2H, t, J = 7.5 Hz) ), 2.24 (3H, s), 2.42 (3H, s), 4.00 (IH, t, J = 7.2 Hz), 4.20 (2H, q, J = 7.0 Hz), 7.28 (2H, d, J = 8.3 Hz) ), 7.85 (2H, d, J = 8.3 Hz), 9.61 (1H, brs). Example 4-258

_{lH_NMR (300MHz, CDC1 3):} δ 0.90 (3H, t, J = 6.8 Hz), 1.31 (4H, m), 1.42 (4H, m), 1.47 (2H, brquint, J = 6.8 Hz), 1.58 (2H, quint, J = 6.7 Hz), 1.70 (2H, quint, J = 7.3 Hz), 2.11 (2H, t, J = 7.7 Hz) , 2.26 (3H, s), 2.42 (3H, s), 2.95 (2H, t, J = 7.7 Hz), 3.66 (2H, dt, J = 4.5, 6.4 Hz), 7.28 (2H, d, J = 8.3) Hz), 7.85 (2H, d, J = 8.3 Hz), 9.62 (1H, brs).

Elemental analysis: Calculated as _{C 25 H 35 N 3 0 4} S 3: C, 55.84; H, 6,56; N, 7.81; S, 17.89 (%), Found: C, 55.73; H, 6.49 ; N, 7.84; S, 17.87 (%)

Example 4-259

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.91 (3Η, t, J = 6.8 Hz), 1.31 (4H, m), 1.37 (6H, m), 1.45 (2H, brquint, J = 7.0 Hz), 1.69 (2H, brquint, J = 7.5 Hz), 2.11 (2H, t, J = 7.5 Hz), 2.26 (3H, s), 2.42 (3H, s), 2.94 (2H, t, J = 7.5 Hz), 3.65 (2H, brq, J = 5.9 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.63 (1H, brs).

Elemental analysis: Calculated as _{C 26 H 37 N 3 0 4} S 3: C, 56.59; H, 6.76; N, 7.62; S, 17.43 (%), Found: C, 56.52; H, 6.62 ; N, 7.77; S, 17.37 (%)

Example 4-260

'H-NMR (300MHz, CDC1 3): δ 0.89 (3Η, t, J = 6.7 Hz), 0.90 (3H, t, J = 6.8 Hz), 1.29 (6H, m), 1.45 (2H, brquint, J = 7.1 Hz), 1.84 (1H, m), 1.96 (1H, m), 2.10 (2H, t, J = 7.5 Hz), 2.23 (3H, s), 2.42 (3H, s), 4.01 (1H, t) , J = 4.7 Hz), 7.29 (2H, d, J = 7.9 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.64 (1H, br).

Example 4-261

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.90 (3H, t, J = 7.0 Hz), 1.28 (4H, i), 1.41 (2H, brquint, J = 7.3 Hz), 2.06 (2H, t, J = 7.5 Hz), 2.21 (3H, s), 2.40 (3H, s), 5.29 (1H, s), 7.25 (2H, d, J- 8.3 Hz), 7.37 (3H, i), 7.42 (2H, dd, J = 7.5, 3.8 Hz), 7.83 (2H, d, J = 8.3 Hz), 9.63 (1H, brs).

Elemental analysis: Calculated as _{C 27 H 29 N 3 0 5} S 3: C, 56.72; H, 5.11;, 7.35; S, 16.83 (%), Found: C, 56.52; H, 4.96 ; N, 7.29 ; S, 16.73 (%)

Example 4-262

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.89 (3H, t, J = 6.8 Hz), 1.30 (4H, m), 1.45 (2H, brquint, J = 7.3 Hz), 2.09 (2H, t, J = 7.7 Hz), 2.25 (3H, s), 2.41 (3H, s), 3.14 (2H, dd, J = 7.5, 7.3 Hz), 3.27 (2H, dd, J = 7.5, 7.3 Hz), 7.06 (1H, d, J = 1.9 Hz), 7.13 (1H, brdt, J = 1.1, 7.5 Hz), 7.22 (1H, dt, J = 1.1, 7.5 Hz), 7.24 (2H, d, J = 8.3 Hz), 7.38 (1H, d, J = 7.9 Hz), 7.59 (1H, d, J = 7.9) Hz), 7.82 (2H, d, J = 8.3 Hz), 8.10 (1H, brs), 9.63 (1H, brs).

Elemental analysis: C ₂₉ H ₃₂ N ₄ 0 ₃ S ₃ Calculated: C, 59.97; H, 5.55; N, 9.65; S, 16.56 (%), found: C, 59.96; H, 5.78; N, 9.68; S, 16.53 (%).

Example 4-263

_{NMR (300MHz, CDC1 3):} δ 0.91 (3Η, t, J = 6.8 Hz), 0.93 (6H, d, J = 6.4 Hz), 1.32 (4H, m), 1.47 (2H, brquint, J = 7.2 Hz ), 1.57 (2H, m), 1.69 (1H, septet, J = 6.6 Hz), 2.11 (2H, t, J-7.5 Hz), 2.26 (3H, s), 2.42 (3H, s), 2.94 (2H , t, J = 7.7 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.62 (1H, brs).

Elemental _{analysis: C 24 H 33 N 3 0} 3 S 3 Calculated: C, 56.77; H, 6.55 ; N, 8.28; S, 18.95 (%), Found: C, 56.76; H, 6.47 ; N, 8.13; S, 18.89 (%).

Example 4-264

_{lH-NMR (300MHz, CDC1 3} ): δ 0.89 (6Η, d, J = 6.4 Hz), 0.90 (3H, t, J = 6.4 Hz), 1.28 (2H, DI), 1.31 (4H, m), 1.46 (2H, brquint, J = 7.2 Hz), 1.57 (1H, septet, J = 6.8 Hz), 1.68 (2H, m), 2.11 (2H, t, J = 7.4 Hz), 2.26 (3H, s), 2.41 (3H, s), 2.92 (2H, t, J = 7.5 Hz), 7.28 (2H, d, J = 7.9 Hz), 7.85 (2H, d, J = 7.9 Hz), 9.63 (1H, brs).

Elemental analysis: Calculated as _{C 25 H 35 N 3 0 3} S 3: C, 57.55; H, 6.76; N, 8.05; S, 18.44

(%), Found: C, 57.46; H, 6.66; N, 7.95; S, 18.59 (%).

Example 4-265

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.90 (3H, t, J = 6.6 Hz), 1.31 (4H, m), 1.46 (2H, brquint, J = 7.2 Hz), 1.84 (2H, quint, J = 7.2 Hz), 2.10 (2H, t, J = 7.5 Hz), 2.25 (9H, s), 2.40 (2H, t, J = 7.0 Hz), 2.41 (3H, s), 2.99 (2H, t, J = 7.4 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.86 (2H, d, J = 8.3 Hz).

Elemental _{analysis: C 24 H 34 N 4 0} 3 S 3 Calculated: C, 55.14; H, 6.56 ; N, 10.72; S, 18.40 (%), Found: C, 54.87; H, 6.37 ; N, 10.80; S, 18.29 (%). Example 4-266

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.91 (3H, t, J = 6.8 Hz), 1.30 (4H, m), 1.42 (2H, brquint, J = 7.4 Hz) ', 2.07 (2H, t, J = 7.5 Hz), 2.21 (3H, s), 2.41 (3H, s), 3.75 (3H, s), 5.26 (1H, s), 7.26 (2H, d, J-8.3 Hz), 7.36 (5H, m ), 7.83 (2H, d, J = 8.3 Hz), 9.58 (1H, brs).

Elemental _{analysis: C 28 H 31 N 3 0} 5 S 3 Calculated: C, 57.41; H, 5.33 ; N, 7.17; S, 16.42

(%), Found: C, 57.22; H, 5.23; N, 7.39; S, 16.42 ().

Example 4-267

'H-NMR (300MHz, CDC1 3): δ 0.90 (3Η, t, J = 6.8 Hz), 0.94 (3H, t, J = 6.8 Hz), 1.30 (4H, m), 1.45 (2H, brquint, J = 7.3 Hz), 1.66 (2H, quint, J = 7.4 Hz), 2.11 (2H, t, J = 7.5 Hz), 2.26 (3H, s), 2.42 (3H; s), 2.95 (2H, t, J = 7.5 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.63 (1H, brs).

Elemental _{analysis: C 23 H 31 N 3 0} 3 S 3 Calculated: C, 55.95; H, 6.33 ; N, 8.51; S, 19.48 (%), Found: C, 55.79; H, 6.62 ; N, 8.62; S, 19.50 (%).

Example 4-268

_{[H - NMR (300MHz, CDC1 3} ) δ 0.90 (3Η, t, J = 6.8 Hz), 0.91 (3H, t, J = 6.8 Hz), 1.31 (4H, m), 1.36 (4H, m), 1.47 (2H, brquint, J = 7.4 Hz), 1.68 (2H, quint, J = 7.3 Hz), 2.11 (2H, t, J = 7.7 Hz), 2.26 (3H, s), 2.41 (3H, s), 2.94 (2H, t, J = 7.5 Hz), 7.28 (2H, d, J- 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.63 (1H, brs).

Elemental analysis: Calculated as _{C 24 H 33 N 3 0 3} S 3: C, 56.77; H, 6.55; N, 8.28; S, 18.95

(), Found: C, 56.63; H, 6.65; N, 8.39; S, 18.92 ().

Example 4-269

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.90 (3H, t, J = 6.8 Hz), 0.90 (3H, t, J = 6.8 Hz), 1.31 (10H, m), 1.37 (3H, d, J = 6.8 Hz), 1.47 (2H, brquint, J- 7.3 Hz), 1.65 (2H, m), 2.12 (2H, t, J = 7.5 Hz), 2.26 (3H, s), 2.41 (3H, s), 3.46 (1H, tq, J = 6.8, 6.8 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.86 (2H, d, J = 8.3 Hz), 9.63 (1H, brs).

Elemental _{analysis: C 26 H 37 N 3 0} 3 S 3 Calculated: C, 58.28; H, 6.96 ; N, 7.84; S, 17.95 (%), Found: C, 58.43; H, 6.96; N, 7.64; S, 17.79 (%).

 'H-NMR (300 MHz, in double-mouthed form): δ 0.90 (3Η, t, J = 7.2 Hz), 0.97 (6H, t, J = 7.5 Hz), 1.33 (8H, m), 1.47 (2H , brquint, J = 7.2 Hz), 1.60 (2H, m), 1.67 (2H, m), 2.12 (2H, t, J = 7.5 Hz), 2.25 (3H, s), 2.41 (3H, s), 3.33 (1H, quint, J = 6.4 Hz), 7.27 (2H, d, J = 8.3 Hz), 7.86 (2H, d, J-8.3 Hz), 9.63 (1H, brs).

Elemental analysis: Calculated as _{C 26 H 37 N 3 0 3} S 3; C, 58.28; H, 6.96; N, 7.84; S, 17.95

(%), Found; C, 58.04; H, 7.12; N, 7.80; S, 17.94 (%).

Example 4-271

_{Ή-NR (300MHz, CDC1 3} ): 6 0.90 (3H, t, J = 6.8 Hz), 0.92 (6H, t, J = 7.3 Hz), 1.31 (4H, m), 1.44 (6H, m), 1.61 (4H, m), 2.12 (2H, t, J- 7.5 Hz), 2.26 (3H, s), 2.41 (3H, s), 3.40 (1H, quint, J = 6.4 Hz), 7.27 (2H, d, J = 8.3 Hz), 7.86 (2H, d, J = 8.3 Hz), 9.63 (1H, brs). ■ Elemental analysis: Calculated as C ₂₆ H ₃₇ N ₃ 0 ₃ S ₃ : C, 58.28; H, 6.96; N, 7.84; S, 17.95

(%), Found: C, 58.26; H, 6.88; N, 7.58; S, 17.78 (%).

Example 4-272

^{L H-NMR (300MHz, CDC1} 3): δ 0.91 (3Η, t, J = 6.6 Hz), 1.31 (4H, m), 1.47 (2H, brquint, J = 7.3 Hz), 2.04 (2H, quint, J = 7.0 Hz), 2.12 (2H, t, J = 7.5 Hz), 2.26 (3H, s), 2.43 (3H, s), 2.48 (2H, t, J = 7.0 Hz), 3.07 (2H, t, J = 7.0 Hz), 7.30 (2H, d, J = 7.9 Hz), 7.84 (2H, d, J = 7.9 Hz), 9.67 (1H, brs).

Elemental analysis: Calculated for C ₂₃ H ₂₈ N ₄ 0 ₃ S ₃ : C, 54.74; H, 5.59; N, 11.10; S, 19.06

(), Found: C, 54.78; H, 5.60; N, 11.15; S, 19.21 (%).

Example 4-273

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.91 (3H, t, J = 6.8 Hz), 1.32 (4H, m), 1.47 (2H, brquint, J = 7.3 Hz), 1.82 (4H, m), 2.11 (2H, t, J = 7.5 Hz), 2.26 (3H, s), 2.38 (2H, t, J = 6.6 Hz), 2.42 (3H, s), 2.98 (2H, t, J = 7.0 Hz), 7.30 (2H, d, J = 8.3 Hz), 7.84 (2H, d, J = 8.3 Hz), 9.64 (1H, brs).

Elemental analysis: C ₂₄ H _3. Calculated for N ₄ 0 ₃ S ₃ : C, 55.57; H, 5.83; N, 10.80; S, 18.55 Found: C, 55.37; H, 5.70; N, 10.74; S, 18.45 (%).

'H-NMR (300MHz, CDC1 3): <5 0.91 (3H, t, J = 6.8 Hz), 1.32 (4H, m), 1.47 (2H, brquint, J = 7.2 Hz), 1.60 (2H, m) , 1.70 (4H, m), 2.11 (2H, brt, J = 7.5 Hz), 2.26 (3H, s), 2.37 (2H, t, J = 6.8 Hz), 2.42 (3H, s), 2.96 (2H, t, J = 7.2 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.84 (2H, d, J = 8.3 Hz), 9.65 (1H, brs).

Elemental _{analysis: C 25 H 32 N 4 0} 3 S 3 Calculated: C, 56.36; H, 6.05 ; N, 10.52; S, 18.06

(%), Found: C, 56.24; H, 5.91;, 10.53; S, 18.06 (%).

Example 4-275

_{lH-NMR (300MHz, CDC1 3} ): δ 0.91 (3H, t, J = 6.6 Hz), 1.32 (4H, m), 1.47 (6H, m), 1.69 (4H, m), 2.11 (2H, t, J = 7.5 Hz), 2.26 (3H, s), 2.36 (2H, t, J = 7.0 Hz), 2.42 (3H, s), 2.95 (2H, t, J = 7.4 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.64 (1H, brs).

Elemental analysis: C ₂₆ H ₃₄ N ₄ 0 ₃ S ₃ Calculated: C, 57.11; H, 6.27; N, 10.25; S, 17.59 (%), found: C, 57.13; H, 6.13; N, 10.28; S, 17.71 ().

Example 4-276

_{Ή- NMR (300MHz, CDC1 3)} : δ 0.90 (3Η, t, J- 6.8 Hz), 1.31 (4H, m), 1.47 (2H, brquint, J = 7.5 Hz), 2.12 (2H, t, J = 7.7 Hz), 2.26 (3H, s), 2.42 (3H, s), 2.67 (1H, dd, J = 4.9, 1.9 Hz), 2.85 (1H, t, J = 4.3 Hz), 3.06 (1H, dd, J = 13.2, 4.5 Hz), 3.19 (1H, m), 3.24 (1H, dd, J = 13.2, 4.9 Hz), 7.30 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.60 (1H, brs).

Elemental analysis: Calculated as _{C 22 H 27 N 3 0 4} S 3: C, 53.53; H, 5.51;, 8.51; S, 19.49

(%) ゝ Found: C, 53.28; H, 5.37; N, 8.39; S, 19.34 (%).

Example 4-277

_{Ή-NMR (300MHz, CDC1 3} ): - δ 0.9'1 (3Η, t, J- 6.6 Hz), 1.31 (4H, m), 1.46 (2H, brquint, J = 7.2 Hz), 1.73 (4H, m ), 2.09 (2H, t, J = 7.5 Hz), 2.25 (3H, s), 2.39 (3H, s), 2.64 (2H, t, J = 7.0 Hz), 2.95 (2H, t, J = 7.0 Hz) ), 7.16 (2H, d, J = 7.5 Hz), 7.20 (1H, t, J- 7.5 Hz), 7.24 (2H, d, J = 8.3 Hz), 7.29 (2H, t, J = 7.5 Hz), 7.84 (2H, dt, J = 8.3, 2.2 Hz), 9.62 (1H, brs). Elemental analysis: C ₂₉ H ₃₅ N ₃ 0 ₃ S ₃ Calculated: C, 61.13; H, 6.19; N, 7.37 (%), found: C, 60.83; H, 5.99; N, 7.27 (%) .

Example 4-278

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.89 (3Η, t, J = 6.8 Hz), 1.30 (4H, m), 1.46 (2H, brquint, J = 7.3 Hz), 2.11 (2H, t, J = 7.7 Hz), 2.26 (3H, s), 2.40 (3H, s), 3.34 (2H, t, J = 6.6 Hz), 4.18 (2H, t, J = 6.8 Hz), 6.89 (2H, d, J = 7.9 Hz), 6.99 (1H, t, J = 7.3 Hz), 7.25 (2H, d, J = 8.3 Hz), 7.30 (2H, i, J = 8.0 Hz), 7.85 (2H, d, J = 8.3 Hz) ), 9.64 (1H, brs).

Elemental _{analysis: C 27 H 31 N 3 0} 4 S 3 Calculated: C, 58.14; H, 5.60 ; N, 7.53; S, 17.25 (%), Found: C, 57.99; H, 5.58 ; N, 7.60; S, 17.37 (%).

Example 4-279

_{¾-NMR (300MHz, CDC1 3} ): δ 0.88 (3H, t, J = 6.8 Hz), 1.28 (4H, i), 1.45 (2H, brquint, J = 7.2 Hz), 2.10 (2H, t, J = 7.2 Hz), 2.26 (3H, s), 2.40 (3H, s), 3.38 (4H, s), 7.26 (2H, d, J = 7.9 Hz), 7.50 (2H, t, J = 7.5 Hz), 7.61 (1H, t, J = 7.3 Hz), 7.84 (2H, d, J = 8.3 Hz), 7.96 (2H, d, J = 8.3 Hz), 9.63 (1H, brs). Elemental analysis: C ₂₈ H _{31 N 3 0 4 S 3 · 0.2} 0 calculated: C, 58.65; H, 5.52 ; N, 7.32 (), Found: C, 58.64; H, 5.47 ; N, 7.06 (%) ·

Example 4-280

_{¾-NMR (300MHz, CDC1 3} ): δ 0.90 (3Η, t, J = 6.8 Hz), 1.30 (4H, m), 1.45 (2H, brquint, J = 7.4 Hz), 2.09 (2H, t, J = 7.5 Hz), 2.15 (2H, quint, J = 7.0 Hz), 2.25 (3H, s), 2.38 (3H, s), 3.09 (2H, t, J = 7.2 Hz), 3.14 (2H, t, J = 6.8 Hz), 7.24 (2H, d, J = 8.3 Hz), 7.48 (2H, i, J = 7.5 Hz), 7.59 (1H, tt, J = 7.3, 2.0 Hz), 7.84 (2H, d, J = . 8.3 Hz), 7.96 (2H , d, J = 7.9 Hz), 9.64 (1H, brs) elemental analysis: C ₂₉ calculated _{¾ 3 N 3 0 4 S 3} : C, 59.66; H, 5.70; N , 7.20; S, 16.48 (%), found: C, 59.81; H, 5.70; N, 7.15; S, 16.21 (%).

Example 4-281

'H-NMR (300MHz, CDC1 3): δ 0.86 (3Η, t, J = 6.8 Hz), 1.25 (4H, m), 1.38 (2H, brquint, J- 7.2 Hz), 2.03 (2H, t, J = 7.5 Hz), 2.23 (3H, s), 2.40 (3H, s), 4.46 (2H, s), 7.26 (2H, d, J = 8.3 Hz), 7.51 (2H, t, J = 7.5 Hz), 7.64 (1H, tt, J = 7.5, 2.0 Hz), 7.85 ( 2H, d, J = 8.3 Hz), 7.96 (2H, d, J = 7.9 Hz), 9.63 (1H, brs) Elemental _{analysis:. C 27 H 29 N 3} 0 4 S Calculated as ₃ : C, 58.35; H, 5.26; N, 7.56; S, 17.31

(%), Found: C, 58.45; H, 5.26; N, 7.54; S, 17.11 (%).

Example 4-282

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.89 (3H, t, J = 6.8 Hz), 1.30 (4H, m), 1.46 (2H, brquint, J = 7.3 Hz), 2.11 (2H, i, J = 7.7 Hz), 2.26 (3H, s), 2.40 (3H, s), 3.34 (2H, t, J = 6.6 Hz), 4.18 (2H, t, J = 6.8 Hz), 6.89 (2H, d, J = 7.9 Hz), 6.99 (1H, t, J = 7.3 Hz), 7.25 (2H, d, J = 8.3 Hz), 7.30 (2H, t, J = 8.0 Hz), 7.85 (2H, d, J = 8.3 Hz) ), 9.64 (1H, brs).

Elemental analysis: C ₂₇ H ₃₁ N ₃ 0 Calculated _{4 S 3: C, 58.14;} H, 5.60; N, 7.53; S, 17.25 {%), Found: C, 57.99; H, 5.58 ; N, 7.60; S, 17.37 (%).

Example 4-283

_{¾-NMR (300MHz, CDC1 3} ): <5 0.91 (3H, t, J = 6.8 Hz), 1.30 (4H, m), 1.42 (2H, brquint, J = 7.2 Hz), 2.05 (2H, t, J = 7.5 Hz), 2.24 (3H, s), 2.41 (3H, s), 3.12 (4H, s), 7.26-7.35 (5H, m), 7.41 (2H, brdt, J = 6.8, 1.5 Hz), 7.84 (2H, d, J = 8.3 Hz), 9.63 (1H, brs).

Elemental analysis: Calculated as _{C 27 H 31 N 3 0 3} S 4: C, 56.51; H, 5.45;, 7.32; S, 22.35

(%), Found: C, 56.58; H, 5.47; N, 7.25; S, 22.40 ().

Example 4-284

'H-NMR (300MHz, CDC1 3): δ 0.90 (3H, t, J = 6.6 Hz), 1.31 (4H, m), 1.46 (2H, brquint, J = 7.3 Hz), 1.66 (1H, m), 1.91 (2H, quint, J = 7.0 Hz), 2.05 (1H, m), 2.10 (2H, t, J = 7.5 Hz), 2.25 (3H, s), 2.41 (3H, s), 3.02 (1H, dd , J = 13.2, 6.0 Hz), 3.18 (1H, dd, J- 13.2, 5.7 Hz), 3.78 (1H, dt, J = 8.3, 6.8 Hz), 3.87 (1H, dt, J = 8.3, 6.8 Hz) , 4.10 (1H, quint, J = 6.4 Hz), 7.28 (2H, d, J- 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.63 (1H, brs).

Elemental analysis: Calculated as _{C 24 H 31 N 3 0 4} S 3: C, 55.25; H, 5.99;, 8.05; S, 18.44

(%), Found: C, 55.12; H, 5.91;, 8.13; S, 18.70 (%).

Example 4-285

Ή-麵 R (300MHz, CDCi ₃ ): δ 0.91 (3H, t, J = 6.8 Hz), 1.32 (4H, m), 1.47 (2H, brquint, J = 7.2 Hz), 2.10 (2H, t, J = 7.5 Hz), 2.41 (3H, s), 2.46 (3H, s), 7.28

(2H, d, J = 8.3 Hz), 7.84 (2H, d, J = 8.3 Hz), 9.63 (1H, brs).

Elemental analysis: C _2. Calculated for H ₂₅ N ₃ 0 ₃ S ₃ : C, 53.19; H, 5.58; N, 9.30; S, 21.30

(%), Found: C, 53.20; H, 5.47; N, 9.24; S, 21.27 ().

Example 4-286 _t

 ¾-NMR (300 MHz, in double-mouthed form): δ 0.90 (3Η, t, J = 6.8 Hz), 1.31 (4H, 'm), 1.36 (3H, t, J = 7.4 Hz), 1.47 (2H , brquint, J = 7.2 Hz), 2.11 (2H, t, J = 7.5 Hz), 2.26 (3H, s), 2.42 (3H, s), 2.98 (2H, q, J = 7.5 Hz), 7.28 (2H , d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.64 (1H, brs).

Elemental analysis: Calculated as _{C 21 H 27 N 3 0 3} S 3; C, 54.17; H, 5.84; N, 9.02; S, 20.66

(%), Found; C, 54.12; H, 5.55; N, 8.87; S, 20.64 (%).

Example 4-287

_{Ή-NMR (300MHz, CDC1 3} ): 6 0.90 (3H, t, J = 6.8 Hz), 1.32 (4H, m), 1.39 (6H, d, J = 6.8 Hz), 1.48 (2H, brquint, J = 7.4 Hz), 2.12 (2H, t, J = 7.7 Hz), 2.26 (3H, s), 2.42 (3H, s), 3.62 (1H, sept, J = 6.8 Hz), 7.28 (2H, d,] = . 8.3 Hz), 7.86 (2H , d, J = 8.3 Hz), 9.66 (1H, brs) - elemental analysis: calculated _{C 22 H 29 N 3 0 3} S 3: C, 55.09; H, 6.09; N, 8.76; S, 20.05

(%), Found: C, 55.09; H, 6.03; N, 8.71; S, 19.92 (%).

Example 4-288

'H-NMR (300MHz, CDC1 3): 6 0.91 (3H, t, J = 7.0 Hz), 1.03 (3H, t, J = 7.4 Hz), 1.32 (4H, in), 1.47 (2H, brquint, J = 7.2 Hz), 1.79 (3H, tq, J = 7.3, 7.5 Hz), 2.11 (2H, t, J-7.5 Hz), 2.26 (3H, s), 2.41 (3H, s), 2.92 (2H, t , J = 7.3 Hz), 7.28 (2H, d, J- 8.3 Hz), 7.85 (2H, dt, J = 8.3, 1.5 Hz), 9.62 (1H, brs). Elemental analysis: C ₂₂ H ₂₉ N ₃ 0 ₃ S ₃ calculated: C, 55.09; H, 6.09 ; N, 8.76; S, 20.05 (%), Found: (;, 55.10; H, 6.01;, 8.76; S, 20.04 (%).

Example 4-289

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.91 (3Η, t, J = 6.8 Hz), 1.31 (4H, m), 1.45 (2H, brquint, J = 7.3 Hz), 1.72 (1H, m), 1.84 (1H, m), 1.87 (1H, brt, J = 3.4 Hz), 1.91 (2H, m), 2.09 (2H, brt, J = 7.8 Hz), 2.25 (3H, s), 2.39 (3H, s) , 2.97 (2H, dt, J = 2.3, 7.0 Hz), 4.70 (1H, brt, J = 4.0 Hz), 7.24 (2H, d, J = 8.3 Hz), 7.34 (5H, m), 7.83 (2H, d, J = 8.3) Hz), 9.63 (1H, brs).

Elemental analysis: Calculated as _{C 29 H 35 N 3 0 4} S 3: C, 59.46; H, 6.02;, 7.17; S, 16.42 (%), Found: C, 59.42; H, 6.16 ; N, 7.33 ; S, 16.41 (%).

Example 4-290

_{Ή-NMR (300MHz, CDC1 3} ): d 0.81 (3H, t, J = 7.0 Hz), 1.13 (4H, m), 1.34 (2H, quint, J = 7.3 Hz), 1.92 (2H, dd, J = 8.0, 7.3 Hz), 2.42 (3H, s), 4.26 (2H, s), 7.15 (2H, m), 7.26 (2H, d, J = 8.3 Hz), 7.35 (5H, s), 7.38 (3H, s) m), 7.83 (2H, d, J = 8.3 Hz), 9.49 (1H, brs).

Elemental analysis: C ₃₁ H ₃₁ N ₃ 0 ₃ S ₃ Calculated: C, 63.13; H, 5.30; N, 7.12; S, 16.31 (%), found: C, 63.03; H, 5.19; N, 7.00; S, 16.13 (%).

Example 4-291

_{¾-NMR (300MHz, CDC1 3} ): 6 0.89 (3H, t, J = 6.8 Hz), 1.28 (6H, brs), 1.46 (2H, brquint, J = 7.2 Hz), 2.07 (2H, brt, J = 7.2 Hz), 2.42 (3H, s), 2.78 (2H, t, J = 7.2 Hz), 3.24 (2H, t, J = 7.2 Hz), 6.50 (1H, brt, J = 1 Hz), 7.30 (2H , d, J = 8.3 Hz), 7.84 (2H, d, J = 8.3 Hz), 9.7 (1H, br).

Example 4-292

_{Ή-NMR (300MHz, CDC1 3} ): 6 0.89 (3H, t, J = 6.8 Hz), 1.28 (6H, brs), 1.45 (2H, brquint, J = 7.5 Hz), 2.04 (2H, brt, J = 7.2 Hz), 2.39 (3H, s), 2.59 (2H, t, J = 7.5 Hz), 3.30 (2H, t, J = 7.5 Hz), 6.15 (1H, brt, J = 5.7 Hz), 6.46 (1H , s), 7.27 (7H, m), 7.80 (2H, d, J = 8.3 Hz).

Example 4-293

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.89 (3H, brt, J = 6.9 Hz), 1.28 (4H, m), 1.31 (2H, in), 1.46 (2H, brquint, J = 7.1 Hz), 1.61 (3H, s), 1.69 (3H, s), 1.69 (3H, s), 2.06 (4H, brs), 2.06 (2H, brt, J = 7.1 Hz), 2.41 (3H, s), 3.66 (2H, d, J = 7.6 Hz), 5.07 (1H, brt, J = 5.9 Hz), 5.24 (1H, brt, J = 7.6 Hz), 6.50 (1H, brs), 7.28 (2H, d, J = 8.2 Hz) , 7.83 (2H, d, J = 8.2 Hz), 9.73 (1H, brs).

Elemental analysis: C ₂₉ H ₂₉ N ₃ 0 ₃ S ₃ · 0.2 計算 0 Calculated: C, 60.32; H, 6.88; N, 7.28; S, 16.66 (%), found: C, 60.27; H, 6.59 ; N, 7.26; S, 16.67 (%). Example 4-294,

_{¾-NMR (300MHz, CDC1 3} ): δ 0.89 (3H, t, J = 6.9 Hz), 1.28 (4H, m), 1.30 (2H, m), 1.44 (2H, brquint, J- 6.9 Hz), 2.04 (2H, brt, J = 7.1 Hz), 2.42 (3H, s), 4.17 (2H, s), 6.47 (1H, brs), 7.21 (1H, m), 7.27 (2H,), 7.27 (2H, d , J = 8.3 Hz), 7.31 (1H, m), 7.81 (2H, d, J = 8.3 Hz), 9.72 (1H, brs).

Elemental analysis: Calculated for C ₂₆ H ₂₈ N ₃ 0 ₃ S ₃ C1: C, 55.55; H, 5.02; N, 7.47; S, 17.11; C1, 6.31 (%), found: C, 55.44; H , 4.86; N, 7.45; S, 17.2,8; C1, 6.24 (%).

_{Ή-NMR (300MHz, CDC1 3} ): <5 0.89 (3H, t, J = 6.9 Hz), 1.28 (4H, m), 1.31 (2H, m), 1.43 (2H, brquint, J = 7.0 Hz), 2.04 (2H, brt, J = 7.0 Hz), 2.43 (3H, s), 4.15 (2H, s), 6.46 (1H, brt, J = 0.5 Hz), 7.19 (2H, d, J = 8.4 Hz), 7.27 (2H, d, J = 8.3 Hz), 7.45 (2H, dt, J = 8.4, 1.8 Hz), 7.80 (2H, d, J = 8.3 Hz), 9.71 (1H, brs).

Elemental _{analysis: C 26 H 28 N 3 0} 3 S 3 Br Calculated: C, 51.48; H, 4.65 ; N, 6.93; S, 15.86; Br, 13.17 (%), Found: C, 51.29; H , 4.43; N, 6.74; S, 15.48; Br, 13.01 (%).

Example 4-296

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.89 (3Η, t, J = 6.9 Hz), 1.27 (4H, m), 1.31 (2H, m), 1.43 (2H, brquint, J = 7.0 Hz), 2.03 (2H, brt, J = 7.0 Hz), 2.42 (3H, s), 4.24 (2H, s), 6.46 (1H, brt, J = 0.5 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.44 (2H, brd, J = 8.2 Hz), 7.58 (2H, brd, J = 8.2 Hz), 7.81 (2H, d, J = 8.3 Hz), 9.72 (1H, br).

Elemental _{analysis: C 27 H 28 N 3 0} 3 Calculated _{S 3 F 3: C, 54.44} ; H, 4.74; N, 7.05; S, 16.15 (), Found: C, 54.33; H, 4.75 ;. N, 6.94; S, 15.99 (%)

Example 4-297

'H-NMR (300MHz, CDC1 3): δ 0.89 (3Η, t, J = 6.9 Hz), 1.27 (4H, m), 1.31 (2H, m), 1.43 (2H, brquint, J = 6.8 Hz), 2.04 (2H, brt, J = 7.0 Hz), 2.42 (3H, s), 4.24 (2H, s), 6.46 (1H, brt, J = 0.5 Hz), 7.27 (2H, brd, J = 8.3 Hz), 7.47 (1H, q, J = 7.8 Hz), 7.57 (2H, brs), 7.81 (2H, d, J = 8.3 Hz), 9.72 (1H, br). Elemental analysis: C „H ₂₈ N ₃ 0 ₃ S ₃ F ₃ Calculated: C, 54.44; H, 4.74; N, 7.05; S, 16.15

(%), Found: C, 54.28; H, 4.48; N, 7.10; S, 16.12 (%)

Example 4-298

'H-NMR (300MHz, CDC1 3): δ 0.88 (3Η, t, J = 7.0 Hz), 1.27 (4H, brs), 1.30 (2H, m), 1.43 (2H, brquint, J = 6.9 Hz), 2.04 (2H, brt, J = 7.1 Hz), 2.39 (3H, s), 4.38 (2H, s), 6.46 (1H, brt, J = 0.5 Hz), 7.22 (2H, brd, J = 8.3 Hz), 7.42 (1H, dd, J = 8.4, 1.7 Hz), 7.51 (2H, m), 7.80 (4H, m), 7.81 (2H, d, J = 8.3 Hz), 9.73 (1H, brs).

Elemental analysis: C _3. H ₃₁ N ₃ 0 ₃ S ₃ Calculated: C, 62.36; H, 5.41;, 7.27; S, 16.65 (%), Found: C, 62.29; H, 5.21; N, 7.32; S, 16.60 (% )

Example 4-299

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.90 (3Η, t, J = 6.8 Hz), 1.30 (4H, brs), 1.32 (2H, m), 1.47 (2H, brquint, J- 7.3 Hz), 2.08 (2H, brt, J = 7.0 Hz), 2.38 (3H, s), 4.70 (2H, s), 6.50 (1H, brt, J = 0.5 Hz), 7.10 (2H, brd, J = 8.3 Hz), 7.44 (1H, dd, J = 8.0, 7.3 Hz), 7.52 (1H, brd, J = 7 Hz), 7.55 (1H, m), 7.55 (1H, d, J = 8.6 Hz), 7.69 (2H, d, J = 8.3 Hz), 7.86 (1H, d, J = 8.1 Hz), 7.91 (1H, m), 8.02 (1H, m), 9.69 (1H, brs).

Example 4-300

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.89 (3H, t, J = 6.9 Hz), 1.27 (4H, m), 1.29 (2H, m), 1.43 (2H, brquint, J = 7.3 Hz), 2.04 (2H, brt, J = 7.2 Hz), 2.42 (3H, s), 4.40 (2H, s), 6.45 (1H, brt, J = 0.5 Hz), 7.29 (2H, brd, J = 8.3 Hz), 7.43 (1H, ddd, J = 7.7, 6.6, 2.2 Hz), 7.58 (1H, d, J = 7.4 Hz), 7.58 (1H, d, J = 7.4 Hz), 7.59 (1H, m), 7.67 (1H, brd, J = 7.7 Hz), 7.82 (2H, d, J = 8.3 Hz), 9.72 (1H, brs).

Elemental analysis: C ₂₇ H ₂₈ N ₄ 0 ₃ S ₃ · 0.5 H ₂ 0 Calculated: C, 57.73; H, 5.20; N, 9.97; S, 17.12 (%), found: C, 57.69; H , 5.11;, 10.14; S, 17.06 (%).

Example 4-301

'H-NMR (300MHz, CDC1 3): δ 0.89 (3H, t, J = 6.9 Hz), 1.24 (9H, s), 1.29 (4H, m), 1.32 (2H, m), 1.47 (2H, brquint , J = 7.3 Hz), 2.07 (2H, brt, J = 7.2 Hz), 2.40 (3H, s), 4.28 (2H, s), 6.49 (1H, brt, J = 0.5 Hz), 7.26 (2H, brd, J = 8.1 Hz), 7.28 (2H, di,. J = 8.2 Hz) , 7.34 (2H, dm, J = 8.2 Hz), 7.35 (1H, brd, J = 8.0 Hz), 7.41 (1H, dt, J = 7.6, 1.3 Hz), 7.50 (1H, dt, J = 7.8, 1.5 Hz), 7.80 (2H, d, J = 8.1 Hz), 7.80 (1H, d, J = 8 Hz), 9.75 (1H, brs).

Elemental _{analysis: C 37 H 37 N 3 0} 5 S 3 · 0.6H 2 0 Calculated: C, 62.53; H, 5.42 ; N, 5.91; S, 13.53 (%), Found: C, 62.56; H , 5.55; N, 5.93; S, 13.50 (%).

Example 4-302

E -賺_{(300MHz, CDC1 3): δ} 0.89 (3Η, t, J = 6.9 Hz), 1.28 (4H, m), 1.30 (2H, m), 1.45 (2H, brquint, J = 7.1 Hz), 2.05 (2H, brt, J = 7.1 Hz), 2.41 (3H, s), 4.25 (2H, s), 6.47 (1H, brt, J = 0.5 Hz), 7.07 (1H, ddd, J = 9.8, 8.5, 1.0 Hz), 7.13 (1H, dt, J = 7.5, 1.0 Hz), 7.26 (2H, d, J = 8.3 Hz), 7.30 (1H, m), 7.37 (1H, dt, J = 7.7, 1.6 Hz), 7.81 (2H, d, J = 8.3 Hz), 9.71 (1H, brs).

Elemental _{analysis: C 26 H 2S N 3 0} 3 S 3 F Calculated: C, 57.22; H, 5.17 ; N, 7.70; S, 17.63; F, 3.48 (%), Found: C, 57.18; H , 5.18; N, 7.90; S, 17.62; F, 3.19 ().

_{Ή-NR (300MHz, CDC1 3} ): δ 0.89 (3H, t, J = 6.9 Hz), 1.28 (4H, m), 1.30 (2H, m), 1.43 (2H, brquint, J = 6.8 Hz), 2.04 (2H, bri, J = 7.1 Hz), 2.42 (3H, s), 4.19 (2H, s), 6.47 (1H, brt, J = 0.5 Hz), 7.02 (2H, m), 7.10 (1H, brd, J = 7.8 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.31 (1H, bri, J = 7.8 Hz), 7.81 (2H, d, J = 8.3 Hz).

Elemental _{analysis: C 26 H 28 N 3 0} 3 S 3 F Calculated: C, 57.22; H, 5.17 ; N, 7.70; S, 17.63; F, 3.48 (%), Found: C, 57.10; H , 5.04; N, 7.69; S, 17.79; F, 3.31 (%).

_{Ή-NMR (300MHz, CDC1 3} ) δ 0.89 (3Η, t, J = 6.9 Hz), 1.29 (4H, m), 1.30 (2H, m), 1.33 (9H, s), 1.45 (2H, brquint, J = 6.8 Hz), 2.06 (2H, brt, J = 7.2 Hz),

2.41 (3H, s), 4.20 (2H, s), 6.47 (1H, brt, J = 0.5 Hz), 7.25 (2H, d, J = 8.3 Hz), 7.25 (2H, d, J = 8.3 Hz), 7.35 (2H, d, J = 8.3 Hz), 7.80 (2H, d, J = 8.3 Hz), 9.70 (1H, br).

Elemental analysis: C _3. H ₃₇ N ₃ 0 ₃ S ₃ Calculated: C, 61.77; H, 6.39 ; N, 7.20; S, 16.48 (%), Measured: C, 61.62; H, 6.24;, 7.36; S, 16.63 (%) · Example 4-305

'H-NMR (300MHz, CDC1 3): δ 0.89 (3H, t, J = 6.9 Hz), 1.26 (4H, brs), 1.29 (2H, m), 1.38 (2H, brquint, J = 6.6 Hz), 1.98 (2H, brt, J = 7.1 Hz), .2.41 (3H, s), 4.17 (2H, s), 6.43 (1H, brt, J = 0.5 Hz), 7.26 (2H, d, J = 8.3 Hz) , 7.32 (3H, m), 7.37 (5H, m), 7.47 (1H, m), 7.80 (2H, d, J = 8.3 Hz), 9.67 (1H, brs) elemental analysis:. C ₃₂ N ₃ 0 Calculated for ₃ S ₃ : C, 63.65; H, 5.51;, 6.96; S, 15.93

(%), Found: C, 63.61; H, 5.39; M, 6.72; S, 15.88 (%).

Example 4-306

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.88 (6H, d, J = 6.8 Hz), 0.89 (3H, t, J = 6.9 Hz), 1.18 (2H, brquint, J = 7.2 Hz), 1.29 (6H , M), 1.33 (2H, m), 1.38 (2H, m), 1.47 (2H, brquint, J = 7.1 Hz), 1.53 (1H, quint, J = 7.1 Hz), 1.69 (2H, quint, J = 7.2 Hz), 2.07 (2H, brt, J = 7.3 Hz), 2.42 (3H, s), 2.96 (2H, t, J = 7.6 Hz), 6.51 (1H, brs), 7.28 (2H, d, J = 7.9 Hz), 7.85 (2H, d, J = 7.9 Hz), 9.71 (1H, brs).

Elemental analysis: C ₂₇ H ₃₉ N ₃ 0 ₃ S ₃ · 0.2H ₂ O Calculated: C, 58.60; H, 7.18; N, 7.59; S, 17.38 (), found: C, 58.55; H, 6.87; N, 7.82; S, 17.49 (%).

Example 4-307

'H-NMR (300MHz, CDC1 3): δ 0.88 (6H, d, J = 6.8 Hz), 0.89 (3H, t, J = 6.9 Hz), 1.20 (2H, m), 1.29 (4H, m), 1.31 (2H, m), 1.38 (2H, in), 1.46 (2H, brquint, J = 7.2 Hz), 1.54 (1H, quint, J = 6.8 Hz), 1.67 (2H, quini, J = 7.5 Hz), 2.07 (2H, brt, J = 7.2 Hz), 2.42 (3H, s), 2.96 (2H, t, J = 7.3 Hz), 6.51 (1H, brt, J = 0.5 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.84 (2H , d, J = 8.3 Hz), 9.72 (1H, brs) elemental _{analysis: C 26 H 37 N 3 0} 3 S 3 calculated:. C, 58.28; H, 6.96; N, 7.84; S, 17.95 (%), Found: C, 58.17; H, 6.97; N, 7.94; S, 17.94 (%).

Example 4-308

E - thigh _{(300MHz, CDC1 3): δ} 0.89 (3Η, t, J- 7.2 Hz), 1.29 (4H, br), 1.32 (2H, m), 1.49 (2H, brquint, J = 6.9 Hz), 2.07 (2H, brt, J = 6.8 Hz), 2.08 (1H, br), 2.09 (2H, s), 2.42 (3H, s), 6.45 (1H, brt, J = 0.5 Hz), 7.30 (2H, d, J = 8.3 Hz), 7.82 (2H, d, J = 8.3 Hz), 9.63 (1H, brs).

Elemental _{analysis: C 22 ¾ 5 N 3 0} 3 S 3 Calculated: C, 55.55; H, 5.30 ; N, 8.83; S, 20.22

(%), Found: C, 55.27; H, 5.09; N, 8.97; S, 20.38 (%).

Example 4-309

ΐ-NM (300MHz, DMSO- d ₆ ) δ 0.85 (3Η, t, J = 6.8 Hz), 1.26 (4H, br), 1.28 (2H, m), 1.41 (2H, brquint, J = 6.4 Hz), 2.14 (2H, brt, J = 7.0 Hz), 2.35 (3H, s), 4.37 (2H, s), 6.63 (1H, brs), 7.32 (4H, m), 7.39 (1H, dd, J = 7.5, 1.11), 7.41 (2H, brt, J = 7.9 Hz), 7.46 (1H, dt, J = 1.1, 7.5 Hz), '7.57 (1H, dt, J = 1.1, 7.5 Hz), 7.73 (1H, dd , J = 7.5, 1.1 Hz), 7.81 (2H, d, J = 8.3 Hz), 11.77 (1H, br), 12.76 (1H, br).

Example 4-310

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.88 (3H, t, J = 6.8 Hz), 1.28 (4H, brs), 1.31 (2H, m), 1.46 (2H, brquint, J = 7.3 Hz), 2.06 (2H, brt, J = 7.0 Hz), 2.40 (3H, s), 3.82 (2H, dd, J = 7.2, 1.1 Hz), 6.18 (1H, dt, J = 15.5, 7.2 Hz), 6.49 (1H, brt, J = 0.5 Hz), 6.61 (1H, d, J = 15.8 Hz), 7.27 (2H, d, J = 8.3 Hz), 7.30 (1H, m), 7.35 (4H, m), 7.84 (2H, d, J = 8.3 Hz), 9.75 (1H, brs).

Elemental _{analysis: C 28 H 31 N 3 0} 3 S 3 Calculated: C, 60.73; H, 5.64 ; N, 7.59; S, 17.37

(%), Found: C, 60.68; H, 5.53; N, 7.74; S, 17.39 (%).

Example 4-311

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.89 (3H, t, J = 6.8 Hz), 1.14 (2H, brdq, J = 4.4,

12.1 Hz), 1.28 (6H, m), 1.46 (2H, m), 1.46 (9H, s), 1.69 (1H, m), 1.79 (2H, brd, J = 13.6 Hz), 2.06 (2H, brt, J = 7.2 Hz), 2.41 (3H, s), 2.68 (2H, brt, J =

12.2 Hz), 2.87 (2H, d, J = 6.8 Hz), 4.11 (2H, brd, J = 14 Hz), 6.51 (1H, brt, J = 0.5 Hz), 7.27 (2H, d, J = 8.3 Hz) ), 7.85 (2H, d, J = 8.3 Hz).

Elemental analysis: C _{3. H 42 N 4 0 5 S 3} · 0.7H 2 0 Calculated: C, 55.65; H, 6.76 ;, 8.65; S, 14.85 (%), Found: C, 55.67; H, 6.47 ; N, 8.58; S, 14.84 ().

Example 4-312

Ή-NMR (300 MHz, DMSO-d ₆ ): δ 0.86 (3H, t, J = 6.6 Hz), 1.26 (4H, m), 1.30 (2H, m), 1.38 (2H, 'm), 1.81 (1H , i), 1.87 (2H, brd, J = 15.4 Hz), 2.13 (2H, brt, J = 7.0 Hz), 2.38 (3H, s), 2.86 (2H, brq, J = 11.3 Hz), 2.97 (2H, d, J = 6.4 Hz), 3.30 (2H, brd, J = 14 Hz), 6.63 (1H, brs), 7.37 (2H, d, J = 7.9 Hz), 7.83 (2H, d, J = 7.9 Hz), 8.19 (1H, brs), 8.50 (1H, br), 11.80 (1H, br) .

Elemental analysis: Calculated as _{C 27 H 35 N 4 0 5} S 3 F 3: C, 49.98; H, 5.44; N, 8.64; S, 14.83; F, 8.78 (%), Found: C, 49.72; H, 5.33; N, 8.70; S, 14.86 (%).

Example 4-313

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.89 (3Η, t, J = 6.6 Hz), 1.29 (6H, br), 1.39 (2H, m), 1.43 (2H, brquint, J = 7.2 Hz), 1.56 (1H, m), 1.81 (2H, brd, J = 13.8 Hz), 2.02 (2H, brt, J = 11.7 Hz), 2.06 (2H, t, J = 7.3 Hz), 2.39 (3H, s), 2.87 (2H, d, J = 6.8 Hz), 2.97 (2H, brt, J = 11.3 Hz), 3.57 (2H, s), 6.49 (1H, brt, J = 0.5 Hz), 7.26 (2H, m), 7.32 (5H, s), 7.85 (2H, d, J- 8.3 Hz).

Example 4-314

_{¾-NMR (300MHz, CDC1 3} ): δ 0.89 (3H, t, J = 6.8 Hz), 1.28 (6H, m), 1.44 (2H, brquint, J = 6.8 Hz), 2.04 (2H, t, J = 7.0 Hz), 2.31 (3H, s), 2.41 (3H, s), 4.20 (2H, s), 6.47 (1H, brt, J = 0.5 Hz), 7.06 (2H, dt, J = 8.7, 1.9 Hz) , 7.27 (2H, d, J = 8.3 Hz), 7.33 (2H, dt, J = 8.7, 2.6 Hz), 7.81 (2H, d, J = 8.3 Hz), 9.72 (1H, brs).

Elemental analysis: C ₂₈ H ₃₁ N ₃ 0 ₅ S ₃ Calculated: C, 57.41; H, 5.33; N, 7.17; S, 16.42 (%), found: C, 57.35; H, 5.06; N, 7.21; S, 16.37 ().

Example 4-315

'H-NMR (300MHz, CDC1 3): δ 0.89 (3Η, t, J = 6.6 Hz), 1.29 (6H, m), 1.48 (2H, brquint, J = 7.3 Hz), 2.06 (2H, t, J = 7.0 Hz), 2.41 (3H, s), 3.27 (2H, t, J = 7.0 Hz), 3.99 (2H, t, J = 7.0 Hz), 6.47 (1H, brt, J = 0.5 Hz), 7.26 ( 2H, d, J = 7.9 Hz), 7.75 (2H, dd, J = 5.3, 3.0 Hz), 7.81 (2H, d, J = 8.3 Hz), 7.86 (2H, dd, J = 5.3, 3.0 Hz), 9.69 (1H, brs).

Elemental analysis: C ₂₉ H ₃₀ N ₄ 0 ₅ S ₃ · 0.5 H ₂ 0 Calculated: C, 56.20; H, 5.04; N, 9.04; S, 15.52 (%), found: C, 56.11; H , 5.01; N, 9.15; S, 15.65 (%).

Example 4-316

'H-NMR (300MHz, CDC1 3): δ 0.89 (3Η, t, J = 6.8 Hz), 1.27 (6H, m), 1.40 (2H, brquint, J = 7.0 Hz), 1.99 (2H, t, J = 7.2 Hz), 2.07 (2H, quint, J = 6.8 Hz), 2.39 (3H, s), 2.99 (2H, t, J = 7.5 Hz) , 3.76 (2H, t, J = 6.8 Hz), 6.47 (1H, brt, J = 0.5 Hz), 7.27 (2H, d, J = 8.3 Hz), 7.74 (2H, dd, J = 5.3, 3.0 Hz) , 7.83 (2H, d, J = 8.3 Hz), 7.86 (2H, dd, J = 5.7, 3.0 Hz), 9.72 (1H, brs).

Elemental analysis: C _3. H ₃₂ N ₄ 0 ₅ S ₃ Calculated: C, 57.37; H, 5.16 ; N, 8.9-7; S, 15.40 (%), Found: C, 57.64; H, 5.11 ;, 9.13; S, 15.45 (%).

. Example 4-317 'Ή-NMR (300MHz, CDC1 3): δ 0.88 (3Η, t, J = 6.8 Hz), 1.23 (4H, m), 1.27 (2H, m), 1.32 (2H, m) , 1.93 (2H, t, J = 7.2 Hz), 2.42 (3H, s), 5.90 (1H, s), 6.35 (1H, brt, J = 0.5 Hz), 7.26 (2H, d, J = 8.3 Hz) , 7.30 (2H, m), 7.33 (8H, m), 7.83 (2H, d, J = 8.3 Hz), 9.70 (1H, brs).

Elemental analysis: Calculated as _{C 32 N 3 0 3 S 3} : C, 63.65; H, 5.51; N, 6.96; S, 15.93

(%), Found: C, 63.61; H, 5.43; N, 7.05; S, 16.08 (%).

Example 4-318

_{^ - MR (300MHz, CDC1 3} ): δ 0.89 (3H, t, J = 6.8 Hz), 1.28 (6H, m), 1.45 (2H, brquint, J = 7.0 Hz), 2.06 (2H, t, J = 7.0 Hz), 2.41 (3H, s), 4.33 (2H, s), 6.48 (1H, brt, J = 0.5 Hz), 7.26 (2H, d, J = 8.3 Hz), 7.27 (2H, m), 7.41 (2H, m), 7.81 (2H, d, J = 8.3 Hz), 9.71 (1H, brs).

Elemental _{analysis: C 26 H 28 N 3 0} 3 S 3 C1 · 0.5H 2 O: C, 54.67; H, 5.12; N, 7.36; S, 16.84; CI, 6.21 (%), Found: C, 54.63 ; H, 5.24; N, 7.39; S, 16.82; CI, 6.29 (%). Example 4-319

'H-NMR (300MHz, CDC1 3): δ 0.86 (3H, t, J = 6.6 Hz), 1.23 (6H, m), 1.37 (2H, brquint, J = 7.2 Hz), 1.97 (2H, t, J = 7.0 Hz), 2.43 (3H, s), 4.57 (2H, s), 6.34 (1H, brt, J = 0.5 Hz), 7.29 (2H, m), 7.30 (2H, d, J = 8.3 Hz), 7.68 (2H, dd, J = 6.0, 3.0 Hz), 7.82 (2H, d, J = 8.3 Hz).

Elemental _{analysis: C 27 H 29 N 5 0} 3 S 3 · 0.2H 2 0 Calculated:. C, 56.76; H, 5.19;, 12.26; S, 16.83 (%) Found: C, 56.68; H, 5.20; N, 12.33; S, 16.87 (%).

Example 4-320

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.86 (3H, i, J = 6.8 Hz), 1.22 (4H, m), 1.25 (2H, m), 1.38 (2H, brquint, J- 7.0 Hz), 2.01 (2H, t, J = 7.5 Hz), 2.40 (3H, s), 4.55 (2H, s), 6.45 (1H, brs), 7.24 ( 2H, d, J = 8.3 Hz), 7.54 (1H, d, J = 8.7 Hz), 7.58 (1H, brt, J = 7.9 Hz), 7.75 (1H, dt, J = 7.7, 1.0 Hz), 7.83 ( 2H, d, J = 8.3 Hz), 7.84 (1H, brd, J = 8.3 Hz), 8.07 (1H, brd, J = 8.7 Hz), 8.17 (1H, d, J = 8.3 Hz), 9.73 (1H, brs).

Elemental analysis: C _29. Calculated for N ₄ 0 ₃ S ₃ : C, 60.18; H, 5.22; N, 9.68; S, 16.62 (%), found: C, 59.87; H, 5.23; N, 9.72; S, 16.51 ().

Example 4-321

Over丽_{R (300MHz, CDC1 3):} 6 0.89 (3H, t, J = 6.4 Hz), 1.28 (6H, br), 1.43 (2H, brquint, J = 6.8 Hz), 2.04 (2H, t, J = 7.0 Hz), 2.42 (3H, s), 4.17 (2H, s), 6.46

(1H, brs), 7.27 (6H, m), 7.80 (2H, d, J = 7.8 Hz), 9.72 (1H, brs).

Elemental analysis: C ₂₆ H ₂₈ N ₃ 0 ₃ S ₃ C 1 · 0.3 H ₂ 0, calculated: C, 55.02; H, 5.08; N, 7.40;

S, 16.95; CI, 6.25 (%), Found: C, 55.02; H, 5.10; N, 7.40; S, 17.15; Cl,

6.19 (%). '

Example 4-322

Ή one _{NMR (300MHz, CDC1 3):} δ 0.89 (3Η, t, J = 6.6 Hz), 1.27 (6H, br), 1.41 (2H, brquint, J = 6.6 Hz), 2.02 (2H, t, J = 7.2 Hz), 2.43 (3H, s), 4.15 (2H, s), 6.52 (1H, brs), 7.26 (2H, d, J = 5.7 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.82 (2H, d, J = 8.3 Hz), 8.57 (2H, d, J = 5.7 Hz).

Elemental _{analysis: C 25 H 28 N 4 0} 3 S 3 Calculated:. C, 56.79; H, 5.34; N, 10.60; S, 18.19 (%) Found: C, 56.59; H, 5.23 ; N, 10.52; S, 18.08 (%).

Example 4-323

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.88 (3Η, t, J = 6.8 Hz), 1.28 (6H, m), 1.45 (2H, brquint, J = 6.7 Hz), 2.06 (2H, t, J = 7.2 Hz), 2.40 (3H, s), 4.26 (2H, s), 6.48 (1H, brs), 7.26 (2H, d, J = 7.9 Hz), 7.37 (1H, i), 7.39 (2H, d, J = 8.3 Hz), 7.46 (2H, t, J = 7.4 Hz), 7.56 (2H, d, J = 8.7 Hz), 7.59 (2H, dm, J = 8 Hz), 7.81 (2H, d, J = 8.3 Hz), 9.74 (1H, brs).

Elemental _{analysis: C 32 H 33 N 3 0} 3 S 3 Calculated: C, 63.65; H, 5.51 ; N, 6.96; S, 15.93 (), Found: C, 63.49; H, 5.28 ; N, 6.85 ; S, 15.90 (%) Example 4-324

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.89 (3H, t, J = 6.8 Hz), 1.28 (6H, m), 1.45 (2H, brqoint, J = 6.8 Hz), 2.06 (2H, t, J = 7.2 Hz), 2.41 (3H, s), 4.34 (2H, s), 6.48 (IH, brt, J = 0.5 Hz), 7.19 (IH, dt, J = 1.5, 7.5 Hz), 7.26 (2H, d, J = 8.3 Hz), 7.30 (IH, dt, J = 1.1, 7.5 Hz), 7.43 (IH, dd, J = 7.5, 1.5 Hz), 7.58 (IH, dd, J = 7.9, 1.1 Hz), 7.82 ( 2H, d, J = 8.3 Hz), 9.70 (IH, brs).

Example 4-325

_{-NMR (300MHz, CDC1 3):} δ 0.89 (3H, t, J = 6.8 Hz), 1.29 (6H, m), 1.46 (2H, brquint, J = 6.8 Hz), 2.06 (2H, t, J = 7.0 Hz), 2.41 (3H, s), 4.32 (2H, s), 6.48 (IH, brt, J = 0.5 Hz), 7.01 (IH, dt, J = 1.5, 7.5 Hz), 7.26 (2H, d, J = 8.3 Hz), 7.34 (1H, dt, J = 1.1, 7.2 Hz), 7.43 (IH, dd, J = 7.5, 1.5 Hz), 7.82 (2H, d, J = 8.3 Hz), 7.86 (IH, dd , J = 7.5, 1.5 Hz), 9.70 (IH, brs).

Elemental _{analysis: C 26 H 28 N 3 0} 3 S 3 I Calculated: C, 47.78; H, 4.32 ; N, 6.43; S, 14.72; I, 19.42 (%), Found: C, 47.89; H , 4.29; N, 6.38; S, 14.73; I, 19.20 ().

'H-NMR (300MHz, CDC1 3): δ 0.88 (3Η, t, J = 6.6 Hz), 1.28 (6H, br), 1.44 (2H, brquint, J = 6.7 Hz), 2.04 (2H, t, J = 7.0 Hz), 2.41 (3H, s), 3.15 (2H, dd, J = 7.5, 7.2 Hz), 3.30 (2H, brt, J = 7.5 Hz), 6.47 (IH, brt, J = 0.5 Hz), 7.07 (1H, d, J = 2.3 Hz), 7.13 (IH, dt, J = 0.8, 7.4 Hz), 7.22 (1H, dt, J = 1.1, 7.5 Hz), 7.25 (2H, d, J = 8.3 Hz) ), 7.38 (IH, d, J = 7.9 Hz), 7.58 (IH, d, J = 7.5 Hz), 7.81 (2H, d, J = 8.3 Hz), 8.07 (IH, brs), 9.71 (1H, brs) ).

Elemental _{analysis: C 29 H 32 N 4 0} 3 S 3 Calculated: C, 59.97; H, 5.55 ; N, 9.65; S, 16.56

(%), Found: C, 59.88; H, 5.60; N, 9.62; S, 16.66 (%)

Example 4-327

_{Ή-NMR (300MHz, CDC1 3} ): 6 0.89 (3H, t, J = 6.6 Hz), 1.28 (6H, br), 1.43 (2H, brquint, J = 7.3 Hz), 2.03 (2H, t, J = 7.0 Hz), 2.42 (3H, s), 4.56 (2H, s), 6.45 (IH, brs), 7.29 (2H, d, J = 8.3 Hz), 7.50 (IH, m), 7.61 (2H, m) , 7.81 (2H, d, J = 8.3 Hz), 8.05 (IH, d, J = 7.9 Hz), 9.70 (IH, brs).

Elemental analysis: C ₂₆ H ₂₈ N ₄ 0 ₅ S ₃ · 0.2 H ₂ 0 Calculated: C, 54.18; H, 4.97;, 9.72; S, 16.69 (), Found: C, 54.06; H, 4.86; N, 9.73; S, 16.65 (%).

Example 4-328

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.89 (3H, t, J = 6.8 Hz), 1.27 (6H, m), 1.43 (2H, brquint, J = 7.0 Hz), 2.04 (2H, t, J = 7.2 Hz), 2.41 (3H, s), 4.38 (2H, s), 6.48 (1H, brs), 7.25 (2H, d, J = 8.3 Hz), 7.44 (1H, brt, J = 7.5 Hz), 7.55 (1H, brt, J = 7.5 Hz), 7.61 (1H, brd, J = 7.5 Hz), 7.69 (1H, brd, J = 7.9 Hz), 7.80 (2H, d, J = 8.3 Hz), 9.72 (1H , Brs).

Elemental analysis: Calculated as _{C 27 N 3 0 3 S 3} F 3: C, 54.44; H, 4.74; N, 7.05; S, 16.15; F, 9.57 (%), Found: C, 54.48; H, 4.70; N, 7.08; S, 16.36; F, 9.48 (%). Example 4-329

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.90 (3Η,, J = 7.1 Hz), 1.29 (6H, m), 1.47 (2H, brquint, J = 7.2 Hz), 2.07 (2H, t, J = 7.4 Hz), 2.41 (3H, s), 4.28 (2H, s), 6.48 (1H, brs), 6.93 (2H, t, J = 7.9 Hz), 7.25 (2H, d, J = 8.3 Hz), 7.34 ( 1H, tt, J = 8.7, 6.8 Hz), 7.80 (2H, d, J = 8.3 Hz), 9.72 (1H, brs).

Elemental _{analysis: C 26 H 27 N 3 0} 3 S 3 F 2 Calculated: C, 55.40; H, 4.83 ; N, 7.45; S, 17.07; F, 6.74 (%), Found: C, 55.24; H, 4.97; N, 7.45; S, 17.14; F, 6.72 () .Example 4-330

'H-NMR (300MHz, CDC1 3): δ 0.90 (3Η, t, J = 6.6 Hz), 1.30 (6H, m), 1.48 (2H, brquint, J = 7.2 Hz), 2.08 (2H, t, J = 7.2 Hz), 2.40 (3H, s), 4.55 (2H, s), 6.50 (1H, brs), 7.23 (1H, dd, J = 9.0, 7.2 Hz), 7.24 (2H, d, J = 7.9 Hz) ), 7.36 (2H, dd, 1 = 8.3, 0.8 Hz), 7.79 (2H, d, J = 8.3 Hz), 9.70 (1H, brs).

Elemental analysis: C ₂₆ H ₂₇ N ₃ 0 ₃ S ₃ C ₁₂ · 0.3 H ₂ 0 Calculated: C, 51.87; H, 4.62;, 6.98;

S, 15.98; CI, 11.78 (%), Found: C, 51.85; H, 4.69; N, 7.02; S, 15.97; CI,

11.65 (%).

Example 4-331

_{Ή - NMR (CDC1 3, 300} MHz): δ 0.89 (3H, brt, J = 7.0 Hz), 1.28 (6H, brs), 1.44 (2H, brquint, 6.9 Hz), 2.03 (2H, brt, J = 7.2 Hz), 2.16 (2H, quint, J = 7.0 Hz), 2.39 (3H, s), 2.75 (3H, s), 3.11 (2H, t, J = 7.1 Hz), 3.14 (2H, t, J = 6.8) Hz), 6.48 (1H, brt, J = 1 Hz), 7.25 (2H, d, J = 8.3 Hz), 7.49 (2H, t, J = • (s J 'Ηΐ) ΐΖ'6' (in Ή2) 56 -06 '(πι ¾ΐ) 09 -83' (ω 'ΕΖ) IS'-'A' (ω) '(ω' ΗΖ)

90_ _86'9 '(s Jq' Ηΐ) 8 9 ^£ (s 'ΗΖ) OZ'f' (ZH0 "A = fΊ q 'Μ) 90 * Ζ' (ω ΊΚ) 8f (ω Ή9) ^ -Η '(ΖΗ0' = 1 '1' HS) 060ί>: ( ^ε 13α3 'ZHW 00S) ^ ΝΝ-Η,

'Μ) 86 "ΐ ' 'Η8) ΐ-ΟΓΐ '( 6·9=ί ¾S) 68Ό ： (^εΙ003 ^£ZHW 008) N-H_t '(m' Η ΐ) 09 · 9ΖΊ '(s Jq' HI) t '9' (s)

'Μ) 86 "ΐ''Η8)ΐ-ΟΓΐ' (6.9 = ί ¾S) 68Ό: ( ^ε Ι003 ^£ ZHW 008) NH _t

'(ω ¾1) 80 -8-80 "8' (in 'Η2) OS 96Ζ-68Ζ Ζ' 'Η9) Α S-SfΖ Ζ' (s ¾t) Α 9 '(s Έ2) AS * 'WZ-f' 1 Jq 2) 0 '(in' Η8) 8f 1-0Π '(ΖΗ0 = Γ Ί' HS) 68

• (in 'Ηΐ) AZ-6-t9 "6' (in Z) S6 · ー 68 · '(m¾S) Id'L-ZfL' (m ^£ H9)

 '(s Jq' Ηΐ) 8f 9 '(s' ΗΖ) ΖΙ '(¾0Α = ί Ή Ή2) SO' (ω 'HZ) ST 6fl-88-I' (ω 'Η9) ζξ-Ζ' \ '(ΖΗ8 · 9 = ί ¾ ¾8) 68 · 09: (3 (D' ζ 删 OS) ¾ -Η,

• () · 9Ι 'S: 9ΐ ·' Ν 'Η 69 Ό: Thigh pull (%) 91' S: ΖΓ 'Ν: Ζ0 · 9' Η: 9 · 69 '3: ΐ!} ? θ ¥ ¾ ⁶ : Army 挲

 • (s' HI) '(8 "8 = Γ' P ¾) Ζ8 · '(ω ¾S)' Ζ OX

'(ZH 8 * 8 = 1' Ρ 'Μ) SZ''(sjq ¾t) 6 9' (zH 9'S = i 'Ηΐ) U''(ΖΗ8'9'Ζ'Ζ = 1 'IP ¾2) 66 '(s ¾8) Of Z' (ZH Z Ί = i '1' HZ) SO '(ZH 9' Ζ = ί '^ Q Ήΐ) 86' (m 'HI) 06' (m 'ΕΖ) 98' ( m Ήΐ) ΓΙ '(ZH 8 * 9 = ί'? uini) jq ¾) SI '(SJq ¾9) 62Ί' (ΖΗ 6.9 = ί 'HS) 68 680 Q: (zffl 008 ^<ε ΐθα3) -H _t

"(%) 'S: 6Ζ · λ' N: 69 'S ¾: 99'69 Ό: 蘄 嗨 traction (%)

8 · 9ΐ 'S'ΟΖ'ί'Ν: 0i S Ή: 99 · 63' 3: Ϊ ^ Ί-Ι Ί? ^S s ¾ ^6Z 3: 挲

• (SJq 'Ηΐ)' 6 '(ZH ΐ'I'L = ί 'IP' ΗΖ) 96 '' ( ^Ζ Η g'8 = f 'Ρ' ΕΖ) 88 "A '^ Η Γΐ' = ί ' 11 'Ηΐ) 09 · Ζ' (ZH S "i-

0t9t0 / Z0dr / lDd 909Ζ60 / Ζ0 OAV Example 4-337

Ή-NMR (300 MHz, CDC1 3): 50.89 (3H, t, J = 7.0Hz), 1.24-1.37 (6H, m), 1.40-1.51 (2H, m), 2.05 (2H, br t, J = 7.1Hz), 3.82 (3H, s), 4.19 (2H, s), 6.49 (IH, br s), 6.83-6.89 (2H, m), 7.21-7.26 (2H, m), 7.43-7.50 (2H, m), 7.52-7.59 (1H, m), 7.90-7.95 (2H, m), 9.71 (IH, br s).

Elemental analysis: Calculated as _{C 26 H 29 N 3 0 4} S 3: C; 57.43, H; 5.37, N; 7.72 (%), actual Hakachi C; 57.58, H; 5.30, N; 7.70 (%) .

Example 4-338

Ή-NR (300 MHz, CDC1 3): 50.89 (3H, t, J = 7.0Hz), 1.24-1.35 (6H, m), 1.38-1.51 (2H, m), 2.05 (2H, br t, J = 6.9Hz), 2.31 (3H, s), 4.21 (2H, s), 6.48 (IH, br s), 7.03-7.09 (2H, m), 7.30-7.36 (2H, m), 7.43-7.59 (3H, m), 7.90-7.96 (2H, m), 9.60-9.85 (IH, m).

Elemental analysis: C „H ₂₉ N ₃ 0 ₅ S ₃ Calculated: C; 56.72, H; 5.11, N; 7.34 (%), found C; 56.61, H; 5.08, N; 7.42 (%) .

Example 4-339

'H-NMR (300 MHz, CDC1 3): 50.89 (3H, t, J = 7.0Hz), 1.23-1.48 (8H, m), 2.03 (2H, br t, J = 7.0Hz), 4.23 (2H, s), 6.46 (IH, br s), 7.42-7.53 (4H, m), 7.56-7.65 (3H, m), 7.91-7.96 (2H, m), 9.65-9.86 (IH, m).

Elemental analysis: Calculated for C _M H ₂₆ N ₄ 0 ₃ S ₃ : C; 57.96, H; 4.86, N; 10.40 (), found C; 57.84, H; 4.98, N; 10.35 (%).

Example 4-340

'H-NMR (300 MHz, CDC1 3): 50.90 (3H, t, J = 7.0Hz), 1.23-1.37 (6H, m), 1.40-1.56 (2H, m), 2.09 (2H, t, J = 7.3Hz), 4.71 (2H, s), 6.52 (IH, s), 7.23-7.32 (2H, m), 7.40-7.59 (5H, m), 7.78-7.95 (4H, m), 7.99-8.03 (IH , m), 9.65-9.77 (IH, m).

Elemental _{analysis: C 29 H 29 N 3 0} 3 S 2 Calculated: C; 61.78, H; 5.18 , N; 7.45 (%), actual Hakachi C; 61.39, H; 4.95, N; 7.47 (%) .

Example 4-341

'H-NMR (300 MHz, CDC1 3): δ 0.88 (3Η, t, J = 7.0Hz), 1.22-1.34 (6H, m), 1.37-1.49 (2H, m), 2.04 (2H, brt, J = 7.0Hz), 4.39 (2H, s), 6.47 (1H, s), 7.39-7.57 (6H, m), 7.77-7.86 (4H, m), 7.90-7.95 (2H, m), 9.74 (1H, brs).

Elemental analysis: Calculated as _{C 29 H 29 N 3 0 3} S 3: C; 61.78, H; 5.18, N; 7.45 (%), actual Hakachi C; 61.92, H; 5.25, N; 7.47 (%) .

Example 4-342

Ή-NMR (300 MHz, CDC1 3): ά 0.89 (3Η, t, J = 7.0Hz), 1.24-1.51 (8H, m), 2.06 (2H, brt, J = 7.2Hz), 3.17 (2H, t , J = 6.0Hz), 3.85 (2H, t, J = 6.0Hz), 6.50 (1H, brs), 7.46-7.61 (3H, m), 7.94-7.99 (2H, m), 9.50-10.0 (1H, m).

Example 4-343

Ή-NMR (300 MHz, CDC1 3): δ 0.90 (3H, t, J = 6.9Hz), 1.22-1.38 (6H, m), 1.41-1.53 (2H, m), 2.09 (3H, brt, J = (7.3Hz), 2.34 (3H, s), 4.71 (2H, s), 6.51 (1H, brs), 7.08 (1H, brd, J = 7.4Hz), 7.20 (1H, brt, J = 7.7Hz), 7.34 -7.59 (5H, m), 7.82-8.01 (4H, m).

Example 4-344

Ή-NMR (300 MHz, CDC1 3): 60.89 (3H, t, J = 7.0Hz), 1.22-1.53 (8H, m), 2.06 (2H, t, J = 7.1Hz), 2.47 (6H, s) , 2.84 (2H, t, J = 7.9Hz), 3.23 (2H, t, J = 7.9Hz), 6.48 (1H, br s), 7.25-7.34 (2H, m), 7.45 (1H, ddd, J = 7.5, 7.5, 1.2Hz), 8.01 (1H, dd, J = 7.6, 1.6Hz).

Example 4-345

 NMR-NMR (300 MHz, DMSO): 50.86 (3H, t, J = 6.8Hz), 1.20-1.47 (8H, m), 2.15 (2H, t, J = 6.8Hz), 2.64-2.71 (2H, m ), 2.66 (3H, s), 3.16-3.23 (2H, m), 6.62 (1H, s), 7.34-7.42 (2H, m), 7.48-7.56 (1H, in), 8.04-8.11 (1H, m ), 11.5-11.7 (1H, m).

Example 4-346

Ή-NMR (300 MHz, CDC1 3): 50.89 (3H, t, J = 6.8Hz), 1.23-1.50 (8H, m), 2.05 (2H, brt, J = 7.3Hz), 2.66 (3H, s) , 4.23 (2H, s), 6.48 (1H, brs), 7.22-7.37 (7H, m), 7.44 (1H, brt, J = 7.4Hz), 7.99 (1H, brd, J = 7.9Hz), 9.71 -9.76 (1H, m).

Elemental analysis: Calculated as C ₂₆ H ₂₉ N ₃ O ₃ S ₃ '0.25¾O: C; 58.67, H; 5.59, N; 7.90 (%)> Found C; 58.66, H; 5.54, N; 7.97 (%).

Example 4-347

Ή-NMR (300 MHz, CDC1 3): 50.89 (3H, t, J = 6.9Hz), 1.22-1.50 (8H, m), 2.05 (2H, br t, J = 7.1Hz), 2.69 (3H, s ), 4.18 (2H, s), 6.47 (IH, brs), 7.18-7.33 (6H, m), 7.45 (1H, ddd, J = 7.4, 7.4, 1.1Hz), 8.00 (IH, dd, J = 7.4) , 1.4Hz), 9.74 (IH, brs).

Elemental _{analysis: C 26 H 26 N 3 0} 3 S 3 C1 Calculated: C; 55.75, H; 4.68 , N; 7.50 (%), Found C; 55.70, H; 4.87, N; 7.49 (%) .

Example 4-348

_{Ή-NMR (CDC1 3):} 50.88 (3H, t, J = 7.0Hz), 1.20-1.50 (8H, m), 2.05 (2H, br t, J = 7.1Hz), 2.65 (3H, s), 4.40 (2H, s), 6.47 (IH, brs), 7.20-7.31 (2H, m), 7.38-7.46 (2H, m), 7.48-7.55 (2H, m), 7.77-7.86 (4H, in), 7.99 (IH, dd, J = 8.9, 1.0Hz), 9.74 (IH, brs).

Elemental analysis: C _3. Calculated as _{H 31 N 3 0 3 S 3} : C; 62.36, H; 5.41,; 7.27 (%), actual Hakachi C; 62.30, H; 5.38, N; 7.26 (%).

Example 4-349

_{'H-NMR (CDC1 3)} : 50.89 (3H, t, J = 7.0Hz), 1.20-1.44 (8H, in), 1.97 (2H, br t, J = 7.0Hz), 2.64 (3H, s), 4.18 (2H, s), 6.43 (IH, brs), 7.22-7.48 (12H, m), 8.00 (IH, brd, J = 7.7Hz), 9.63-9.77 (IH, m).

Example 4-350

 'H-NMR (300 MHz, in double-mouthed form): δ 0.89 (3Η, t, J = 7.2 Hz), 1.03 (3H, t, J = 7.2 Hz), 1.29 (4H, brs), 1.32 (2H , m), 1.47 (2H, brquint, J = 7.2 Hz),

1.73 (2H, sixtet, J =, 7.5 Hz), 2.07 (2H, t, J = 7.4 Hz), 2.96 (2H, t, J = 7.3 Hz), 6.51 (1H, brs), 7.02 (2H, d, ] = 8.7 Hz), 7.06 (2H, brd, J = 7.9 Hz), 7.21 (IH, t, J = 7.2 Hz), 7.40 (2H, t, J = 8.3 Hz), 7.91 (2H, dt, J = 8.7, 1.5 Hz),

9.74 (IH, brs).

Example 4-351

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.90 (3H, t, J- 7.1 Hz), 1.29 (2H, m), 1.30 (2H, m), 1.31 (2H, 'm), 1.43 (2H, brquint , J = 6.8 Hz), 2.09 (2H, brdd, J = 7.9, 7.2 Hz), 2.24 (3H, s), 2.40 (3H, s), 4.20 (2H, s), 7.24 (2H, d, J = 8.3 Hz), 7.32 (5H, s), 7.81 (2H, d, J = 8.3 Hz), 9.62 (1H, br).

Elemental analysis: C ₂₇ H ₃₁ N ₃ 0 ₃ S ₃ Calculated: C, 59.86; H, 5.77; N, 7.76; S, 17.76 (%), found: C, 59.99; H, 5.67; N, 7.73; S, 17.95 ().

Example 4-352

Recrystallized from ethyl acetate-disopropyl ether.

Melting point 112-114 ° C. Infrared absorption spectrum (IR) (in KBr) Re: 3240, 2957, 2930, 2870,

^{.! 2857, 1732, 1657,} 1615, 1557, 1495 cm "1 H-NMR (CDC1 3): δ 0.892 (3Η, t, J = 6.6

Hz), 1.03 (6H, d, J-6.6 Hz), 1.20-1.54 (8H, m), 1.82-1.98 (1H, m), 2.11 (2H, t, J = 8.0 Hz), 2.26 (3H, s ), 2.41 (3H, s), 2.82 (2H, t, J = 7.0 Hz), 7.28 (2H, d, J = 8.0 Hz), 7.86 (2H, d, J = 8.4 Hz), 9.62 (1H, bs ).

Elemental _{analysis: C 24 H 33 N 3 0} 3 S 3 Calculated: C, 56.77; H, 6.55 ; N, 8.28; S, 18.95 (%), Found: C, 56.88; H, 6.42 ; N, 8.44; S, 19.03 (%).

Example 4-353

Melting point 144-6 ° C

Infrared absorption spectrum (IR) (in KBr) V 3240, 2957, 2930, 2857, 1734, 1694, 1659,

1611, 1563, 1495 cm " ¹ .

_{'H-NMR (CDC1 3)} : δ 0.892 (3Η, t, J = 6.2Hz), 0.912 (3H, t, J = 7.0Hz), 1.24-1.78 (14H, m), 2.11 (2H, t, J = 8.4 Hz), 2.26 (3H, s), 2.42 (3H, s), 2.94 (2H, t, J = 7.8 Hz), 7.28 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.2 Hz), 9.62 (1H , bs) elemental _{analysis: C 25 H 35 N 3 0} 3 S calculated _{3:.. C, 57.55;} H, 6.70; N, 8.05; S, 18.44 (%), Found: C, 57.55; H, 6.58; N, 8.17; S, 18.38 (%).

Example 4-354

Ή- thigh _{(CDC1 3, 200 MHz):} δ 1.02 (6H, d, J = 6.6 Hz), 1.09 (3H, t, J = 7.4 Hz), 1.91 (1H, quint, J = 6.6 Hz), 2.18 ( 2H, q, J = 7.4 Hz), 2.27 (3H, s), 2.83 (2H, d, J = 7.0 Hz), 2.95 (1H, quint, J = 7.0 Hz), 7.50 (3H, m), 7.99 ( 2H, dm, J = 8.4 Hz), 9.65 (1H, brs).

Elemental analysis: C ₁₉ H ₂₃ N ₃ 0 ₃ S ₃ Calculated: C, 52.15; H, 5.30; N, 9.60; S, 21.98 (%), found: C, 52.04; H, 5.17; N, 9.61; S, 22.01 (%) Example 4-355

_{¾-NMR (CDC1 3, 200} MHz): δ 1.09 (3H, t, J = 7.4 Hz), 2.14 (2H, q, J = 7.2 Hz), 2.27 (3H, s), 2.98 (2H, dd, J = 8.4, 5.6 Hz), 3.20 (2H, dd, J = 8.8, 6.2 Hz), 7.17-34 (5H, m), 7.50 (3H, m), 7.95 (2H, dm, J = 8.6 Hz), 9.66 (1H, brs). Elemental analysis: Calculated for C ₂₃ N ₃ 0 ₃ S ₃ : C, 56.88; H, 4.77; N, 8.65; S, 19.81 (%), found: C, 56.74; H, 4.72; N, 8.58; S, 19.72 (%).

Example 4-356

- Awakening: _{(CDC1 3, 200 MHz):} δ 1.08 (3Η, t, J = 7.5 Hz), 1.43 (4H, m), 1.50-1.75 (4H, m), 2.13 (2H, q, J = 7.8 Hz) , 2.26 (3H, s), 2.41 (3H, s), 2.95 (2H, brt, J = 7.3 Hz), 3.66 (2H, brt, J = 6.2 Hz), 7.28 (2H, d, J = 8.0 Hz) , 7.85 (2H, d, J = 8.4 Hz), 9.65 (1H, brs).

Elemental analysis: Calculated as _{C 22 H 29 N 3 0 4} S 3: C, 53.31; H, 5.90;, 8.48; S, 19.41

(%), Found: C, 53.16; H, 5.87;, 8.60; S, 19.28 ().

Example 4-357

^ -NMR (CDCI3, 200 MHz): δ 1.09 (3H, t, J = 7.2 Hz), 2.14 (2H, q, J = 7.8 Hz), 2.26 (3H, s), 2.42 (3H, s), 2.98 (2H, brdd, J = 8.8, 5.4 Hz), 3.18 (2H, brdd, J = 8.8, 5.4 Hz), 7.17-35 (7H, m), 7.83 (2H, d, J = 8.4 Hz), 9.63 ( 1H, brs).

Elemental _{analysis: C 24 H 25 N 3 0} 3 S 3 Calculated: C, 57.69; H, 5.04 ; N, 8.41; S, 19.25 (%), Found: C, 57.80; H, 5.07 ; N, 8.52; S, 19.09 (%).

Example 4-358

lH-NMR (CDCI3, 200 MHz): d 1.07 (3H, t, J = 7.4 Hz), 2.11 (2H, q, J = 7.4 Hz), 2.15 (2H, quint, J = 7.0 Hz), 2.25 (3H , S), 2.38 (3H, s), 3.09 (2H, t, J = 7.0 Hz), 3.14 (2H, t, J = 7.0 Hz), 7.24 (2H, d, J = 8.4 Hz), 7.49 (2H , brt, J = 7.8 Hz), 7.59 (1H, .brt, J = 7.4 Hz), 7.84 (2H, d, J = 8.0 Hz), 7.96 (2H, dm ,; J = 8.0 Hz), 9.65 (1H , brs).

Elemental _{analysis: C 26 H 27 N 3 0} 4 S 3 Calculated: C, 57.65; H, 5.02 ; N, 7.76; S, 17.76

(%), Found: C, 57.49; H, 5.10; N, 7.93; S, 17.61 (%).

Example 4-359 One _{NMR (200MHz, CDC1 3):} δ 1.09 (3H, t, J = 7.5 Hz), 2.13 (2H, q, J = 7.5 Hz), 2.26 (3H, s), 2.34 (3H, s), 2.42 ( 3H, s), 2.94 (2H, dd, J = 8.8, 7.4 Hz), 3.16 (2H, dd, J = 8.8, 6.2 Hz), 7.10 (2H, d, J2 8.6 Hz), 7.11 (2H, d , J = 8.8 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.83 (2H, d, J = 8.4 Hz), 9.64 (1H, brs).

Elemental _{analysis: C 25 H 27 N 3 0} 3 S 3 Calculated: C, 58.45; H, 5.30 ; N, 8.18; S, 18.73 (), Found: C, 58.44; H, 5.34 ; N, 8.12 S, 18.71 ().

Melting point: 133.5-135.0 ° C

Example 4-360

_{¾-NMR (200MHz, CDC1 3} ): 6 1.09 (3H, t, J = 7.5 Hz), 2.13 (2H, q, J = 7.5 Hz), 2.26 (3H, s), 2.43 (3H, s), 2.95 (2H, dd, J = 8.3, 6.8 Hz), 7.12 (2H, d, J = 8.1 Hz), 7.27 (4H, m), 7.81 (2H, dd, J = 7.6, 7.0 Hz) d, J = 8.1 Hz), 9.63 (1H, brs).

Elemental analysis: Calculated as _{C 24 H 24 N 3 0 3} S 3 C1: C, 53.97; H, 4.53; N, 7.87; S, 18.01; CI, 6.64 (%), Found: C, 53.84; H , 4.46; N, 7.88; S, 17.84; CI, 6.84 (%). Melting point. 174.5-176.0 ° C

Example 4-361

_{Ή- NMR (200MHz, CDC1 3)} : 6 1.09 (3H, t, J = 7.5 Hz), 2.14 (3H, q, J = 7.4 Hz), 2.26 (3H, s), 2.43 (3H, s), 2.94 (1H, brdd, J = 8.0, 6.8 Hz), 3.16 (2H, dd, J = 8.2, 6.4 Hz), 6.98 (2H, d, J = 8.5 Hz), 7.14 (2H, brt, J = 8.5 Hz) , 7.27 (2H, d, J = 8.4 Hz), 7.82 (2H, d, J = 8.4 Hz), 9.64 (1H, brs).

Elemental _{analysis: C 24 H 24 N 3 0} 3 S 3 F Calculated: C, 55.68; H, 4.67 ; N, 8.12; S, 18.58; F, 3.67 (%), Found: C, 55.73; H , 4.40; N, 8.03; S, 18.33; F, 3.68 ()

Example 4-362

'H-NMR (200MHz, CDC1 3): δ 1.09 (3H, t, J = 7.4 Hz), 2.13 (2H, q, J = 7.4 Hz),

2.26 (3H, s), 2.42 (3H, s), 2.91 (2H, dd, J = 8.6, 7.2 Hz), 3.16 (2H, dd, J = 8.8, 6.6 Hz), 3.80 (3H, s), 6.85 (2H, d, J = 8.4 Hz), 7.12 (2H, d, J = 8.8 Hz),

7.27 (2H, d, J = 8.4 Hz), 7.83 (2H, d, J = 8.4 Hz), 9.63 (1H, brs).

Elemental analysis: Calculated as _{C 25 H 27 N 3 0 4} S 3: C, 56.69; H, 5.14; N, 7.93; S, 18.16 (), Found: C, 56.59; H, 5.27; N, 7.88; S, 18.14 (%). Melting point. 163.5-174.0 ° C

Example 4-363

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.09 (3H, t, J = 7.4 Hz), 1.75 (2H, brq, J = 9.0 Hz), 1.88 (2H, ni), 2.13 (2H, brq, J = 7.3 Hz), 2.15 (2H, m), 2.26 (3H, s), 2.41 (3H, s), 2.57 (1H, quint, J = 7.7 Hz), 3.04 (2H, d, J = 7.8 Hz), 7.27 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J- 8.0 Hz), 9.62 (1H, brs).

Elemental analysis: Calculated for C ₂₁ N ₃ 0 ₃ S ₃ : C, 54.40; H, 5.43; N, 9.06; S, 20.75 (%), found: C, 54.17; H, 5.56; N, 9.12; S, 20.48 (%).

Melting point.156.5-157.0 ° C

Example 4-364

Ή one _{NMR (200MHz, CDC1 3):} δ 0.95 (2Η, brq, J = 12.0 Hz), 1.08 (3H, t, J = 7.3 Hz), 1.19 (2H, m), 1.56 (1H, m), 1.61 (2H, m), 1.71 (2H, m), 2.13 (2H, q, J = 7.5 Hz), 2.26 (3H, s), 2.41 (3H, s), 2.82 (2H, d, J = 7.0 Hz) , 7.27 (2H, d, J = 8.0 Hz), 7.86 (2H, d, J = 8.0 Hz), 9.63 (1H, brs).

Elemental _{analysis: C 23 H 29 N 3 0} 3 S 3 Calculated: C, 56.18; H, 5.94 ; N, 8.55; S, 19.56

(%), Found: C, 56.10; H, 5.93; N, 8.56; S, 19.59 (%).

Melting point.161.0-161.5 ° C

Example 4-365

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.09 (3H, t, J = 7.4 Hz), 1.10 (2H, m), 1.50-1.90 (9H, m), 2.14 (2H, brq, J = 7.4 Hz) , 2.26 (3H, s), 2.41 (3H, s), 2.95 (2H, t, J = 7.5 Hz), 7.28 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.0 Hz) , 9.65 (IH, brs) elemental _{analysis: C 23 H 29 N 3 0} 3 S 3 calculated:. C, 56.18; H, 5.94;, 8.55; S, 19.56 (%), Found: C, 56.19 H, 5.94; N, 8.62; S, 19.64 (%).

Melting point.161.0- 161.5 ° C

Example 4-366

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.08 (2H, m), 1.08 (3H, t, J = 7.5 Hz), 1.42 (2H, m), 1.50-1.80 (9H, m), 2.13 (2H, brq, J = 7.5 Hz), 2.26 (3H, s), 2.41 (3H, s), 2.94 (2H, t, J = 7.4 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.65 (1H, brs).

Elemental analysis: Calculated as _{C 24 H 31 N 3 0 3} S 3: C, 57.00; H, 6.18; N, 8.31; S, 19.02

(%), Found: C, 56.90; H, 6.11; N, 8.07; S, 19.09 (%).

Melting point.- 158.5-159.O

Example 4-367

_{¾-NMR (200MHz, CDC1 3} ): δ 1.09 (3H, t, J = 7.5 Hz), 1.25 (2H, m), 1.59 (4H, m), 1.85 (2H, m), 2.12 (1H, quint, J = 7.3 Hz), 2.13 (2H, brq, J = 7.5 Hz), 2.26 (3H, s), 2.41 (3H, s), 2.95 (2H, d, J = 7.3 Hz), 7.27 (2H, d, J = 8.2 Hz), 7.86 (2H, d, J = 8.2 Hz), 9.60 (1H, brs).

Elemental _{analysis: C 22 H 27 N 3 0} 3 S 3 Calculated: C, 55.32; H, 5.70 ;, 8.80; S, 20.14 (%), Found: C, 55.18; H, 5.70 ; N, 8.76 ; S, 20.15 ().

Melting point.168.0-169.5 ° C

Example 4-368

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.09 (3H, t, J = 7.4 Hz), 2.13 (2H, q, J = 7.5 Hz), 2.27 (3H, s), 2.42 (3H, s), 2.47 (3H, s), 7.29 (2H, d, J = 8.4 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.63 (1H, br).

Elemental _{analysis: C 17 H 19 N 3 0} 3 S 3 Calculated: C, 49.86; H, 4.86 ; N, 10.26; S, 23.49

(%), Found: C, 50.02; H, 4.82; N, 10.02; S, 23.42 (%).

Melting point.205.0-206.0 ° C

Example 4-369

'H-NMR (200MHz, CDC1 3): δ 0.93 (6H, d, J = 6.2 Hz), 1.09 (3H, t, J = 7.5 Hz), 1.58 (2H, quint, J = 7.0 Hz), 1.70 ( 1H, quint, J = 6.6 Hz), 2.14 (2H, q, J = 7.5 Hz), 2.26 (3H, s), 2.42 (3H, s), 2.95 (2H, t, J = 7.7 Hz), 7.28 ( 2H, d, J- 8. Hz), 7.85 (2H, d, J = 8.4 Hz), 9.65 (1H, brs).

Elemental analysis: Calculated for C ₂₁ H ₂₇ N ₃ 0 ₃ S ₃ : C, 54.17; H, 5.84; N, 9.02; S, 20.66 (%), found: C, 54.07; H, 5.87; N, 9.03; S, 20.50 ().

146.0-146.5 ° C.

Example 4-370

Ή-1 NMR (200MHz, CDCL): <5 0.89 (6H, d, J = 6.6 Hz), 1.08 (3H, t, J = 7.3 Hz), 1.28 (2H, brq, J = 7.5 Hz), 1.57 (1H, quint, J = 6.6 Hz), 1.68 (2H, quint, J = 7.8 Hz), 2.13 (2H, q, J = 7.5 Hz), 2.26 ( 3H, s), 2.41 (3H, s), 2.92 (2H, t, J = 7.4 Hz), 7.28 (2H, d, J = 8.2 Hz), 7.85 (2H, d, J = 8.2 Hz), 9.63 ( . 1H, brs) elemental _{analysis: C 22 H 29 N 3 0} 3 S 3 calculated: C, 55.09; H, 6.09 ; N, 8.76; S, 20.05 (%) Found: C, 54.83; H, 6.00; N, 8.71; S, 19.89 (%).

143.5- 144. St

Example 4-371

Melting point 155-156 ° C

Infrared absorption spectrum (IR) (in KBr): 3214, 2963, 2932, 2872, 1732, 1659, 1615, 1557, 1495 cm-

_{¾-NMR (CDC1 3):} δ 0.941 (3Η, t, J = 7.4Hz), 1.09 (3H, t, J = 7.2 Hz), 1.37-1.54 (2H, m), 1.54-1.76 (2H, m) , 2.14 (2H, q, J = 7.4 Hz), 2.26 (3H, s), 2.42 (3H, s), 2.95 (2H, t, J = 7.6 Hz), 7.30 (2H, d, J = 8.4 Hz) , 7.85 (2H, d, J = 8.6 Hz), 9.63 (1H, bs).

Elemental analysis: C _2. H ₂₅ N ₃ 0 ₃ S ₃ Calculated: C, 53.19; H, 5.58; N, 9.30; S, 21.30 (%), Found:, (;, 53.45; H, 5.56; N, 9.52; S, 21.48 (%)

Example 4-372

Melting point 157-159 ° C

Infrared absorption spectrum (IR) (in KBr) V: 3158, 2953, 2928, 2865, 1725, 1655, 1599, 1557 cm " ¹ .

 Ή-NMR (CDCI3): δ 0.912 (3Η, t, J = 6.6 Hz), 1.09 (3H, t, J = 7. Hz), 1.31-1.45 (4H, m), 1.60-1.76 (2H, m) , 2.13 (2H, q, J = 7.8 Hz), 2.26 (3H, s), 2.42 (3H, s), 2.94 (2H, t, J = 7.4 Hz), 7.28 (2H, d, J = 8.4 Hz) , '7.86 (2H, d, 1 = 8: 4 Hz), 9.62 (1H, bs).

Elemental analysis: Calculated for C ₂₁ H ₂₇ N ₃ 0 ₃ S ₃ : C, 54.17; H, 5.84; N, 9.02; S, 20.66 (%), found: C, 54.04; H, 6.10; N, 8.99; S, 20.60 ().

Example 4-373

160-162 ° C

Infrared absorption spectrum (IR) (in KBr) V: 3156, 2953, 2932, 1726, 1657, 1603, 1559 cm " ¹ .

_{Ή-NMR (CDC1 3):} 6 0.901 (3H, t, J = 6.6Hz), 1.09 (3H, t, J = 7.4 Hz), 1.25-1.50 (6H, 111), 1.58-1.75 (2H, m) , 2.14 (2H, q, J = 7.8 Hz), 2.26 (3H, s), 2.42 (3H, s), 2.94 (2H, t,] = 7.6 Hz), 7.28 (2H, d, J = 8.4 Hz) , 7.86 (2H, d, J = 8.4Hz), 9.62 (1H, bs).

Elemental _{analysis: C 22 H 29 N 3 0} 3 S 3 Calculated: C, 55.09; H, 6.09 ; N, 8.76; S, 20.05

(%), Found: C, 54.95; H, 6.00;, '8.61; S, 19.98 (%).

Example 4-374

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.06 (3H, t, J = 7.5 Hz), 2.01 (2H, quint, J = 7.5 Hz), 2.10 (2H, q, J = 7 · 5 Hz), 2.26 (3H, s), 2.39 (3H, s), 2.72 (2H, t, J = 7.3 Hz), 2.93 (2H, t, J = 7.5 Hz), 7.16 (2H, brd, J = 7.2 Hz), 7.24 -7.30 (5H, m), 7.86 (2H, d, J = 8.0 Hz), 9.64 (1H, brs).

Elemental analysis: Calculated as C ₂₅ H „N ₃ 0 ₃ S ₃ : C, 58.45; H, 5.30; N, 8.18; S, 18.73

(%), Found: C, 58.55; H, 5.28; N, 7.95; S, 18.73 (%)

Melting point.168.5-169.5 ° C

Example 4-375

_{NMR (200MHz, CDC1 3):} δ 1.08 (3H, t, J = 7.5 Hz), 1.39 (3H, d, J = 6.2 Hz), 2.13 (2H, q, J = 7.5 Hz), 2.25 (3H, s ), 2.42 (3H, s), 3.04 (1H, m), 3.10 (1H, m), 3.23 (1H, quint, J = 5.6 Hz), 7.23 (3H, n, 7.28 (2H, d, J = 8.4) Hz), 7.29 (2H, m), 7.79 (2H, d, J = 8.4 Hz), 9.61 (1H, brs).

Elemental analysis: Calculated as _{C 25 H 27 N 3 0 3} S 3: C, 58.45; H, 5.30; N, 8.18; S, 18.73

(%), Found: C, 58.29; H, 5.25; N, 8.16; S, 18.66 (%).

Melting point. 171.5- 172. O

Example 4-376

 'H-NMR (CDClg, 200 MHz): δ 1.01 (3H, t, J = 7.5 Hz), 2.07 (2H, q, J = 7.3 Hz), 2.24 (3H, s), 2.41 (3H, s), 4.47 (2H, s), 7.27 (2H, d, J = 8.2 Hz), 7.51 (2H, brt, J = 7.3 Hz), 7.65 (1H, brt, J = 7.2 Hz), 7.85 (2H, d, J = 8.4 Hz), 7.97 (2H, d, J = 8 Hz).

Elemental analysis: Calculated as _{C 24 H 23 N 3 0 4} S 3: C, 56.12; H, 4.51;, 8.18; S, 18.73 (%), Found: C, 56.07; H, 4.61; N, 8.12; S, 18.64 (%).

Example 4-377

 N- [8- (cyclohexylsulfanyl) -6-ethyl-5-methyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine- Ylidene] -4-methylbenzenesulfonamide

 To a suspension of the compound obtained in Example 3-5 (499 mg, 1.26 mmol) and carbon dioxide (261 mg, 1.89 mmpl) in DMF (8.0 ml) was added cycloheptyl iodide (pure) while stirring at 35. 70%, 484 mg, 1.51 ol) and the reaction mixture was stirred for 16 hours. 1N Hydrochloric acid (2.52 ml) was added to the reaction solution, diluted with methanol / water (1: 1, 6 ml), and stirred at room temperature for 3 hours. The precipitate was collected by filtration, washed with methanol / water (1: 1 and 2: 1), and dried to give the title compound (484 mg, 0.984 tmol) as a red-purple powder.

_{lH- NMR (200MHz, CDC1 3)} : δ 1.09 (3H, t, J = 7.5 Hz), 1.5-1.8 (10H, m), 2.06 (2H, m), 2.14 (2H, q, J = 7.5 Hz) , 2.26 (3H, s), 2.42 (3H, s), 3.54 (1H, septet, J = 4.4 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.86 (2H, d, J = 8.4 Hz) , 9.66 (1H, brs) elemental analysis: calculated _{C 23 H 29 N 3 0 3} S 3:. C, 56.18; H, 5.94; N, 8.55; S, 19.56 (%), Found: C, 56.48; H, 5.92; N, 8.36; S, 19.29 ().

mp.144.5-146.0 ° C

Example 4-378

 N- {8- [(2-cyclohexylethyl) sulfanyl] -6-ethyl-5-methyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] Thiazine-triylidene} -4-methylbenzenesulfonamide ''

 To a suspension of the compound obtained in Example 3-5 (292 mg, 0.738 mol) and potassium carbonate (153 mg, 1.11 alcohol) in DMF (5 ml) was stirred at room temperature while stirring at room temperature to give 2-cyclohexane bromide. Kicilletil

(159 mg, 0.812 finol) was added, and the reaction solution was stirred at 80 for 1.5 hours. 1N Hydrochloric acid (1.5 ml) and methanol-water (1: 1, 5 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol / water (1: 1) and methanol, and dried to give the title compound (366 mg, 0.724 mmol) as a red powder. '

_{Ή-NMR (200MHz, CDC1 3} ): δ 0.94 (2Η, brquint, J = 11.0 Hz), 1.09 (3H, t, J = 7.4 Hz), 1.19 (2H, brd, J = 9.2 Hz), 1.21 (1H , m), 1.31 (2H, m), 1.57 (2H, q, J = 7.5 Hz), 1.71 (4H, brd, J = 10.6 Hz), 2.13 (2H, q, J = 7.4 Hz), 2.26 (3H, s), 2.41 (3H, s), 2.96 (2H, i, J = 7.7 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.85 (2H, d, J = 8.4 Hz) 9.64 (1H, brs).

Elemental _{analysis: C 24 H 3l N 3 0} 3 S 3 Calculated: C, 57.00; H, 6.18 ; N, 8.31; S, 19.02 (%), Found: C, 56.86; H, 6.11 ; N, 8.32; S, 18.71 (%).

mp. 185.5-186.5 ° C

Example 4-379

_{Ή-NMR (CDC1 3, 200} MHz): δ 1.03 (6Η, d, J = 7.0 Hz), 1.32 (3H, t, J = 7.2 Hz), 1.93 (1H, sept, J = 6.6 Hz), 2.76 ( 3H, s), 2.88 (2H, d, J = 7.0 Hz), 4.26 (2H, q, J = 7.2 Hz), 7.52 (3H, m), 7.98 (2H, dm, J = 7.6 Hz), 9.80 ( IH, brs) elemental analysis:. C _2. H ₂₃ N ₃ 0 ₅ S ₃ Calculated: C, 49.88; H, 4.81 ; N, 8.72; S, 19.97

(%), Found: C, 49.77; H, 4.75; N, 8.76; S, 19.96 (%).

Example 4-380

_{'H-NMR (CDC1 3,} 200 MHz): δ 1.34 (3Η, t, J = 7.4 Hz), 2.76 (3H, s), 2.99 (2H, dd, J = 8.6, 6.2 Hz), 3.23 (2H, dd, J = 8.6, 6.2 Hz), 4.27 (2H, q, J = 7.4 Hz), 7.18-33 (5H, m), 7.52 (2H, m), 7.94 (2H, dm, J = 7.6 Hz), . 9.79 (1H, brs) elemental _{analysis: C 24 H 23 N 3 0} 5 S 3 calculated: C, 54.42; H, 4.38 ; N, 7.93; S, 18.16

(%), Found: C, 54.19; H, 4.33; N, 8.10; S, 18.05 (%).

Example 4-381

'H-NMR (CDCl ₃ -DMS0-d ₆ = 19: 1, 300 MHz): 6 2.43 (3H, s), 2.77 (3H, s), 2.97 (2H, brdd, J = 8.3, 7.2 Hz), 3.25 (2H, brdd, J = 8.3, 7.2 Hz), 7.20 (2H, brd, J = 8 Hz), 7.25-31 (5H, i), 7.83 (2H, d, J = 8.3 Hz), 10.43 (1H , Brs).

Elemental analysis: Calculated for C ₂₁ N ₃ 0 ₅ S ₃ : C, 53.57; H, 4.11;, 8.15; S, 18.66 (%), found: C, 53.50; H, 4.03; N, 8.25; S , 18.67 (%).

Example 4-382

lH-NMR (CDCl ₃ , 300 MHz): δ 2.41 (3Η, s), 2.75 (3H, s), 3.80 (3H, s), 4.25 (2H, s), 7.25 (2H, d, J = 8.3 Hz ), 7.33 (5H, m), 7.79 (2H, d, J = 8.3 Hz), 9.81 (1H, brs).

Example 4-383 _{Ή-NMR (300MHz, CDC1 3} ): δ 1.32 (3H, t, J = 7.1 Hz), 2.41 (3H, s), 2.74 (3H, s), 4.25 (2H, s), 4.26 (2H, q, J = 7.1 Hz), 7.25 (2H, d, J = 8.3 Hz), 7.33 (5H, s), 7.80 (2H, d, J = 8.3 Hz), 9.77 (1H, br).

Example 4-384

_{Ή-NMR (CDC1 3, 200} MHz): δ 1.32 (3H, t, J = 7.1 Hz), 1.43 (4H,), 1.54-1.75 (4H, m), 2.42 (3H, s), 2.75 (3H, s), 3.00 (2H, brt, J = 7.5 Hz), 3.65 (2H, t, J = 6.2 Hz), 4.26 (2H, q, J = 7.0 Hz), 7.29 (2H, d, J = 8.0 Hz) , 7.85 (2H, d, J = 8.4 Hz), 9.83 (1H, brs).

Elemental analysis: C ₂₃ H ₂₉ N ₃ 0 ₆ S ₃ · 0.2H ₂ 0 Calculated: C, 50.85; H, 5.45; N, 7.73; S, 17.71 (%), Observed: C, 50.68; H , 5.33; N, 7.96; S, 17.82 (%).

Example 4-385

_{Ή-NMR (CDC1 3, 300} MHz): δ 1.03 (6Η, d, J = 6.7 Hz), 1.33 (3H, t, J = 7.1 Hz), 1.93 (1H, tq, J = 6.8, 6.7 Hz), 2.42 (3H, s), 2.75 (3H, s), 2.87 (2H, d, J = 6.8 Hz), 4.26 (2H, q, J = 7.1 Hz), 7.29 (2H, d, J = 8.1 Hz), 7.83 (2H, brd, J = 8.3 Hz), 9.79 (1H, brs).

Elemental analysis: Calculated for C ₂₁ H ₂₅ N ₃ 0 ₅ S ₃ : C, 50.89; H, 5.08; N, 8.48; S, 19.41

(%), Found: C, 50.80; H, 5.20; N, 8.54; S, 19.36 ().

Example 4-386

Recrystallization from ethyl acetate-methyl-tetrahydrofuran yielded dark red crystals. Melting point: 142-144 ° C.

Infrared absorption spectrum (IR) (in KBr): 3219, 2957, 2928, 2855, 1761, 1717, 1674, 1638, 1563, 1497 cnf ¹ .

_{Ή-NMR (CDC1 3):} 6 0.910 (. 3H, t, J = 7 Hz), 1.22-1.44 (4H, m), 1.32 (3H, t, /=6.6 Hz), 1.63-1.76 (2H, m ), 2.42 (3H, s), 2.75 (3H, s), 2.99 (2H, t, J = 7.4 Hz), 4.26 (2H, q, J = 7.2 Hz), 7.29 (2H, d, J = 8.0 Hz) ), 7.85 (2H, d, J = 8.0 Hz), 9.77 (m, bs).

Elemental _{analysis: C 22 H 27 N 3 0} 5 S 3 Calculated: C, 51.84; H, 5.34 ; N, 8.24; S, 18.87

(%), Found: C, 51.69; H, 5.41; about 8.17; S, 18.85 (%).

Example 4-387 ¾-NMR (CDClg, 300 MHz): δ 1.32 (3H, t, J = 7.1 Hz), 1.70-1.95 (4H, m), 1.94 (1H, br), 2.40 (3H, s), 2.75 (3H, s), 3.03 (2H, brt, J = 6.3 Hz), 4.26 (2H, q, J = 7.1 Hz), 4.71 (1H, br), 7.25 (2H, d, J = 8.3 Hz), 7.35 (5H, m), 7.83 (2H, d, J = 8.3 Hz), 9.73 (1H, s).

Elemental analysis: Calculated as _{C 27 H 29 N 3 0 6} S 3: C, 55.18; H, 4.97; N, 7.15; S, 16.37 (%), Found: C, 55.12; H, 4.81 ;, 7.05 ; S, 16.40 ().

Example 4-388

 'H-NMRCCDClg, 300 MHz): δ 1.32 (3H, t, J = 7.1 Hz), 2.16 (2H, quint, J = 7.0 Hz), 2.38 (3H, s), 2.75 (3H, s), 3.14 ( 4H, t, J = 7.0 Hz), 4.25 (2H, q, J = 7.1 Hz), 7.25 (2H, d, J = 8.3 Hz), 7.49 (2H, t, J = 7.7 Hz), 7.59 (1H, tt, J = 7.3, 1.2 Hz), 7.83 (2H, d, J = 8.3 Hz), 7.96 (2H, d, J = 7.2. Hz), 9.84 (1H, brs).

Elemental analysis: Calculated as _{C 27 H 27 N 3 0 6} S 3: C, 54.53; H, 4.74; N, 7.07; S, 16.18 (%), Found: C, 54.46; H, 4.58 ; N, 7.18; S, 16.27 (%).

Example 4-389

_{^ -NMR (CDC1 3, 200 MHz} ): 6 1.03 (6H, d, J = 6.6 Hz), 1.33 (3H, t, J = 7.2 Hz), 1.93 (1H, quint, J = 6.7 Hz), 2.42 ( 3H, s), 2.76 (3H, s), 2.88 (2H, d, J = 6.6 Hz), 4.26 (2H, q, J = 7.0 Hz), 7.38 (2H, brd, J = 5.2 Hz), 7.76 ( 2H, brs), 9.79 (1H, brs).

Elemental analysis: C ₂₁ H ₂₅ N ₃ 0 ₅ S ₃ Calculated: C, 50.89; H, 5.08; N, 8.48; S, 19.41 (%), found: C, 50.78; H, 5.34; N, 8.50; S, 19.46 (%).

Example 4-390

_{Ή-NMR (CDC1 3, 200} MHz): δ 1.34 (3Η, t, J- 7.0 Hz), 2.43 (3H, s), 2.76 (3H, s), 2.99 (2H, dd,] = 9.2, 6.6 Hz ), 3.23 (2H, dd, J = 8.4, 5.8 Hz), 4.27 (2H, q, J = 6.6 Hz), 7.28 (5H,), 7.38 (2H, brd, J = 5.2 Hz), 7.76 (2H, brs), 9.79 (1H, brs).

Elemental _{analysis: C 25 H 25 N 3 0} 5 S 3 Calculated: C, 55.23; H, 4.63 ; N, 7.73; S, 17.69

(%), Found: C, 54.92; H, 4.76; N, 7.74; S, 17.71 (%).

Example 4-391 'H-NMR (CDCI3, 200 MHz): <5 1.03 (6H, d, J = 6.6 Hz), 1.32 (3H, t, J = 7.0 Hz), 1.93 (1H, sept, J = 6.8 Hz), 2.75 (3H, s), 2.80 (3H, s), 2.90 (2H, d, J = 6.6 Hz), 4.26 (2H, q, J = 7.2 Hz), 7.31 (2H, brd, J = 7 Hz), 7.44 (1H, tm, J = 7.4 Hz), 8.02 (1H, dm, J = 8.6 Hz), 9.84 (1H, brs).

Elemental analysis: Calculated for C ₂₁ H ₂₅ N ₃ 0 ₅ S ₃ : C, 50.89; H, 5.08; N, 8.48; S, 19.41 (%), found: C, 55.69; H, 5.00; N, 8.66; S, 19.36 {%).

Example 4-392

¾ - thigh _{(CDC1 3, 200 MHz):} δ 1.33 (3H, t, J = 7.4 Hz), 2.72 (3H, s), 2.75 (3H, s), 2.98 (2H, brdd, J = 8.0, 7.0 Hz ), 3.26 (2H, dd, J = 8.0, 7.0 Hz), 4.27 (2H, q, J = 7.0 Hz), 7.20 (2H, m), 7.28 (5H, m), 7.46 (1H, brt, J = 7.4 Hz), 8.01 (1H, dm, J = 7 Hz), 9.82 (1H, brs).

Elemental _{analysis: C 25 H 25 N 3 0} 5 S 3 Calculated: C, 55.23; H, 4.63 ; N, 7.73; S, 17.69

(%), Found: C, 55.06; H, 4.51;, 7.90; S, 17.75 (%).

Example 4-393

LH-NMR (CDCI3, 200 MHz): δ 1.04 (6Η, d, J = 7.0 Hz), 1.33 (3H, t, J = 7.0 Hz), 1.93 (1H, sept, J = 6.7 Hz), 2.76 (3H , s), 2.89 (2H, d, J = 6.6 Hz), 4.27 (2H, q, J = 7.2 Hz), 7.46 (2H, dt, J = 8.8, 2.0 Hz), 7.91 (2H, dt, J = 8.8, 2.0 Hz)., 9.77 (1H, brs).

Elemental analysis: Calculated as _{C 20 H 22 N 3 0 5} S 3 C1: C, 46.55; H, 4.30; N, 8.14; S, 18.64; C1, 6.87 (%), Found: C, 46.26; H , 4.07; N, 8.14; S, 18.69; C1, 6.74 (%).

_{Ή-NMR (CDC1 3, 200} MHz): δ 1.34 (3Η, t, J = 7.0 Hz), 2.77 (3H, s), 2.99 (2H, dd, J = 8.0, 7.0 Hz), 3.26 (2H, dd , J = 8.4, 6.6 Hz), 4.27 (2H, q, J = 6.8 Hz), 7.17-33 (5H, m), 7.45 (2H, d, J = 8.8 Hz), 7.86 (2H, d, J- 8.4 Hz)., 9.78 (1H, brs).

Elemental _{analysis: C 24 H 22 N 3 0} 5 S 3 C1 Calculated: C, 51.10; H, 3.93 ; N, 7.45; S, 17.05; C1, 6.28 (%), Found: C, 50.96; H , 3.83; N, 7.47; S, 17.06; CI, 6.10 (%).

Ή-NMR (CDCK, 200 MHz): δ 1.03 (6H, d, J = 6.6 Hz), 1.33 (3H, t, J = 7.2 Hz), 1.93 (1H, quint, J = 6.4 Hz), 2.76 (3H, s), 2.89 (2H, d, J = 7.0 Hz), 4.27 (2H, q, J = 7.2 Hz), 7.16 (2H, t, J = 7.0 Hz), 7.99 (2H, dd, J = 7.4, 5.2 Hz), 9.77 (1H, brs).

Elemental _{analysis: C 20 H 22 N 3 O} 5 S 3 F Calculated: C, 48.08; H, 4.44 ; N, 8.41; S, 19.25; F, 3.80 (%), Found: C, 47.75; H , 4.45; N, 8.41; S, 19.26; F, 3.94 (%).

_{¾-NMR (CDC1 3, 200} MHz): δ 1.34 (3Η, t, J = 7.0 Hz), 2.77 (3H, s), 2.99 (2H, dd, J = 8.6, 7.0 Hz), 3.25 (2H, dd , J = 8.0, 7.8 Hz), 4.27 (2H, q, J = 7.2 Hz), 7.15 (2H, t, J = 8.8 Hz), 7.26 (5H, m), 7.94 (2H, dd, J = 8.8, . 5.0 Hz), 9.75 (1H , brs) ' elemental _{analysis: C 24 H 22 N 3 0} 5 S 3 F calculated: C, 52.64; H, 4.05 ; N, 7.67; S, 17.57; F, 3.47 (%), Found: C, 52.45; H, 4.08; N, 7.64; S, 17.60; F, 3.68 (). Examples 4-397

_{Ή-NMR (CDC1 3, 200} MHz): δ 1.03 (6Η, d, J = 6.6 Hz), 1.33 (3H, t, J = 7.4 Hz), 1.93 (IH, quint, J = 6.6 Hz), 2.76 ( 3H, s), 2.88 (2H, d, J = 6.6 Hz), 4.27 (2H, q, J = 7.4 Hz), 7.02 (2H, d, J = 8.4 Hz), 7.06 (2H, d, J = 7.4 Hz) Hz), 7.21 (IH, t, J = 7.0 Hz), 7.40 (2H, t, J = 8.0 Hz), 7.91 (2H, d, J = 8.8 Hz), 9.78 (1H, brs).

Elemental analysis: Calculated as _{C 26 H 27 N 3 0 6} S 3: C, 54.43; H, 4.74;, 7.32; S, 16.77 (%), Found: C, 54.34; H, 4.75 ; N, 7.64 ; S, 16.77 (%).

Example 4-398

_{Ή-NMR (CDC1 3, 200} MHz): δ 1.34 (3H, t, J = 7.2 Hz), 2.76 (3H, s), 2.99 (2H, dd, J = 8.4, 6.6 Hz), 3.25 (2H, dd , J = 8.6, 6.6 Hz), 4.27 (2H, q, J = 7.2 Hz), 7.00 (2H, d, J = 9.2 Hz), 7.07 (2H, d, J = 7.8 Hz), 7.23 (6H, m ), 7.41 (2H, bri, J = 8.0 Hz), 7.87 (2H, d, J = 8.8 Hz), 9.70 (IH, brs).

Elemental analysis: C _3. H „N ₃ 0 ₆ S ₃ · 0.5 ¾0, Calculated: C, 57.13; H, 4.47; N, 6.66; S, 15.25 (%), Found: C, 56.96; H, 4.47; N, 6.89; S , 15.29 (%).

Example 4-399

_{Ή-NMR (CDC1 3, 300} MHz): <5 1.07 (6H, d, J = 6.4 Hz), 1.34 (3H, t, J = 7.2 Hz), 1.96 (1H, sept, J = 6.8 Hz), 2.76 (3H, s), 2.91 (2H, d, J = 7.2 Hz), 3.11 (3H, s), 4.28 (2H, q, J = 7.2 Hz), 9.64 (1H, brs).

Elemental _{analysis: C 15 H 21 N 3 0} 5 S 3 Calculated: C, 42.94; H, 5.05 ; N, 10.02; S, 22.93

(%), Found: C, 42.89; H, 5.14; N, 10.06; S, 22.91 (%).

Example 4-400

lH-丽_{(CDC1 3, 300 MHz):} δ 1.35 (3H, t, J = 7.2 Hz), 2.77 (3H, s), 3.02 (2H, dd, J = 8.7, 7.2 Hz), 3.09 (3H, s ), 3.26 (2H, dd, J = 8.7, 7.2 Hz), 4.28 (2H, q, J = 7.2 Hz), 7.24 (2H, brd, J = 7.5 Hz), 7.27-7.36 (3H, m), 9.60 . (1H, brs) elemental _{analysis: C 19 H 21 N 3 0} 5 S 3 calculated: C, 48.80; H, 4.53 ; N, 8.99; S, 20.57

(%), Found: C, 48.78; H, 4.65; N, 9.03; S, 20.59 (%).

Example 4-401

_{Ή-NMR (CDC1 3, 300} MHz): δ 1.33 (3Η, t, J = 7.2 Hz), 2.20 (2H, quint, J = 7.0 Hz), 2.76 (3H, s), 3.09 (3H, s), 3.17 (3H, s), 3.14 (2H, brt, J = 6.6 Hz), 3.18 (2H, t, J = 7.7 Hz), 4.27 (2H, q, J = 7.2 Hz), 7.48 (2H, brt, J = 7.9 Hz), 7.59 (1H, t, J = 7.5 Hz), 7.97 (2H, brd, J = 7.9 Hz), 9.63 (1H, brs).

Elemental _{analysis: C 21 H 23 N 3 0} 6 S 3 Calculated: C, 49.49; H, 4.55 ; N, 8.25; S, 18.88

(%), Found: C, 49.49; H, 4.67; N, 8.29; S, 18.92 (%).

Example -402

_{Ή-NM (CDC1 3, 300} MHz): δ 1.04 (6Η, d, J = 6.4 Hz), 1.92 (1H, sept, J = 6.8 Hz), 2.41 (3H, s), 2.42 (3H, s), 2.63 (3H, s), 2.90 (2H, d, J = 7.2 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.86 (2H, d, J = 8.3 Hz), 9.81 (1H, brs).

Elemental analysis: C _2. H ₂₃ N30 ₄ S ₃ Calculated: C, 51.59; H, 4.98 ; N, 9.02; S, 20.66

(%), Found: C, 51.69; H, 5.05;, 8.93; S, 20.64 ().

Example -403

_{Ή-NMR (CDC1 3, 300} MHz): 6 2.41 (3H, s), 2.43 (3H, s), 2.63 (3H, s), 2.99 (2H, brdd, J = 8.3, 7.5 Hz), 3.27 (2H , brdd, J = 8.3, 7.2 Hz), 7.20 (2H, brd, J = 8 Hz), 7.26-7.32 (5H, m), 7.83 (2H, d, J = 8.3 Hz), 9.80 (1H, brs) . elemental _{analysis: C 24 H 23 N 3 0} 4 S 3 · 0.2H 2 0 calculated: C, 55.73; H, 4.56 ; N, 8.12; S, 18.60 (%), Found: C, 55.85; H, 4.52; N, 7.97; S, 18.26 () Example 4-404

_{¾-NMR (CDC1 3, 300} MHz): δ 2.17 (2H, quint, J = 7.2 Hz), 2.39 (3H, s), 2.40 (3H, s), 2.62 (3H, s), 3.14 (2H, t , J = 6.8 Hz), 3.15 (2H, t, J = 7.2 Hz), 7.27 (2H, d, J = 8.3 Hz), 7.48 (2H, t, J = 7.5 Hz), 7.59 (1H, tt, J = 7.2, 1.8 Hz), 7.84 (2H, d, J = 8.3 Hz), 7.95 (2H, brd, J = 7.5 Hz), 9.81 (1H, brs).

Elemental analysis: C ₂₆ H ₂₅ N ₃ 0 ₅ S ₃ · 0.25 H ₂ O Calculated: C, 55.75; H, 4.59; N, 7.50; S, 17.17 (%) Found: C, 55.76; H, 4.52; N, 7.55; S, 17.11 (%).

Example 4-405

_{lH- NMR (CDC1 3, 300 MHz} ): δ 1.19 (3H, t, J = 7.2 Hz), 2.43 (3H, s), 2.48 (3H, s), 2.96 (2H, brdd, J = 8.3, 7.5 Hz ), 3.22 (2H, brdd, J = 8.3, 7.4 Hz), 3.36

(2H, dq, J = 5.7, 7.2 Hz), 5.86 (1H, brt, J = 6 Hz), 7.19 (2H, brd, J-8 Hz),

7.26-32 (5H, m), 7.83 (2H, d, J = 8.3 Hz), 9.71 (1H, brs).

Elemental analysis: Calculated as _{C 25 H 26 N 4 0 4} S 3: C, 55.33; H, 4.83; N, 10.32; S, 17.73 (%) Found: C, 55.13; H, 4.84 ; N, 10.16 ; S, 17.74 (%).

Example 4-406

The crystals were recrystallized from ethyl acetate to obtain orange crystals.

Melting point 165-167 ° C.

Infrared absorption spectrum (IR) (in KBr) V:. 3190, 2957 , 2932, 2210, 1742, 1622, 1597, 1551 cm- 1 Ή-NMR (CDC1 3): δ 0.910 (3Η, t, J = 7.0 Hz), 1.24-1.80 (6H, m), 2.43 (3H, s), 2.58 (3H, s), 2.94 (2H, t, 1 = 1.2 Hz), 7.30 (2H, d, J = 8.0 Hz), 7.83 (2H, d, J = 8.0 Hz), 9.69 (1H, bs).

Elemental analysis: C _2. H ₂₂ N ₄ 0 ₃ S ₃ · 0.7H ₂ 0 Calculated: C, 50.55; H, 4.96; N, 11.79; S, 20.24 (%), Found: C, 50.51; H, 4.83; N, 11.63 ; S, 20.41 (%).

Example 4-407

_{Ή-NMR (300MHz, CDC1 3} + TFA): <5 2.42 (3H, s), 2.45 (2H, brt, J = 7.3 Hz), 2.61 (2H, brt, J = 7.3 Hz), 4.24 (2H, s ), 6.64 (1H, s), 7.26 (2H, d, J = 8.2 Hz), 7.34 (5H, s), 7.82 (2H, d, J- 8.2 Hz), 10.22 (1H, brs).

Elemental analysis: C ₂₃ H ₂₁ N ₃ 0 ₅ S ₃ Calculated: C, 53.58; H, 4.10; N, 8.15; S, 18.66 (), found: C, 53.26; H, 4.14; N, 7.92 ; S, 18.58 (%) Example 4-408

■ ¾-NMR (300MHz, CDC1 3): δ 2.39 (2H, m), 2.41 (3H, s), 2.48 (2H, brt, J = 6.5 Hz), 3.70 (3H, s), 4.21 (2H, s ), 6.53 (1H, brs), 7.26 (2H, d, J = 8.3 Hz), 7.32 (5H, s), 7.80 (2H, d, J = 8.3 Hz), 9.74 (1H, brs).

Elemental analysis: C ₂₄ H ₂₃ N ₃ 0 ₅ S ₃ Calculated: C, 54.23; H, 4.40;, 7.91; S, 18.10 (%), found: C, 53.91; H, 4.18; N, 7.91 ; S, 18.43 (%).

 Example 4-409

¾ -Crash (300MHz, CDC1 ₃ + TFA): δ 1.80 (2H, quint, J = 7.4 Hz), 2.21 (2H, dd, J = 8.1, 7.4 Hz), 2.27 (3H, s), 2.41 (3H, s), 2.45 (2H, t, J- 7.1 Hz), 4.21 (2H, s), 7.25 (2H, d, J = 8.3 Hz), 7.33 (5H, s), 7.82 (2H, d, J = 8.3) Hz), 10.06 (1H, br).

Elemental _{analysis: C 25 H 25 N 3 0} 5 S 3 · 0.4Η 2 Calculated: C, 54.51; H, 4.72 ; N, 7.63; S, 17.46 (%), Found: C, 54.50; H, 4.33; N, 7.63; S, 17.51 (%).

 Example 4-410

One _{NMR (300MHz, CDC1 3):} δ 1.77 (2Η, quint, J = 7. Hz), 2.16 (2H, brdd, J = 8.0, 7.3 Hz), 2.25 (3H, s), 2.34 (2H, t, J = 7.1 Hz), 2.40 (3H, s), 3.69 (3H, s), 4.19 (2H, s), 7.24 (2H, d, J = 8.3 Hz), 7.32 (5H, s), 7.81 (2H, d, J = 8.3 Hz), 9.65 (1H, br).

Elemental analysis: C ₂₆ H ₂₇ N ₃ 0 ₅ S ₃ Calculated: C, 55.99; H, 4.88; N, 7.53; S, 17.25 (), found: C, 55.74; H, 4.90; N, 7.37 ; S, 17.41 (%).

 Example 4-411

Ή one _{NMR (300MHz, DMS0 - d 6} ): δ 2.36 (3Η, s), 4.29 (2H, s), 5.44 (1H, t, J = 7.9 Hz), 6.68 (1H, d, J = 7.9 Hz) , 7.32 (2H, d, J = 8.2 Hz), 7.33 (1H, m), 7.36 (4H, m), 7.79 (2H, d, J = 8.2 Hz), 11.78 (1H, br).

Elemental analysis: C _2. H ₁₇ N ₃ 0 ₃ S ₃ · 0.5H ₂ 0 Calculated: C, 53.08; H, 4.01;, 9.28; S, 21.25 (%), Found: C, 53.10; H, 3.86; N, 9.26; S, 21.41 (%).

 Example 4-412

Ή-NMR (300 MHz, DMSO-d ₆ ): δ 2.15 (3H, d, J = 1.1 Hz), 2.36 (3H, s), 4.27 (2H, s), 5.13 (1H, q J = 1.1 Hz), 7.31 (2H, d, J = 8.3 Hz), 7.32 (2H, m), 7.36 (3H, m), 7.79 (2H, d, J = 8.3 Hz), 11.70 (1H, br).

Elemental _{analysis: C 21 H 19 N 3 0} 3 Calculated _{S 3 · 0.2¾0:. C,} 54.69; H, 4.24; N, 9.11; S, 20.85 (%) Found: (;, 54.69; H, 4.12; N, 9.17; S, 21.08 (%).

Example 4-413

_{Ή-NMR (CDC1 3, 300} MHz): δ 1.01 (6Η, d, J = 6.6 Hz), 1.90 (1H, sept, J = 6.7 Hz), 2.27 (3H, d, J = 1.0 Hz), 2.42 ( 3H, s), 2.78 (2H, d, J = 6.9 Hz), 4.63 (1H, q, J = 1.1 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz) Hz), 9.68 (1H, brs).

Elemental _{analysis: C l8 H 21 N 3 0} 3 S 3 Calculated: C, 51.04; H, 5.00 ; N, 9.92; S, 22.71 (%), Found: C, 50.83; H, 4.89 ; N, 10.10; S, 22.74 (%).

Example 4-414

_{Ή-NMR (CDC1 3, 300} MHz): 6 2.27 (3H, d, J = 1.1 Hz), 2.43 (3H, s), 2.97 (2H, brdd, J = 8.7, 7.1 Hz), 3.15 (2H, brdd , J = 9.1, 6.4 Hz), 4.63 (1H, brq, J = 1.1 Hz), 7.18 (2H, brd, J = 8 Hz), 7.25-7.32 (5H, m), 7.82 (2H, d, J = 8.3 Hz), 9.67 (1H, brs).

Elemental _{analysis: C 22 H 2l N 3 0} 3 S 3 Calculated: C, 56.03; H, 4.49 ; N, 8.91; S, 20.40

(%), Found: C, 56.12; H, 4.52; N, 8.83; S, 20.28 (%).

Example 4-415

_{'H-NMR (CDC1 3,} 300 MHz): δ 2.14 (2Η, quint, J = 7.2 Hz), 2.26 (3H, d, J = 1.5 Hz), 2.38 (3H, s), 3.05 (2H, t, J = 7.2 Hz), 3.12 (2H, t, J = 7.2 Hz), 4.61 (1H, brq, J = 1.1 Hz), 7.25 (2H, d, J = 8.3 Hz), 7.48 (2H, t, J = 7.5 Hz), 7.59 (1H, tt, J = 7.2, 1.9 Hz), 7.83 (2H, d, J = 8.3 Hz), 7.95 (2H, brd, J = 8 Hz), 9.68 (1H, brs).

Elemental _{analysis: C 24 H 23 N 3 0} 4 S 3 Calculated: C, 56.12; H, 4.51 ; N, 8.18; S, 18.73 ()> Found: C, 55.85; H, 4.48 ; N, 8.25 ; S, 18.65 (%).

Example 4-416

8- (Isopentylsulfanyl) -1-([(4-methylphenyl) sulfonyl] iminoto 3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine- 5-Carboxylate The compound obtained in Example 3-20 (400 mg, 0.940 mmol) and carbonated lime (195 mg, Isopentyl iodide (0.137 il, 1.03 t) was added to a suspension of 1.41 t) in DMF (6.5 ml) while stirring at 60 ° C, and the mixture was stirred for 3 hours. 1N Hydrochloric acid (1.9 ml) and methanol / aqueous a: l (10 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol / water (2: 1 and 1: 1), and dried to give the title compound (439 mg, 0.886 mol) as a red powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 0.92 (6H, d, J = 6.2 Hz), 1.32 (3H, t, J = 7.1 Hz), 1.55 (2H, q, J = 7.6 Hz), 1.64 (1H , sept, J = 6.6 Hz), 2.43 (3H, s), 2.95 (2H, t, J = 7.5 Hz), 4.32 (1H, q, J = 7.2 Hz), 5.89 (1H, s), 7.31 (2H , D, J = 8.4 Hz), 7.86 (2H, d, J = 8.2 Hz), 9.76 (1H, brs).

Elemental analysis: Calculated for C ₂₁ H ₂₅ N ₃ 0 ₅ S ₃ : C, 50.89; H, 5.08; N, 8.48; S, 19.41 (%), found: C, 50.85; H, 5.20; N, 8.34; S, 19.29 (%).

Melting point.158.5-158.8 ° C

Example 4-420

! H - Ran _{R (300MHz, CDC1 3):} δ 0.89 (3Η, t, J = 6.9 Hz), 1.28 (6H, s), 1.31 (2H, m), 1.40 (2H, m), 1.70 (2H, brquint, J = 7.4 Hz), 2.43 (3H, s), 2.97 (2H, dd,

J = 7.6, 7.3 Hz), 4.98 (1H, s), 7.21 (2H, dd, J = 7.9, 2.0 Hz), 7.31 (2H, d,

J = 8.3 Hz), 7.37 (3H, m), 7.88 (2H, d, J = 8.3 Hz), 9.68 (1H, brs).

Elemental _{analysis: C 27 H 31 N 3 0} 3 S 3 Calculated: C, 59.86; H, 5.77 ; N, 7.76; S, 17.76 (%), Found: C, 59.65; H, 5.73 ; N, 7.75; S, 17.95 ().

Example 4-421

'H-NMR (300MHz, CDC1 3): δ 0.90 (3Η, t,] = 6.9 Hz), 1.29 (6H, brs), 1.32 (2H, m), 1.41 (2H, brquint, J = 7.2 Hz), 1.71 (2H, brquint, J = 7.4 Hz), 2.43 (3H, s), 2.97 (2H, t, J = 7.4 Hz), 5.04 (1H, s), 7.27 (2H, d, J = 8.2 Hz), 7.31 (2H, d, J = 8.2 Hz), 7.36 (1H, brt, J = 7.2 Hz), 7.44 (2H, brt, J = 7.7 Hz), 7.58 (2H, d, J = 8.2 Hz), 7.59 ( 2H, brd, J = 7.2 Hz), 7.89 (2H, d, J = 8.2 Hz), 9.72 (1H, brs).

Example 4-422

'H-NMR (300MHz, CDC1 3): δ 1.30 (3H, t, J = 7.2 Hz), 2.43 (3H, s), 3.74 (2H, s), 4.24 (2H, q, J = 7.2 Hz), 4.94 (1H, s), 6.94 (2H, dt, J = 7.7, 1.9 Hz), 7.05 (2H, dq, J = 8.3, 0.8 Hz), 7.14 (2H, d, J = 8.7 Hz), 7.15 (1H, m), 7.31 (2H, d, J = 8.3 Hz), 7.36 (2H, brt, J = 7.5 Hz), 7.87 (2H, d, J = 8.3 Hz), 9.67 (1H, brs).

Elemental _{analysis: C 29 H 25 N 3 0} 6 S 3 Calculated: C, 57.31; H, 4.15 ; N, 6.91; S, 15.83 (), Found: C, 57.35; H, 4.12 ; N, 7.31 ; S, 15.88 (%).

Example 4-423

_{lH- NMR (300MHz, CDC1 3)} : δ 2.38 (3H, s), 3.81 (2H, s), 4.90 (1H, s), 6.88 (2H, brd, J = 7. 9 Hz), 7.02 (2H, brd, J = 7.9 Hz), 7.08 (2H, brd, J = 8.3 Hz), 7.13 (1H, brt, J = 7.2 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.32 (2H, t, J = 7.8 Hz), 7.86 (2H, d, J = 7.9 Hz).

Example 4-424

Recrystallization from ethyl acetate-n-hexane gave dark red crystals with a melting point of 155-157 ° C.

Infrared absorption spectrum (IR) (in KBr) So: 3550-3000, 2928, 2905, 2857, 1732, 1651, 1611, 1557 cm " ¹ .

_{- NMR (CDC1 3): δ} 0.909 (3Η, t, J = 7.0 Hz), 1.20-1.48 (4H, m), 1.56-1.76 (2H, m), 2.34 (3H, s), 2.42 (3H, s ), 2.97 (2H, t, J = 7.6 Hz), 4.25 (2H, d, J = 6.0 Hz), 7.29 (2H, d, J = 8.0 Hz), 7.86 (2H, d, J = 8.4 Hz), 9.67 (1H, bs).

Elemental analysis value C _2. As H ₂₅ N ₃ 0 ₄ S ₃

Calculated (¾): C, 51.37; H, 5.39; N, 8.99; S, 20.57.

Found (¾): C, 51.23; H, 5.48; N, 8.77; S, 20.59.

Example 4-425

_{Ή-NMR (300MHz, CDC1 3} ): δ 2.41 (3Η, s), 2.48 (2H, brt, J = 6.6 Hz), 3.81 (2H, i, J = 6.6 Hz), 4.22 (2H, s), 6.62 (1H, brs), 7.25 (2H, brd, J = 8.3 Hz), 7.32 (5H, s), 7.73 (1H, dt, J = 1.1, 7.5 Hz), 7.79 (2H, d, J = 8.2 Hz) , 7.80 (1H, dt, J = 1.6, 7.5 Hz), 7.92 (1H, d, J = 7.6 Hz), 7.95 (1H, d, J = 7.5 Hz), 9.69 (1H, brs).

Elemental analysis: C ₃₀ ¾ ₄ N ₄ 0 ₅ S ₃ · 0.2H ₂ 0 Calculated: C, 58.08; H, 3.96; N, 9.03; S, 15.51 (%), found: C, 57.97; H , 3.96; N, 8.92; S, 15.58 (%), Example 4-426 Ή-NR (300 MHz, DMS0-d ₆ ): δ 2.33 (2H, brt, J = 6.3 Hz), 2.36 (3H, s), ca.2.5 (2H, brt, J = 6.3 Hz), 4.32 (2H, s), 6.68 (1H, brs), 7.31 (2H, brd, J = 8.2 Hz), 7.34 (5H, m), 7.39 (1H, dd, J-7.6, 1.6 Hz), 7.52 (2H, dquint, J = 2.0, 7.6 Hz), 7.77 (1H, dd, J = 7.6, 1.6 Hz), 7.79 (2H, d, J = 8.2 Hz), 8.41 (1H, brt, J = 5.7 Hz), 11.81 (1H, br ), 12.92 (1H, brs).

Elemental _{analysis: C 30 H 26 N 4 0} 6 S Calculated _{3 · 0.5¾0:. C, 55.97} ; H, 4.23; N, 8.70; S, 14.94 (%) Found: C, 56.09; H, 4.29 ; N, 8.76; S, 15.05 {%)

Example 4-427

 'HNR (CDClg, 200 MHz): δ 1.10 (6H, d, J = 6.8 Hz), 1.44 (4H, m), 1.5-1.7 (4H, m), 2.28 (3H, s), 2.41 (3H, s), 2.95 (1H, quint, J = 7.2 Hz), 2.98 (2H, i, J- 7.2 Hz), 3.66 (2H, t, J = 6.2 Hz), 7.28 (2H, d, J = 7.0 Hz) , 7.85 (2H, d, J = 8.4 Hz), 9.67 (1H, brs).

Elemental _{analysis: C 23 H 31 N 3 0} 4 S 3 Calculated: C, 54.20; H, 6.13 ; N, 8.24; S, 18.87 (%), Found: C, 54.19; H, 6.18 ; N, 8.37; S, 18.59 (%)

Example 4-428

E -賺_{(CDC1 3, 200 MHz):} <5 1.03 (6H, d, J = 6.8 Hz), 1.10 (6H, d, J = 7.0 Hz), 1.91 (1H, sept, J = 6.6 Hz), 2.28 (3H, s), 2.41 (3H, s), 2.86 (2H, d, J = 7.0 Hz), 2.95 (1H, quint, J = 7.0 Hz), 7.28 (2H, d, J = 8.0 Hz), 7.87 (2H, d, J = 8.4 Hz), 9.64 (1H, brs).

Elemental analysis: Calculated for C ₂₁ H ₂₇ N ₃ 0 ₃ S ₃ : C, 54.17; H, 5.84; N, 9.02; S, 20.66 (%), found: C, 53.96; H, 5.80; N, 9.14; S, 20.63 (%).

Example 4-429

_{Ή-NMR (CDC1 3, 200} MHz): δ 1.11 (6Η, d, J = 6.8 Hz), 2.28 (3H, s), 2.42 (3H, s), 2.96 (1H, quint, J = 7.0 Hz), 2.99 (2H, brdd, J = 8.8, 5.2 Hz), 3.21 (2H, dd, J = 9.2, 5.6 Hz), 7.18-34 (7H, m), 7.84 (2H, d, J = 8. Hz), . 9.66 (1H, brs) elemental _{analysis: C 25 H 27 N 3 0} 3 S 3 calculated: C, 58.45; H, 5.30 ; N, 8.18; S, 18.73

(%), Found: C, 58.55; H, 5.24; N, 8.21; S, 18.62 (%).

Example 4-430

E -丽_{(CDC1 3, 200 MHz):} δ 1.08 (6Η, d, J = 7.0 Hz), 2.16 (2H, quint, J = 6.9 Hz), 2.27 (3H, s), 2.38 (3H, s), 2.94 (1H, quint, J = 7.0 Hz), 3.13 (2H, t, J = 7.0 Hz), 3.15 (2H, t, J = 7.0 Hz), 7.24 (2H, d, J = 8.0 Hz), 7.48 (2H, t, J = 7.4 Hz), 7.59 (1H, t, J- 7.2 Hz), 7.84 (2H, d, J = 8.4 Hz) ), 7.96 (2H, dm, J = 7.8 Hz), 9.66 (1H, brs).

Elemental _{analysis: C 27 H 29 N 3 0} 4 S 3 Calculated: C, 58.35; H, 5.26 ; N, 7.56; S, 17.31 (%) Found: C, 58.19; H, 5.24 ; N, 7.61 S, 17.29 ().

Example 4-431

Ή-NMR (300MHz, DMSO— d ₆ ): δ 0.85 (3Η, t, J = 6.8 Hz), 1.25 (6H, brs), 1.30 (2H, m), 1.42 (2H, brquint, J = 6.5 Hz) , 2.17 (3H, s), 2.38 (3H, s), 2.62 (2H, t, J = 7.2 Hz), 3.14 (2H, t, J = 7.2 Hz), 7.37 (2H, d, J = 8.3 Hz) , 7.83 (2H, d, J = 8.3 Hz), 11.67 (1H, br), 12.50 (1H, br).

Elemental _{analysis: C 24 H 31 N 3 0} 5 S 3 Calculated: C, 53.61; H, 5.81 ; N, 7.81; S, 17.89 (%), Found: C, 53.31; H, 5.73 ; N, 7.82; S, 17.85 (%).

Example 4-432

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.89 (3H, t, J = 6.8 Hz), 1.28 (8H, brs), 1.43 (2H, brquint, J = 7 Hz), 2.09 (2H, dd, J = 7.9, 7.2 Hz), 2.24 (3H, s), 2.40 (3H, s)., 4.20 (2H, s), 7.24 (2H, d, J = 8.3 Hz), 7.32 (5H, s), 7.81 (2H , d, J = 8.3 Hz), 9.64 (1H, br).

Elemental analysis: C ₂₈ H ₃₃ N ₃ 0 ₃ S ₃ Calculated: C, 60.51; H, 5.98; N, 7.56; S, 17.31 (%), found: C, 60.22; H, 5.78; N, 7.75; S, 17.61 (%).

Example 4-433

Ή-NMR (300 MHz, CDCI ₃ ): δ 0.89 (3Η, t, J = 6.9 Hz), 1.28 (6H, brs), 1.31 (2H, m), 1.44 (2H, brquint, J = 6.6 Hz), 2.04 (2H, brdd, J = 7.4, 7.1 Hz), 2.41 (3H, s), 4.22 (2H, s), 6.47 (1H, brt, J = 0.5 Hz), 7.25 (2H, d, J = 8.3 Hz) , 7.32 (5H, s), 7.80 (2H, d, J = 8.3 Hz), 9.72 (1H, br).

Elemental _{analysis: C 27 H 31 N 3 0} 3 S 3 Calculated: C, 59.86; H, 5.77 ; N, 7.76; S, 17.76

Found: C, 59.87; H, 5.70; N, 7.74; S, 17.63 (%).

Example 4-434

_{Ή-NR (300MHz, CDC1 3} ): <5 0.85 (3H, t, J = 7.2 Hz), 1.19 (6H, brs), 1.25 (2H, m), 1.43 (2H, brquint, J = 7.5 Hz), 2.39 (2H, brdd, J = 8.3, 6.5 Hz), 2.42 (3H, s), 2.59 (2H, dd, J = 7.9, 7.2 Hz), 3.55 (2H, dd, J = 7.9, 7.2 Hz), 4.48 (2H, d, J = 6.0 Hz), 6.57 (1H, brt, J = 5.7 Hz), 7.25 (2H, m), 7.30 (2H, d , J = 8.3 Hz), 7.33 (3H, m), 7.45 (5H, s), 7.71 (2H, d, J = 8.3 Hz), 9.52 (1H, brs).

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.88 (3H, t, J = 7.2 Hz), 1.27 (8H, brs), 1.30 (3H, t, J = 7.2 Hz), 1.44 (2H, brquint, J = 7.2 Hz), 2.05 (2H, brdd, J = 7.5, 6.5 Hz), 2.42 (3H, s), 3.74 (2H, s), 4.23 (2H, q, J = 7.2 Hz), 6.49 (1H, brt, J = 1 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.80 (1H, br).

Elemental _{analysis: C 25 H 33 N 3 0} 5 S 3 Calculated: C, 54.42; H, 6.03 ; N, 7.62; S, 17.43

(%), Found: C, 54.42; H, 6.06; N, 7.46; S, 17.46 ().

Example 4-436

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.88 (3Η, brt, J = 7.2 Hz), 1.26 (10H, brs), 1.44 (2H, brquint, J = 6.8 Hz), 2.05 (2H, brt, J = 7.2 Hz), 2.40 (3H, s), 3.81 (2H, s), 6.49 (1H, brt, J = 1 Hz), 6.91 (1H, s), 7.29 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.98 (1H, br).

Elemental _{analysis: C 23 H 29 N 3 0} 5 S 3: C, 52.75; H, 5.58; N, 8.02 (%).

Found: C, 52.51; H, 5.58; N, 8.06 (%).

Example 4-437

_{Ή-NR (300MHz, CDC1 3} ): δ 0.89 (3H, t, J = 6.8 Hz), 1.27 (10H, brs), 1.44 (2H, brquint, J = 7 Hz), 2.04 (2H, brdd, J = 7.2, 6.8 Hz), 2.41 (3H, s), 4.22 (2H, s), 6.47 (1H, s), 7.25 (2H, d, J = 8.3 Hz), 7.32 (5H, s), 7.80 (2H, d, J = 8.3 Hz), 9.72 (1H, br).

Example 4-438

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.88 (3H, brt,] = 6.8 Hz), 0.95 (3H, brt, J = 7.5 Hz), 1.26 (10H, brs), 1.44 (2H, m), 1.68 (2H, q, J = 7.2 Hz), 2.41 (3H, s), 2.44 (2H, brdd, J = 7.5, 7.2 Hz), 3.75 (2H, s), 4.13 (2H, t, J = 6.8 Hz) , 6.49 (1H, s), 7.28 (2H, d, J = 8.3 Hz), 7.85 (2H, d, J = 8.3 Hz).

Elemental analysis: Calculated as _{C 26 H 35 N 3 0 5} S 3: C, 55.20; H, 6.24;, 7.43 (), the real Found: C, 55.01; H, 6.13;, 7.52 (%).

Example -439

_{¾-NMR (300MHz, CDC1 3} ): 6 0.88 (3H, t, J = 7.2 Hz), 1.26 (18H, brs), 1.44 (2H, brquint, J = 7 Hz), 2.04 (2H, t, J = 7.0 Hz), 2.41 (3H, s), 4.22 (2H, s), 6.47 (m, s), 7.25 (2H, d, J = 8.2 Hz), 7.32 (5H, s), 7.80 (2H, d, J = 8.2 Hz), 9.71 (1H, br).

Elemental analysis: Calculated as _{C 32 H 41 N 3 0 3} S 3: C, 62.81; H, 6.75;, 6.87; S, 15.72

(%), Found: C, 62.42; H, 6.64; N, 6.94; S, 15.76 (%).

Example 4-440

_{Ή-NR (300MHz, CDC1 3} ): δ 2.42 (3H, s), 4.29 (2H, s), 6.90 (1H, s), 7.28 (2H, d, J = 8.3 Hz), 7.34 (5H, s) , 7.37 (5H, s), 7.82 (2H, d, J = 8.3 Hz), 9.77 (1H, br).

Elemental analysis: Calculated for C ₂₆ H ₂₁ N ₃ 0 ₃ S ₃ : C, 60.09; H, 4.07; N, 8.09; S, 18.51

(%), Found: C, 60.03; H, 4.11; N, 8.07; S, 18.59 (%) ·

Example 4-441

Ή one _{NMR (300MHz, CDC1 3):} δ 0.72 (3Η, t, J = 7.2 Hz), 1.15 (2H, dq, J = 14.8, 7.2 Hz), 1.31 (2H, m), 2.42 (3H, s) , 2.59 (2H, brdd, J = 7.7, 7.4 Hz), 4.17 (2H, s), 7.25 (2H, m), 7.26 (2H, d, J = 8.3 Hz), 7.31 (5H, m), 7.39 ( 1H, m), 7.39 (2H, m), 7.83 (2H, d, J = 8.3 Hz), 9.67 (1H, br).

Elemental analysis: C _3. Calculated for H ₂₉ N ₃ 0 ₃ S ₃ : C, 62.58; H, 5.08; N, 7.30; S, 16.71

(%), Found: C, 62.53; H, 5.03; N, 7.33; S, 16.83 (%).

Example 4-442

'H-NMR (300MHz, CDC1 3): δ 0.88 (3Η, t, J = 6.9 Hz), 1.26 (6H, brs), 1.30 (2H, m), 1.38 (2H, brquint, J = 7.2 Hz), , 1.68 (2H, brquint, J = 7.4 Hz), 2.44 (3H, s), 2.96 (2H, t, J = 7.5 Hz), 7.04 (4H, i), 7.17 (6H, m), 7.31 (2H, d, J = 8.3 Hz), 7.89 (2H, d, J = 8.3 Hz), 9.62 (1H, brs).

Elemental _{analysis: C 33 H 35 N 3 0} 3 S 3 Calculated:. C, 64.15; H, 5.71; N, 6.80; S, 15.57 (%) Found: C, 64.15; H, 5.71 ; N, 6.77; S, 15.72 ().

Example 4-443 _{Ή-NMR (300MHz, CDC1 3} ): δ 2.42 (3H, s), 4.22 (2H, s), 6.99 (2H, dd, J = 7.5, 2.1 Hz), 7.04 (2H, dd, J = 8.0, 1.5 Hz), 7.16 (6H, m), 7.27 (2H, d, J = 8.3 Hz), 7.32 (5H, s), 7.84 (2H, d, J = 8.3 Hz), 9.59 (1H, br).

Elemental analysis: C ₃₂ H ₂₅ N ₃ 0 ₃ S ₃ · 0.3 H ₂ 0 Calculated: C, 63.93; H, 4.29; N, 6.99 (%), found: C, 63.90; H, 4.14; N , 7.38 (%).

Example 4-444

_{Ή-NMR (300MHz, CDC1 3} ): δ 2.40 (3H, s), 3.35 (2H, s), 4.13 (2H, s), 6.55 (1H, brt, J = 1 Hz), 7.18-7.35 (12H, . m), 7.79 (2H, d, J = 8.3 Hz), 9.72 (1H, br) elemental analysis: calculated _{C 27 H 23 N 3 0 3} S 3: C, 60.76; H, 4.34; N, 7.87; S, 18.02 (%), Found: C, 60.74; H, 4.46; N, 7.73; S, 18.18 (%).

Example 4-445

160-162 ° C

Infrared absorption spectrum (IR) (in KBr) v: 3260, 3162, 2961, 2928, 1738, 1657, 1615, 1559, 1495 cm—

_{¾-NMR (CDC1 3):} 50.953 (6H, d, J = 6.6 Hz), 1.72-1.88 (1H, m), 2.36 (3H, s), 2.41 (3H, s), 2.73 (2H, d, J = 6.4 Hz), 3.50 (2H, s), 7.17-7.40 (7H, i), 7.86 (2H, d, J = 8.4 Hz), 9.66 (IH, bs).

Elemental analysis: Calculated as _{C 25 H 27 N 3 0 3} S 3: C, 58.45; H, 5.30;, 8.18; S, 18.73 (%), Found: (:, 58.27; H, 5.27; N, 8.08; S, 18.66 (%).

Example 4-446

The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals.

Melting point: 147-149.

Infrared absorption spectrum (IR) (in KBr) V: 3250, 2926, 1732, 1659, 1615, 1559, 1495 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 0.820-0.942 (3Η, m), 1.20-1.38 (4H, m), 1.48-1.70 (2H, m), 2.42 (3H, s), 2.85 (2H, t, J -7.2 Hz), 3.50 (2H, s), 7.15-7.42 (7H, m), 7.86 (2H, d, J = 8.4 Hz), 9.65 (IH, bs).

Elemental _{analysis: C 26 H 29 N 3 0} 3 S 3 Calculated: C, 59.18; H, 5.54 ; N, 7.96; S, 18.23 (%), Found: C, 59.02; H, 5.47 ; N, 7.89; S, 18.37 (%) Example 4-448

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.92 (3H, t, J- 7.2 Hz), 1.34 (2H, m), 1.44 (2H, m), 2.05 (2H, brt, J = 7.1 Hz), 2.41 (3H, s), 4.51 (2H, s), 4.76 (2H, s), 4.82 (2H, s), 5.78 (2H, s), 6.44 (1H, brt, J = 0.5 Hz), 7.24 (2H, s) m), 7.28 (2H, brd, J = 8.3 Hz), 7.29 (1H, m), 7.33 (5H, m), 7.40 (2H, brd, J = 6.8 Hz), 7.94 (2H, d, J = 8.3 Hz) Hz).

Elemental analysis: C ₃₃ 0 ₅ S ₃ Calculated: C, 60.99; H, 5.43 ; N, 6.47; S, 14.80

(%), Found: C, 60.85; H, 5.45; N, 6.47; S, 14.53 (%).

Example 4-449

_{Ή-NMR (300MHz, CDC1 3} ): d 0.90 (3H, t, J = 6.8 Hz), 1.30 (4H, m), 1.47 (2H, brquint, J = 7.2 Hz), 2.10 (2H, t, J = 7.5 Hz), 2.23 (3H, s), 2.42 (3H, s), 4.51 (2H, s), 4.78 (2H, s), 4.83 (2H, s), 5.75 (2H, s), 7.22-7.31 (6H, m), 7.33 (4H, m), 7.42 (2H, .brd, J = 7.2 Hz), 7.95 (2H, d, J = 8.3 Hz).

Elemental _{analysis: C 35 H 39 N 3 0} 5 S 3 Calculated: C, 62.01; H, 5.80 ; N, 6.20; S, 14.19

Found: C, 61.85; H, 5.90; N, 6.26; S, 14.37 (%).

Example 4-450

_{^ -NMR (CDC1 3, 300 MHz} ): δ 0.86 (6Η, d, J = 6.8 Hz), 0.90 (3H, brt, J = 7 Hz), 1.30 (4H, m), 1.47 (2H, brquint, J = 7.2 Hz), 1.70 (1H, brsept, J = 6.8 Hz), 2.11 (2H, brt, J = 7.7 Hz), 2.29 (3H, s), 2.40 (3H, s), 2.70 (2H, d, J = 6.4 Hz), 3.70 (3H , s), 7.25 (2H, d, J = 8.3 Hz), 7.92 (2H, d, J- 8.3 Hz) elemental _{analysis:.. C 24 H 33 N} 3 0 3 S Calculated as ₃ : C, 56.77; H, 6.55; N, 8.28; S, 18.95

(%), Found: C, 56.65; H, 6.36; N, 8.34; S, 19.02 (%).

Example 4-451

Ή-NMR (200 MHz, CDCI ₃ ): δ 1.26 (3Η, t, J = 7.2 Hz), 1.80 (3H, brq, J = 1.2 Hz), 2.29 (3H, brq, J = 0.8 Hz), 2.43 (3H , s), 2.49 (2H, t, J = 7.4 Hz), 3.05 (2H, t, J = 7.3 Hz), 3.51 (3H, s), 4.15 (2H, q, J = 7.2 Hz), 5.60 (2H , s), 7.28 (2H, d, J = 8.4 Hz), 7.89 (2H, d, J = 8.4 Hz).

Elemental analysis: Calculated as _{C 22 H 27 N 3 0 6} S 3: C, 50.27; H, 5.18; N, 7.99; S, 18.30 (%), Found: C, 50.32; H, 5.22 ; N, 8.03; S, 18.31 (%). Melting point.89.5- 92.0

Example 4-452

'H-NMR (200MHz, CDC1 3): <5 1.09 (3H, t, J = 7.5 Hz), 2.14 (2H, q, J = 7.5 Hz),

2.30 (3H, s), 2.32 (3H, s), 2.42 (3H, s), 3.50 (3H, s), 5.61 (2H, s), 7.27 (2H, d, J = 8.2 Hz), 7.90 (2H , d, = 8.4 Hz), elemental analysis: calculated _{C 19 H 23 N 3 0 4} S 3:. C, 50.31; H, 5.11; N, 9.26; S, 21.21

(%), Found: C, 50.16; H, 5.13; N, 9.27; S, 21.25 ().

142.5- 143.0 ° C

Example 4-453

_{Ή- NMR (200MHz, CDC1 3)} : δ 1.80 (3H, q, J = 1.0 Hz), 2.30 (3H, q, J = 1.0 Hz), 2.32 (3H, s), 2.42 (3H, s), 3.71 (3H, s), 7.28 (2H, d, J = 8.0 Hz), 7.90 (2H, d, J = 8.4 Hz).

Elemental analysis: Calculated as _{C 17 H l9 N 3 0 3} S 3: C, 49.86; H, 4.68;, 10.26; S, 23.49 (), Found: C, 49.88; H, 4.66 ; N, 9.98; S, 23.52 ().

Melting point. 203.2-203.7 ° C

Example 4-454

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.79 (3H, q, J = 1.2 Hz), 2.30 (3H, q, J = 1.2 Hz),

2.31 (3H, s), 2.42 (3H, s), 3.50 (3H, s), 5.61 (2H, s), 7.27 (2H, d, J = 8.0 Hz), 7.90 (2H, d, J = 8.4 Hz) ).

Elemental _{analysis: C 18 H 21 N 3 0} 4 S 3 Calculated: C, 49.18; H, 4.82 ; N, 9.56; S, 21.88 (%), Found: C, 49.19; H, 5.04 ; N, 9.52; S, 21.95 (%).

Melting point.153.0-153.5t:

Example 4-455

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.75 (3H, q, J = 1.2 Hz), 2.28 (3H, q, J = 1.2 Hz), 2.39 (3H, s), 3.52 (3H, s), 4.31 (2H, s), 5.'62 (2H, s), 7.21 (2H, d, J = 8.0 Hz), 7.50 (2H, t, J = 7.5 Hz), 7.64 (1H, t, J = 7.4 Hz) ), 7.89 (4H, m).

Elemental analysis: C ₂₅ H ₂₅ N ₃ 0 ₅ S ₃ · 0.50 Calculated: C, 54.33; H, 4.74; N, 7.60; S, 17.41 (%), found: C, 54.39; H, 4.59 ; N, 7.58; S, 17.40 (%).

Melting point. 186.5-187.0 ° C Example 4-456

 N- (5,6-Dimethyl-3-oxo-1--1- [2- (3-Chenyl) ethyl] -8-{[2- (3-Chenyl) ethyl] sulfanyl} -2,3-dihydro- While stirring at 0 ° C DIAD ( 0.319 ml, 1.57 marl ol) was added dropwise, and the mixture was stirred for 30 minutes.The compound (30 mg, 0.797 mmol) obtained in Example 3-4 and 2- (3-Chenyl) ethanol (123 mg , 0.944 ol) and the reaction solution was cooled to room temperature and stirred for 27 hours, during which time triphenylphosphine (108 mg, 0.400 mmol) and DIAD (83 mg, 0.400 mmol) were added. The residue was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate, 0.1N hydrochloric acid, water and saturated saline, dried over sodium sulfate and concentrated.The residue was chromatographed on silica gel (10 g) (ethyl acetate). Hexane, to 1: 9-4: 6) in the paper seminal to give compound (85 mg, and 0.141 negation ol) as a purple-red solid.

- title _{R (200MHz, CDC1 3):} δ 1.79 (3Η, q, J = 1.2 Hz), 2.28 (3H, q, J = 1.0 Hz), 2.41 (3H, s), 2.79 (2H, t, J = 7.3 Hz), 3.05 (2H, t, J = 7.3 Hz), 3.18 (2H, brt, J = 8.5 Hz), 4.42 (2H, brt, J = 8.1 Hz), 6.83 (2H, d, J = 4.0 Hz) ), 7.17-7.28 (2H, m), 7.92 (2H, d, J = 8.4 Hz).

Elemental _{analysis: C 27 H 27 N 3 0} 3 S 5 Calculated: C, 53.88; H, 4.52 ; N, 6.98; S, 26.64 (%), Found: C, 54.13; H, 4.45 ; N, 7.01; S, 26.71 (%).

Example 4-457

 N- (5,6-Dimethyl-3-oxo-Ϊ- [3- (3-pyridinyl) propyl] -8-{[3- (3-pyridinyl) propyl] sulfanyl} _2,3-dihydro-1H- Imidazo [5, 1-c] [1,4] thiazine-triylidene) -4_methylbenzenesulfonamide

Of the compound (163 mg, 0.427 mmol) obtained in Example 3-4, 3- (3-pyridyl) -topropanol (90 mg, 0.641 mol) and triphenylphosphine (231 mg, 0.855 mol). DEAD (0.142 ml, 0.855 mmol) was added dropwise to the THF (3.3 ml) suspension while stirring at room temperature, and the reaction solution was stirred at room temperature for 19 hours. To the reaction solution, triphenylphosphine α (16 mg, 0.427) and DEAD (0.071 ml, 0.427) were added, and the reaction solution was stirred at room temperature for 19 hours. Dilute with ethyl acetate (25 ml), add 2% aqueous sodium bicarbonate, The extract was washed with water and saturated saline, dried and concentrated. The residue was chromatographed on silica gel (10 g) [ethyl acetate-hexane (1: 1), ethyl acetate and methanol-ethyl acetate (1:19 and 1: 9)]. The methanol-ethyl acetate fraction was concentrated and dried, and then crystallized from ethyl acetate to give the title compound (115 mg, 0.186 mol) as a purple powder.

_{- NMR (300MHz, CDC1 3 +} TFA): <5 1.78 (3H, q, J = 1.2 Hz), 1.90 (2H, quint, J = 7.2 Hz), 2.28 (3H, q, J = 1.2 Hz), 2.29 (2H, m), 2.35 (3H, s), 2.73 (2H, t, J- 7.8 Hz), 2.82 (2H, t, J = 6.9 Hz), 2.99 (2H, t, J = 7.8 Hz), 4.29 (2H, t, J = 7.6 Hz), 7.27 (2H, d, J = 8.4 Hz), 7.77 (1H, t, J = 5.7 Hz), 7.80 (1H, t, J = 5.1 Hz), 7.88 (2H , D, J = 8.1 Hz), 8.02 (1H, d, J = 8.1 Hz), 8.31 (1H, d, J = 7.5 Hz), 8.72 (3H, m), 8.81 (1H, brs).

Elemental analysis: C ₃₁ H ₃₃ N ₅ 0 ₃ S ₃ · 0 · 30 Calculated: C, 59.55; Η, 5.42; Ν, 11.20; S, 15.39 (%), found: C, 59.38; Η , 5.47; Ν, 11.00; S, 15.41 (%).

150.5-152. O

Example 4-458

N- (5,6-Dimethyl-3-oxo-2- [3- (4-pyridinyl) propyl] -8-{[3- (4-pyridinyl) propyl] sulfanyl 2,3-dihydro-1H- Imidazo [5,1-c] [1,4] thiazine The compound obtained in Example 3-4 (219 mg, 0.574 tmol), 3- (4-pyridyl) -tripropanol (121 mg, 0.861 mmol) ) And triphenylphosphine (310 mg, 1.15 bandol) in THF (4. ml) were added dropwise with stirring at room temperature while DEAD (0.190 ml, 1.15 mmol) was added dropwise, and the reaction solution was stirred at room temperature for 19 hours. Triphenylphosphine (155 mg, 0.574 mmol) and DEAD (0.095 ml, 0.574 mmol) were added to the reaction solution, and the reaction solution was stirred at room temperature for 4 hours, and diluted with ethyl acetate (30 ml). The residue was washed with a 2% aqueous sodium carbonate solution, a 2% aqueous sodium hydrogen carbonate solution and saturated saline, dried and concentrated.The residue was chromatographed on silica gel (10 g) [ethyl acetate-hexane (1: 1), ethyl acetate and methyl ethyl acetate (1:19 and 1: 9)] The fraction of methanol-ethyl acetate was concentrated to dryness and then crystallized from methanol to give the title compound (178). mg, 0.287 mmo 1) as a purple powder. _{Ή-NMR (300MHz, CDC1 3} + TFA): δ 1.77 (3H, s), 1.93 (2H, quint, J = 6.6 Hz), 2.27 (3H, s), 2.36 (2H, m), 2.37 (3H, s), 2.78 (2H, m), 2.82 (2H, t, J = 7.2 Hz), 3.05 (2H, t, J = 6.9 Hz), 4.33 (2H, t, J = 7.5 Hz), 7.29 (2H, d, J = 8.1 Hz), 7.56 (2H, brs), 7.81 (2H, d, J = 5.4 Hz), 7.89 (2H, d, J = 8.1 Hz), 8.76 (4H, brd, J = 5.4 Hz) , 8.31 (1H, d, J = 7.5 Hz), 8.72 (3H, m), 8.81 (1H, brs) elemental _{analysis: C 31 N 5 0 3 S} 3 .0.3¾0 calculated: C, 59.55;. H, 5.42; N, 11.20; S, 15.39 (%), found: C, 59.63; H, 5.39; N, 11.09; S, 15.60 (%).

Melting point.

Example 4-459

Recrystallization from ethyl acetate-diisopropyl ether gave dark red crystals.

Melting point 178-180.

IR (KBr) V: 2957, 2926, 2859, 1738, 1713, 1644, 1624, 1609, 1561, 1535, 1507 cur ¹ .

E -丽_{R (CDC1 3): 50.932 (} 3H, t, J = 6.6 Hz), 1.34-1.50 (2H, m), 1.66-1.80 (2H, Hi), 1.84 (3H, s), 2.23 (3H, s), 2.39 (6H, s), 3.01 (2H, t, J = 7.8 Hz), 7.20 (2H, d, J = 8.4 Hz), 7.25 (2H, d, J = 8.4 Hz), 7.80 (2H, d, J = 8.0Hz), 8.02 (2H, d, J-8.0 Hz).

Elemental analysis: C ₂₉ H _{3 I} N ₃ 0 ₃ S ₂ · Calculated as 0.3¾0 (%): C, 64.61; H, 5.91; N, 7.79; S, 11.90. Observed (¾): C, 64.62; H, 5.88; N, 7.67; S, 12.09.

Example 4-460

 8- (isopentylsulfanyl) -6-methyl-1-([(4-methylphenyl) sulfonyl] iminoto 3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1, 4] Thiazine-5-potassium rubonate

To a suspension of the compound obtained in Example 3-21 (57 mg, 0.130 mmol) and potassium carbonate (27 mg, 0.195 mmol) in F (1.0 ml) was stirred at 60 with isopentyl iodide (0.021 ml, 0.156 mmol) was added and the mixture was stirred for 40 minutes. 1N Hydrochloric acid (0.26 ml) and methanol / water (1: 1, 3 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol / water (1: 1) and methanol, and dried to give the title compound (53 mg, 0.104 tmol) as a red-purple powder. _{Ή-NR (200MHz, CDC1 3} ): δ 0.93 (6H, d, J = 6.4 Hz), 1.33 (3H, t, J = 7.1 Hz), 1.56 (2H, brq, J = 7.5 Hz), 1.67 (1H , sixtet, J = 6.2 Hz), 1.92 (3H, s), 2.43 (3H, s), 2.96 (2H, t, J = 7.7 Hz), 4.33 (2H, q, J = 7.2 Hz), 7.30 (2H , d, J2 8.6 Hz), 7.85 (2H, d, J = 8.0 Hz), 9.69 (1H, br).

Elemental _{analysis: C 22 H 27 N 3 0} 5 S 3 Calculated: C, 51.84; H, 5.34 ; N, 8.24; S, 18.87 (%), Found: C, 51.60; H, 5.15 ; N, 8.13; S, 18.84 (%).

Melting point: 150.0-150.5 ° C

Example 4-461

 6-methyl-{{((4-methylphenyl) sulfonyl] imino} -3-oxo-8-[(2-phenylpropyl) sulfanyl] -2,3-dihydro-1H-imidazo [5, tric] [ 1,4] thiazine-5-carboxylate

 To a suspension of the compound obtained in Example 3-21 (0.59 g, 1.2 mol) and carbonated lime (0.25 g, 1.8 mol ol) in DMF (10 ml) was added 2-phenylphenyl iodide while stirring at 60. (0.208 ml, 1.2 mmol) was added and the mixture was stirred for 4 hours. During this time, iodoani 2-phenylpropyl (0.021 ml, 0.12 mmol) was added to the reaction solution. 1N Hydrochloric acid (2.4 ml) and methanol-water (1: 1, 10 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 60 minutes. The precipitate was collected by filtration, washed with methanol-water (1: 1) and methanol, and dried to give the title compound (570 mg, 1.02 mmol) as a purple powder.

 Thigh (200MHz, double-mouthed holm): 6 1.33 (3Η, t, J = 7.2 Hz), 1.37 (3H, d, J = 6.4 Hz), 1.91 (3H, s), 2.43 (3H, s), 3.03 (1H, m), 3.11 (1H, m), 3.24 (1H, quint, J = 6.2 Hz), 4.33 (2H, q, J = 7.1 Hz), 7.19 (2H, m), 7.29 (5H, m) , 7.80 (2H, d, J = 8.4 Hz), 9.67 (1H, brs).

Elemental analysis: Calculated as _{C 26 H 27 N 3 0 5} S 3; C, 55.99; H, 4.88; N, 7.53; S, 17.25 (%), Found; C, 56.16; H, 5.08 ; N, 7.65; S, 16.95 (%). Melting point: 144.5-145.5T: Example 4-462

 8- (Isopentylsulfanyl) -6-methyl-1-{[(4_methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-imidazo [5, tri (;) [1 , 4] thiazine-5-carboxylic acid

Compound (1.10 g, 1.88 mmol) obtained in Example 1-48 in THF-methanol (1: 1, 20 ml) To the suspension was added potassium hydroxide (0.37 g, 5.64 liters) while stirring at room temperature, and the reaction solution was stirred at room temperature for 40 minutes. 1N Hydrochloric acid (5.64 ml) and water (10 ml) were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 2% and saturated saline, dried over sodium sulfate, and concentrated to give a yellow oil (0.99 g). To a suspension of this yellow oil (0.99 g) and potassium carbonate (0.39 g, 2.82 bandol) in DMF (15 ml) was added isopentyl iodide (0.30 ml, 2.26 mmol) with stirring at 60 ° C. The mixture was stirred for 2.5 hours. The reaction solution was extracted and purified in the same manner to obtain a tan oil (1.06 g).

_{¾-NMR (200MHz, CDC1 3} ): δθ.92 (6Η, d, J = 6.2 Hz), 1.29 (3H, d, J- 6.6 Hz), 1.53 (9H, s), 2.43 (3H, s), 2.99 (2H, m), 3.51 (1H, q, J = 7.0 Hz), 4.95 (1H, s), 7.30 (2H, d, J = 8.2 Hz), 7.88 (2H, d, J = 8.4 Hz), 9.59 (1H, brs). Suspension of the obtained tan oil (1.06 g), acetic anhydride (0.543 ml, 5.64 mmol) and p-TsOH hydrate (358 mg, 1.88 oi) in toluene (20 ml). The solution was stirred at 80 ° C for 50 minutes. The reaction mixture was extracted and purified in the same manner, and oil was obtained. Jethyl ether was added, and the precipitate was collected by filtration, washed with getyl ether and dried to give the title compound (333 mg, 0.693 mmol) as a red-orange powder As obtained.

 Ή-NR (200 MHz, double-mouthed form): δ 0.93 (6Η, d, J = 6.2 Hz), 1.56 (2H, brq, J = 6.7 Hz), 1.66 (1H, sixtet, J = 6.4 Hz), 2.00 (3H, s), 2.41 (3H, s), 2.97 (2H, t, J = 7.6 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.87 (2H, d, J = 8.4 Hz), 10.19 (1H, brs).

Elemental _{analysis: C 20 H 23 N 3 O} 5 S 3 - 0.2Et 2 0 Calculated: C, 50.32; H, 5.08 ; N, 8.46; S, 19.38 (¾), Found; C, 50.35; H , 5.15;, 8.47; S, 19.33 (%). Melting point: 193.0-195.0 ° C

Example 4-465

 N- [8- (Isopentylsulfanyl) -6-methyl-5- (4-morpholinylcarbonyl) -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4 ] Thiazine-1-ylidene] -4-methylbenzenesulfonamide

(Method 1) A suspension of the compound obtained in Example 3-23 (purity 80¾, 0.26 g, 0.45 mmol) and potassium carbonate (93 mg, 0.68 mmol) in DMF (4.0 ml) was stirred at 70 ° C. While adding isopentyl iodide (0.072 ml, 0.54 iiol), the mixture was stirred for 40 minutes. IN hydrochloric acid (0.90 ml) and 0.05N hydrochloric acid (20 ml) were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, ^ and saturated saline, dried over sodium sulfate and concentrated. Getyl ether was added to the residual solid, which was then pulverized. The precipitate was collected by filtration, washed with diethyl ether, and dried to obtain the title compound (235 mg, 0.427 benzyl) as a red powder.

(Method 2) A solution of the compound obtained in Example 4-462 (0.60 g, 1.25 bandol), H0BT (169 mg, 1.25 mmol) and WSC (249 mg, 1.30 mmol) in THF (15 ml) was added at room temperature. Stirred for 4 hours. During this time, WSC (48 mg, 0.25 bandol) was added to the reaction solution twice every hour. The reaction mixture was concentrated, diluted with ethyl acetate, washed with dilute hydrochloric acid, 2% sodium bicarbonate, water and saturated saline, dried over sodium sulfate, and concentrated. Getyl ether was added to the residue, and the precipitate was collected by filtration to obtain a H0BT ester (399 mg, 0.666 tmol) of the compound obtained in Example 4-462 as a dark red solid. To a solution of this dark red solid (399 mg, 0.666 mmol) in THF (8 ml) was added morpholine (0.178 ml, 2.00 ol) at room temperature, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated, diluted with ethyl acetate, washed with dilute hydrochloric acid, 2% sodium bicarbonate, 5% saline and saturated saline, dried over sodium sulfate, and concentrated. The residue was chromatographed on silica gel (10 g) (ethyl acetate-hexane, 2: 8-6: 4). The ethyl acetate-hexane (6: 4) fraction was concentrated and crystallized from getyl ether to give the title compound (47 mg, 0.085 mmol) as a red powder. _{Ή-NMR (200MHz, CDC1 3} ): δ 0.93 (6Η, d, J = 6.2 Hz), 1.56 (2H, brd, J = 7.2 Hz), 1.67 (1H, quint, J = 6.4 Hz), 1.80 (3H , s), 2.43 (3H, s), 2.95 (2H, t, J = 7.7 Hz), 3.49 (2H, m), 3.66 (4H, m), 3.80 (2H, m), 7.30 (2H, d, J = 8.4 Hz), 7.83 (2H, d, J = 8.4 Hz), 9.73 (1H, brs).

Elemental analysis: C ₂₄ H _3. Calculated _{N 4 0 5 S 3: C} , 52.34; H, 5.49;, 10.17; S, 17.47 (%), Found: C, 52.30; H, 5.46 ; N, 10.29; S, 17.35 (%).

Melting point: 199.5-201.5 ° C.

Example 4-466

_{Ή-NMR (200MHz, CDC1 3} ): δ 0.93 (6H, d, J = 6.2 Hz), 1.08 (3H, t, J = 7.5 Hz), 1.61 (3H, m), 1.82 (3H, s), 2.42 (3H, s), 2.78 (2H, q, J = 7.5 Hz), 2.94 (2H, t, J = 7.5 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.86 (2H, d, J = 8.4 Hz), 9.63 (1H, brs).

Melting point: 142.5-143.5 ° C

Example 4-468

 4-Methyl-N- {6-methyl-8-[(2-methylbutyl) sulfanyl] -3-oxo-5-propionyl-2,3-dihydro-1H-imidazo [5, tric] [1,4 ] Thiazine-triylidene} benzene sulfonamide

 A suspension of the compound obtained in Example 3-22 (171 mg, 0.404 mmol) and potassium carbonate (84 mg, 0.606 mol) in DMF (3.0 ml) was stirred at 80 ° C. with stirring. 2-Methylbutane (93 mg, 0.444 ol) was added and the mixture was stirred for 40 minutes. 1N Hydrochloric acid (0.81 ml) and methanol / water (1: 1, 4 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol-water (1: 1) and methanol, and dried to give the title compound (63 mg, 0.128 bandol) as a red-brown powder.

_{Ή-NMR (200MHz, CDC1 3} ) δ 0.92 (3Η, t, J = 7.3 Hz), 1.00 (3H, d, J = 6.6 Hz), 1.17 (3H, t, J = 7.3 Hz), 1.27 (1H, sixtet, J = 7.1 Hz), 1.50 (1H, m), 1.67 (1H, m), 1.76 (3H, s), 2.43 (3H, s), 2.57 (2H, q, J = 7.2 Hz), 2.79 ( 1H, dd, J = 12.4, 7.4 Hz), 2.97 (1H, dd, J = 12.6, 5.8 Hz), 7.30 (2H, d, J = 8.4 Hz), 7.86 (2H, d, J = 8.4 Hz), 9.74 (1H, brs).

Elemental _{analysis: C 22 H 27 N 3 0} 4 S 3 Calculated: C, 53.53; H, 5.51 ; N, 8.51 (%), actual Hakachi: C, 53.48; H, 5.53 ; N, 8.24 (% ).

Example 4-469

 -[8- (Isopentylsulfanyl) -6-methyl-3-oxo-5-propionyl-2,3 dihydro-1H-imidazo [5, tric] [1,4] thiazine-triylidene] -4-methylbenzenesulfonamide

Isopentyl iodide (0.95 g) was added to a suspension of the compound (1.83 g, 4.33 alcohol) obtained in Example 3-22 and potassium carbonate (897 mg, 6.49 mmol) in DMF (30 ml) while stirring at 70 ° C. g, 4.76 mmol) and the mixture was stirred for 40 minutes. Isobentyl iodide (95 mg, 0.433 mmol) was added to the reaction solution, and the mixture was stirred for 30 minutes. 1N Hydrochloric acid (8.7 ml) and methanol / water (1: 1, 20ffll) were added to the reaction solution, and the mixture was stirred at room temperature for 60 minutes. The precipitate is collected by filtration, washed with methanol (1: 1) and methanol, dried and dried The compound (2.04 g, 4.13 mmol) was obtained as a red powder.

_{lH-NMR (200MHz, CDC1 3} ): 6 0.93 (6H, d, J- 6.2 Hz), 1.17 (3H, t, J = 7.3 Hz), 1.57 (2H, brq, J = 7.5 Hz), 1.69 (1H , quint, J = 6.7 Hz), 1.76 (3H, s), 2.43 (3H, s), 2.58 (2H, q, J = 7.2 Hz), 2.97 (2H, t, J = 7.7 Hz), 7.30 (2H , d, J = 8.0 Hz), 7.85 (2H, dt, J = 8.4, 1.8 Hz), 9.74 (1H, brs).

Elemental _{analysis: C 22 H 27 N 3 0} 4 S 3: C, 53.53; H, 5.51; N, 8.51 (%) Found: C, 53.60;

H, 5.67; N, 8.51 (%).

Example 4-472

_{Ή-NMR (CDC1 3, 200} MHz): 6 1.02 (6H, d, J = 6.6 Hz), 1.79 (3H, brs), 1.90 (1H, sept, J = 6.7 Hz), 2.27 (3H, brs), 2.82 (2H, d, J = 7.0 Hz), 7.50 (3H, m), 7.99 (2H, brd, J = 6.2 Hz), 9.64 (1H, m).

Elemental analysis: Calculated for C ₁₈ H _2l N ₃ 0 ₃ S ₃ : C, 51.04; H, 5.00; N, 9.92; S, 22.71 (%), found: C, 50.88; H, 5.16; N, 10.10; S, 22.67 (%).

Example 4-473

N- [8- (Isopentylsulfanyl) -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1- Ilidene] benzenesulfonamide

 A suspension of the compound (243 mg, 0.661 mmol) obtained in Example 3-9 and potassium carbonate (137 mg, 0.992 mol) in DMF (4.0 ml) was stirred at 60 ° C while isopentyl iodide ( 159 mg, 0.794 thigh) and stirred for 1.5 hours. To the reaction solution was added 1N hydrochloric acid (1.32 ml), and the mixture was stirred at room temperature for 30 minutes, and then diluted with methanol-water (1: 1, 10 mi). The precipitate was collected by filtration, washed with methanol / water (1: 1) and methanol, and dried to give the title compound (265 mg, 0.606 mmol) as a grey-red powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 0.93 (6Η, d, J = 6.2 Hz), 1.56 (1H, q, J = 7.1 Hz),

I.60 (1H, brq, J = 6.0 Hz), 1.69 (1H, m), 1.79 (3H, q, J = 1.2 Hz), 2.27 (3H, q, J- 0.8 Hz), 2.95 (2H, brq , J = 7.7 Hz), 7.51 (3H, m), 7.98 (2H, dd, J = 8.4,

1.8 Hz), 9.67 (1H, brs).

Elemental _{analysis: C 19 H 23 N 3 0} 3 S 3 Calculated: C, 52.15; H, 5.30 ; N, 9.60; S, 21.98

(%), Found: C, 51.99; H, 5.06; N, 9.52; S, 21.97 (%).

170.5-172.5t: Example 4-474

 'HNR (CDC 13, 200 MHz): d 1.79 (3H, brs), 2.27 (3H, brs), 2.96 (2H, dd, J = 9.2, 5.6 Hz), 3.19 (2H, dd, J = 8.4, 6.6 Hz), 7.17-32 (5H, m), 7.50 (2H, m), 7.95 (2H, brd, J = 6.6 Hz), 9.65 (1H, brs).

Elemental analysis: Calculated for C ₂₂ H ₂₁ N ₃ 0 ₃ S ₃ : C, 56.03; H, 4.49; N, 8.91; S, 20.40 (%), found: C, 55.84; H, 4.65; N, 8.99; S, 20.30 (%).

Example 4-475

lH- thigh _{(CDC1 3, 200 MHz):} δ 1.02 (6Η, d, J = 6.6 Hz), 1.79 (3H, brs), 1.91 (1H, sept, J = 6.7 Hz), 2.26 (3H, s), 2.81 (3H, s), 2.84 (2H, d, J = 7.0 Hz), 7.30 (2H, m), 7.44 (1H, tm, J = 7.2 Hz), 8.03 (1H, dm, J = 8 Hz), 9.68 (1H, brs).

Elemental _{analysis: C 19 H 23 N 3 0} 3 S 3 Calculated: C, 52.15; H, 5.30 ; N, 9.60; S, 21.98 (%), Found: C, 51.99; H, 5.09 ; N, 9.76; S, 21.98 ().

Example 4-476

丽_{(CDC1 3, 200 MHz):} 6 1.78 (3H, s), 2.26 (3H, brq, J = 0.6 Hz), 2.72 (3H, s), 2.96 (2H, brdd, J = 8.0, 7.0 Hz), 3.21 (2H, dd, J = 8.0, 6.6 Hz), 7.15-34 (7H, m), 7.45 (1H, tm, J = 7.2 Hz), 8.02 (1H, dm, J = 7.4 Hz), 9.66 (1H , brs). Elemental analysis: Calculated for C ₂₃ N ₃ 0 ₃ S ₃ : C, 56.88; H, 4.77; N, 8.65; S, 19.81 (%), found: C, 56.93; H, 4.75; N, 8.91; S, 19.72 (%).

Example 4-477

_{'H-NMR (CDC1 3,} 200 MHz): δ 1.02 (6H, d, J = 6.6 Hz), 1.79 (3H, s), 1.91 (1H, sept, J- 6.8 Hz), 2.27 (3H, s) , 2.41 (3H, s), 2.82 (2H, d, J = 7.0 Hz), 7.36 (2H, m), 7.79 (2H, m), 9.63 (1H, brs).

Elemental _{analysis: C ig H 23 N 3 0} 3 S 3 Calculated: C, 52.15; H, 5.30 ; N, 9.60; S, 21.98 (%), Found: C, 52.02; H, 5.37 ; N, 9.61; S, 21.93 (%).

Example 4-478

N- [8- (Isopentylsulfanyl) -5,6-dimethyl-3-oxo-2,3-dihydrido-1H-imidazo [5, tric] [1,4] thiazine-triylidene ] -3-Methylbenzenesulfonamide The compound obtained in Example 3-25 (258 mg, 0.676 mmol) and potassium carbonate Q40 mg, 1.01 mmol) in DMF (4.0 ml) while stirring at 60 ° C.

(163 rag, 0.812 benzene) was added thereto, followed by stirring for 1.5 hours. 1N Hydrochloric acid (1.35 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes and diluted with methanol-water (1: 1, 10 ml). The precipitate was collected by filtration, washed with methanol / water (1: 1) and methanol, and dried to give the title compound (282 mg, 0.624 bandol) as a dark red powder.

'H-NMR (200MHz, CDC1 3): δ 0.93 (6H, d, J = 6.2 Hz), 1.56 (1H, q, J = 7.0 Hz), 1.60 (1H, brq, J = 6.6 Hz), 1.67 ( 1H, in), 1.79 (3H, q, J = 0.8 Hz), 2.27 (3H, q, J = 1.2 Hz), 2.42 (3H, s), 2.95 (2H, brt, J = 7.7 Hz), 7.37 ( 2H, dd, J = 5.4, 1.4 Hz), 7.77 (2H, m), 9.65 (1H, brs).

Elemental analysis: C _{M 5} N ₃ 0 ₃ S ₃ Calculated: C, 53.09; H, 5.58; N, 9.30; S, 21.30 (%), found: C, 53.16; H, 5.67; N, 9.42 ; S, 21.35 (%),.

Melting point.150.0- 150.8 ° C

Example 4-479

_{'H-NMR (CDC1 3,} 200 MHz): δ 1.79 (3Η, q, J = 1.0 Hz), 2.27 (3H, q, J = 0.6 Hz), 2.42 (3H, s), 2.97 (2H, dd, J = 9.2, 5.6 Hz), 3.18 (2H, dd, J = 9.2, 5.8 Hz), 7.26 (5H, m), 7.36 (2H, m), 7.76 (2H, brs), 9.65 (1H, brs).

Elemental _{analysis: C 23 H 23 N 3 0} 3 S 3 Calculated: C, 56.88; H, 4.77 ; N, 8.65; S, 19.81

(%), Found: C, 56.97; H, 4.99; N, 8.56; S, 19.59 (%).

Example 4-480

_{¾-NMR (CDC1 3, 200} MHz): δ 1.02 (6H, d, J = 6.6 Hz), 1.79 (3H, q, J = 1.2 Hz), 1.91 (1H, quint, J = 6.7 Hz), 2.27 ( 3H, q, J = 1.2 Hz), 2.83 (2H, d, J = 6.6 Hz), 7.15 (2H, t, J = 8.8 Hz), 8.00 (2H, dd, J = 8.8, 4.8 Hz), 9.65 ( 1H, brs).

Elemental analysis: C ₁₈ H _2. Calculated as N ₃ 0 ₃ S ₃ F-1 / 3H ₂ 0: C, 48.30; H, 4.58; N, 9.39; S, 21.49; F, 4.24 (%), found: C, 48.24; H, 4.56 ; N, 9.45; S, 21.65; F, 4.44 (%).

Example 4-481 '

4-Fluoro-N- [8- (isopentylsulfanyl) -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, lc] [l, 4] thiazine Ilidene] benzenesulfonamide To a suspension of the compound obtained in Example 3-35 (340 mg, 0.882 mmol) and carbon dioxide lime Q83 mg (1.32 bunol) in DMF (6.0 ml) was stirred at 60 ° C while isopentyl iodide (60 mg). To the reaction mixture was added 1N hydrochloric acid (1.76 ml), the mixture was stirred at room temperature for 30 minutes, and diluted with methanol / water (1: 1, 10 ml). The product was collected by filtration, washed with methanol / water (1: 1) and methanol, and dried to give the title compound (373 mg, 0.819 mmol) as a red-brown powder.

'H-NMR (200MHz, CDC1 3): δ 0.93 (6Η, d, J = 6.2 Hz), 1.56 (1H, q, J = 7.0 Hz), 1.59 (1H, q, J = 7.0 Hz), 1.66 ( 1H, m), 1.80 (3H, q, J = 1.2 Hz), 2.28 (3H, q, J = 1.0 Hz), 2.95 (2H, brt, J = 7.7 Hz), 7.16 (2H, tt, J = 8.8 , 2.2 Hz), 7.98 (2H, ddt, J = 8.8, 4.8, 2.6 Hz), 9.64 (1H, brs).

Elemental analysis: Calculated for C ₁₉ H ₂₂ N ₃ 0 ₃ S ₃ F: C, 50.09; H, 4.87; N, 9.22; S, 21.11; F, 4.17 (%), found: C, 50.03; H , 4.76; N, 9.21; S, 21.17; F, 4.14 (%)

Example 4-482

_{'H-NMR (CDC1 3,} 200 MHz): δ 1.80 (3H, brq, J = 0.6 Hz), 2.27 (3H, brq, J = 1.2 Hz), 2.97 (2H, brdd, J = 8.0, 6.2 Hz) , 3.20 (2H, dd, J = 8.4, 6.6 Hz), 7.14 (2H, t, J = 8.4 Hz), 7.20 (2H, d, J = 6.2 Hz), 7.29 (3H, m), 7.95 (2H, dd, J = 9.2, 5.2 Hz), 9.60 (1H, brs).

Elemental _{analysis: C 22 H 20 N 3 0} 3 S 3 F Calculated:. C, 53.97; H, 4.12; N, 8.58; S, 19.65; F, 3.88 (%) Found: C, 53.93; H , 3.87; N, 8.49; S, 19.68; F, 3.75 (%).

_{Ή-NMR (CDC1 3, 200} MHz): δ 0.98 (6H, d, J = 6.6 Hz), 1.80 (3H, brs), 1.88 (m, sept, J = 6.6 Hz), 2.30 (3H, s), 2.80 (2H, d, J = 7.0 Hz), 7.41 (1H, m), 7.48 (2H, m), 8.19 (1H, d, J = 7.0 Hz), 9.73 (1H, brs).

Elemental analysis: Calculated as _{C 18 H 20 N 3 0 3} S 3 C1: C, 47.20; H, 4.40; N, 9.17; S, 21.00; Cl, 7.74 (%), Found: C, 46.99; H , 4.25; N, 9.17; S, 20.86; C1, 7.71 (%).

4 Monochrome—N- {5,6-dimethyl-3-oxo-8-[(4,4,5,5,5-pentafluoropentyl) sulfanyl] _2,3-dihydro-1H-imidazo [ 5, 1-c] [1,4] thiazine-1-ylidene Nzensulfonamide

 A suspension of the compound obtained in Example 3-6 (364 nig, 0.906 thigh) and potassium carbonate (188 mg, 1.36 IMOI) in DMF (6 ml) was obtained in Reference Example 5 with stirring at 60 ° C. 4,4,5,5,5-Pentafluoropentyl methanesulfonate (278 mg, 1.09 marl) was added, and the reaction solution was stirred at 60 ° C for 5.5 hours and at room temperature for 3 days. During this time, 4,4,5,5,5-pentanofluorenepentyl methanesulfonate (70 mg, 0.27 mol) was added to the reaction mixture. To the reaction solution was added 1N hydrochloric acid (1.81 ml), diluted with methanol / water (1: 1, 5 ml), and stirred at room temperature for 10 minutes. The precipitate was collected by filtration, washed with methanol / water (1: 1) and methanol, and crystallized from methanol-THF to give the title compound (315 mg, 0.560 mmol) as a red-purple powder.

_{H - NMR (200MHz, CDC1 3} ): δ 1.80 (3H, q, J = 0.8 Hz), 2.05 (2H, m), 2.14 (2H, m), 2.28 (3H, q, J = 0.6 Hz), 3.03 (2H, t, J = 7.1 Hz), 7.47 (2H, d, J = 8.8 Hz), 7.90 (2H, dt, J = 8.8, 1.8 Hz), 9.62 (1H, brs).

Elemental analysis: Calculated as _{C 19 H 17 N 3 0 3} S 3 C1F 7: C, 40.61; H, 3.05; N, 7.48; S, 17.12; C1, 6.31; F, 16.90 (%), Found: C, 40.49; H, 2.78; N, 7.49; S, 17.19; CI, 6.32; F, 17.09 '(%)

 Melting point. 173.5-175.0 ° C

 Example 4-487

_{'H-NMR (CDC1 3,} 200 MHz) :, δ 1.43 (4H, m), 1.55-1.70 (4H, m), 1.79 (3H, q, J = 0.8 Hz), 2.28 (3H, brq, J = 0.8 Hz), 2.96 (2H, t, J = 7.0 Hz), 3.66 (2H, t, J = 6.2 Hz), 7.46 (2H, d, J = 8.8 Hz), 7.91 (2H, d, J = 8.8 Hz) ), 9.66 (1H, brs).

Elemental _{analysis: C 21 H 27 N 3 0} 4 S 3 C1 Calculated: C, 47.84; H, 4.82 ; N, 8.37; S, 19.16; - C1, 7.06 (%), Found: C, 47.51; H, 4.67; N, 8.52; S, 19.23; C1, 6.87 (%). Example 4-488

Ή- testimony _{(CDC1 3, 200 MHz):} δ 1.03 (6Η, d, J = 6.6 Hz), 1.79 (3H, q, J = 1.2 Hz), 1.91 (lH, sept, J = 6.6 Hz), 2.27 ( 3H, q, J = 0.8 Hz), 2.83 (2H, d, J = 7.0 Hz), 7.45 (2H, d, J = 8.8 Hz), 7.92 (2H, d, J = 8.8 Hz), 9.62 (1H, brs). Elemental analysis: Calculated for C ₁₈ H ₂₀ N ₃ 0 ₃ S ₃ C1: C, 47.20; H, 4.40; N, 9.17; S, 21.00; CI, 7.74 (%), Found: C, 47.02; H, 4.29; N, 9.18; S, 20.98; CI, 7.69 (%).

_{Ή-NMR (CDC1 3, 200} MHz): d 1.80 (3H, brs), 2.27 (3H, brs), 2.97 (2H, dd, J = 8.0, 7.0 Hz), 3.20 (2H, dd, J = 8.0, 6.6 Hz), 7.19 (2H, brd, J- 7.6 Hz), 7.29 (3H, brt, J = 7.0 Hz), 7.44 (2H, d, J = 8.8 Hz), 7.87 (2H, d, J = 8.8 Hz) ), 9.62 (m, brs).

Elemental analysis: Calculated for C ₂₀ H ₂₀ N ₃ 0 ₃ S ₃ C1: C, 52.21; H, 3.98; N, 8.30; S, 19.01; C1, 7.01 (%), found: C, 52.25; H , 4.10; N, 8.30; S, 18.87; C1, 6.77 (%)

_{'H-NMR (CDC1 3,} 200 MHz): d 1.02 (6H, d, J = 6.6 Hz), 1.79 (3H, brq, J = 0.8 Hz), 1.91 (1H, sept, J- 6.7 Hz), 2.27 (3H, q, J = 1.0 Hz), 2.82 (2H, d, J = 7.0 Hz), 7.01 (2H, d, J = 8.8 Hz), 7.06 (2H, dm, J = 8 Hz), 7.20 (1H , t, J = 7.2 Hz), 7.40 (2H, t, J = 8.0 Hz), 7.92 (2H, dm, J = 9.2 Hz), 9.60 (1H, brs). Elemental analysis: C ₂₄ H ₂₅ N ₃ 0 ₄ S ₃ calculated: C, 55.90; H, 4.89 ; N, 8.15; S, 18.65

(%), Found: C, 55.78; H, 4.91;, 8.38; S, 18.56 (%).

Example 4-494

Ή- thigh _{(CDC1 3, 200 MHz):} δ 1.80 (3Η, brs), 2.27 (3H, brs), 2.97 (2H, dd, J = 8.4, 7.8 Hz), 3.20 (2H, dd, J = 8.2, 7.0 Hz), 7.00 (2H, d, J = 8.8 Hz), 7.07 (2H, d, J = 7.4 Hz), 7.23 (6H, m), 7.41 (2H, t, J = 8.2 Hz), 7.88 (2H , d, J = 9.2 Hz), 9.61 (1H, brs).

Elemental _{analysis: C 2S H 25 N 3 0} 4 S 3 Calculated: C, 59.66; H, 4.47 ; N, 7.45; S, 17.07

(%), Found: C, 59.43; H, 4.39; N, 7.56; S, 17.05 (%).

Example 4-495

4-N- [8- (cyclooctylsulfanyl) -5,6-dimethyl-3-oxo-2,3-dihydro- 1H-imidazo [5, tric] [1, [Thiazine-triylidene] benzenesulfonamide A suspension of the compound obtained in Example 3-6 (279 mg, 0.694 mmol) and potassium carbonate (144 _mg , 1.04 mmol) in DMF (4.5 ml) was added at 50 ° C. While stirring with bromocyclooctane (178 mg, 0.902 cafe), the mixture was stirred for 44 hours. During the reaction, bromocyclooctane (178 mg, 0.902 mmol) was added three times and potassium carbonate (48 mg, 0.347 mmol) Was added to the reaction twice. The reaction solution was worked up as in Example 4-164 to give the title compound (130 mg, 0.254 mmol) as a purple powder.

¾ over丽_{R (200MHz, CDC1 3):} δ 1.50-1.80 (10H, m), 1.80 (3H, q, J = 0.8 Hz), 2.00 (4H, 111), 2.27 (3H, q, J = 1.2 Hz ), 3.60 (1H, sept, J = 4.7 Hz), 7.46 (2H, dt, J = 8.8, 2.0 Hz), 7.92 (2H, dt, J = 8.8, 2.0 Hz), 9.60 (1H, brs).

Elemental analysis: Calculated for C 2 2 ₆ N ₃ 0 ₃ S ₃ C1: C, 51.60; H, 5.12; N, 8.21; S, 18.78; CI, 6.92 (%),

Found: C, 51.36; H, 4.93; N, 8.27; S, 18.88; C1, 7.03 (%).

Immediate. 177.5-179.5 ° C.

Example 4-496

 4-chloro-N- {8-[(2,2-dimethylbutyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1, 4] thiazine-1-ylidene} benzenesulfonamide

 A suspension of the compound obtained in Example 3-6 (3Q8 mg, 0.766 mmol), 2,2-dimethylbutanol (144 mg, 0.996 mmol) and triphenylphosphine (290 mg, 1.07 mol) in THF (6.0 ml). While stirring at room temperature, getyl azodicarboxylate (hereinafter may be abbreviated as DEAD) (0.178 ml, 1.07 mL) was added dropwise to the solution, and the reaction solution was added at room temperature for 3 hours at 50 ° C. Stirred for 23 hours. The reaction mixture was diluted with ethyl acetate (35 ml), washed with 0.1N hydrochloric acid, water and saturated saline, dried, concentrated and crystallized from methanol to give the title compound (198 mg, 0.407 benzyl) in purple Obtained as a powder.

_{Ή-NMR (200MHz, CDC1 3} ): (50.85 (3H, t, J = 7.5 Hz), 0.97 (6H, s), 1.35 (2H, q, J = 7.5 Hz), 1.79 (3H, brs), 2.27 (3H, brs), 2.89 (2H, s), 7.44 (2H, brd, J = 8.6 Hz), 7.93 (2H, brd, J = 8.4 Hz), 9.58 (1H, brs).

Elemental _{analysis: C 20 H 24 N 3 0} 3 S 3 C1 Calculated: C, 49.42; H, 4.98 ; N, 8.64; S, 19.79; C1, 7.29.

Found: C, 49.20; H, 4.85 .; N, 8.71; S, 19.76; CI, 7.28.

mp. 191.0-193.0 ° C

Example 4-497

4-bromo-N- {8-[(2,2-dimethylbutyl) sulfanyl] -5,6-dimethyl-3-oxo -2,3-dihydro-1H-imidazo [5, 1-c] [1,4] thiazine-1-ylidene} benzenesulfonamide

THF (6.5 ml) of the compound obtained in Example 3-7 (299 mg, 0.670 mmol), 2,2-dimethylbutanol (75 mg, 0.737 tmol) and triphenylphosphine (254 mg, 0.938 mol) DEAD (0.155 ml, 0.938 liter) was added dropwise to the suspension while stirring at room temperature, and the reaction solution was stirred at room temperature for 4 hours and at 50 ° C for 46 hours. The reaction mixture was diluted with ethyl acetate (35 ml), washed with 0.1N hydrochloric acid, water and saturated saline, dried, concentrated and crystallized from methanol to give the title compound (232 mg, 0.438 mmol) as a purple color Obtained as a powder. Ή-丽_{(200MHz, CDC1 3): 60.85} (3H, t, J = 7.3 Hz), 0.98 (6H, s), 1.35 (2H, q, J = 7.5 Hz), 1.80 (3H, s), 2.27 ( 3H, s), 2.89 (2H, s), 7.61 (2H, d, J = 8.8 Hz), 7.85 (2H, d, J = 8.8 Hz), 9.57 (1H, brs).

Elemental analysis: C _2. Calculated for H _M N ₃ 0 ₃ S ₃ Br: C, 45.28; H, 4.56; N, 7.92; S, 18.13; Br, 15.06.

Found: C, 45.22; H, 4.65; N, 7.94; S, 18.15; Br, 14.84.

mp. 198.5-199.5t:

Example 4-498

4-bromo-N _: -[8- (cyclooctylsulfanyl) -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine -Tylidene] benzenesulfonamide A suspension of the compound obtained in Example 3-7 (273 mg, 0.612 ol) and potassium carbonate (169 mg, 1.22 ol) in DMF (4.5 ml) at 50 ° C. While stirring, bromocyclooctane (120 mg, 0.612 mmol) was added, and the mixture was stirred for 29 hours. During the reaction, bromocyclooctane (120 mg, 0.612 mmol) was added twice to the reaction solution. The reaction solution was worked up in the same manner as in Example 4-164 to give the title compound (133 mg, 0.239 mmol) as a purple powder. 'H-NMR (300MHz, CDC1 3): δ 1.50-1.70 (10Η, m), 1.74 (2H, m), 1.81 (3H, q, J = 0.9 Hz), 1.98 (2H, m), 2.27 (3H , q, J = 0.9 Hz), 3.60 (1H, sept, J = 3.6 Hz), 7.62 (2H, dt, J = 8.4, 1.5 Hz), 7.84 (2H, dt, J = 9.0, 2.3 Hz), 9.60 . (1H, brs) elemental _{analysis: C 22 H 26 N 3 0} 3 S 3 Br calculated: C, 47.48; H, 4.71 ; N, 7.55; S, 17.28; Br, 14.36.

Found: C, 47.33; H, 4.57; N, 7.66 ;. S, 17.16; Br, 14.26. mp.176.7-181.0 ° C

Example 4-499

 4_Chloro-N- {8-[(2,2-difluoro-3-methylbutyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihid-1H-imidazo [5,1 -c] [1,4] thiazine-1-ylidene} benzenesulfonamide

 The trifluorome obtained in Reference Example 104 was added to a suspension of the compound obtained in Example 3-6 (298 mg, 0.741 ol) and potassium carbonate (154 mg, 1.11 ol) in DMF (5.0 ml) while stirring at 50. 2,2-Difluoroisopentyl sulfonic acid (purity 60%, 270 mg, 0.741 acetyl) was added in two portions and stirred for 12 hours. 1N Hydrochloric acid (1.48 ml) was added to the reaction solution, diluted with methanol-water (1: 1, 3 ml), and stirred at room temperature for 20 minutes. The precipitate was collected by filtration, washed with methanol-water (1: 1) and methanol, and dried to give the title compound (258 mg, 0.508 bandol) as a purple powder.

_{Ή-NMR (200MHz, CDC1 3} ): 51.05 (6H, d, J = 6.8 Hz), 1.81 (3H, q, J = 0.8 Hz), 2.18 (2H, sept, J = 6.9 Hz), 2.26 (3H, q, J = 0.8 Hz), 3.39 (2H, t, J = 14.8 Hz), 7.47 (2H, dt, J = 8.4, 1.8 Hz), 7.92 (2H, di, J = 8.8, 2.1 Hz), 9.60 ( 1H, brs).

Elemental analysis: C ₁₉ H _2. N ₃ 0 ₃ S ₃ C1F ₂ Calculated: C, 44.92; H, 3.97 ; N, 8.27; S, 18.94; CI, 6.98; F, 7.48.

Found: C, 45.03; H, 3.96; N, 8.27; S, 18.70; CI, 6.93; F, 7.27.

mp.165.7-167.5 ° C

Example 4-500

 4-bromo-N- {8-[(2,2-difluoro-3-methylbutyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene} benzenesulfonamide

50 in a suspension of the compound obtained in Example 3-7 (253 rag, 0.567 ol) and potassium carbonate (118 mg, 0.850 ol) in DMF (4.0 ml). While stirring with C, 2,2-difluoroisopentyl trifluoromethanesulfonate obtained in Reference Example 104 (purity 60%, 206 mg, 0.567 mmol) was added in two portions, and the mixture was stirred for 12 hours. 1N Hydrochloric acid (1.13 ml) was added to the reaction solution, diluted with methanol / water (1: 1, 3 ml), and stirred at room temperature for 20 minutes. Precipitate Was collected by filtration, washed with methanol-one water (1: 1) and methanol, and dried to give the title compound (210 mg, 0.380 mol) as a purple powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.05 (6H, d, J = 6.6 Hz), 1.81 (3H, q, J = 0.8 Hz), 2.18 (2H, sept, J = 6.9 Hz), 2.26 (3H , q, J = 0.8 Hz), 3.39 (2H, t, J = 15.0 Hz), 7.63 (2H, d, J = 8.8 Hz), 7.85 (2H, dt, J = 8.4, 1.8 Hz), 9.66 (1H , brs). Elemental analysis: _{Cl 9} ¾. Calculated for N ₃ 0 ₃ S ₃ BrF ₂ : C, 41.31; H, 3.65; N, 7.61; S, 17.41; Br, 14.46; F, 6.88.

Found: C, 41.43; H, 3.47; N, 7.49; S, 17.26; Br, 14.02; F, 6.82.

mp. 164.5-165.0 ° C

Example 4-501

 N- [5,6-dimethyl-3-oxo-8-[(6,6,7,7,7-pentafluoroheptyl) sulfanyl]-2,3-dihydro-1H-imidazo [5, lc] [1,4] thiazine-1-ylidene] -4-methylbenzenesulfonamide

N- (5,6-Dimethyl-3-oxo-8-sulfanyl-2,3-dihydrone-1H-imidazo [5,1-c] [1,4] thiazine- obtained in Example 3-4 A suspension of 1-ylidene) -4-methylbenzenesulfonamide (300 mg, 0.786 marl ol) and potassium carbonate (163 mg, 1.18 ramol) in N, N-dimethylformamide (5.00 ml) was prepared according to Example 52. A solution of 6,6,7,7,7-pentafluorofuran heptyl ester (268 mg, 0.944 tmol) of methanesulfonate obtained in the above in N, N-dimethylformamide (1.00 ml) was added. After heating the reaction mixture at 80 ° C for 2.5 hours, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (88.7 mg, 20%) as a dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 149-151 ° C.

IR (KBr) V: 3067, 2948, 1742, 1723, 1661, 1618, 1561 cm— ¹ .

_{Ή-NMR (CDC1 3):} 51.43-1.67 (4H, m), 1.67-1.80 (2H, m), 1.79 (3H, d, 1 = 0.9

Hz), 2.03 (2H, heptet, J = 8.4 Hz), 2.27 (3H, d, J-0.9 Hz), 2.42 (3H, s), 2.95

(2H, t, J = 7.5 Hz), 7.29 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.62 (1H, bs).

Elementary analysis: as _{C 22 H 24 N 3 0 3} S 3 F 3 Calculated value (¾): C, 46.39; H, 4.25;, 7.38; S, 16.89.

Found (値): C, 46.33; H, 4.18; N, 7.56; S, 16.94.

Example 4-5Q2'N- [5,6-Dimethyl-3-oxo-8-[(3,3,4,4,4-pentafluorofluorobutyl) sulfanyl] -2,3-dihydro-1Η-imidazo [5, tric] [1,4] thiazine-1-ylidene] -4-methylbenzenesulfonamide

N- (5,6-Dimethyl-3-oxo-8-sulfanyl-2,3-dihidido-1H-imidazo [5,1-c] [1,4] thiazine obtained in Example 3-4- To a suspension of 1-ylidene) -4-methylbenzenesulfonamide (300 mg, 0.786 marl) and potassium carbonate (163 mg, 1.18 mmol) in Ν, Ν-dimethylformamide (5.00 ml) A solution of 1,1,2,2,2-pentafluorobutane (267 mg, 0.944 mmol) in N, N-dimethylformamide (1.00 ml) was added. After heating the reaction mixture at 80 ° C. for 1 hour, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO ₄₎ After the solvent was distilled off under reduced pressure to give the title compound (305 mg, 74¾) was synthesized. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 182-184 ° C.

IR (KBr) V 3235, 2982, 2930, 1759, 1665, 1626, 1566 cm- ¹ .

_{Ή-NMR (CDC1 3):} 51.81 (3H, d, J = l.2 Hz), 2.27 (3H, d, J = 1.2 Hz), 2.34-2.60 (2H, m), 2.43 (3H, s), 3.14 (2H, t, J = 8.6 Hz), 7.30 (2H, d, J = 8.0 Hz), 7.83 (2H, d, J = 8.0 Hz), 9.63 (1H, bs).

Elemental analysis: as C ₁₉ H ₁₆ N ₃ 0 ₃ S ₃ F ₃

Calculated value (¾): C, 43.42; H, 3.07; N, 8.00; S, 18.30.

Found (値): C, 43.16; H, 3.37; N, 7.83; S, 18.35.

Example 4-503

 N- {8-[(2,2-dimethylpentyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine -1-ylidene} -4-methylbenzenesulfonamide ''

A solution of 2,2-dimethylvaleric acid (purity 95%, 7.50 g, 54.7 mmol) and concentrated hydrochloric acid (9.12 ml, 0.109 mol) in methanol (80 ml) was stirred at room temperature for 27 hours. The reaction mixture was neutralized with sodium bicarbonate, and purified by extraction with ethyl acetate. A pale yellow oil of methyl rerylate was obtained. A powder of lithium aluminum hydride (purity 80, 2.59 g, 54.7 bandages 01) was added several times to the obtained solution of methyl 2,2-dimethylvalerate in getyl ether a50 ml while stirring with TC. The mixture was stirred for 4 hours at 0 ° C. Extracted with getyl ether, dried and concentrated to dryness to give 2,2-dimethylpentanol (purity 87, 89¾, 4.85 g, 37.1 mmol). A colorless oil was obtained.

_{Ή-NMR (200MHz, CDC1 3} ): δ 0.87 (6H, s), 0.91 (3H, t, J = 7.5 Hz), 1.23 (2H, m), 1.28 (2H, m), 3.32 (2H, brs) .

 Of the compound (461 mg, 1.21 mmol) obtained in Example 3-4, 2,2-dimethylphenol (189 mg, 1.45 mmol) and triphenylphosphine (457 mg, 1.69 tmol) obtained above. DEAD (0.280 ml, 1.69 mmol) was added dropwise to the suspension of THF (9.0 ml) with stirring at room temperature, and the reaction mixture was stirred at room temperature for 12 hours and 5 (TC for 33 hours. (35 ml), diluted with 0.2 N hydrochloric acid, 0.1 hydrochloric acid, water and saturated saline, dried, concentrated, and diluted with methanol The precipitate was collected by filtration, washed with methanol, and dried. The title compound (313.mg, 0.652 t) was obtained as a purple powder.

'H-NMR (200MHz, CDC1 3): (50.90 (3H, brt, J = 6. Hz), 0.98 (6H, s), 1.27 (4H, brd, J = 3.4 Hz), 1.78 (3H, brs) , 2.26 (3H, s), 2.41 (3H, s), 2.88 (2H, s), 7.27 (2H, d, J = 8.6 Hz), 7.87 (2H, d, J = 8.4 Hz), 9.59 (1H, brs).

Elemental _{analysis: C 22 H 29 N 3 0} 3 S 3 Calculated:. C, 55.09; H, 6.09; N, 8.76; S, 20.05 Found: C, 55.10; H, 6.20 ; N, 8.65; S , 19.86.

mp. 172.0-172.5 ° C

Example 4-504

 4-Buguchi-N- {8-[(2,2-dimethylpentyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [4] thiazine-triylidene} benzenesulfonamide

THF (8.7 ml) of the compound obtained in Example 3-7 (435 mg, 0.975 mmol), 2,2-dimethylpentanol (140 rag, 1.07 mmol) and triphenylphosphine (343 mg, 1.27 mol) DEAD (0.210 ml, 1.27 iraiol) was added dropwise to the suspension at room temperature with stirring, and the reaction solution was stirred at 50 ° C for 35 hours. The reaction mixture was diluted with ethyl acetate (35 ml), washed with 0.1 hydrochloric acid, water and saturated saline, dried, concentrated and diluted with methanol. The precipitate was collected by filtration, washed with methanol, and crystallized from ethyl acetate and getyl ether to give the title compound (249 mg, 0.457 methylol) as a dark purple powder.

_{Ή-NMR (300MHz, CDC1 3} ): 50.91 (3H, m), 0.99 (6H, s), 1.27 (4H, brd, J = 3.6 Hz), 1.79 (3H, q, J = 0.9 Hz), 2.27 ( 3H, q, J = 0.9 Hz), 2.89 (2H, s), 7.61 (2H, dt, J = 8.7, 1.8 Hz), 7.85 (2H, dt, J- 9.0, 2.1 Hz), 9.56 (1H, brs .) elemental _{analysis: C 21 H 26 N 3 0} 3 S 3 Br calculated: C, 46.32; H, 4.81 ;, 7.72; S, 17.67; Br, 14.67.

Found: C, 46.41; H, 4.75; N, 7.71; S, 17.63; Br, 14.57.

mp. 182.0-184.5

Example 4-505

 4-bromo-Ν- {8-[(6-hydroxyhexyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] Thiazine-1-ylidene} benzenesulfonamide

 DMF (18 ml) of the compound obtained in Example 3-7 (1.09 g, 2.43 mmol), 6-node-1-hexanol (671 mg, 2.68 mmol) and potassium carbonate (504 mg, 3.65 mmol) ) Was stirred at 60 ° C for 100 minutes. 1N Hydrochloric acid (4.9 ml) was added to the reaction solution, diluted with water (10 ml), and stirred at room temperature. The precipitate was collected by filtration, washed with methanol-water (1: 1) and methanol, and dried to give the title compound (α.15 g, 2.10 mmol) as a red-purple powder.

Ή-NMR (300 MHz, CDCI ₃ ): δ 1.43 (4Η, m), 1.57 (2H, m), 1.70 (2H, brquint, J = 7.5 Hz), 1.80 (3H, q, J- 0.9 Hz), 2.28 (3H, q, J = 0.9 Hz), 2.95 (2H, t, J = 7.5 Hz), 3.66 (2H, t, J = 6.3 Hz), 7.63 (2H, dt, J = 8.7, 2.0 Hz), 7.83 (2H, dt, J = 9.0, 2.3 Hz), 9.61 (1H, brs).

Elemental _{analysis: C 20 H 24 N 3 0} 4 S 3 Br Calculated: C, 43.95; H, 4.43 ; N, 7.69; S, 17.60; Br, 14.62 (%) · Found: C, 43.90; H , 4.32; N, 7.71; S, 17.54; Br, 14.68 (%).

132.5-134.5 ° C

Example 4-506

N- [5,6-dimethyl-3-oxo-8-[(6,6,6-trifluorohexyl) sulfani ]-2,3-Dihydro_1H-imidazo [5, tric] [1, 4] thiazine-1-ylidene] _4-methylbenzenesulfonamide

N- (5,6-Dimethyl-3-oxo-8-sulfanyl-2,3-dihydrone-1H-imidazo obtained in Example 3-4 [5,1-c] [1,4] To a suspension of thiazine-triylidene) -4-methylbenzenesulfonamide (1.00 g, 2.62 thigh 01) and potassium carbonate (543 mg, 3.93 marauder 01) in Ν, Ν-dimethylformamide (15.0 ml), A solution of methanesulfonic acid 6,6,6-trifluorohexyl ester (737 mg, 3.15 mmol) obtained in Reference Example 56 in N, N-dimethylformamide (5.00 ml) was added. After heating the reaction mixture at 80 ° C for 4 hours, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (958 mg, 70%) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 140-142 ° C. IR (KBr) Seo: 3139, 3063, 2944, 1744, 1728, 1661, 1617, 1559 cm " ¹ .

Ή one _{NMR (CDC1 3): ά 1.40-1.84} (6H, m), 1.78 (3H, s), 1.98-2.18 (2H, ra), 2.26 (3H, s), 2.42 (3H, s), 2.94 ( 2H, t, J = 7.4 Hz), 7.29. (2H, d, J = 8.0 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.62 (1H, bs).

Elementary analysis: as _{C 21 H 24 N 3 0 3} S 3 F 3

Calculated)): C, 48.54; H, 4.66; N, 8.09; S, 18.51.

Found (%): C, 48.35; H, 4.64; N, 8.37; S, 18.36.

Example 4-507

N- {8-[(7-hydroxyheptyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-1 -Vene} -4-Methylbenzenesulfonamide

To a suspension of the compound obtained in Example 3-4 (1.11 g, 2.91 marl ol) and potassium carbonate (603 mg, 4.36 mmol) in DMF (16 ml) was added 7-bromo-1- while stirring at 60 ° C. Heptanol (681 rag, 3.49 mmol) was added in three portions at 30 minute intervals, and the reaction solution was stirred for 100 minutes. 1N Hydrochloric acid (6.4 ml) was added to the reaction solution, diluted with water (10 ml), and stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol / water (1: 1) and methanol, and crystallized from ethyl acetate and getyl ether to give the title compound (998 mg, 2.01 mol) as a red powder. _{Ή-NMR (300MHz, CDC1 3} ): 51.37 (6H, m), 1.60 (2H, m), 1.65 (2H, m), 1.78 (3H, brs), 2.26 (3H, brs), 2.42 (3H, s ), 2.93 (2H, t, J = 7.5 Hz), 3.66 (2H, brt, J = 7.0 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.62 (1H, brs) elemental analysis:. as _{C 22 H 29 N 3 0 4} S 3 -0.2H 2 0

Calculated: C, 52.92; H, 5.94; N, 8.42; S, 19.27 (%).

Found: C, 52.89; H, 5.87; N, 8.33; S, 19.53 (%).

Immediate. 118.0-119.0 ° C

Example 4-508

 N- [5,6-Dimethyl-3-oxo-8-[(5_fluoropentyl) sulfanyl] -2,3-dihydrone-1H-imidazo [5, tric] [1,4] thiazine-1-ylidene ] -4-Methylbenzenesulfone amide

Example 1

N- (5,6-Dimethyl-3-oxo-8-sulfanyl-2,3-dihydro obtained in Example 3-

-1H-imidazo [5, 1-c] [1,4] thiazine-toylidene)-N, N of 4-methylbenzenesulfonamide (1.00 g, 2.62 band01) and potassium carbonate (543 mg, 3.93 mmol) N-N-dimethylformamide (5.00 ml) solution of methanesulfonic acid 5-fluoropentyl ester (579 mg, 3.15 mmol) obtained in Reference Example 60 in a suspension of _dimethylformamide (15.0 ml) Was added. After heating the reaction mixture at 80 ° C for 2 hours, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), and the solvent was distilled off under reduced pressure to give the title compound (1.60 g, 65%) as a dark red crystals. Recrystallization from ethyl acetate-ethyl acetate gave dark red crystals with a melting point of 167-169 ° C.

Example 2

N- (2,3-dihydro-5,6-dimethyl-3-oxo-8-sulfanyl-1H-imidazo [5, lc] [1,4] thiazine-1-) obtained in Example 3-4 To a suspension of (ylidene) -4-methylbenzenesulfonamide (4.00 g, 10.5 ol) and potassium carbonate (2.17 g, 15.7 t ol) in Ν, 2.1-dimethylformamide (75.0 ml), refer to Example 60. A solution of the methanesulfonic acid 5-fluoropentyl ester (2.32 g, 12.6 mmol) obtained in the above in N, N-dimethylformamide (5.00 ml) was added. After heating the reaction mixture at 80 ° C. for 2.5 hours, 1N hydrochloric acid was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent under reduced The residue was evaporated under reduced pressure to give the title compound (3.44 g, 70%) as dark red crystals.

IR (KBr) V: 3243, 3054, 2924, 1728, 1661, 1615, 1557 cm " ¹ .

_{Ή-NMR (CDC1 3):} (51.81 (3H, d, J = 1.2 Hz), 2.27 (3H, d, J = 1.2 Hz), 2.34-2.60 (2H, m), 2.43 (3H, s), 3.14 (2H, t, J = 8.6 Hz), 7.30 (2H, d, J = 8.0 Hz), 7.83 (2H, d, J = 8.0 Hz), 9.63 (1H, bs).

Elemental analysis: as C ₁₉ H ₁₆ N ₃ 0 ₃ S ₃ F ₃

Calculated value (¾): C, 43.42; H, 3.07; N, 8.00; S, 18.30.

Found (%): C, 43.16; H, 3.37; N, 7.83; S, 18.35.

Another way

N- [5,6-Dimethyl-3-oxo-8-[(5-hydroxypentyl) sulfanyl] -2,3-dihydrido-1H-imidazo [5,1-] obtained in Example 4-520 C] [1,] Thiazine-toylidene] -4-methylbutylsulfonamide (3.00 g, 6.41 mmol) in dichloromethane (150 ml) was mixed with dimethylaminosulfur trifluoride (1.33 ml, 9.62 t01) in dichloromethane ( 30.0 ml) The solution was slowly added dropwise at -70 ° C. The reaction mixture - 7 (After stirring 3.5 hours at T, distillation was added under ice cooling saturated sodium hydrogen Natoriumu aqueous issued extracted with dichloromethane extract was washed with water, dried (MgSO _4), the solvent under reduced pressure. Thus, the title compound (3.22 g, ca. 100 °) was obtained as dark red crystals.

Example 4-509

 N- {8-[(4-Fluoro-4-methylpentyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine -Triylidene}-4-methylbenzenesulfonamide

 A suspension of the compound obtained in Example 3-4 (601 mg, 1.58 mol) and potassium carbonate (327 mg, 2.36 mmol) in DMF (10 ml) was obtained in Reference Example 37 while stirring at 60 ° C. 4-Fluoro-4-methylpentyl mesylate (344 mg, 1.73 mmol) was added, and the reaction solution was stirred for 10 hours. 1N Hydrochloric acid (3.5 ml) was added to the reaction solution, diluted with water (5 ml), and stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol / water (1: 1) and methanol, and dried to give the title compound (593 mg, 1.23 mmol) as a purple powder.

_{Ή-NMR (300MHz, CDC1 3} ): 51.32 (3H, s), 1.39 (3H, s), 1.69 (2H, m), 1.76 (2H, m), 1.79 (3H, q, J = 1.2 Hz), 2.27 (3H, q, J = 0.9 Hz), 2.42 (3H, s), 2.96 (2H, ί, J = 7.1 Hz), 7.29 (2H, d, J = 8.1 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.65 (1H, brs).

Elemental analysis: C ₂₁ H ₂₆ N ₃ 0 ₃ S ₃ F · 0.2¾0

Calculated: C, 51.77; H, 5.46; N, 8.62; S, 19.74; F, 3.90 (%).

Found: C, 51.79; H, 5.31 ;, 8.59; S, 19.65; F, 3.57 (%).

mp. 173.0-174.0 ° C

Example 4-510

_4-k-bromo - N- {8- [(4- Furuoro _4 - methyl-pentyl) sulfanyl] -5, 6-dimethyl - 3 - Okiso -2, 3-dihydro - 1H-imidazo [5, Bok c] [ 1,4] thiazine-triylidene} benzenesulfonamide

 A suspension of the compound (502 mg, 1.12 mmol) obtained in Example 3-7 and potassium carbonate (233 mg, 1.69 mmol) in DMF (8 ml) was obtained in Reference Example 37 while stirring at 60 ° C at 60 ° C. 4-Fluoro-4-methylpentyl mesylate (245 mg, 1.24 mmol) was added, and the reaction solution was stirred for 7.5 hours. 1N Hydrochloric acid (2.5 ml) was added to the reaction solution, diluted with water (5 ml) and methanol (5 ml), and stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol-water (1: 1) and methanol, and dried to give the title compound (391 mg, 0.713 mmol) as a purple powder.

_{^ -NMR (300MHz, CDC1 3)} : 51.33 (3H, s), 1.40 (3H, s), 1.69 (2H, m), 1.77 (2H, m), 1.80 (3H, q, J = 1.2 Hz), 2.28 (3H, q, J = 0.9 Hz), 2.98 (2H, t, J = 7.2 Hz), 7.63 (2H, dt, J = 8.7, 2.0 Hz), 7.84 (2H, dt, J = 8.7, 2.1 Hz) ), 9.64 (1H, brs).

Elemental analysis: C _2. H ₂₃ N ₃ 0 ₃ S _{3 As} BrF

Calculated: C, 43.79; H, 4.23; N, 7.66; S, 17.54; Br, 14.57; F, 3.46 (%). Found: C, 43.68; H, 4.15; N, 7.79; S, 17.41; Br. , 14.30; F, 3.39 (%) mp.181.0-181.5t:

Example 4-511

N- {5,6-Dimethyl-8-[(4-methyl-3-pentenyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] Thiazine-1-ylidene}-4-amide A suspension of the compound obtained in Example 3-4 (483 mg, 1.27 ol) and potassium carbonate (262 mg, 1.90 ol) in DMF (8 ml) was stirred at 60 ° C with 4-methyl- 3-Pentenyl mesylate (0.27 g, 1.52 mol) was added, and the reaction solution was stirred for 7.5 hours. 1N Hydrochloric acid (2.8 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol / water (1: 1) and methanol, and dried to give the title compound (412 mg, 0.889 bandol) as a purple powder.

_{Ή-NMR (300MHz, CDC1 3} ): (51.62 (3H, s), 1.71 (3H, s), 1.78 (3H, q, J = 1.2 Hz), 2.26 (3H, q, J = 0.9 Hz), 2.35 (2H, q, J = 7.1 Hz), 2.42 (3H, s), 2.93 (2H, t, J = 7.2 Hz), 5.10 (1H, tt, J = 7.2, 1.4 Hz), 7.25 (2H, d, J = 8.4 Hz), 7.85 (2H, d, J = 8.1 Hz), 9.63 (1H, brs).

Elemental _{analysis: C 2l H 25 N 3 0} 3 S 3 Calculated: C, 54.40; H, 5.43 ; N, 9.06; S, 20.75

(%), Found: C, 54.15; H, 5.43; N, 9.24; S, 20.76 (%).

Example 4-512

tert-butyl 5-[(5,6-dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydrido-1H-imidazo [5,1-c] [1,4] thiazine-8-yl) sulfanyl] pentyl carbamate

 A suspension of the compound obtained in Example 3-4 (2.03 g, 5.32 liolol) and potassium carbonate (1.10 g, 7.98 Hffliol) in DMF (29 ml) was obtained in Reference Example 19 while stirring at 60 ° C. N_Boc-5-aminopentyl mesylate (1.90 g, 5.85 Miol) was added in two portions, and the reaction solution was stirred for 22 hours. 1N Hydrochloric acid (11.7ml) was added to the reaction mixture, diluted with ethyl acetate (200nil), washed with 0.1N hydrochloric acid, water and saturated saline, dried over sodium sulfate, and concentrated to obtain a dark red oil. Was. This was purified by chromatography on silica gel (20 g)-(ethyl acetate-hexane, 3: 7-4: 6), and crystallized from methanol to give the title compound (1.29 g, 2.28 mol) as a red-brown powder.

'H-NMR (300MHz, CDC1 3): (51.45 (9H, s), 1.47 (2H, m), 1.70 (2H, quint, J = 7.5 Hz), 1.79 (3H, q, J = 0.9 Hz), 2.26 (3H, q, J = 1.2 Hz), 2.42 (3H, s), 2.93 (2H, t, J = 7.5 Hz), 3.11 (2H, brq, J = 6.9 Hz), 4.54 (1H, m), 7.29 (2H, d, J = 8.1 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.63 (1H, brs).

Elementary analysis: as _{C 25 H 34 N 4 0 5} S 3 Calculated: C, 52.98; H, 6.05; N, 9.89; S, 16.97 ().

Found: C, 53.09; H, 6.13; N, 10.10; S, 16.78 (%).

mp. 144.0-145.0 ^:

Example 4-513

tert-Butyl 6-[(5,6-dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydrido-1H-imidazo [5,1-c] [1, 4] thiazine-8-yl) sulfanyl] hexylkabamate

 A suspension of the compound obtained in Example 3-4 (2.06 g, 5.39 mol) and potassium carbonate (1.12 g, 8.09 mmol) in DMF (30 ml) was obtained in Reference Example 20 with stirring at 60 ° C. N-Boc-6-amino-to-bexyl bromide (1.88 g, 5.39 benzyl) was added in two portions, and the reaction solution was stirred for 3 hours. 1N Hydrochloric acid (8 ml) was added to the reaction solution, diluted with methanol / water (1: 1, 10 ml), and stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol-water (1: 1) and methanol, and dried to give the title compound (2,60 g, 4.48 pt) as a red powder.

_{Ή-NMR (300MHz, CDC1 3} ): 51.37 (2H, m), 1.45 (9H, s), 1.47 (2H,), 1.68 (2H, quint, J = 7.2 Hz), 1.79 (3H, brs), 2.26 (3H, q, J = 0.9 Hz), 2.42 (3H, s), 2.92 (2H, t, J = 7.5 Hz), 3.11 (2H, brq, J = 6.3 Hz), 4.53 (1H, m), 7.29 (2H, d, J = 8.7 Hz), 7.85 (2H, d, J = 8.1 Hz), 9.63 (1H, brs).

Elementary analysis: as _{C 26 H 36 N 4 0 5} S 3

Calculated: C, 53.77; H, 6.25; N, 9.65; S, 16.56 ().

Found: C, 53.69; H, 6.17; N, 9.85; S, 16.26 ().

mp.136.0-136.5 ° C

Example 4-514

-(5,6-Dimethyl-8-{[(trihexanoyl-4-piridinyl) methyl] sulfanyl} -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [ 1,4] thiazine-triylidene) -4-Example 4-N- (5,6-dimethyl-8-{[(4-piberidinyl) methyl] sulfanyl} -3-oxo-2 obtained in U6 , 3-Dihydrido-1H-imidazo [5,1-c] [1,4] thiazine-trilidene) -4-methylbenzenesulfonamide hydrochloride (152 mg, 0.295 mmol) and n-hexane To a solution of acetic acid (0.0493 ml, 0.354 bandol) in Ν, Ν-dimethylformamide (5.00 ml) was added DEPC (0.0572 ml, 0.354 ml) followed by triethylamine (0.0987 ml, 0.708 ηιπιο1). After stirring the reaction mixture at room temperature for 15 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure to give the title compound (74.9 rag, 44¾) as a dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 183-185 ° C.

IR (KBr) V: 3233, 2930, 2870, 2859, 1759, 1622, 1557 cm ' ¹ .

_{Ή-NMR (CDC1 3):} 50.905 (3H, t, J = 6.6 Hz), 0.980-1.45 (6H, m), 1.45-2.00

(5H, m), 1.79 (3H, d, J = 1.0 Hz), 2.27 (3H, d, J = 0.8 Hz), 2.32 (2H, t, J = 7.4 Hz), 2.43 (3H, s), 2.43 (1H, bt, J = 14.6 Hz), 2.85 (2H, t, J = 6.2 Hz), 2.99

(1H, bt, J = 12.6 Hz), 3.87 (1H, bd, J = 13.2 Hz), 4.66 (1H, bd.J = 12.8 Hz), 7.29

(2H, d, J = 8.0 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.63 (1H, bs).

Elemental analysis: C ₂₇ ¾ ₆ N ₄ 0 ₄ S ₃ 0.3H ₂ 0

Calculated value (%): C, 55.70; H, 6.34; N, 9.62; S, 16.52.

Found (%): C, 55.67; H, 6.15; N, 9.62; 'S, 16.56.

Example 4-515

 NU-[(5,6-Dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydrido-1H-imidazo [5,1-c] [1,4] Thiazine-8-yl) sulfanyl] butyl} hexaneamide

N- (5,6-Dimethyl-3-oxo-8-sulfanyl-2,3-dihidido-1H-imidazo [5, l_c] [1,4] thiazine obtained in Example 3-4 A suspension of (ylidene) -4-methylbenzenesulfonamide (200 mg, 0.524 ol) and potassium carbonate (109 mg, 0.786 mmol) in Ν, Ν-dimethylformamide (3.00 ml) was obtained in Reference Example 63. A solution of the obtained methanesulfonic acid 4-hexanoylaminobutyl ester (209 mg, 0.786 mmol) in N, N-dimethylformamide (1.00 ml) was added. After heating the reaction mixture at 80 ° C. for 3 hours, 1N hydrochloric acid was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to synthesize the title compound (110 mg, 38¾). Recrystallized from ethyl acetate-getyl ether to give a dark red color with a melting point of 118-120 ° C A crystal was obtained.

IR (KBr) v: 3250, 2928, 2859, 1748, 1645, 1615, 1559 cm " ¹ .

Ή-NMR (CDClg): δ 0.894 (3H, t, J = 6.9Hz), 1.22-1.40 (4H, m), 1.50-1.84 (6H, m), 1.78 (3H, d, J = 0.9 Hz), 2.16 (2H, t, J = 7.2 Hz), 2.26 (3H, d, J = 0.9 Hz), 2.42 (3H, s), 2.96 (2H, t, J = 6.9 Hz), 3.28 (2H, q, J -6.3 Hz), 5.52 (1H, bs), 7.29 (2H, d, J = 7.8 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.63 (1H, bs).

Elemental analysis: C ₂₅ H ₃₅ N ₄ 0 ₄ S ₃ · 0.4H ₂ 0

Calculated value (%): C, 53.72; H, 6.46; N, 10.02; S, 17.21.

Found (¾): C, 53.75; H, 6.03; N, 10.19; S, 17.22.

Example 4-516

 N- (4-{(5,6-dimethyl-tolu [[(4-methylphenyl) sulfonyl] iminoto 3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] Thiazine-8-yl) sulfanyl] ethyl} phenyl) hexaneamide

N- (5,6-Dimethyl-3-oxo-8-sulfanyl-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine- obtained in Example 3-4 To a suspension of 1-ylidene) -4-methylbenzenesulfonamide (200 mg, 0.524 mmol) and potassium carbonate (109 mg, 0.786 mmol) in N, N-dimethylformamide (3.00 ml), refer to Reference Example 65. A solution of the obtained methanesulfonate 2- (4-hexanoylaminophenyl) ethyl ester (197 mg, 0.786 mmol) in N, N-dimethylformamide (1.00 ml) was added. After heating the reaction mixture at 80 ° C for 3 hours, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (GS0 _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to synthesize the title compound (48.4 mg, 15¾). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 180-182 ° C.

IR (KBr): 3300, 2955, 2928, 2868, 1732, 1663, 1607, 1559 cm— ¹ .

_{Ή-NMR (CDC1 3):} 0.910 (3H, i, J = 6.6Hz), 1.28-1.43 (4H, m), 1.65-1.82 (2Η, m), 1.78 (3Η, s), 2.26 (3H, s ), 2.35 (2H, t, J = 7.2 Hz), 2.42 (3H, s), 2.92 (2H, t, J = 8.8 Hz), 3.15 (2H, t, J = 8.8 Hz), 7.09 (1H, bs ), 7.14 (2H, d, J = 8.4 Hz), 7.28 (2H, d, J = 8.0 Hz), 7.47 (2H, d, J = 8,8 Hz), 7.82 (2H, d, J = 8.4 Hz) ), 9.60 (1H, bs).

Elemental analysis: C ₂₉ H ₃₄ N ₄ 0 ₄ S ₃ 0.3 H ₂ 0

Calculated value (%): C, 57.65; H, 5.77; N, 9.27; S, 15.92.

Found (値): C, 57.61; H, 5.62; N, 9.30; S, 15.55.

Example 4-518

 N- [2,3-dihydro_5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene] -4 -Fluoro mouth methylbenzene sulfonamide

N- [2,3-Dihydrido-5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-1H-imidazo [5, tric] obtained in Examples 7-8 1,4] Thiazine-1-ylidene] -4-hydroxymethylbenzenesulfonamide (259 mg, 0.554 mmol) in dichloromethane (3.00 ml) solution, dimethylaminosulfur trifluoride (0.114 ml, 0.830 mmol) in dichloromethane (2.00 ml) The solution was slowly added dropwise at -70 ° C. After stirring the reaction mixture at -70 ° C for 20 minutes, a saturated aqueous solution of sodium hydrogen carbonate was added thereto under ice-cooling, and the mixture was extracted with methane. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (30.5 mg, 12%) as a dark red crystals. Acetate Echiru - was recrystallized from Jechiruete Le give a dark red crystals, mp 178- 180 ^D C.

IR (KBr): 3221, 2959, 2934, 2851, 1753, 1663, 1609, 1559 cm—

_{¾-NMR (CDC1 3):} 50.931 (6H, d, J = 6.3Hz), 1.50-1.62 (2H, m), 1.69 (1H, septet, J = 6.9 Hz), 1.79 (3H, d, J = 0.9 Hz), 2.27 (3H, d, J-0.9 Hz), 2.95 (2H, t, J = 7.8 Hz), 4.62 (2HX0.331, s, CI), 5.46 (2HX0.669, d, J = 47.1 Hz) , F), 7.48 (2H X0.669, d, J = 8.4Hz, F), 7.51 (2HX0.331, d, J = 8.7 Hz, CI), 7.96 (2HX0.331, d, J = 8.7 Hz, CI), 8.00 (2HX0.661, d, J = 7.8 Hz), 9.61 (1H, bs).

Elemental analysis: C _2. H ₂₄ N ₃ 0 ₃ S ₃ F (67¾), CI (as 33D

Calculated value (¾): C, 50.56; H, 5.09; N, 8.85; S, 20.25.

Observed value (¾): C, 50.47; H, 4.85; N, 8.78; S, 20.11.

Example 4- 519

6-Methyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-8-[(5,5,6,6,6-pentafluoro) sulfanyl] -2,3-dihydro- 1H-imidazo [5, 1-c] [1,4] thiazine -5_Ethyl carboxylate

 A suspension of the compound obtained in Example 3-21, α.68 g, 3.82 mol) and potassium carbonate (0.792 g, 5.73 mmol) in DMF (25 ml) was stirred at 70 ° C. with iodide 5, 5,6,6,6-Pentafluorohexyl (purity 87, 1.33 g, 3.82 mmol) was added in three portions, and the reaction solution was stirred for 6 hours. 1N Hydrochloric acid (8.4 ml) was added to the reaction solution, diluted with methanol-water (2: 3, 25 ml), and stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol / water (1: 1) and methanol, and dried to give the title compound (2.00 g, 3.26 mmol) as an orange powder.

_{Ή-NMR (200MHz, CDC1 3} ): 51.33 (3H, t, J = 7.1 Hz), 1.72 (4H, m), 1.92 (3H, s), 2.05 (2H, m), 2.43 (3H, s), 2.99 (2H, t, J = 7.0 Hz), 4.33 (2H, q, J = 7.1 Hz), 7.30 (2H, d, J = 8.2 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.70 ( . 1H, brs) elemental _{analysis: C 23 H 24 N 3 0} 5 S 3 F 5 calculated: C, 45.02; H, 3.94 ; N, 6.85; S, 15.68; F, 15.48.

Found: C, 45.13; H, 4.11; N, 6.83; S, 15.74; F, 15.27.

mp. 195.0-196.5 ° C

Example 4-520

 N- [5,6-dimethyl-3-oxo-8-[(5-hydroxypentyl) sulfanyl] -2,3-dihydro-1H-imidazo [5, 1-c] [1,4] thiazine-toylidene ] -4-Methylbenzenesulfonamide

N- (5,6-Dimethyl-3-oxo-8-sulfanyl-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine obtained in Example 3-4 To a suspension of 1-ylidene) -4-methylbenzenesulfonamide (3.00 g, 7.86 tmol) and potassium carbonate (1.63 g, 11.8 mmol) in N, N-dimethylformamide (55.0 ml) was added 5-bromobenzene. A solution of -topentanol (1.58 g, 9.44 mmol) in N, N-dimethylformamide (5.00 ml) was added. After heating the reaction mixture at 80 for 1.5 hours, 1N hydrochloric acid was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (3.04 g, 83%) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 182-184 ° C.

IR (KBr): 3700-2700, 2932, 2863, 1730, 1661, 1615, 1557 cm- ¹ . ^{l H - NMR (CDClg):} (51.44-1.64 (4H, m), 1.67-1.77 (2H, m), 1.79 (3H, d, J = 0.9 Hz), 2.26 (3H, d, J-0.6 Hz) , 2.42 (3H, s), 2.95 (2H, t, J = 7.5 Hz), 3.66 (2H, t, J = 6.3 Hz), 7.29 (2H, d, J = 8.1 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.63 ( 1H, bs) Elementary analysis:. a _{C 2D H 25 N 3 0 4} S 3

Calculated (): C, 51.37; H, 5.39; N, 8.99.

Found (¾): C, 51.33; H, 5.39; N, 8.92.

Example 4-521

Ethyl 5-methyl-tri {[(4-methylphenyl) sulfonyl] imino} -3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -2,3-dihydric -1H-Midazo [5,1-c] [1,4] thiazine-6-carboxylate

Ethyl 5-methyl_1-{[((4-methylphenyl) sulfonyl] iminoto 3_oxo-8-sulfanyl_2,3-dihydro-1H-imidazo [5,1-c] obtained in Example 3-3 Example of a suspension of 1,4] thiazine-6-carboxylate (6.98 g, 16.8 n legs 1) and potassium carbonate (3.48 g, 25.2 thigh 01) in Ν, （-dimethylformamide (100 ml) A solution of methanesulfonic acid 5,5,6,6,6-pentafluorohexyl ester (5.45 g, 20.2 mmol) obtained in 9 in N, N-dimethylformamide (40.0 ml) was added. After heating the reaction mixture at 80 ° C. for 1 hour, 1N hydrochloric acid was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (9.00 g, 87¾) and the obtained as dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 134-136 ° C.

IR (KBr) Re:. 3220, 2984, 2944, 2884, 1748, 1713, 1678, 1622, 1557 cm "1 Ή - thigh _{(CDC1 3): 51.32 (.} 3H, t, J = 7 Hz), 1.64- 1.80 (4H, m), 1.80-2.20 (2H, m), 2.42 (3H, s), 2.75 (3H, s), 3.02 (2H, t, J = 7.0 Hz), 4.26 (2H, q, J = 7.Hz), 7.29 (2H, d, J = 8.4 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.78 (1H, bs).

Elemental analysis: as C ₂₃ H ₂₄ N ₃ 0 ₅ S ₃ F ₅

Calculated value (¾): C, 45.02; H, 3.94; N, 6.85; S, 15.68.

Found (値): C, 45.07; H, 4.05; N, 6.99; S, 15.89.

Example 4-522

Ethyl 5-[(5,6-dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oki So-2,3-dihydro_1H-imidazo [5, 1-c] [1,4] thiazine-8-yl) sulfanyl] pentanoate

N- (5,6-Dimethyl-3-oxo-8-sulfanyl-2,3-dihydrido-1H-imidazo [5,1-c] [1,4] thiazine- obtained in Example 3-4 A suspension of 1-ylidene) -4-methylbenzenesulfonamide (500 mg, 1.31 thigh) and potassium carbonate (272 mg, 1.97 thigh) in N, N-dimethylformamide (5.00 ml) was added to the suspension. A solution of N-N-dimethylformamide (5.00 ml) in -ethyl bromovalerate (259 l, 1.57 t) was added. After heating the reaction mixture at 80 ° C. for 30 minutes, 1N hydrochloric acid was added and extracted with ethyl acetate. Washed with water extract exudates, dried (MgSO _4), was synthesized solvent was distilled off under reduced pressure the title compound (459 rag, 69¾). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 162-164T :.

IR (KBr): 3221, 2980, 2936, 1732, 1663, 1564 cm— ¹ .

_{Ή-NMR (CDC1 3):} 51.27 (3H, t, J = 7.2 Hz), 1.67-1.82 (4Η, m), 1.79 (3Η, d,

J = 1.0Hz), 2.26 (3H, d, J = 1.2Hz), 2.28-2.38 (2H, m), 2.42 (3H, s), 2.88-2.98 (2H, m), 4.14 (2H, q, J = 7.2 Hz), 7.29 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.4

Hz), 9.61 (1H, bs).

Elementary analysis: as _{C 22 H 27 N 3 0 5} S 3

Calculated value (¾): C, 51.85; H, 5.34; N, 8.24.

Found (¾): C, 51.68; H, 5.29; N, 8.16.

Example 4-523

Ethyl 4-[(5,6-dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-1,3-dihydro-1H-imidazo [5,1-c] [1, 4] Thiazine-8-yl) sulfanyl] butane

N- (5,6-Dimethyl-3-oxo-8-sulfanyl-2,3-dihydrido-1H-imidazo [5,1-c] [1,4] thiazine- obtained in Example 3-4 To a suspension of 1-ylidene) -4-methylbenzenesulfonamide (500 mg, 1.31 mmol) and potassium carbonate (272 mg, 1.97 marl) in Ν, Ν-dimethylformamide (5.00 ml) was added 4-bromobenzene. A solution of ethyl butyrate (0.234 ml, 1.57 bandol) in Ν, Ν-dimethylformamide (5.00 ml) was added. After heating the reaction mixture at 80 ° C for 30 minutes, hydrochloric acid was added and extracted with ethyl acetate. Extraction Washing liquid, dried (MgSO _4), the solvent was evaporated under reduced pressure to give the title compound (396 mg, 61¾) was obtained as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with mp 10-142.

IR (KBr) V: 3200, 2976, 2924, 1728, 1661, 1611, 1563 cm " ¹ .

_{Ή-NMR (CDC1 3):} 51.28 (3H, t, J = 7.2 Hz), 1.79 (3H, d, J = 0.6 Hz), 2.00 (2H, quint, J = 7.2 Hz), 2.26 (3H, d, J = l.2 Hz), 2.42 (3H, s), 2.43 (2H, t, J = 6.9 Hz), 3.00 (2H, t, J = 7.5 Hz), 4.15 (2H, q, J-6.9 Hz) , 7.30 (2H, d, J = 7.8 Hz), 7.85 (2H, d, J = 8.1 Hz), 9.61 (1H, bs).

Elemental analysis: C ₂₁ H ₂₅ N ₃ 0 ₅ S ₃

Calculated values): C, 50.89; H, 5.08; N, 8.48; S, 19.71.

Found (¾): C, 50.77; H, 4.93; N, 8.53; S, 19.32.

Example 4-524

 N- {8- [(2-Hydroxixethyl) sulfanyl]-5, 6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, lc] [1,4] thiazine-1- Ilidene}-4-methylbenzenesulfonamide

 To a suspension of the compound obtained in Example 3-4 (1.06 g, 2.79 tmol) and potassium carbonate (558 mg, 4.18 mmol) in DMF (16 ml) was added 2-fluoroethanol while stirring at 50 ° C. (0.265 ml, 3.34 mmol) in DMF (2 ml) was added dropwise over 30 minutes, and the reaction solution was further stirred for 5 hours. During the reaction, 2-MF ethanol (0.200 ml, 2.51 thigh 01) in DMF (2 ml) was added. 1N Hydrochloric acid (5.6 ml) was added to the reaction mixture, and the mixture was diluted with methanolic water (1: 3, 20 ml). The precipitate was collected by filtration, washed with methanol / water (1: 1) and methanol, and suspended in THF (70 ml). The precipitate was collected by filtration, washed with ethyl acetate, and dried to give the title compound (286 mg, 0.672 mmol) as a gray-violet powder. The mother liquor was crystallized from methanol and ethyl acetate to give the title compound (695 mg, 1.63 alcohol) as a grey-violet powder.

'H-NMR (300MHz, DMS0-d ₆ ): δ 1.79 (3Η, s), 2.17 (3H, s), 2.38 (3H, s), 3.07 (2H, t, J = 6.5 Hz), 3.60 (2H , brq, J = 4.2 Hz), 5.11 (1H, brt, J = 3 Hz), 7.37 (2H, d, J = 7.1 Hz), 7.85 (2H, d, J = 8.1 Hz), 11.63 (1H, brs ).

Elementary analysis: as _{C 17 H 19 N 3 0 4} S 3 Calculated: C, 47.98; H, 4.50;, 9.87; S, 22.61 (%).

Found: C, 47.95; H, 4.41; N, 9.77; S, 22.52 (¾) ·

mp. 214.0-216.0 ° C

Example 4-525

4-chloro-N- {8-[(2-hydroxyethyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4 ] Thiazine-1-ylidene} benzenesulfonamide

To a suspension of the compound (1.02 g, 2.54 mmol) obtained in Example 3-6 and potassium carbonate (702 mg, 5.08 mmol) in DMF (15 ml) was added 2_ ethanol (50 ml) while stirring at 50 ° C. A solution of 0.403 ml, 5.08 bandol) in DMF (2 ml) was added dropwise over 30 minutes, and the reaction solution was further stirred for 50 minutes. 1N Hydrochloric acid (8.0 ml) was added to the reaction solution, diluted with methanol / water (1: 2, 15 ml) and stirred for 2 hours. The precipitate was collected by filtration, washed with methanol / water (1: 1) and methanol, and suspended in THF (70 ml). The precipitate was collected by filtration, washed with ethyl acetate, and dried to give the title compound (778 mg, 1.74 mol, 68.7%) as a purple powder. Ή one _{NMR (300MHz, DMS0-d 6} ): δ 1.80 (3Η, s), 2.18 (3H, s), 3.08 (2H, t, J = 6.5 Hz), 3.61 (2H, t, J = 6.3 Hz) , 5.12 (1H, br), 7.65 (2H, d, J = 9.0 Hz), 7.97 (2H, d, J = 9.0 Hz), 11.78 (1H, brs).

Elemental _{analysis: C 16 H 16 N 3 0} 4 as S ₃ C1 'Calculated: C, 43.09; H, 3.62 ; N, 9.42; S, 21.57; C1, 7.95 (¾).

Found: C, 42.78; H, 3.55; N, 9.40; S, 21.67; C1, 7.98 (¾)

Immediately. 207.5-209.0

Example 4-526

 N- (5,6-dimethyl-3-oxo-8-{[2- (methoxyethoxy) methyl] sulfanyl} -2,3-dihydro-1H-imidazo [5,1-c] [1,4 ] Thiazine-1-ylidene) -4-methylbenzenesulfonamide

N- (5,6-Dimethyl-3-oxo-8-sulfanyl-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine- obtained in Example 3-4 Suspension of 1-ylidene) -4-methylbenzenesulfonamide H (200 mg, 0.524 mmol) and Ν, Ν-diisopropylethylamine (0.113 ml, 0.629 mmol) in N, N-dimethylformamide (4.00 ml) Add 2- (methoxyethoxy) to the solution B) Methyl chloride (75.6 mg, 0.577 t ol) was added. After stirring 20 minutes the reaction mixture at room temperature, diluted with acetic acid Echiru, washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (72.7 mg, 30¾) as a dark red crystals . The crystal was recrystallized from ethyl acetate-ethyl ether to give a dark red crystal having a melting point of 91.0-93. (TC.

IR (KBr) V: 3250, 2922, 1744, 1665, 1615, 1564 cm

_{Ή-NMR (CDC1 3):} 61.79 (3H, s), 2.25 (3H, s), 2.42 (3Ή, s), 3.38 (3H, s), 3.54 (2H, t, J = 4.8 Hz), 3.72 ( 2H, t, J = 4.8 Hz), 5.09 (2H, s), 7.29 (2H, d, J = 7.8 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.64 (1H, bs). as _{C 19 H 23 N 3 0 5} S 3: analysis

Calculated value (¾): C, 48.60; H, 4.94; N, 8.95; S, 20.48.

Found (¾): C, 48.24; H, 5.03; N, 8.95; S, 20.38.

Example 4-527

 N- (5,6-Dimethyl-8- {3-[(2-methoxyethoxy) propyl] sulfanyl} -3-oxo-2,3-dihydrogen 1H-imidazo [5,1-c] [ 1,4] thiazine-1-ylidene)-4-methylbenzene benzenesulfonamide

-(5,6-Dimethyl-3-oxo-8-sulfanyl-2,3-dihydrone-1H-imidazo [5, 1-c] [1,4] thiazine obtained in Example 3-4 To a suspension of (ylidene) -4-methylbenzenesulfonamide (200 mg, 0.524 mmol) and potassium carbonate (109 mg, 0.786 mmol) in N, N-dimethylformamide (3.00 ml) was added 3- (2-methoxy). A solution of ethoxy) propyl bromide (124 mg, 0.629 bandol) in N, N-dimethylformamide (1.00 ml) was added. After heating the reaction mixture at 80 ° C. for 15 minutes, 1N hydrochloric acid was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO ₄₎ After the solvent was distilled off under reduced pressure to give the title compound (171 mg, 66¾) was synthesized. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 117-119 ° C.

IR (KBr): 3227, 2921, 2878, 1738, 1663, 1615, 1559 cm " ¹ .

_{¾-NM (CDC1 3):} <51.78 (3H, d, J-1.2 Hz), 1.91-2.03 (2H, m), 2.26 (3H, d, J = 0.9 Hz), 2.42 (3H, s), 3.05 (2H, t, J = 6.9 Hz), 3.39 (3H, s), 3.52-3.60 (6H, m), 7.29 (2H, d, J = 8.1 Hz), 7.85 (2H, d, J = 8. Hz) ), 9.59 (1H, bs).

Elemental analysis: C ₂₁ H ₂₇ N ₃ 0 ₅ S ₃ Calculated value (%): C, 50.68; H, 5.47; N, 8.44; S, 19.33.

Found (¾): C, 50.57; H, 5.61;, 8.56; S, 19.28.

Example 4-528

 N- (5,6-dimethyl-8-{[2- (4-fluorobutoxy) ethyl] sulfanyl} -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4 ] Thiazine-triylidene) -4_methylbenzenesulfonamide

N- (5,6-Dimethyl-3-oxo-8-sulfanyl-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1 obtained in Example 3- Reference Example 81 was added to a suspension of メ チ ル, Ν-dimethylformamide (3.00 ml) of -ylidene) -4-methylbenzenesulfonamide (200 mg, 0.524 mmol) and potassium carbonate (109 mg, 0.786 tmol). A solution of 2- (4-fluorobutoxy) ethyl methanesulfonate (135 ig, 0.629 mmol) obtained in the above in N, N-dimethylformamide (l.OOml) was added. After the reaction mixture was heated at 80 ° C for 30 minutes, 1N hydrochloric acid was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure to give the title compound (59.7 mg, 23¾) as a dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 107-109. ,

IR (KBr) V: 3231, 2950, 2874, 1728, 1661, 1616, 1559 cm ¹ .

_{¾- NMR (CDC1 3): 51.66-1.86} (4H, m), 1.79 (3H, d, J = 0.9 Hz), 2.26 (3H, d, J = 0.9 Hz), 2.42 (3H, s), 3.15 ( 2H, t, J = 6.6Hz), 3.50 (2H, t, J = 6.3Hz), 3.65 (2H, t, J = 6.6Hz), 4.46 (2H, dt, J = 47.4, 6.0Hz), 7.29 ( 2H, d, J = 8.7 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.62 (1H, bs).

Elementary analysis: as _{C 21 H 26 N 3 0 4} S 3 F

Calculated (%): C, 50.48; H, 5.25; N, 8.41; S, 19.25.

Found (¾): C, 50.22; H, 4.81; N, 8.80; S, 19.39.

Example 4- 529

 N- {6-ethyl-8-[(5-fluoropentyl) sulfanyl] -5-methyl-3-oxoV-2,3-dihydro-1H-imidazo [5,1-c] [1, 4] thiazine-triylidene} -4_methylbenzenesulfonamide

N- (6-Ethyl-5-methyl-3-oxo-8-sulfanyl -2,3-obtained in Example 3-5 Dihydro-1H-imidazo [5, l_c] [1,4] thiazin-1-ylidene) -4-methylbenzenesulfonamide (770 mg, 1.96 alcohol) and potassium carbonate (406 mg, 2.93 orchid 01) N, To a suspension of N-dimethylformamide (15.0 ml) was added a solution of 1-promo-5-fluoropentane (364 mg, 2.15 bandol) obtained in Reference Example 61 in N, N-dimethylformamide (5.00 ml). Was. After heating the reaction mixture at 80 t: for 1 hour, 1N hydrochloric acid was added and extracted with ethyl acetate. The obtained extract was washed with water, dried (MgSO _4), solvent was distilled off under reduced pressure the title of compound (967 mg, ca. 100%) as a dark red crystals. Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 156-158 ° C.

IR (KBr): 3218, 2967, 2934, 2868, 1738, 1659, 1617, 1557 cm—

¾ one _{NMR (CDC1 3): 61.09 (} 3H, d, J = 7.6 Hz), 1.50-1.88 (6H, m), 2.14 (2H, q, J = 7.4Hz), 2.26 (3H, s), 2.42 ( 3H, s), 2.96 (2H, i, J = 7.4 Hz), 4.45 (2H, dt, J = 47.2, 6.0 Hz), 7.28 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.0 Hz), 9.62 (1H, bs).

Elementary analysis: as _{C 21 H 26 N 3 0 3} S 3 F

Calculated value (¾): C, 52.15; H, 5.42; N, 8.69; S, 19.89.

Found (¾): C, 51.89; H, 5.41; N, 8.50; S, .19.74.

Example 4-530

 N- {6-butyl-8-[(5-fluoropentyl) sulfanyl] -5-methyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine -1-ylidene methylbenzenesulfonamide

N- (6-Ethyl-5-methyl-3-oxo-8-sulfanyl_2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine- obtained in Example 3-15 A suspension of 1-ylidene) -4-methylbenzenesulfonamide (2.00 g, 4.72 mmol) and potassium carbonate (979 mg, 5.19 band01) in Ν, Ν-dimethylformamide (40.0 ml) was added to Reference Example 61. A solution of tribromo-5-fluoropentane (878 mg, 5.19 bandol) obtained in the above in N, N-dimethylformamide (10.0 ml) was added. After heating the reaction mixture at 80 ° C for 1 hour, 1N hydrochloric acid was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), was synthesized solvent was distilled off under reduced pressure the title of compound a (2.39 g, 99¾). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 170-172 ° C. IR (KBr) v: 3262, 2957, 2934, 2868, 1734, 1657, 1617, 1561 cm one ^1.

_{'H-NMR (CDC1 3)} : δ 0.929 (3H, t, J = 6.9Hz), 1.30-1.62 (6H, m), 1.62-1.72 (4H, m), 2.12 (2H, t, J = 8.1 Hz ), 2.26 (3H, s), 2.42 (3H, s), 2.96 (2H, t, J = 7.5 Hz), 4.45 (2H, dt, J = 47.21, 5.7 Hz), 7.29 (2H, d, J = 8.7 Hz), 7.84 (2H, d, J = 8.1 Hz), 9.62 (1H, bs).

Elemental analysis: C ₂₃ H _3. N ₃ 0 ₃ S ₃ F

Calculated value (%): C, 53.99; H, 5.91; N, 8.21; S, 18.80. 'Actual value (¾): C, 53.85; H, 5.85; N, 8.01; S, 18.71.

Example 4-531

N- (5,6-dimethyl-3_oxo-8-{[5_ (2,2,2-trifluoroethoxy) pentyl] sulfanyl} -2,3-dihydro-m-imidazo [5,1- c] [1,4] Thiazine-1-ylidene) -4-me N- (2,3-dihydro-5,6-dimethyl-3-oxo-8-sulfanyl obtained in Example 3-4 -1H-imidazo [5,1-c] [1,4] thiazine-triylidene) -4-methylbenzenesulfonamide 960 mg, 2.52 maraudal 01) and potassium carbonate (522 mg, 3.77 mmol) N, N- To a suspension of dimethylformamide (15.0 ml) was added 1_bromo-5- (2,2,2_trifluoroethoxy) pentyne (1.57 g, 6.30 mmol) obtained in Reference Example 73 as N, An N-dimethylformamide (5.00 ml) solution was added. After the reaction mixture was heated at 80 ° C for 20 minutes, 1N hydrochloric acid was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (1.01 g, 73%) as a dark red crystals. Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 153-155 ° C.

IR (KBr) V: 3133, 3061, 2936, 1744, 1728, 1661, 1615, 1557 cm—

_{Ή-NMR (CDC1 3):} 51.44-1.84 (6H, m), 1.79 (3H, s), 2.26 (3H, d, J = 0.8 Hz), 2.42 (3H, s), 2.94 (2H, t, J = 7.6 Hz), 3.61 (2H, t, J = 6.2 Hz), 3.81 (2H, q, J = 8.8 Hz), 7.29 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.0 Hz) Hz), 9.62 (1H, bs ) Elementary analysis:. as _{C 22 H 26 N 3 0 4} S 3 F 3

Calculated)): C, 48.07; H, 4.77; N, 7.64; S, 17.50.

Obtained value (%): C, 48.08; H, 4.53; N, 7.59; S, 17.53.

Example 4-532 N- (5,6-dimethyl-3-oxo-8-{[4- (2,2,2-trifluoroethoxy) butyl] sulfanyl} -2,3-dihydro-1H-imidazo [5, c] [1,4] thiazine-1-ylidene) -4-methyl N- (2,3-dihydro_5,6-dimethyl-3-oxo-8-sulfanyl-1H obtained in Example 3-4. Of N-imidazo [5,1-c] [1,4] thiazine-1-ylidene) -4_methylbenzenesulfonamide (1.00 g, 2.62 bandol ol) and potassium carbonate (543 mg, 3.92 bandol ol) To a suspension of N-dimethylformamide (15.0 ml) was added 1-bromo-4- (2,2,2-trifluoroethoxy) butane (1.54 g, 6.55 t ) In N, N-dimethylformamide (5.00 ml) was added. After heating the reaction mixture with for 20 minutes, 1N hydrochloric acid was added and extracted with ethyl acetate. The obtained extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (1.34g, 96¾) as a dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 144-146 ° C. IR (KBr) V: 3229, 2922, 1750, 1719, 1661, 1619, 1561 cm ¹ .

_{Ή-NMR (CDC1 3):} 51.62-1.90 (4H, m), 1.78 (3H, d, J = 1.2 Hz), 2.26 (3H, d, J = 0.8 Hz), 2.42 (3H, s), 2.97 ( 2H, t, J = 6.8Hz), 3.63 (2H, t, J-5.4Hz), 3.81 (2H, q, J = 8.8 Hz), 7.29 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.0 Hz), 9.61 (1H, bs).

Elementary analysis: as _{C 2I H 24 N 3 0 4} S 3 F 3

Calculated value (%): C, 47.09; H, 4.52; N, 7.85; S, 17.96.

Found (%): C, 47.29; H, 4.33; N, 8.06; S, 18.32.

Example 4-533

 N- (5,6-dimethyl-3-oxo-8-{[2- (3-fluoropropoxy) ethyl] sulfanyl} _2,3-dihydro-1H-imidazo [5,1-c] [1 , 4] Thiazine-1-ylidene) -4-methylbenzenesulfonamide

N- (5,6-Dimethyl-3-oxo-8_sulfanyl-2,3-dihydrone-1H-imidazo [5,1-c] [1,4] thiazine obtained in Example 3-4 A reference example was prepared using a suspension of 1-ylidene) -4-methylbenzenesulfonamide (269 mg, 0.706 ol) and potassium carbonate (146 mg, 1.06 mmol) in N, N-dimethylformamide (4.00 ml). N, N-Dimethylmethane-2- (3-fluoropropoxy) ethyl ester (320 mg, 1.77 acetyl) obtained in Step 80 A solution of methylformamide (1.00 ml) was added. After the reaction mixture was heated at 80 for 10 minutes, 1N hydrochloric acid was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (34.7 mg, 10%) as dark red crystals. Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 144-6 ° C.

IR (KBr) V: 3243, 2969, 2928, 2905, 2872, 1748, 1721, 1661, 1615, 1557 cm- Ή-NMR (CDC1 3): 51.79 (3H, d, J = 1.0 Hz), 1.93 (2H , dt, J = 25.6, 6.2 Hz), 2.26 (3H, d, J = 1.2 Hz), 2.42 (3H, s), 3.15 (2H, t, J-6.2 Hz), 3.57 (2H, t, J = 5.8 Hz), 3.66 (2H, t, J = 6.2 Hz), 4.53 (2H, dt, J = 47.4, 6.0 Hz), 7.28 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.62 (1H, bs).

Elemental analysis: C _2. As _{H 24 N 3 0 4 S 3} F

Calculated (¾): C, 49.47; H, 4.98; N, 8.65; S, 19.81.

Found (¾): C, 49.34; H, 4.92; N, 8.63; S, 19.98.

Example 4-534

 N- (5,6-dimethyl-3-oxo_8-{[2- (5-fluoropentyloxy) ethyl] sulfanyl 2,3-dihydro-1H-imidazo [5,1-c] [ 1,4] thiazine-1-ylidene) -4-methylbenzenesulfonamide

N- (5,6-Dimethyl-3-oxo-8-sulfanyl-2,3-dihydrone-1H-imidazo [5,1-c] [1,4] thiazine- obtained in Example 3-4 Example of a suspension of 1-ylidene) -4-methylbenzenesulfonamide (1.00 g, 2.62 benzylol) and potassium carbonate (543 mg, 3.93 melamineol) in N, N-dimethylformamide (15.0 ml). A solution of 2- (5-fluoropentyloxy) ethyl methanesulfonate (898 mg, 3.93 band01) obtained in 82 in N, N-dimethylformamide (5.00 ml) was added. After heating the reaction mixture at 80 ° C. for 1.5 hours, 1N hydrochloric acid was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (1.23 g, 94%) as dark red crystals. The crystals were recrystallized from ethyl acetate-getyl ether to obtain dark red crystals having a melting point of 119-12 °. IR (KBr): 3241, 2940, 2865, 1748, 1721, 1663, 1615, 1559 cm " ¹ .

_{'H-NMR (CDC1 3)} : 61.40-1.80 (6H, m), 1.79 (3H, d, J = 1.2 Hz), 2.26 (3H, d, J = 0.9 Hz), 2.42 (3H, s), 3.14 (2H, t, J = 6.9 Hz), 3.46 (2H, t, J = 6.3 Hz), 3.64 (2H, t, J = 6.6 Hz), 4.45 (2H, dt, J = 47.1, 6.0 Hz), 7.29 (2H, d, J = 7.8 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.62 (1H, bs).

兀素analysis: as _{C 22 H 28 N 3 0 4} S 3 F

Calculated (¾) C, 51.44; H, 5.49; N, 8.18; S, 18.73.

Found (¾) C, 51.30; H, 5.35; N, 8.18; S, 18.93.

Example 4-535

 N- {8-[(4,4-difluorocyclohexyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine -Trident 4-methylbenzenesulfonamide,

 Reference Example 21. A suspension of the compound (2.49 g, 6.53 alcohol) obtained in Example 3-4 and potassium carbonate (1.35 g, 9.79 thigh) in DMF (50 ml) was prepared. A solution of mouth cyclohexane (purity 45%, 4.9 g, 9.0 tol) in DMF (50 ml) was added dropwise at 60 t: over 2 hours, and the reaction solution was stirred for 11 hours. To the reaction solution, 1N hydrochloric acid (13.1 ml), water (15 ml) and methanol (15 ml) were added. The precipitate was collected by filtration, washed with methanol-water (1: 1) and methanol, and dried. The powder (2.14 g) obtained was crystallized from ethyl acetate, washed with ethyl acetate and geethyl ether, and dried. This gave a reddish purple powder (1.35 g). This was crystallized from ethyl acetate-THF to give the title compound (469 mg, 0.939 ol) as a purple powder.

_{Ή-NMR (300MHz, CDC1 3} ): (51.79 (3H, s), 1.84 (2H, m), 2.10 (4H, brq, J = 9.3 Hz), 2.26 (3H, q, J = 1.2 Hz), 2.43 (3H, s), 3.47 (1H, m), 7.30 (2H, d, J = 8.1 Hz), 7.84 (2H, d, J = 8.7 Hz), 9.65 (1H, brs).

Elemental analysis: C ₂₁ H ₂₃ N ₃ 0 ₃ S ₃ F ₂ Calculated: C, 50.48; H, 4.61;, 8.41; S, 19.25; F, 7.61 (%), found: C, 50.55; H , 4.63; N, 8.41; S, 19.34; F, 7.13 (%). Immediately.

Example 4-536

N- {8-[(4,4-Difluorocyclohexyl) methyl] sulfanyl} -5,6 "dimethyl-3- Oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene) -4-methylbenzenesulfonamide

 4,4-Difluoro-1 obtained in Reference Example 22 was added to a suspension of the compound obtained in Example 3-4 (3.31 g, 8.68 IMOI) and potassium carbonate (1.80 g, 13.0 mmol) in DMF (60 ml). A solution of -methylcyclohexane (51% ethyl acetate solution, 5.6 g, 11 R ol) in DMF (5 ml) was added dropwise at 60 ° C over 1.5 hours, and the reaction solution was stirred for 12 hours. To the reaction solution were added 1N hydrochloric acid (19 ml), water (26 ml) and methanol (20 ml), and the mixture was stirred for 1 hour. The precipitate was collected by filtration, washed with methanolic water (1: 1) and methanol, and dried to obtain a magenta powder (4.00 g). This was crystallized from ethyl acetate-THF to give the title compound (0.81 g, 1.58 imnol) as a purple powder.

'H-NM (300MHz, CDC1 3): 51.33 (2H, brq, J = 12.3 Hz), 1.62 (2H, m), 1.74 (1H, m), 1.79 (3H, q, J = 1.2 Hz), 1.92 (2H, brd, J = 13.8 Hz), 2.10 (2H, m), 2.26 (3H, q, J = 0.9 Hz), 2.42 (3H, s), 2.86 (2H, d, J = 6.9 Hz), 7.29 (2H, d, J = 8.7 Hz), 7.85 (2H, d, J = 8.7 Hz), 9.63 (1H, brs).

Elemental _{analysis: C 22 H 25 N 3 0} 3 S 3 F 2 Calculated: C, 51.44; H, 4.91 ; N, 8.18; S, 18.73; F, 7.40 (%), Found: C, 51.63; H, 4.88; N, 8.22; S, 18.77; F, 6.91 (%). Immediately. 207.0-207.5 ° C

Example 4-537 '

 N_ (5,6-Dimethyl-3_oxo-8-{[2- (propoxy) ethyl] sulfanyl chloride 2,3-dihydro-1H-imidazo [5, tri c] [1,4] thiazine-1- (Ylidene) _4-methylbenzenesulfonamide, synthesized in the same manner as in Example 4-533, and recrystallized from ethyl acetate-dimethyl ether to obtain dark red crystals having a melting point of 147-149.

IR (KBr) V:. 3258 , 2963, 2932, 2870, 1748, 1721 ,, 1663, 1611, 1557 cm "1 ¾-NMR (CDC1 3): 50.921 (3H, t,] = 7.2 Hz), 1.53- 1.66 (2H, m), 1.79 (3H, d, J = 0.9 Hz), 2.26 (3H, d, J = l.2 Hz), 2.42 (3H, s), 3.15 (2H, t, J = 6.6 Hz) ), 3.41 (2H, t, J = 6.6 Hz), 3.64 (2H, t, J = 6.3 Hz), 7.27 (2H, d, J = 8.1 Hz), 7.85 (2H, d, J = 8.1 Hz), 9.62 (1H, bs).

Elementary analysis: as _{C 2Q H 25 N 3 0 4} S 3 Calculated value (¾): C, 51.37; H, 5.39; N, 8.94; S, 20.62.

Found (¾): C, 51.09; H, 5.39;, 8.94; S, 20.62.

Example 4-538

 N- [5,6-dimethyl-3_oxo-8 _ ({[4- (tetrahydro-2H-pyran-2_yloxy) cyclohexyl] methyl] sulfanyl) -2,3-dihydro-1H-imidazo [ 5, 1-c] [1,4] thiazin-1-ylidene] -4-methylbenzenesulfonamide

 The cis iodide obtained in Reference Example 23 was stirred in a suspension of the compound obtained in Example 3-4 (3.02 g, 7.92 alcohol) and potassium carbonate (1.64 g, 11.9 mmol) in DMF (45 ml) while stirring. -A solution of 4- (2-tetrahydroviranyl) oxycyclohexylmethyl (2.70 g, 8.33 tmol) in DMF (5 ml) was added dropwise over 90 minutes, and the reaction solution was stirred at 60 ° C for 3.5 hours. During the reaction, iodide (0.257 g, 0.792 mmol) was added twice, and the mixture was further stirred at 40 ° C for 60 hours. 1N Hydrochloric acid (15.8 ml), water (200 ml) and saturated saline (30 ml) were added to the reaction solution, and the mixture was extracted once with ethyl acetate (200 ml). The organic layer was washed with water and saturated saline, dried over sodium sulfate, and concentrated. The residue oil (5.0 g) was chromatographed on silica gel (50 g) (ethyl acetate-hexane, 2: 8-4: 6), and the ethyl acetate-hexane (4: 6) fraction was concentrated. After drying, it was diluted with getyl ether. The precipitate was collected by filtration, washed with diethyl ether, and dried to give the title compound (2.18 g, 3.77 mol, 7.6%) as a red powder. The mother liquor and the washings were concentrated to dryness to give the title compound (1.15 g, 1.99 mL, 25. \%) as a red solid.

_{-NMR (200MHz, CDC1 3):} 51.41 (2H, brq, J = 8.0 Hz), 1.5-1.7 (10H, m), 1.70 (1H, m), 1.79 (3H, brq, J = 0.6 Hz), 1.84 (2H, m), 2.26 (3H, s), 2.41 (3H, s), 2.86 (2H, d, J = 5.8 Hz), 3.49 (1H, dt, J = 11.0, 4.7 Hz), 3.88 (2H, m), 4.64 (1H, brs), 7.28 (2H, d, J-8.4 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.63 (1H, brs).

Elemental analysis: C ₂₇と し て₅ N ₃ 0 ₅ S ₃ Calculated: C, 56.13; H, 6.11; N, 7.27; S, 16.65 (%), found (%): C, 56.15; H, 6.12 ; N, 7.41; S, 16.64.

mp.144.5-146.5 ° C

Example 4-540

Acetic acid 5-[(5,6-dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo -I, 3-Dihydrido-1H-imidazo [5, 1-c] [1,] thiazin-8-yl) sulfanyl] cyclooctyl

 In Reference Example 24, a suspension of the compound obtained in Example 3-4 (566 mg, 1.48 tmol) and potassium carbonate (0.41 g, 2.97 benzene 01) in DMF (9 ml) was stirred at 80 ° C. A solution of the obtained cis_5-acetoxycyclooctyl iodide (0.81 g, 1.6 mol) in DMF (5 ml) was added dropwise over 90 minutes, and the reaction solution was further stirred for 1.5 hours. To the reaction solution were added 1N hydrochloric acid (3.5 ml), 0.1 IN hydrochloric acid (15 ml), water (10 ml) and saturated saline (5 ml), and the mixture was extracted with ethyl acetate (40 ml). The organic layer was washed with 5%, 15% and saturated saline, dried over sodium sulfate, and concentrated. The residue was subjected to chromatography on silica gel (10 g)-(ethyl acetate-hexane, 2: 8-4: 6), and the ethyl acetate-hexane (4: 6) fraction was concentrated to dryness. And diluted with methanol. The precipitate was collected by filtration, washed with methanol, and dried to give the title compound (457 mg, 0.831 ol, 56.2%) as a red-brown powder.

_{Ή-NMR (300MHz, CDC1 3} ): ά 1.65-1.90 (10Η, m), 1.80 (3H, s), 2.03 (3H, s), 2.03 (2H, m), 2.26 (3H, q, J = 0.8 Hz), 2.42 (3H, s), 3.53 (1H, m), 4.88 (1H, m), 7.28 (2H, dd, J = 8.0, 1.8 Hz), 7.85 (2H, d, J = 8.0 Hz), . 9.63 (1H, brs) elemental analysis: as _{C 25 H 31 N 3 0 5} S 3: C, 54.62; H, 5.68; N, 7.64; S, 17.50 (%), calculated: C, 54.55; H , 5.86; N, 7.60; S, 17.59 (%).

mp. 158.0-159.5t

Example 4-541

N- (5,6-dimethyl-3-oxo-8-{[2- (propoxy) ethyl] sulfanyl chloride 2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine- 1-ylidene) -4-methylbenzenesulfonamide

 Synthesized in the same manner as in Example 4-533.

Infrared absorption spectrum (IR) (in KBr) V: 3228, 2961, 2928, 2870, 1721, 1661, 1611, 1557 cnr ¹ .

_{Ή-NMR (CDC1 3):} . Δ 0.923 (3Η, d, J = 7.5 Hz), 1.30-1.44 (2H, m), 1.50-1.62 (2H, m), 1.79 (3H, d, J = 0.9 Hz ), 2.26 (3H, d, J = 1.2 Hz), 2.42 (3H, s), 3.15 (2H, t, J = 6.6 Hz), 3.45 (2H, t, J = 6.6 Hz), 3.63. (2H, t, J = 6.9 Hz), 7.28 (2H, d, J = 8.0 Hz), 7.84 (2H, d, J = 7.8 Hz), 9.61 (1H, bs). Example 4-542

Ethyl 5-[(6-hexyl-5-methyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-3H-imidazo [5,1-c] [1,4] thiazine- 8-yl) sulfanyl] pen evening noate

N- (6-Hexyl-5-methyl-3-oxo-8-sulfanyl-2,3-dihydro-1H-imidazo [5, tric] [1, 4,] thiazine obtained in Example 3-17 -Tolylidene) -4_methylbenzenebenzenesulfonamide (600 mg, 1.33 liters) and potassium carbonate (275 mg, 1.99 mmol) in N, N-dimethylformamide (12.0 ml) were suspended in Ethylester sterate (0.257 ml, 1.59 ol) was added. After heating the reaction mixture at 80 for 1.5 hours, 1N hydrochloric acid was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (639 mg, 83%) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 110-11 ° C. IR (KBr) V: 3212, 2957, 2928, 2857, 1732, 1657, 1615, 1563 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 0.892 (3Η, t, J = 7.2Hz), 1.27 (. 3H, t, J = 7 Hz), 1.20-1.38 (6H, m), 1.38-1.54 (2H, m ), 1.65-1.82 (4H, m), 2.11 (2H, t, J = 8.2 Hz), 2.26 (3H, s), 2.33 (2H, t, J = 6.8 Hz), 2.41 (3H, s), 2.95 (2H, t, J = 6.8 Hz), 4.14 (2H, q, J = 7.2 Hz), 7.29 (2H, d, J = 8.0 Hz), 7.84 (2H, d, J = 8.0 Hz), 9.60 (1H , Bs).

Elementary analysis: as _{C 27 H 37 N 3 0 5} S 3

Calculated value (%): C, 55.93; H, 6.43; N, 7.25; S, 16.59.

Found (%): C, 55.82; H, 6.70; N, 7.28; S, 16.71.

Example 4-543

Ethyl 5-[(6-benzyl-5-methyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-3H-imidazo [5,1-c] [1,4] thiazine-8 -Ill) Sulfanyl] Pen Evening Noate

N- (6-benzyl-5-methyl-3-oxo-8-sulfanyl-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine obtained in Example 3-19 A suspension of 1-ylidene) -4_methylbenzenebenzenesulfonamide (600 mg, 1.31 acetylol) and potassium carbonate (272 mg, 1.97 thiol) in N, N-dimethylformamide (12.0 ml) was added to the suspension. Promoter valeric acid Stell (0.254 ml, 1.57 mmol) was added. After heating the reaction mixture at 80 ° C for 1.5 hours, 1N hydrochloric acid was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (567 mg, 74%) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 108-110 ° C. IR (KBr) V: 3270, 2930, 1732, 1657, 1617, 1559 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 1.25 (3Η, t, J = 7.4Hz), 1.59-1.72 (4H, m), 2.22-2.30 (2H, m), 2.37 (3H, s), 2.42 (3H, s), 2.79-2.90 (2H, m), 3.50 (2H, s), 4.12 (2H, q, J = 7.4 Hz), 7.18-7.38 (7H, m), 7.84 (2H, d, J = 8.0 Hz ), 9.65 (1H, bs). Elemental analysis: C ₂₈ H ₃₁ N ₃ 0 ₅ S ₃

Calculated (%): C, 57.41; H, 5.33; N, 7.17; S, 16.42.

Found (¾): C, 57.20; H, 5.18; N, 7.31; S, 16.45.

Example 4-545

 (2S) -4-[(5,6_Dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydrido-1H-imidazo [5,1-c] [ 1, 4] thiazin-8-yl) sulfael]-1-tert-butyl 2-methyl 1,2-piperidinedicarboxylate

 In Reference Example 35, a suspension of the compound obtained in Example 3-4 (1.00 g, 2.62 ol) and potassium carbonate (543 mg, 3.93 ol) in DMF (17 ml) was stirred at 60 ° C. The obtained (2S) -N-Boc-4-ode-L-proline methyl ester (purity 80%, 1.29 g, 2.90 mmol) was added, and the reaction solution was stirred for 4 hours. 1N Hydrochloric acid (5.3 ml), water (15 ml) and 5% saline (100 ml) were added to the reaction solution, and the mixture was extracted with ethyl acetate (70 ml). The organic layer was washed successively with 5% and saturated saline, dried over sodium sulfate, and concentrated to give a dark red oil. This was subjected to silica gel (20 g) chromatography (ethyl acetate-hexane, 2: 8-5: 5), and the ethyl acetate-hexane (4: 6-5: 5) fraction was concentrated to dryness. Diluted with ethyl ether. The precipitate was collected by filtration, washed with getyl ether, and dried to give the title compound (947 mg, 1.56 mmol, 59.3%) as a red powder.

_{Ή-NMR (300MHz, CDC1 3} ): δ 1.42 (6Η, s), 1.48 (3H, s), 1.78 / 1.80 (3H, s), 2.09 (1H, dt, J = 13.5, 7.2 Hz), 2.26 ( 3H, s), 2.37 (1H, brdd, J = 15.6, 7.5 Hz), 2.43 (3H, s), 2.74 (1H, dt, J = 13.2, 7.8 Hz), 3.41 (1H, dd, J = 11.1, 7.5 Hz), 3.75 / 3.76 (3H, s), 3.85 / 3.95 (1H, q, J = 7.9 / 9.6 Hz), 4.09 / 4.01 (1H, dd, J = 12.6, 8.7 Hz), 4.30 / 4.38 (1H, t / m, J = 7.7 Hz), 7.31 (2H, d, J = 8.1 Hz), 7.83 (2H, d, J = 8.1 Hz), 9.64 (1H, brs).

Elemental analysis: Calculated as _{C 26 H 32 N 4 0 7} S 3: C, 51.30; H, 5.30; N, 9.20; S, 15.80 (%), Found: C, 51.21; H, 5.19 ;, 9.06 S, 15.51 ().

mp.140.0-140.5 ° C

Example 4-546

 (2S, 4S)-2-{[(5,6-dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo [5,1 -c] [1,4] thiazin-8-yl) sulfanyl] methyl} -4_fluoro mouth tert-butyl 1-pyrrolidinecarbonate

 Compound obtained in Example 3-4 (0.89 g, 2.33 mmol), obtained in Reference Example 25

A suspension of the crude material (1.00 g) of (2S, 4S) -N-Boc-4-fluoro-2-iodomethylpyrrolidine and potassium carbonate (0.48 g, 3.5 mmol) in DMF (15 ml) was prepared. Stirred at ° C for 6 days. 1N Hydrochloric acid (4.7 ml), water (60 ml) and saturated saline (20 ml) were added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml and 70 ml). The organic layer was washed successively with 2% sodium carbonate, 2% aqueous sodium hydrogen carbonate solution, 5¾ and saturated brine, dried over sodium sulfate, and concentrated to obtain a dark red oil. This was purified by chromatography on silica gel (20 g) (ethyl acetate-hexane, 2: 8-4: 6), and the resulting red oil was crystallized from ethyl acetate-ethyl acetate-terdiisopropyl ether. The title compound (177 mg, 0.303 bandol, 9.5%) was obtained as a red powder.

'H-NMR (200MHz, CDC1 3): δΐ.48 (9Η, s), 1.79 (3H, s), 2.20-2.50 (2H, m), 2.25 (3H, s), 2.42 (3H, s), 2.92 (1H, dd, J = 13.0, 10.2 Hz), 3.50 (1H, in), 3.62 (1H, m), 3,68 (1H, brd, J = 27.8 Hz), 4.10 (1H, m), 5.20 (1H, brd, J = 52.0 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.63 (1H, brs). Elemental analysis: C ₂₅ H ₃₁ N ₄ 0 ₅ S ₃ F calculated: C, 51.53; H, 5.36 ; N, 9.61; S, 16.51; F, 3.26 (%), Found: C, 51.52; H, 5.40 ; N, 9.75; S , 16.26; F, 3.12 (%). Immediately. 132.5-135.5 ° C

Example 4-547

N- {8-[(5,5-difluorocyclooctyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4 ] Thiazine-1-yl 4-methylbenze Sulfonic acid

 Suspension of 5,5-difluorocyclooctyl tosylate (purity 85%, 0.48 g, 1.28 tmol) and sodium iodide (576 mg, 3.84 l) obtained in Reference Example 26 in acetone (10 ml) The liquid was heated to reflux for 3 hours. The reaction solution was extracted with diisopropyl ether-hexane to obtain a crude substance of 5,5-difluoro-1-hydroxycyclooctane as a brown oil. A suspension of the obtained oil, the compound obtained in Example 3-4 (488 mg, 1.28 mmol) and potassium carbonate (265 mg, 1.92 ol) in DMF (8 ml) was stirred at room temperature for 30 minutes. Then, the mixture was stirred for 6 hours with TC. 10TC saline was added to the reaction solution, and extracted with ethyl acetate (50 mi and 20 ml) .The organic layer was washed twice with 2% sodium carbonate, 0.1N hydrochloric acid, Washed sequentially with ^ and saturated brine, dried over sodium sulfate and concentrated to give a dark red oil which was crystallized from methanol to give the title compound (236 mg, 0.447 mmol, 34.9%) as a dark purple color Obtained as a powder.

Ή—band R (200MHz, CDCI ₃ ): (51.75 (6H, m), 1.80 (3H, q, J = 0.8 Hz), 2.00-2.20 (6H, m), 2.26 (3H, q, J = 1.2 Hz) ), 2.42 (3H, s), 3.54 (1H,), 7.29 (2H, d, J = 8.6 Hz), 7.84 (2H, d, J = 8.6 Hz), 9.64 (1H, brs).

Elemental analysis: calculated as C ₂₃ H ₂₇ N ₃ 0 ₃ S ₃ F ₂ : C, 52.35; H, 5.16; N, 7.96; S, 18.23; F, 7.20 (%), found: C, 52.43; H , 5.17; N, 8.01; S, 18.28; F, 7.03 (). Immediately. 169.0-170.5 ° C

Example 4-548.

N- {5,6-Dimethyl-3-oxo-8-[(5-oxo-cyclohexyl) sulfanyl] -2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine- 1-ylidene} -4-methylbenzenesulfonamide

A suspension of 5-oxocyclooctyl tosylate (purity 70%, 0.48 g, 1.13 mmol) and sodium iodide (0.51 g, 3.40 mmol) in acetone (10 ml) obtained in Reference Example 26 was heated for 5.5 hours. Refluxed. The reaction solution was extracted with diisopropyl ether to obtain a crude 5-oxo-1-hydroxycyclooctane as a brown oil. A suspension of the obtained oil, the compound obtained in Example 3-4 (0.43 g, 1.13 bandol) and carbonated rim (234 mg, 1.70 mmol) in DMF (7 ml) was added at room temperature for 10 minutes. Then, the mixture was stirred at 50 for 12 hours and further at 60 ° C for 24 hours. Add 1N hydrochloric acid (2.3 ml) and methanol Lou water (1: 1, 20 ml) was added and the mixture was stirred at room temperature, and the deposited precipitate was separated from the supernatant and washed with methanol-water (1: 1). The obtained oil was dissolved in THF-acetonitrile-ethyl acetate and concentrated, and methanol was added to the residue. The precipitate was collected by filtration, washed with methanol, and dried to give the title compound (230 mg, 0.455 orchid ol, 40.3%) as a red-purple powder. ,

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.80 (3Η, q, J = 1.0 Hz), 1.85-2.10 (8H, m), 2.25 (3H, q, J = 1.0 Hz), 2.32 (2H, dd, J = 13.2, 8.8 Hz), 2.42 (3H, s), 2.61 (2H, ddd, J = 13.2, 8.4, 3.0 Hz), 3.13 (1H, tin, J = 8.6 Hz), 7.28 (2H, d, J = 8.0 Hz), 7.83 (2H, d, J = 8.0 Hz), 9.61 (1H, brs).

. Elemental _{analysis: C 23 H 27 N 3 0} 4 S 3 H 2 0 Calculated: G, 52.75; H, 5.58 ; N, 8.02; S, 18.37 (%), Found: C, 52.73; H, 5.61; N, 8.17; S, 18.76 (%)

Example 4-549

Acetic acid ((5R, 7S) -3-{[(5,6-dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo [5, 1-c] [1,4] thiazin-8-yl) sulfanyl] methyl} tris [[3.1.1.1.1-3,7Ίdec_1-yl) methyl

 The compound obtained in Example 3-4 (3.02 g, 7.92 mol), 3-iodomethyl adamantan-1-methyl acetate obtained in Reference Example 27 (762 nig, 2.19 mmol) and potassium carbonate (434 mg, 3.14 mmol) A suspension of TMF (13 ml) in DMF (13 ml) was stirred at room temperature for 30 minutes and then at 70 ° C for 24 hours. 1N Hydrochloric acid (4.1 ml) and methanol / water (1: 1, 12 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol-water (1: 1) and methanol, and dried to give the title compound (647 mg, 1.08 bandol, 51.4 «) as a red-purple powder.

_{¾-NMR (300MHz, CDC1 3} ): (51.35 (2H, brs), 1.46 (2H, brs), 1.50 (2H, brs), 1.56 (4H, brs), 1.58 (2H, m), 1.78 (3H, s), 2.06 (3H, s), 2.10 (2H, m), 2.26 (3H, q, J- 0.9 Hz), 2.41 (3H, s), 2.80 (2H, s), 3.70 (2H, s), 7.26 (2H, d, J = 8.1 Hz), 7.86 (2H, d, J = 8.1 Hz), 9.56 (1H, brs).

Elemental _{analysis: C 29 H 35 N 3 0} 5 S 3 .0.5 0 Calculated: C, 57.02; H, 5.94 ;, 6.88; S, 15.75 '(%), Found: C, 56.84; H, 5.95 ; N, 6.88; S, 15.66 ().

Immediate. 171.0- 172.0 ° C Example 4-550

Acetic acid (3-{[(5,6-dimethyl-to {[(4-methylphenyl) sulfonyl] iminoto 3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine -8-yl) sulfanyl] methyl} A suspension of the compound obtained in Example 3-4 (1.45 g, 3.80 ol) and potassium carbonate (788 mg, 5.70 mmol) in DMF (20 ml) was added at 70 ° C. Then, a solution of xanthromethyl acetate (1.24 g, 4.18 mmol) in DMF (5 ml) was added dropwise to the mouth of 3-hydroxymethylcycline obtained in Reference Example 28 over 20 minutes, and the reaction solution was stirred at 70 for 3 hours. 1N Hydrochloric acid (7.6 ml) and methanol / water (1: 1, 20 ml) were added to the reaction mixture, and the precipitate was collected by filtration, washed with methanol / water (1: 1) and methanol, and dried. The title compound (1.71 g, 3.11 mmol, 81.9%) was obtained as a red-purple powder.

'H-NMR (300MHz, CDC1 3): (50.90 / 0.71 (2H, brq / q, J = 12.6 / 12.3 Hz), 1.29 / 1.49 (2H, brq / m, J = 12.6Hz), 1.63 (2H, m), 1.75 / 1.86 (2H, m), 1.79 (3H, s), 1.92 / 1.88 (2H, m), 2.06 / 2.05 (3H, s), 2.26 (3H, s), 2.41 (3H, s) , 2.83 / 2.89 (2H, d, J = 6.9 Hz), 3.89 / 3.96 (2H, d, J = 6.3 / 6.9 Hz), 7.26 (2H, d, J = 8.4 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.60 (1H, brs).

Elemental _{analysis: C 25 H 31 N 3 0} 5 S 3 Calculated: C, 54.62; H, 5.68 ; N, 7.64; S, 17.50

(%), Found: C, 54.51; H, 5.54; N, 7.60; S, 17.43 (%).

Immediately. 163.5-166.0 ° C

Example 4-551

 N- [8-({[3- (Fluoromethyl) cyclohexyl] methyl} sulfanyl) -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [ 1, 4] thiazine-1-ylidene] _4-methylbenzenesulfonamide

A suspension of acetone (4 ml) of 3-fluoromethylcyclohexane-1-methyltosylate (170 mg, 0.566 mmol) and sodium iodide (254 mg, 1.70 mmol) obtained in Reference Example 29 was added to 17 Heated to reflux for an hour. The reaction solution was extracted with diisopropyl ether, concentrated to dryness, and dried to obtain 3-fluoromethylcyclohexane-1-methyl iodide (about 140 mg) as a colorless oil. A suspension of this oil, the compound obtained in Example 3-4 (200 mg, 0.524 ol) and potassium carbonate (109 mg, 0.786 ol) in DMF (4 ml) Was stirred at room temperature for 10 minutes and then at 40 at 3.5 days. The reaction solution was diluted with 1N hydrochloric acid (1.05 ml), and then added with methanol / water (1: 1, 5 ml) and stirred at room temperature for 60 minutes. The precipitate was collected by filtration, washed with methanol / water (1: 1) and methanol, and dried to give the title compound (230 ing, 0.451 ol, 86.1%) as a red powder.

_{Ή-NMR (300MHz, CDC1 3} ): 50.96 / 0.75 (2H, qm / q, J = 12.8 / 12.6 Hz), 1.34 (2H, m), 1.62 (2H, m), 1.75-2.00 (4H, m) , 1.79 (3H, s), 2.26 (3H, s), 2.41 (3H, s), 2.84 / 2.91 (2H, d, J = 6.6 / 7.0 Hz), 4.24 / 4.28 (2H, ddd / dd, 1 = 47.6, 5.8, 2.6 / 47.2, 7.4 Hz), 7.28 (2H, d, J = 8.0 Hz), 7.86 (2H, d, J = 8.0 Hz), 9.61 (1H, brs).

Elemental _{analysis: C 23 H 28 N 3 0} 3 S 3 F Calculated: C, 54.20; H, 5.54 ; N, 8.24; S, 18.87; F, 3.73 {%), Found: C, 54.16; H , 5.66; N, 8.39; S, 18.79; F, 3.95 (%) mp. 172.5-173.5 ° C

Example 4-552

Acetic acid 5-[(5,6-dimethyl-1 _ {[(4-methylphenyl) sulfonyl] imino}-3-oxo-2,3-dihydrido-1H-imidazo [5,1-c] [1, [Thiazine-8-yl) sulfanyl]-3,3-Dimethylpentyl

 Compound obtained in Example 3-4 (1.81 g, 4.75 g ol), 5-Eodo-3,3-dimethylpentyl acetate obtained in Reference Example 30 (purity 90%, 1.50 g, 4.75 gall ol) and potassium carbonate A suspension of (985 mg, 7.13 mmol) in DMF (30 ml) was stirred at room temperature for 30 minutes and then at 30 ° C. for 2.5 days. The reaction mixture was diluted with 1N hydrochloric acid (9.5 ml), diluted with water (10 ml) and methanol (15 ml), and stirred at room temperature for 60 minutes. The precipitate was collected by filtration, washed with methanol / water (1: 1) and methanol, and dried to give the title compound (2.19 g, 4.07 mmol, 85.7¾) as a red-brown powder.

_{Ή-NR (300MHz, CDC1 3} ): «50.96 (6H, s), 1.34 (2H, m), 1.59 (2H, t, J = 7.5 Hz), 1.60 (2H, m), 1.79 (3H, q, J = 0.9 Hz), 2.04 (3H, s), 2.26 (3H, q, J = 0.9 Hz), 2:42 (3H, s), 2.90 (2H, m), 4.11 (2H, t, J = 7.5 Hz), 7.28 (2H, d, J = 8.1 Hz), 7.86 (2H, d, J = 8.1 Hz), 9.62 (1H, brs).

Calculated elemental analysis _{C 24 H 31 N 3 0 5} S 3: C, 53.61; H, 5.81;, 7.81; S, 17.89 (%), Found: C, 53.47; H, 5.67 ; N, 7.84; S, 18.03 (%) mp.141.5-143.0 ° C

Example 4-553

 N- (8-{[2- (1-adamantyl) ethyl] sulfanyl} -5,6-dimethyl-3-oxo-2,3-dihydro_m-imidazo [5,1-c] [1,4] thiazine -1-ylidene) _4-methylbenzenesulfonamide

 Compound (1.87 g, 4.90 mmol) obtained in Example 3-4, tri (2-hydroethyl) adamantane (purity 86%, 1.53 g, 5.27 mmol) obtained in Reference Example 31 and potassium carbonate (1.02 g, A suspension of 7.35 tmol) of DMF (32 ml) was stirred at 40 ° C for 18 hours and then at 60 for 1.5 hours. During the reaction, the above iodide (284 mg, 0.98 ol) was added. The reaction mixture was diluted with 1N hydrochloric acid (9.8 ml), diluted with water (10 ml) and methanol (10 ml), and stirred at room temperature for 60 minutes. The precipitate was collected by filtration, washed with methanol-water (1: 1) and methanol, dissolved in THF-acetonitrile and concentrated, and methanol was added to the residue. The precipitate was collected by filtration, washed with methanol, and dried to give the title compound (2.28 g, 4.20 bandol, 85.7%) as a red-purple powder.

_{Ή-NMR (300MHz, CDC1 3} ): (51.43 (2H, m), 1.50 (6H, d, J = 2.1 Hz), 1.63 (3H, brd, J = 12.0 Hz), 1.71 (3H, brd, J = 12.3 Hz), 1.79 (3H, q, J = 0.9 Hz), 1.97 (3H, brs), 2.26 (3H, q, J = 0.9 Hz), 2.41 (3H, s), 2.91 (2H, i), 7.27 (2H, d, J = 8.1 Hz), 7.83 (2H, d, J = 8.4 Hz), 9.61 (1H, brs).

Elemental _{analysis: C 27 H 33 N 3 0} 3 S 3: C, 59.64; H, 6.12 ;., 7.73; S, 17.69 (%), Found: C, 59.66; H, 6.02 ; N, 7.89; S , 17.83 (%)

Immediately. 189.5-190.5 ° C

Example 4-554

 N- {8-[(1-adamantylmethyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine- 1-ylidene 4-methylbenzenesulfonamide

DMF (30 ml) of the compound obtained in Example 3-4 (1.85 g, 4.84 mmol), 1-odomethyladamantane obtained in Reference Example 32 (1.43 g, 5.18 mmol) and potassium carbonate (1.01 g, 7.27 mmol) Was stirred at room temperature for 30 minutes and then at 60 ° C. for 42 hours. To the reaction mixture was added 1N hydrochloric acid (9.7 mi), diluted with water (10 ml) and methanol (10 ml). Stir for 30 minutes. The precipitate was collected by filtration, washed with methanol / water (1: 1) and methanol, and dried to give the title compound (1.16 g, 2.19 pt, 45.2) as a red-brown powder. _{Ή-NMR (300MHz, CDC1 3} ): 51.55 (6H, d, J = 2.4 Hz), 1.60 (3H, brd, J = 12.3 Hz), 1.71 (3H, brd, J = 12.3 Hz), 1.78 (3H, q, J = 0.9 Hz), 2.00 (3H, brs), 2.26 (3H, q, J = 0.9 Hz), 2.40 (3H, s), 2.75 (2H, s), 7.25 (2H, d, J = 7.8 Hz), 7.87 (2H, d, J = 8.1 Hz), 9.55 (1H, brs).

Elemental _{analysis: C 26 H 31 N 3 0} 3 S 3 Calculated: C, 58.95; H, 5.90 ; N, 7.93; S, 18.16

(%), Found: C, 58.59; H, 5.95; N, 7.96; S, 18.09 ().

mp. 207.0-209.0 ° C

Example 4-555

 (2S, 4R) -2-{[(5,6-dimethyl-tolu [[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3, -dihydro-1H-imidazo [5,1 -c] [1,4] thiazin-8-yl) sulfanyl] methyl} -tert-butyl 4-hydroxy-1-pyrrolidinecarboxylate

(Method 1) DMF (25 ml) of the compound obtained in Example 3-4 (1.35 g, 3.54 ol), sodium iodide (0.53 g, 3.54 thigh 01) and potassium carbonate (734 mg, 5.31 mmol) The (2S, 4R) -N-Boc-4- (2-tetrahydrobilanyloxy) pyrrolidine-2-methyl mesylate (1.35 g, 3.55 leaks) obtained in Reference Example 33-1 was stirred into the suspension at 60 ° C. A solution of 1) in DMF (5 ml) was added dropwise over 90 minutes, and the reaction solution was further stirred for 20 hours. To the reaction solution were added 1N hydrochloric acid (7.1 ml), water (70 ml) and saturated saline (15 l), and the mixture was extracted with ethyl acetate (140 ml). The organic layer was washed successively with sodium carbonate, 2% aqueous sodium bicarbonate, 0.05N hydrochloric acid, 5% and saturated saline. The washed layer was extracted with ethyl acetate (100 ml). The organic layer was dried over sodium sulfate and concentrated to give a dark red oil (1.39 g). This was dissolved in methanol (25 ml) and stirred with CSA (95 mg, 0.41 ol) at room temperature for 1.5 hours. The reaction mixture was concentrated, diluted with ethyl acetate (100 ml), washed successively with 0.05N hydrochloric acid, 5¾ and saturated saline, dried over sodium sulfate, and concentrated to give a dark red oil (1.39 g). Obtained. This was subjected to chromatography on silica gel (10 g) (ethyl acetate, _{1: 7: 3} ), and the ethyl acetate-hexane (7: 3) fraction was concentrated to dryness. Diluted with getyl ether. The precipitate was collected by filtration, washed with getyl ether, and dried to give the title compound (592 mg, 1.02 mmol, 28.8) as a red powder As obtained.

_{Ή-NMR (200MHz, CDC1 3} ): (51.48 (9H, s), 1.70 (1H, m), 1.78 (3H, q, J = 1.2 Hz), 2.01 (1H, ddd, J = 13.2, 8.0, 4.8 Hz), 2.ίθ (1H, m), 2.26 (3H, q, J = 1.2 Hz), 2.42 (3H, s), 3.15 (1H, m), 3.36 (1H, dd, J = 11.6, 3.6 Hz ), 3.40 (1H, brd, J = 12 Hz), 3.60 (1H, m), 4.25 (1H, m), 4.41 (1H, m), 7.30 (2H, d, J = 8.2 Hz), 7.83 (2H , d, J = 8.4 Hz), 9.64 (1H, brs).

Elemental analysis: Calculated as _{C 25 H 32 N 4 0 6} S 3: C, 51.70; H, 5.55;, 9.65; S, 16.56

(%), Found: C, 51.59; H, 5.34;, 9.71; S, 16.55 ().

mp. 166.5-168.5

(Method 2) In Reference Example 33-2, a suspension of the compound obtained in Example 3-4 (473 mg, 1.24 ol) and potassium carbonate (257 mg, 1.86 ol) in DMF (8 ml) was prepared. The obtained (2S, 4R) -N-Boc-4-hydroxypyrrolidine-2-methyl iodide (406 mg, 1.24 liter) was added, and the reaction solution was stirred at 50 ^DC for 15 hours. 1N Hydrochloric acid (2.5 il), water (20 ml) and saturated saline (5 ml) were added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml and 20 ml). The organic layer was washed sequentially with 5% and saturated saline, dried over sodium sulfate, concentrated, and ethyl acetate and getyl ether were added to the residue. The precipitate was collected by filtration, washed with diethyl ether, and dried to give the title compound (508 mg, 0.875 mmol, 70.5%) as a red powder.

(Method 3) The (2S, 4R) -N-Boc-2-hydroxymethyl-4- (2-tetrapyranyloxy) pyrrolidine (5.50 g, 18.2 t) obtained in Reference Example 33-1 and methanesulfonyl chloride ( A solution of triethylamine (3.04 ml, 21.9 mmol) in THF (10 ml) was added dropwise to a solution of 2.22 g, 19.2 mol) in THF (100 ml) with stirring at 0 ° C over 40 minutes. The mixture was stirred at ° C for 1 hour. Purification by ethyl acetate extraction gave a colorless oil of (2S, 4R) _N-Boc-4_ (2-tetrabiranyloxy) pyrrolidine-2-methyl mesylate (6.74 g, 17.7 marshal, 1, 97.6%). A suspension of this oil and sodium iodide (5.32 g, 35.5 marol) in acetone (130 ml) was heated under reflux for 20 hours. The reaction mixture was extracted with ethyl acetate-hexane (2: 1), dehydrated, dried and concentrated to dryness to give crude (2S, 4R) -N-Boc-2-odomethyl-4- (2-tetrapyranyloxy) ) Pyrrolidine (purity 70%, 3.92 g, 6.67 mmol, 37.7%) was obtained as a brown oil. The compound obtained in Example 3-4 (2.55 g, 6.68 t ol), the above (2S, 4R) -N-Boc-2-odomethyl-4- (2-tetrapyranyloxy) pyrrolidine (purity 70 3.92 g) , 6.67 mmol) and potassium carbonate (1.39 g, 10.0 bandol) in DMF (43 ml) was stirred at room temperature for 10 minutes and then at 60 ° C for 14 hours. 1N Hydrochloric acid (13.4 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate to obtain a red oil (4.64 g). This was dissolved in methanol (100 ml), concentrated hydrochloric acid (0.166 ml, 2.01 marl) was added, and the mixture was stirred at room temperature for 18 hours. To the reaction solution was added p-toluenesulfonic acid hydrate (255 mg, 1.34 mmol), and the mixture was stirred at 60 ° C for 1 hour. The reaction solution was neutralized and extracted with ethyl acetate to obtain a dark red oily substance, which was purified by chromatography on silica gel (40 g) (ethyl acetate-hexane, 1: 7: 3). The title compound (1.31 g, 2.26 mL, 33.8%) was obtained as a red powder by crystallizing from chillue tyl ether.

Example 4-556

Acetic acid (2-{[(5,6-dimethyl-tolu [[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4 ] Thiazine-8_yl) sulfanyl] methyl} cyclohexylmethyl) methyl

 The compound obtained in Example 3-4 (1.85 g, 4.85 mmol), trans-2-odomethylcyclohexane-1_methyl acetate obtained in Reference Example 34 (1.48 g, 5.00 mmol) and lithium carbonate (1.01 g) , 7.27 mmol) in DMF (30 ml) was stirred at room temperature for 30 minutes and then at 60 ° C for 41 hours. 1N Hydrochloric acid (9.7 ml) was added to the reaction solution, diluted with water (10 ml) and methanol (10 ml), and stirred at room temperature for 60 minutes. The precipitate was collected by filtration, washed with methanol (1: 1) and methanol, and dried to give the title compound (2.41 g, 4.39 orchid ol, 90.5%) as a red powder. '

_{Ή- NMR (300MHz, CDC1 3)} : (51.07 (1H, brq, J = 12.6 Hz), 1.16 (1H, brq, J = 13.2 Hz), 1.22 (2H, brq, J = 7.5 Hz), 1.54 (2H , m), 1.75 (3H, brs), 1.78 (3H, q, J = 0.9 Hz), 1.95 (1H, brd, J = 14.1 Hz), 2.06 (3H, s), 2.26 (3H, q, J = 0.9 Hz), 2.41 (3H, s), 2.75 (1H, dd, J = 12.6, 8.1 Hz), 3.29 (1H, dd, J = 12.6, 3.0 Hz), 4.03 (1H, dd, J = 11.1,. 5 Hz), 4.05 (1H, dd, J = 11.4, 4.2 Hz), 7.27 (2H, dt, J = 8.4, 0.6 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.58 (1H, brs) .

Elemental _{analysis: C 25 H 31 N 3 0} 5 S 3 Calculated: C, 54.62; H, 5.68 ; N, 7.64; S, 17.50 (%), Found: C, 54.48; H, 5.78;, 7.52; S, 17.44 (%) .mp. 147.5-148.0 ° C

Example 4-557

 N- [5,6-dimethyl-3-oxo-8-({[(2S) -5-oxopiperidinyl] methyl} sulfanyl)-2,3-dihydro-1H-imidazo [5,1-c ] [1, 4] thiazine-1-ylidene] -4-methylbenzenesulfonamide

 THF of the compound obtained in Example 3-4 (1.81 g, 4.74 mmol), (2S) -5-hydroxymethyl-2-pyrrolidone (619 mg, 5.21 mmol) and triphenylphosphine (1.67 g, 6.16 mol) DEAD (1.02 ml, 6.16 mmol) was added dropwise to the suspension (36 ml) while stirring at room temperature, and the reaction solution was stirred at room temperature for 19 hours. The reaction solution was extracted with ethyl acetate, dehydrated, dried and concentrated, and methanol was added to the obtained red oil. The precipitate was collected by filtration, washed with methanol and getyl ether, and dried to give the title compound (1.26 g, 2.63 mmol, 55.4) as a red-purple powder.

One _{NMR (200MHz, CDC1 3):} 51.79 (3H, q, J = 0.6 Hz), 1.82 (1H, m), 2.26 (3H, q, J = 1.0 Hz), 2.30 (1H, m), 2.36 (2H , m), 2.43 (3H, s), 2.96 (1H, dd, J = 14.0, 7.8 Hz), 3.12 (1H, dd, J = 13.8, 5.0 Hz), 3.88 (1H, brquint, J = 6.4 Hz) , 5.90 (1H, brs), 7.32 (2H, d, J = 8.0 Hz), 7.84 (2H, d, J = 8.6 Hz), 9.69 (1H, brs).

Elemental _{analysis: C 20 H 22 N 4 O} 4 S 3 O.5H 2 0: C, 49.26; H, 4.75; N, 11.49; S, 19.73 (%), Found: C, 48.99; H, 4.63 ; N, 11.30; S, 19.34 (%).

Example 4-558

 3-{[(5,6-dimethyl-tolu [[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine -8-yl) sulfanyl] methyl} -tert-butyl topiperidinecarboxylate

N-Boc-3-hydroxymethylpiberidine (1.13 g) prepared from the compound obtained in Example 3-4 (1.82 g, 4.77 tmol), 3-hydroxymethylpiberidine and ditert-butyl bicarbonate. g, 5.24 mmol) and triphenylphosphine (1.68 g, 6.20 mmol) in THF (36 ml) were added dropwise with stirring at room temperature while DEAD (1.03 ml, 6.20 mmol) was added dropwise. For 24 hours. The reaction solution was extracted with ethyl acetate, dehydrated, dried and concentrated The resulting red oil was purified by chromatography on silica gel (30 g) (ethyl acetate-hexane, 2: 8-5.5) and crystallized from ethyl acetate-ethyl ether to give the title compound (587 mg, 1.01 mmol, 21.2%) as a red-purple powder.

Ή one _{NMR (300MHz, CDC1 3):} 51.26 (2H, m), 1.45 (9H, s), 1.50 (2H, m), 1.63 (1H, m), 1.78 (3H, q, J = 1.2 Hz), 1.92 (1H, brd, J = 11.7 Hz), 2.26 (3H, q, J = 0.9 Hz), 2.41 (3H, s), 2.78 (1H, dd, J = 11.7, 7.5 Hz), 2.90 (1H, dd , J = 11.7, 6.3 Hz), 2.86 (2H, br), 3.75 (IH, m), 3.90 (1H, br), 7.28 (2H, d, J = 8.1 Hz), 7.84 (2H, d, J = 8.1 Hz), 9.61 (IH, brs).

Elemental _{analysis: C 26 H 34 N 4 0} 5 S 3 O.2Et 2 0: C, 54.23; H, 6.11; N, 9.44; S, 16.21 (%), Found: C, 54.28; H, 6.29 ; N, 9.08; S, 16.25. (%).

Immediately. 154.0-155.0 ^D C

Example 4-559 '

 (2S)-2-{[(5,6-dimethyl-1-{[(4_methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydrido-1H-imidazo [5,1-c] [1,4] thiazine-8-yl) sulfanyl] methyl} -tert-butyl topyrrolidinecarboxylate

 (Method 1) The compound obtained in Example 3- (1.90 g, 4.98 mmol), (S) -N-Boc-2-hydridoxymethylpyrrolidine (purity 94.7%, 1.18 g, 5.55 thigh 01) and triphenylphosphine DEAD (1.07 ml, 6.47 mmol) was added dropwise to a suspension of [(40 ml) in (1.75 g, 6.47 Cafe 01) with stirring at room temperature, and the reaction solution was stirred at room temperature for 63 hours. The reaction solution was extracted with ethyl acetate, dehydrated and dried, and concentrated to obtain a red oil (5.6 g). This was purified by chromatography on silica gel (40 g) (ethyl acetate-hexane, 3: 7-4: 6) and crystallized from ethyl acetate-ethyl ether and then methanol to give the title compound (964 mg, 1.71 mmol, 34.3 »as a purple powder.

_{Ή-NMR (200MHz, CDC1 3} ): δΐ.47 (9Η, s), 1.78 (3H, q, J = 0.8 Hz), 1.83 (3H, m), 1.98 (IH, m), 2.26 (3H, s ), 2.42 (3H, s), 2.90-3.10 (IH, m), 3.33 (2H, m), 3.40 (IH, m), 4.01 (IH, m), 7.28 (2H, d, J = 8.4 Hz) , 7.84 (2H, d, J = 8.4 Hz), 9.61 (IH, brs).

Elemental _{analysis: C 25 H 32 N 4 0} 5 S 3 Calculated: C, 53.17; H, 5.71 ; N, 9.92; S, 17.03 (%), Found: C, 53.06; H, 5.74 ; N, 9.70; S, 17.06 (). mp. 168.0-168.5t:

 (Method 2) To a solution of (S) -N-Boc-2-hydroxymethylpyrrolidine (purity 94.7, 1.05 g, 4.94 mmol) and methanesulfonyl chloride (0.406 ml, 5.19 r.l.ol) in DMF (10 ml) at 0 ° C While stirring with, a solution of triethylamine (0.822 ml, 5.93 mL) in DMF (1 ml) was added dropwise over 30 minutes, and the reaction solution was stirred with Ot: for 1 hour. The reaction solution was added dropwise at 40 ° C over 40 minutes to a suspension of the compound obtained in Example 3-4 (1.45 g, 3.79 mmol) and potassium carbonate (1.05 g, 7.58 substitution 01) in DMF (15 ml). Then, the reaction solution was stirred at 40 ° C. for 18 hours, and then at 80 ° C. for 2 hours. The reaction mixture was added with 1N hydrochloric acid (12 ml), extracted with ethyl acetate, dehydrated and dried, and concentrated to give a red oil (5.6 g). This was purified by chromatography on silica gel (40 g) (ethyl acetate-hexane, 3: 7-4: 6) and crystallized from methanol to give the title compound (650 mg, 1.15 marl, 30.4%) in purple Obtained as a powder. Example 4-560

N- {1,6-dioxo-4-[(5,5,6,6,6-pentafluorohexyl) sulfanyl]-1,2,6,7,8,9-hexahydro-3H -Imidazo [5,1-c] [1,4] benzothiazine-3-y N- (1,6-dioxo-4-sulfanyl-1,2,6,7,8 obtained in Example 3-38 , 9-Hexahydro-3H-imidazo [5,1-c] [1,4] benzothiazine-3-ylidene) -4-methylbenzensulfonamide (300 mg, 0.712 bandol) and potassium carbonate (148 mg, 1.07 mmol) of N, N-dimethylformamide (5.00 ml) was added to a suspension of methanesulfonic acid 5,5,6,6,6-pentafluoromethylhexyl ester (231 mg, 0.854) obtained in Reference Example 9. A solution of t-ol) in Ν, Ν-dimethylformamide (1.00 ml) was added. After heating the reaction mixture at 80 for 2 hours, 1N hydrochloric acid was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (L49 g, 89%) as dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 194-196 ° C.

IR (KBr) V: 3220, 2938, 1759, 1651, 1624, 1595, 1553 cm " ¹ .

- Awakening: _{R (CDC1 3): (51.66-1.86} (4H, m), 1.96-2.15 (4H, m), 2.42 (3H, s), 2.51

(2H, t, J = 6.3 Hz), 3.07 (2H, t, J = 7.5 Hz), 3.22 (2H, i, J = 6.0Hz), 7.30 (2H, d, J = 7.5 Hz), 7.84 (2H, d, J = 8.7 Hz), 9.87 (1H, bs).

Elementary analysis: as _{C 23 H 22 N 3 0 4} S 3 F 5 -0.4H 2 0

Calculated)): C, 45.83; H, 3.81;, 6.97; S, 15.96.

Found (¾): C, 45.80; H, 3.76; N, 7.06; S, 15.84.

Example 4-561

 N- {1,6-Dioxo-4-[(5_fluoropentyl) sulfanyl] -1,2,6,7,8,9-hexahydro-3H-imidazo [5, tric] [1,4] Benzothiazine-4-ylidene} _4-methylbenzenesulfonamide

N- (1,6-Dioxo-4-sulfanyl-1,2,6,7,8,9-hexahydro-3H-imidazo obtained in Example 3-38 [5,1-c] [1 [, 4] Benzothiazine-4-ylidene) _4-methylbenzenesulfonamide (2.00 g, 4.74 mmol) and potassium carbonate (984 mg, 7.12 faceol) in Ν, Ν-dimethylformamide (50.0 ml) Topromo_5_fluoropentane obtained in Reference Example 61 (962 mg, 5.69 bandages 01) was added. After heating the reaction mixture at 80 for 30 minutes, 1N hydrochloric acid was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (2.07 g, 86¾) and the obtained as dark red crystals. The crystals were recrystallized from ethyl acetate-tetrahydrofuran-methyl alcohol to obtain dark red crystals having a melting point of 235-237.

IR (KBr) V: 3169, 3059, 2961, 2942, 2909, 2253, 1740, 1649, 1609, 1584, 1547 cm- ¹ .

_{Ή-NMR (CDC1 3):} «51.50-1.90 (6H, s), 1.98-2.14 (2H, m), 2.43 (3H, s), 2.51 (2H, t, J = 7.0 Hz), 3.05 (2H, t, J = 7.0Hz), 3.21 (2H, t, J = 6.0 Hz), 4.45 (2H, dt, J = 47.2, 6.0 Hz), 7.30 (2H, d, J = 8.Hz), 7.84 (2H , d, J = 8.Hz), 9.85 (1H, bs).

Elementary analysis: as _{C 22 H 24 N 3 0 4} S 3 F

Calculated value (¾): C, 51.85; H, 4.75; N, 8.25; S, 18.88.

Found (¾): C, 51.84; H, 4.62; N, 8.18; S, 18.64.

Example 4-562

N- {1,6-dioxo-4-[(5,5,5-trifluoropentyl) sulfanyl]-1,2,6,7,8,9-hexahydro-3H-imidazo [5,1-c ] [1, 4] Benzothiazine-4-ylide N- (1,6-Dioxo-4-sulfanyl-1,2,6,7,8,9-hexahydro-3H-imidazo [5, tric] [1, obtained in Example 3-38 4] Benzothiazine-4-ylidene) _4-methylbenzenesulfonamide (200 mg, 0.443 ol) and potassium carbonate (91.8 mg, 0.664 mmol) in Ν, Ν-dimethylformamide (50.0 ml) suspension A solution of methanesulfonic acid 5,5,5-trifluoropentyl ester (117 mg, 0.532 mmol) obtained in Example 53-4 in N, N-dimethylformamide (1.00 ml) was added. After heating the reaction mixture at 80 ° C for 1 hour, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (121 ig, 50%) as a dark red crystals. The crystals were recrystallized from ethyl acetate-tetrahydrofuran-methyl to obtain dark red crystals having a melting point of 235-237.

IR (KBr) Les:. 3177, 3071, 2965, 2882, 2259, 1740, 1655, 1609, 1586, 1549 cm- 1 Ή-NMR (CDC1 3): δ 1.60-1.90 (4Η, s), 1.97-2.21 (4H, m), 2.42 (3H, s), 2.51 (2H, t, J = 7.0 Hz), 3.05 (2H, t, J = 7.0 Hz), 3.21 (2H, t, J = 6.2 Hz), 7.30 (2H, d, J = 7.6 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.88 (1H, bs).

Elementary analysis: as _{C 22 H 22 N 3 0 4} S 3 F 3

 Calculated value (%): C, 48.43; H, 4.06; N, 7.70; S, 17.63.

― Actual value (¾): C, 48.50; H, 4.09; N, 7.73; S, 17.62.

 Example 4-563

N- {8,8-dimethyl-1,6-dioxo-4 _ [(5,5,6,6,6-pentafluorohexyl) sulfanyl]-1,2,6,7,8,9- Xahydrido-3H-imidazo [5,1-c] [1,4] benzothiazine N- (8,8-dimethyl_1,6-dioxo-4-sulfanyl-1,2,2 obtained in Example 3-42 6,7,8,9-Hexahydro-3H-imidazo [5,1-c] [1,4] benzothiazine-4-ylidene) -4-methylbenzenesulfonamide (200 mg, 0.445 alcohol) and carbonic acid To a suspension of potassium (92.2 mg, 0.667 mmol) in N, N-dimethylformamide (4.00 ml) was added to the methanesulfonic acid 5,5,6,6,6-phenol obtained in Reference Example 9 A solution of xyl ester (144 mg, 0.534 ol) in N, N-dimethylformamide (1.00 ml) was added. After heating the reaction mixture at 80 ° C. for 30 minutes, 1N hydrochloric acid was added and extracted with ethyl acetate. Lottery Washed with water exudates, dried (MgSO _4), the solvent was evaporated under reduced pressure to give the title compound (227 mg, 82¾) was obtained as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 234-236.

IR (KBr) V:. 3177 , 3065, 2957, 2872, 1738, 1661, 1615, 1591, 1549 cm "1 lH - NMR (CDC1 3): (51.12 (6H, s), 1.67-1.86 (4H, m ), 1.96-2.14 (2H, m), 2.36 (2H, s), 2.42 (3H, s), 3.06 (2H, t, J = 7.2 Hz), 3.08 (2H, s), 7.30 (2H, d, J = 8.1 Hz), 7.84 (2H, d, J = 8.1 Hz), 9.87 (1H, bs).

Elementary analysis: as _{C 25 H 26 N 3 0 4} S 3 F 5

 Calculated (¾): C, 48.14; H, 4.20; N, 6.74; S, 15.42.

 Found (¾): C, 48.30; H, 4.03; N, 6.70; S, 15.63.

 Example 4-564

 N- {9,9-dimethyl-1,6-dioxo-4-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -1,2,6,7,8, 9-Hexahydro-3H-imidazo [5, 1-c] [1,4] benzothiazine-4-ylidene} -4-methylbenzenesulfonami H

In the same manner as in Example 4-563, N- (9,9-dimethyl-1,6-dioxo-4-sulfanyl-1,2,6,7,8,9 obtained in Example 3-43 was obtained. -Hexahydrid- 3H-imidazo [5, 1-c] [1, 4] benzothiazine-4-ylidene) -4-methylbenzenesulfonamide (200 mg, 0.445 awake ol) from the title compound (160 mg, 58% ) Was synthesized. The crystals were recrystallized from ethyl acetate-tetrahydrofuran-getyl ether to obtain dark red crystals having a melting point of 216-218. IR (KBr) v: 3177, 3073, 2970, 2932, 2865, 2255, 1742, 1649, 1611, 1588, 1549, cm- ¹ .

_{Ή-NMR (CDC1 3):} δΐ.15 (6Η, s), 1.67-1.90 (4H, m), 1.86 (2H, t, J = 6.0 Hz), 1.95-2.14 (2H, m), 2.42 (3H , s), 3.06 (2H, t, J = 7.2 Hz), 3.22 (2H, t, J = 6.3 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.83 (2H, d, J = 8.4 Hz) ), 9.86 (1H, bs).

Elementary analysis: as _{C 25 H 26 N 3 0 4} S 3 F 5

 Calculated (%): C, 48.14; H, 4.20; N, 6.74; S, 15.42.

 Found (%): C, 48.24; H, 4.14; N, 6.80; S, 15.70.

 Example 4-565

N- {1,6-dioxo-8-methyl-4-[(5,5,6,6,6-pentafluorohexyl) sulfani L] -1,2,6,7,8,9-Hexahydro-3H-imidazo [5, lc] [1,4] benzothiazine-4-y Example 3 was prepared in the same manner as in Example 4-563. N- (1,6_dioxo-8-methyl-4-sulfanyl-1,2,6,7,8,9-hexatide obtained imidazo [5, tric] [1,4] The title compound (4.55 g, 93%) was synthesized from [benzothiazine-4-ylidene) -4-methylbenzenesulfonamide (3.51 g, 8.06 mmol). Recrystallization from ethyl acetate tetrahydrofuran-getyl ether gave dark red crystals with a melting point of 214-216. IR (Br) Li: 3167, 2957, 2876, 1742, 1655, 1613, 1590, 1549 cm " ¹ .

_{¾-NMR (CDC1 3):} άΐ.14 (3Η, d, J-6.2 Hz), 1.62-1.88 (4H, m), 1.88-2.30 (4H, m), 2.42 (3H, s), 2.80-2.96 (2H, m), 3.06 (2H, i, J = 6.8 Hz), 3.57 (1H, dd, J = 18.8, 3.0 Hz), 7.30 (2H, d, J = 8.0 Hz), 7.83 (2H, d, J = 8.4 Hz), 9.86 ( 1H, bs) ' elemental analysis:. as _{C 24 H 24 N 3 0 4} S 3 F 5

Calculated (¾): C, 47.28; H, 3.97; N, 6.89; S, 15.78.

Found (値): C, 47.58; H, 4.01; N, 6.98; S, 15.99.

Example 4-566

Ethyl 5-[(1,6-dioxo-3-{[(4-methylphenyl) sulfonyl] iminoto 2,3,6,7,8,9_hexahydro-1H-imidazo [5,1-c] [ 1, 4] Benzothiazine _4 -yl) sulfanyl] pennoate

N- (1,6-dioxo-4-sulfanyl-1,2,6,7,8,9-hexahydro-3H-imidazo obtained in Example 3-38 [5, tric] [1, 4] Benzothiazine-4-ylidene) -4-methylbenzenesulfonamide (600 mg, 1.42 mmol) and potassium carbonate (295 mg, 0.2.14 phenol) in N, N-dimethylformamide (12.0 ml) To the solution was added 5-ethyl ethyl valerate (0.276 ml, 1.71 r. Ol). After heating the reaction mixture at 80 for 20 minutes, 1N hydrochloric acid was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), and the solvent was distilled off under reduced pressure to give the title compound (521 mg, 67%) as a dark red crystals. Recrystallization from ethyl acetate gave dark red crystals with a melting point of 190-192 ° C. ^_

Infrared absorption spectrum (IR) (in KBr) V: 3177, 3065, 2926, 1740, 1657,1607, 1584, 1545 cm ¹ . ¾-NMR (CDCI3): δΐ.27 (3H, t, J = 7.2 Hz), 1.72-1.82 (4H, m), 2.00-2.10 (2H, m), 2.30-2.39 (2H, m), 2.43 ( 3H, s), 2.51 (2H, t, J = 6.9 Hz), 3.00-3.09 (2H, m), 3.21 (2H, t, J-6.0 Hz), 4.15 (2H, q, J = 7.2 Hz), 7.31 (2H, d, 1 = 7.8 Hz), 7.84 (2H, d, J = 8.1 Hz), 9.86 (1H, bs).

Elementary analysis: as _{C 24 H 27 N 3 0 6} S 3

Calculated (¾): C, 52.44; H, 4.95; N, 7.64; S, 17.50.

Found (%): C, 52.34; H, 4.81; N, 7.794; S, 17.41.

Example 4-567

 5-[(1,6-dioxo-3-{[(4-methylphenyl) sulfonyl] iminoto 2,3,6,7,8,9-hexahydro-1H-imidazo [5, tric] [1,4 [Benzothiazine-4-yl) sulfanyl] -N-hexylpentanamide

 The compound was synthesized in the same manner as in Example 4-566, and recrystallized from ethyl acetate to obtain dark red crystals having a melting point of 112 to 114 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3277, 2930, 2859, 1748, 1645, 1595, 1557, 1522 cm—

_{Ή-NMR (CDC1 3):} 50.800-0.920 (3H, m), 1.10-1.90 (14H, m), 1.98-2.14 (2H, m), 2.14-2.28 (2H, m), 2.43 (3H, s) , 2.40-2.56 (2H, m), 2.96-3.08 (2H, m), 3.14-3.30 (2H, m), 5.52 (1H, bs), 7.30 (2H, d, J = 8.0 Hz), 7.83 (2H , D, J = 8. Hz), 9.86 (1H, bs).

Example 4-568

 N- {1-oxo- 4-[(5,5,6,6,6-pentafluorofluoropentyl) sulfanyl] _1,2-dihydro-3H-imidazo [5,1-c] [1,4] benzothiazine -3-ylidene 4-methylbenzene sulfonamide

Ν'-α-oxo-4-sulfanyl-1,2-dihydro-3Η-imidazo [5, tric] [1,4] benzothiazine-3-ylidene) -4-methyl obtained in Example 3-37 To a suspension of benzene, sulfonamide (150 mg, 0.372 mmol) and potassium carbonate (77.1 mg, 0.558 marl) in Ν, Ν-dimethylformamide (30.0 ml) was added methanesulfonic acid 5 obtained in Reference Example 9. , 5,6,6,6-Pentate fluoropentyl ester (121 mg, 0.446 mol) in N, N-dimethylformamide (1.00 ml) was added. Heat the reaction mixture at 80 ° C for 1 hour After that, IN hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (1.49 g, 89) as dark red crystals. The crystals were recrystallized from ethyl acetate-getyl ether to obtain dark red crystals having a melting point of 189-191 ° C.

IR (KBr) V: 3216, 3063, 2934, 1728, 1630, 1588, 1557, 1485 cm " ¹ .

_{Ή-NMR (CDC1 3):} 51.64-1.90 (4H, m), 1.90-2.24 (2H, in), 2.42 (3H, s), 3.04 (2H, t, J = 6.8 Hz), 6.95 (1H, dd , J = 7.8, 1.6 Hz), 7.08 (1H, dt, J-7.4, 1.2 Hz), 7.22 (1H, dt, J = 8.4, 1.8 Hz), 7.30 (2H, d, J = 8.2 Hz), 7.86 (2H, d, J = 8.4 Hz), 8.46 (1H, dd, J = 8.2, 1.2 Hz), 9.79 (1H, bs).

Elemental analysis: C ₂₃ H _2. N ₃ 0 ₃ S ₃ F ₆

Calculated (¾): C, 47.83; H, 3.49; N, 7.27; S, 16.65.

Found (%): C, 47.91; H, 3.42; N, 7.30; S, 16.38.

Example 4- 569

4 口 口 -N- {2_ (2,2-dimethylpentyl) -8-[(2,2-dimethylpentyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro -1H -Imidazo [5, 1-c] [1, 4] thiazine-1- Chromatography of silica gel (10 g) on crude material obtained by combining the crystal mother liquor and washing solution in Example 7-64 (to ethyl acetate) Xan, 1: 9-3: 7). The ethyl acetate-hexane (1: 9) fraction was concentrated to dryness and then crystallized from methanol to give the title compound (66 mg, 0.110 mol) as a dark red powder.

_{Ή-NMR (300MHz, CDC1 3} ): δθ.76 (6Η, s), 0.87 (3H, t, J = 6.6 Hz), 0.91 (3H, m), 1.01 (6H, s), 1.01 (2H, t , J = 8.2 Hz), 1.15 (2H, m), 1.35 (4H, brs), 1.80 (3H, q, J = 1.2 Hz), 2.28 (3H, q, J = 1.2 Hz), 2.73 (2H, s ), 4.17 (2H, s), 7.40 (2H, dt, J = 8.7, 1.8 Hz), 7.92 (2H, dt, J = 8.2, 1.8 Hz).

Example 4-570

4-bromo-N- {2- (2,2-dimethylpentyl) -8-[(2,2-dimethylpentyl) sulfanyl] -5,6-dimethyl_3-oxo-2,3-dihydro-1H- Imidazo [5, 1-c], 4] thiazine-1- The crude material obtained by combining the crystal mother liquor and the washing solution in Example 4-504 was subjected to silica gel (10 g) chromatography (ethyl acetate-hexane, 1: 9-3: 7). The ethyl acetate-hexane (1: 9) fraction was concentrated to dryness and crystallized from methanol to give the title compound (72 mg, 0.112 rnmol) as a dark red powder.

_{lH - NMR (300MHz, CDC1 3} ): ά 0.76 (6Η, s), 0.87 (3H, t, J = 7.1 Hz), 0.91 (3H, m), 1.01 (6H, s), 1.01 (2H, m) , 1.17 (2H, m), 1.35 (4H, m), 1.80 (3H, q, J = 0.6 Hz), 2.28 (3H, q, J = 0.9 Hz), 2.73 (2H, s), 4.16 (2H, s), 7.57 (2H, d, J = 8.4 Hz), 7.85 (2H, d, J = 8.7 Hz).

Example 4-571

6 _ [(Z) -2-Methoxy-2-oxoethylidene] -1-{[(4-methylphenyl) sulfonyl] imino} _3-oxo-8-[(5,5,6,6,6-penn Fluorohexyl) sulfanyl] -2,3,5,6-tetrahydro_-imidazo [5,1-c] [1,4] Methyl thiazine-5-carboxylate

 5,5,6,6,6-pentafluoroiodide was added to a suspension of the crude compound (2.28 g) obtained in Example 3-41 and potassium carbonate (0.98 g, 7.07 rnmol) in DMF (30 ml). Hexyl (purity: 87, 1.64 g, 4.71 mmol) was added dropwise to 6 (TC) and the mixture was stirred for 1.5 hours. 1N hydrochloric acid (9.4 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (120 ml). The obtained organic layer was washed with a 7% and 15% saline solution adjusted to be acidic, then with a saturated saline solution, dried over sodium sulfate and concentrated to dryness, and the residue was subjected to chromatography on silica gel (20 g). The residue was subjected to ethyl acetate-hexane (3: 7-4: 6), and the yellow fraction of ethyl acetate-hexane (3: 7-4: 6) was concentrated to dryness to give the title compound (0.81 g, 1.23 mmol). , 30.2 »was obtained as a yellow-orange powder The orange fraction of ethyl acetate-hexane (4: 6) was concentrated to dryness to give the crude title compound (1.13 g, 1.72 mol, 2.2%, isomer) Mixture) orange It was obtained as an end.

_{Ή-NMR (300MHz, CDC1 3} ): (51.67 (4H, m), 1.99 (2H, m), 2.43 (3H, s), 2.94 (1H,), 2.99 (2H, q, J = 7.2 Hz), 3.77 (3H, s), 3.81 (3H, s), 5.52 (1H, s), 6.33 (1H, s), 7.32 (2H, d, J- 8.1 Hz), 7.87 (2H, d, J = 8.4 Hz) .), 9.83 (1H, br ) elemental _{analysis: C 24 H 24 N 3 0} 7 S 3 F 5 calculated: C, 43.83; H, 3.68 ; N, 6.39; S, 14.63; F, 14.44 (% ), Found: C, 43.70; H, 3.62; N, 6.41; S, 14.57 (%).

Example 4-572 ' N- [5,6-dimethyl_3-oxo-8-[(5-bromopentyl) sulfanyl] -2,3-dihydro-1H-imidazo [5, ic] [1,4] thiazine-triylidene] _4 -Methylbenzenesulfonamide

N- (5,6-Dimethyl-3-oxo-8-sulfanyl-2,3-dihydrido obtained in Reference Example 3-4-1H-imidazo [5,1-c] [1,4] thiazine- To a suspension of 1-ylidene) -4-methylbenzenesulfonamide (300 mg, 0.786 ol) and potassium carbonate (163 mg, 1.18 ol) in N, N-dimethylformamide (4.00ral), 5-Dibromopentane (0.168 ml, 1.18 mmol) was added. After heating the reaction mixture at 60 ° C. for 4 hours, 1N hydrochloric acid was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (234 mg, 56%) as dark red crystals. Recrystallization from ethyl acetate-ethyl acetate gave dark red crystals with a melting point of 158-160 ° C.

IR (KBr): 3250, 3044, 2926, 2857, 1728, 1661, 1615, 1557 cm— ¹ .

_{¾-NMR (CDC1 3):} 51.47- 1.84 (4H, m), 1.79 (3H, d, J = 1.0 Hz), 1.84- 1.96 (2H, m), 2.26 (3H, d, J = 1.0 Hz), 2.42 (3H, s), 2.95 (2H, i, J = 7.4 Hz), 3.41 (2H, t, J = 6.6 Hz), 7.29 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.62 (1H , bs) elemental analysis:. C _2. As _{H 24 N 3 0 3 S 3} Br

Calculated value (¾): C, 45.28; H, 4.56; N, 7.92; S, 18.13.

Found (%): C, 45.46; H, 4.48; N, 7.81; S, 18.12.

Example 4-573

N_ [8-({[1,4-cis-4- (hydroxymethyl) cyclohexyl] methyl} sulfanyl) -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [ 5,1-c] [1,4] thiazine-1- The compound (2.50 g, 6.55 mmol) obtained in Example 3-4, 4-odomethylcyclohexane-1-methanol (1.83 g) obtained in Reference Example 36. g, 7.20 mmol, cis / trans = 92: 8 mixture) and potassium carbonate (1.36 g, 9.83 mmol) in DMF (40 ml) were also stirred at room temperature for 4 days. 1N Hydrochloric acid (13.lml) was added to the reaction solution, diluted with water (20ml), and stirred at room temperature for 2 hours. The precipitate was collected by filtration, washed with methanolic water (1: 1) and methanol, and the red-purple powder (2.96 g) obtained was crystallized from THF-ethyl acetate to give the title compound. (2.34 g, 4.61 mmol, 70.4%, cis / trans = 92: 8 mixture) was obtained as a purplish red powder. 'H-NMR (200MHz, CDC1 3): 51.28 (1H, br), 1.43 (4H, m), 1.58 (4H, m), 1.66 (1H, m), 1.79 (3H, q, J = 0.9 Hz) , 1.82 (1H, m), 2.26 (3H, q, J = 1.2 Hz), 2.41 (3H, s), 2.91 (2H, d, J 7.5 Hz), 3.55 (2H, d, J = 6.6 Hz), 7.26 (2H, d, J = 8.4 Hz), 7.84 (2H, d, J = 8.7 Hz), 9.61 (1H, brs).

Elemental analysis: C ₂₃ 0 ₄ S ₃ · 0.3Η ₂₀ Calculated: C, 53.84; Η, 5.81;, 8.19; S, 18.75 (%), found: C, 53.80; Η, 5.81; Ν, 8.27; S, 19.06 (%).

Melting point: 170.5-172.0 ° C

Example 4-574

N- [8-({[l, 4-trans-4- (hdroxymethyl) cyclohexyl] methyl} sulfanyl) -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, 1-c] [1,4] thiazine-1- The compound obtained in Example 3-4 (1.27 g, 3.32 mol), the trans-4-hydroxymethylcyclohexane obtained in Reference Example 38 A suspension of 1_ methanol (0.92 g, 3.62 pt) and potassium carbonate (688 mg, 4.98 mmol) in DMF (20 ml) was stirred at room temperature for 15 minutes, then at 40 ° C for 15 hours. The reaction mixture was diluted with 1N hydrochloric acid (6.64 ml), diluted with water (14 ml) and methanol (2 ml), and stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with methanol / water (1: 1) and methanol, and dried to give the title compound (1.53 g, 3.01 ol, 90.8¾) as a red-purple powder.

- brittleness _{(300MHz, CDC1 3): 50.99} (4H, brt, J = 10.8 Hz), 1.31 (1H, brs), 1.45 (1H, m), 1.53 (1H, m), 1.79 (3H, q, J = 1.2 Hz), 1.84 (2H, in), 1.93 (2H, m), 2.26 (3H, q, J = 0.9 Hz), 2.41 (3H, s), 2.83 (2H, d, J = 6.9 Hz), 3.47 (2H, m), 7.26 (2H, dt, J = 7.6, 1.8 Hz), 7.84 (2H, dt, J = 7.6, 1.8 Hz), 9.61 (1H, brs).

Elemental _{analysis: C 23 H 29 N 3 0} 4 S 3 Calculated: C, 54.41; H, 5.76 ; N, 8.28; S, 18.95 (%), Found: C, 54.19; H, 5.77 ; N, 8.40; S, 18.79 (%).

Example 4-575

4-Methylbenzoic acid 5-[(5,6_dimethyl-{{((4_methylphenyl) sulfonyl] imino} -3-oxo-2,3_dihydro-1H-imidazo [5, lc] [l , 4] thiazine-8-yl) sulfa Nil] -4,4-dimethylpentyl

 The compound obtained in Example 3-4 (639 mg, 1.67 mmol), 5-hydroxy-4,4-dimethylpentyl p-toluate obtained in Reference Example 39 (476 mg, 1.90 dragonol) and triphenylphosphine ( DEAD (0.389 ml, 2.34 mol) was added dropwise to a suspension of 634 mg (2.34 mmol) in THF (13 ml) with stirring at room temperature, and the reaction mixture was allowed to stand at room temperature for 2.5 hours and then at 50 ° C for 20 hours. While stirring. The reaction mixture was diluted with ethyl acetate, washed with 0.1N hydrochloric acid, 5% and saturated brine, dried and concentrated to obtain a crude oil. This was subjected to chromatography on silica gel (20 g) (ethyl acetate-hexane, 2: 8-7: 3), and after concentration of the red fraction, medanol was added. The precipitate was collected by filtration, washed with methanol, and crystallized from ethyl acetate-ethyl ether to give the title compound (588 mg, 0.958 mmol, 57.4%) as a red-purple powder.

_{^ -NMR (300MHz, CDC1 3)} : 51.03 (6H, s), 1.45 (2H, m), 1.72 (2H, m), 1.77 (3H, q, J = 0.9 Hz), 2.25 (3H, q, J = 0.9 Hz), 2.39 (3H, s), 2.40 (3H, s), 2.90 (2H, s), 4.26 (2H, t, J = 6.6 Hz), 7.22 (2H, d, J = 8.1 Hz), 7.25 (2H, d, J = 8.7 Hz), 7.85 (2H, d, J = 8.1 Hz), 7.91 (2H, d, J = 8.1 Hz), 9.56 (1H, brs).

 N- (5,6-dimethyl-8-{[(1-methylcyclohexyl) methyl] sulfanyl} -3-oxo-2,3-dihydrido-1H-imidazo [5,1-c] [ 1,4] thiazine-1-ylidene) -4-methylbenzenesulfonamide

The compound obtained in Example 3-4 (639 mg, 1.67 mmol), the trimethylcycline hexane-trimethanol obtained in Reference Example 40 (purity 91.8%, 1.04 g, 7.45 mmol) and triphenylphosphine (2.25 g, 8.3311111101) ) ^? DEAD (1.38 ml, 8.33 liters) was added dropwise to the suspension (45 ml) at room temperature with stirring, and the reaction solution was stirred at room temperature for 2.5 hours and then at 50 ° C for 2.5 days. The reaction mixture was diluted with ethyl acetate (150 ml), washed with 0.1 hydrochloric acid, and then mixed with sodium bicarbonate (100 ml). The precipitate was collected by filtration, washed with methanol, dissolved in ethyl acetate-THF (2: 1, 200 ml), washed with 0.1N hydrochloric acid and saturated saline, dried and concentrated. Methanol was added to the residue, the precipitate was collected by filtration, washed with methanol, and dried to give the title compound (1.00 g, 2.03, 01, 34.2%) as a red-purple powder. _{Ή-NR (200MHz, CDC1 3} ): δΐ.00 (3H, s), 1.38 (4H, m), 1.45 (6H, m), 1.79 (3H, q, J = 0.6 Hz), 2.26 (3H, q , J = 1.2 Hz), 2.41 (3H, s), 2.92 (2H, s), 7.26 (2H, d, J = 7.6 Hz), 7.87 (2H, d, J = 8.0 Hz), 9.57 (1H, brs ).

Elemental _{analysis: C 23 H 29 N 3 0} 3 S 3 Calculated:. C, 56.18; H, 5.94; N, 8.55; S, 19.56 Found: C, 56.21; H, 5.95 ; N, 8.38; S , 19.54.

Melting point: 180.0-181.0 ° C

Example 4-577

 N- {8-[(5-Fluoro-2,2-dimethylpentyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [ 1,4] thiazine-1-ylidene} -4-methylbenzensulfonamide

 The compound obtained in Example 3-4 (1.71 g, 4.48 dragonol), 5-fluoro-2,2-dimethylpentanol obtained in Reference Example 41 (1.40 g, a 1: 1 mixture of ethyl acetate) and triphenyl To a suspension of nilphosphine (1.57 g, 5.82 mmol) in THF (35 ml) was added dropwise DEAD (0.965 ml, 5.82 bandol) while stirring at room temperature, and the reaction was allowed to stand at room temperature for 11 hours, Stirred at ° C for 26 hours. After concentrating the reaction solution, methanol was added. The precipitate was collected by filtration, washed with methanol, and crystallized from acetic acid-THF to give the title compound (874 mg, 1.76 mmol) as a red powder.

_{Ή-NMR (300MHz, CDC1 3} ): δΐ.01 (6Η, s), 1.41 (2H, m), 1.68 (2H, m), 1.78 (3H, s), 2.26 (3H, s), 2.41 (3H , s), 2.89 (2H, s), 4.41 (2H, dt, J = 47.4, 5.9 Hz), 7.27 (2H, d, J = 8.4 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.58 (1H, brs).

Elemental _{analysis: C 22 H 28 N 3 0} 3 S 3 F 0.4H 2 0 Calculated:. C, 52.34; H, 5.75;, 8.32; S, 19.05 (%) Found: C, 52.57; H, 5.68; N, 8.29; S, 18.76).

Melting point: 179.0 180: 5:

Example 4-578

4-N- {8-[(2,2-Dimethylpentyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydric-1H-imidazo [5,1-c ] [1,] thiazine-1-ylidene} benzenesulfonamide

The compound obtained in Example 3-6 (427 mg, 1.06 lol), 2,2-dimethylpentanol (153 mg, 1.17 mmol) and triphenylphosphine (373 mg, 1.38 ranol) in THF (8.5 DEAD (0.229 ml, 1.38 mL) was added dropwise to the suspension at room temperature while stirring at room temperature, and the reaction solution was stirred at 50 ° C for 35 hours. The reaction mixture was diluted with ethyl acetate (35 ml), washed with 0.1 IN hydrochloric acid, water and saturated saline, dried, concentrated and diluted with methanol. The precipitate was collected by filtration, washed with methanol, and crystallized from ethyl acetate and diethyl ether to give the title compound (224 n) g, 0.448 mmol) as a purple powder.

_{Ή-NMR (300MHz, CDC1 3} ): (50.92 (3H, m), 0.98 (6H, s), 1.27 (4H, brd, J = 3.6 Hz), 1.79 (3H, q, J = 0.9 Hz), 2.26 (3H, q, J = 1.2 Hz), 2.89 (2H, s), 7.44 (2H, dt, J = 8.7, 1.8 Hz), 7.87 (2H, dt, J = 8.7, 2.1 Hz), 9.56 (1H, brs). Elemental analysis: Calculated for C ₂₁ H ₂₆ N ₃ 0 ₃ S ₃ C1: C, 50.44; H, 5.24; N, 8.40; S, 19.24; C1, 7.09 (), found C, 50.43; H, 5.18; N, 8.38; S, 19.20; C1, 7.12 () .mp.185.5-186.5

Example 4-579

 N- (5,6-dimethyl-3-oxo-8-{[2- (2,2,2-trifluoroethoxy) edyl] sulfanylto 2,3-dihydro-1H-imidazo [5,1-c ] [1,4] thiazine-triylidene) -4-methylbenzenesulfonamide

N- (5,6-Dimethyl-3-oxo-8-sulfanyl-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine- obtained in Example 3-4 To a suspension of 1-ylidene) -4-methylbenzenesulfonamide (200 mg, 0.524 acetyl) and potassium carbonate (109 mg, 0.786 mmol) in Ν, Ν-dimethylformamide (3.00 ml) was added Reference Example 71. A solution of 2- (2,2,2-trifluoroethoxy) ethyl methanesulfonate (140 mg, 0.629 ol) in N, N-dimethylformamide (l.OOml) obtained in the above was added. After heating for 30 minutes at the reaction mixture 8 (TC, and extracted with acetic acid Echiru addition of 1N hydrochloric acid. The extract was washed with water, dried (MgSO ₄₎ After the title compound was evaporated under reduced pressure (87.9 mg, 33¾) as dark red crystals, which were recrystallized from ethyl acetate-ethyl ether to give dark red crystals having a melting point of 167-168 ° C.

IR (KBr) V 3243, 2932, 1755, 1742, 1665, 1624, 1561 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 1.79 (3Η, d, J = 1.2 Hz), 2.26 (3H, d, J = 0.9 Hz), 2.42 (3H, s), 3.17 (2H, t, J = 6.6 Hz ), 3.83 (2H, t, J = 8.4 Hz), 3.84 (2H, q, J = 8.7 Hz), 7.29 (2H, d, J = 8.1 Hz), 7.84 (2H, d, J = 8.Hz) , 9.63 (1H, bs). Elemental analysis: C ₁₉ ¾. N ₃ 0 ₄ S ₃ F ₃

Calculated (%): C, 44.96; H, 3.97; N, 8.28; S, 18.95.

Found (%): C, 45.37; H, 3.99; N, 8.41; S, 19.32.

Example 4-580

N- (5,6-dimethyl-3-oxo-8-{[2- (2-fluoroethoxy) ethyl] sulfanyl} -2,3_dihydro-1H-imidazo [5,1-c] [1,4 ] Thiazine-1-ylidene) -4-methylbenzenesulfonamide

N- (5,6-Dimethyl-3-oxo-8-sulfanyl-2,3-dihydro-1H-imidazo [5, c] [1,4] thiazine-1- obtained in Example 3-4 A suspension of N, N-dimethylformamide (15.0 ml) of (ylidene) -4-methylbenzenesulfonamide (1.50 g, 3.93 t01) and potassium carbonate (815 mg, 5.90 mmol) was obtained in Reference Example 85. A solution of the obtained methanesulfonic acid 2- (2-fluoroethoxy) ethyl ester (879 mg, 4.72 mmol) in Ν, Ν-dimethylformamide (5.00 ml) was added. After the reaction mixture was heated at 80 for 2 hours, 1N hydrochloric acid was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (34.7 mg, 10%) as dark red crystals. Recrystallization from ethyl acetate-jetil ether gave dark red crystals with a melting point of 156-158 ° C.

IR (KBr) V: 3241, 2951, 1742, 1663, 1620, 1561 cm " ¹ .

_{Ή-NR (CDC1 3):} δ 1.79 (3Η, d, J = 1.0 Hz), 2.26 (3H, d, J = 1.2 Hz), 2.42 (3H, s), 3.17 (2H, t, J = 6.6Hz ), 3.72 (2H, dt, J = 29.8, 4.0 Hz), 3.74 (2H, t, J = 6.6

Hz), 4.56 (2H, dt, J = 47.6, 4.Hz), 7.29 (2H, d, J = 8.0Hz), 7.85 (2H, d, J = 8.

Hz), 9.59 (1H, bs).

Elementary analysis: as _{C 19 H 22 N 3 0 4} S 3 F

Calculated (%): C, 48.39; H, 4.70; N, 8.91; S, 20.40.

Found (%): C, 48.48; H, 4.79; N, 8.88; S, 20.40. Example 5-1

 N- {2,3-dihydro-5,6-dimethyl-3-oxo-8- (4-toluidino) -1H-imidazo [5,1-c] [1,4] thiazine-1_ylidene} -4 -Methylbenzenesulfonamide

N- [2,3-dihydro-5,6-dimethyl-8- (pentylsulfanyl) -3-oxo-1H-imidazo [5,1-c] [1,4] obtained in Example-24 A mixture of] thiazine-1-ylidene] -4-methylbenzenesulfonamide (200 mg, 0.443 tmol) and p-toluidine (102 mg, 0.930 mmol) was stirred with 120 ^ for 3 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (74.2 mg, 37 °) as orange crystals. Recrystallization from ethyl acetate-ethyl ether gave orange crystals of melting point 237-239T :.

Infrared absorption spectrum (IR) (in KBr) V: 3164, 3031, 2924, 1717, 1653, 1607, 1588, 1557, 1514, 1485 cm " ¹ .

_{• H-NMR (CDC1 3)} : δ 1.77 (3Η, d, J = 0.6 Hz), 2.37 (6H, s), 2.41 (3H, s), 7.05 (2H, d, J = 8.6Hz), 7.19 ( 2H, d, J = 8.2 Hz), 7.28 (2H, d, J = 8.0 Hz), 7.80 (2H, d, J = 8.2 Hz), 9.58 (1H, bs), 10.45 (1H, bs).

Elemental analysis: C ₂₂ H ₂₂ N ₄ 0 ₃ S ₂ · 0.2 H ₂ 0

Calculated value (%): C, 57.67; H, 4.93; N, 12.23; S, 14.00.

Found (%): C, 57.62; H, 4.90; N, 12.02; S, 14.24.

Example 5-2

 N- {5,6-Dimethyl-8- [methyl (2-phenylethyl) amino] -3-oxo-2,3_dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1- Ylidene} -4-methylbenzenesulfonamide

N- [8-[(5-Phenylpentyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydrido-1H-imidazo [5,1- c] A solution of [1,4] thiazine-1-ylident 4-methylbenzenesulfonamide (200 mg, 0.411 nimo'l) and N-methylphenethylamine (0.179 ml, 1.23 mmol) in tetrahydrofuran (3.00 ml) was prepared. Heated reflux for 16 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The extract was washed with water, after Drying (MgSO _4), the solvent was distilled off under reduced pressure. The residue is purified by silica gel column chromatography. The title compound (7.2 mg, 3.9¾) was obtained as orange amorphous crystals by elution with n-hexane-ethyl acetate (10: 1, v / v).

Infrared absorption spectrum (IR) (in KBr) V: 3368, 3260, 3061, 3027, 2926, 1728, 1663, 1601, 1537, 1497 cm " ¹ .

_{'H-NMR (CDC1 3)} : δ 1.83 (3H, d, J = 1.0 Hz), 2.26 (3H, d, J = 0.6 Hz), 2.38 (3H, s), 2.82 (2H, t, J = 7.0 Hz), 3.28 (3H, s), 3.7 (2H, t, J = 7.4 Hz), 7.02-7.10

(2H, m), 7.14-7.24 (5H, m), 7.79 (2H, d, J = 8.0 Hz), 9.67 (1H, bs).

Elemental analysis: as C ₂₄ H ₂₆ N ₄ 0 ₃ S ₂ · 0.60

Calculated (): C, 58.42; H, 5.56; N, 11.35; S, 13.00.

Found (%): C, 58.06; H, 5.36; N, 11.11; S, 13.52.

The following is a list of the compounds synthesized in Examples 5-1 and 5-2 and the compounds synthesized in the same manner. ,

(Table 67)

Replacement rules 26) The data of the compounds synthesized in Examples 5-3 to 5-8 are shown below.

Example 5-3

The crystals were recrystallized from ethyl acetate-getyl ether to give orange crystals.

216-218 ^. '

Infrared absorption spectrum (IR) (in KBr): 3358, 3235, 2921, 1732, 1661, 1605, 1539 cur ¹ .

_{Ή-NMR (CDC1 3):} δ 1.89 (3Η, d, J-1.0 Hz), 2.31 (3H, d, J = 1.0 Hz), 2.40 (3H, s), 3.17 (6H, s), 7.26 (2H , d, J = 8.2 Hz), 7.79 (2H, d, J = 8.4 Hz), 9.69 (1H, bs).

Elemental analysis: C ₁₇ H _2. Calculated for N ₄ 0 ₃ S ₂ : C, 52.02; H, 5.14; N, 14.27; S, 16.34 (%), Found: C, 52.09; H, 5.12; N, 14.21; S, 16.60 (%) .

Example 5-4

Infrared absorption spectrum (IR) (in KBr) v 3353, 2930, 2859, 1728, 1661, 1607, 1537 cm " ¹ .

Ή-NMR (CDCI3): δ 0.855 (3Η, i, J = 6.6Hz), 1.10-1.34 (6H, m), 1.44-1.64 (2H, m), 1.90 (3H, s), 2.31 (3H, s ), 2.39 (3H, s), 3.25 (3H, s), 3.39 (2H, t, J = 7.2 Hz), 7.24 (2H, d, J = 8.0 Hz), 7.77 (2H, d, J = 8.2 Hz) ), 9.75 (1H, bs).

Example 5-5

The crystals were recrystallized from ethyl acetate-ethyl ether to obtain orange crystals.

207-209 ° C.

Infrared absorption spectrum (IR) (in KBr): 3252, 2971, 2924, 2859, 1732, 1661, 1611, 1539, 1497 cm ¹ .

 Ή-NMR (CDCI3): (51.88 (3H, d, J = 0.8 Hz), 2.31 (3H, d, J = 1.0 Hz), 2.41 (3H, s), 3.37 (2H, t, J = 4.8 Hz) , 3.72 (2H, t, J = 5.2 Hz), 7.29 (2H, d, J = 8.0 Hz), 7.78 (2H, d, J = 8.4 Hz), 9.67 (1H, bs).

Elemental analysis: C ₁₉ H ₂₂ N ₄ 0 ₄ S ₂ '0.20 Calculated: C, 52.08; H, 5.15;, 12.79; S, 14.64 (%), found: C, 52.07; H, 5.23; N, 12.74; S, 14.84 (%).

Example 5-6

The crystals were recrystallized from ethyl acetate-ethyl ether to obtain orange crystals. Mp 21 ° C 213 ° C.

Infrared absorption spectrum (IR) (in KBr): 3287, 2944, 2880, 1728, 1655, 1607, 1534, 1497 cm " ¹ .

] H- thigh _{(CDC1 3): δ 1.58-1.76 (} 6Η, m), 1.89 (3H, d, J = 1.2 Hz), 2.31 (3H, d, J = 1.2 Hz), 2.40 (3H, s), 3.35-3.44 (4H, m), 7.25 (2H, d, J = 8.4Hz), 7.78 (2H, d, J = 8.4Hz), 9.66 (1H, bs).

Elemental analysis: C _2. H ₂₄ N ₄ 0 ₃ S ₂ Calculated: C, 55.53; H, 5.59; N, 12.95; S, 14.83 (%), Found: C, 55.14; H, 5.50;, 12.75; S, 14.57 () .

Example 5-7

The crystals were recrystallized from ethyl acetate-ethyl ether to obtain orange crystals.

192-194 ° C.

Infrared absorption spectrum (IR) (in KBr) Re:. 2922, 1726, 1663, 1605, 1537, 1495 cm- 1 Ή-NMR (CDC1 3): δ 1.20-1.82 (5Η, m), 1.88 (3H, d, J = 1.0 Hz), 2.30 (3H, d, J = 0.8Hz), 2.39 (3H, s), 2.53 (2H, d, J = 7.4 Hz), 2.98-3.18 (2H, m), 3.56- 3.72 (2H, m), 7.12 (2H, d, J = 6.6 Hz), 7.20-7.38 (5H, m), 7.77 (2H, d, J = 8.4 Hz), 9.65 (1H, bs).

Example 5-8

The crystals were recrystallized from ethyl acetate-disopropyl ether to give orange crystals.

Melting point: 194-196 ° C.

Infrared absorption spectrum (IR) (in KBr): 3362, 3027, 2926, 1732, 1663, 1601, 1539, 1495 cm—

Ή one _{NMR (CDC1 3): δ 1.89} (3Η, d, J = 0.6 Hz), 2.30 (3H, d, J = 1.0 Hz), 2.41 (3H, s), 2.96-3.06 (4H, m), 3.56 -3.66 (4H, m), 7.06-7.22 (4H, m), 7.25 (2H, d, J = 8.4 Hz), 7.77 (2H, d, J = 8.Hz), 9.71 (1H, bs).

Elemental analysis: Calculated as C ₂₅ H ₂₆ N ₄ 0 ₃ S ₂ -0.2H ₂ 0 (¾): C, 60.27; H, 5.34; N, 11.24; S, 12.87. Observed (¾): C, 60.18; H, 5.42; N, 10.97; S, 12.82.

Example 6-1

1-Amino-5,6-dimethyl-8- (pentylsulfanyl) -3H-imidazo [5,1-c] [1,4] thiazin-3-one Method a

N- [5,6-Dimethyl-3-oxo-8- (pentylsulfanyl) -2,3-dihydro-1H-imidazo [5, tric] [1,4] obtained in Example-24 [Thiazine-1-ylidene] -4-methylbenzenesulfonamide (220 mg, 0.487 mmol) was dissolved in tetrahydrofuran (4.00 ml), and 25% aqueous ammonia (500 ml) was added. After the reaction mixture was heated in a sealed tube at 80 ° C. for 17 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (62.4 mg, 43%) as dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 127-129 ° C.

Infrared absorption spectrum (IR) (in KBr): 3397, 3279, 3104, 2957, 2932, 2861, 1715, 1636, 1605, 1545 cm—

_{¾-NMR (CDC1 3):} δ 0.919 (3Η, t, J = 6.6Hz), 1.33-1.46 (4H, m), 1.66-1.77 (2H, m), 1.74 (3H, d, J = 0.8 Hz) , 2.27 (3H, d, J-0.8 Hz), 2.92 (2H, t, J = 7.8 Hz), 7.36 (2H, bs).

Elementary analysis: as C ₁₃ H ₁₉ N ₃ 0S ₂

Calculated value (%): C, 51.56; H, 6.52; N, 13.88; S, 21.18.

Found (%): C, 51.37; H, 6.27; N, 13.81; S, 21.15.

Example 6-2

Triamino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5,1-c] [1,4] thiazin-3-one

Method a

 In the same manner as in Example 6-1, the N- [5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydrido-1H obtained in Example 4-9 was obtained. The title compound (1.14 g, 86%) was synthesized from -imidazo [5,1-c] [1,4] thiazine-triylidene] -4-methylbenzenesulfonamide (2.00 g, 4.43 mmol). Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 174-176 ° C.

Infrared absorption spectrum (IR) (in KBr) So: 3403, 3115, 2957, 2870, 1715, 1634, 1605, 1543 cm- ¹ . ¾ Single stroke R (CDCI3): δ 0.946 (6Η, d, J = 6.2 Hz)., 1.50-1.70 (3H, in), 1.74 (3H, d, J = 1.2 Hz), 2.27 (3H, d, J) = 1.2 Hz), 2.93 (2H, t, J = 8.0 Hz), 7.05 (1H, bs). Elemental analysis: C ₁₃ H ₁₉ N ₃ 0S ₂

Calculated value (%): C, 52.49; H, 6.44; N, 14.13; S, 21.56.

Found (%): C, 52.50; H, 6.34; N, 14.11; S, 21.47.

Example 6-3

 1-Amino-5,6-dimethyl-8-[(4,4,5,5,5-pentafluoropentyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazine- 3-on

 In the same manner as in Example 6-1, the N- [5,6-dimethyl-3-oxo--8-[(4,4,5,5,5-pentanofluoropentyl) obtained in Example 4-34 was obtained. ) Sulfanyl] -2,3-dihydro-1H-imidazo [5, l_c] [1,4] thiazine-triy.den] _4-methylbenzenesulfonamide (2.00 g, 4.43 mmol) from the title compound (1.34 g) , 94¾). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 173-175.

Infrared absorption spectrum (IR) (in KBr) V:. 3387, 2940 , 1713, 1669, 1605, 1539 cm "1 Ή-NMR (CDC1 3): δ 1.74 (3Η, d, J = 1.0 Hz), 2.00 -2.24 (4H, m), 2.26 (3H, d, J = 1.0 Hz), 3.01 (2H, t, J = 7.2 Hz), 7.27 (2H, bs).

Elementary analysis: as _{C 13 H 14 N 3 0S 2} F 5

Calculated (¾): C, 40.30; H, 3.64; N, 10.85; S, 16.55.

Found (%): C, 40.34; H, 3.46; N, 10.93; S, 16.72.

Example 6-4

 1-Amino-5,6-dimethyl-8-[(3-fluoro-3-methylbutyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one

 In the same manner as in Example 6-1, N- [5,6-dimethyl-8-[(3-fluoro-3-methylbutyl) sulfanyl] -3-oxo-2, obtained in Example 4-40. 3-Dihydrid-1H-dimidazo [5, tric] [l, 4] thiazine-triylidene] -4-methylbenzenesulfonamide (526 mg, 1.12 hid ol) from the title compound (320 mg, 91%) Was synthesized. Recrystallization from ethyl acetate-ethyl ether gave a dark red crystal with a melting point of 188-190 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3387, 2978, 2936, 1717, 1655, 1636, 1605, 1541 cm- ¹ . ^{l H - NMR (CDCI3):} δ 1.41 (6H, d, J = 21.2 Hz), 1.74 (3H, d, J = 1.0 Hz), 1.90-2.10 (2H, m), 2.28 (3H, d, J = 1.2 Hz), 2.98-3.08 (2H, m), 7.03 (2H, bs).

Elementary analysis: as _{C 13 H 18 N 3 0S 2} F

Calculated (¾): C, 49.50; H, 5.75; N, 13.32; S, 20.33.

Found (%): C, 49.54; H, 5.72; N, 13.39; S, 20.00.

Example 6-5

Toamino-5,6-dimethyl-8-[(3,3-dimethylbutyl) sulfanyl] -3H-imidazo

[5, 1-c] [1, 4] thiazin-3-one

 In the same manner as in Example 6-1, the N- [5,6-dimethyl-8-[(3,3-dimethylbutyl) sulfanyl] -3-oxo-2,3 obtained in Example 4-143 was obtained. -Dihydro-1H-imidazo

[5, tric] [1,4] thiazine-triylidene] -4_methylbenzenesulfonamide (1.82 g,

The title compound (665 mg, 55%) was synthesized from 3.91 mmol). The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 191 ° -193 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3385, 3287, 2957, 2863, 1717, 1628, 1605, 1543 cm- ¹ .

 Ή-NMR (CDCI3): δ 0.949 (9Η, s), 1.52-1.70 (2H, m), 1.75 (3H, s), 2.27 (3H, s), 2.83-2.95- (2H, m), 7.34 ( 2H, bs).

Example 6-6

Triamino-5,6-dimethyl-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazine- 3-on

 In the same manner as in Example 6-1, the N- [5,6-dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluoride) obtained in Example 4-35 was obtained. Xyl) sulfanyl 3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene] -4-methylbenzenesulfonamide (2.00 g, 3.60 bandol) from the title compound (781 g) , 54%). The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 155 to 157 ° C.

Infrared absorption spectrum (IR) (in KBr): 3397, 3283, 2944, 1715, 1626, 1605, 1551 cm " ^1. '

One thigh _{R (CDC1 3): δ 1.66-1.89} (4Η, m), 1.74 (3H, d, J = 1.2 Hz), 1.94-2.24 (2H, m), 2.27 (3H, d, J = 1.0 Hz) , 2.95 (2H, t, J-7.2 Hz), 7.29 (2H, bs). Elemental analysis: as C ₁₄ H ₁₆ N ₃ OS ₂ F ₅

Calculated value (%): C, 41.89; H, 4.02; N, 10.47; S, 15.98.

Found (%): C, 41.83; H, 3.89; N, 10.55; S, 15.93.

Example 6-7

Tomino-5,6-dimethyl-8-[(5,5,5-trifluoropentyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one

Method b

N- {5,6-dimethyl-3-oxo-8-[(5,5,5-trifluoropentyl) sulfanyl] obtained in Example 4-31] -2,3-dihydro-1H-imidazo [ 5, tri c] [1,4] thiazine-1-ylidene} -4-methylbenzenesulfonamide (800 mg, 1.58 mmol) and ammonium formate (1.05 g, 15.8 eol) in ethanol (30.0 ml) The suspension was heated at 80 ° C. for 15 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: l, 'v / v) to give the title compound (354 mg, 64¾) as dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 150-152 ° C.

Infrared absorption spectrum (IR) (in KBr) V 3397, 3279, 2940, 1715, 1628, 1605, 1545 cm " ¹ .

_{'H-NMR (CDC1 3)} : δ 1.50-1.86 (4Η, m), 1.74 (3H, s), 2.00-2.32 (2H, m), 2.26 (3H, s), 2.94 (2H, t, J- 7.4 Hz), 7.30 (2H, bs).

Elementary analysis: as _{C 13 H 16 N 3 0S 2} F 3

Calculated (%): C, 44.43; H, 4.59; N, 11.96; S, 18.25.

Obtained): C, 44.40; H, 4.68; N, 11.89; S, 18.50.

Example 6-8

Triamino-5,6-dimethyl-8-[(4,4,4-trifluoromethyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazine-3-one

Method b

N- [5,6-dimethyl-3-oxo-8-[(4,4,4-trifluorofluoro) sulfanyl] obtained in Example 4-41 by a method similar to that of Example 6-7. -2,3-dihydro-1H-imida The title compound (475 mg, 84¾) was synthesized from azo [5,1-c] [1,4] thiazine-triylidene] -4-methylbenzenesulfonamide (830 mg, 1.69 tmol). The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 170-172.

Infrared absorption spectrum (IR) (in KBr) V: 3409, 3289, 3096, 3042, 1715, 1634, 1605, 1539 cm- ¹ .

_{Ή-NMR (CDC1 3):} δ 1.74 (3Η, d, J = 1.2 Hz), 2.01 (2H, quintet, J = 8.1 Hz), 2.16-2.36 (2H, m), 2.26 (3H, d, J = 1.2 Hz), 2.99 (2H, t, J = 7.8 Hz), 7.61 (2H, bs).

Elementary analysis: as _{C 12 H 14 N 3 0S 2} F 3

Calculated value (%): C, 42.72; H, 4.18; N, 12.45; S, 19.01.

Found (%): C, 42.48; H, 4.12; N, 12.34; S, 19.10.

The following is a list of compounds synthesized in Examples 6-1 to 6-8 and compounds synthesized in the same manner.

(Table 68)

(弒 (ί2φ (Table 69)

Substitution rules 26) (Table 70)

弒 mm for replacement (Table 7 1)

差替え用弒 (m 以下に実施例 6-9〜6- 51で合成した化合物のデータを示す。

弒 (m The data of the compounds synthesized in Examples 6-9 to 6-51 are shown below.

Example 6-9

The crystals were recrystallized from ethyl acetate-diisopropyl ether to obtain red crystals.

Melting point: 116-118 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3318, 3025, 2924, 2835, 1713, 1655, 1590, 1518, 1497 cm " ¹ .

_{ΐ-NMR (CDC1 3):} δ 1.72 (3Η, s), 2.26 (3H, s), 2.28 (3H, s), 2.96 (2H, t,

J = 6.6 Hz), 3.80 (2H, dt, J = 6.6, 6.2 Hz), 7.18-7.42 (6H, m).

Elemental _{analysis: C 17 H 19 N 3 0S} 2 Calculated: C, 59.10; H, 5.54 ; N, 12.16; S, 18.56

(%), Found: C, 59.10; H, 5.51; N, 12.03; S, 18.01 (%).

Example 6-10

The crystals were recrystallized from ethyl acetate-diisopropyl ether to obtain red crystals.

Melting point: 117-119 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3310, 2959, 2932, 2857, 1701, 1661, 1582 cm " ¹ .

 NMR (CDCI3): δ 0.910 (3Η, t, J = 6.2 Hz), 1.24-1.44 (4H, m), 1.60-1.72 (2H, m), 1.74 (3H, d, J = 1.2 Hz), 2.26 ( 3H, d, J = 1.0 Hz), 2.48 (3H, s), 3.50 (2H, dt, J = 7.0, 5.8 Hz), 7.41 (1H, bs).

Elemental _{analysis: C 14 H 21 N 3 0S} 2 Calculated: C, 53.99; H, 6.80 ; N, 13.49; S, 20.59

(%), Found: C, 53.83; H, 6.65; N, 13.40; S, 20.52 (%).

Examples 6-11

Recrystallization from ethyl acetate-diisopropyl ether gave red crystals.

Melting point: 130-132.

Infrared absorption spectrum (IR) (in KBr) V: 3320, 2957, 2932, 2859, 1715, 1591, 1516 cm " ¹ .

_{'H-NMR (CDC1 3)} : δ 0.866 (3Η, t, J = 7.0Hz), 1.22-1.36 (4H, m), 1.52-1.66 (2H, m), 1.73 (3H, s), 2.28 (3H , s), 2.35 (3H, s), 2.84 (2H, t, J = 7.8 Hz), 4.65 (2H, d, J-5.4 Hz), 7.12-7.30 (4H, m), 7.71 (1H, bs) .

Elemental analysis: Calculated as C ₂₁ H ₂₇ N ₃₀ S ₂ : C, 62.81; H, 6.78; N, 10.46; S, 15.97 (%), Found: C, 62.58; H, 6.65;, 10.29; S, 16.02 (%).

Dark red oil.

Infrared absorption spectrum (IR) (in KBr) V: 3230, 3027, 2955, 2930, 1717, 1655, 1590, 1518, 1497 cm " ¹ .

_{Έ-NMR (CDC1 3):} 50.903 (3H, t, J = 6.6 Hz), 1.16-1.40 (4H, m), 1.40-1.64 (2H, m), 1.71 (3H, s), 2.26 (3H, d , J = 0.8 Hz), 2.71 (2H, t, J = 7.8 Hz), 2.96 (2H, t, J = 6.6 Hz), 3.80 (2H, q, J = 6.2 Hz), 7.15-7.37 (5H, m ), 7.43 (1H, bs).

_{NMR (DMSO- d 3, 300 MHz} ): 6 2.45 (3H, s), 5.19 (1H, d, J = 7.9 Hz), 6.54 (1H, d, J = 7.9 Hz), 7.46 (1H, br), 8.69 (1H, br).

Elemental analysis: C ₇ H ₇ N ₃ OS ₂ · 0.15 0 Calculated: C, 38.93; H, 3.41; N, 19.46; S, 29.69 (%), found: C, 39.15; H, 3.40; N , 19.18; S, 29.78 (%).

Example 6-14

 3-[(1-imino-5,6_dimethyl-3_oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,] thiazin-8-yl) sulfael] ethyl propionate

 A suspension of the compound (705 mg, 1.46 mmol) obtained in Example 2-5 and ammonium formate (486 mg, 7.32 tmol) in ethanol (24 ml) was heated under reflux for 15 hours. The reaction mixture was diluted with ethyl acetate (50 ml), washed with 10% aqueous ammonium chloride solution and saturated saline, dried over sodium sulfate, concentrated to dryness, and the residue was crystallized from ethyl acetate and getyl ether. To give the title compound (264 mg, 0.808 mmol) as a dark purple powder.

'H-NMR (300MHz, CDC1 3): δ 1.28 (3Η, t, J = 7.2 Hz), 1.74 (3H, s), 2.26 (3H, s), 2.75 (2H, t, J = 6.9 Hz), 3.19 (2H, t, J = 6.9 Hz), 4.18 (2H, q, J = 7.2 Hz), 7.3 (1H, br), 8.61 (1H, br).

. Elemental _{analysis: C 13 H 17 N 3 0} 3 S 2 · 0.1¾0 Calculated: C, 47.43; H, 5.20 ; N, 12.76; S, 19.47 (), Found: C, 47.55; H, 5.26 ; N, 12.47; S, 19.23 (%).

Melting point.159.5-161.0 ° C

Example 6-15

8- (cycloheptylsulfanyl) -1-imino-5,6-dimethyl-1,2-dihydric -3H-di Midazo [5,1-c] [1,4] thiazin-3-one

 A suspension of the compound (603 mg, 1.26 mmol) obtained in Example 4-103 and ammonium formate (419 mg, 6.31 bandol) in ethanol (20 ml) was heated under reflux for 22 hours. The reaction solution was concentrated, diluted with ethyl acetate (40 ml), washed with a 10% aqueous solution of sodium chloride and saturated brine, dried over sodium sulfate, and concentrated to dryness. The residue was crystallized from ethyl acetate and dimethyl ether to give the title compound (303 mg, 0.937-1) as a red-brown powder.

_{lH- NMR (300MHz, CDC1 3)} : d 1.50-1.80 (10H, m), 1.73 (3H, q, J = 0.6 Hz), 2.11 (2H, in), 2.26 (3H, q, J = 0.6 Hz) , 3.46 (1H, sept, J = 4.5 Hz), 7.30 (1H, br), about 8.2 (1H, br).

Elemental _{analysis: C 15 H 21 N 3 0S} 2 Calculated: (:, 55.69; H, 6.54; N, 12.99; S, 19.83

(%), Found: C, 55.58; H, 6.49; N, 12.86; S, 19.83 (%).

202.5- 203.5 = 0,

Example 6-16

Trimino-5,6-dimethyl-8-[(4-methylpentyl) sulfanyl] -1,2-dihydro-3H-imidazo [5,1-c] [1,4] thiazin-3-one

 A suspension of the compound obtained in Example 4-84 (495 mg, 1.06 ol) and ammonium formate (353 mg, 5.32, 01) in ethanol (20 ml) was stirred at 70 for 3 days and at 80 ° C for 6.5 hours. . The reaction solution was concentrated, diluted with ethyl acetate (50 ml), washed with a 10% aqueous solution of ammonium chloride and saturated saline, dried over sodium sulfate, and concentrated to dryness. The residue was purified by silica gel (10 g) chromatography (ethyl acetate-hexane, 1: 8: 2, containing 0.1¾formic acid) and crystallized from getyl ether to give the title compound (238 mg, 0.764 vol). Obtained as a purple powder.

_{Ή-NM (300MHz, CDC1 3} ): δ 0.90 (6H, d, J = 6.6 Hz), 1.29 (2H, brq, J = 8.7 Hz), 1.59 (1H, sept, J = 6.5 Hz), 1.71 (2H , m), 1.74 (3H, q, J = 1.0 Hz), 2.26 (3H, q, J- 0.6 Hz), 2.92 (2H, t, J = 7.5 Hz), 7.26 (1H, s), 8.12 (1H , s).

Elemental analysis: C ₁₄ iN ₃ 0S ₂ · 0.40 Calculated: C, 52.77; H, 6.90; N, '13 .18; S, 20.12 (%), found: C, 52.85; H, 6.80; N, 13.20; S, 19.83 (%).

136.8-137. Ot Example 6-17

 8-[(cyclohexylmethyl) sulfanyl] -trimino-5,6-dimethyl-1,2-dihydro- -imidazo [5, tric] [1,4] thiazin-3-one

 A suspension of the compound (559 mg, 1.17 mol) obtained in Example 4-68 and ammonium formate (388 mg, 5.85 mmol) in ethanol (19 ml) was heated under reflux for 40 hours. During this time, ammonium formate (230 mg, 3.51 mmol) was added twice to the reaction solution. The reaction solution was concentrated, diluted with ethyl acetate (40 ml), washed with a 10% aqueous solution of ammonium chloride and saturated saline, dried over sodium sulfate, and concentrated to dryness. The residue was crystallized from ethyl acetate to give the title compound (258 mg, 0.798 mmol) as a reddish purple powder.

One _{NMR (200MHz, CDC1 3):} δ 0.98 (2H, brq, J = 12 Hz), 1.25 (3H, m), 1.61 (1H, m), 1.70-1.90 (5H, m), 1.74 (3H, brs ), 2.26 (3H, brs), 2.83 (2H, d, J = 7.0 Hz), about 7.5 (1H, br), about 8.2 (1H, br).

Elemental _{analysis: C 15 H 21 N 3 OS} 2 Calculated: C, 55.69; H, 6.54 ; N, 12.99; S, 19.83 (%), Found: C, 55.56; H, 6.51 ;, 12.83; S , 19.83 (%).

Melting point.190.0- 192.0 ° C

Examples 6-18

Tomino-5,6-dimethyl-8-[(4-fluorobutyl) sulfanyl] _3H-imidazo [5,1-c] [1,4] thiazin-3-one

N- {5,6-dimethyl-8-[(4-fluorobutyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] obtained in Example -33 A suspension of 1,4] thiazine-1-ylidene} -4-methylbenzenesulfonamide (204 mg, 0.448 mol) and ammonium formate (297 mg, 4.48 mmol) in ethanol (8.00 ml) was added at 80 ° C. After heating for 20 hours, water was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (116 mg, 86¾) as dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 118-120 ° C.

IR (KBr): 3393, 3283, 2965, 2938, 1713, 1628, 1625, 1548 cm " ¹ .

_{'H-NMR (CDC1 3)} : (51.74 (3H, d, J = 1.2 Hz), 1.62-1.96 (4H, m), 2.26 (3H, d, J = 1.0 Hz), 2.98 (2H, t, J = 7.4 Hz), 4.50 (2H, dt, J = 47.2, 5.4 Hz), 7.64 (2H, bs).

Elemental analysis: as C ₁₂ H _{1 ()} N ₃ 0S ₂ F

Calculated (%): C, 47.82; H, 5.35; N, 13.94; S, 21.28.

Found (%): C, 47.62; H, 5.39; N, 13.80; S, 21.24.

Example 6-19

 8-[(2,2-dimethylpentyl) sulfanyl] -1-imino-5,6-dimethyl-1,2, -dihydro-3H-imidazo [5, tric] [1,4] thiazine-3- On

 A suspension of the compound (1.04 g, 2.17 mmol) obtained in Example 4-503 and ammonium formate (720 mg, 10.9 band01) in ethanol (20 ml) was heated under reflux for 20 hours. After the reaction solution was concentrated, it was extracted with ethyl acetate. The organic layer was washed with 10% aqueous ammonium chloride solution and saturated saline, dried over sodium sulfate, concentrated to dryness, and the residue was chromatographed on silica gel (10 g) (ethyl acetate, hexane, 3: 7-7: 3) The fraction of ethyl acetate-hexane (6: 4-7: 3) was concentrated to dryness and crystallized from ethyl acetate and getyl ether to give the title compound (338 mg, 1.04 mmol) as a purple powder.

_{Ή-NMR (300MHz, CDC1 3} ): 50.92 (3H, dt, J = 1.8, 4.5 Hz), 1.01 (6H, s), 1.29 (4H, brd, J = 3.6 Hz), 1.75 (3H, q, J = 1.2 Hz), 2.26 (3H, q, J = 1.2 Hz), 2.92 (2H, s).

Elemental _{analysis: C 15 H 23 N 3 OS} 2 O.2H 2 0 Calculated: C, 54.74; H, 7.17 ; N, 12.77; S, 19.49 (%), Found: C, 54.78; H, 7.09 N, 12.99; S, 19.51 ().

nip.139.0-140.3 ° C

Example 6-20

Triamino-5,6-dimethyl-8-[(3,3,4,4,4-pentafluorobutyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazine- 3-year-old

N- {5,6-Dimethyl-3-oxo-8-[(3,3,4,4,4-pentafluoromethylbutyl) sulfael] obtained in Example 4-502 -2,3-Dihydrido -1H-imidazo [5, tric] [1, 4] thiazine-1-ylidene} -4-methylbenzenesulfonamide (311 mg, 0.593 mmol) and ammonium formate (393 mg, 5.93 mmol) in ethanol (12.0 was heated at 80 ° C for 20.5 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO ₄₎ Thereafter, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (256 mg, 89¾) ′ as dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 172-174 ° C.

IR (KBr) V: 3397, 2940, 1732, 1715, 1701, 1655, 1607, 1535 cm " ¹ .

_{Ή-NMR (CDC1 3):} (51.75 (3H, s), 2.27 (3H, s), 2.38-2.58 (2H, m), 3.15 (2H, t, J = 8.1 Hz), 7.34 (2H, bs) .

Elemental analysis: as C ₁₂ H ₁₂ N ₃ OS ₂ F ₅ -0.3H ₂₀

 Calculated (): C, 38.05; H, 3.35; N, 11.09; S, 16.93.

Found (¾): C, 38.09; H, 3.09; N, 11.14; S, 17.27.

Example 6-21

 Triamino-5,6-dimethyl-8-[(6,6,7,7,7-pentafluoroheptyl) sulfanyl] -3H imidazo [5, tric] [1,4] thiazin-3-one ·

 According to a method similar to that of Example 6-7, N- [5,6-dimethyl-3-oxo- 8-[(3,3,4,4,4-pentenefluoro) obtained in Example 4-501 was obtained. Butyl) sulfanyl] -2,3-dihydro-1H-imidazo [5, lc] [1,4] thiazin-1-ylidene] -4-methylbenzenesulfonamide (750 mg, 1.32 mmol) from the title compound (250 mg mg, 46%). The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 1U-116 ° C.

 IR (KBr) V: 3399, 3289, 3104, 3032, 2946, 1868, 1715, 1632, 1605, 1541 cm "'.. ¾-NMR (CDCI3): (51.40-1.86 (6H, m), 1.74 (3H , d, J = 1.2 Hz), 1.90-2.20 (2H, m), 2.26 (3H, s), 2.93 (2H, t, J = 7.6 Hz), 7.78,. (2H, bs).

Elementary analysis: as _{C 15 H 18 N 3 0S 2} F 5

Calculated (): C, 43.37; H, 4.37; N, 10.11; S, 15.44.

Found (%): C, 43.55; H, 4.57; N, 10.09; S, 15.18.

Example 6-

1-Amino-5,6-dimethyl-8-[(6,6,6-trifluorohexyl) sulfanyl] -3H-imidazo [5, I-c] [1,4] thiazin-3-one

In the same manner as in Examples 6-7, N_ [5,6-dimethyl-3-oxo-8 (6,6,6-trifluorohexyl) sulfanyl] -2, obtained in Example 4-506. 3-dihydro-1H-imi The title compound (290 mg, 63%) was synthesized from dazo [5, tric] [1,4] thiazine-triylidene] -4-methylbenzenesulfonamide (658 mg, 1.27 mrnol). Recrystallization from ethyl acetate-ethyl ether yielded dark red crystals with a melting point of 114-116 ° C.

IR (KBr) V:. 3399 , 3285, 3108, 3021, 2942, 1715, 1626, 1605, 1541 cm- 1 ¾-NMR (CDC1 3): δ 1.40-1.86 (6Η, m), 1.74 (3H, d , J = 0.8 Hz), 1.98-2.22 (2H, m), 2.26 (3H, s), 2.93 (2H, t, J = 7.8 Hz), 7.50 (2H, bs).

Elemental analysis: as OS ₂ F ₅

 Calculated value (%): C, 46.01; H, 4.96; N, 11.50; S, 17.55.

 Found (%): C, 45.79; H, 5.13; N, 11.67; S, 17.68.

 Example 6-23

 1-Amino-5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one

{5,6-Dimethyl-3-oxo-8-[(3,3,4,4,4-benzoylfluorobutyl) sulfanyl] -2,3-dihydro-m obtained in Example 4-508 -Imidazo [5,1-c] [1,4] thiazine-triylidene}-Ethanol (38.0 ml) of 4-methylbenzenesulfonamide (900 mg, 1.92 mmol) and ammonium formate (1.27 g, 19.2 mmol) The suspension was heated at 80 ° C for 18 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (583 mg, 96%) as dark red crystals. Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 140-142 ° C.

IR (KBr) Re: 3403, 3285, 3112, 2936 , 2863, 1715, 1634, 1605, 1541 cm- Ή one _{NMR (CDC1 3): 51.50-1.64 (} 2H, m), 1.64-1.86 (4H, m) , 1.74 (3H, d, J = 0.9 Hz), 2.27 (3H, d, J = 1.2 Hz), 2.94 (2H, t, J = 7, 5 Hz), 4.47 (2H, dt, J = 47.1, 5.4 Hz), 7.43 (2H, bs).

Elementary analysis: as _{C 13 H 18 N 3 0S 2} F

Calculated value (¾): C, 49.50; H, 5.75; ' ^! N, 13.32; S, 20.33.

 Found (¾): C, 49.48; H, 5.60; N, 13.35; S, 20.32.

Examples 6-24 Ethyl 5- [triamino-5,6-dimethyl-3-oxo-3H-imidazo [5, tric] [1,4] thiazine-8-yl] sulfanyl] pen

Ethyl obtained in Example 4-522 5-[(5,6-Dimethyl-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo [5, Suspension of 1-c] [1,4] thiazine-8-yl) sulfanyl] pentanoate (1.34 g, 2.63 ol) and ammonium formate (1.75 g, 26.3 ol) in ethanol (26.0 ml) After the solution was heated at 80 ° C for 17 hours, water was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (695 mg, 74%) as dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 92.0-94.0 ° C.

IR (KBr) V:. 3405 , 3283, 3115, 2978, 2936, 1723, 1634, 1665, 1537 cm "1 Ή-NMR (CDC1 3): 51.26 (3H, d, J = 6.9 Hz), 1.70-1.84 (4H, m), 1.74 (3H, s), 2.26 (3H, s), 2.32-2.40 (2H, m), 2.88-2.98 (2H, m), 4.14 (2H, q, J = 6.9 Hz), 7.51 (2H, bs).

Elemental analysis: as C ₁₅ H ₂₁ N ₃ 0 ₃ S ₂

Calculated (¾): C, 49.92; H, 5.87; N, 11.64; S, 17.77.

Found (%): C, 49.94; H, 5.79; N, 11.41; S, 17.72.

Example 6-25

8- (cyclooctylsulfanyl) -1-imino-5,6-dimethyl-1,2-dihydro-3H-imidazo [5,1-c] [1,4] thiazin-3-one

A suspension of the crude compound obtained in Example 4-164 (purity 80%, 4.00 g, 6.5 t ol) and ammonium formate (1.73 g, 26 t ol) in ethanol (100 ml) was heated under reflux for 20 hours. Was. During the reaction, ammonium formate (2.26 g, 33 ol) was added in five portions. The reaction solution was concentrated and diluted with ethyl acetate (180 ml) and water (100 ml). The aqueous layer was extracted with ethyl acetate-THF (4: 1, 50 ml). The organic layer was washed with aqueous ammonium chloride solution and saturated saline, dried over sodium sulfate, concentrated to dryness, and the residue was diluted with methanol. The precipitate was collected by filtration, washed with methanol and getyl ether, and then crystallized from methyl ethyl acetate to give the title compound (1.46 g, 4.32 g, 1, 66.3%) in dark purple. Obtained as a colored powder.

_{Ή-NMR (300MHz, CDC1 3} ): (51.60 (8H, brs), 1.73 (3H, s), 1.75 (4H, m), 2.01 (2H, m), 2.26 (3H, q, J = 0.9 Hz) , 3.54 (1H, it, J = 9.0, 4.1 Hz), 7.35 (1H, br), 8.43 (1H, br).

Elemental analysis: C ₁₆ H ₂₃ N ₃₀ S ₂ Calculated: C, 56.94; H, 6.87; N, 12.45; S, 19.00 (%), found: C, 56.66; H, 6.67; N, 12.36; S, 19.03 (%).

mp.179.5-181.0 ° C

Example 6-26

Tamino-5,6-dimethyl-8-{[2- (2,2,2-trifluoroethoxy) ethyl] sulfanyl} -311-imidazo [5,1-c] [1,4] thiazine- 3-on

N- (5,6-Dimethyl-3-oxo-8-{[2- (2,2,2-trifluoro mouth ethoxy) ethyl] sulfanyl} obtained in Example 4-579} -2,3-dihydro- Ethanol of 1H-imidazo [5,1-c] [1,4] thiazine-triylidene) -4_methylbenzenesulfonamide (1.08 g, 2.13 band01) and ammonium formate (1.41 g, 21.3 thigh01) (20.0 ml) was heated at 80 ° C for 16.5 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (144 mg, 19¾) as dark red crystals. The crystals were recrystallized from ethyl acetate-getyl ether to obtain dark red crystals having a melting point of 143 to 145 ° C.

IR (KBr) V: 3393, 3289, 3011, 1717, 1667, 1659, 1605, 1539 cm- ¹ .

_{'H-NMR (CDC1 3)} : 51.73 (3H, d, J = 1.2 Hz), 2.26 (3H, d, J = 1.2 Hz), 3.12 (2H, t, J = 5.7 Hz), 3.85 (2H, t , J = 5.1 Hz), 3.88 (2H, q, J = 8.4 Hz), 7.16 (2H, bs). Elemental analysis: As C ₁₂ H ₁₄ N ₃ 0 ₂ S ₂ F ₃

Calculated value (¾): C, 40.79; H, 3.99; N, 11.89; S, 18.15.

Measured value (D: C, 41.07; H, 3.88; N, 11.86; S, 18.01.'Example 6-27

 1-amino-6-ethyl-8-[(5-fluoropentyl) sulfanyl] -5-methyl-3H-imidazo [5,1-c] [1,4] thiazin-3-one

N- {6-ethyl-8-[(5-fluoropentyl) sulfani obtained in Example 4-529 ] -5-methyl-3-oxo-2,3-dihydro-1H-imidazo [5, 1-c] [1,4] thiazine-tolylidene} -4-methylbenzenesulfonamide (810 mg, 1.67 t )) And a suspension of ammonium formate (1.11 g, 16.7 band01) in ethanol (17.0 ml) were heated at 80 ° C for 15 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (316 mg, 58%) as dark red crystals. Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 115-117 ° C.

IR (KBr) Re:. 3403, 3293, 3100, 2965, 2934, 2868, 1715, 1634, 1603, 1539 era- 1 Ή-NMR (CDC1 3): δ 1.08 (3Η, d, J = 7.5 Hz), 1.50-1.62 (4H, m), 1.66-1.84 (4H, m), 2.11 (2H, q, J = 7.2 Hz), 2.27 (3H, s), 2.95 (2H, t, J = 7.5 Hz), 4.46 (2H, dt, J = 47.4, 5.7 Hz), 7.37 (2H, bs).

Elemental analysis: C ₁₄ H _2. N ₃ 0S ₂ F

Calculated value (%): C, 51.04; H, 6.12; N, 12.75; S, 19.47.

Found (¾): C, 50.92; H, 6.05; N, 12.66; S, 19.52.

Example 6-28

 1-Amino-6-butyl 8-[(5-fluoropentyl) sulfanyl] -5-methyl-3H-imidazo [5,1-c] [1,4] thiazin-3_one

N- {6-butyl-8-[(5-fluoropentyl) sulfanyl] -5-methyl-3-oxo-2,3-dihydro-1H-imidazo [5, tric] obtained in Example 4-530 ] A suspension of [1,4] thiazine-1-ylidene} -4-methylbenzenesulfonamide (2.19 g, 4.28 mmol) and ammonium formate (2.84 g, 4.28 mmol) in ethanol (43.0 ml) was prepared. After heating at 80 for 15 hours, water was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / y) to synthesize the title compound (1.12 g, 74¾). Recrystallization from ethyl acetate-getyl ether gave a dark red crystal with a melting point of 124-126.

IR (KBr) V: 3389, 3287, 2963, 2934, 2861, 1717, 1688, 1661, 1603, 1541 cm— ^1. .-NMR (CDCI3): (50.928 (3H, t, J = 7.2 Hz), 1.30 -1.64 (6H, m), 1.65-1.84 (4H, m), 2.07 (2H, t, J = 6.6 Hz), 2.26 (3H, s), 2.94 (2H, t, J = 7.5 Hz), 4.46 (2H, dt, J = 47., 5.7 Hz), 7.48 (2H, bs).

Elemental analysis: as C ₁₆ H ₂₄ N ₃₀ S ₂ F

Calculated (¾): C, 53.75; H, 6.77; N, 11.75; S, 17.94.

Found (¾): C, 53.80; H, 6.70; N, 11.78; S, 17.95.

Example 6-29

Toamino-5,6-dimethyl-8-{[5- (2,2,2-trifluoroethoxy) pentyl] sulfanyl} -3H-imidazo [5,1-c] [1,4] thiazine-3 -ON

N- (5,6-Dimethyl-3-oxo-8-{[5- (2,2,2-trifluoro-mouth ethoxy) pentyl] sulfanyl 2-, 3-dihydroxy- obtained in Example 4-531 Ethanol of 1H-imidazo [5, 1-c] [1,4] thiazine-1-ylidene) -4-methylbenzenesulfonamide (1.01 g, 1.84 difficult ol) and ammonium formate (1.22 g, 18.4 bandan 01) (18.0 ml) was heated at 80 ° C. for 15.5 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (526 mg, 72%) as dark red crystals. The crystals were recrystallized from ethyl acetate-getyl ether to obtain dark red crystals having a melting point of 110-112 ° C.

IR (KBr) S: 3407, 3279, 3110, 3048, 2936, 2867, 1713, 1632, 1605, 1547 cm— ¹ .

_{Ή-NMR (CDC1 3):} 51.40-1.84 (6H, m), 1.74 (3H, s), 2.26 (3H, s), 2.93 (2H, t, J = 7.6 Hz), 3.62 (2H, t, J = 6.2 Hz), 3.81 (2H, q, J = 8.8 Hz), 7.41 (2H, bs). Elemental analysis: C ₁₅ H _2fl N ₃ 0 ₂ S ₂ F ₃

Calculated value (%): C, 45.56; H, 5.10; N, 10.63; S, 16.22.

Found (¾): C, 45.68; H, 5.00; N, 10.60; S, 16.43.

Example 6-30

Toamino-5,6-dimethyl-8-{[4- (2,2,2-trifluoroethoxy) butyl] sulfanyl} -3H-imidazo [5,1-c] [1,4] thiazine- 3-one

N- (5,6-Dimethyl-3-oxo-8-{-[4- (2,2,2-trifluoro-mouth ethoxy) butyl] sulfanyl} -2,3-dihydro- obtained in Example 4-532 1H-imidazo [5,1-c] [1,4] thiazine-triylidene) -4-methylbenzenesulfonamide (1.12 g, 2.09 mmol) A suspension of ammonium acid (1.39 g, 20.9 thigh 01) in ethanol (20.0 ml) was heated at 80 ° C for 15.5 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (352 mg, 44%) as dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 108-110 ° C.

IR (KBr): 3387, 2944, 115, 1628, 1605, 541 cm " ¹ .

_{Ή-NMR (CDC1 3):} (51.66-1.90 (6H, m), 1.74 (3H, d, J = 0.9 Hz), 2.27 (3H, d, J = 1.2Hz), 2.97 (2H, t, J = 7.5 Hz), 3.65 (2H, t, J = 6.0 Hz), 3.82 (2H, q, J = 8.4 Hz), 6.94 (2H, bs).

Elemental _{analysis: C 14 H 18 N 3 0} 2 S 2 F 3 to

Calculated value (¾): C, 44.08; H, 4.76; N, 11.02; S, 16.81.

Found (¾): C, 44.10; H, 4.74; N, 10.88; S, 16.88.

Example 6-31

 8-[(4,4-Difluorocyclohexyl) sulfanyl] -trimino-5,6-dimethyl-1,2, -dihydro-3H-imidazo [5, 1-c] [1,4] thiazine-3- Talent

 A solution of the compound obtained in Example 4-535 (212 mg, 0.424 bandol) and ammonium formate Q41 mg, 2.12 mmol) in ethanol (7 ml) was heated under reflux for 12 hours. The reaction solution was concentrated to dryness, diluted with ethyl acetate (25 ml), washed with water and saturated saline, and dried over sodium sulfate. After concentration to dryness, the residue was subjected to silica gel chromatography (eluent, ethyl acetate-hexane, 5: 5-8: 2), and the ethyl acetate-hexane (7: 3-8: 2) fraction was obtained. After concentration to dryness, the mixture was diluted with ethyl acetate and ethyl ether. The precipitate was collected by filtration, washed with getyl ether, and dried to give the title compound (115 mg, 0.333 ol, 78.5%) as a red-brown powder.

_{¾ - NMR (300MHz, CDC1 3} ): (51.73 (3H, s), 1.82 (4H, m), 2.19 (4H, brd, J = 9.2

Hz), 2.26 (3H, brq, J = 0.8 Hz), 3.37 (1H, m), 7.30 (2H, br).

Elemental _{analysis: C 14 H 17 N 3 0S} 2 F 2 Calculated: C, 48.68; H, 4.96 ; N, 12.16; S, 18.57

(%), Found: C, 48.95; H, 4.66; N, 12.12; S, 18.82 (%).

mp. 203.0-204.O: Example 6-32

8-{[(4,4-difluorocyclohexyl) methyl] sulfanyl} -trimino-5,6-dimethyl-1,2-dihydro-3H-imidazo [5, 1-c] [1,4] Thiazine-3-one

 A solution of the compound obtained in Example 4-536 (468 mg, 0.911 mmol) and ammonium formate (302 mg, 4.56 mmol) in ethanol (12 ml) was heated under reflux for 48 hours. During the reaction, THF (3 ml) and ammonium formate (270 mg, 4.07 mmol) were added. The reaction mixture was concentrated to dryness, diluted with ethyl acetate (40 ml), washed with water and saturated saline, and dried over sodium sulfate. After concentration to dryness, the residue was diluted with methanol. The precipitate was collected by filtration and washed with methanol. The combined filtrate and washings were subjected to silica gel chromatography (elution solvent, ethyl acetate-hexane, 5: 5-9: 1), and the ethyl acetate-hexane (8: 2-9: 1) fraction was concentrated to dryness. Later, Jechil: diluted with 1 liter. The precipitate was collected by filtration, washed with getyl ether, and dried to give the title compound (α05 mg, 0.2'92 mmol, 32.1) as a gray-red powder.

_{¾- NMR (300MHz, CDC1 3)} : 51.38 (2H, brq, J = 13.2 Hz), 1.71 (2H, m), 1.74 (3H, s), 1.82 (4H, m), 1.95 (2H, brd, J = 13.2 Hz), 2.13 (2H, m), 2.26 (3H, s),

2.88 (2H, d, J = 7.2 Hz), 7.30 (1H, br), 8.88 (1H, br).

Elemental _{analysis: C 15 H 19 N 3 0S} 2 F 2 Calculated: C, 50.12; H, 5.33 ; N, 11.69; S, 17.84 (%), Found: C, 50.31; H, 5.19 ; N, 11.70; S, 17.74 (%).

mp. 175.5-177.0 ° C

Example 6-33

Triamino-5,6-dimethyl-8-{[2- (4-fluorobutoxy) ethyl] sulfanyl} -3H-imidazo [5,1-c] [1,4] thiazine-3-one

N- (5,6-Dimethyl-8-{[2- (4-fluorobutoxy) ethyl] sulfanyl) obtained in Example 18-23} -3-oxo-2,3-dihydrido-1H-imidazo [5,1-c] [1,4] thiazine-triylidene) -4-methylbenzenesulfonamide (290 mg, 0.580 mmol) and ammonium formate (385 mg, 5.80 thigh 01) in ethanol (5.80 ml) After heating the suspension at 80 ° C for 16 hours, water was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (100 mg, 50¾) Was obtained as amorphous crystals.

IR (KBr) Re:. 3403, 3287, 3106, 2965, 2868, 1715, 1636, 1607, 1545 cm "1 'Η- Awakening: _{R (CDC1 3): (51.67-1.92} (4H, m), 1.72 (3H , d, J = 1.2 Hz), 2.25 (3H, d, J = 1.2 Hz), 3.08 (2H, t, J = 5.7 Hz), 3.51 (2H, t, J = 6.3 Hz), 3.66 (2H , t, J = 5.7 Hz), 4.47 (2H, dt, J = 47., 5.7 Hz), 7.50 (2H, bs).

Example 6-34

Triamino-5,6-dimethyl-8-{[2- (5-fluoropentyloxy) ethyl] sulfanyl} -3H-imidazo [5,1-c] [1,4] thiazine-3- On

N- (5,6-dimethyl-8-{[2- (5-fluoropentyloxy) ethyl] sulfanilto 3-oxo-2,3-dihydro-1H- obtained in Example 4-534 Imidazo [5,1-c] [1,4] thiazin-triylidene) -4-methylbenzenesulfonamide (1.03 g, 2.01 thigh ol) and ammonium formate (1.36 g, 20.6 seq.) In ethanol (20.0 ml) ) Was heated at 80 for 16.5 hours, water was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (427 mg, 55¾) as amorphous crystals.

 IR (KBr): 3389, 3285, 2942, 2865, 1715, 1651, 1605, 1543 cm—

_{'H-NMR (CDC1 3)} : 51.34-1.85 (6H, m), 1.72 (3H, d, J = 0.8 Hz), 2.25 (3H, d, J = 1.0 Hz), 3.07 (2H, t, J = 5.8 Hz), 3.47 (2H, t, J = 6.6 Hz), 3.65 (2H, t, J = 5.8 Hz), 4.45 (2H, dt, J = 47.2, 5.8 Hz), 7.94 (2H, bs).

Example 6-35

 5-[Toramino-5,6-dimethyl-3-oxo-3H-imidazo [5,1-c] [1,4] thiazine-8-yl] sulfanyl] -N-hexylpentanamide

5 _ [(5,6_dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo [5, obtained in Example 4-528 1-c] [1,4] thiazin-8-yl) sulfanyl] -N-hexylpentanamide (520 mg, 0.921 bandol) and ammonium formate (611 mg, 9.21 bandol) in ethanol (9.20 ml) ) Was heated at 80 ° C for 21 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography. After elution with n-hexane-ethyl acetate (10: 1, v / v), the title compound (201 nig, 53) was obtained as dark red crystals. Recrystallization from ethyl acetate-jetil ether gave dark red crystals with a melting point of 142-144 ° C.

IR (KBr) V 3385, 3287, 3058, 2928, 2859, 1705, 1642, 1605, 1545 cm " ¹ .

_{Ή-NMR (CDC1 3):} 50.885 (3H, t, J = 6.9Hz), 1.22-1.36 (6H, m), 1.43-1.56 (2H, m), 1.70-1.85 (4H, m), 1.73 (3H , d, J = 0.9 Hz), 2.20 (2H, t, J = 6.6 Hz), 2.26

(3H, d, J = 0.9 Hz), 2.94 (2H, t, J = 6.0 Hz), 3.24 (2H, q, J = 6.0 Hz), 5.56 (1H, bs), 7.46 (2H, bs).

Elemental analysis:. N ₄ 0 ₂ S ₂ 0.2Η ₂₀

Calculated (%): C, 55.10; H, 7.40; N, 13.53; S, 15.48.

Found (値): C, 55.06; H, 7.27; N, 13.70; S, 15.46.

Example 6-36

 1-amino-5,6-dimethyl-8-{[2- (3-fluoropropoxy) ethyl] sulfani M-3H-imidazo [5, tric] [1,4] thiazine-3-

N- (5,6-Dimethyl-8-{[2- (3-fluoropropoxy) ethyl] sulfanyl} _3-oxo-2,3-dihydro-1H obtained in Example 4-533 -Imidazo [5,1-c] [1,4] thiazine-triylidene) -4-methylbenzenesulfonamide (370 mg, 0.762 mmol) and ammonium formate (505 mg, 7.62 thigh 01) in ethanol (7.50 ml) ) Was heated at 80 ° C for 15 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (181 mg, 72%) as amorphous crystals.

IR (KBr) V: 3391, 3289, 3113, 3038, 2969, 2932, 2870, 1715, 1651, 1634, 1605, 1543 cm " ¹ .

 Ή-NMR (CDCI3): 51.73 (3H, d, J = 0.9 Hz), 1.97 (2H, dt, J = 27.0, 6.0 Hz), 2.25 (3H, d, J = 0.9 Hz), 3.08 (2H, t , J = 6.0 Hz), 3.60 (2H, t, J = 6.0 Hz), 4.45 (2H, dt, J = 47.4, 6.0 Hz), 7.50 (2H, bs).

Example 6_38

tert-Butyl 3-[(triamino-5,6-dimethyl_3-oxo-3H-imidazo [5,1-c] [1,4] Thiazine-8-yl) sulfanyl] propyl

A suspension of the compound (1.22 g, 2.26 thigh 01) obtained in the same manner as in Example 4-106 and ammonium formate (752 mg, 11.3 mmol) in ethanol (25 ml) was heated under reflux for 23 hours. During the reaction, ammonium formate (300 mg, 4.52 ol) was added. The reaction solution was filtered, washed with ethanol, and dried to give the title compound (318 mg, 0.827 mol, 36.6%) as a purple powder. After concentration, the mother liquor was diluted with ethyl acetate (30 ml) and water (30 ml). The precipitate was collected by filtration, washed with methanol / water (1: 1), getyl ether, and ethyl acetate, and dried to give the title compound (287 mg, 0.746 bandol, 33.0%) as a gray-violet powder. 'H-NMR (200MHz, CDC1 3): 51.45 (9H, s), 1.73 (3H, brs), 1.90 (2H, quint, J = 7.0 Hz), 2.26 (3H, s), 2.96 (2H, t, J = 7.3 Hz), 3.26 (2H, q, J = 6.4 Hz), 4.69 (1H, m), 7.42 (2H, br).

Elemental _{analysis: C 16 H 24 N 4 0} 3 S 2 Calculated: C, 49.98; H, 6.29 ; N, 14.57; S, 16.68

(%), Found: C, 49.89; H, 6.19; N, 14.59; S, 16.57 ().

Immediately. 197.5-198.5 ° C

Example 6-39

 N- {3-[(Tamino-3,6-dimethyl-3-oxo-3H-imidazo [5,1-c] [1,4] thiazin-8-yl) sulfanyl] propyl} hexanamide

 A suspension of the compound obtained in Examples 18 to 13 (520 mg, 0.969 mmol) and ammonium formate (322 mg, 4.84 mol) in ethanol (10 ml) was heated under reflux for 15 hours. During the reaction, ammonium formate (95 mg, 1.43 mmol) was added. The reaction solution was concentrated, diluted with ethyl acetate (40 ml), and washed with 5% sodium hydrogen carbonate, 5% saline, and saturated saline. The precipitate was collected by filtration, washed with water, aqueous methanol and ethyl acetate, and dried to give the title compound (88 mg, 0.230 mol, 23.7%) as a gray-violet powder. The organic layer of the filtrate was separated, dried over sodium sulfate and concentrated, and the residue was diluted with ethyl acetate. The precipitate was collected by filtration, washed with ethyl acetate and getyl ether, and dried to give the title compound (153 mg, 0.400 ml, 41.3%) as a gray-violet powder.

_{¾-NMR (200MHz, CDC1 3} ): (50.89 (3H, t, J = 6.6 Hz), 1.30 (4H,), 1.63 (2H, brquint, 1 = 7.7 Hz), 1.73 (3H, q, J = 1.2 Hz), 2.18 (2H, t, J = 7.5 Hz), 2.25 (3H, q, J = 1.0 Hz), 2.95 (2H, i, J = 7.1 Hz), 3.38 (2H, q, J = 6.5 Hz) , 6.02 (1H, m), 7.76 (2H, br).

Elemental _{analysis: C 17 H 26 N 4 0} 2 S 2 Calculated: C, 53.37; H, 6.85 ; N, 14.65; S, 16.76

(%), Found (%): C, 53.25; H, 6.99; N, 14.71; S, 16.68.

mp.162.0-163.5 ° C

Example 6-40

 8-{[2- (1-Adamantyl) ethyl] sulfanyl} -1-imino-5,6-dimethyl-1,2-dihydro-3H-imidazo [5,1-c] [1,4] Thiazine-3-one

 A suspension of the compound (1.96 g, 3.60 mmol) obtained in Example 4-553 and ammonium formate (1.20 g, 18.0 mmol) in ethanol (50 ml) was heated under reflux for 26 hours. During the reaction, ammonium formate (1.20 g, 18,0 mmol) was added. After the reaction solution was concentrated, it was extracted with ethyl acetate-THF (5: 1). The organic layer was washed with aqueous ammonium chloride solution and saturated saline, dried over sodium sulfate, concentrated to dryness, and the residue was diluted with methanol. The precipitate was collected by filtration, washed with methanol, and then crystallized from methanol-ethyl acetate to give the title compound (983 mg, 2.52 alcohol 01, '70 .1 ») as a dark purple powder.

_{- NMR (300MHz, CDC1 3)} : (51.45 (2H, m), 1.51 (6H, d, J = 2.4 Hz), 1.63 (3H, brd, J = 11.7 Hz), 1.72 (3H, brd, J = 12 Hz), 1.75 (3H, q, J = 0.9 Hz), 1.98 (3H, brs), 2.27 (3H, q, J = 0.9 Hz), 2.88 (2H, m), 7.56 (2H, br).

Elemental analysis: C _{2. H 27 N 3 0S 2 · 0.2Η} 2 0 Calculated: C, 60.82; Η, 7.04 ; Ν, 10.64; S, 16.24 (%),

Elemental analysis: C ₂₀ H ₂₇ N ₃ OS ₂ · 0. Calculated as leak Ac: C, 61.35; H, 7.08; N, 10.32; S, 15.75 (%),

Found: C, 61.03; H, 6.89; N, 10.29; S, 15.58 (%).

mp. 184.0- 185.5

Example 6-41

8-[(adamantylmethyl) sulfanyl] -tomino-5,6-dimethyl-1,2-dihydro-3H-imidazo [5,1-c] [1,4] thiazin-3-one

A suspension of the compound (875 mg, 1.65 mmol) obtained in Example 4-554 and ammonium formate (548 mg, 8.26 mmol) in ethanol (20 ml) was heated under reflux for 35 hours. During the reaction, ammonium formate (0.88 g, 13.2 ol) was added in two portions. After concentrating the reaction solution, acetic acid Extracted with ethyl-THF (5: 1). The organic layer was washed with an aqueous solution of ammonium chloride 10 and saturated saline, dried over sodium sulfate, and concentrated to dryness to obtain a dark purple oil. This was purified by chromatography on silica gel (10 g) (ethyl acetate, hexane, 7: 3-8: 2) and crystallized from THF-ethyl acetate to give the title compound (240 mg, 0.639 ol, 38.7%) Was obtained as a deep purple powder.

'H-NMR (200MHz, CDC1 3): (51.60 (6H, brs), 1.63 (3H, brd, J = 12 Hz), 1.72 (3H, brd, J = 12 Hz), 1.75 (3H, q, J = 1.0 Hz), 2.02 (3H, brs), 2.27 (3H, q, J = 0.6 Hz), 2.79 (2H, s), 7.38 (2H, br).

Elemental analysis: C ₁₉ H ₂₅ N ₃₀ S ₂ Calculated: C, 60.76; H, 6.71;, 11.19; S, 17.08 (%), found: C, 60.58; H, 6.76; N, 10.84; S , 16.83 (%).

Immediately. 199.0- 201. (T

Example 6-42

 1-T-mino-8-[(Six-octylmethyl) sulfanyl] -5,6-dimethyl-3H-imidazo

[5, 1-c] [1, 4] thiazine-3-one

 The compound obtained in Example 4-94 (1.95 g, 3.86 tmol) and ammonium formate (1.28 g,

A suspension of 19.3 mmol) in ethanol (40 ml) was heated under reflux for 22 hours. During the reaction, ammonium formate (1.28 g, 19.3 IM01) was added. After concentrating the reaction solution, the residue was diluted with methanol, and the precipitate was collected by filtration, washed with methanol, and dried to give the title compound (936 mg,

2.66 mmol, 69.0%) as a purple powder.

'H-NMR (200MHz, CDC1 3): δ 1.42 (2Η, brq, J = 10.4 Hz), 1.40-1.80 (13H, m),

1.74 (3H, q, J = 1.0 Hz), 2.27 (3H, q, J = 1.0 Hz), 2.84 (2H, d, J = 6.6 Hz),

7.54 (2H, br).

Elemental _{analysis: C 17 H 25 N 3 OS} 2 Calculated: C, 58.08; H, 7.17 ; N, 11.95; S, 18.24 (%), Found: C, 57.80; H, 7.47 ; N, 11.74; S, 18.18 ()

Immediate. 190.0-191.5 ° C

Example 6-43

 1-Amino-5,6-dimethyl-8 _ {[2- (2-fluoroethoxy) ethyl] sulfanyl} -3H-imidazo [5, 1-c] [1,4] thiazin-3-one

N- (5,6-dimethyl-3-oxo-8-{[2- (2-fluoroethoxy) obtained in Example 4-580 C) Ethyl] sulfanyl}-2,3-dihydric 1H-imidazo [5,1 丄 c] [1,] thiazine-1-ylidene) -4-methylbenzenesulfonamide (770 mg, 1.63 mmol) and ammonium formate A suspension of ethanol (l, 08 g, 16.3 ol) in ethanol (16.0 ml) was heated at 80 ° C for U hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (313 mg, 61%) as dark red crystals. The crystals were recrystallized from ethyl acetate-getyl ether to obtain dark red crystals having a melting point of 120-122.

IR (KBr) V: 3385, 3283, 3121, 2976, 2932, 1715, 1634, 1607 cm " ¹ .

_{¾-NMR (CDC1 3):} (51.72 (3H, s), 2.26 (3H, s), 3.09 (2H, t, J = 5.8 Hz), 3.73

(2H, dt, J = 31.6, 3.6 Hz), 3.74 (2H, t, J = 5.8 Hz), 4.57 (2H, dt, J = 47.6, 4.0

Hz), 7.40 (2H, bs).

Elementary analysis: as _{C 12 H 16 N 3 0 2} S 2 F

Example 6-44

Triamino-5,6-dimethyl-8-({[(2S) -5-oxopiridinyl] methyl} sulfanyl) -3H-imidazo [5,1-c] [1,4] thiazine-3-one

 A suspension of the compound (660 mg, 1.38 mol) obtained in Example 4-557 and ammonium formate (458 mg, 6.89 mmol) in ethanol (14 ml) was heated under reflux for 22 hours. During the reaction, ammonium formate (275 mg, 4.14 mmol) was added. After concentration of the reaction solution, the residue was diluted with methanol. The precipitate was collected by filtration, washed with methanol / water (1: 1), methanol and getyl ether, and dried to give the title compound (184 mg, 0.567 imol, 41.1%) as a purple powder.

_{Ή- NMR (200MHz, CDC1 3)} : 51.71 (3H, q, J = 1.0 Hz), 1.79 (1H, m), 2.25 (3H, q, J = 1.2 Hz), 2.31 (1H, m), 2.40 ( 2H, m), 3.07 (1H, dd, J = 13.8, 5.4 Hz), 3.31 (1H, dd, J = 13.4, 4.0 Hz), 4.09 (1H, m), 7.2-7.8 (2H, br), 8.33 (1H, brs).

Elemental _{analysis: C) 3 H 16 N 4} 0 2 S 2 Calculated: C, 48.13; H, 4.97 ; N, 17.27; S, 19.77

(%), Found: C, 48.15; H, 4.73; N, 17.13; S, 19.95 (%).

Immediate. 197.0-200.0 ° C Example 6-45

 3-{[(Tamino-5,6-dimethyl-3-oxo-3H-imidazo [5,1-c] [1,4] thiazin-8-yl) sulfanyl] methyl} -1_piperidine Tert-butyl carboxylate

 The crude 3-{[(5,6-dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3_oxo-2,3-dihydro-1H obtained in the same manner as in Example 4-558 -Imidazo [5,1-c] [1,4] thiazin-8-yl) sulfanyl] methyl} -tert-butyl topiperidinecarboxylate (purity 50¾, 2.0 g, 1.7 mmol) and ammonium formate (0.57 g) , 8.6 bandol) in ethanol (40 ml) was heated to reflux for 23 hours. During the reaction, ammonium formate (0.34 g, 5.2 inmol) was added. After the reaction solution was concentrated, it was extracted with ethyl acetate. The organic layer was washed with ^ and saturated saline, dried over sodium sulfate, and concentrated to dryness to obtain a dark purple oil. This was purified by chromatography on silica gel (12 g) (ethyl acetate-hexane, 4: 6-8: 2) and crystallized from ethyl acetate and geethyl ether to give the title compound (201 mg, 0.473 t, 27.4). %) As a dark purple powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.35 (2Η, m), 1.46 (9H, s), 1.66 (1H, m), 1.74 (3H, s), 1.89 (2H,), 2.26 (3H, s ), 2.81 (1H, m), 2.86 (2H, m), 2.98 (1H, brt, J = 9.8 Hz), 3.74 (1H, brd, J = 13.8 Hz), 3.90 (1H, brd, J = 14.4 Hz) ), 7.55 (2H, br),

Elemental analysis: C ₁₉ H ₂₈ N ₄ 0 ₃ S ₂ Calculated: C, 53.75; H, 6.65; N, 13.20; S, 15.10 (%), found: C, 53.72; H, 6.66; N, 13.05; S, 14.97 (%)

mp.163.0-164.5 ° C

Example 6-46

 (2S, 4R) -2-{[(Tamino-5,6-dimethyl-3-oxo-3Η-imidazo [5,1-c] [1,4] thiazin-8-yl) sulfanyl] methyl } _Tert-butyl 4-hydroxy-1-pyrrolidinecarboxylate

Crude (2S) -4-[(5,6-)-1,2_ (2S, 4R) -2-{[(5,6-dimethyl-1-{obtained in the same manner as in Example 4-555 [(4-Methylphenyl) sulfonyl] imino} -3-oxo-1,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazin-8-yl) sulfanyl] methyl} -4 A suspension of tert-butyl-1-hydroxy-1-pyrrolidinecarboxylate (purity 70%, 1.6 g, 1.9 mmol) and ammonium formate (0.64 g, 9.7 benzene) in ethanol (30 ml) was heated and returned for 18 hours. Shed. During the reaction, ammonium formate (0.51 g, 7.7 mmol) was added. After the reaction solution was concentrated, it was extracted with ethyl acetate. The organic layer was washed with 5% and saturated saline, dried over sodium sulfate, and concentrated to dryness to obtain a dark purple oil. This was purified by chromatography on silica gel (15 g) (ethyl acetate-methanol, 1: 99-7: 93) and crystallized from ethyl acetate and getyl ether to give the title compound (198 mg, 0.464 ol, 23.9%) as a dark purple powder.

_{¾-NMR (300MHz, CDC1 3} ): 51.48 (9H, s), 1.72 (3H, q, J = 0.6 Hz), 1.99 (1H, ddd, J = 13.5, 7.8, 4.8 Hz), 2.24 (3H, q , J = 0.9 Hz), 2.97 (1H, m), 3.27 (1H, m), 3.40 (1H, brs), 3.45 (1H, brs), 3.50 (1H, m), 3.64 (1H, m), 4.25 (1H, m), 4.45 (1H, brs), 7.49 (2H, br).

Elemental analysis: C ₁₈ H ₂₆ N ₄ 0 ₄ S ₂ Ό.2 As ethyl acetate

Calculated: C, 50.84; Η, 6.26; Ν, 12.61; S, 14.44 (%).

Found: C, 50.66; Η, 6.23; Ν, 12.62; S, 14.38 (%).

Example 6-47

3-Amino-4-[(5-fluoropentyl) sulfanyl] _8,9-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1,6 (711) -dione

N- {1,6-Dioxo-4-[(5-fluoropentyl) sulfanyl]-1,2,6,7,8,9-hexahydrid-3H-imidazo obtained in Example 4-561 [5,1-c] [1,4] benzothiazine-4-ylidene} -4-methylbenzenesulfonamide (1.50 g, 2.94 mmol) and ammonium formate (1.95 g, 29.4 mmol) in ethanol (30.0 ml) After heating the suspension at 80 ° C for 15 hours, water was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (185 mg, 18¾) as dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals, mp 191-193 ° C.

IR (KBr): 3387, 3287, 2948, 2240, 1721, 1653, 1642, 1563 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 1.50-1.70 (2Η, m), 1.70-1.90 (4 m), 1.92-2.10 (2H, m), 2.48 (2H, t, J = 7.2 Hz), 3.04 (2H , t, J = 7.2 Hz), 3.30 (2H, t, J = 6.4 Hz), 4.46 (2H, dt, J = 47.2, 5.6 Hz), 7.31 (2H, bs). Elementary analysis: as _{C 15 H 18 N 3 0 2} S 2 F

Calculated value (¾): C, 50.69; H, 5.10; N, 11.82; S, 18.04.

Found (¾): C, 50.71; H, 5.02; N, 11.55; S, 17.82.

Example 6-48

(2S) -2-{[(Tamino-5,6-dimethyl-3-oxo-3H-imidazo [5, tric] [1,4] thiazin-8-yl) sulfanyl] methyl} _1-pyrrolidine Tert-butyl carboxylate

A suspension of the compound (885 mg, 1.57 mol) obtained in Example 4-559 and ammonium formate (520 mg, 7.84 bandol) in ethanol (20 ml) was heated under reflux for 17 hours. During the reaction, ammonium formate (313 mg, 4.71 mmol) was added. After concentrating the reaction solution, the organic layer obtained by extraction with ethyl acetate was washed with sodium bicarbonate and saturated saline, dried over sodium sulfate, and concentrated to dryness to obtain a dark purple oil. This was purified by chromatography on silica gel (10 g) (ethyl acetate-hexane, 4: 6-8: 2) and crystallized from getyl ether to give the title compound (467 mg, l.Hmmol, 72.5% ) Was obtained as a red powder. _{Ή- NMR (200MHz, CDC1 3)} : (51.48 (9H, s), 1.73 (3H, s), 1.89 (3H, m), 2.07 (1H, m), 2.26 (3H, q, J = 1.0 Hz) , 2.94 / 3.06 (1H, br), 3.29 (1H, d, J = 4.0 Hz), 3.35 (1H, dd, J = 4.0 Hz), 3.40 (1H, m), 4.05 (1H, m), 7.19 ( 2H, br).

Elementary analysis: as _{C 18 H 26 N 4 0 3} S 2 O.5H 2 0: C, 51.53; H, 6.49; N, 13.35; S, 15.29

(%), Found: C, 51.62; H, 6.47; N, 13.30; S, 15.18 (%).

Melting point: 175.0-176.0 ° C

Example 6-49

 1-Amino-8-[(5,5-difluorocyclooctyl) sulfanyl] -5,6-dimethyl-3H_ imidazo [5,1-c] [1,4] thiazin-3-one

A suspension of the compound (653 mg, 1.24 benzyl) obtained in Example 4-547 and ammonium formate (0.41 g, 6.19 maraudal 01) in ethanol a5 ml) was heated under reflux for 16 hours. During the reaction, ammonium formate (247 mg, 3.72 tmol) was added. After concentrating the reaction solution, the organic layer obtained by extraction with ethyl acetate was washed with 2% sodium bicarbonate and saturated saline, dried over sodium sulfate, and concentrated. added. The precipitate was collected by filtration, washed with methanol, and dried to give the title compound (245 mg, 0.656 mol, 52.9) as a purple-brown powder. _{¾-NMR (300MHz, CDC1 3} ): <51.72 (4H, m), 1.74 (3H, q, J = 0.9 Hz), 1.91 (2H, m), 2.10 (6H, m), 2.26 (3H, q, J = 0.9 Hz), 3.46 (1H, bri, J = 8 Hz), 7.25 (1H, br), 8.60 (1H, br).

Elemental analysis: C ₁₆ H ₂₁ N ₃ OS ₂ F ₂ Calculated: C, 51.45; H, 5.67;, 11.25; S, 17.17; F, 10.17 (%), found: C, 51.54; H, 5.61 ;, 11.22; S, 16.90; F, 10.08 (%)

Melting point: 182.5-183.0 ° C

Example 6-50

 1-Amino-8-({[3- (fluoromethyl) cyclohexyl] methyl} sulfanyl) -5,6-dimethyl-3H-imidazo [5,1-c] [1,4] thiazin-3-one

 A suspension of the compound (1.55 g, 3.04 mol) obtained in Example 4-551 and ammonium formate (1.01 g, 15.2 mol) in ethanol (31 ml) was heated under reflux for 23 hours. During the reaction, ammonium formate (605 mg, 9.12 imol) was added twice. After the reaction solution was concentrated, it was extracted with ethyl acetate (80 ml). The organic layer was washed with water, 2% sodium hydrogen carbonate and saturated saline, dried over sodium sulfate, and concentrated to dryness to obtain a dark purple oil. This was purified by chromatography on silica gel (10 g) (ethyl acetate-hexane, 4: 6-8: 2) and crystallized from methanol to give the title compound (448 Dig, 1.26 mol, 41.5) as a purple powder. Obtained. .

Ή- testimony _{(200MHz, CDC1 3, 1:} 1 c is / trans mixture): ά 0.96 / 0.80 (2H , m / q, J = 12.4 Hz), 1.35 (2H, m), 1.50-1.80 (3H, m ), 1.75 (3H, s), 1.93 (3H, m), 2.26 (3H, s), 2.86 / 2.94 (2H, d, J = 6.0 / 7.2 Hz), 4.25 / 4.32 (2H, ddd / dd, J = 47.4, 5.3, 1.7 / 47.4, 6.6 Hz), about 7.6 (2H, br).

Elemental analysis: Calculated for C ₁₆ H ₂₂ N ₃ OS ₂ F: C, 54.06; H, 6.24; Ν, .11.82; S, 18.04; F, 5.34 (%), found: C, 53.99; Η, 6.40; Ν, 11.61; S, 18.17; F, 5.39 (%) · Melting point: 168.5-169.5 ° C

Example 6-51

 1-amino-5,6-dimethyl-8-{[(1-methylcyclohexyl) methyl] sulfanyl} -3H imidazo [5,1-c] [1,4] thiazin-3-one

The compound obtained in Example 4-576 (427 mg, 0.868 mmol) and ammonium formate (288 A suspension of mg, 4.34 hall 01) in ethanol (10 ml) was heated under reflux for 22 hours. Ammonium formate (28 mg, 4.34 mmol, and 170 mg, 2.60 bandol) was added during the reaction. After the reaction solution was concentrated, it was extracted with ethyl acetate (40 ml). The organic layer was washed with water, 2% sodium hydrogen carbonate and saturated saline, dried over sodium sulfate, and concentrated to obtain a dark purple oil. This was crystallized from methanol to give the title compound (168 mg, 0.498 mol, 57.3%) as a gray purple powder.

_{Ή-NMR (300MHz, CDC1 3} ): (51.02 (3H, s), 1.37 (5H, m), 1.48 (5H, m), 1.75 (3H, q, J = 1.2 Hz), 2.26 (3H, q, J = 0.9 Hz), 2.95 (2H, s), about 7.4 (1H, br), about 7.8 (1H, br).

Elemental analysis C _l6 H ₂₃ N ₃ 0S ₂ Calculated: C, 56.94; H, 6.87 ; N, 12.45; S, 19.00 (%), Found: C, 56.88; H, 7.02 ;, 12.36; S, 19.05 (%).

Melting point: 186.0-188.5 ° C

Example 7-1

2,4-Dichloro-N- [5,6-dimethyl-3-oxo-8- (pentylsulfanyl) -2,3-dihydro-1H-imidazo [5,1-c] [1 , 4] Thiazine-1-ylidene] benzenesulfonamide triamino-5,6-dimethyl-8_ (pentylsulfanyl) -3H-imidazo obtained in Example 6-1 [5, tric] [1, 4] Thiazin-3-one (200 mg, 0.672 mmol) was dissolved in pyridine (2.00 ml), and 2,4-dichlorobenzenesulfonyl chloride (330 mg, 1.34 t ol) was added. After stirring the reaction mixture at room temperature for 24 hours, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (15.7 mg, 4.6%) as dark red crystals. Recrystallization from ethyl acetate-diisopropyl ether gave dark red crystals with a melting point of 168-170 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3264, 2961, 2930, 2859, 1748, 1725, 1663, 1615, 1557 cm- ¹ .

_{¾-NMR (CDC1 3):} δ 0.894 (3Η, t, J = 7.0Hz), 1.23-1.40 (4H, m), 1.57-1.75 (2H, m), 1.81 (3H, s), 2.30 (3H, s), 2.92 (2H, t, J = 7.2 Hz), 7.38 (2H, dd, J = 8.8, 2.2 Hz), 7.51 (1H, d, J = 2.2 Hz), 8.12 (1H, d, J = 8.4 Hz), 9.69 (1H, bs ) Elementary analysis:. as _{C 19 H 21 N 3 0 3} S 3 C 1 2

Calculated (¾): C, 45.06; H, 4.18; N, 8.30; S, 18.99.

Found (%): C, 44.98; H, 3.88; N, 8.18; S, 18.85.

Example 7-2

 N- [5,6-dimethyl-3-oxo-8- (pentylsulfanyl) -2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-triylidene] -4-trifluoromethylbenzenesulfonamide

Method A

In the same manner as in Example 7-1, the compound of Example 6-1 was obtained using 4-trifluoromethylbenzenesulfonyl chloride (220 mg, 0.883 benzyl) instead of 2,4-dichlorobenzenesulfonyl chloride. Triamino-5,6-dimethyl-8- (pentylsulfanyl) -3H-imidazo [5,1-c] [1,4] thiazin-3-one (200 mg, 0.67 bandol ol) From there, the title compound (29.5 mg, 8.7 合成) was synthesized. Recrystallization from ethyl acetate-getyl ether gave dark red crystals.

Method B

1-amino-5,6-dimethyl-8- (pentylsulfanyl) -3H-imidazo [5,1-c] [1,4] thiazin-3-one obtained in Example 6-1 (175 mg, 0.588 mmol) was dissolved in tetrahydrofuran (2.00 ml), and 4-trifluoromethylbenzenesulfonyl chloride (220 mg, 0.883 mmol) and triethylamine (0.164 ml, 1.18 thigh) were sequentially added. After stirring the reaction mixture at room temperature for 16 hours, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure to give the title compound (114 mg, 39¾) as a dark red crystals. The crystals were recrystallized from ethyl acetate-jetil ether to give reddish crystals having a melting point of 162-164 ° C.

Infrared absorption spectrum (IR) (in KBr): 3231, 2961, 2932, 2861, 1761, 1748, 1663, 1620, 1557 cm- ¹ .

_{Ή-NMR (CDC1 3):} δ 0.910 (3Η, t, J = 7.0 Hz), 1.31-1.47 (4H, m), 1.60-1.75 (2H, m), 1.80 (3H, d, J-1.0 Hz) , 2.28 (3H, d, J = 1.2 Hz), 2.96 (2H, t, J = 7.4 Hz), 7.75 (2H, d, J = 8.0 Hz), 8.11 (2H, d, J = 8.0 Hz) , 9.60 (1H, bs).

Elemental analysis: as C ₂₀ H ₂₂ N ₃ 0 ₃ S ₃

Calculated)): C, 47.51; H, 4.19; N, 8.31; S, 19.03.

Found (¾): C, 47.20; H, 4.32; N, 8.14; S, 18.94.

Example 7-3

 N- [5,6-Dimethyl-3-oxo-8- (pentylsulfael) -2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene ] -4-nitrobenzenesulfonamide

 According to a method similar to that of Example 7-1, 4-nitrobenzenesulfonyl chloride (183 mg, 0.808 ol) was used in place of 2,4-dichlorobenzenesulfonyl chloride to obtain 1- The title compound (160 mg, 0.539 t ol) was obtained from amino-3,6-dimethyl-8- (pentylsulfanyl) -3H-imidazo [5,1-c] [1,4] thiazin-3-one. 4.3 mg, 1.7¾) was synthesized. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 183-185 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3108, 2957, 2928, 2868, 1750, 1723, 1661, 1603, 1557, 1532 cm " ¹ .

'.Eta.丽_{R (CDC1 3): δ 0.916} (3Η, t, J = 6.8Hz), 1.31-1.44 (4H, m), 1.64-1.76 (2H, m), 1.81 (3H, s), 2.29 ( 3H, d, J = 0.8 Hz), 2.97 (2H, t, J = 7.2 Hz), 8.16 (2H, d, J = 9.2 Hz), 8.34 (2H, d, J = 8.8 Hz), 9.59 (1H, bs).

Example 7-4,

 4-({[5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-triylidene] amino } Sulfanyl) benzoic acid Example 7-2 By a method similar to that of Method B, using 4- (chlorosulfanyl) benzoic acid (174 mg, 0.756 bandol) instead of 4-trifluoromethylbenzenesulfonyl chloride, 1-Amino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5,1-c] [1,4] thiazin-3-one obtained in Example 6-2 (350 The compound (258 mg, 46%) was synthesized from the compound (258 mg, 1.18 t). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 178-180 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3700-2800, 3275, 2957, 2928, 2872, 1730, 1659, 1624, 1599, 1572, 1553, 1539 cm " ¹ .

 'H-NMR (CDCI3): δ 1.01 (6Η, d, J = 6.4 Hz), 1.50-1.82 (3H, m), 1.87 (3H, d, J = 1.2 Hz), 2.38 (3H, d, J = 0.6 Hz), 3.11 (2H, t, J-7.8 Hz), 8.11 (2H, d, J = 8.4 Hz), 8.55 (2H, d, J = 8.8 Hz), 11.13 (1H, bs).

Example 7-5

4- (bromomethyl) -N- [5,6-dimethyl-8- (isopentylsulfinyl) -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4 [Thiazine-1-ylidene] benzenesulfonamide

 Example 7-2 In the same manner as in Method B, 4-bromomethylbenzenesulfonyl chloride (204 mg, 0.756 t) was used in place of 4-trifluoromethylbenzenesulfonyl chloride, and Example 6-2 was used. -5,6-Dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5,1-c] [1,4] thiazin-3-one (350 mg, 1.18 mmol) )) To give the title compound (20.0 mg, 7.5%). Recrystallization from ethyl acetate-getyl ether gave dark red crystals. '

Method C To a suspension of sodium hydride (20.2 mg, 0.504 mmol) (60% oil) in tetrahydrofuran (1.00 ml) was added the triamino-5,6-dimethyl-8- (isopentylsulfurate) obtained in Example 6-2. Nil) -3H-imidazo [5, tric] [1,4] thiazin-3-one (100 nig, 0.336 t ol) in tetrahydrofuran (1.00 ml) was added thereto, and the mixture was stirred under ice cooling for 10 minutes. To this was added a solution of 4-bromomethylbenzenesulfonyl chloride (136 mg, 0.504 mmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (139 mg, 78%) as a dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain red-red crystals having a melting point of 187-188 ° C. Infrared absorption spectrum (IR) (KBr, medium): 3120, 2959, 2926, 2870, 1742, 1728, 1663, 1605, 1553 cm- ¹ .

_{'H-NMR (CDC1 3)} : δ 0.935 (6Η, d, J = 6.2 Hz), 1.50-1.76 (3H, m), 1.80 (3H, s), 2.28 (3H, d, J = 0.6 Hz), 2.96 (2H, t, J = 8.0 Hz), 4.49 (2H, s, 75% Br), 4.61 (2H, s, 25¾ CI), 7.50 (2H, d, J = 8.6 Hz), 7.94 (2H, d , J = 8.0 Hz), 9.60 (1H, bs).

Elementary analysis: as _{C 20 H 24 N 3 0 3} S 3 Br 75.2¾ C 20 H M N 3 0 3 S 3 C1 24 · 8%

Calculated value (%): C, 46.28; H, 4.66;, 8.09; S, 18.51.

Found (¾): C, 45.91; H, 4.67; N, 8.13; S, 18.32.

Example 7-6

N- [5,6-Dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydrido-1H-dimidazo [5,1-c] [1,4] thiazine-1-ylidene ] -4_Ethoxymethylbenzenesulfonamide

4- (Promomethyl) [5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5, tric] obtained in Example 7-5 [1,4] Thiazine-1-ylidene] benzenesulfonamide (259 mg, 0.489 mmol), potassium acetate (145 mg, 1.47 mmol) and potassium hydroxide (96.8 mg, 1.47 mmol) in ethanol (5.00 ml) The suspension was heated at reflux for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. Washed with water extract exudates, dried (MgSO _4), to obtain the solvent was distilled off under reduced pressure the title compound (82.4mg, 34%). Recrystallized from Ethyl acetate-Jetil ether to form a dark red color with a melting point of 116-118 ° C A crystal was obtained.

Infrared absorption spectrum (IR) (in KBr): 3223, 2957, 2932, 2870, 1748, 1663, 1618, 1565 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 0.929 (6Η, d, J = 6.6 Hz), 1.26 (3H, t, J = 7.0 Hz), 1.48-1.78 (3H, m), 1.79 (3H, s), 2.27 (3H, s), 2.94 (2H, t, J = 7.6 Hz), 3.57 (2H, q, J = 7.0 Hz), 4.56 (2H, s), 7.46 (2H, d, J = 8.2 Hz), 7.94 (2H, d, J = 8.0 Hz), 9.61 (1H, bs).

Elementary analysis: as _{C 22 H 29 N 3 0 4} S 3

Calculated (¾): C, 53.31; H, 5.90; N, 8.48; S, 19.41.

Found (¾): C, 53.28; H, 5.79; N, 8.42; S, 19.80.

Example 7-7

Acetic acid 4-{[5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene ] Sulfin namoyoxy benzyl ester

4- (Promomethyl) -N- [5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydrido-1H-imidazo obtained in Example 7-5 [ Acetonitrile of 5, 1-c] [1,4] thiazine-tolylidene] benzenesulfonamide (315 mg, 0.595 mmol), potassium acetate (177 mg, 1.78 pt. Ol) and potassium hydroxide (118 mg, 1.78 dl) (5.00 ml) The suspension was heated to reflux for 3 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (5: 1, v / v) to give the title compound (110 mg, 36%). This product was used for the next reaction without further purification.

Infrared absorption spectrum (IR) (in KBr) So: 3250, 2957, 2934, 2872, 1744, 1663, 1615, 1559 cm " ¹ .

^ -NR (CDCI3): δ 0.934 (6Η, d, J = 6.2 Hz), 1.48-1.77 (3H, m), 1.79 (3H, d, J = 1.2 Hz), 2.13 (3H, s), 2.27 ( 3H, d, J = 1.2 Hz), 2.95 (2H, t, J = 7.4 Hz), 5.16 (2H, s), 7.46 (2H, d, J = 8.4 Hz), 7.96 (2H, d, J = 8.4) Hz), 9.60 (1H, bs). N- [5,6-Dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-dimidazo [5,1-c] [1,4] thiazine-1 -Ylidene] -4-hydroxymethylbenzenesulfonamide

Acetic acid 4-{[5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1Η-imidazo [5,1-c] obtained in Examples 7-7 [1,4] Thiazine-triylidene] sulfinnamoyloxy} benzyl ester (110 mg) was dissolved in a mixture of tetrahydrofuran (1.00 ml) and ethanol (1.00 ml), and 1N aqueous sodium hydroxide solution (0.647 ml) And stirred for 10 minutes. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain the solvent was distilled off under reduced pressure the title compound (58.2 ig, 58%). Recrystallization from ethyl acetate-disopropyl ether gave dark red crystals with a melting point of 165-167.

Infrared absorption spectrum (IR) (in KBr) V 3449, 3380-2720, 2959, 2934, 2872, 1748, 1665, 1611, 1553 cm " ¹ .

Ή one _{NMR (CDC1 3): (50.931} (6H, d, J = 6.6 Hz), 1.49-1.78 (3H, m), 1.79 (3H, s), 2.27 (3H, d, J = 1.2 Hz), 2.95 (2H, t, J = 7.6 Hz), 4.79 (2H, d, J = 5.0 Hz), 7.49 (2H, d, J = 8.4 Hz), 7.96 (2H, d, J = 8.4 Hz), 9.61 (1H , bs).

Elemental analysis value C _2. As H ₂₅ N ₃ 0 ₄ S ₃

Calculated (¾): C, 51.37; H, 5.39; N, 8.99; S, 20.57.

Found (¾): C, 51.18; H, 5.41;, 9.08; S, 20.56.

Example 7-9

 N- [5,6-Dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-1-ylidene ] -4-Methoxybenzenesulfonamide Example 7-5 Method was performed in the same manner as in Method C, except that 4-methoxybenzenesulfonyl chloride (208 mg, 1.01 mraol) was used instead of 4-bromomethylbenzenesulfonyl chloride. Triamino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5,1-c] [1,4] thiazin-3-one obtained in Example 6-2 (350 mg, The title compound (222 mg, 95%) was synthesized from 1.18. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 181-182.

Infrared absorption spectrum (IR) (in KBr) V: 3235, 2955, 2840, 1736, 1663, 1613, 1597, 1563, 1499 cm " ¹ .

_{¾- NMR (CDC1 3): δ} 0.927 (6H, d, J = 6.6 Hz), 1.46-1.74 (3H, m), 1.79 (3H, s), 2.24 (3H, d, J = 1.0 Hz), 2.94 (2H, t, J = 7.6 Hz), 3.87 (3H, s), 6.96 (2H, d, J = 8.8 Hz), 7.90 (2H, d, J-8.8 Hz), 9.61 (1H, bs).

Elementary analysis: as _{C 2Q H 25 N 3 0 4} S 3.

Calculated)): C, 51.37; H, 5.39; N, 8.99; S, 20.57.

Found (): C, 51.23; H, 5.40; N, 9.09; S, 20.48.

Example 7-10

 N- [5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-triylidene ] -4-Ethylbenzenesulfonamide Example 7-5 In the same manner as in Method C, 4-ethylmethylsulfonyl chloride (115 mg, 0.504 mmol) was used instead of 4-bromomethylbenzenesulfonyl chloride. The 1-amino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5, tric] [1,4] thiazin-3-one obtained in Example 6-2 (100 mg, 0.336 bandol ol) to give the title compound (92.8 mg, 59 mg). The crystals were recrystallized from ethyl acetate-getyl ether to give dark red crystals having a melting point of 169-171 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3208, 2955, 2934, 1870, 1748, 1717, 1661, 1615, 1559 cm "'.

 ¾-NMR (CDCI3): δ 0.927 (6Η, d, J = 6.6 Hz), 1.25 (3H, t, J = 7.6 Hz), 1.48-1.75 (3H, m), 1.79 (3H, d, J = 0.8 Hz), 2.26 (3H, d, J = 0.8 Hz), 2.71 (2H, q, J = 7.4 Hz), 2.94 (2H, t, J = 7.6 Hz), 7.30 (2H, d, J = 8.4 Hz) , 7.87 (2H, d, J = 8.4 Hz), 9.60 (1H, bs).

Elemental analysis: as C ₂₁ H ₂₇ N ₃ 0 ₃ S ₃

Calculated value (%): C, 54.17; H, 5.84; N, 9.02; S, 20.66.

Found (%): C, 54.09; H, 5.96; N, 8.99; S, 20.69.

Example 7-11

N- [5,6-Dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1- Ylidene] -4-isopropylbenzenesulfonamide Example 7-5 was obtained in the same manner as in Method C, except that 4-isopropylbenzenesulfonyl chloride (113 mg> 0.504 mmol) was used instead of 4-bromomethylbenzenesulfonyl chloride. The title compound (109 mg) was obtained from 1-amino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5, tric] [1,4] thiazin-3-one (100 mg, 0.336 t). mg, 68¾). Recrystallization from ethyl acetate-ethyl ether yielded dark red crystals with a melting point of 198-200 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 2959, 2928, 2892, 1744, 1728, 1663, 1607, 1551 cm— ¹ .

_{¾-NMR (CDC1 3):} δ 0.932 (6Η, d, J-6.2 Hz), 1.26 (6H, d, J = 7.0 Hz), 1.50-1.76 (3H, m), 1.79 (3H, d, J = 1.0 Hz), 2.27 (3H, d, J = 1.0 Hz), 2.95 (2H, t, J = 7.8 Hz), 2.89-3.03 (1H, m), 7.33 (2H, d, J = 8.2 Hz), 7.88 (2H, d, J = 8.4 Hz), 9.61 (1H, bs).

Elementary analysis: as _{C 22 H 29 N 3 0 3} S 3

Calculated value (%): C, 55.09; H, 6.09; N, 8.76; S, 20.05.

Found (¾): C, 55.11; H, 6.14; N, 8.71; S, 19.98.

Example 7-12,

 3-chloro-N- [5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5, l_c] [1,4] thiazine-1 -Ylidene] benzenesulfonamide Example 7-5 Method was performed in the same manner as in Method C, except that benzenesulfonyl chloride (145 mg, 0.672) was used instead of 4-bromomethylbenzenesulfonyl chloride. 1-Amino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5, tric] [1,4] thiazin-3-one obtained in Example 6-2 (100 mg, 0.336 mmol) to give the title compound (116 mg, 74%). The crystals were recrystallized from ethyl acetate-getyl ether to give dark red crystals having a melting point of 154-156.

Infrared absorption spectrum (IR) (in KBr) V 3229, 2955, 2907 , 2870, 1755, 1661, 1620, 1557 cm- Ή- R (CDC1 3): δ 0.932 (6Η, d, J = 6.6Hz), 1.46-1.76 (3H, m), 1.80 (3H, d, J = 1.0 Hz), 2.28 (3H, d, J-1.2 Hz), 2.97 (2H, t, J = 7.8 Hz), 7.38-7.56 (2H , m), 7.85 (1H, dt, J = 7.8, 2.0 Hz), 7.99 (1H, t, J = 2.0 Hz), 9.58 (1H, bs). Elemental analysis: C ₁₉ H ₂₂ N ₃ 0 ₃ S _{3 As} C1 Calculated value (%): C, 48.34; H, 4.70; N, 8.90; S, 20.38.

Found (%): C, 48.39; H, 4.46; N, 8.86; S, 20.37.

Example 7-13

 2-chloro-N- [5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] Thiazine-triylidene] benzenesulfonamide Example 7-5 Method 2-5 was used in the same manner as in Method C, except that 4-bromomethylbenzenesulfonyl chloride was used instead of 2-bromobenzenebenzenesulfonyl chloride (145 mg, 0.672 bandol). Thus, 1-amino_5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5, tric] [1,4] thiazin-3-one (100) obtained in Example 6-2 mg, 0.336 mol) to give the title compound (113 mg, 72 mol). The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 178-180 ° C.

Infrared absorption spectrum (IR) (in KBr) So: 3245, 2957, 2909, 2872, 1728, 1661, 1607, 1549 cm- ¹ .

_{Ή-NMR (CDC1 3):} δ 0.894 (6Η, d, J = 6.2 Hz), 1.46-1.73 (3H, m), 1.81 (3H, s), 2.30 (3H, d, J = 1.0Hz), 2.92 (2H, t, J = 7.6 Hz), 7.36-7.54 (3H, m), 8.20 (1H, d, J = 6.6 Hz), 9.74 (1H, bs).

Elementary analysis: as _{C 19 H 22 N 3 0 3} S 3 CI

Calculated (¾): C, 48.34; H, 4.70; N, 8.90; S, 20.38.

Found (%): C, 48.16; H, 4.66; N, 8.92; S, 20.34.

Example 7-14

 N- [5,6-Dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydrido-1H-dimidazo [5,1-c] [1,4] thiazine-1 -Ylidene] -4- (trifluoromethoxy) benzenesulfonamide

Example 7-5 Method In the same manner as in Method C, but using 4-trifluoromethoxybenzenesulfonyl chloride (0.116 ml, 0.672 mmol) instead of 4-bromomethylbenzenesulfonyl chloride, the procedure of Example 6-2 was repeated. The resulting triamino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5, tric] [1,4] thiazin-3-one (100 mg, 0.336 t ol )) To give the title compound (152 mg, 87%). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 200-201 ° C. Infrared absorption spectrum (IR) (in KBr) V: 3227, 2959, 2932, 2913, 2872, 1759, 1748, 1663, 1620, 1559, 1495 cm- ¹ .

¾ one _{NMR (CDC1 3): 6 0.933} (6H, d, J-6.2 Hz), 1.50-1.78 (3H, m), 1.80 (3H, d, J = 1.0 Hz), 2.28 (3H, d, J = 1.0 Hz), 2.96 (2H, t, J = 7.6 Hz), 7.31 (2H, d, J = 8.0 Hz), 8.02 (2H, d, J = 8.8 Hz), 9.60 (1H, bs).

Elemental analysis: C _2. As H ₂₂ N ₃ 0 ₄ S

 Calculated value (%): C, 46.05; H, 4.25; N, 8.06; S, 18.44.

 Found (%): C, 45.78; H, 4.43; N, 8.16; S, 18.44.

 Example 7-15

 N- [4-({[5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] Thiazine-1-ylidene] amino} sulfonyl) phenyl] acetamide

 Example 7-5 In the same manner as in Method C, but using 4-acetamidobenzenesulfonyl chloride (157 mg, 0.672 mmol) instead of 4-bromomethylbenzenesulfonyl chloride, the procedure of Example 6-2 was repeated. The title compound (154 mg) was obtained from the obtained triamino-5,6-dimethyl_8- (isopentylsulfanyl) -3H-imidazo [5, tric] [1,4] thiazin_3-one (100 mg, 0.336 mmol). mg, 93¾). Recrystallization from ethyl acetate-ethyl ether-tetrahydrofuran gave dark red crystals with a melting point of 213-215 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3343, 3279, 3189, 2955, 2930, 2915, 2872, 1752, 1738, 1692, 1667, 1615, 1591, 1559, 1537, 1497 cm " ¹ .

_{'H-NMR (CDC1 3)} : δ 0.934 (6Η, d, J = 6.2 Hz), 1.50-1.78 (3H, m), 1.79 (3H, d, J = 0.8 Hz), 2.22 (3H, s), 2.27 (3H, d, J = 1.2 Hz), 2.94 (2H, t, J = 7.2 Hz), 7.34 (1H, bs), 7.63 (2H, d, J = 9.2 Hz), 7.91 (2H, d, J = 8.8 Hz), 9.59 (1H, bs).

, N- [5,6-dimethyl-8_ (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-1-ylidene] -3 , 4-Dimethoxybenzenesulfonamide

Example 7-5 By the same method as in Method C, 3,4-dimethoxybenzenesulfonyl chloride (130 mg, 0.538 mg) was used instead of 4-bromomethylbenzenesulfonyl chloride. Using the IMOI), the triamino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5,1-c] [1,4] thiazine-3 obtained in Example 6-2 The title compound Q23 mg, 92%) was synthesized from -one (80.0 mg, 0.269 mmol). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 160-162 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3362, 2953, 1740, 1665, 1620, 1563, 1508 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 0.924 (6Η, d, J-6.4 Hz), 1.48-1.78 (3H, m), 1.79 (3H, d, J = 0.8 Hz), 2.27 (3H, d, J = 1.0 Hz), 2.95 (2H, t, J = 7.8 Hz), 3.93 (3H, s), 3.94 (3H, s), 6.91 (1H, d, J = 8.Hz), 7.45 (1H, d, J = 1.8Hz), 7.57 (2H, dd, J = 8.4, 2.2 Hz), 9.60 (1H, bs).

Elemental analysis: C ₂₁ H „N ₃ 0 ₅ S ₃ '0.4¾0

Calculated (¾): C, 49.96; H, 5.55; N, 8.32; S, 19.05.

Found (¾): C, 50.17; H, 5.44; N, 8.10; S, 18.71.

Example 7-17

4-Bumo-N- [5,6-Dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-m-imidazo [5, tric] [1,4] Thiazine-triylidene] benzenesulfonamide To a suspension of sodium hydride (269 mg, 6.72 Aging 01) (60¾ oily) in tetrahydrofuran (10.0 ml) was added triamino-5,6 obtained in Example 6-2. A solution of -dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5,1-c] [1,4] thiazin-3-one (1.00 g, 3.36 bandol) in tetrahydrofuran (5.00 ml) was added. The mixture was stirred for 5 minutes under ice cooling. To this was added a solution of 4-bromobenzenesulfonyl chloride (1.75 g, 6.72 / 1) in tetrahydrofuran (5.00 ml), and the mixture was further stirred for 3 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), was synthesized solvent was distilled off under reduced pressure the title compound (1.61 g, 93¾). The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 178-180 ° C.

Infrared absorption spectrum (IR) (in KBr) y: 3229, 2955, 2926, 1759, 1663, 1653, 1622, 1559 cm- ¹ .

_{Ή-NMR (CDC1 3):} δ 0.935 (6Η, d, J = 6.4 Hz), 1.46-1.78 (3H, m), 1.80 (3H, d, J = 1.0 Hz), 2.28 (3H, d, J = 0.6 Hz), 2.95 (2H, t, J = 7.2 Hz), 7.63 (2H, d, J = 8.8 Hz), 7.84 (2H, d, J = 8.8 Hz), 9.59 (1H, bs).

Elementary analysis: as _{C 19 H 22 N 3 0 3} S 3 Br

Calculated (%): C, 44.18; H, 4.29; N, 8.14; S, 18.63.

Found (¾): C, 44.12; H, 4.23; N, 8.21; S, 18.56.

Examples 7-18

 N- [5,6-Dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene]- 4-Vinylbenzenesulfonamide Example 7-5 In the same manner as in Method C, except that P-styrenesulfonyl chloride (88.7 mg, 0.538 ol) was used instead of 4-bromomethylbenzenesulfonyl chloride. Triamino-5,6-dimethyl 8- (isopentylsulfanyl) -3H-imidazo [5,1-c] [1,4] thiazin-3-one obtained in 6-2 (80.0 mg, The title compound (25.5 mg, 20 mg) was synthesized from 0.269 bandol ol). The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 173-175 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3218, 2953, 2903, 2872, 1746, 1661, 1620, 1559 cm- ¹ .

 'Η-thigh (CDC "): δ 0.928 (6Η, d, J = 6.2 Hz), 1.50-1.78 (3H, m), 1.79 (3H, d, J = 1.0 Hz), 2.27 (3H, d, J = 1.2Hz), 2.95 (2H, t, J = 7.6 Hz), 5.41 (1H, d, J = 11.0 Hz), 5.87 (1H, d, J = 17.6 Hz), 6.75 (1H, dd, J = 18.0) , 10.5 Hz), 7.50 (2H, d, J = 8.4 Hz), 7.92 (2H, d, J = 8.4 Hz), 9.63 (1H, bs).

Elemental analysis: as C ₂₁ H ₂₅ N ₃ 0 ₃ S ₃

(Calculated%): C, 54.40; H, 5.43; N, 9.06; S, 20.75.

Found (¾): C, 54.13; H, 5.62; N, 8.92; S, 20.65.

Examples 7 to 19

N- [5,6-Dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-dimidazo [5,1-c] [1,4] thiazine-triylidene] [1 , 1'-biphenyl] -4-sulfonamide Example 7-5 Method 4-Biphenylsulfonyl chloride (156 mg, 0.555 mmol) in place of 4-bromomethylbenzenesulfonyl chloride in the same manner as in Method C Was used to obtain 1-amino-5,6-dimethyl 8- (isopentylsulfanyl) -3H-imidazo [5,1-c] [1,4] thiazine obtained in Example 6-2. Title from -3-one (82.5 mg, 0.277 mmol) The title compound (110 mg, 78%) was synthesized. Recrystallization from ethyl acetate-ethyl ether gave dark red crystals, mp 183-185C.

Infrared absorption spectrum (IR) (in KBr): 3239, 2955, 2828, 2868, 1738, 1663, 1615, 1559 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 0.928 (6Η, d, J = 6.2 Hz), 1.50-1.76 (3H, m), 1.79 (3H, s),

2.28 (3H, s), 2.96 (2H, t, J = 7.6 Hz), 7.39-7.54 (3H, m), 7.56-7.64 (2H, m),

7.69 (2H, d, J = 8.4 Hz), 8.03 (2H, d, J = 8.4 Hz), 9.65 (1H, bs).

Elemental analysis: as C ₂₅ H ₂₇ N ₃ 0 ₃ S ₃

Calculated value (¾): C, 57.84; H, 5.36; N, .8.09.

Found (¾): C, 58.15; H, 5.66; N, 7.85.

Example 7-20

 N- [5,6-Dimethyl-8 (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5,1c] [1,4] thiazine-ylidene] (phenyl ) Methanesulfonamide Example 7-5 was obtained in the same manner as in Method C, except that benzylsulfonyl chloride (128 nig, 0.672 mmol) was used instead of 4-bromomethylbenzenesulfonyl chloride. 1-Amino-5,6-dimethyl 8- (isopentylsulfanyl) -3H-imidazo [5,1-c] [1,1¾thiazin-3-one (100 mg, 0.336 mmol) to give the title compound (104 mg, 69 mg) was synthesized. Recrystallization from ethyl acetate-ethyl ether-tetrahydrofuran gave dark red crystals with a melting point of 188-190 ° C.

Infrared absorption spectrum (IR) (in KBr) d: 3139, 2957, 2928, 1732, 1663, 1615, 1561, 1541 cm- ¹ .

 Ή-NMR (CDCI3): δ 0.974 (6Η, d, J = 6.2 Hz), 1.50-1.78 (3H, m), 1.80 (3H, d, J = 0.8 Hz), 2.21 (3H, d,] = 2 Hz), 3.00 (2H, i, J = 8.0 Hz), 4.35 (2H, s), 7.30-7.47 (5H, m), 9.11 (1H, bs).

Elemental analysis: C _{2. 3} N ₃ 0 ₃ S ₃

Calculated value (%): C, 53.43; H, 5.16; N, 9.35; S, 21.40.

Found (%): C, 53.07; H, 5.50; N, 9.24; S, 21.23.

Example 7-21

N- [5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-di Midazo [5,1-c] [1,4] thiazine-1-ylidene] -tobutanesulfonamide Example 7-2 Method 4-Trifluoromethylbenzenesulfonyl chloride instead of 4_trifluoromethylbenzenesulfonyl chloride Using butanesulfonyl chloride (0.0872 ml, 0.672 mmol), triamino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo obtained in Example 6-2 [5, tric] The title compound (96.0 mg, 68%) was synthesized from [1,4] thiazin-3-one (100 mg, 0.336 mmol). Recrystallization from ethyl acetate-jetil ether gave dark red crystals with a melting point of 180-182 ° C.

Infrared absorption spectrum (IR) (in KBr): 3156, 2963, 2922, 2872, 1753, 1736, 1663, 1622, 1572 cm " ¹ .

¾ - employment _{R (CDC1 3): δ 0.945} (6H, d, J = 6.2Hz), 0.951 (3H, t, J = 7.0Hz), 1.40-1.78 (5H, m), 1.81 (3H, d, J -1.0 Hz), 1.78-1.96 (2H, m), 2.28 (3H, d, J = 0.6 Hz), 2.98 (2H, t, J = 7.8 Hz), 3.12 (2H, t, J = 8.0 Hz), 9.45 (1H, bs).

Elementary analysis: as _{C 17 H 27 N 3 0 3} S 3

Calculated value (¾): C, 48.89; H, 6.52; N, 10.06; S, 23.04.

Found (¾): C, 48.81; H, 6.24; N, 10.33; S, 22.99.

Examples 7 to 22

 N- [5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-trilidene ] -2,2,2-Trifluoroethanesulfonamide

 Example 7-5 Method was carried out in the same manner as in Method C, except that 2,2,2-trifluorobenzenesulfonyl chloride (129 mg, 0.672 mmol) was used instead of 4-bromomethylbenzenesulfonyl chloride. Triamino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5,1-c] [1,4] thiazin-3-one (100 The title compound (5.8 mg, 3.9%) was synthesized from the compound (0.3 mg, 0.336 t). Recrystallization from n-hexane gave dark red crystals with a melting point of 161-163 ° C.

Infrared absorption spectrum (IR) (in KBr) So: 3202, 2959, 2928, 2874, 1750, 1661, 1597, 1557 cnf ¹ .

_{lH - NMR (CDC1 3):} δ 0.950 (6Η, d, J = 6.2 Hz), 1.44-1.78 (3H, m), 1.82 (3H, d, J = 1.0 Hz), 2.31 (3H, d, J = 1.2 Hz), 3.00 (2H, t, J-7.6 Hz), 3.91 (2H, q, J = 9.2 Hz), 9.51 (1H, bs).

Example 7-23

 N- [5,6-Dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5, l_c] [1,4] thiazine-1-ylidene] -Tonaphthalene sulfonamide

 Example 7-5 Triamino obtained in Example 6-2 was prepared in the same manner as in Method C, except that tronaphthalenesulfonyl chloride (122 mg, 0.538 mmol) was used instead of 4-bromomethylbenzenesulfonyl chloride. -5,6-Dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5, tric] [1,4] thiazin_3-one (80.0 mg, 0.269 mmol) from the title compound (114 mg, 87% ) Was synthesized. Recrystallization from ethyl acetate-getyl ether-gave dark red crystals with a melting point of 190-192 ° C.

Infrared absorption spectrum (IR) (in KBr) Re: 3260, 2957, 1732, 1661, 1613, 1553, 1507 cm- ¹ .

_{Ή-NMR (CDC1 3):} δ 0.905 (6Η, d, J = 6.6 Hz), 1.42-1.74 (3H, in), 1.75 (3H, d,

J = 1.2 Hz), 2.25 (3H, d, J = 0.6 Hz), 2.90 (2H, t, J = 7.8 Hz), 7.50-7.68 (3H, m), 7.88-7.95 (1H, m), 8.05 ( 1H, dd, J = 8.0, 1.2 Hz), 8.29 (1H, dd, J = 7.4,

1.0 Hz), 8.88-8.98 (1H, m), 9.67 (1H, bs).

Elemental _{analysis: C 23 H 25 N 3 0} 3 S 3: as

Calculated value (%): C, 56.65; H, 5.17; N, 8.62; S, 19.73.

Found (%): C, 56.52; H, 4.99; N, 8.82; S, 19.62.

Examples 7-24

 N- [5,6-Dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydrido-1H-imidazo [5,1-c] [1,] thiazine-1-ylidene] -2-Naphthalenesulfonamide

 Example 7-5 According to the method similar to that of Method C, 2-naphthalenesulfonyl chloride (91.4 mg, 0.403 tmol) was used in place of 4-bromomethylbenzenesulfonyl chloride to obtain Example 6-2. Title compound from triamino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5,1-c] [1,4] thiazin-3-one (80.0 mg, 0.269 mmol) (85.4 mg, 87 mg) was synthesized. The crystals were recrystallized from ethyl acetate-getyl ether to give dark red crystals having a melting point of 172-174 ° C.

Infrared absorption spectrum (IR) (in KBr): 3231, 2957, 2915, 2867, 1736, 1663, 1615, 1557, 1505 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 0.909 (6H, d, J = 6.6 Hz), 1.48-1.76 (3H, m), 1.79 (3H, s), 2.27 (3H, d, J = 1.2 Hz), 2.94 (2H, t, J = 7.4 Hz), 7.58-7.70 (2H, m), 7.86-8.04 (4H, m), 8.52 (1H, s), 9:69 (1H, bs).

Elemental analysis: C ₂₃ ¾ ₅ N ₃ 0 ₃ S ₃

Calculated value (%): C, 56.65; H, 5.17; N, 8.62; S, 19.73.

Observed value (): C, 56.63; H, 5.27; N, 8.56; S, 19.67.

Example 7-25

 N- [5,6-Dimethyl-8- (isopentylsulfanyl) _3_oxo-2,3-dihydro-1H-imidazo [5, lc] [1,4] thiazine-1_ylidene] -8_quinoline Sulfonamide

 Example 7-5 In the same manner as in Method C, except that 4-bromomethylbenzenesulfonyl chloride was replaced with 8_quinoline sulfonyl chloride (91.4 mg, 0.403 t ol), the product was obtained in Example 6-2. Title from triamino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5,1-c] [1,4] thiazin-3_one (70.0 mg, 0.235 bandol ol) The title compound (74.3 mg, 65%) was synthesized. Recrystallization from ethyl acetate-diisopropyl ether gave dark red crystals with a melting point of 194-195 ° C.

Infrared absorption spectrum (IR) (in KBr) So: 3364, 2957, 2930, 2909, 2870, 1738, 1663, 1615, 1557, 1495 cm—

_{¾-NMR (CDC1 3):} δ 0.853 (6Η, d, J = 6.2 Hz), 1.40-1.70 (3H, m), 1.79 (3H, s), 2.32 (3H, s), 2.86 (2H, t, J = 7.6 Hz), 7.51 (1H, dd, J = 8.8, 4.8 Hz), 7.66 (1H, t, J = 8.0 Hz), 8.03 (1H, dd, J = 8.0, 1.4 Hz), 8.25 (1H, dd, J = 8.0, 1.4 Hz), 8.64 (1H, dd, J = 7.4, 1.4 Hz), 8.97 (1H, dd, J = 4.4, 1.4 Hz), 11.19 (1H, bs). Elemental analysis: C ₂₂ H ₂₄ N _{40 s As} S ₃

Calculated value (%): C, 54.07; H, 4.95; N, 11.47; S, 19.69.

Observed value (¾): C, 54.09; H, 4.72; N, 11.35; S, 19.60.

Example 7-26

5-cyclo-N- [5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] Thiazine-1-ylidene] -2-thiophenesulfonic acid Example 7-5 According to a method similar to that of Method C, 5-chlorothiophene-2-sulfonyl chloride (120 nig, 0.538 mmol) was used instead of 4-bromomethylbenzenesulfonyl chloride, and Example 6-2 was used. 1-Amino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5,1-c] [1,4] thiazin-3-one (80.0 nig, 0.269 )) To give the title compound (90.5 mg, 70%). The crystals were recrystallized from ethyl acetate-ethyl ether to give dark red crystals having a melting point of 154-156.

Infrared absorption spectrum (IR) (in KBr) V: 3231, 2957, 1757, 1663, 1617, 1555, 1520 cm—

_{'H-NMR (CDC1 3)} : δ 0.946 (6Η, d, J = 6.2 Hz), 1.52-1.78 (3H, m), 1.81 (3H, d, J = 0.6 Hz), 2.29 (3H, d, J = 1.0 Hz), 2.98 (2H, t, J = 7.Hz), 6.85 (1H, d, J = 4.0

Hz), 7.45 (1H, d, J-4.0 Hz), 9.51 (1H, bs).

Elementary analysis: as _{C 17 H 20 N 3 0 3} S 4 C1

Calculated value (%): C, 42.71; H, 4.22; N, 8.79; S, 26.83.

Found (¾): C, 42.53; H, 4.04; N, 8.81; S, 26.91.

Example 7-27

 2,5-dic-mouth-N- [5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [ 1,4] thiazine-1-ylidene] -3-thiophenesulfonamide

 Example 7-5 Method was performed in the same manner as in Method C, except that 2,5-dichlorothiophene-3-sulfonyl chloride (144 mg, 0.535 t) was used instead of 4-bromomethylbenzenesulfonyl chloride. 1-Amino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5,1-c] [1,4] thiazin-3-one obtained in Example 6-2 ( The title compound (104 mg, 73%) was synthesized from 82.5 mg (0.277 benzyl). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 168-170 ° C.

Infrared absorption spectrum (IR) (in KBr) Re: 3337, 2961, 2926, 2868, 1744, 1661, 1611, 1559, 1510 cur ¹ .

_{lH - NMR (CDC1 3):} δ 0.936 (6H, d, J = 6.6 Hz), 1.50-1.78 (3H, m), 1.81 (3H, d, J = 1.0 Hz), 2.30 (3H, d, J = 0.8 Hz), 2.98 (2H, t, J = 7.8Hz), 7.20 (1H, s), 9.63 (1H, bs). Elementary analysis: as _{C 17 H l9 N 3 0 3} S 4 C "

Calculated value (%): C, 39.84; H, 3.74; N, 8.20; S, 25.03.

Found (¾): C, 39.62; H, 3.65; N, 8.28; S, 25.02.

Examples 7-28

N_ [5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-triylidene] -2 1,3-benzoxazol-4-sulfonamide

 Example 7-5 Method was performed in the same manner as in Method C, except that benzofurazan-4-sulfonyl chloride (103 mg, 0.471 marl) was used instead of 4-bromomethylbenzenesulfonyl chloride to obtain Example 6-2. 1-Amino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5,1-c] [1,4] thiazin-3-one (70.0 mg, 0.235 t ol) The title compound (46.8 mg, 42%) was synthesized. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 197-198 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3202, 2148, 2961, 2932, 1725, 1657, 1615, 1584 cur ¹ .

_{^ -NMR (CDC1 3): δ} 0.876 (6H, d, J = 6.6 Hz), 1.42-1.68 (3H, m), 1.80 (3H, d, J = 0.8Hz), 2.33 (3H, d, J = 1.0Hz), 2.89 (2H, t, J = 7.8Hz), 7.54 (1H, dd, J = 9.0, 6.6 Hz), 8.06 (1H, dd, J = 9.2, 0.8 Hz), 8.13 (1H, dd, J = 7.0, 0.6 Hz), 9.87 (1H, bs).

Elementary analysis: as _{C 19 H 21 N 5 0 4} S 3

Calculated (%): C, 47.58; H, 4.41;, 14.60; S, 20.06.

Found (%): C, 47.49; H, 4.34; N, 14.41; S, 19.91.

Example 7-29

 N- [5,6-Dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-lirident 2 , 4, 6-trimethylbenzenesulfonamide

Example 7-5 In the same manner as in Method C, except that 4-bromomethylbenzenesulfonyl chloride was replaced with 2,4,6-trimethylbenzenesulfonyl chloride (150 mg, 0.672 bandol), the procedure of Example 7-5 was repeated. 6-Diamino-5,6-dimethyl-8- (iso The title compound (102 mg, 63 mg) was synthesized from (pentylsulfanyl) -3H-imidazo [5, tric] [1,4] thiazin-3-one (100 mg, 0.336 t ol). Recrystallization from ethyl acetate-jetil ether gave dark red crystals with a melting point of 161-163.

Infrared absorption spectrum (IR) (in Br) Re: 3378, 3245, 2957, 2936, 2870, 1744, 1726, 1661, 1615, 1557 cm " ¹ .

- Awakening: _{R (CDC1 3): δ 0.913} (6Η, d, J = 6.6 Hz), 1.45-1.59 (2H, m), 1.59-1.72 (IH, m), 1.78 (3H, s), 2.26 (3H, s), 2.28 (3H, s), 2.71 (6H, s), 2.93 (2H, t, J = 6.6 Hz), 6.92 (2H, s), 9.66 (1H, bs).

Example 7-30

4,5-Dimethyl PN-C5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1, 4,] Thiazine-triylidene] -2-thiophenesulfonamide

 Example 7-5 In the same manner as in Method C, except that 4,5-dichlorothiophene-2-sulfonyl chloride (174 mg, 0.672 bandol) was used instead of 4-bromomethylbenzenesulfonyl chloride. Triamino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5, tric] [1,4] thiazin-3-one obtained in 6-2 (100 mg, The title compound (104 mg, 60%) was synthesized from 0.336 benzyl). Recrystallization from ethyl acetate-jetil ether gave dark red crystals with a melting point of 203-205.

Infrared absorption spectrum (IR) (in KBr) Re: 3451, 3214, 3079, 2955, 1757, 1742, 1661, 1615, 1553 cm "" ¹ .

_{Ή-NMR (CDC1 3):} 6 0.951 (6H, d, J = 6.6Hz), 1.56-1.68 (2H, m), 1.68-1.77 (IH, m), 1.82 (3H, d, J = 1.2 Hz) , 2.30 (3H, d, J = 1.2 Hz), 3.00 (2H, t, J = 7.8 Hz), 7.44 (1H, s), 9.50 (IH, bs).

Elementary analysis: as _{C n H 19 N 3 0 3} S 4 C

Calculated value (¾): C, 39.84; H, 3.74; N, 8.20; S, 25.03.

Found (): C, 39.66; H, 3.70; N, 8.08; S, 24.93.

Example 7-31

3,4-Dichloro-N- [5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4 [Thiazine-1-ylidene] benzenesulfone Do

 Example 7-5 Method 6-2 was repeated in the same manner as in Method C, except that benzenesulfonyl chloride (168 mg, 0.672 miol) was used instead of 4-bromomethylbenzenesulfonyl chloride. -5,6-Dimethyl-8_ (isopentylsulfanyl) -3H-imidazo [5, tric] [1,4] thiazin-3-one (100 mg, 0.336 fraction ol) (112 mg, 66%) was synthesized. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 162 to 164 ° C.

Infrared absorption spectrum (IR) (in KBr): 3227, 3092, 2957, 2930, 2872, 1759, 1661, 1620, 1557 cur ¹ .

_{Ή-NMR (CDC1 3):} δ 0.938 (6Η, d, J = 6.6Hz), 1.51-1.63 (2H, m), 1.63-1.78 (1H, m), 1.80 (3H, d, J-0.8 Hz) , 2.29 (3H, d, J = 1.2 Hz), 2.97 (2H, t, J = 7.8 Hz),

7.56 (1H, d, J = 8.Hz), 7.79 (1H, dd, J = 8.0, 1.8 Hz), 8.08 (1H, d, J = 2.2 Hz),

9.57 (1H, bs).

Elemental analysis: as C ₁₉ H ₂₁ N ₃ 0 ₃ S ₃ C ₁₂

Calculated value (%): C, 45.06; H, 4.18; N, 8.30; S, 18.99.

Found (¾): C, 45.27; H, 4.18; N, 8.04; S, 18.65.

Example 7-32

 2,5-Dicyclo-N- [5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [ 1,4] thiazine-1-ylidene] benzenesulfonamide

 Example 7-5 In the same manner as in Method C, except that 4-bromomethylbenzenesulfonyl chloride was replaced with 2,5-dichlorobenzenesulfonyl chloride (168 mg, 0.672 mmol), the procedure of Example 6-2 was repeated. Title obtained from the obtained triamino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5,1-c] [1,4] thiazin-3-one (100 mg, 0.336 mmol) Compound (146 mg, 85¾) was synthesized. The crystals were recrystallized from ethyl acetate-getyl ether to obtain reddish crystals having a melting point of 180-182 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3245, 3090, 2961, 2928, 1725, 1663, 1605, 1543 cm- ¹ .

Ή-NMR (CDCI3): δ 0.906 (6Η, d, J = 6.2 Hz), 1.47-1.62 (2H, m), 1.62-1.74 (1H, m), 1.81 (3H, d, J = 1.0 Hz), 2.31 (3H, d, J = 0.8 Hz), 2.94 (2H, t, J = 7.6 Hz), 7.43 (IH, s), 7.44 (IH, d, J = 0.8 Hz), 8.20 (IH, t, J = 1.0 Hz), 9.71 (1H, bs) Elementary analysis:. as _{C 19 H 21 N 3 0 3} S 3 C1 2

Calculated: C, 45.06; H, 4.18; N, 8.30; S, 18.99.

Found (¾): C, 44.96; H, 4.45; N, 8.40; S, 18.86.

Example 7-33

 2,5-difluoro-N- [5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine- 1-ylidene] benzenesulfonamide

 Example 7-5 In the same manner as in Method C, except that 2,4-difluorobenzenesulfonyl chloride (143 mg, 0.672 ol) was used instead of 4-bromomethylbenzenesulfonyl chloride. 1-Amino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5,1-c] [1,4] thiazin-3-one obtained in Step 2 (100 mg, 0.336 mmol )) To give the title compound (85.1 mg, 54%). The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 187-189 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3384, 3248, 3102, 2955, 2930, 2870, 1728, 1661, 1603, 1557, 1481 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 0.954 (6Η, d, J = 6.6 Hz), 1.46-1.62 (2H, m), 1.62-1.75 (1H, m), 1.81 (3H, d, J = 0.8 Hz) , 2.30 (3H, d, J = 1.0 Hz), 2.93 (2H, t, J = 7.6 Hz), 6.86-7.05 (2H, m), 7.94-8.08 (IH, m), 9,69 (IH, bs ).

Elemental analysis: as C ₁₉ H ₂₁ N ₃ 0 ₃ S ₃ F ₂

Calculated value (%): C, 48.19; H, 4.47; N, 8.87; S, 20.31.

Found (%): C, 47.96; H, 4.39; N, 8.92; S, 20.21.

Example 7-34

2-c-mouth- 4-fluoro-N- [5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro- mouth-1H-imidazo [5,1-c ] [1,4] thiazine-1-ylidene] benzenesulfonamide

Example 7-5 According to a method similar to that of Method C, 4-bromomethylbenzenesulfonyl chloride was used instead of 4-bromomethylbenzenesulfonyl chloride (154 mg, Using the 0.672 thigh ol), the triamino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5,1-c] [1,1) obtained in Example 6-2 was obtained. 4] The title compound (107 mg, 65%) was synthesized from thiazin-3-one (100 mg, 0.336 tmol). 'Recrystallization from ethyl acetate-getyl ether yielded dark red crystals with a melting point of 204-206 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3210, 2957, 2934, 2872, 1734, 1715, 1661, 1609, 1588, 1555 cm- ¹ .

_{Ή-NMR (CDC1 3):} δ 0.904 (6Η, d, J = 6.2Hz), 1.45-1.61 (2H, m), 1.61-1.74 (1H, m), 1.81 (3H, s), 2.30 (3H, s), 2.93 (2H, t, J = 7.2 Hz), 7.04-7.16 (1H, m),

7.22-7.32 (1H, m), 8.20 (1H, dd, J = 8.8, 5.8 Hz), 9.71 (1H, bs).

Elemental analysis: as C ₁₉ H ₂₁ N ₃ 0 ₃ S ₃ C1F

Calculated (%): C, 46.57; H, 4.32; N, 8.57; S, 19.63.

Found (¾): C, 46.50; H, 4.26; N, 8.59; S, 19.43.

Example 7-35

 3,4-Difluoro-N- [5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine- 1-ylidene] benzenesulfonamide

 Example 7-5 Method 6-2 was repeated in the same manner as in Method C, except that 3,4-difluorobenzenesulfonyl chloride (143 mg, 0.672 mmol) was used instead of 4-bromomethylbenzenesulfonyl chloride. 1-amino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5,1-c] [1,4] thiazin-3-one (100 mg, 0.336 t )) To give the title compound (80.5 mg, 51%). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 153-155 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3206, 3069, 2963, 2909, 2872, 1757, 1744, 1744, 1663 cm- ¹ .

Ή-NMR (CDCI3): δ 0.939 (6Η, d, J = 6.2 Hz), 1.50-1.63 (2H, m), 1.63-1.78 (1H, m), 1.81 (3H, d, J = 1.2 Hz), 2.28 (3H, d, J-0.8 Hz), 2.97 (2H, t, J = 7.6 Hz), 7.18-7.35 (1H, m), 7.70-7.79 (1H, m), 7.80-7.88 (1H, m) , 9.57 (1H, bs). Elemental analysis: _{Cl 9} H ₂₁ N ₃ 0 ₃ S ₃ F ₂

Calculated (%): C, 48.19; H, 4.47; N, 8.87; S, 20.31. Found (%): C, 48.26; H, 4.28; N, 8.88; S, 20.39.

Example 7-36

 N- [5,6-Dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine Ilidene] octanesulfonamide

 Example 7-5 Method 1-Amino obtained in Example 6-2 was obtained in the same manner as in Method C, except that octanesulfonyl chloride (129 mg, 0.605 mol) was used instead of 4-bromomethylbenzenesulfonyl chloride. -5,6-Dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5,1-c] [1,4] thiazin-3-one (100 mg, 0.336 mmol) from the title compound ( 24.9 mg, 17%). The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 153 to 155 ° C.

Infrared absorption spectrum (IR) (in KBr) V 3210, 2955, 2924, 2857, 1755, 1738, 1663, 1622, 1570 cm " ¹ .

_{'H-NMR (CDC1 3)} : δ 0.881 (3Η, t, J = 6.6Hz), 0.945 (6H, d, J = 6.2Hz), 1.22-1.64 (12H, m), 1.64-1.78 (1H, m ), 1.81 (3H, s), 1.83-1.97 (2H, m), 2.28 (3H, s), 2.98 '(2H, t, J = 8.0 Hz), 3.11 (2H, t, J = 8.0 Hz), 9.45 (1H, bs).

Elemental analysis: as C ₂₁ H ₃₅ N ₃ 0 ₃ S ₃

Calculated value (%): C, 53.24; H, 7.45; N, 8.87.

Found (%): C, 52.95; H, 7.40; N, 8.56.

Example 7-37

4-Acetyl-N- [5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4 ] Thiazine-1-ylidene] benzenesulfonamide Example 7-5 Method similar to Method C, using 4-acetylbenzenesulfonyl chloride (136 mg, 0.605 mmol) instead of 4-bromomethylbenzenesulfonyl chloride. The triamino_5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5,1-c] [1,4] thiazin-3-one obtained in Example 6-2 (90.0 mg The title compound (85.9 mg, 59%) was synthesized from the following compounds. The crystals were recrystallized from ethyl acetate-jetil ether to obtain dark red crystals having a melting point of 176-178 ° C.

Infrared absorption spectrum (IR) (in KBr): 3231, 2957, 2934, 2870, 1759, 1694, 1663, 1620, 1557 cm- ¹ . Ή-NMR (CDCI3): δ 0.935 (6Η, d, J = 6.4 Hz), 1.44-1.77 (3H, m), 1.80 (3H, s), 2.28 (3H, s), 2.65 (3H, s), 2.96 (2H, i, J = 7.4 Hz), 8.06 (4H, s), 9.62 (1H, bs).

Elemental analysis: - as _{C 21 ¾ 5 N 3 0 4} S 3

Calculated value (¾): C, 52.59; H, 5.25; N, 8.76; S, 20.06.

Found (%): C, 52.23; H, 5.11; N, 8.67; S, 20.01.

Example 7-38

 N- [5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-1-ylidene ] -2-Methoxy-4-methylbenzenesulfonamide

 Example 7-5 In the same manner as in Method C, using 2-methoxy-4-methylbenzenesulfonyl chloride (134 mg, 0.605 hall) instead of 4-bromomethylbenzenesulfonyl chloride, Triamino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5,1-c] [1,4] thiazin-3-one obtained in 2 (90.0 nig, 0.303 mmol) to give the title compound (123 mg, 84%). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 192-194 ° C.

Infrared absorption spectrum (IR) (in KBr): 3262, 2953, 2926, 2867, 1717, 1663, 1615, 1557 cm " ¹ .

¾-NMR (CDCI3): δ 0.886 (6Η, d, J-6.2 Hz), 1.45-1.72 (3H, m), 1.80 (3H, s), 2.30 (3H, s), 2.40 (3H, s), 2.89 (2H, t, J = 7.6 Hz), 3.87 (3H, s), 6.77 (1H, s), 6.85 (1H, dd, J = 7.8, 1.0 Hz), 7.90 (1H, d, J = 7.8 Hz) ), 9.85 (1H, bs). Elemental analysis: C ₂₁ H ₂₇ N ₃ O ₄ S ₃ '0.3EtOAc

Calculated (¾): C, 52.48; H, 5.83; N, 8.27; S, 18.93.

Found (¾): C, 52.31; H, 5.63; N, 8.22; S, 18.74.

Example 7-39 ■

3-Cupro-N- [5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1 , 4] Thiazine-1-ylidene] -4-methylbenzenesulfonamide

Example 7-5 Method 4-bromomethylbenzenesulfonyl chloride was obtained in the same manner as in Method C. Using trichloro-4-methylbenzenesulfonyl chloride (136 mg, 0.605 mmol) instead of chloride, triamino-5,6-dimethyl-8- (isopentylsulfanyl) obtained in Example 6-2 was used. ) The title compound (123 mg, 83%) was synthesized from -3H-imidazo [5,1-c] [1,4] thiazin-3-one (90.0 mg, 0.303 mmol). Recrystallization from ethyl acetate-jetil ether gave dark red crystals with a melting point of 166-168 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3237, 2955, 2926, 2868, 1757, 1663, 1620, 1561 cm " ¹ .

丽_{R (CDC1 3): δ 0.934} (6Η, d, J = 6.2Hz), 1.51-1.64 (2H, m), 1.64-1.77 (1H, m), 1.80 (3H, d, J-0.8 Hz), 2.28 (3H, s), 2.43 (3H, s), 2.96 (2H, t, J = 7.6 Hz), 7.34 (1H, d, J = 8.2 Hz), 7.74 (1H, dd, J = 8.0, 1.8 Hz) ), 7.96 (1H, d, J = 1.8

Hz), 9.57 (1H, bs).

Elemental analysis: C _{2. 4} N ₃ 0 ₃ S ₃ C1

Calculated (%): C, 49.42; H, 4.98; N, 8.64; S, 19.79.

Found (%): C, 49.22; H, 4.82; N, 8.71; S, 19.71.

Example 7-40

 N- [5,6-Dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-1-ylidene ] -4-methyl-3-nitrobenzenesulfonamide

 Example 7-5 In the same manner as in Method C, using 4-methyl-3-nitrobenzenesulfonyl chloride (317 mg, 1.3 mmol) instead of 4-bromomethylbenzenesulfonyl chloride, the procedure of Example 6-2 was repeated. From the obtained 1-amino-5,6-dimethyl-8- (isobenzylsulfanyl) -3H-imidazo [5, tric] [1,4] thiazin-3-one (200 mg, 0.672 mmol) The title compound (296 mg, 89%) was synthesized. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 163-165 ° C.

Infrared absorption spectrum (IR) (in KBr) v: 3220, 2959, 2934, 2870, 1759, 1661, 1618, 1557, 1532 cm—

_{Ή-NMR (CDC1 3):} δ 0.940 (6Η, d, J = 6.6 Hz), 1.52-1.65 (2H, m), 1.65-1.78 (1H, m), 1.81 (3H, d, J = 1.2 Hz) , 2.29 (3H, d, J = 1.0 Hz), 2.67 (3H, s), 2.98 (2H, t, J = 7.8 Hz), 7.49 (1H, d, J = 8.0 Hz), 8.07 (1H, dd, J = 8.0, 2.2 Hz), 8.61 (1H, d, J = 1.8 Hz), 9.57 (1H, bs).

Elemental analysis: C _2. H ₂₄ N ₄ 0 ₅ S ₃

Calculated value (%): C, 48.37; H, 4.87; N, 11.28; S, 19.37.

Found (%): C, 48.48; H, 4.80; N, 11.15; S, 19.46.

Example 7-41

 N- [5,6-Dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-1-ylidene ] -1_Methyl-4-imidazolesulfonami F

 Example 7-5 Method A method similar to that of Example C was repeated, except that 1-methyl-4-imidazolsulfonyl chloride (115 mg, 0.605 mniol) was used instead of 4-bromomethylbenzenesulfonyl chloride. From 1-amino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5, tric] [1,4] thiazin-3-one (90.0 mg, 0.303 t) obtained in The title compound (62.5 mg, 47¾) was synthesized. Recrystallization from ethyl acetate-getyl ether yielded dark red crystals with a melting point of 213-215 ° C.

Infrared absorption spectrum (IR) (in KBr) So: 3248, 3117, 2957, 2930, 2870, 1769, 1732, 1665, 1617, 1559, 1532 cm " ¹ .

 Ή-NMR (CDC "): δ 0.919 (6Η, d, J-6.2 Hz), 1.42-1.76 (3H, m), 1.80 (3H, d, J = 0.8 Hz), 2.28 (3H, d, J = 0.6 Hz), 2.94 (2H, t, J = 7.8Hz), 3.75 (3H, s), 7.48 (1H, s), 7.51 (1H, s).

Elementary analysis: as _{C 17 H 23 N 5 0 3} S 3

Calculated value (¾): C, 46.24; H, 5.25; N, 15.86; S, 21.78.

Found (¾): C, 46.13; H, 5.23; N, 15.98; S, 21.86.

Example 7-42

3-bromo-N- [5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-tri [Ilidene] benzenesulfonamide Example 7-5 Method 6 was repeated in the same manner as in Method C, except that 3-bromobenzenesulfonyl chloride (137 mg, 0.538 mmol) was used instead of 4-bromomethylbenzenesulfonyl chloride. -5,6-Dimethyl-8- (isopentylsulfanyl) _3H-imidazo [5, tric] [1,4] thiazin-3-one obtained in -2 (80.0 mg, 0.269 thigh 01) Or The title compound (114 mg, 75%) was synthesized. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 152-154 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3231, 3086, 2955, 2932, 2868, 1757, 1663, 1618, 1557 cnf ¹ .

_{¾-NMR (CDC1 3):} δ 0.936 (6Η, d, J = 6.6 Hz), 1.52-1.78 (3H, m), 1.80 (3H, d, J = 1.0 Hz), 2.28 (3H, d, J = 1.2Hz), 2.97 (2H, t, J = 7.6 Hz), 7.36 (1H, t, J = 7.8 Hz), 7.64-7.72 (1H, m), 7.86-7.94 (1H, m), 8.14 (1H, t, J = 1.8Hz), 9.58 (1H, bs).

Elementary analysis: as _{C 19 H 22 N 3 0 3} S 3 Br

Calculated (%): C, 44.18; H, 4.29; N, 8.14; S, 18.63.

Found (¾): C, 44.04; H, 4.12; N, 8.34; S, 18.62.

Example 7-43

 4-Cyano-N- [5,6-dimethyl-8- (isopentylsulfanyl) _3-oxo-2,3-dihydrogen-1H-imidazo [5,1-c] [1,4] Thiazine-triylidene] benzenesulfonamide Example 7-5 In the same manner as in Method C, using 4-cyanobenzenesulfonyl chloride (203 mg, 1.01 mol) instead of 4-bromomethylbenzenesulfonyl chloride. Triamino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5, tric] [1,4] thiazin-3-one obtained in Example 6- (150 mg, The title compound (207 mg, 89%) was synthesized from 0.504 Ryuol). The crystals were recrystallized from ethyl acetate-getyl ether to give dark red crystals with a melting point of 197-199 ° C.

Infrared absorption spectrum (IR) (in KBr): 3227, 2957, 2932, 2872, 2234, 1750, 1661, 1607, 1553 cm " ¹ .

 ¾-NMR (CDCI3): δ 0.942 (6Η, d, J = 6.6 Hz), 1.51-1.78 (3H, m), 1.81 (3H, s), 2.29 (3H, d, J = 0.6 Hz), 2.97 ( 2H, t, J = 7.6 Hz), 7.79 (2H, d, J = 8.4 Hz), 8.09 (2H, d, J = 8.8 Hz), 9.59 (1H, bs).

Elemental analysis: C _2. H ₂₂ N ₄ 0 _{3 As} S ₃

Calculated value (%): C, 51.93; H, 4.79; N, 12.11; S, 20.79

Obtained): C, 51.87; H, 4.76; N, 12.20; S, 20.80.

Example 7-44 ' 3-cyano-N- [5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] Thiazine-triylidene] benzenesulfonamide Example 7-5 By a method similar to Method C, using 3-cyanobenzenesulfonyl chloride (203 ing, 1.01 ininol) instead of 4-bromomethylbenzenesulfonyl chloride, 1-Amino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5,1-c] [1,4] thiazin-3-one obtained in Example 6-2 (150 mg, 0.504 mniol) to give the title compound (216 mg, 93¾). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 133-135 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3247, 3073, 2959, 2930, 2870, 2234, 1748, 1663, 1615, 1557 cm " ¹ .

_{^{L H-NMR (CDC1 3)}} : δ 0.946 (6Η, d, J = 6.4 Hz), 1.52-1.78 (3H, m), 1.81 (3H, s),

2.29 (3H, s), 2.99 (2H, t, J = 7.6 Hz), 7.63 (1H, t, J = 7.8 Hz), 7.80-7.86 (1H, m), 8.19 (1H, dt, J = 8.2, 1.8 Hz), 8.29 (1H, t, J = 1.8 Hz), 9.57 (1H, bs). Elemental analysis: C _2Q H ₂₂ N ₄ 0 ₃ S ₃ '0.2H ₂ 0

Calculated (%): C, 51.53; H, 4.84; N, 12.02; S, 20.63.

Found (%): C, 51.49; H, 4.81; N, 11.88; S, 20.46.

Example 7-45

 N- [5,6-Dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene] _2 -Thiophene sulfonamide

 Example 7-5 According to the method similar to Method C, 2-thiophenesulfonyl chloride (195 nig, 0.536 ramol) was used in place of 4-bromomethylbenzenesulfonyl chloride to obtain Example 1-5. -Amino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5, 1-c] [1,4] thiazin-3-one (50.0 mg, 0.168 bandol) from the title compound (46.0 mg, 62 mg) was synthesized. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 182-184 ° C.

Infrared absorption spectrum (IR) (in KBr) V 3290, 2955, 2926, 2874, 1736, 1713, 1661, 1607, 1557, 1507 cm- ¹ .

_{Ή-NMR (CDC1 3):} δ 0.934 (6Η, d, J = 6.2 Hz), 1.50-1.78 (3H, m), 1.80 (3H, d, J = l.0 Hz), 2.28 (3H, d, J = 1.0Hz), 2.96 (2H, t, J-7.6Hz), 7.05 (1H, dd, J = 4.8, 3.6 Hz), 7.57 (1H, dd, J = 5.2, 1.0 Hz), 7.68 (1H, dd, J = 3.2, 0.8 Hz), 9.56 (1H, bs).

Elementary analysis: as _{C l7 H 21 N 3 0 3} S 4

Calculated (%): C, 46.03; H, 4.77; N, 9.47; S, 28.91,

Found (%): C, 46.01; H, 4.72; N, 9.59; S, 28.80.

Example 7-46

 5 -Buguchi _N_ [5,6-Dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine -1-ylidene] -2-thiophene sulfone

 Example 7-5 Method 6-5 was repeated in the same manner as in Method C, except that 5-bromo-2-thiophenesulfonyl chloride (352 mg, 1.34 tmol) was used instead of 4-bromomethylbenzenesulfonyl chloride. From 1-amino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5, tric] [1,4] thiazin-3-one (200 mg, 0.672 mmol) (272 mg, 78 mg) was synthesized. Recrystallization from ethyl acetate-ethyl acetate yielded dark red crystals, mp 163-165.

Infrared absorption spectrum (IR) (in KBr) V: 3227, 2957, 1757, 1663, 1615, 1559, 1516 cm " ¹ .

_{¾-NMR (CDC1 3):} δ 0.947 (6Η, d, J = 6.6 Hz), 1.46-1.78 (3H, m), 1.81 (3H, d, J = 1.2 Hz), 2.28 (3H, s), 2.99 (2H, t, J = 8.0 Hz), 7.02 (2H, d, J = 4.0 Hz), 7.41 (2H, d, J = 4.0 Hz), 9.39 (1H, bs).

Example 7-47

N- [5,6_, Dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydrido-1H-imidazo [5, tric] [1,4] thiazine-triylidene]- 4-Eodobenzenesulfonamide Example 7-5 By the same method as in Method C, 4-bromoodobenzenesulfonyl chloride was substituted for 4-bromomethylbenzenesulfonyl chloride (219 mg, 0.672 mmol). And the triamino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5,1-c] [1,4] thiazine-3- obtained in Example 6-2. The title compound (169 mg, 89%) was synthesized from ON (100 mg, 0.336 mmol). Recrystallization from ethyl acetate-jetil ether gave dark red crystals with melting point 186-188. Infrared absorption spectrum (IR) (in KBr): 3229, 2953, 2928, 2907, 2868, 1759, 1663, 1620, 1557 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 0.937 (6Η, d, J = 6.2 Hz), 1.50-1.76 (3H, ni), 1.80 (3H, d, J = 1.0 Hz), 2.28 (3H, d, J = 1.0 Hz), 2.95 (2H, t, J = 7.6 Hz), 7.68 (2H, d, J = 8.8 Hz), 7; 85 (2H, d, 1 = 8.8 Hz), 9.58 (1H, bs).

Elemental analysis: as C ₁₉ H ₂₂ N ₃ 0 ₃ S ₃ I

Calculated value (¾): C, 40.50; H, 3.94; N, 7.46; S, 17.07.

Found (%): C, 40.53; H, 3.79; N, 7.60; S, 17.09.

Example 7-48

2,6-dic-mouth-N- [5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo_2,3-dihydro- 1H-imidazo [5,1-c] [ 1,4] thiazine-triylidene] benzenesulfonami F

 Example 7-5 Method 6-2 was repeated in the same manner as in Method C, except that benzenesulfonyl chloride (174 mg, 0.672 mmol) was used instead of 4-bromomethylbenzenesulfonyl chloride. From the 1-amino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5, 1-c] [1,4] thiazin-3-one (100 mg, 0.336 mmol) obtained in The title compound (161 mg, 95%) was synthesized. Recrystallization from ethyl acetate-ethyl ether yielded dark red crystals with a melting point of 198-200 ° C.

Infrared absorption spectrum (IR) (in KBr): 3250, 2957, 2932, 2868, 1736, 1717, 1661, 1611, 1553 cm " ¹ .

ΐ-NMR (CDCI3): δ 0.953 (6Η, d, J = 6.2 Hz), 1.46-1.76 (3H, m), 1.81 (3H, s),

2.30 (3H, d, J = 0.6 Hz), 2.94 (2H, t, J = 7.6 Hz), 7.30 (1H, dd, J = 9.2, 7.0 Hz),

7.40-7.48 (2H, m), 9.68 (1H, bs).

Elementary analysis: as _{C 19 H 21 N 3 0 3} S 3 C 1 2

Calculated value (%): C, 45.06; H, 4.18; N, 8.30; S, 18.99.

Found (%): C, 44.84; H, 4.13; N, 8.22; S, 18.82.

Example 7-49

2,4-Dicyclo-N- [5,6-dimethyl-8- (isopentylsulfanyl) -3oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] Thiazine-1-Iri H,

 Example 7-5 In the same manner as in Method C, using 2,4-dichlorobenzenesulfonyl chloride (230 mg, 1.34 t ol) instead of 4-bromomethylbenzenesulfonyl chloride, the procedure of Example 6-2 was repeated. Title obtained from the obtained triamino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5,1-c] [l, 4] thiazin-3-one (200 mg, 0.672 listening). Compound (231 mg, 68%) was synthesized. Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 187-189 ° C.

Infrared absorption spectrum (IR) (in KBr): 3281, 2955, 2934, 2468, 1750, 1725, 1663, 1615, 1557 cnf ¹ .

_{Ή-NMR (CDC1 3):} δ 0.906 (6Η, d, J = 6.2 Hz), 1.45-1.78 (3H, m), 1.81 (3H, d, J = 0.8Hz), 2.30 (3H, d, J = l.0 Hz), 2.93 (2H, t, J = 7.6 Hz), 7.38 (1H, dd, J = 8.6, 2.0 Hz), 7.51 (1H, d, J = 1.8 Hz), 8.12 (1H, d, J = 8.4 Hz), 9.69 ( 1H, bs) Elementary analysis:. a _{C 19 II 21 N 3 0 3} S 3 C1 2

Calculated (¾): C, 45.06; H, 4.18; N, 8.30; S, 18.99.

Found (¾): C, 45.09; H, 4.12; N, 8.39; S, 18.99.

Example 7-50

 -[5, 6-Dimethyl-8- (isopentylsulfanyl) _3_oxo -2,3-dihydrido-1H-imidazo [5, 1-c] [1,4] thiazine-1-ylidene]- 5-dimethylamino-naphthalenesulphonamide

 Example 7-5 Method 1-Amino obtained in Example 6-2 was obtained in the same manner as in Method C, except that dansyl chloride (185 mg, 0.672 t ol) was used instead of 4-bromomethylbenzenesulfonyl chloride. -5,6-Dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5, 1-c] [1, 4] thiazin-3-one (100 mg, 0.336 ol) The title compound (164 mg, 92%) was synthesized. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 186-188.

Infrared absorption spectrum (IR) (in KBr) V: 3241, 2955, 2868, 2832, 2786, 1732, 1663, 1615, 1557, 1505 cnf ¹ .

E - Anonymous _{(CDC1 3): δ 0.914 (} 6Η, d, J = 6.2 Hz), 1.42-1.74 (3H, m), 1.75 (3H, d, J = 1.2 Hz), 2.25 (3H, d, J = 0.8 Hz), 2.87 (6H, s), 2.91 (2H, t, J = 7.2 Hz), 7.16 (1H, dd, J = 7.8, 0.8 Hz), 7.46-7.58 (3H, m), 8.28 (1H, dd, J = 7.4, 1.2 Hz), 8.52 (1H, d, J = 8.0 Hz), 8.59 ( 1H, d, J = 8.8 Hz), 9.67 (1H, bs).

Elemental analysis: C ₂₅ ¾. As N ₄ 0 ₃ S ₃

Calculated (%): C, 56.58; H, 5.70; N, 10.56; S, 18.13.

Found (¾): C, 56.31; H, 5.62; N, 10.46; S, 17.92.

Example 7-51

 N- {5,6-dimethyl-8-[(4,4,5,5,5-pentafluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5, 1-c] [1,4] thiazine-triylidene} (phenyl) methanesulfonamide

Method C

To a suspension of sodium hydride (41.3 mg, 1.03 mmol) (freedom of 60) in tetrahydrofuran (2.00 ml) was added 1-amino-5,6-dimethyl-8-[(obtained in Example 6-3. 4,4,5,5,5-pentapentafluoropentyl) sulfanyl] -3H-imidazo [5,1-C] [1,4] thiazine-3-one (200 mg, 0.516 mmol) in tetrahydrofuran (1.00 ml) The solution was added, and the mixture was stirred under ice cooling for 5 minutes. To this was added a solution of benzylsulfonyl chloride (197 mg, 1.03 mmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 19 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO ₄₎ After the solvent was distilled off under reduced pressure to give the title compound (206 mg, 74¾) was synthesized. Recrystallization from ethyl acetate-jetil ether gave dark red crystals with a melting point of 192-19'4 ° C.

Infrared absorption spectrum (IR) (in KBr) d: 3150, 3079, 2965, 2942, 2714, 1740, 1661, 1615, 1564, 1497 cm " ¹ .

Ή one _{NMR (CDC1 3): δ 1.80} (3Η, d, J = 1.2 Hz), 1.98-2.36 (4H, m), 2.21 (3H, s), 3.06 (2H, t, J = 7.4 Hz), 4.36 (2H, s), 7.32-7.47 ( 5H, m), 9.14 (1H, bs) elemental analysis:. C _2. N ₃ 0 ₃ S ₃ F ₅

Calculated value (%): C, 44.35; H, 3.72; N, 7.76; S, 17.76.

Found (%): C, 44.47; H, 3.69; N, 7.60; S, 17.68.

Example 7-52

₄ - bromo - _N one _{5, 6-dimethyl - 3- Okiso 8- [(4, 4, 5, 5, 5 - penta Full O b pentyl) sulfanyl] -2, 3-Jihido port - IH - Imidazo [5, 1-c] [1,] thiazin-1-ylidene Nzensulfonamide

Method C

To a suspension of sodium hydride (82.6 mg, 2.07 thigh 01) (60% oily) in tetrahydrofuran (4.00 ml) was added the triamino-5,6-dimethyl-8-[( 4,4,5,5,5-Penyu fluoropentyl) sulfanyl] -3H-imidazo [5, tric] [1,4] thiazin-3-one (400 mg, 1.03 bandol) in tetrahydrofuran (2.00 ml), and the mixture was stirred under ice-cooling for 5 minutes. To this was added a solution of 4-bromobenzenesulfonyl chloride (538 mg, 2.07 mmol) in tetrahydrofuran (2.00 ml), and the mixture was further stirred for 40 minutes. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO ₄₎ After the solvent was distilled off under reduced pressure to give the title compound (602 mg, 96¾) was synthesized. Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 189-191 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3237, 3090, 2932, 1759, 1665, 1622, 1563 cm " ¹ .

_{^ - MR (CDC1 3):} δ 1.80 (3Η, d, J = 0.9 Hz), 1.95-2.26 (4H, m), 2.28 (3H, d, J = 1.2Hz), 3.03 (2H, t, J = 7.2 Hz), 7.63 (2H, d, J = 8.7Hz), 7.82 (2H, d, J = 9.0

Hz), 9.60 (1H, bs).

Elementary analysis: as _{C ig H 17 N 3 0 3} S 3 BrF 5

Calculated (¾): C, 37.63; H, 2.83; N, 6.93; S, 15.86.

Found (%): 'C, 37.79; H, 2.84; N, 7.04; S, 15.85.

Example 7-53

 N- {5,6-dimethyl-3-oxo-8-[(4,4,5,5,5-pentafluoropentyl) sulfanyl]-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-trident 4-fluorobenzenesulfonamide

According to a method similar to that of Example 7-51, 4-fluorobenzenesulfonyl chloride (311 mg, 1.55 recited ol) was used instead of benzylsulfonyl chloride, and the 1-amino- 5,6-Dimethyl-8-[(4,4,5,5,5-pentafluorofluoropentyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (312 mg, 74%) to give the title compound (602 mg, 96%). The crystals were recrystallized from ethyl acetate-getyl ether to obtain dark red crystals having a melting point of 189-190 ° C. Infrared absorption spectrum (IR) (in KBr) ν 3227, 3079, 2948, 1759, 1665, 1622, 1593, 1564, 1497 cm ” ¹ .

Ή-Maraudal R (CDC1 ₃ ): δ 1.80 (3Η, d, J = 0.9 Hz), 1.95-2.26 (4H, m), 2.28 (3H, d, J = 1.2 Hz), 3.02 (2H, t, J) = 7.2 Hz), 7.17 (2H, d, J = 8.4 Hz), 7.94-8.00 (2H, m), 9.60 (1H, bs).

Elementary analysis: as _{C 19 H 17 N 3 0 3} S 3 F 6

Calculated (): C, 41.83; H, 3.14; N, 7.70; S, 17.63.

Found: C, 41.99; H, 3.19; N, 7.89; S, 17.82.

Example 7-54

5-kuguchi-N- {5,6-dimethyl-3-oxo- 8-[(4,4,5,5,5-pentylfluoropentyl) sulfanyl] -2,3-dihydro-1H-imidazo [ 5, tric] [1,4] thiazine-1-ylidene} -2-thiophene sulfonamide

 According to a method similar to that of Example 7-51, 5-chlorothiophene-2-sulfonyl chloride (231 mg, 1.03 mmol) was used in place of benzylsulfonyl chloride, and the amino acid obtained in Example 6-3 was used. 5,6-Dimethyl-8 _ [(4,4,5,5,5-pentafluoropentyl) sulfanyl] -3H-imidazo [5, tric] [1,4] thiazin-3-one (200 mg, 0.516 orchid ol) to give the title compound (242 mg, 83¾). Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 160-162 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3223, 3081, 2926, 1755, 1663, 1617, 1559, 1520 cm- ¹ .

 'H-NMR (CDCI3): δ 1.8Γ (3Η, d, J-1.0 Hz), 1.96-2.26 (4H, m), 2.29 (3H, d, J = 1.0 Hz), 3.06 (2H, t, J = 7.0 Hz), 6.89 (2H, d, J = 4.0 Hz), 7.46 (2H, d, J = 4.0 Hz), 9.51 (1H, bs).

Elementary analysis: as _{C 17 H 15 N 3 0 3} S 4 CIF 5

Calculated value (%): C, 35.95; H, 2.66; N, 7.40; S, 22.58., Measured value (¾): C, 35.92; H, 2.73; N, 7.38; S, 22.57.

Example 7-55

4-bromo-N- {5,6-dimethyl-8-[(3-fluoro-3-methylbutyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1 , 4] thiazine-1-ylidene} benzene Sulfonamide

 According to a method similar to that of Example 7-51, 4-bromobenzenesulfonyl chloride (230 nig, 1.34 mol) was used instead of benzylsulfonyl chloride, and 1-amino-5,6 obtained in Example 6-4 was used. -Dimethyl-8-[(3-Fluoro mouth-3-methylbutyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] Thiazin-3-one (200 mg, 0.634 mmol) The title compound (284 mg, 84%) was synthesized. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 160-162 ° C.

Infrared absorption spectrum (IR) (in KBr): 3231, 2980, 2938, 1759, 1663, 1622, 1559, 1470 cur ¹ .

_{Ή-NMR (CDC1 3):} δ 1.40 (6Η, d, J = 21.4Hz), 1.80 (3H, d, J = 0.8 Hz), 1.88 - 2.08 (2H, m), 2.28 (3H, s), 3.01 -3.12 (2H, m), 7.63 (2H, d, J = 8.4 Hz), 7.83 (2H, d, J = 8.4 Hz), 9.60 (1H, bs).

Example 7-56

 5-bromo_N- {5,6-dimethyl-8-[(3,3-dimethylbutyl) sulfanyl] -3-oxo-2,3-, dihydro-1H-imidazo [5, lc] [1,4] Thiazine-1-ylidene} benzenesulfonamide

 According to a method similar to that of Example 7-51, 4-bromobenzenesulfonyl chloride (493 mg, 1.89 mmol) was used in place of benzylsulfonyl chloride, and the triamino-5,6- obtained in Example 6-5 was used. Dimethyl-8-[(3,3-dimethylbutyl) sulfanyl] -3H-imidazo [5, tric] [1,4] thiazin-3-one (300 mg, 0.945 mmol) from the title compound (379 mg, 76¾) was synthesized. The crystals were recrystallized from ethyl acetate-jetil ether to obtain dark red crystals having a melting point of 210-212 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3285, 2949, 2909, 1750, 1715, 1657, 1611, 1557 cm ' ¹ .

 Ή-NMR (CDCI3): δ 0.945 (9Η, s), 1.51-1.63 (2H, m), 1.80 (3H, s), 2.28 (3H, d, J = 0.8 Hz), 2.84-2.98 (2H, m ), 7.63 (2H, d, J = 8 Hz), 7.83 (2H, d, J = 8.8 Hz), 9.60 (1H, bs).

Example 7-57

4-bromo-N- {5,6-dimethyl-3-oxo-8-[(5,5; 6,6,6- ぺ Sulfanyl] -2,3-dihydrido-1H-imidazo [5, 1-c] [1,] thiazine-1-ylidene} benzenesulfonamide

 According to a method similar to that of Example 7-51, 4-bromobenzenesulfonyl chloride (493 mg, 1.89 mol) was used in place of benzylsulfonyl chloride, and 1-amino-5,5 obtained in Example 6-6 was used. 6-dimethyl-8-[(5,5,6,6,6-pentahexafluorohexyl) sulfanyl] -3H-imidazo [5, tric] [1,4] thiazin-3-one (300 The title compound (330 mg, 69 mg) was synthesized from the compound (0.7 mg, 0.770 t). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 166-168 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3233, 3090, 2926, 2859, 1759, 1665, 1622, 1561 cm- ¹ .

_{Ή-NMR (CDC1 3):} δ 1.64-1.68 (4Η, ι), 1.80 (3H, s), 1.88-2.22 (2H, 1), 2.28 (3H, s), 2.98 (2H, t, J = 7.0 Hz), 7.63 (2H, d, J = 8.8 Hz), 7.82 (2H, d, J-8.8 Hz), 9.61 (1H, bs).

Elemental analysis: C _2. H ₁₉ N ₃ 0 ₃ S _{3 As} BrF ₅

Calculated (%): C, 38.71; H, 3.09; N, 6.77; S, 15.50.

Found (¾): C, 38.74; H, 2.99; N, 6.67; S, 15.40.

Example 7-58

 4-N- {5,6-dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -2,3-dihydro- 1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene} benzenesulfonamide,

 According to a method similar to that of Example 7-51, benzylsulfonyl chloride was replaced by 4-chlorobenzenebenzenesulfonyl chloride (398 mg, 1.88 ol), to obtain 1-amino-5,5 obtained in Example 6-6. 6-dimethyl-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (378 mg , 0.942 mmol) to give the title compound (319 mg, 59¾). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 183-185 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3241, 2948, 1759, 1665, 1622, 1559 era— ^1. Ή-NMR (CDCI3): δ 1.65-1.85 (4Η, m), 1.80 (3H, d , J = 0.9 Hz), 1.96-2.16 (2H, m), 2.28 (3H, d, J = 0.9 Hz), 2.98 (2H, t, J = 7.2 Hz), 7.46 (2H, dt, J = 9.0, 2.1 Hz), 7.90 (2H, dt, J = 8.7, 1.8 Hz), 9.59 (1H, bs).

Elemental analysis: as C _2Q H ₁₉ N ₃ 0 ₃ S ₃ C1F ₅

Calculated (¾): C, 41.70; H, 3.32; N, 7.29; S, 16.70.

Found (%): C, 41.55; H, 3.21;, 7.10; S, 16.85.

Example 7-59

 4-Promo {5,6-dimethyl-3-oxo-8-[(5,5,5-anil) -2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-1 -Ylidene} benzene sulfonamide

 According to a method similar to that of Examples 7-51, 4-aminobenzenesulfonyl chloride (445 mg, 1.71 mmol) was used in place of benzylsulfonyl chloride, and the amino-5,6-dimethyl- obtained in Example 6-7 was used. 8-[(5,5,5-Trifluoropentyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (300 mg, 0.854 mmol) from the title compound (356 mg, 73%) was synthesized. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 179-180 ° C.

Infrared absorption spectrum (IR) (in KBr): 3245, 2932, 1759, 1746, 1665, 1622, 1559 cm ^-1 .

- belly _{(CDC1 3): δ 1.62-1.82 (} 4Η,), 1.80 (3H, d, J = 1.2 Hz), 2.04-2.21 (2H, m), 2.28 (3H, d, J = 0.6 Hz), 2.97 (2H, t, J = 7.5 Hz), 7.63 (2H, dt, J = 8.7, 2.1 Hz), 7.86 (2H, dt, J = 9.0, 2.1 Hz), 9.59 (1H, bs).

Elementary analysis: as _{C l9 H 19 N 3 0 3} S 3 BrF 3

Calculated (¾): C, 40.00; H, 3.36; N, 7.37; S, 16.86.

Found (¾): C, 39.95; H, 3.24; N, 7.39; S, 16.92.

Example 7-60

 4-bromo-N- {5,6-dimethyl-3-oxo-8-[(4,4,4-trifluoropropyl) sulfanyl] -2,3-dihydro-1H-imidazo [5,1 -c] [1,4] thiazine-1-ylidene} benzenesulfonamide

According to a method similar to that of Example 7-51, 4-bromobenzenesulfonyl chloride (275 mg, 1.30 mol) was used in place of benzylsulfonyl chloride, and the amino and triamino-5, 6 obtained in Example 6-8 were used. -Dimethyl-8-[(4,4,4-trifluorobutyl) sulfani [3] -H-imidazo [5,1-c] [1,4] thiazin-3-one (220 mg, 0.652 t ol) to give the title compound (298 mg, 82%). The crystals were recrystallized from ethyl acetate-getyl ether to obtain dark red crystals having a melting point of 177-179 ° C.

Infrared absorption spectrum (IR) (in KBr) Re:. 3233, 2928, 1761, 1665, 1622, 1561 cm "1 'H-NMR (CDC1 3): δ 1.80 (3Η, d, J = 1.2 Hz), 1.97 (2H, quintet, J = 7.2 Hz), 2.13-2.30 (2H, m), 2.28 (3H, d, J = 0.9 Hz), 3.01 (2H, t, J-7.2 Hz), 7.64 (2H, dt , J = 8.7, 2.1 Hz), 7.82 (2H, dt, J = 9.0, 2.4 Hz), 9.60 (1H, bs).

Elementary analysis: as _{C l8 H 17 N 3 0 3} S 3 BrF 3

Calculated value (%): C, 38.85; H, 3.08; N, 7.55; S, 17.29.

Found (¾): C, 38.89; H, 3.13; N, 7.49; S, 17.25.

Example 7-61

 4-chloro Π-Ν- {5,6-dimethyl-3-oxo-8-[(4,4,4-trifluorobutyl) sulfanyl] -2,3-dihydro-1H-imidazo [5, 1-c] [1,4] thiazine 1-ylidene} benzenesulfonamide

 According to a method similar to that of Examples 7-51, 4-amino benzenesulfonyl chloride (275 mg, 1,30 t ol) was used in place of benzylsulfonyl chloride, and the amino-amino compound obtained in Example 6-8 was used. 5,6-Dimethyl-8-[(4,4,4-trifluorobutyl) sulfanyl] -3H-imidazo [5, tric] [1,4] thiazin-3-one (220 mg, 0.652 t )) To give the title compound (207 mg, 62%). The crystals were recrystallized from ethyl acetate-ethyl ether to obtain red-red crystals having a melting point of 171-173 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3233, 3094, 2936, 1761, 1665, 1624, 1563 cm- ¹ .

 Ή-NMR (CDCI3): δ 1.80 (3Η, d, J = 1.2 Hz), 1.97 (2H, quintet, J = 7.5 Hz), 2.13-2.30 (2H, m), 2.28 (3H, d, J = 0.9 Hz), 3.01 (2H, t, J = 7.5 Hz), 7.47 (2H, dt, J = 9.0, 2.1 Hz), 7.90 (2H, dt, J = 9.0, 2.4 Hz), 9.61 (1H, bs).

Elementary analysis: as _{C 18 H 17 N 3 0 3} S 3 C1F 3

Calculated value (¾): C, 42.23; H, 3.35; N, .8.21; S, 18.79.

Found (%): C, 42.24; H, 3.20; N, 8.26; S, 18.85.

Example 7-62 N- {5,6-Dimethyl-3-oxo-8-[(4,4,5,5,5-pentafluoropentyl) sulfanyl]-2,3-dihydro-1H-imidazo [5,1-c ] [1,4] thiazine-1-ylidene} -4-hydroxymethylbenzenesulfonamide

To a suspension of sodium hydride (145 mg, 3.61 band01) (60% oil) in tetrahydrofuran (15.0 ml) was added 1-amino-5,6-dimethyl-8- [ (4,4,5,5,5-pentanofluoropentyl) sulfanyl] -3H-imidazo [5,1-C] [1,4] thiazin-3-one (700 mg, 1.81 mmol) in tetrahydrofuran (4.00 ml ) The solution was added, and the mixture was stirred under ice cooling for 10 minutes. To this was added a solution of 4-bromomethylbenzenesulfonyl chloride (1.00 g, 3.61 ol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO ₄₎ 'After the solvent was distilled off under reduced pressure 4- (Promo methyl) -N_ [5,6 - di methyl-3- Okiso 8- [(4, 4, 5,5,5-pentafluoropentyl) sulfanyl] -2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene] benzenesulfonamide (220 mg, 20¾) was obtained as dark red crystals. This product was used for the next reaction without further purification.

4- (Bromomethyl) -N- [5,6-dimethyl-3-oxo-8-[(4,4,5,5,5-pentylfluoropentyl) sulfanyl] -2,3-dihydro-1H- Imidazo [5,1-c] [1,4] thiazine-trilidene] benzenesulfonamide (220 mg, 0.355 t ol), potassium acetate (105 mg, 1.06 bandol) and potassium hydroxide ( A suspension of 70.2 mg, 1.06 dl) of acetonitrile (4.00 ml) was heated to reflux for 50 minutes. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give acetic acid 4-{[5,6-dimethyl-3-oxo- 8- [ (4,4,5,5,5-Pen fluoropentyl) sulfanyl] -2,3-Dihydrido-1H-imidazo [5,1-c] [1,4] Thiazine-1-ylidene] sulfinnamoylo Xyl} benzyl ester (42.0 mg, 20%) was obtained. This product was used for the next reaction without further purification.

Infrared absorption spectrum (IR) (in KBr) Les:. 3210, 2938, 1748, 1667, 1622, 1559 cm "1 Ή-NR (CDC1 3): δ 1.80 (3Η, s), 1.92-2.24 (4H, m), 2.13 (3H, s), 2.27 (3H, s), 3.02 (2H, t, J = 6.6 Hz), 5.16 (2H, s), 7.47 (2H, d, J = 8.8 Hz), 7.95 ( 2H, d, J = 8.0 Hz), 9.62 (1H, bs).

The above acetic acid 4-{[5,6-dimethyl-3-oxo-8-[(4,4,5,5,5-pentafluoropentyl) sulfanyl] -2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-1-ylidene] sulfinnamoyloxy} benzyl ester (42.0 mg, 0.0700 benzyl) in a mixture of tetrahydrofuran (1.00 ml) and ethanol (1.00 ml) , And a 1N aqueous sodium hydroxide solution (210 ml) was added thereto, followed by stirring for 10 minutes. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to give the title compound and the solvent was removed reduced pressure to (6.30mg, 16¾). Recrystallization from ethyl acetate-diisopropyl ether gave dark red crystals with a melting point of 144-146 ° C.

Infrared absorption spectrum (IR) (in KBr) V 3463, 3350-2800, 1748, 1667, 1622, 1557 cm—

_{Ή- NMR (CDC1 3) δ:} 1.80 (3Η, s), 1.90-2.22 (4H, m), 2.27 (3H, s), 3.02 (2H, t, J = 6.4 Hz), 4.79 (2H, s) , 7.50 (2H, d, J = 8.0 Hz), 7.95 (2H, d, J = 8.4 Hz), 9.63 (1H, bs).

The following is a list of compounds synthesized in Examples 7-1 to 7-62 and compounds synthesized in the same manner.

(Table 7 2)

For difference (Μ2β) (Table 7 3)

Substitution (Rule 26) (Table 74)

Shuffle paper (¾ Rule 2δ) (Table 75)

Shuffle paper (»2β) (Table 76)

Replacement C 就 1W (Table 7 7)

Replacement rules 26) (Table 78)

Replacement pig (MMI26) (Table 79)

(For replacement 弒 m) (Table 80)

Replacement form (Rule 26) (Table 8 1)

Replacement form (Rule 26) (Table 8 23

Customs form (Rule 2 (Table 83)

Paper (m (Table 84)

Difference ぇ (MM26) (Table 85)

Replacement paper (Rule 2 (Table 86)

Replacement paper (Si! (Table 8.7)

For replacement (Chief rule 26) (Table 88)

Replacement form (Rule 2β) (Table 89)

Substitution (Rule 26) (Table 90)

眷 f勰 m 以下に実施例 7- 63〜7- 206で合成した化合物のデ一夕を示す。

F 勰 m The following shows the results of the compounds synthesized in Examples 7-63 to 7-206.

Example 7-63

 4_Chloro-N- [5,6-dimethyl-3-oxo-8-[(4,4,4-trifluorobutyl) sulfanyl] -2,3-dihydro-1H-imidazo [5,1 -c] [1,4] thiazine-1 -ylidene] benzenesulfonamide

To a suspension of sodium hydride (52.2 mg, 1.30 sol) (60% oil) in tetrahydrofuran (2.00 ml) was added 1-amino-5,6-dimethyl 8-[(obtained in Example 6-8. 4,4,4-Trifluoroptyl) sulfanyl] -31-toimidazo [5,1-c] [1,4] thiazin-3-one (220 mg, 0.652 mmol) in tetrahydrofuran (1.00 ml) was added, and ice was added. Stir for 5 minutes under cooling. To this was added a solution of benzenesulfonyl chloride 4-chloro (275 mg, 1.30 mmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (207 mg, 62%) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 171-173 ° C. IR (KBr): 3233, 3094, 2936, 1761, 1665, 1624, 1563 cm " ¹ .

One _{NMR (CDC1 3): δ 1.80} (3Η, d, J = 1.2 Hz), 1.97 (2H, quintet, J = 7.5 Hz), 2.13-2.30 (2H, m), 2.28 (3H, d, J-0.9 Hz), 3.01 (2H, t, J = 7.5 Hz), 7.47 (2H, dt, J = 9.0, 2.1 Hz), 7.90 (2H, dt, J = 9.0, 2.4 Hz), 9.61 (1H, bs).

Elementary analysis: as _{C 18 H 17 N 3 0 3} S 3 C1F 3

Calculated value (¾): C, 42.23; H, 3.35; N, 8.21; S, 18.79.

Found (%): C, 42.24; H, 3.20; N, 8.6; S, 18.85.

Example 7-65

 4- ク mouth Π-Ν- [5,6-dimethyl-3-oxo-8-[(5,5,5-trifluoropentyl) sulfanyl] -2,3-dihydro mouth-1H-imidazo [5 , 1-c] [1,4] thiazine-toylidene] benzenesulfonamide

To a suspension of sodium hydride (101 mg, 2.52 mmol) (60 oily) in tetrahydrofuran (3.00 ml) was added 1-amino-5,6-dimethyl 8-[(5,5) obtained in Example 6-7. 5,5-Trifluoropentyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (442 mg, 1.26 t ol) in tetrahydrofuran (2.00 ml) and ice-cooling Lower 5 Stir for a minute. To this was added a solution of benzenesulfonyl chloride 4-chloro (531 mg, 2.52 mmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (191 mg, 29%) as a dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 166-168 ° C.

IR (KBr): 3248, 2944, 1759, 1665, 1622, 1561 cm " ¹ .

E - thigh _{(CDC1 3): δ 1.62-1.93 (} 4Η, m), 1.80 (3H, d, J = 0.9 Hz), 2.04-2.20 (2H, m), 2.27 (3H, d, J = 0.9 Hz) , 2.96 (2H, t, J = 7.2 Hz), 7.46 (2H, di, J = 8.7, 2.4 Hz), 7.90 (2H, dt, J = 8.4, 1.5 Hz), 9.59 (1H, bs).

Elementary analysis: as _{C 19 H 19 N 3 0 3} S 3 C1F 3

Calculated (¾): C, 43.38; H, 3.64; N, 7.99; S, 18.29.

Found (¾): C, 43.51; H, 3.74; N, 8.18; S, 18.58.

Example 7-66

4-Chloro-Π-Ν- [5,6-dimethyl-8-[(3-fluoromethyl-3-methylbutyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene] benzene sulfonamide

To a suspension of sodium hydride (5.07 mg, 0.127 acetyl) (60% oil) in tetrahydrofuran (0.50 ml) was added the triamino-5,6-dimethyl 8-[(3) obtained in Example 6-4. -Fluoro-3-methylbutyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (20.0 mg, 0.0634 mmol) in tetrahydrofuran (0.50 ml) was added and the mixture was cooled on ice. Stir for 5 minutes. To this was added a solution of benzenesulfonyl chloride (39.4 mg, 0.127 benzyl) in tetrahydrofuran (0.50 ml), and the mixture was further stirred for 30 minutes. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (15.8 mg, 51%) was synthesized. Recrystallization from ethyl acetate-ethyl ether yielded dark red crystals, mp 163-165.

IR (KBr) V: 3227, 2984, 2928, 1757, 1663, 1622, 1559 cm " ¹ .

E - testimony _{(CDC1 3): (51.40 (} 6H, d, J = 21.4 Hz), 1.80 (3H, s), 1.86-2.06 (2H, m), 2.28 (3H, s), 3.06 (2H, t, J = 8.6 Hz), 7.47 (2H, d, J = 8.8 Hz), 7.90 (2H, d, J = 8.8 Hz), 9.58 (1H, bs).

Elemental analysis: as C ₁₉ H ₂₁ N ₃ 0 ₃ S ₃ C1F

Calculated (%): C, 46.57; H, 4.32; N, 8.57; S, 19.63.

Found (%): C, 46.28; H, 4.61; N, 8.45; S, 19.28.

Example 7-67

 4-Bumo-N- [5,6-dimethyl-8-[(4-fluorobutyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4 [Thiazine-1-ylidene] benzenesulfonamide

To a suspension of sodium hydride (60.1.51 mol) (60-free) in tetrahydrofuran (3.00 ml) was added 1-amino-5,6-dimethyl 8-[(4 -Fluorobutyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (227 mg, 0.754 mmol) in tetrahydrofuran (2.00 ml) was added, and the mixture was stirred under ice cooling for 5 minutes. Was. To this was added a solution of 4-bromobenzenesulfonyl chloride (393 mg, 1.51 mol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was evaporated reduced pressure to give the title compound (120 mg, 31%) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 168-170 ° C.

IR (KBr) V: 3233, 2965, 1759, 1663, 1622, 1561 cm " ¹ .

_{Ή-NMR (CDC1 3):} 51.70-1.88 (4H, m), 1.80 (3H, d, J = 0.9 Hz), 2.28 (3H, d, J = 0.9 Hz), 3.01 (2H, t, J = 7.2 Hz), 4.48 (2H, dt, J = 47.1, 5.7 Hz), 7.63 (2H, dt, J = 8.7, 1.8 Hz), 7.83 (2H, dt, J = 8.7, 1.8 Hz), 9.59 (1H, bs ).

Elementary analysis: as _{C 18 H ig N 3 0 3} S 3 BrF

Calculated value (¾): C, 41.54; H, 3.68; N, 8.07; S, 18.48.

Found (¾): C, 41.31; H, 3.67; N, 8.04; S, 18.58.

Example 7-68

 4-bromo-N- [5,6-dimethyl-3-oxo-8-[(3,3,4,4,4-pentafluorobutyl) sulfanyl] -2,3_dihydro-1H-imidazo [5, 1-c] [1, 4] thiazine-triylidene] benzenesulfonamide

Sodium hydride (49.2 mg, 1.23 mmol) (60% oil) in tetrahydrofuran (2.00 ml) in the suspension of triamino-5,6-dimethyl 8-[(3,3,4,4,4-pentafluorofluortyl) sulfanyl] -3H-imidazo obtained in Example 6-20. A solution of 5, 1-c] [1,4] thiazine-3-one (200 mg, 0.615 mmol) in tetrahydrofuran (1.00 ml) was added, and the mixture was stirred under ice cooling for 5 minutes. To this was added a solution of 4-bromobenzenesulfonyl chloride (321 mg, 1.23 mmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO ₄₎ After the solvent was distilled off under reduced pressure to give the title compound (167 mg, 46¾) was synthesized. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 180-182 ° C.

IR (KBr) V: 3221, 3088, 2928, 1761, 1665, 1624, 1563 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 1.81 (3Η, s), 2.28 (3H, d, J = 1.0 Hz), 2.30-2.60 (2H, m), 3.16 (2H, t, J = 8.8 Hz), 7.64 (2H, dt, J = 8.4, 1.8 Hz), 7.81 (2H, dt, J = 8.4, 2.2 Hz), 9.60 (1H, bs).

Elementary analysis: as _{C 18 H 15 N 3 0 3} S 3 BrF 5

Calculated (¾): C, 36.49; H, 2.55; N, 7.09; S, 16.24.

Found (¾): C, 36.53; H, 2.34; N, 7.07; S, 16.17.

Example 7-69

 4-({[5,6-Dimethyl-8- (isopentylsulfanyl) -3-oxo-3H-imidazo [5,1-c] [1,4] thiazine-triyl] imino} sulfonyl) benzyl Acetate Synthesized in the same manner as in Examples 7-63.

Infrared absorption spectrum (IR) (in KBr) v: 3250, 2957, 2934, 2972, 1744, 1663, 1615, 1559 cm—

_{'H-NMR (CDC1 3)} : δ 0.934 (6Η, d, J = 6.2 Hz), 1.48-1.77 (3H, m), 1.79 (. 3H, d, J = 1 Hz), 2.13 (3H, s) , 2.27 (3H, d, J = 1.2 Hz), 2.95 (3H, d, J = 7.4 Hz), 5.16 (2H, s), 7.46 (2H, d, J = 8.4 Hz), 7.96 (2H, d, J = 8.4 Hz), 9.60 (1H, bs).

 4_Bromo 6-dimethyl-3-oxo-8-[(6,6,7,7,7-pentylfluoroheptyl) sulfanyl] -2,3-dihydro-1H-imidazo [5,1-c ] [1,4] thiazine-1-ylidene] benzenesulfonamide

Sodium hydride (38.5 mg, 0.963 marl ol) (60% oil) tetrahydrofuran (2.00% ml) of the suspension of triamino-5,6-dimethyl 8-[(6,6,7,7,7-pentafluoroheptyl) sulfanyl] -3H obtained in Example 6-21. A solution of -imidazo [5,1-c] [1,4] thiazin-3-one (200 mg, 0.481 inraol) in tetrahydrofuran (1.00 ml) was added, and the mixture was stirred under ice-cooling for 5 minutes. To this was added a solution of 4-bromobenzenesulfonyl chloride (251 mg, 0.963 ol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 2.5 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, after Drying (MgSO _4), was synthesized solvent was distilled off under reduced pressure the title compound (117 mg, 39%). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 160-162T :.

IR (KBr) y: 3227,2949, 1759, 1665, 1622, 1559 cm— ¹ .

_{'H-NMR (CDC1 3)} : (51.40-1.84 (6H, m), 1.80 (3H, s), 1.96-2.24 (2H, m), 2.27

(3H, s), 2.30-2.60 (2H, m), 2.95 (2H, t, J = 7.6 Hz), 7.63 (2H, d, J-8.8 Hz),

7.83 (2H, d, J = 8.4 Hz), 9.59 (1H, bs).

Elemental analysis: C ₂₁ H ₂₁ N ₃ 0 ₃ S ₃ BrF ₅

Calculated)): C, 39.75; H, 3.34; N, 6.62; S, 15.16.

Found (¾): C, 39.55; H, 3.05; N, 6.53; S, 15.14.

Example 7-71

 4-bromo-N- [5,6-dimethyl-3-oxo-8-[(6,6,6-trifluorohexyl) sulfanyl] -2,3-dihydro-1H-imidazo [5,1- c] [1,4] thiazine-triylidene] benzenesulfonamide

To a suspension of sodium hydride (43.8 mg, 1.09 mmol) (60% oil) in tetrahydrofuran (2.00 ml) was added the triamino-5,6-dimethyl 8 _ [(6,6 , 6-Trifluorohexyl) .sulfanyl]-3H-imidazo [5, 1-c] [1,4] thiazin-3-one (200 mg, 0.547 marl) and a solution of tetrahydrofuran (1.00 ml) The mixture was stirred for 5 minutes under ice cooling. To this was added a solution of 4-bromobenzenesulfonyl chloride (285 mg, 1.09 tmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 2.5 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (160 mg, 50%) was synthesized. Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 156-158. IR (KBr) v: 3239, 3071, 2949, 1759, 1665, 1622, 1559 cm- ¹ .

_{'H-NMR (CDC1 3)} : δ 1.40-1.84 (6H, m), 1.80 (3H, s), 1.87-2.19 (2H, m), 2.28 (3H, d, J = 1.0 Hz), 2.96 (2H , t, J = 7.8 Hz), 7.63 (2H, d, J = 8.8 Hz), 7.83 (2H, d, J = 8.8 Hz), 9.59 (1H, bs).

Elemental analysis: C _2. H ₂₁ N ₃ 0 ₃ S _{3 As} BrF ₃

Calculated (¾): C, 41.10; H, 3.62; N, 7.19; S, 16.46.

Found (%): C, 40.78; H, 3.34; N, 7.16; S, 16.56.

Example 7-72

 4-p-mo-N- [5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-III-imidazo [5,1-c] [1 , 4] Thiazine-1-ylidene] benzenesulfonamide

Example 1

A suspension of sodium hydride (143 mg, 3.58 mmol) (60% oil) in tetrahydrofuran (3000 ml) was added to the suspension of 1-amino-5,6-dimethyl 8- [obtained in Example 6-23. (4-Fluorobutyl) sulfanyl] -3H-imidazo [5, tric] [1,4] thiazin-3-one (564 mg, 1.79 mmol) in tetrahydrofuran (5.00 ml) was added, and the mixture was cooled on ice for 5 minutes. Stirred. To this was added a solution of 4-bromobenzenesulfonyl chloride (933 mg, 3.58 ml) in tetrahydrofuran (2.00 ml), and the mixture was further stirred for 30 minutes. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was evaporated reduced pressure to give the title compound (820 mg, 86%) as a dark red crystals. Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 183-185 ° C.

Example 2

To a suspension of sodium hydride (71.3 mg, 1.78 marl ol) (60 oily) in tetrahydrofuran (2 ml) was added 1-amino-5,6-dimethyl 8 _ [(5_ Fluoropentyl) sulfanyl] _3H-imidazo [5, tric] [1,4] thiazin-3-one (281 mg, 0.891 tmol) in tetrahydrofuran (2 ml) was added, and the mixture was stirred under ice cooling for 5 minutes. To this was added a solution of 4-bromobenzenesulfonyl chloride (465 mg, 1.78 mmol) in tetrahydrofuran (2 ml), and the mixture was further stirred for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO ₄₎ after reduction the solvent Evaporation under pressure gave the title compound (260 mg, 55%) as dark red crystals.

IR (KBr) V:. 3218 , 3092, 2963, 2936, 2867, 1759, 1665, 1622, 1559 cm "1 Ή-NMR (CDC1 3): (51.44-1.84 (6H, m), 1.80 (3H, d , J-1.0 Hz), 2.28 (3H, d, J = 0.8 Hz), 2.97 (2H, d, J = 7.4 Hz), 4.46 (2H, dt, J = 47.4, 5.8 Hz), 7.63 (2H, d , J = 8.8 Hz), 7.83 (2H, d, J = 8.8 Hz), 9.59 (1H, bs).

Elementary analysis: as _{C 19 H 21 N 3 0 3} S 3 BrF

Calculated (%): C, 42.70; H, 3.96; N, 7.86; S, 18.00.

Found (%): C, 42.66; H, 3.90; N, 7.86; S, 17.88.

Example 7-73

N- [5,6-dimethyl-3-oxo-8 [(4,4,5,5,5-pentafluoropentyl) sulfanyl] -2,3-dihydro-1H-imidazo [5,1- c] [1,4] thiazine-1-ylidene] -4-bierbenzensulfonamide

To a suspension of sodium hydride (62.4 mg, 1.56 marl 01) (60% oil) in tetrahydrofuran (3.00 ml) was added the triamino-5,6-dimethyl 8-[(4 , 4,5,5,5-Pentyl fluorene pentyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (300 mg, 0.780 imol) in tetrahydrofuran (2.00 ml) ) The solution was added and stirred for 5 minutes under ice cooling. To this was added a solution of P-styrenesulfonyl chloride (340 mg, 1.56 mol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (278 mg, 65%) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether yielded dark red crystals with a melting point of 176-178 ° C. IR (KBr) V: 3229, 2944, 1755, 1665, 1622, 1563 era " ¹ .

Ή-NMR (CDCI3): 51.80 (3H, d, J = 0.6 Hz), 1.90-2.30 (4H, m), 2.27 (3H, s), 3.02 (2H, t, J = 4.6 Hz), 5.42 (1H , d, J = 7.0 Hz), 5.87 (1H, d, J = 11.6 Hz), 6.74 (1H, dd, J = 12.0, 7.4 Hz), 7.51 (2H, d, J = 5.6 Hz), 7.91 (2H , d, J = 6.0 Hz), 9.64 (1H, bs).

Elemental analysis: as C ₂₁ H ₂₀ N ₃ 0 ₃ S ₃ F ₅

Calculated (%): C, 45.56; H, 3.64; N, 4.59; S, 17.38.

Found (%): C, 45.12; H, 3.34; N, 7.37; S, 17.48. Example 7-74

 N- [5,6-Dimethyl-3-oxo- 8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl]-2,3-dihydro-1H-imidazo [5,1- c] [1,4] thiazine-1-ylidene] -4-bierbenzensulfonamide

To a suspension of sodium hydride (59.84 mg, 1.49 ol) (60% oily) in tetrahydrofuran (3.00 ml) was added the triamino-5,6-dimethyl 8-[(5 , 5,6,6,6-pentahexafluorohexyl) sulfanyl] -3H-imidazo [5, tric] [1,4] thiazin-3-one (300 mg, 0.747 bandol) in tetrahydrofuran (2.00 ml) The solution was added, and the mixture was stirred under ice cooling for 5 minutes. To this was added a solution of P-styrenesulfonyl chloride (326 mg, 1.49 mmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure to give the title compound (278 mg, 65¾) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 160-162 ° C. IR (KBr) V: 3237, 3075, 2948, 1755, 1665, 1622, 1561 cm " ¹ .

_{'H-NMR (CDC1 3)} : 1.68 - 1.84 (4H, m), 1.79 (3H, d, J = 1.2 Hz), 1.92-2.20 (2H, m), 2.27 (. 3H, d, Jl Hz), 2.30-2.60 (2H, m), 2.97 (2H, t, J = 6.6 Hz), 5.42 (1H, d, J = 11.0 Hz), 5.87 (1H, d, J = 17.6Hz), 6.74 (1H, dd , J = 17.6, 10.6 Hz), 7.50 (2H, d, J = 8.0 Hz), 7.91 (2H, d, J = 8.Hz), 9.63 (1H, bs).

Elementary analysis: as _{C 22 H 22 N 3 0 3} S 3 F 5

Calculated (): C, 46.55; H, 3.91;, 7.40; S, 16.95.

Found (%): C, 46.32; H, 4.17; N, 7.43; S, 17.11.

Example 7-75

 4-Chloromethyl-N- [5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine -1-ylidene] benzenesulfonamide

Recrystallization from ethyl acetate-jetil ether gave dark red crystals with a melting point of 185-187 ^.

Infrared absorption spectrum (IR) (in KBr) V: 3237, 2955, 2928, 2872, 1752, 1663, 1607, 1553 cm " ¹ . ^L H- 丽 R (CDClg): δ 0.934 (6H, d, J = 6.3Hz), 1.54-1.62 (4H, in), 1.69 (2H, septe, J = 6.9Hz), 1.80 (3H, d, J = 0.9Hz), 2.27 (3H, d, J = 0.9 Hz), 2.95 (2H, t, J-7.5 Hz), 4.62 (2H, s), 7.51 (2H, d, J = 8.7 Hz), 7.96 ( 2H, d, J = 8.7 Hz), 9.61 (1H, bs).

Elemental analysis: C _2. H ₂₄ N ₃ 0 ₃ S ₃ C1

Calculated value (¾): C, 49.42; H, 4.98; N, 8.64; S, 19.79.

Found (¾): C, 49.07; H, 4.91; N, 8.38; S, 19.55.

Example 7-76

 N- {4-[({5,6-dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl]-2,3-dihydro-1H -Imidazo [5, tric] [1,4] thiazine-trilidene} ami

A mixture of N-benzylhexamide (1.12 g, 5.45 ol) and chlorosulfonic acid (0.665 g, 5.45 ol) was stirred at room temperature for 7 hours and at 70 ° C. for 13 hours. To the reaction solution was added sulfonic acid (0.665 g, 5.45 tmol) and the mixture was further stirred at room temperature for 3 days. The reaction mixture was treated in the same manner as in Example 7-122 to give a mixture of N- (4-chlorosulfonylbenzyl) hexamide and the raw materials (1: 4, 0.77 g, chloride purity 38) as a white solid. Obtained. Sodium hydride (purity 60%, 57.3 mg, 1.43 mmol) was added to a suspension of the compound obtained in Example 6-6 (230 mg, 0.573 ol) in THF (5.0 ml) at room temperature, and the mixture was added for 20 minutes. After stirring, a solution of the above white solid (purity 38%, 533 mg, 0.573 bandol) in THF (1 ml) was added, and the mixture was further stirred for 50 minutes. The reaction mixture was diluted with 1N hydrochloric acid (1.43 ml), diluted with ethyl acetate (30 ml), washed with 0.1N hydrochloric acid, water and saturated saline, and dried over sodium sulfate. After concentrating to dryness, the residue was chromatographed on silica gel (10 g) (Eluoxane acetate, 3: 7-7: 3). The ethyl acetate-hexane (5: 5-6: 4) fraction was concentrated to dryness and crystallized from methanol to give the title compound (103 mg, 0.154 mol) as a red-brown powder.

_{Ή-NMR (300MHz, CDC1 3} ): 50.90 (3H, t, J = 6.6 Hz), 1.32 (4H, brquint, J = 3.7 Hz), 1.68 (2H, m), 1.75 (4H, m), 1.80 ( 3H, q, J = 0.9 Hz), 2.06 (2H, m), 2.24 (2H, t, J = 7.8 Hz), 2.27 (3H, q, J = 0.9 Hz), 2.97 (2H, t, J = 7.2) Hz), 4.50 (2H, d, J = 6.0 Hz), 5.89 (1H, br), 7.37 (2H, d, J = 8.4 Hz), 7.90 (2H, d, J = 8.7 Hz), 9.65 (1H, brs).

Elemental _{analysis: C 27 N 4 0 4 S} 3 F 5 Calculated: C, 48.49; H, 4.97 ; N, 8.38; S, 14.38; F, 14.20 (%), Found: C, 48.56; H, 5.17; N, 8.59; S, 14.27; F, 14.20 (%) .mp. 154.0-156. O

Example 7-77

 N- (2- {4-[({5,6-dimethyl-3-oxo--8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -sulfanyl] -2,3- Dihydro-1H-imidazo [5,1-c] [1,4] thiazine-triylidene} amino) sulfonyl] phenyl} ethyl) hexaneamide

 A mixture of N_ (2-phenethyl) hexamide (5.3 g, 23.6 mmol) and chlorosulfonic acid (4.86 ml, 70.8 diol) was stirred at room temperature for 6 hours and at 40 for 60 hours. The reaction solution was treated in the same manner as in Example 7-122 to give N- [2- (4-clothrosulfonylphenyl) ethyl] hexamide (purity 80%, 5.27 g, 13.3 t ol) as a yellow oil. Obtained.

¾ one _{NMR (200MHz, CDC1 3):} 50.89 (3H, t, J = 6.6 Hz), 1.28 (4H, m), 1.60 (2H, brquint, J = 7.5 Hz), 2.15 (2H, t, J = 7.5 Hz), 2.97 (2H, t, J = 6.9 Hz), 3.56 (2H, q, J = 6.6 Hz), 5.60 (1H, br), 7.45 (2H, d, J = 8.4 Hz), 7.98 (2H, q, J = 8.4 Hz).

 To a suspension of the compound obtained in Example 6-6 (268 mg, 0.668 alcohol) in THF (5.5 ml) was added sodium hydride (purity 60%, oily, 74.8 mg, 1.87 mol) at room temperature. After stirring for 1 minute, the above-mentioned yellow oil (purity 80%, 265 mg, 0.668 mmol) was added, and the mixture was further stirred for 2 hours. The reaction solution was diluted with ethyl acetate (30 ml), washed with 0.1N hydrochloric acid, water and saturated saline, and dried over sodium sulfate. After concentration to dryness, the residue was diluted with getyl ether. The precipitate was collected by filtration, washed with diethyl ether, and dried to give the title compound (408 mg, 0.598 mmol) as a red powder.

_{Ή-NMR (300MHz, CDC1 3} ): 50.89 (3H, t, J = 6.6 Hz), 1.30 (4H, m), 1.75 (6H, m), 1.80 (3H, s), 2.06 (2H, m), 2.31 (2H, t, J = 7.5 Hz), 2.28 (3H, s), 2.89 (2H, t, J = 6.9 Hz), 2.98 (2H, t, J = 7.0 Hz), 3.52 (2H, brq, J = 6.4 Hz), 5.47 (1H, m), 7.31 (2H, d, J = 8.4 Hz), 7.90 (2H, .d, J = 8.7 Hz), 9.65 (1H, br). Elemental analysis: C ₂₈ Calculated for H ₃₅ N ₄ 0 ₄ S ₃ F ₅ : C, 49.25; H, 5.17; N, 8.21; S, 14.09; F, 13.91 (%), found: C, 49.15; H, 5.16; N, 8.27; S, 14.08; F, 13.90 (). mp.146.0-147.5 ° C

Example 7-78

 N- {5,6-dimethyl-3-oxo-8-[(5,5,6,6,6-pen

] -2,3-Dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene} [(IS, 4R) -7,7-dimethyl 2-oxobicyclo [2.2.1] hept-tolyl] methanesulfonamide

To a suspension of sodium hydride (49.8 mg, 1.25 t ol) (60% oily) in tetrahydrofuran (2.00 ml) was added 1-amino-5,6-dimethyl 8-[(obtained in Example 6-6. 5,5,6,6,6-pentafluorohexyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (250 mg, 0.623 ol) in tetrahydrofuran (2.00 ml), and the mixture was stirred under ice-cooling for 5 minutes. To this was added a solution of 10-(+)-camphorsulfonyl chloride (312 mg, 1.25 mmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 45 minutes. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO ₄₎ after solvent was obtained as a distilled to give the title compound (209 mg, 55%) dark red crystals under reduced pressure. The crystals were recrystallized from ethyl acetate-getyl ether to obtain dark red crystals having a melting point of 14-143.

IR (KBr) V 3220, 2961, 1744, 1665, 1618, 1566 cm " ¹ .

_{lH_NMR (CDC1 3): δ 0.868} (3Η, s), 1.10 (3H, s), 1.38-1.51 (1H, m), 1.68-1.87

(4H, m), 1.81 (3H, s), 1.93 (2H, d, J = 18.0 Hz), 1.99-2.18 (4H, m), 2.29 (3H, s), 2.33-2.45 (1H, m), '2.46-2.59 (1H, m), 3.00 (2H, t, J = 7.2 Hz), 3.08 (1H, d, J = 15.0 Hz), 3.61 (1H, d, J = 14.7 Hz), 9.80 (1H, bs).

Elementary analysis: as _{C 24 H 3Q N 3 0 4} S 3 F 5

Calculated value (%): C, 46.82; H, 4.91; N, 6.82; S, 15.62.

Found (¾): C, 46.56; H, 4.85; N, 6.87; S, 15.72.

Example 7-79

N- {5,6-dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -2,3-dihydro-1H-imidazo [5, 1-c] [1,4] Thiazine-1-ylidene} [(1R, 4S) -7,7-dimethyl-2-oxobicyclo [2 · 2.1] hept-1-yl] Methanesulfonamide To a suspension of sodium hydride (49.8 mg, 1.25 mniol) (60 oils) in tetrahydrofuran (2.00 ml) was added the triamino-5,6-dimethyl 8-[(5,5) obtained in Example 6-6. , 6,6,6-Pentafluorohexyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (250 mg, 0.623 mmol) in tetrahydrofuran (2.00 ml) In addition, the mixture was stirred for 5 minutes under ice cooling. To this was added a solution of 10-(-)-camphorsulfonyl chloride (312 mg, 1.25 tmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 45 minutes. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. Wash and dry the extract

(MgSO ₄₎ After the solvent was distilled off under reduced pressure to give the title compound (256 rag, 67%) was synthesized. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 141-143 ° C.

IR (KBr) V: 3216, 2959, 1744, 1665, 1618, 1566 cm " ¹ .

_{[H-NMR (CDC1 3)} : δ 0.867 (3H, s), 1.10 (3H, s), 1.38-1.48 (1H, m), 1.70-1.86 (4H, m), 1.81 (3H, d, J = 1.2 Hz), 1.93 (2H, d, J = 18.6 Hz), 1.98-2.17 (4H, m), 2.29 (3H, d, J = 1.2 Hz), 2.33-2.44 (1H, m), 2.46-2.58 ( 1H, m), 3.00 (2H, t, J = 6.9 Hz), 3.08 (2H, t, J = 15.0Hz), 3.61 (1H, d, J = 14.7 Hz), 9.80 (1H, bs). value: C ₂₄ H _3. N ₃ 0 ₄ S ₃ F ₅

Calculated (¾): C, 46.82; H, 4.91; N, 6.82; S, 15.62.

Found (%): C, 46.72; H, 5.01; N, 6.88; S, 15.46.

Example 7-80

3-({[5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene ] Amino} sulfonyl) benzoic acid

To a suspension of sodium hydride (134 mg, 3.36 fraction 01) (60% oily) in tetrahydrofuran (2.00 ml) was added 1-amino-5,6-dimethyl-8- (obtained in Example 6-2. Isopentylsulfanyl) -3H-imidazo [5, tric] [1,4] thiazin-3-one (500 mg, 1.68 bandol) in tetrahydrofuran (6.00 ml) was added and stirred under ice cooling for 5 minutes. . To this was added a solution of (3-chlorosulfonyl) benzoic acid (742 mg, 3.36 mmol) in tetrahydrofuran (2.00 ml), and the mixture was further stirred for 28 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), and the solvent was evaporated under reduced pressure to synthesize the title compound (243 mg, 30%). Recrystallized from ethyl acetate-getyl ether This gave dark red crystals with a melting point of 182-184 ° C.

IR (KBr) Seo:. 3400-2800, 2959, 2932, 2872, 1740, 1661, 1622, 1593, 1541 cm "1 Ή-NMR (CDC1 3): 50.997 (6H, d, J = 6.6Hz), 1.68 -1.79 (2H, m), 1.79-1.88 (1H, m), 1.86 (3H, d, J = 0.9 Hz), 2.38 (3H, d, J = 1.2 Hz), 3.12 (2H, t, J = 7.8 Hz), 7.71 (1H, t, J = 7.5 Hz), 8.16 (1H, dt, J = 9.0, 0.9 Hz), 8.56 (1H, dt, J = 7.5, 0.8 Hz), 9.20 (1H, t, J = 1.8 Hz), 11.03 (1H, bs).

Example 7-81

 4-({[5,6-Dimethyl-8_ (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene] amino } Sulfonyl) -N-hexylbenzamide

4-({[5,6-Dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo obtained in Example 7-4 [5,1-c] [1 , 4] Thiazine-1-ylidene] amino} sulfonyl) benzoic acid (150 mg, 0.311 tmol) and trihexylamine (0.0454 ml, 0.343 mmol) in N, N-dimethylformamide (6.00 ml) Getyl phosphate (0.55 il, 0.343 mmol) was added, followed by triethylamine (0.0478 ml, 0.343 t ol). After stirring the reaction mixture at room temperature for 19.5 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (20.2 mg, U%) as a dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 182-183 ° C.

IR (KBr): 3345, 3247, 2957, 2934, 2870, 1740, 1663, 1617, 1597, 1557 cm " ^{1. ]} H-NMR (CDCI3): (50.849 (3H, t, J = 7.2 Hz), 1.00 (6H, d, J = 6.3Hz), 1.16-1.32 (6H, m), 1.40-1.53 (2H, m), 1.64-1.74 (2H, in), 1.74-1.83 (1H, 1), 1.86 ( 3H, s), 2.37 (3H, s), 2.97 (2H, q. J = 6.6 Hz), 3.09 (2H, t, J = 7.5 Hz), 4.33 (1H, bs), 7.92 (2H, d, J = 8.7 Hz), 8.45 (2H, d, J = 8.4 Hz), 11.11 (1H, bs).

 N- [5,6-Dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -2,3-dihydro-1H-imidazo [5, tric ] [1,4] thiazine-1-ylidene]-4-fluorobenzenesulfonamide

Sodium hydride (39.9 mg, 0.996 mmol) (60% oily) in tetrahydrofuran (1.00 ml) of the suspension of triamino-5,6-dimethyl 8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -3H obtained in Example 6-6. A solution of -imidazo [5,1-c] [1,4] thiazin-3-one (200 mg, 0.498 mmol) in tetrahydrofuran (2.00 ml) was added, and the mixture was stirred under ice cooling for 5 minutes. To this was added a solution of 4-fluorobenzenesulfonyl chloride (194 mg, 0.996 tmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 2 hours. Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. Wash and dry the extract

It was synthesized (MgSO ₄₎ After the solvent was distilled off under reduced pressure to give the title compound (208 mg, 75%). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 177-179.

IR (KBr) V: 3220, 2946, 2859, 1755, 1665, 1622, 1593, 1559, 1497 cm " ¹ .

_{Ή-NMR (CDC1 3):} 51.66-1.84 (4H, m), 1.80 (3H, d, J = 1.2 Hz), 1.96-2.16 (2H, m), 2.27 (3H, d, J = 0.9 Hz), 2.98 (2H, t, J = 7.2 Hz), 7.16 (2H, dd, J = 9.3, 0.6

Hz), 7.97 (2H, dd, J = 8.7, 3.6 Hz), 9.61 (1H, bs).

Elemental analysis: C _2. H ₁₉ N ₃ 0 _{3 As} S ₃ F ₆

Calculated value (¾): C, 42.93; H, 3.42; N, 7.51; S, 17.19.

Found (¾): C, 42.95; H, 3.34; N, 7.51; S, 17.11.

Example 7-83

 N- [2,3-dihydro-5,6-dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -1H-imidazo [5, 1-c] [1, 4] thiazine-triylidene] -4-odobenzenesulfonamide

To a suspension of sodium hydride (i99 mg, 4.98 歷 01) (60% oily) in tetrahydrofuran (2.50 ml) was added 1-amino-5,6-dimethyl 8-[(5 , 5,6,6,6-pentafluorohexyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (1.00 g, 2.49 awake ol) in tetrahydrofuran (5.00 ml ) The solution was added and stirred for 5 minutes under ice cooling. To this was added a solution of 4-hydrobenzenesulfonyl chloride (1.51 g, 4.98 tmol) in tetrahydrofuran (2.50 ml), and the mixture was further stirred for 19 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), was synthesized and the solvent evaporated under reduced pressure to give the title compound the title compound (1.59 g, 96%). Recrystallization from ethyl acetate-ethyl ether yielded dark red crystals with a melting point of 1-173. Was.

IR (KBr) v:. 3223 , 3086, 2946, 2863, 1759, 1748, 1665, 1622, 1557 cm "1 'H-NMR (CDC1 3): δ 1.66-1.84 (4H, m), 1.80 (3H, d, J = 0.9 Hz), 1.96-2.16 (2H, m), 2.28 (3H, d, J = 0.6 Hz), 2.98 (2H, t, J = 7.2 Hz), 7.67 (2H, d, J = 8.7 Hz), 7.85 (2H, dd, J = 8.7 Hz), 9.61 (1H, bs).

Elemental analysis: C _2. H ₁₉ N ₃ 0 ₃ S ₃ F ₅ I

Calculated (¾): C, 35.99; H, 2.87; N, 6.30; S, 14.41.

Found (値): C, 36.08; H, 2.87; N, 6.39; S, 14.57.

Example 7-84

4-cyano-N-[-5,6-dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -2,3-dihydric 1H-imidazo [ 5, 1-c] [1,] thiazine-triylidene] benzenesulfonamide

To a suspension of sodium hydride (341 mg, 8.5 mmol) (60% oily) in tetrahydrofuran (5.00 ml) was added triamino-5,6-dimethyl 8-[(5,5) obtained in Example 6-6. 5,6,6,6-Pentafluorohexyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (1.71 g, 4.26 t) of tetrahydrofuran (10.0 ml) The solution was added, and the mixture was stirred under ice cooling for 5 minutes. To this was added a solution of 4-cyanobenzenesulfonyl chloride (1.72 g, 8.52 mmol) in tetrahydrofuran (5.00 ml), and the mixture was further stirred for 15 minutes. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), was synthesized and the solvent evaporated under reduced pressure to give the title compound the title compound (1.96 g, 81¾). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 169-171 ° C.

IR (KBr) V: 3229, 2944, 2875, 2234, 1744, 1663, 1607, 1553 cm " ¹ .

_{Ή-NM (CDC1 3):} δ 1.68-1.86 (4Η, m), 1.81 (3H, d, J = 0.9 Hz), 1.98-2.15 (2H, 1), 2.29 (3H, d, J = 0.9 Hz) , 3.00 (2H, t, J = 7.2 Hz), 7.79 (2H, d, J = 8.7 Hz), 8.08 (2H, dd, J = 9.0 Hz), 9.62 (1H, bs).

Elemental analysis: C ₂₁ H _2. N ₄ 0 ₃ S ₃ F ₅

Calculated value (¾): C, 44.44; H, 3.55; N, 9.87; S, 16.95.

Found (¾): C, 44.46; H, 3.48; N, 10.03; S, 17.08. Example 7-85

 N- {4-[({5,6-dimethyl-3-oxo-8-[(4,4,5,5,5-phanyl] -2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-1-ylidene} amino) sulfonyl] phenyl} acetamide

 Crude triamino-5,6-dimethyl-8-[(4,4,5,5,5-pentafluoropentyl) sulfanyl] -3H-imidazo [5, obtained in the same manner as in Example 6-3 1-c] [1,4] Thiazine-3-one (purity 70%, 553 mg, 1.0 bandol) in THF (10 ml) suspension was added to sodium hydride (purity 60% oil, 160 mg, 4.0 mg). Was added at room temperature and stirred for 20 minutes, followed by addition of Shii-Dai 4_asemidobenzenesulfonyl (313 mg, 1.30 mmol) and further stirring for 30 minutes. The reaction solution was diluted with ethyl acetate (30 ml), washed with 0.2N hydrochloric acid, 0.1N hydrochloric acid, water and saturated saline, and dried over sodium sulfate. After concentration to dryness, the residue was diluted with ethyl acetate and getyl ether. The precipitate was collected by filtration, washed with ethyl acetate-ethyl ether (1: 1) and dimethyl ether, and dried to give the title compound (270 mg, 0.462 mmol) as a red-purple powder.

'H-NMR (300MHz, DMS0 - d 6): 51.79 (3H, q, J = 1.0 Hz), 1.84 (2H, quint, J = 7.8 Hz), 2.08 (3H, s), 2.17 (3H, q, J = 0.6 Hz), 2.31 (2H, m), 3.07 (2H, t, J = 7.3 Hz), 7.74 (2H, dt, J = 9.2, 2.2 Hz), 7.86 (2H, d, J = 8.8 Hz) , 10.30 (1H, brs), 11.65 (1H, brs).

Elemental analysis: Calculated for C ₂₁ H ₂₁ N ₄ 0 ₄ S ₃ F ₅ : C, 43.14; H, 3.62; N, 9.58; S, 16.45; F, 16.25 (), found: C, 42.86; H , 3.76; N, 9.53; S, 16.32; F, 16.00 () .mp.187.0-189.0 ° C

Example 7-86

 N- {4-[({5,6-Dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl]-2,3-dihydro-1H -Imidazo [5, tric] [1,4] thiazine-1-ylidene} amino) sulfonyl] phenyl} acetamide

Crude 1-amino-5 ^ -dimethyl 8-[(5,5,6,6,6-d-fluorohexyl) sulfanyl] -3H-imidazo [obtained in the same manner as in Example 6-6] Sodium hydride (60% pure oily, 107 mg, 2.68) was added to a suspension of 5,1-c] [1,4] thiazine-3-amine (431 mg, 1.07 marl) in THF (8.6 ml). Ol) at room temperature and stir for 10 minutes, then add 4-acetamidoben chloride Zensulfonyl (285 mg, 1.18 t ol) was added, and the mixture was further stirred for 60 minutes. 1N Hydrochloric acid (2.68 ml) was added to the reaction solution, diluted with methanol-water (1: 1, 5 ml) and stirred for 30 minutes. The precipitate was collected by filtration, washed with methanol-water (1: 1) and methanol, and dried to give the title compound (518 mg, 0.865 mmol) as a red-purple powder.

E - Awakening: _{R (300MHz, DMS0 - d 6} ): 51.59 (2H, m), 1.70 (2H, m), 1.79 (3H, s), 2.08 (3H, s), 2.17 (3H, s), 2.22 ( 2H, m), 3.02 (2H, t, J = 7.2 Hz), 7.73 (2H, d, J = 8.7 Hz), 7 _r 86 (2H, d, J = 9.0 Hz), 10.30 (1H, s), . 11.62 (1H, brs) elemental _{analysis: C 22 H 23 N 4 0} 4 S 3 F 5 calculated: C, 44.14; H, 3.87 ; N, 9.36; S, 16.07; F, 15.87 (%), Found: C, 44.20; H, 3.83; N, 9.26; S, 16.05; F, 15.72 (%). Mp. 211.5-212.5 ° C

Example 7-87

 4-Cu-N- [5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [ 1,4] thiazine-leileiden] benzenesulfonamide

To a suspension of sodium hydride (131 mg, 3.27 recited 01) (60% oil) in tetrahydrofuran (2.00 ml) was added 1-amino-5,6-dimethyl-8-[(obtained in Example 6-23. 4-Fluorobutyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (515 mg, 1.63 mmol) in tetrahydrofuran (6.00 ml) was added, and the mixture was cooled on ice for 5 minutes. Stirred. To this was added a solution of benzenesulfonyl chloride (690 mg, 3.27 band01) in tetrahydrofuran (2.00 ml), and the mixture was further stirred for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to give the title compound was evaporated Solvent under reduced pressure (168 mg, 21%) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 180-. IR (KBr) V 3227, 2940, 2861, 1757, 1663, 1621, 1559 cm " ¹ .

_{Ή-NMR (CDC1 3):} (51.52-1.62 (2H, m), 1.64-1.83 (4H, m), 1.79 (3H, d, J = 0.9 Hz), 2.27 (3H, d, J = 0.6 Hz) , 2.97 (2H, i, J = 7.5 Hz), 4.46 (2H, dt, J = 47.1, 5.7), 7.46 (2H, d, J = 9.0 Hz), 7.90 (2H, d, J = 8.7 Hz), 9.59 (1H, bs). Elemental analysis: C ₁₉ H ₂₁ N ₃ 0 ₃ S ₃ C1F

Calculated value (%): C, 46.57; H, 4.32; N, 8.57; S, 19.63. Found (%): C, 46.69; H, 4.41; N, 8.45; S, 19.40.

Example 7-88

Methyl 2-({[5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] Thiazine-1-ylidene] amino} sulfonyl) benzoate

To a suspension of sodium hydride (134 mg, 3.36 mmol) (60 oily) in tetrahydrofuran (2.00 ml) was added 1-amino-5,6-dimethyl-8- (isopentylsulfuric acid) obtained in Example 6-2. A solution of nil) -3H-imidazo [5, tric] [1,4] thiazin-3-one (500 mg, 1.68 mmol) in tetrahydrofuran (6.00 ml) was added, and the mixture was stirred under ice cooling for 5 minutes. To this was added a solution of methyl (4-chlorosulfonyl) benzoate (789 mg, 3.36 thigh 01) in tetrahydrofuran (2.00 ml), and the mixture was further stirred for 24.5 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to give the solvent was evaporated reduced pressure the title compound (U8mg, 14%) as a dark red crystals. Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 147-U9 ° C.

IR (KBr) v: 3260, 2955, 2932, 2870, 1732, 1663, 1615, 1557 cr ¹ .

_{¾-NMR (CDC1 3):} δθ.909 (6Η, d, J = 6.6 Hz), 1.49-1.58 (2H, m), 1.60-1.74 (1H, m), 1.79 (3H, d, J = 0.9 Hz ), 2.29 (3H, d, J-0.9 Hz), 2.93 (2H, t, J = 7.5 Hz), 3.95 (3H, s), 7.57-7.62 (3H, m), 8.14-8.20 (1H, m) , 9.86 (1H, bs).

Elemental analysis: as C ₂₁ H ₂₅ N ₃ 0 ₅ S ₃

Calculated value (%): C, 50.89; H, 5.08; N, 8.48.

Found (%): C, 50.68; H, 5.09; N, 8.12.

Example 7-89

 2-({[5,6-Dimethyl-8- (isopentylsulfinole) -3-oxo-2,3-dihydro_1H-imidazo [5,1-c] [1,4] thiazine- Trilidene] amino} sulfonylbenzoic acid

The methyl 2-({[5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5,1 -c] [1,4] Thiazine-1-ylidene] amino} sulfonyl) benzoate (89.4 mg, 0.180 mmol) in ethanol (1.00 ml) and tetrahydrofuran (1.00 ml) was added to a 1N sodium hydroxide solution. An aqueous solution (0.541 ml) was added. After stirring the reaction mixture at room temperature for 3 hours, the solvent was distilled off under reduced pressure. Was. IN hydrochloric acid was added to the residue, and the resulting precipitate was collected by filtration, washed with water, and dried to give the title compound (70.5 mg, 81¾) as dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 162-164 ° C.

IR (KBr) V:. 3700-2700 , 2957, 2930, 2870, 1732, 1661, 1615, 1557 cm "1 Ή-NMR (CDC1 3): 60.921 (6H, d, J = 6.2 Hz), 1.52-1.78 (3H, m), 1.79 (3H, d, J = l.2 Hz), 2.28 (3H, d, J = 1.0 Hz), 2.96 (2H, t, J = 7.6 Hz), 7.61-7.70 (2H, m), 7.88-7.96 (1H, m), 8.12-8.18 (1H, m), 9.83 (1H, bs).

Elemental analysis: C _2. H ₂₃ N ₃ 0 ₅ S ₃

Calculated)): C, 49.88; H, 4.81; N, 8.72; S, 19.97.

Found (%): C, 49.90; H, 4.56; N, 8.51; S, 19.72.

Example 7-90

 N- {5,6-Dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -2,3-dihydro-1H-imidazo [5,1- c] [1,4] thiazine-1 -ylidene} -3,4-dimethylbenzenesulfonamide

1-amino-5,6-dimethyl-8 obtained in Example 6-6 was added to a suspension of sodium hydride (189 mg, 4.72 bunol) (60% oily) in tetrahydrofuran (5.00 ml). -[(5,5,6,6,6-pentahexafluorohexyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (948 mg, 2.36 recitation 01) A solution of tetrahydrofuran (10.0 ml) was added, and the mixture was stirred under ice cooling for 5 minutes. To this was added a solution of 3,4-dimethylbenzenesulfonyl chloride (910 ig, 4.45 tmol) in tetrahydrofuran (5.00 ml), and the mixture was further stirred for 2.5 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, after Drying (MgSO _4), and the solvent was evaporated under reduced pressure to synthesize the title compound (206 mg, 15%). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with melting point 155-157.

IR (KBr): 3227, 2932, 1721, 1663, 1618, 1563 cm-】.

_{Ή-NMR (CDC1 3):} 51.64-1.84 (4H, Hi), 1.79 (3H, s), 1.95-2.16 (2H, m), 2.26 (3H, d, J = 1.2 Hz), 2.36 (3H, s ), 2.73 (3H, s), 2.92-3.04 (2H, m), 7.11 (1H, s), 7.30 (1H, t, J-7.5 Hz), 7.88 (1H, t, J = 8.7 Hz), 9.65 (1H, bs).

Elementary analysis: as _{C 22 H 24 N 3 0 3} S 3 F 5 Calculated value (%): C, 46.39; H, 4.25; N, 7.38; S, 16.89.

Found (%): C, 46.21; H, 4.02; N, 7.50; S, 17.09.

Example 7-91

 -{5,6-Dimethyl-3-oxo-8-[(5,5,6,6,6-pentahexylhexyl) sulfanyl] _2,3-dihydrido-1H-imidazo [5,1 -c] [1,4] thiazine-tolydent 2,1,3_benzothiadiazol-4-sulfonamide

A suspension of sodium hydride (39.9 mg, 0.996 ol) (60% oil) in tetrahydrofuran (1.00 ml) was added to a suspension of 1-amino-5,6-dimethyl-8- [obtained in Example 6-6. (5,5,6,6,6-pentahexafluorohexyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (200 mg, 0.498 benzyl) tetrahydrofuran ( 2.00 ml) solution and stirred under ice-cooling for 5 minutes. To this was added a solution of 2,1,3-benzothiadiazol-4-sulfonyl chloride (241 mg, 0.996 bandol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), was synthesized solvent was distilled off under reduced pressure the title compound (249 mg, 84%). The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 170-172 ° C.

IR (KBr): 3245, 2942, 2253, 1740, 1663, 1615, 1557, 1524 cm " ¹ .

_{^ -NMR (CDC1 3): δ} 1.48-1.76 (4Η, m), 1.80 (3H, d, J = 1.0 Hz), 1.84-2.14 (2H, m), 2.33 (3H, d, J = 0.8 Hz) , 2.89 (2H, t, J-7.4 Hz), 7.72 (1H, dd, J = 8.8, 7.0 Hz), 8.22 (1H, dd, J = 8.8, 1.0 Hz), 8.37 (1H, dd, J = 7.0 , 1.0 Hz), 10.10 (1H, bs).

Elemental analysis: C _2. H _1S N ₅ 0 _{3 As} S ₄ F ₅

Calculated values): C, 40.06; H, 3.03; N, 11.68; S, 21.39.

Found (%): C, 40.06; H, 2.96; N, 11.52; S, 21.5.4.

Example 7-92

 N- {5,6-dimethyl-3-oxo-8 _ [(5,5,6,6,6-pentafluorohexyl) sulfanyl] -2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-1-ylident 2,1,3-benzothiadiazol-5-sulfonamide

Sodium hydride (39.9 mg, 0.996 mmol) (60% oily) in tetrahydrofuran (1.00 of the 1-amino-5,6-dimethyl-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -3H obtained in Example 6-6. A solution of -imidazo [5, tric] [1,4] thiazin-3-one (200 mg, 0.498 acetyl) in tetrahydrofuran (2.00 ml) was added, and the mixture was stirred under ice cooling for 5 minutes. To this was added a solution of 2,1,3-benzothiadiazole-5-sulfonyl chloride (234 mg, 0.996 tmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), and the solvent was evaporated under reduced pressure to synthesize the title compound (254 mg, 85%). The crystals were recrystallized from ethyl acetate-getyl ether to give red crystals with a melting point of 123-125 ° C.

IR (KBr) V: 3250, 2944, 2260, 1738, 1663, 1615, 1557, 1518 cm " ¹ .

_{Ή-NMR (CDC1 3):} (51.70-1.86 (4H, m), 1.80 (3H, d, J = 1.2 Hz), 1.92-2.20 (2H, m), 2.29 (3H, d, J = 1.0 Hz) , 2.99 (2H, t, J = 7.0 Hz), 8.11 (2H, d, J = 1.2 Hz),

8.69 (1H, t, J = 1.2 Hz), 9.68 (1H, bs).

Elemental analysis: C _2. H ₁₈ N ₅ 0 ₃ S ₄ F ₅

Example 7-93

 N- {5,6-Dimethyl-3-oxo-8-[(5,5,6,6,6-pentylfluorohexyl) sulfanyl] -2,3-dihydro-1H-imidazo [5, l_c] [1,4] thiazine-1-ylidene} -1_benzothiophene-3-sulfonamide

A suspension of sodium hydride (39.9 mg, 0.996 ol) (60% oil) in tetrahydrofuran (1.00 ml) was added to a suspension of 1-amino-5,6-dimethyl-8- [obtained in Example 6-6. (5,5,6,6,6-pentafluorohexyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (200 mg, 0.498 ol) in tetrahydrofuran ( 2.00 ml) solution and stirred under ice-cooling for 5 minutes. To this was added a solution of 1-benzothiophene-3-sulfonyl chloride (239 mg, 0.996 mmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 2 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO ₄₎ After the solvent was distilled off under reduced pressure to give the title compound (218 mg, 73¾) was synthesized. Recrystallization from ethyl acetate-getyl ether gave dark red crystals mp 194-196.

IR (KBr) V: 3220, 3102, 2946, 1748, 1728, 1663, 1615, 1559, 1495 cm one ^1. 'H-NMR (CDCI3): δ 1.6 1.76 (4Η, m), 1.77 (3H, d, J = 0.9 Hz), 1.92-2.12 (2H, m), 2.26 (3H, d, J = 0.9 Hz) , 2.94 (2H, t, J = 6.6 Hz), 7.40-7.50 (2H, m), 7.86-7.90 (1H, m), 8.25 (1H, s), 8.34-8.40 (1H, m), 9.66 (1H , Bs).

Elemental analysis: C ₂₂ H _2. N ₃ 0 ₃ S ₄ F ₅

 Calculated value (%): C, 44.21; H, 3.37; N, 7.03; S, 21.46.

 Found (¾): C, 44.05; H, 3.21;, 6.91; S, 21.63.

 Example 7-94

 N- {5,6-dimethyl-3-oxo- 8-[(5,5,6,6,6-pentahexylhexyl) sulfanyl] -2,3-dihidid-1H-imidazo [5 , 1-c] [1,4] thiazine-1-ylidentate 3,5-dimethyl-4-isoxazolylsulfonamide

To a suspension of sodium hydride (39.9 mg, 0.996 ethanol) (60% oil) in tetrahydrofuran (1.00 ml) was added the triamino-5,6-dimethyl-8- [obtained in Example 6-6. (5,5,6,6,6-difluorofluorohexyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (200 mg, 0.498 mmol) in tetrahydrofuran (2.00 ml) solution was added and stirred under ice cooling for 5 minutes. To this was added a solution of 3,5-dimethylisoxazole-4-sulfonyl chloride (201 mg, 0.996 mol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 2 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO ₄₎ After the solvent was distilled off under reduced pressure to give the title compound (109 mg, 39¾) was synthesized. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 176-178 t.

IR (KBr) V: 3260, 2930, 1732, 1665, 1617, 1595, 1559 cm " ¹ .

 Ή-NMR (CDCI3): 51.66-1.84 (4H, m), 1.82 (3H, d, J = 1.2 Hz), 1.97-2.17 (2H, m), 2.29 (3H, d, J = 1.2 Hz), 2.48 (3H, s), 2.66 (3H, s), 3.01 (2H, t, J = 6.9 Hz), 9.55 (1H, bs).

Elemental analysis: as C ₁₉ H ₂₁ N ₄ 0 ₄ S ₃ F ₅

 Calculated value (%): C, 40.71; H, 3.78; N, 9.99; S, 17.16.

 Found (%): C, 40.63; H, 3.94; N, 10.08; S, 17.34.

 Example 7-95

N- {5,6-dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfani ] -2,3-Dihydro-1H-imidazo [5, tric] [1,4] thiazine-1-ylidene 2,3-dihydro-1,4-benzodioxin-6-sulfonamide

To a suspension of sodium hydride (39.9 mg, 0.996 ol) (60% oil) in tetrahydrofuran (1.00 ml) was added triamino-5,6-dimethyl-8-[(obtained in Example 6-6. 5,5,6,6,6-pentafluoromethylhexyl) sulfanyl] -3H-imidazo [5,1-C] [1,4] thiazine-3_one (200 mg, 0.498 tmol) of tetrahydrofuran (2.00 ml) ) The solution was added and stirred for 5 minutes under ice cooling. To this was added a solution of 2,3-dihydro-1,4-benzodioxin-6-sulfonyl chloride (241 mg, 0.996 tmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 2 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), was synthesized solvent was distilled off under reduced pressure the title compound (228 mg, 77%). The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 162-164.

IR (KBr) V: 3230, 2948, 1730, 1665, 1617, 1563, 1497 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 1.60-1.85 (4Η, m), 1.79 (3H, s), 1.90-2.22 (2H, m), 2.26 (3H, d, J = 1.0 Hz), 2.97 (2H, t, J = 7.0 Hz), 4.24-4.36 (4H, m), 6.93 (1H, d, J = 8.4 Hz), 7.45 (1H, dd, J = 8.4, 2.2 'Hz), 7.48 (1H, d, J = 1.8 Hz), 9.58 (1H, bs).

Elementary analysis: as _{C 22 H 22 N 3 0 5} S 3 F 5

Calculated value (%): C, 44.07; H, 3.70; N, 7.01; S, 16.04.

Found (¾): C, 44.01; H, 3.63; N, 7.05; S, 16.12.

Example 7-96

 N- {5,6-Dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -2,3-dihydro-1H-imidazo [5, tric ] [1,4] Thiazine-1-ylidene} -2,3-Dihydrido-1-benzofuran-5-sulfonamide

To a suspension of sodium hydride (39.9 mg, 0.996 dol ol) (60% oily) in tetrahydrofuran (1.00 ml) was added the triamino-5,6-dimethyl-8-[(obtained in Example 6-6. 5,5,6,6,6-pentanofluorhexyl) sulfanyl] _3H-imidazo [5,1-c] [1,4] thiazin-3-one (200 mg, 0.498 tmol) of tetrahydrofuran ( 2.00 ml) solution and stirred under ice-cooling for 5 minutes. This is followed by 2,3-dihydro-1-benzofuran-5-sulfonyl chloride A solution of lido (225 mg, 0.996 bandol) in tetrahydrofuran (1.00 ml) was added, and the mixture was further stirred for 2.5 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. Washed with water extract exudates, dried (MgSO _4), was synthesized solvent was distilled off under reduced pressure the title compound (208 mg, 72%). Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 164-165 ° C.

IR (KBr) V: 3225, 2948, 1732, 1661, 1615, 1559, 1487 cm " ¹ .

_{Ή-NMR (CDC1 3):} 51.65-1.85 (4H, m), 1.79 (3H, s), 1.96-2.16 (2H, m), 2.26 (3H, s), 2.96 (2H, t, J = 6.9 Hz ), 3.25 (2H, t, J-8.7 Hz), 4.66 (2H, t, J = 9.0 Hz), 6.82 (1H, d, J = 8.4 Hz), 7.75 (1H, d, J = 8.1 Hz), 7.76 (1H, s), 9.62 (1H, bs).

Elementary analysis: as _{C 22 H 22 N 3 0 4} S 3 F 5

Calculated value (%): C, 45.28; H, 3.80; N, 7.20; S, 16.48.

Found (%): C, 45.41; H, 3.62; N, 7.04; S, 16.68.

Example 7-97

N- {5,6-Dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -2,3-dihydro-1H-imidazo [5, 1-c] [1,4] thiazine-triylidene} dibenzo [b, d] furan-2-sulfonamide

To a suspension of sodium hydride (53.5 mg, 1.34 tmol) (60% oil) in tetrahydrofuran (2.00 ml) was added the triamino-5,6-dimethyl-8-[(obtained in Example 6-6. 5,5,6,6,6-Pentafluorohexyl) sulfanyl] -3H-imidazo [5, tric] [1,4] thiazin-3-one (268 mg, 0.668 Substituted ol) in tetrahydrofuran (2.00 ml ) The solution was added and stirred for 5 minutes under ice cooling. To this was added a solution of dibenzo [b, d] furan-2-sulfonyl chloride (356 mg, 1.34 bandol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 2.5 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, Drying (MgSO _4), was synthesized solvent was distilled off under reduced pressure the title compound (83.6mg, 20¾). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 176-178.

IR (KBr) V 3231, 3069, 3031, 2932, 1744, 1665, 1617, 1559 cm- ¹ .

_{Ή-NMR (CDC1 3):} (51.62-1.82 (4H, m), 1.78 (3H, d, J = 0.9Hz), 1.92-2.12 (2H, m), 2.27 (3H, d, J-1.2 Hz), 2.95 (2H, t, J = 6.9 Hz), 7.41 (1H, dt, J = 7.8, 1.2 Hz), 7.53 (1H, dt, J = 6.9 , 1.2 Hz), 7.64 (2H, t, J-8.7 Hz), 8.00 (1H, d, J = 7.8 Hz), 8.08 (1H, dd, J = 8.7, 1.8 Hz), 8.59 (1H, d, J = 1.5 Hz), 9.69 (1H , bs) Elementary analysis:. as _{C 26 H 22 N 3 0 4} S 3 F 5

Calculated (¾): C, 49.44; H, 3.51;, 6.65; S, 15.23.

Found (¾): C, 49.65; H, 3.50; N, 6.38; S, 15.51.

Example 7-98

 N- {5,6-dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -2,3-dihydro-1H-imidazo [5,1- c] [1,4] thiazine-1-ylidene} (phenyl) methansulfonamide

To a suspension of sodium hydride (39.9 mg, 0.996 mmol) (60% oily) in tetrahydrofuran (1.00 ml) was added 1-amino-5,6-dimethyl-8-[(obtained in Example 6-6. 5,5,6,6,6_ pentaylfluorohexyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (200 mg, 0.498 acetylol) of tetrahydrofuran ( 2.00 ml) solution and stirred under ice-cooling for 5 minutes. To this was added a solution of benzylsulfonyl chloride (190 mg, 0.996 mmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain the solvent was distilled off under reduced pressure the title compound (187 mg, 68) as a dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 195-196. IR (KBr) v: 3250, 2919, 1740, 1665, 1618, 1561 cm ¹ .

_{• H-NMR (CDC1 3)} : δ 1.70-1.94 (4Η, m), 1.80 (3H, d, J = 1.0 Hz), 1.94-2.28 (2H, m), 2.21 (3H, d, J = 1.2 Hz ), 3.02 (2H, t, J = 7.0 Hz), 4.35 (2H, s), 7.31-7.46 (5H, m), 9.11 (1H, bs).

Elemental analysis: as C ₂₁ H ₂₂ N ₃ 0 ₃ S ₃ F ₅

Calculated value (%): C, 45.40; H, 3.99; N, 7.56; S, 17.31.

Found (¾): C, 45.76; H, 4.09; N, 7.39; S, 17.22.

Example 7-99

N- {5,6-Dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydrido-1H-imidazo [5,1-c] [1,4] thiazine- 1-ylidene} (phenyl) methanesulfone Mid

A suspension of sodium hydride (50.7 mg, 1.27 mmol) (60% oily) in tetrahydrofuran (1.00 ml) was added to the triamino-5,6-dimethyl-8-[(5 -Fluoropentyl) sulfanyl] -3H-imidazo [5, tric] [1,4] thiazin-3-one (200 mg, 0.634 mmol) in tetrahydrofuran (2.00 ml) was added and stirred under ice-cooling for 5 minutes. mixed. To this was added a solution of benzylsulfonyl chloride (242 mg, 1.27 mmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 2.5 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was evaporated reduced pressure to give the title compound (191 mg, 64%) as a dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 196-198 ° C.

IR (KBr): 3140, 3069, 2963, 2940, 2922, 1734, 1663, 1617, 1563 cm— ¹ .

_{Ή-NMR (CDC1 3):} 51.50-1.92 (6H, m), 1.79 (3H, s), 2.20 (3Η, s), 3.01 (2H, t, J = 7.2 Hz), 4.35 (2H, s), 4.48 (2H, dt, J = 47.4, 6.0 Hz), 7.29-7.47 (5H, m), 9.12 (1H, bs).

Elemental analysis: C _2. H ₂₄ N ₃ 0 _{3 As} S ₃ F

Calculated (¾): C, 51.15; H, 5.15; N, 8.95; S, 20.48.

Found (%): C, 51.09; H, 5.00; N, 8.76; S, 20.24.

Example 7-100

 4-Fluoro-N- {5,6-dimethyl-8-[(5-fluoroopentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1, 4] thiazine-1-ylidene} benzenesulfonamide

To a suspension of sodium hydride (63.4 mg, 1.59 t ol) (60% oily) in tetrahydrofuran (1.00 ml) was added 1-amino-5,6-dimethyl-8- [obtained in Example 6-23. (5-Fluoropentyl) sulfanyl] -3H-imidazo [5, tric] [1,4] thiazin-3-one (250 mg, 0.793 mmol) in tetrahydrofuran (2.00 ml) was added, and the mixture was cooled under ice-cooling. Stir for a minute. To this was added a solution of 4-fluorobenzenesulfonyl chloride (308 mg, 1.59 marl) in tetrahydrofuran (l.OOral), and the mixture was further stirred for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO ₄₎ After the solvent was distilled off under reduced pressure to give the title compound (226 mg, 61¾) was synthesized. Ethyl acetate Recrystallization from ethyl ether gave dark red crystals with a melting point of 170-2 ° C.

IR (KBr) Re:. 3223, 2963, 2940, 2863, 1755, 1663, 1622, 1591, 1563, 1495 cm "1 - negation _{R (CDC1 3): δ 1.44} - 1.86 (6Η, m), 1.79 (3H , s), 2.27 (3H, s), 2.97 (2H, t, J = 7.6Hz), 4.45 (2H, dt, J = 47.0, 5.8 Hz), 7.16 (2H, d, J = 8.8Hz), 7.94 -8.04 (2H, m), 9.59 (1H, bs).

Elemental analysis: as C ₁₉ H ₂₁ N ₃ 0 ₃ S ₃ F ₂

Calculated value (¾): C, 48.19; H, 4.47; N, 8.87; S, 20.31.

Found (¾): C, 48.13; H, 4.46; N, 8.71; S, 20.05.

Example 7-102

N- {5,6-dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfani) 1-2,3-dihydro-1H-imidazo [5,1- c] [1,4] thiazine-1-ylident 2,1,3-benzoxaziazol-4-sulfonamide

To a suspension of sodium hydride (39.9 mg, 0.996 ol) (60% oil) in tetrahydrofuran (1.00 ml) was added the triamino-5,6-dimethyl-8 _ [(5 , 5, 6, 6, 6-Pentafluorohexyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (200 mg, 0.498 mmol) in tetrahydrofuran (2.00 ml) The solution was added, and the mixture was stirred under ice cooling for 5 minutes. To this was added a solution of 1,1,3_benzoxodiazole-4-sulfonyl chloride (218 mg, 0.996 mmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), was synthesized solvent was distilled off under reduced pressure the title compound (154 mg, 53%). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 192_194.

IR (KBr) V: 3202, 2946, 1746, 1725, 1661, 1618, 1557 cm " ¹ .

_{^ -NMR (CDC1 3): δ} 1.50-1.78 (4Η, m), 1.80 (3H, d, J = 0.8 Hz), 1.85-2.16 (2H, m), 2.22 (3H, d, J = 1.2 Hz) , 2.91 (2H, t, J = 6.6 Hz), 7.55 (1H, dd, J = 8.8, 6.6 Hz), 8.06 (1H, dd, J = 9.2, 0.6 Hz), 8.13 (1H, dd, J = 6.6 , 0.6 Hz), 9.87 (1H, bs).

Elemental analysis: C _2. H ₁₈ N ₅ 0 ₄ S ₃ F ₅

Calculated value (%): C, 41.16; H, 3.11; N, 12.00; S, 16.48. Found (%): C, 41.21; H, 3.02; N, 11.94; S, 16.67.

Example 7-103

 N '-{5,6-Dimethyl-3-oxo-8-[(5,5,6,6,6-pentylfluorohexyl) sulfanyl] -2,3-dihydro-1H-imidazo [5 C] [1,4] thiazine-tolylidene}-Ν, Ν-dimethyl-rea

To a suspension of sodium hydride (39.9 mg, 0.996 mmol) (60% oily) in tetrahydrofuran (100 ml) was added the triamino-5,6-dimethyl-8- [obtained in Example 6-6. (5,5,6,6,6-hexylfluorohexyl) sulfanyl] _3H-imidazo [5,1-c] [1,4] thiazin-3-one (200 mg, 0.498 alcohol) in tetrahydrofuran (2.00 ml) solution was added and stirred under ice cooling for 5 minutes. The solution (2.00 ml) obtained in Method A of Reference Example 45 was added thereto, and the mixture was further stirred at room temperature for 2 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (142 mg, 60%) as a dark red crystals. The crystals were recrystallized from ethyl acetate-jetil ether to obtain red-red crystals having a melting point of 147-149 ° C.

IR (KBr) level: 3256, 2938, 1732, 1667, 1644, 1613, 1584 cm— ¹ .

Ή one _{NMR (CDC1 3): δ 1.70-1.88} (4Η, m), 1.80 (3H, d, J-0.9 Hz), 1.98-2.17 (2H, m), 2.27 (3H, d, J = 0.9 Hz) , 3.00 (3H, s), 3.00 (2H, t, J = 7.1 Hz), 3.21 (3H, s), 10.73 (1H, bs).

Elemental analysis: as C ₁₇ H ₂₁ N ₄ 0 ₃ S ₂ F ₅

Calculated value (%): C, 43.21; H, 4.48; N, 11.86; S, 13.57.

Found (%): C, 43.05; H, 4.40; N, 11.74; S, 13.70.

Example 7-104

 N- {5,6-dimethyl-3-oxo-8-[(5,5,6,6,6_pentafluorohexyl) sulfanyl] -2,3-dihydrido-1H-imidazo [5,1 -c] [1,4] thiazine-1-ylidene} -4- (1H-villazol-1-yl) benzenesulfonamide

A mixture of triphenylpyrazol (2.11 g, 14.3 mmol) and chlorosulfonic acid (6.07 g, 50.5 t) was stirred at room temperature for 6 days and at 50 ° C for 4 days. The reaction solution was diluted with toluene (50 ml), poured into ice (90 g), and extracted with ethyl acetate (100 ml). The organic layer was washed with water, saturated sodium bicarbonate, and saturated saline, and dried over sodium sulfate. The mixture was concentrated to dryness to give a mixture of Shiridani 4- (topyrazolyl) benzenesulfonyl and tofenylpyrazole (2: 3 1.70 g) as a white solid.

 To a suspension of the compound obtained in Example 6-6 (209 rag, 0.521 dish ol) in THF (4.0 ml) was added sodium hydride (purity 60% oily, 58.3 mg, 1.46 ml) at room temperature, and the mixture was added for 15 minutes. After stirring, a solution of 4- (1-pyrazolyl) benzenesulfonyl (purity 53%, 217 mg, 0.472 mmol) in THF (2.0 ml) was added, and the mixture was further stirred for 60 minutes. IN hydrochloric acid (4.0 ml) and water (20 ml) were added to the reaction solution, and the mixture was extracted with ethyl acetate (35 ml). The organic layer was washed with water and saturated saline, and then dried over sodium sulfate. After concentration to dryness, the residue was diluted with methanol. The precipitate was collected by filtration, washed with methanol, and dried to give the title compound (22i mg, 0.364 mmol, 69.8%) as a gray-red powder. '

_{ΐ-NMR (200MHz, CDC1 3} ): δ 1.75 (4Η, m), 1.80 (3H, q, J = 1.0 Hz), 2.05 (2H, m), 2.28 (3H, q, J = 0.6 Hz), 2.97 (2H, t, J = 7.0 Hz), 6.52 (1H, dd, J = 2.6, 1.8 Hz), 7.77 (1H, d, J = 1.4 Hz), 7.84 (2H, d, J = 8.8 Hz), 7.99 (1H, d, J = 2.6 Hz), 8.04 (2H, d, J = 8.8 Hz), 9.64 (1H, br).

Elemental _{analysis: C 23 H 22 N 5 0} 3 S 3 F 5 Calculated: C, 45.46; H, 3.65 ; N, 11.53; S, 15.83; F, 15.63 (%), Found: C, 45.49; H, 3.87; N, 11.65; S, 16.02; F, 15.61.mp.182.5-186. Ot:

Example 7-105

Ethyl 5-{[5,6-dimethyl-3-oxo-1-({[4- (trifluoromethyl) phenyl] sulfonyl} imino) -2,3-dihydro-1H-imidazo [5,1- c] [1,4] thiazine-8-yl] sulfanil} pen

 To a suspension of sodium hydride (230 mg, 5.74 mmol) (60% oil) in tetrahydrofuran (10.0 ml) was added the ethyl 5- [triamino-5,6-dimethyl-3 obtained in Example 6-24. -Oxo-3H-imidazo [5,1-c] [1,4] thiazin-8-yl) sulfanyl] pentanoate (1.02 g, 2.87 tmol) in tetrahydrofuran (5.00 ml) was added, and the mixture was cooled on ice.

Stir for 5 minutes. To this was added a solution of 4- (trifluoromethyl) benzenesulfonyl chloride (1.40 g, 5.74 band01) in tetrahydrofuran (5.00 ml), and the mixture was further stirred at room temperature for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. Washed with water extract exudates dried (MgSO ₄₎ After the title compound and the solvent was evaporated under reduced pressure (1.15g, 71¾) Was obtained as dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 146-148 ° C.

IR (KBr) V: 3235, 2984, 2936, 1759, 1738, 1663, 1620, 1559 cm— ¹ .

Ή-NM (CDC1 ₃ ): δΐ.26 (3Η, d, J = 7.2 Hz), 1.70-1.78 (4H, m), 1.80 (3H, d, J = 1.2 Hz), 2.28 (3H, d, J = 0.9 Hz), 2.31-2.38 (2H, m), 2.94-3.00 (2H, m), 4.14 (2H, q, J = 7.2 Hz), 7.77 (2H, d, J-8.7 Hz), 8.11 (2H , d, J = 9.0 Hz), 9.61 (1H, bs).

Elementary analysis: as _{C 22 H 24 N 3 0 5} S 3 F 3

Calculated value (¾): C, 46.88; H, 4.29; N, 7.46; S, 17.07.

Found (%): C, 46.86; H, 4.17; N, 7.62; S, 17.16.

Example 7-106

 N- {5,6-Dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -2,3-dihydro-1H-imidazo [5, 1-c] [1,4] thiazine-1-ylidene 3-pyridinesulfonamide

To a suspension of sodium hydride (64.6 mg, 1.61 ol) (60% oil) in tetrahydrofuran (2.50 ml) was added 1-amino-5,6-dimethyl-8 _ [( 5,5,6,6,6-pentafluorohexyl) sulfanyl] imidazo [5,1-c] [1,4] thiazin-3-one (324 mg, 0.807 mmol) in tetrahydrofuran (2.50 ml) And stirred under ice cooling for 5 minutes. A solution of the residue obtained in Method B of Reference Example 45 in tetrahydrofuran (1.00 ml) was added thereto, and the mixture was further stirred at room temperature for 17 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (348 mg, 79%) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 174-176 ° C. IR (KBr) Re: 2940, 1742, 1732, 1663, 1609, 1557 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 1.68-1.84 (4Η, m), 1.81 (3H, d, J = 0.6 Hz), 1.96-2.16 (2H, m), 2.29 (3H, d, J = 0.6 Hz) , 2.98 (2H, t, J = 6.9 Hz), 7.44 (1H, dd, J = 7.8, 4.8 Hz), 8.24 (1H, dt, J = 8., 1.5 Hz), 8.78 (1H, dd, J = 5.1, 1.2 Hz), 9.19 (1H, d, J-2.1 Hz), 9.64 (1H, bs).

Elemental analysis: as C ₁₉ H ₁₉ N ₄ 0 ₃ S ₃ F ₅ Calculated value (%): C, 42.06; H, 3.53;, 10.33; S, 17.73.

Found (¾): C, 41.90; H, 3.38; N, 10.23; S, 18.00.

Example 7-107

 7-Cupro-N- {5,6-dimethyl-3-oxo-8-[(5,5,6,6,6-pentylfluorohexyl) sulfanyl] _2,3-dihydro-1H- Imidazo [5, lc] [1,4] thiazine-trilidene}-2,1,3-benzoxazole-4-sulfonamide

To a suspension of sodium hydride (39.9 mg, 0.996 mmol) (60% oily) in tetrahydrofuran (1.00 ml) was added triamino-5,6-dimethyl-8-[(5 , 5,6,6,6-Pentate fluoridylhexyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (200 mg, 0.498 tmol) in tetrahydrofuran ( 2.00 ml) solution and stirred under ice-cooling for 5 minutes. To this was added a solution of 2,1,3-benzoxazol-4-sulfonyl chloride (252 mg, 0.996 bandol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred at room temperature for 2 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. Washed with water extract exudates, to give after drying (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (143 mg, 47%) as a喑赤white crystals. Recrystallization from ethyl acetate-jetil ether gave dark red crystals with a melting point of 198-200 ° C.

 IR (KBr) V: 3239, 3081, 2946, 1746, 1663, 1609, 1559, 1520 cm

_{¾-NMR (CDC1 3):} δ 1.60-1.76 (4Η, m), 1.81 (3H, d, J = 0.9 Hz), 1.90-2.12 (2H, m), 2.33 (3H, d, J = 0.6 Hz) , 2.92 (2H, t, J = 7.2 Hz), 7.54 (1H, d, J = 7.2 Hz), 8.06 (1H, d, J = 7.5 Hz), 9.85 (1H, bs).

Elemental analysis: C _2. H ₁₇ N ₅ 0 ₄ S ₃ C1F ₅

Calculated (%): C, 38.87; H, 2.77; N, 11.33; S, 15.57.

Found (¾): C, 38.95; H, 2.68; N, 11.41; S, 15.64.

Example 7-108

N- {5,6-dimethyl-3-oxo-8 _ [(5,5,6,6,6-pentafluorohexyl) sulfanyl]-2,3_dihydro-1H-imidazo [5,1-c ] [1,4] thiazine-1-ylidene} -2,1,3-benzoxaziazol-4-sulfonamide

To a suspension of sodium hydride (265 mg, 6.64 mmol) (60% oil) in tetrahydrofuran (10.0 ml) was added the toamino-5,6-dimethyl-8-[(5,5) obtained in Example 6-6. 5, 6, 6, 6- Add a solution of pentafluorohexyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (1.48 g, 3.69 dish ol) in tetrahydrofuran (15.0 ml), and cool under ice-cooling. Stir for a minute. To this was added a solution of 4-methoxybenzenesulfonyl chloride (1.37 g, 6.64 mmol) in tetrahydrofuran (5.00 ml), and the mixture was further stirred at room temperature for 18.5 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), was synthesized solvent was distilled off under reduced pressure the title compound (1.37 g, 65¾). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 160-162.

IR (KBr) Re: 3241, 2948, 2845, 1755, 1665, 1624, 1597, 1564, 1501 cnf ¹ .

_{Ή-NMR (CDC1 3):} 51.66-1.82 (4H, in), 1.79 (3H, d, J = 1.2 Hz), 1.96-2.14 (2H, m), 2.26 (3H, d, J = 0.9 Hz), 2.96 (2H, t, J = 6.9 Hz), 3.86 (3H, s), 6.96 (2H, d, J = 9.0 Hz), 7.89 (2H, d, J = 9.3 Hz), 9.62 (1H, bs).

Elementary analysis: as _{C 21 H 22 N 3 0 4} S 3 F 3

Calculated (¾): C, 44.13; H, 3.88; N, 7.35; S, 16.83.

Found (¾): C, 43.94; H, 3.66; N, 7.48; S, 16.93.

Example 7-109

 N- {5,6-Dimethyl-3-oxo-8-[(5,5,6,6,6-pentylfluorohexyl) sulfanyl] -2,3-dihydrido-1H-imidazo [5 , 1-c] [1, 4] thiazine-1-ylidene} -2_methoxy-4_methylbenzenesulfonamide

To a suspension of sodium hydride (59.8 mg, 1.49 mmol) (60% oil) in tetrahydrofuran (2.00 ml) was added the triamino-5,6-dimethyl-8-[(5 , 5,6,6,6-Pentafluorohexyl) sulfanyl] -3H-imidazo [5,1-c] [1,] thiazin-3-one (300 mg, 0.747 t) of tetrahydrofuran (2.00 ml) The solution was added, and the mixture was stirred under ice cooling for 5 minutes. To this was added a solution of 2-methoxy-4-methylbenzenesulfonyl chloride (337 mg, 1.49 marl) in tetrahydrofuran (2.00 ml), and the mixture was further stirred at room temperature for 20 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), was synthesized solvent was distilled off under reduced pressure the title compound (332 mg, 76%). The crystals were recrystallized from ethyl acetate-getyl ether to give dark red crystals with a melting point of 192-194 ° C. ' IR (KBr) v 3270, 2946, 1717, 1665, 1613, 1557 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 1.62-1.78 (4H, m), 1.80 (3H, d, J = 0.8 Hz), 1.86-2.16 (2H, m), 2.30 (3H, d, J = 1.0 Hz) , 2.40 (3H, s), 2.91 (2H, t, J = 7.4 Hz), 3.87 (3H, s), 6.78 (1H, s), 6.86 (1H, d, J = 7.6 Hz), 7.89 (1H, d, J = 7.6 Hz), 9.85 (1H, bs).

Elementary analysis: as _{C 22 H 24 N 3 0 4} S 3 F 5 -0.5H 2 0

Calculated value (¾): C, 44.44; H, 4.24; N, 7.07; S, 16.18.

Found (¾): C, 44.36; H, 4.09; N, 7.11; S, 16.43.

Example 7-110

5-bromo-N- {5,6-dimethyl-3-oxo-8 _ [(5,5,6,6,6-pentafluorohexyl) sulfanyl] _2,3-dihydro-1H-imidazo [5, c] To a suspension of [1,4] thiazine-triide sodium hydride (59.8 mg, 1.49 mmol) (60% oily) in tetrahydrofuran (2.00 ml) was added 1- obtained in Example, 6-6. Amino-5,6-dimethyl-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (300 mg, 0.747 t ol) in tetrahydrofuran (2.00 ml) was added, and the mixture was stirred under ice cooling for 5 minutes. To this was added a solution of 5-bromo-2-methoxybenzenesulfonyl chloride (436 mg, 1.49 t) in tetrahydrofuran (2.00 ml), and the mixture was further stirred at room temperature for 3 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. Washed with water extract exudates, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (380 mg, 78%) was synthesized. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 169-170 ° C.

IR (KBr) V:. 3241 , 1721, 1663, 1611, 1557, 1481 cm- 1 'Ή - thigh _{(CDC1 3): (51.64-1.86 (} 4H, m), 1.82 (3H, d, J = 1.2 Hz ), 1.88-2.18 (2H, m), 2.31 (3H, d, J-1.0 Hz), 2.94 (2H, t, J = 6.8 Hz), 3.08 (3H, s), 6.87 (1H, d, J = 8.8 Hz), 7.60 (1H, dd, J = 8.8, 2.6 Hz), 8.17 (1H, d, J = 2.2 Hz), 9.81 (1H, bs).

Elementary analysis: as _{C 21 H 21 N 3 0 4} S 3 BrF s

Calculated value (%): C, 38.77; H, 3.25; N, 6.46; S, 14.79. Found (¾): C, 38.40; H, 3.19; N, 6.38; S, 14.93.

Example 7-112

2,4-Dic-mouth D-6-[{5,6-Dimethyl-3-oxo-3--8-[(5,5,6,6,6-Pentafluorohexyl) sulfanyl]-2,3 -Dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene} amino] sulfonyl] phenyl-3,5-dichlorobenzenesulfonamide sodium hydride (79.7 mg, 1.99 mol ) (60% oily) in tetrahydrofuran (2.00 ml) was added to the suspension of triamino-5,6-dimethyl-8-[(5,5,6,6,6- Pentafluorohexyl) sulfanyl] -3H-imidazo [5, tric] [1,4] thiazin-3-one (200 mg, 0.498 mmol) in tetrahydrofuran (1.00 ml) was added, and the mixture was cooled on ice. Stir for a minute. To this was added a solution of 3,5-dichloro-2-hydroxybenzenesulfonyl chloride (263 mg, 0.996 mmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred at room temperature for 25 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure to give the title compound (302 mg, 71¾) as a dark red crystals. The crystals were recrystallized from ethyl acetate-getyl ether to obtain dark red crystals having a melting point of 181-183 ° C.

IR (KBr): 3700-2800, 3083, 2930, 1738, 1661, 1607, 1551 cm " ¹ .

Ή-NMR (CDC "): δ 1.68-1.86 (4Η, m), 1.82 (3H, d, J = 1.2 Hz), 1.97-2.16 (2H, m), 2.30 (3H, d, J = 0.9 Hz) , 3.03 (2H, t, J = 7.5 Hz), 7.52 (1H, d, J = 2.7 Hz), 7.66 (1H, d, J = 3.0 Hz), 7.89 (1H, d, J = 2.4 Hz), 8.07 (1H, d, J = 2.4 Hz), 8.73 (m, bs), 9.60 (1H, bs).

Elemental analysis: C ₂₆ H _2. N ₃ 0 ₇ S ₄ C1 ₄ F ₅

Calculated (¾): C, 36.67; H, 2.37; N, 4.93; S, 15.06.

Found (%): C, 36.83; H, 2.38; N, 5.01; S, 15.29.

Example 7-113

3,5-Dichloro-N- {5,6-dimethyl-3-oxo- 8-[[5,5,6,6,6-pentafluorohexyl) sulfanyl] -2,3-dihydro-1H -Imidazo [5,1-c] [1,4] thiazine-1-ylide 2,4-Dichloro-6-[{5,6-dimethyl-3-oxo-1-8- obtained in Example 7-112 [(5,5,6,6,6-pentahexyl hexyl) sulfanyl] -1,2,3-dihydro-1H-di Midazo [5,1-c] [1,4] thiazin-1-ylidene} amino] sulfonyl] phenyl-3,5-dichlorobenzene benzenesulfonamide (250 nig, 0.294 ol) in ethanol (4.00 ml) and To a solution of tetrahydrofuran (4.00 ml) was added a 1N aqueous solution of sodium hydroxide (0.969 ml). The reaction mixture was stirred at room temperature for 30 minutes and subsequently at 100 ° C. for 2 hours, and the solvent was distilled off under reduced pressure. 1N Hydrochloric acid was added to the residue, and the resulting precipitate was collected by filtration, washed with water, and dried to give the title compound (147 mg, 80 °) as dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 183-184 ° C.

IR (KBr) V: 3700-2800, 3073, 2942, 1744, 1661, 1597, 1549 cm " ¹ .

_{¾-NMR (CDC1 3):} δ 1.69-1.88 (4Η, m), 1.82 (3H, d, J = 1.2 Hz), 1.97-2.16 (2H, m), 2.30 (3H, d, J = 0.9 Hz) , 3.03 (2H, t, 1 = Ί Λ Hz), 7.52 (1H, d, J = 2.4 Hz),

7.66 (1H, d, J = 2.4 Hz), 8.75 (1H, bs), 9.58 (1H, bs).

Elemental analysis: C _2. H _1S N ₃ 0 ₄ S ₃ C1 ₂ F ₅

Calculated (¾): C, 38.34; H, 2.90; N, 6.71; S, 15.36.

Found (¾): C, 38.37; H, 2.82; N, 6.56; S, 15.55.

Example 7-115

 N- {5,6-dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl]-2,3-dihydro-1H-imidazo [5,1- c] A mixture of [1,4] thiazine-1-ylidene} -3- (4-pyriditophenylphenylpyridine (2.16 g, 13.6 ol) and chlorosulfonic acid (4.91 g, 40.9 mmol) at room temperature for 16 hours The mixture was stirred for 3 hours at 60. The reaction solution was diluted with toluene (50 ml), poured into ice (80 g), added with ethyl acetate (50 ml), and neutralized with sodium carbonate. The organic layer was washed with water, saturated sodium bicarbonate and brine, dried over sodium sulfate, and concentrated to dryness to give a pale purple solid. The reaction mixture was dissolved in thionyl chloride (10 ml) and stirred at room temperature for 7 days The reaction mixture was diluted with toluene (100 ml), concentrated, diluted again with toluene (100 ml), concentrated, and the residue was ethyl acetate (50 ml) The precipitate was collected by filtration, washed with ethyl acetate, and dried to give a white solid.

Example 6 To a suspension of the compound obtained in Step 6 (235 mg, 0.585 mmol) in THF (5.0 ml) was added. Sodium hydride (purity 60% oily, 82.0 mg, 2.05 mmol) was added at room temperature, and the mixture was stirred for 15 minutes. Then, the white solid (187 mg) was added, and the mixture was further stirred for 4.5 hours. The reaction mixture was diluted with methanol (1 ml) and 1N hydrochloric acid (3.0 ml), diluted with ethyl acetate (35 ml), washed with 0.1N hydrochloric acid, water and saturated saline, and dried over sodium sulfate. After concentration to dryness, the residue was diluted with ethyl acetate. The precipitate was collected by filtration, washed with ethyl acetate and ethyl ether, and crystallized from methyl ethyl acetate to give the title compound (45 mg, 0.073 mmol, 12.4%) as a gray-red powder.

_{Ή-NMR (300MHz, CDC1 3} ): 61.72 (4H, m), 1.80 (3H, s), 2.02 (2H, m), 2.28 (3H, s), 2.97 (2H, t, J = 6.9 Hz), 7.53 (2H, m), 7.63 (1H, t, J = 8.0 Hz), 7.82 (1H, d, J = 6.6 Hz), 8.04 (1H, brd, J = 7.5 Hz), 8.25 (1H, brs), 8.71 (2H, m). Elemental analysis: Calculated for C ₂₅ N ₄ 0 ₃ S ₃ F ₅ 0.2H ₂ 0: C, 48.25; H, 3.79; N, 9.00; S, 15.46 (%), found : C, 48.03; H, 3.70; N, 8.93; S, 15.72 (%).

mp. 205.0-206.0 ° C

Example 7-118

4-bromo-N- (5,6-dimethyl-3-oxo-8-{[2- (2,2,1-trifluoroethoxy) ethyl] sulfanyl} -2,3 dihydro-1H-imidazo [5, 1-c] [1, 4] Thiazine-1-ylide sodium hydride (28.5 mg, 0.711 mmol) (60% oily) in a suspension of tetrahydrofuran (2.00 ml) was prepared in Example 6-26. The resulting toamino-5,6-dimethyl-8-{[2- (2,2,2-trifluoroethoxy) ethyl] sulfanyl} 鲁 imidazo [5,1-c] [1,4] thiazi A solution of 1-3-one (120 mg, 0.340 tmol) in tetrahydrofuran (1.00 ml) was added, and the mixture was stirred under ice-cooling for 5 minutes, and mixed with 4-bromobenzenesulfonyl chloride (185 mg, 0.711 mmol) in tetrahydrofuran (1.00 ml). ) was added, evaporated and further stirred at room temperature for 1 hour. the reaction mixture was extracted with acetic acid Echiru by adding 1N hydrochloric acid. the extract was washed with water, dried (MgSO _4), of the solvent under reduced pressure Title compound Te (88.6 mg, 46¾) was obtained as a dark red crystalline acetate Echiru -. Jechirue give recrystallized to dark red crystals, mp 158- 159 from scratch ether.

IR (KBr) V 3246, 3096, 2928, 1759, 1744, 1663, 1622, 1559 cm- ¹ .

_{Ή - NMR (CDC1 3):} δ 1.80 (3Η, s), 2.27 (3H, s), 3.19 (2H, t, J = 6.2 Hz), 3.83 (2H, t, J = 5.8 Hz), 3.85 (2H, q, J-8.8 Hz), 7.63 (2H, d, J = 8.4 Hz), 7.83 (2H, d, J = 8.8 Hz), 9.60 (1H , bs).

Elementary analysis: as _{C 18 H 17 N 3 0 4} S 3 BrF 3

Calculated (%): C, 37.77; H, 2.98; N, 7.34; S, 16.80.

Found (¾): C, 37.68; H, 2.79; N, 7.30; S, 16.79.

Example 7-119

N- {5,6-Dimethyl-3-oxo-8-[(5,5,6,6,6-pentylfluorohexyl) sulfanyl] -2,3-dihydrido-1H-imidazo [5 , 1-c] [1,4] thiazine-triylidene} -2- (Trifluodium hydride (39.9 mg, 0.996 丽 ol) (60% oil) in tetrahydrofuran (1.00 ml) suspension 1-Amino-5,6-dimethyl-8-[(5,5,6,6,6-hexylfluorhexyl) sulfanyl] dimidazo obtained in 6-6 [5,1-c] [ A solution of 1,4] thiazin-3-one (200 mg, 0.498 ol) in tetrahydrofuran (2.00 ml) was added, and the mixture was stirred for 5 minutes under ice-cooling, followed by 2- (trifluoromethyl) benzenesulfonyl chloride ( 244 mg, was added tetrahydrofuran (1.00 ml) solution of 0.996 thigh ol), was stirred for 1.5 hours at room temperature further. the reaction mixture was added with 1N hydrochloric acid and extracted with acetic acid Echiru. the extract was washed with water, dried (MgSO ₄ )rear The solvent was synthesized the title compound was evaporated under reduced pressure (182 mg, 60%) acetic acid Echiru -. Jechirue was recrystallized from a ether to give a dark red crystals, mp 189-191 ° C.

IR (KBr): 3218, 2953, 1738, 1717, 1661, '1611, 1557 cm— ¹ .

_{¾-NMR (CDC1 3):} δ 1.62-1.76 (4Η, ι), 1.80 (3H, d, J = 1.0 Hz), 1.86-2.16 (2H, m), 2.29 (3H, d, J = 0.8 Hz) , 2.94 (2H, t, J = 6.6 Hz), 7.65-7.74 (2H, m), 7.79-7.90 (1H, m), 8.32-8.40 (1H, m), 9.66 (1H, bs).

Elemental analysis: as C ₂₁ H ₁₉ N ₃ 0 ₃ S ₃ F ₅

Calculated value (¾): C, 41.38; H, 3.14; N, 6.89; S, 15.78.

Found (¾): C, 41.32; H, 3.06; N, 6.85; S, 16.00.

Example 7-120

N- {5,6-Dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -2,3-dihydro-1H-imidazo [5,1- c] [1,4] thiazine-1-ylidene 2- (triflu A suspension of sodium hydride (39.9 mg, 0.996 mmol) (60 oily) in tetrahydrofuran (1.00 ml) was added to the triamino-5,6-dimethyl-8-[(5,5) obtained in Example 6-6. 5,6,6,6-Pentafluorohexyl) sulfanyl] -31-toimidazo [5,1-c] [1,4] thiazin-3-one (200 mg, 0.498 tmol) of tetrahydrofuran (2.00 ml) The solution was added, and the mixture was stirred under ice cooling for 5 minutes. To this was added a solution of 2- (trifluoromethoxy) benzenesulfonyl chloride (250 mg, 0.959 mmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred at room temperature for 1.5 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), was synthesized solvent was distilled off under reduced pressure the title compound (215 mg, 69%). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 190-192 ° C.

IR (KBr) V: 3252, 2930, 1746, 1726, 1661, 1615, 1559 cm " ¹ .

_{Ή-NMR (CDC1 3):} 61.61-1.77 (4H, m), 1.81 (3H, s), 1.90-2.10 (2H, m), 2.30 (3H, s), 2.94 (2H, t, J = 7.2 Hz ), 7.34-7.44 (2H, m), 7.60 (1H, dt, J = 8.1, 1.5 Hz), 8.14 (1H, dd, J = 7.8, 1.5 Hz), 9.79 (1H, bs).

Elementary analysis: as _{C 21 H 19 N 3 0 4} S 3 F 5

Calculated value (¾): C, 40.32; H, 3.06; N, 6.72; S, 15.38.

Found (%): C, 40.34; H, 2.91; N, 6.77; S, 15.52.

Example 7-121

N-{5,6-dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl]-2,3-dihydro-1H-imidazo [5,1- c] Example 6 was added to a suspension of [1,4] thiazine-1-ylidene}-2- (tonaphthyl sodium hydride (39.9 mg, 0.996 mmol) (60% oil) in tetrahydrofuran (1.00 il). 1-Amino-5,6-dimethyl-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -3H-imidazo [5,1-c] [1, 4] A solution of thiazin-3-one (200 mg, 0.498 dish ol) in tetrahydrofuran (2.00 ml) was added, and the mixture was stirred for 5 minutes under ice-cooling, followed by 2- (tonaphthyl) benzenesulfonyl chloride (250 mg, 0.959 parts). ol) in tetrahydrofuran (1.00 ml), stirred at room temperature for 1.5 hours, added 1N hydrochloric acid to the reaction mixture, and extracted with ethyl acetate. Washing liquid, dried (MgSO _4), was synthesized solvent was distilled off under reduced pressure the title compound (215 mg, 69%). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 139-U0 ° C.

IR (KBr) V: 3200, 3075, 2948, 1755, 1665, 1622, 1566 cm one ^1.

_{Ή- NMR (CDC1 3): (} 51.63-1.80 (4H, m), 1.83 (3H, d, J = 0.9Hz), 1.90-2.10 (2H, m), 2.30 (3H, d, J = 0.9 Hz) , 2.94 (2H, t, J = 7.2 Hz), 3.50-3.57 (2H, m), 3.64-3.73 (2H, m), 7.35-7.43 (2H, m), 7.46-7.56 (2H, m), 7.78 (1H, dd, J = 7.2, 2.4 Hz), 7.86-7.90 (1H, m), 8.04-8.08 (1H, m), 9.50 (1H, bs).

Elemental analysis: as C ₂₆ H ₂₆ N ₃ 0 ₃ S ₃ F ₅

Calculated value (¾): C, 50.39; H, 4.23; N, 6.78; S, 15.52.

Found (%): C, 50.39; H, 4.25; N, 6.80; S, 15.51.

Example 7-122

 N- {5,6-Dimethyl-3-oxo-8-[(5,5,6,6,6-pentylfluorohexyl) sulfanyl] -2,3-dihydro-1H-imidazo [5, l_c] [1,4] thiazine-triylidene}-4- (1-piperidinyl) benzenesulfonamide

A mixture of triphenylbiperidine (2.67 g, 16.2 alcohol) and chlorosulfonic acid (5.84 g, 48.6 marl) was stirred for 6 days at T. The reaction solution was diluted with toluene (50 ml), and ice ( 80 g), ethyl acetate (50 ml) was added, the mixture was neutralized with sodium carbonate, the aqueous layer was extracted with ethyl acetate (50 ml), and the organic layer was washed with water, saturated sodium bicarbonate, and saturated saline. Then, the mixture was dried over sodium sulfate, concentrated to dryness, and concentrated to dryness to give a 1: 4.8 mixture of 4- (topiperidyl) benzenesulfonyl chloride and the raw material (2.50 g, chloride purity 25%, 2.4 mmol, 14.8¾) as a brown oil. To a suspension of the compound obtained in Example 6-6 (254 mg, 0.633 mmol) in THF (5.0 ml) was added sodium hydride (purity: 60, oily: 63.3 mg, 1.58 mol) at room temperature. After stirring for 20 minutes, a solution of the above brown oil (purity 25%, 0.724 g, 0.696 mmol) in THF (1 ml) was added, and the mixture was further stirred for 1 hour. Methanol (1 ml) and IN hydrochloric acid (1.6 ml) were added to the reaction solution, diluted with ethyl acetate (30 ml), washed with 0.1 N hydrochloric acid, water and saturated saline, and dried over sodium sulfate. Thereafter, the residue was diluted with methanol, and the precipitate was collected by filtration, washed with methanol, and dried to obtain the title compound (329 mg, 0.527 mmol, 83.2 »as a brown-purple powder). _{¾-NMR (300MHz, CDC1 3} ): 51.65 (8H, HI), 1.75 (4H, m), 1.78 (3H, q, J = 0.9 Hz), 2.05 (2H, tt, J = 18.2, 7.1 Hz), 2.25 (3H, q, J = 0.6 Hz), 2.95 (2H, t, J = 6.8 Hz), 3.32 (4H, m), 6.86 (2H, d, J = 9.0 Hz), 7.76 (2H, d, J = 9.3Hz), 9.63 (1H, brs).

Elemental analysis: Calculated for C _{25 9} N ₄ 0 ₃ S ₃ F ₅ : C, 48.07; H, 4.68; N, 8.97; S, 15.40; F, 15.21 (%), found: C, 48.20; H , 4.56; N, 8.95; S, 15.47; F, 15.15 (%) .mp. 175.0-179.0 ° C

Example 7-123

 N- {8-[(5-Fluoropentyl) sulfanyl] _5,6-dimethyl-3-oxo-2,3-dihydrone-1H-imidazo [5, tric] [1,4] thiazine-triident 4 -(Topiberidinyl) benzene sulfonamide

 To a suspension of the compound obtained in Example 6-23 (193 mg, 0.612 t) in THF (4.0 ml) was added sodium hydride (purity 60% oily, 61.2 mg, 1.53 t) at room temperature, and the mixture was added for 15 minutes. After stirring, a solution of a crude substance of 4- (topiperidyl) benzenesulfonyl chloride (purity: 25, 0.70 g, 0.673 mL) in THF (1 ml) was added over 20 minutes, and the mixture was further stirred for 1 hour. Methanol (1 ml), IN hydrochloric acid (1.53 ml) and water (20 ml) were added to the reaction solution, and the mixture was extracted with ethyl acetate (30 ml). The organic layer was washed with 0.1N hydrochloric acid, water and saturated saline, and then dried over sodium sulfate. After concentration to dryness, the remaining brew was diluted with methanol. The precipitate was collected by filtration, washed with methanol, and dried to give the title compound (281 mg, 0.521 mmol, 85.2%) as a purple powder.

_{Ή-NMR (300MHz, CDC1 3} ): (51.54 (2H, m), 1.65 (6H, m), 1.73 (4H, m), 1.78 (3H, q, J = 0.9 Hz), 2.25 (3H, q, J = 0.6 Hz), 2.94 (2H, t, J = 7.2 Hz), 3.30 (4H, m), 4.45 (2H, dt, J = 47.4, 5.9 Hz), 6.86 (2H, d, J = 9.0 Hz) , 7.76 (2H, d, J = 9.0 Hz), 9.62 (1H, brs).

Elemental _{analysis: C 24 H 31 N 4 0} 3 S 3 F Calculated: C, 53.51; H, 5.80 ; N, 10.40; S, 17.86; F, 3.53 (%), Found: C, 53.48; H , 5.87; N, 10.28; S, 17.81; F, 3.45 (%). Mp.170.0-171.o

Example 7-124

N- {5,6-Dimethyl-3-oxo-8-[(4,4,5,5,5-pentafluoropentyl) sulfani L] -2,3-Dihydro-1Η-imidazo [5, tric] [1,4] thiazine-1-ylident-4-α-piperi The compound obtained in Example 6-3 (217 mg, 0.560 ol ) In THF (4.0 ml) was added sodium hydride (purity 60%, oily, 56.0 mg, 1.40 mmol) at room temperature, stirred for 45 minutes, and added with salt 4-(1-piperidyl) benzenesulfonyl. A solution of the crude substance (purity 25%, 0.64 g, 0.616 tmol) in THF (1 ml) was added over 30 minutes, and the mixture was further stirred for 2 hours. Methanol (1 ml) and 1N hydrochloric acid (1.5 ml) were added to the reaction solution, diluted with ethyl acetate (30 ml), washed with 0.1N hydrochloric acid, water and saturated saline, and dried over sodium sulfate. After concentration to dryness, the residue was diluted with methanol. The precipitate was collected by filtration, washed with methanol, and dried to give the title compound (280 mg, 0.463 mol, 82.8%) as a gray-red powder.

_{^ -NMR (300MHz, CDC1 3)} : 51.65 (6H, m), 1.78 (3H, brs), 2.03 (2H, brq, J = 7.5 Hz), 2.16 (2H, m), 2.25 (3H, s), 3.00 (2H, t, J = 7.2 Hz), 3.33 (4H, m), 6.86 (2H, d, J = 8.7 Hz), 7.75 (2H, d, J = 9.0 Hz), 9.65 (1H, brs).

Elemental _{analysis: C 24 H 27 N 4 0} 3 S 3 F 5 Calculated: C, 47.20; H, 4.46 ; N, 9.17; S, 15.75; F, 15.56 (%), Found: C, 47.13; H, 4.32; N, 9.12; S, 15.85; F, 15.57 (%) Immediate. 192.0-194.0 ° C

Example 7-125

Methyl 2-[({5,6-dimethyl-3-oxo-8-[(5,5,6,6,6-pentylfluorohexyl) sulfanyl] _2,3-dihydrido-1H-imidazo [ 5, 1-c] [1,4] thiazine-1-ylidene} amino) sulfonyl] benzoate

Synthesized in the same manner as in Examples 7-121.

The crystals were recrystallized from tetrahydrofuran-methanol to obtain dark red crystals having a melting point of 148-150 ° C.

Infrared absorption spectrum (IR) (in KBr): 3370, 3250, 3200, 2953, 1728, 1663, 1618, 1557 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 1.62-1.82 (4Η, m), 1.79 (3H, d, J = 0.9 Hz), 1.94-2.13 (2H, m), 2.29 (3H, d, J = 0.9 Hz) , 2.95 (2H, t, J = 7.2 Hz), 3.95 (3H, s), 7.56-7.62 (3H, m), 8.12-8.19 (1H, m), 9.87 (1H, bs).

Elementary analysis: as _{C 22 H 22 N 3 0 5} S 3 F 5 Calculated value (%): C, 44.07; H, 3.70; N, 7.01; S, 16.04.

 Found (%): C, 43.97; H, 3.69; N, 7.04; S, 16.20.

 Example 7-126

 4-Bumo-N- {6-ethyl-8-[(5-full-aminopentyl) sulfanyl] -5-methyl-3-o, xo-2,3-dihydro-1H-imidazo [5,1 -c] [1,4] thiazine-1-ylidene} benzenesulfonamide

To a suspension of sodium hydride (29.1 mg, 0.728 mmol) (60% oil) in tetrahydrofuran (2.00 ml) was added 1-amino-6-ethyl-8-[(5- Fluorintyl) sulfanyl] -5-methyl-3H-imidazo [5,1-c] [1,4] thiazine-3-amine (120 mg, 0.364 mmol) in tetrahydrofuran (1.00 ml) and ice Stir for 5 minutes under cooling. To this was added a solution of 4-bromobenzenesulfonyl chloride (190 mg, 0.728 mmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred at room temperature for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (180 mg, 90%) as a dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 182-184 ° C.

IR (KBr) V: 3144, 2959, 2936, 2873, 1723, 1657, 1593, 1553 cm— ¹ .

_{Ή-NMR (CDC1 3):} (51.09 (3H, t, J = 7.8 Hz), 1.48-1.62 (2H, m), 1.64-1.84 (4H, m), 2.15 (2H, q, J = 7.2 Hz) , 2.27 (3H, s), 2.98 (2H, t, J = 7.2 Hz), 4.46 (2H, dt, J = 47.4, 5.7 Hz), 7.63 (2H, d, J = 8.4 Hz), 7.83 (2H, d, J = 8.7 Hz), 9.60 (1H, bs).

 Example 7-127

 4-chloro-N- {6-ethyl-8-[(5-full-pentyl) sulfanyl] -5-methyl-3-oxo-2,3-dihydro-1H-imidazo [5,1- c] [1,4] thiazine-1-ylidene} benzenesulfonamide

To a suspension of sodium hydride (35.8 mg, 0.895 mmol) (60% oily) in tetrahydrofuran (2.00 ml) was added 1-amino-6-ethyl-8-[(5- Fluorintyl) sulfanyl] -5-methyl-3H-imidazo [5,1-c] [1,4] thiazin-3-one (160 mg, 0.448 mmol) in tetrahydrofuran (1.00 ml) and ice-cooling 5 minutes below I mixed. To this was added a solution of benzenesulfonyl chloride (189 mg, 0.895 tmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred at room temperature for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), was synthesized solvent was distilled off under reduced pressure the title compound (139 m _g, 62¾). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 174-175.

IR (KBr): 3135, 2963, 2936, 2872, 1728, 1657, 1615, 1557 cm "'.

_{Ή-NMR (CDC1 3):} (51.09 (3H, t, J = 7.5 Hz), 1.48-1.62 (2H, m), 1.64-1.84 (4H, m), 2.15 (2H, q, J = 7.5 Hz) , 2.28 (3H, s), 2.98 (2H, t, J = 7.5 Hz), 4.46 (2H, dt, J = 47.4, 5.7 Hz), 7.46 (2H, d, J = 9.0 Hz), 7.90 (2H, d, J = 8.7 Hz), 9.61 (1H, bs).

Elemental analysis: C _2. H ₂₃ N ₃ 0 ₃ S ₃ C1F

Calculated value (¾): C, 47.66; H, 4.60; N, 8.34; S, 19.08.

Found: C, 47.53; H, 4.51;, 8.16; S, 18.99.

Example 7-128

4-bromo-N- {6-butyl-8-[(5-fluoropentyl) sulfanyl] -5-methyl-3-oxo- 2,3-dihydro-1H-imidazo [5, l_c] [1, 4] thiazine-1-ylidene} benzenesulfonamide

To a suspension of sodium hydride (72.7 mg, 1.82 mrao) (60% oil) in tetrahydrofuran (6.00 ml) was added the triamino-6_butyl-8-[(5-fluoro) obtained in Example 6-28.ぺ ntyl) sulfanyl] -5-methyl-3H-imidazo [5, tric] [1,4] thiazin-3-one (325 mg, 0.909 bandol) in tetrahydrofuran (2.00 ml), and add ice-cooling Stir for 5 minutes. To this was added a solution of 4_bromobenzenesulfonyl chloride (474 mg, 1.82 imol) in tetrahydrofuran (2.00 ml), and the mixture was further stirred at room temperature for 2 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure to give the title compound (349 mg, 67¾) as a dark red crystals. The crystals were recrystallized from ethyl acetate-jetil ether to obtain dark red crystals having a melting point of 179-181 ° C.

IR (KBr) V: 3166, 2955, 2938, 2868, 1725, 1651, 1595, 1557 cm- ¹ .

Ή-NMR (CDCI3): (50.933 (3H, t, J = 7.2Hz), 1.24-1.62 (6H, m), 1.64-1.84 (4H, m), 2.12 (2H, i, J = 7.8 Hz), 2.27 (3H, s), 2.97 (2H, t, J = 7.2 Hz), 4.45 (2H, dt, J = 47.4, 5.7 Hz), 7.63 ( 2H, d, J = 8.1 Hz), 7.83 (2H, d, J = 8.7 Hz), 9.61 (1H, bs).

Elementary analysis: as _{C 22 H 27 N 3 0 3} S 3 Br

Calculated value (¾): C, 45.83; H, 4.72; N, 7.29; S, 16.68.

Found (¾): C, 45.80; H, 4.74; N, 7.16; S, 16.47.

Example 7-129

4_ black mouth -N- {6-butyl-8- [(5-fluoropentyl) sulfanyl] -5-methyl-3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-1-ylidene} benzenesulfonamide

To a suspension of sodium hydride (72.7fflg, 1.82mmo) (60 oily) in tetrahydrofuran (6.00ml) was added 1-amino-6-butyl-8-[(5-fluoro) obtained in Example 6-28. [Pentyl) sulfanyl] -5-methyl-3H-imidazo [5,1-c] [1,4] thiazin-3-one (325 mg, 0.909 mmol) in tetrahydrofuran (2.00 ml), and add ice-cooling Stir for 5 minutes. To this was added a solution of benzenesulfonyl chloride 4-chloro (384 mg, 1.82 mol) in tetrahydrofuran (2.00 mi), and the mixture was further stirred at room temperature for 2 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), was synthesized solvent was distilled off under reduced pressure the title compound (302 mg, 63%). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 173-175 ° C.

IR (KBr) v:. 3166 , 3090, 2955, 2938, 2863, 1725, 1653, 1597, 1557 cm "1 Ή-NMR (CDC1 3): 50.933 (3H, t, J = 6.9Hz), 1.25-1.62 (6H, m), 1.64-1.84 (4H, m), 2.12 (2H, ί, J = 7.5 Hz), 2.27 (3H, s), 2.97 (2H, t, J = 7.2 Hz), 4.45 (2H, dt, J = 47.4, 5.7 Hz), 7.46 (2H, d, J = 8.7 Hz), 7.91 (2H, d, J = 8.4 Hz), 9.60 (1H, bs).

Elementary analysis: as _{C 22 H 27 N 3 0 3} S 3 C1F

Calculated (%): C, 49.66; H, 5.11;, 7.90.

Found (¾): C, 49.57; H, 5.18; N, 7.77.

Example 7-130

4-chloro-N- (5,6-dimethyl-3-oxo-8-{[2- (2,2,2-trifluoroethoxy) ethy L] Sulfanyl}-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-1-ylidene Hydrogenated sodium (29.0 mg, 0.724 ramol) (60% oil) in tetrahydrofuran (2.00 ml ), The triamino-5,6-dimethyl-8-{[2- (2,2,2-trifluoroethoxy) ethyl] sulfanyl obtained in Example 6-26}- A solution of 3H-imidazo [5,1-c] [1,4] thiazin-3-one (128 mg, 0.362 mmol) in tetrahydrofuran (1.00 ml) was added, and the mixture was stirred under ice cooling for 5 minutes. To this was added a solution of 4-chlorobenzenesulfonyl chloride (153 mg, 0.724 mmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred at room temperature for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (148 mg, 11%) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 162-164 ° C.

IR (KBr) V: 3254, 2930, 1759, 1744, 1663, 1622, 1559 cm " ¹ .

_{Ή-NMR (CDC1 3):} 51.80 (3H, d, J = l.2 Hz), 2.27 (3H, d, J = 1.2 Hz), 3.19 (2H, t, J = 6.6 Hz), 3.84 (2H, t, J-6.0 Hz), 3.85 (2H, q, J = 8.7 Hz), 7.46 (2H, dt,

J = 8.7, 2.1 Hz), 7.90 (2H, dt, J = 9.0, 2.1 Hz), 9.62 (1H, bs).

Elementary analysis: as _{C 18 H 17 N 3 0 4} S 3 C1F 3

Calculated (%): C, 40.95; H, 3.25; N, 7.96; S, 18.22.

Found (%): C, 41.15; H, 3.46; N, 7.73; S, 18.16.

Example 7-131

4_bromo-N- (5,6-dimethyl-3-oxo-8-{[5- (2,2,2-trifluoroethoxy) pentyl] sulfanyl} -2,3-dihydro-1H-imidazo Example 6-29 [5, 1-c] [1,4] Thiazine-1-ylide A suspension of sodium hydride (40.5 mg, 1.01 mol) (60% oil) in tetrahydrofuran (2.00 ml) was prepared. -Amino-5,6-dimethyl-8-{[5- (2,2,2-trifluoroethoxy) pentyl] sulfanyl} -3H-imidazo [5,1-c] [1,4 ] A solution of thiazin-3-one (200 mg, 0.506 ιπιοΐ) in tetrahydrofuran (1.00 ml) was added, and the mixture was stirred for 5 minutes under ice-cooling. (1.00 ml) solution. Stir for hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure to give the title compound (220 mg, 71¾) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 172-174 ° C.

IR (KBr) V: 3227, 3086, 2930, 2868, 1759, 1665, 1622, 1559 cm " ¹ .

_{Ή-NMR (CDC1 3):} 61.44-1.82 (6H, m), 1.79 (3H, d, J = 0.6Hz), 2.27 (3H, d, J = 0.6 Hz), 2.96 (2H, t, J = 7.5 Hz), 3.61 (2H, t, J = 6.0Hz), 3.81 (2H, q, J = 8.7 Hz), 7.63 (2H, d, J = 8.7 Hz), 7.83 (2H, d, J = 8.7 Hz) , 9.60 (1H, bs).

Elemental _{analysis: C 21 H 24 N 3 0} 4 S 3 BrF 3 to

Calculated (%): C, 40.98; H, 3.93; N, 6.83; S, 15.63; F, 9.26.

Found (%): C, 41.12; H, 3.71; N, 6.92; S, 15.73; F, 8.92.

Example 7-132

4- ク 口 口 -N- (5,6-dimethyl-3-oxo-8-{[5- (2,2,2-trifluoroethoxy) pentyl] sulfanyl} -2,3-dihydro-II Example 6- Toimidazo [5,1-c] [1,4] thiazine-1-ylide A suspension of sodium hydride (36.9 mg, 0.923 mmol) (60% oil) in tetrahydrofuran (2.00 ml) was prepared. Triamino-5,6-dimethyl-8 {{[5- (2,2,2-trifluoroethyl) pentyl] sulfanyl] obtained in 29} imidazo [5, 1-c] [1, 4] A solution of thiazin-3-one (183 mg, 0.462 mmol) in tetrahydrofuran (1.00 ml) was added, and the mixture was stirred under ice-cooling for 5 minutes, followed by 4-chlorobenzenesulfonyl chloride (195 mg, 0.923 mmol) in tetrahydrofuran. (1.00 ml) was added, further stirred at room temperature for 19 hours. the reaction mixture was extracted with acetic acid Echiru by adding 1N hydrochloric acid. the extract was washed with water, dried (MgSO _4), the solvent It was evaporated under pressure to synthesize the title compound (108 mg, 41%) acetic acid Echiru -. To give a dark red crystals, mp 155-157 recrystallized from Jefferies chill ether.

 IR (KBr) V: 3235, 2940, 1759, 1663, 1622, 1559 cm—

_{Ή-NMR (CDC1 3):} 51.40-1.84 (6H, m), 1.79 (3H, d, J = 0.6 Hz), 2.27 (3H, d, J = 1.0 Hz), 2.96 (2H, t, J = 7.8 Hz), 3.61 (2H, t, J = 5.8Hz), 3.81 (2H, q, J = 8.8 Hz), 7.46 (2H, d, J = 8.4 Hz), 7.90 (2H, d, J = 8.4 Hz) , 9.59 (1H, bs). Example 7-133

4-bromo-N- (5,6-dimethyl-3-oxo-8-{[4- (2,2,2-trifluoroethoxy) butyl] sulfanyl} -2,3-dihydro-1H-imidazo [5, 1-c] [1,4] thiazine-1-ylide A suspension of sodium hydride (37.8 mg, 0.944 tmol) (60% oil) in tetrahydrofuran (2.00 ml) was prepared in Example 6-30. -5,6-dimethyl-8- {[4- (2,2,2-trifluoroethoxy) butyl] sulfanyl} -3H-imidazo [5,1-c] [1,4] A solution of thiazin-3-one (180 mg, 0.472 marl) in tetrahydrofuran (1.00 ml) was added, and the mixture was stirred under ice-cooling for 5 minutes, and mixed with 4-bromobenzenesulfonyl chloride (246 mg, 0.944 mmol) in tetrahydrofuran (1.00 ml). ml) was added and further extracted with acetic Echiru by adding 1N hydrochloric acid. the reaction mixture was stirred for 18 hours at room temperature. the extract was water washed, dried (MgSO _4), of the solvent under reduced pressure And removed by to give the title compound (196 mg, 69%) as a dark red crystalline acetate Echiru -. Jechirue was recrystallized from a ether to give a dark red crystals, mp 154_156 ° C.

IR (KBr) v: 3183, 3063, 2934, 1757, 1663, 1622, 1559 cm— ¹ .

_{Ή-NMR (CDC1 3):} δ 1.64-1.90 (4Η, m), 1.79 (3H, s), 2.27 (3H, s), 2.99 (2H, t, J = 7.0 Hz), 3.63 (2H, t, J = 5.8 Hz), 3.81 (2H, q, J = 8.8 Hz), 7.63 (2H, d, J = 8.8 Hz), 7.83 (2H, d, J = 8.8 Hz), 9.60 (1H, bs).

Elemental analysis: C _{2. H 21 N 3 0 4 S 3} BrF 3 to

Calculated value (%): C, 40.00; H, 3.52; N, 7.00; S, 16.02.

Found (%): C, 40.13; H, 3.53; N, 7.01; S, 16.01.

Example 7-134

4-chloro-N- (5,6-dimethyl-3-oxo-8-{[4- (2,2,2-trifluoroethoxy) butyl] sulfanilto 2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylide sodium hydride (29.8 mg, 0.74 ol) (60% oil) in tetrahydrofuran (2.00 ml) was added to a suspension of Example 6-30. -5,6-Dimethyl-8-{[4- (2,2,2-trifluoroethoxy) butyl] sulfanyl} -3H-imidazo [5, tric] [1,4] A solution of thiazin-3-one (141 mg, 0.372 tmol) in tetrahydrofuran (1.00 ml) was added. The mixture was stirred for 5 minutes under ice cooling. To this was added a solution of benzenesulfonyl chloride (157 mg, 0.744 bandol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred at room temperature for 18 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was water washed, dried (MgSO ₄₎ After the solvent was distilled off under reduced pressure to give the title compound (38.0 mg, 18¾) was form if the. The crystals were recrystallized from ethyl acetate-getyl ether to give dark red crystals with a melting point of 131-133 ° C.

IR (KBr): 3229, 3092, 2932, 2876, 1759, 1663, 1622, 1559 cm " ¹ .

_{ΐ-NMR (CDC1 3):} 51.62-1.90 (4H, m), 1.79 (3H, d, J = 1.0 Hz), 2.27 (3H, d, J = 0.6 Hz), 2.99 (2H, t, J = 7.0 Hz), 3.63 (2H, t, J = 5.8Hz), 3.81 (2H, q, J-8.8 Hz), 7.46 (2H, d, J-8.6 Hz), 7.90 (2H, d, J = 8.Hz) ), 9.59 (1H, bs).

Elemental _{analysis: C 2Q H 21 N 3 0} 4 S 3 C1F 3 to

Calculated value (¾): C, 43.20; H, 3.81; N, 7.56; S, 17.30.

Found (¾): C, 43.19; H, 3.51; N, 7.36; S, 17.27.

Example 7-135

4-bromo-N- {8-[(4,4-difluorocyclohexyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1 , 4] Thiazine-1-ylidene} benzenesulfonamide

 To a suspension of the compound obtained in Example 6-31 (85 mg, 0.246 mmol) in THF (2.5 ml) was added sodium hydride powder (purity 60%, 24.6 mg, 0.615 mmol) at room temperature for 30 min. After the stirring, Shiojiri 4_bromobenzenesulfonyl (75. '5 mg, 0.295 t ol) was added, and the mixture was further stirred for 50 minutes. Methanol (1 ml) and IN hydrochloric acid (0.7 ml) were added to the reaction solution, and the mixture was extracted with ethyl acetate (25 ml). The organic layer was washed with water and saturated saline, and then dried over sodium sulfate. After concentration to dryness, the residue was diluted with methanol. The precipitate was collected by filtration, washed with methanol, and dried to give the title compound (134 mg, 0.237 mol, 96.5%) as a purple powder.

_{Ή-NMR (300MHz, CDC1 3} ): 31.81 (3H, s), 1.83 (4H, m), 2.13 (4H, brd, J = 9.6 Hz), 2.27 (3H, brs), 3.49 (1H, m), 7.64 (2H, dt, J = 8.4, 1.5 Hz), 7.83 (2H, dt, J = 8.1, 1.2 Hz), 9.64 (1H, brs) '.

Elemental analysis: C _2. H _2. Calculated for N ₃ 0 ₃ S ₃ BrF ₂ : C, 42.55; H, 3.57; N, 7.44; S, 17.04 (%), Found: C, 42.72; H, 3.57; N, 7.42; S, 17.17 (%). Immediate. 194.0-195. O

Example 7-136

 4-Bumo-N- (8-{[(4,4-difluorocyclohexyl) methyl] sulfanyl} -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5 [1,4] thiazine-1-ylide Sodium hydride was added to a suspension of the crude compound (purity 80%, 123 mg, 0.278 mmol) of the compound obtained in Example 6-32 in THF (2.5 ml). Was added at room temperature, stirred for 10 minutes, added with 4-bromobenzenesulfonyl chloride (92 mg, 0.361 mmol), and further stirred for 60 minutes. 1 ml) and 1N hydrochloric acid (1.0 ml), diluted with methanol-water (1: 1, 5 ml) and stirred for 30 minutes The precipitate was collected by filtration, washed with methanol-water (1: 1) and methanol After drying, the title compound (118 mg, 0.204 mmol, 73.4%) was obtained as a red powder.

_{¾-NMR (200MHz, CDC1 3} ): 61.34 (2H, brq, J = 13.6 Hz), 1.60 (2H, m), 1.71 (2H, m), 1.80 (3H, q, J = 1.2 Hz), 1.91 ( 2H, brd, J = 13.4 Hz), 2.12 (2H, m), 2.27 (3H, q, J = 1.0 Hz), 2.87 (2H, d, J = 6.6 Hz), 7.62 (2H, dt, J = 8.8 , 2.0 Hz), 7.83 (2H, d, J = 8.8 Hz), 9.63 (1H, brs).

Elemental analysis: Calculated for C ₂₁ H ₂₂ N ₃ 0 ₃ S ₃ BrF ₂ : C, 43.60; H, 3.83; N, 7.26; S, 16.63; Br, 13.81; F, 6.57 (%), found: C, 43.82; H, 3.87; N, 7.30; S, 16.66; Br, 15.80; F, 5.91 (%).

mp. 207.5-208.0 ° C

Example 7-137

 3-bromo-N- {5,6-dimethyl-3-oxo-8-[(5-fluoropentyl) sulfanyl] -2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine -1_ylidene} benzenesulfonamide

To a suspension of sodium hydride (50.7 mg, 1.27 mmol) (60% oily) in tetrahydrofuran (2.00 ml) was added the triamino-5,6-dimethyl-8-{[2 -(5-Fluoroyloxy) ethyl] sulfanyl} 3H-imidazo [5,1-c] [1,4] thiazin-3-one (200 mg, 0.634 bandol ol) in tetrahydrofuran (1.00 ml) Add the solution, The mixture was stirred for 5 minutes under ice cooling. To this was added a solution of 3-bromobenzenesulfonyl chloride (324 mg, 1.27 mmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred at room temperature for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure to give the title compound (329 mg, 97¾) as a dark red crystals. Recrystallization from ethyl acetate-ethyl ether gave a dark red crystal with a melting point of 144-U6 ° C.

IR (KBr) V:. 3225 , 3065, 2961, 2932, 2859, 1755, 1663, 1618, 1559 cm '1 Ή-NMR (CDC1 3): δ 1.48-1.62 (2Η, m), 1.62-1.84 (4H , m), 1.80 (3H, d, J = 1.2 Hz), 2.28 (3H, d, J = 1.2 Hz), 2.99 (2H, t, J = 7.2 Hz), 4.46 (2H, dt, J = 47.1, 6.0 Hz), 7.37 (1H, t, J = 7.8 Hz), 7.65-7.70 (1H, m), 7.8-7.92 (1H, m), 8.14 (1H, t, J = 1.8 Hz), 9.58 (1H, bs).

Elementary analysis: as _{C 19 H 21 N 3 0 3} S 3 BrF

Calculated (¾): C, 42.70; H, 3.96; N, 7.86; S, 18.00; Br, 14.95.

Found (%): C, 43.10; H, 3.84; N, 7.89; S, 17.86; Br, 14.72.

Example 7-138 "

 2-Bromo-N_ {5,6-dimethyl-3oxo_8-[(5_fluoropentyl) sulfanyl] -2,3-dihydrido-1H-imidazo [5,1-c] [1,] thiazine-1 -Ylidene} benzenesulfonamide

To a suspension of sodium hydride (50.7 mg, 1.27 mmol) (60% oil) in tetrahydrofuran (2.00 ml) was added the triamino-5,6-dimethyl-8-{[2 -(5-Fluoropentyloxy) ethyl] sulfanyl}-3H-imidazo [5,1-c] [1,4] thiazin-3-one (200 mg, 0.63 thigh) of tetrahydrofuran (1.00 ml) The solution was added, and the mixture was stirred under ice cooling for 5 minutes. To this was added a solution of 2-bromobenzenesulfonyl chloride (331 mg, 1.27 mmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred at room temperature for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure to give the title compound (258 mg, 76¾) as a dark red crystals. Recrystallization from ethyl acetate-ethyl ether afforded dark red crystals, mp 182-184.

IR (KBr) Re: 3260, 2959, 2938, 2859, 1744, 1725, 1661, 1609, 1553 cm " ¹ . ¾-NMR (CDCI3): δ 1.42-1.60 (2H, m), 1.60-1.78 (4H, m), 1.80 (3H, d, J = 0.9 Hz), 2.30 (3H, d, J = 0.6 Hz), 2.94 (2H, i, J = 7.5 Hz), 4.43 (2H, dt, J = 47.4, 6.0 Hz), 7.46 (1H, dt, J = 7.5, 1.2 Hz), 7.72 (1H, dd, J = 7.5, 1.2 Hz), 8.23 (2H, dd, J = 7.8, 1.8 Hz), 9.72 (1H, bs).

Example 7-139

 4-bromo-N- {5,6-dimethyl-3-oxo-8-[(5-fluoroopentyl) sulfanyl] -2,3-dihydro-1H-imidazo [5,1-c] [1, 4] Thiazine-1-ylidene}-2-fluorobenzensulfonamide '

To a suspension of sodium hydride (50.7 mg, 1.27 t ol) (60% oil) in tetrahydrofuran (2.00 ml) was added triamino-5,6-dimethyl-8-{[obtained in Example 6-23. 2- (5-Fluoropentyloxy) ethyl] sulfanyl} _3H-imidazo [5,1-c] [1,4] thiazin-3-one (200 mg, 0.634 mmol) in tetrahydrofuran (1.00 ml) And stirred under ice cooling for 5 minutes. To this was added a solution of 4-promo-2-fluorobenzenesulfonyl chloride (347 mg, 1.27 mol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred at room temperature for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure to give the title compound (176 mg, 50¾) as a dark red crystals. Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 158-160 ° C.

IR (KBr) Re: 3241, 3096, 2936, 2863, 1728, 1661, 1609, 1590, 1553 cm— ^1. Ή-NR (CDC "): δ 1.42-1.88 (6Η, m), 1.81 (3H, s ), 2.30 (3H, d, J = 0.6 Hz), 2.95 (2H, t, J = 7.4 Hz), 4.44 (2H, dt, J = 47.2, 6.0 Hz), 7.37 (1H, dd, J = 9.0, 1.6 Hz), 7.42 (1H, d, J = 8.6 Hz), 7.86 (1H, t, J = 8.0 Hz), 9.69 (1H, bs). Elemental analysis: C ₁₉ .N ₃ 0 ₃ S ₃ BrF ₂ As

Calculated (¾): C, 41.31; H, 3.65; N, 7.61; S, 17.41; Br, 14.46.

Found (¾): C, 41.41; H, 3.91;, 7.83; S, 17.50; Br, 14.60.

Example 7-140

5-bromo-N- {5,6-dimethyl-3-oxo-8-[(5-fluoropentyl) sulfanyl] -2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine -1-yridident 2-methoxybenzenesulfonamide To a suspension of sodium hydride (50.7 mg, 1.27 tmol) (60% oil) in tetrahydrofuran (2.00 ml) was added the triamino-5,6-dimethyl-8- {obtained in Examples 6 to 23. [2- (5-Fluoropentyloxy) ethyl] sulfanyl} -3H-imidazo [5,1-c] [1,4] thiazin-3-one (200 mg, 0.634 mmol) in tetrahydrofuran ( 1.00 ml) solution and stirred under ice cooling for 5 minutes. To this was added a solution of 5-bromo-2-methoxybenzenesulfonyl chloride (369 mg, 1.27 bandol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred at room temperature for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (289 mg, 81%) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 173-175.

I (KBr) V: 3243, 2942, 2849, 1719, 1661, 1613, 1553 cm- ¹ .

_{Ή-NMR (CDC1 3):} 51.40-1.85 (6H, m), 1.81 (3H, d, J = 1.0 Hz), 2.31 (3H, d, J = 1.2 Hz), 2.93 (2H, t, J = 7.6 Hz), 3.88 (3H, s), 4.43 (2H, dt, J = 47.2, 6.0 Hz), 6.87 (1H, d, J = 8.8 Hz), 7.60 (1H, dd, J = 8.8, 2. Hz) , 8.17 (1H, d, J = 2.6 Hz), 9.80 (1H, bs).

Elemental analysis: C _2. As _{H 23 N 3 0 4 S 3} BrF

Calculated (%): C, 42.55; H, 4.11;, 7.44; S, 17.04; Br, 14.15.

Found (¾): C, 42.68; H, 4.20; N, 7.57; S, 17.03; Br, 14.35.

Example 7-141

5 _ {[1-({[4- (Acetylamino) phenyl] sulfonyl} imino)-5, 6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazin-8-yl] sulfanyl} pentanoate

To a suspension of sodium hydride (203 mg, 5.06 thigh 01) (60% oily) in tetrahydrofuran (12.0 ml) was added the ethyl 5_ [1-amino-5,6-dimethyl- obtained in Example 6-24. Add 3-oxo-3H-imidazo [5,1-c] [1,4] thiazin-8-yl] sulfanyl} pentanoate (1.00 g, 2.81 awake ol) in tetrahydrofuran (4.00 il), and cool with ice. Stir for 5 minutes below. To this was added a solution of 4- (acetylamino) benzenesulfonyl chloride (1.18 g, 5.06 mmol) in tetrahydrofuran (4.00 ml), and the mixture was further stirred at room temperature for 18 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (219 mg, 14%) as a dark red crystals. Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 178-180 ° C.

IR (KBr) V:. 3272 , 2984, 2936, 1728, 1661, 1593, 1557, 1532, 1501 cm "1 ^ -NMR (CDC1 3): 61.27 (3H, t, J = 7.0 Hz), 1.66-1.86 (4H, m), 1.79 (3H, d, J = 0.8 Hz), 2.21 (3H, s), 2.26 (3H, s), 2.28-2.38 (2H, m), 2.90-3.00 (2H, m), 4.14 (2H, q, J = 6.6 Hz), 7.49 (1H, bs), 7.64 (2H, d, J = 8.8 Hz), 7.91 (2H, d, J = 8.6 Hz), 9.58 (1H, bs).

Elementary analysis: as _{C 23 H 29 N 4 0 6} S 3

Calculated (%): C, 49.89; H, 5.28; N, 10.12; S, 17.37.

Found (¾): C, 49.66; H, 5.13; N, 9.90; S, 17.28.

Example 7-142

4-Bumo-N- {5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1 , 4] Thiazine-1-ylidene} -2_Trifluoro sodium hydride (50.7 mg, 1.27 benzyl) (60% oil) in a suspension of tetrahydrofuran (2.00 ml) in Example 6-23. Amino-5,6-dimethyl-8-{[2- (5-fluoropentyloxy) ethyl] sulfanyl} -3H-imidazo [5,1-c] [1,4] thiazin-3-one ( A solution of 200 mg (0.634 mmol) in tetrahydrofuran (1.00 ml) was added, and the mixture was stirred under ice cooling for 5 minutes. To this was added a solution of 4-bromo-2-trifluoromethoxybenzenesulfonyl chloride (431 mg, 1.27 bandol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred at room temperature for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), and the solvent was evaporated under reduced pressure to give the title of compound a (306 mg, 78%) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 139-U1 ° C.

IR (KBr) V: 3196, 2938, 2863, 1740, 1665, 1611, 1557 cm- ¹ .

Ή-NMR (CDCI3): δ 1.46-1.60 (2Η, m), 1.60-1.78 (4H, m), 1.81 (3H, d, J = 1.2 Hz), 2.30 (3H, d, J = 1.2 Hz), 2.94 (2H, t, J = 7.5 Hz), 4.43 (2H, dt, J = 47.1, 6.0 Hz), 7,50-7.58 (2H, m), 8.00 (1H, d, J = 8.1 Hz), 9.75 (1H, bs). Elemental analysis: C _2Q II. N ₃ 0 ₄ S _{3 As} BrF ₄

Calculated (%): C, 38.84; H, 3.26; N, 6.79; S, 15.55; Br, 12.92.

Observed (: C, 39.02; H, 3.19; N, 6.77; S, 15.63; Br, 13.08.

Example 7-143

4-Promo-N- [5,6-dimethyl-3-oxo-8- (pentylsulfanyl) -2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine- Ilidene] benzenesulfonamide

To a suspension of sodium hydride (592 mg, 14.8 thigh 01) (60% oily) in tetrahydrofuran (30.0 ml) was added 1-amino-5,6-dimethyl-8- (obtained in Example 6-1. A solution of (pentylsulfanyl) -3H-imidazo [5, tric] [1,4] thiazin-3-one (2.20 g, 7.40 mmol) in tetrahydrofuran (5.00 ml) was added, and the mixture was stirred under ice cooling for 5 minutes. To this was added a solution of 4-bromobenzenesulfonyl chloride (1.28 g, 7.21 mol) in tetrahydrofuran (5.00 ml), and the mixture was further stirred at room temperature for 1.5 hours. Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (3.43g, 90¾) as a dark red crystals. Recrystallization from ethyl acetate-ethyl ether gave dark red crystals, mp 176-178.

I (KBr) V: 3223, 2957, 2928, 2861, 1759, 1663, 1622, 1559 cm " ¹ .

_{Ή-NR (CDC1 3):} 30.917 (3H, t, J = 6.9Hz), 1.29-1.44 (4H, m), 1.69 (2H, quint, J = 8.1 Hz), 1.79 (3H, d, J = 0.9 Hz), 2.27 (3H, d, J = 0.9 Hz), 2.94 (2H, t, J = 7.8 Hz), 7.63 (2H, dt, J = 9.0, 2.1 Hz), 7.84 (2H, dt, J = 8.7 , 1.8 Hz), 9.60 (1H, bs).

Elementary analysis: as _{C 19 H 22 N 3 0 3} S 3 Br

Calculated (%): C, 44.18; H, 4.29; N, 8.14; S, 18.62; Br, 15.47.

Found (%): C, 44.13; H, 4.20; N, 8.12; S, 18.44; Br, 15.41.

Example 7-144

4-N- [5,6-dimethyl-3-oxo-8- (pentylsulfanyl) -2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine -Triylidene] benzenesulfonamide

To a suspension of sodium hydride (172 mg, 4.30 band01) (60% oil) in tetrahydrofuran (8.00 ml) was added the triamino-5,6-dimethyl-8- (pentylus) obtained in Example 6-1. Ruphanyl) -3H-imidazo [5,1-c] [1,4] thiazin-3-one (640 mg, 2.15 mmol) A solution of tetrahydrofuran (2.00 ml) was added, and the mixture was stirred under ice cooling for 5 minutes. To this was added a solution of benzenesulfonyl chloride (908 mg, 4.30 ol) in tetrahydrofuran (2.00 ml), and the mixture was further stirred at room temperature for 4 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was evaporated reduced pressure to give the title compound (396 mg, 39%) as a dark red crystals. The crystals were recrystallized from ethyl acetate-getyl ether to give reddish crystals having a melting point of 172-174 ° C.

IR (KBr) V: 3225, 2959, 2930, 2863, 1759, 1665, 1622, 1561 cm " ¹ .

_{Ή-NMR (CDC1 3):} «50.916 (3H, t, J = 7.2 Hz), 1.30-1.44 (4H, m), 1.68 (2H, quint, J = 7.5 Hz), 1.80 (3H, d, J = l.2 Hz), 2.28 (3H, d, J = 0.9 Hz), 2.95 (2H, t, J = 7.8 Hz), 7.46 (2H, dt, J = 9.0, 2.1 Hz), 7.91 (2H, dt, J = 9.0, 2.1 Hz), 9.60 (1H, bs).

Elemental analysis: C ₁₉ H ₂₂ N ₃ 0 ₃ S ₃ C1

Calculated value (%): C, 48.34; H, 4.70; N, 8.90; S, 20.38.

Found (¾): C, 48.17; H, 4.72 ;. N, 8.68; S, 20.46.

Example 7-145

 4-Bromo-N- (5,6-dimethyl-8-{[2- (5-fluoropentyloxy) ethyl] sulfanyl} -3- 3-year-old oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene) benzenesulfonamide

To a suspension of hydrogenated sodium (87.7 mg, 2.19 mmol) (60 free) in tetrahydrofuran (4.00 ml) was added the triamino-5,6-dimethyl-8-{[2 -(5-Fluorobenzoyloxy) ethyl] sulfanyl} imidazo [5,1-c] [1,4] thiazin-3-one (427 mg, 1.10 t) in tetrahydrofuran (2.00 ml) And stirred under ice-cooling for 5 minutes. To this was added a solution of 4-bromobenzenesulfonyl chloride (572 mg, 2.19 mmol) in tetrahydrofuran (2.00 ml), and the mixture was further stirred at room temperature for 18 hours. IN hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (245 mg, 39%) as a dark red crystals. The crystals were recrystallized from ethyl acetate-getyl ether to give dark red crystals with a melting point of 130-132 ° C. .

IR (KBr): 3235, 3088, 2936, 2865, 1759, 1663, 1620, 1557 cm— ¹ . Ή-NMR (CDCI3): δ 1.40-1.85 (6Η, m), 1.80 (3Η, d, J = 0.8 Hz), 2.27 (3H, d, J = 1.0 Hz), 3.16 (2H, t, J = 6.6 Hz), 3.47 (2H, t, J-6.2Hz), 3.64 (2H, t, J = 6.6 Hz), 4.45 (2H, dt, J = 47.4, 6.0 Hz), 7.62 (2H, d, J = 8.8 Hz), 7.83 (2H, d, J = 8.8 Hz), 9.60 (1H, bs).

Elementary analysis: as _{C 21 H 25 N 3 0 4} S 3 BrF

Calculated (¾): C, 43.60; H, 4.36; N, 7.26; S, 16.63; Br, 13.81.

Found (%): C, 43.34; H, 4.20; N, 7.50; S, 16.76; Br, 13.91.

Example 7-146

 2-[({5,6-dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -2,3-dihydro-1H-imidazo [5, 1-c] [1,4] thiazine-1-ylidene} amino) sulfonyl] benzoic acid

 It was synthesized in the same manner as in Example 7-145, and recrystallized from tetrahydrofuran-methanol to obtain dark red crystals having a melting point of 152-154 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3400-2300, 3260, 2922, 1748, 1705, 1667, 1620, 1615, 1551 cm—

lH-NMR (CDCI3): δ 1.65-1.87 (4Η, m), 1.79 (3H, s), 1.97-2.16 (2H, m), 2.28

(3H, d, J = 0.9 Hz), 2.98 (2H, t, J = 6.9 Hz), 7.62-7.70 (2H, m), 7.90-7.96 (1H, m), 8.10-8.18 (1H, m), 9.85 (1H, bs).

Elemental analysis: as C ₂₁ H _2D N ₃ 0 ₅ S ₃ F ₅

Calculated value (%): C, 43.07; H, 3.44; N, 7.18; S, 16.43.

Found (%): C, 42.75; H, 3.53; N, 7.08; S, 16.34.

Example 7-148

 4-Bumo-N- (5,6-dimethyl-8-{[2- (4-fluorobutoxy) ethyl] sulfanyl} -3-oxo-2,3-dihydro-1H-imidazo [5, tric ] [1,4] thiazine-1-ylidene) benzenesulfonamide

To a suspension of sodium hydride (31.2 mg, 0.779 mmol) (60% oil) in tetrahydrofuran (2.00 ml) was added the triamino-5,6-dimethyl_8-{[obtained in Example 6-33. 2- (4-Fluorobutoxy) ethyl] sulfanyl} -3H-imidazo [5,1-c] [1,4] thiazine-3-one (135 mg, 0.390 mmol) in tetrahydrofuran (1.00 ml) And cool under ice 5 Stir for a minute. To this was added a solution of 4-bromobenzenesulfonyl chloride (223 mg, 0.779 mmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred at room temperature for 5 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), obtained by the solvent evaporated under reduced pressure to give the title compound (143 mg, 65¾) and a dark red crystals. The crystals were recrystallized from ethyl acetate-getyl ether to give dark red crystals with a melting point of 132-134 ° C.

IR (KBr) V: 3245, 3085, 2961, 2863, 1759, 1663, 1622, 1559 cm " ¹ .

_{[H-NMR (CDC1 3)} : δ 1.66 - 1.78 (4Η, m), 1.80 (3H, d, J = 1.2 Hz), 2.27 (3H, d, J = 1.2 Hz), 3.16 (2H, t, J = 6.3Hz), 3.50 (2H, t, J = 5.7 Hz), 3.65 (2H, t, J = 6.3 Hz), 4.46 (2H, dt, J = 47.4, 6.0 Hz), 7.63 (2H, d, J = 8.7 Hz), 7.83 (2H, d, J = 8.4 Hz), 9.60 (1H, bs).

Example 7-149

N- {5,6-Dimethyl-8-[(5_fluoromethylpentyl) sulfanyl] -3-oxo-2,3-dihidido-1H-imidazo [5, lc] [1,4] thiazine-1 -Ylidene} -3-pyridinesulfonamide To a suspension of sodium hydride (288 mg, 7.21 maraudal 01) (60% oil) in tetrahydrofuran (15.0 ml) was added the toamino-5, obtained in Example 6-23. 6-Dimethyl-8-{[2- (5-fluoropentyloxy) ethyl] sulfanyl} -3H-imidazo [5,1-c] [1,4] thiazine_3-one (1.02 g, 3.23 mmol ) In tetrahydrofuran (5.00 ml) and stirred for 5 minutes under ice-cooling. A solution of 3-pyridinesulfonyl chloride (1.28 g, 7.21 mmol) obtained in Method B of Reference Example 45 in tetrahydrofuran (2.00 ml) was added thereto, and the mixture was further stirred at room temperature for 16 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (1.11 g, 75%) as a dark red crystals. The crystals were recrystallized from ethyl acetate-getyl ether to obtain dark red crystals having a melting point of 135-137.

IR (KBr) v: 2963, 2938, 2863, 1746, 1663, 1607, 1557 cm ¹ .

_{Ή-NMR (CDC1 3):} δ 1.48-1.64 (2H, m), 1.64-1.84 (4Η, m), 1.81 (3H, d, J = 0.9 Hz), 2.29 (3H, d, J = 1.2 Hz) , 2.98 (2H, t, J = 7.8 Hz), 4.46 (2H, dt, J = 47., 5.7 Hz), 7.45 (1H, ddd, J = 8.1, 4.8, 0.6 Hz), 8.25 (1H, ddd, J = 7.8, 2.1, 1.5 Hz), 8.78 (lH, dd, J = 5.1, 1.8 Hz), 9.20 (1H, dd, J = 2.4, 0.6 Hz), 9.63 (1H, bs).

Elemental analysis: as C ₁₈ H ₂₁ N ₄ 0 ₃ S ₃ F ₄

Calculated value (%): C, 47.35; H, 4.64; N, 12.27; S, 21.07.

Obtained): C, 47.51; H, 4.69; N, 12.14; S, 21.25.

Example 7-150

 4-bromo_N- (5,6-dimethyl-8-{[2- (3-fluoropropoxy) ethyl] sulfanilto 3-oxo-2,3-dihydro-1H-imidazo [5,1-c ] [1,4] thiazine-1-ylidene) benzenesulfonamide

To a suspension of sodium hydride (43.8 mg, 1.09 acetyl) (60% oil) in tetrahydrofuran (2.00 ml) was added 1-amino-5,6-dimethyl_8-{[obtained in Example 6-36. 2- (3-Fluoropropoxy) ethyl] sulfanyl} -3H-imidazo [5,1-c] [1,4] thiazine-3-amine (181 mg, 0.547 mmol) in tetrahydrofuran (l.OO ml ) The solution was added and stirred for 5 minutes under ice cooling. To this was added a solution of 4-bromobenzenesulfonyl chloride (285 mg, 1.09 tmol) in tetrahydrofuran (l.OOml), and the mixture was further stirred at room temperature for 2 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (GS0 _4), solvent was obtained as a dark red crystalline title compound was distilled off (128 mg, 43%) under reduced pressure. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 122-124 ° C.

IR (KBr) V: 3223, 3094, 2868, 1759, 1665, 1620, 1561 cm- ¹ .

_{Ή-NMR (CDC1 3):} (51.80 (3H, d, J = 0.9 Hz), 1.95 (2H, dt, J = 26.4, 5.7 Hz),

2.27 (3H, d, J = 0.9 Hz), 3.17 (2H, t, J = 6.3 Hz), 3.58 (2H, t, J = 6.0 Hz), 3.67

(2H, t, J = 6.3 Hz), 4.54 (2H, dt, J = 47.1, 6.6 Hz), 7.63 (2H.dt, J = 8.4, 1.5

Hz), 7.83 (2H, dt, J = 8.7, 1.8 Hz), 9.60 (1H, bs).

Elementary analysis: as _{C 19 H 2l N 3 0 4} S 3 BrF

Calculated (%): C, 41.45; H, 3.85; N, 7.63; S, 17.47; Br, 14.52.

Found (%): C, 41.36; H, 3.85; N, 7.55; S, 17.59; Br, 14.44.

Example 7-151

4-Buguchi-N- (5,6-dimethyl-8-{[2- (2-fluoroethoxy) ethyl] sulfani} -3-oxo-2,3_dihydro-1H-imidazo [5,1-c ] [1,4] thiazine-1-ylidene) be Nzensulfonamide

To a suspension of sodium hydride (63.0 mg, 1.58 ol) (60% oil) in tetrahydrofuran (2.00 ml) was added the triamino-5,6-dimethyl-8-{[obtained in Example 6-43. 2- (2-Fluoroethoxy) ethyl] sulfanyl} -3H-imidazo [5,1-c] [1,]] thiazin-3-one (250 mg, 0.788 ol) in tetrahydrofuran (1.00 ml) was added. The mixture was stirred for 5 minutes under ice cooling. To this was added a solution of 4-bromobenzenesulfonyl chloride (411 mg, 1.58 alcohol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred at room temperature for 6 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), obtained by the solvent evaporated under reduced pressure to give the title compound (131 mg, 31¾) and a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 159-161 ° C.

IR (KBr): 3218, 2930, 1757, 1663, 1622, 1559 cm " ¹ .

_{Ή- NMR (CDC1 3): (} 51.80 (3H, s), 2.27 (3H, s), 3.19 (2H, t, J = 6.6 Hz), 3.73 (2H, dt, J = 30.8, 4.4 Hz), 3.75 (2H, t, J = 6.6 Hz), 4.56 (2H, dt, J = 47.6, 3.6 Hz), 7.63 (2H, d, J = 8.8 Hz), 7.84 (2H, dt, J = 8.Hz), 9.59 (1H, bs) Elementary analysis:. a C _{〖8 H 19 N 3 0 4 S} 3 BrF

Calculated (¾): C, 40.30; H, 3.57; N, 7.83; S, 17.93; Br, 14.89.

Found (%): C, 40.42; H, 3.57; N, 8.04; S, 17.88; Br, 14.96.

Example 7-152

tert-butyl 3-{[(([[4- (acetylamino) phenyl] sulfonyl} imino))-5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c ] [1,4] thiazine-8-yl] sulfanyl} propyl carbamate

Sodium hydride (purity 60%, 105 mg, 2.63 mmol) was added to a suspension of the compound obtained in Example 6-38 (337 mg, 0.876 mol) in THF (8 ml) at room temperature, and the mixture was stirred for 10 minutes. Thereafter, 4-acetamidobenzenesulfonyl chloride (253 mg, 1.05 mmol) was added, and the mixture was further stirred for 2.5 hours. Methanol (1 ml) and 1N hydrochloric acid (3.0 ml) were added to the reaction solution, and the mixture was stirred for 10 minutes. The precipitate was collected by filtration, washed with methanol-water (1: 1) and methanol, and dried to give the title compound (309 mg, 0.531 mmol, 60.6%) as a purple powder. Ή-thigh (200MHz, CDCI3): δ 1.45 (9H, s), 1.78 (3H, brs), 1.85 (2H, quint, J = 7.1 Hz), 2.21 (3H, s), 2.26 (3H, s), 2.95 (2H, t, J = 7.4 Hz), 3.18 (2H, q, J = 7.0 Hz), 4.66 (1H, m), 7.59 (1H, brs) 7.64 (2H, d, J- 8.8 Hz), 7.90 (2H, d, J = 8.4 Hz), 9.59 (1H, brs).

Elemental _{analysis: C 24 H 31 N 5 0} 6 S 3 Calculated: C, 49.55; H, 5.37 ; N, 12.04; S, 16.54 (%), Found: C, 49.55; H, 5.55 ; N, 11.92; S, 16.44 (%).

mp. 170.5-173. Ot:

Example 7-153

 N- {5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine- 1-ylidene}-4-vinylbenzenesulfonamide

To a suspension of sodium hydride (50.7 rag, 1.27 thigh 01) (60% oily) in tetrahydrofuran (2.00 ml) was added 1-amino-5,6-dimethyl-8- [obtained in Example 6-23. (5-Fluo-pentyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (200 mg, 0.634 tmol) in tetrahydrofuran (1.00 ml) and ice-cooled Stir for 5 minutes below. To this was added a solution of 4-vinylbenzenesulfonyl chloride (249 mg, 1.14 删 ο1) in tetrahydrofuran (1.00 ml), and the mixture was further stirred at room temperature for 2 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (258 mg, 85%) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 182_184.

IR (KBr): 3235, 2961, 2936, 2861, 1753, 1663, 1620, 1557 cm- ¹ .

_{Ή- NMR (CDC1 3): δ} 1.48-1.62 (2Η, m), 1.62-1.82 (4H, m), 1.79 (3H, d, J = 0.9 Hz), 2.27 (3H, d, J = 1.2 Hz) , 2.96 (2H, t, J = 7.5 Hz), 4.45 (2H, dt, J = 47., 6.0 Hz), 5.41 (1H, d, J = 10.8Hz), 5.87 (1H, d, J = 17. Hz), 6.74 (1H, dd, J = 17.4, 10.5 Hz), 7.51 (2H, d, J = 8.4 Hz), 7.92 (2H, d, J = 8.4 Hz), 9.63 (1H, bs). 7-154

[(1R, 4S) -7,7-dimethyl-2-oxobisic mouth [2,2,1] hept-1-yl] -N- {5,6-dimethyl-8-[(5-fluoropentyl) Sulfanyl] -3-oxo-2,3-dihydro-m-imidazo [5,1-c] [1,4] thiazine-1-ylidene} methanesulfonamide To a suspension of sodium hydride (50.7 mg, 1.27 leak 1) (60% oil) in tetrahydrofuran (2.00 ml) was added the triamino-5,6-dimethyl-8-[(obtained in Example 6-23. 5-Fluoropentyl) sulfanyl] -3H-imidazo [5, tric] [1,4] thiazin-3-one (200 mg, 0.634 mol) in tetrahydrofuran (1.00 ml) was added, and the mixture was cooled under ice-cooling. Stir for a minute. To this was added a solution of 10-(-)-camphorsulfonyl chloride (286 mg, 1.14 oi) in tetrahydrofuran (1.00 ml), and the mixture was further stirred at room temperature for 2.5 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure to give the title compound (205 mg, 61¾) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 161-163 ° C.

 IR (KBr) Les: 3204, 2957, 1744, 1665, 1617, 1568 cm— '.

_{Ή-NMR (CDC1 3):} (50.867 (3H, s), 1.10 (3H, s), 1.35-2.15 (11H, m), 1.80 (3H, s), 2.29 (3H, s), 2.28-2.45 ( 1H, m), 2.45-2.64 (1H, m), 2.98 (2H, t, J = 7.4 Hz), 3.07 (1H, d, J = 14.6 Hz), 3.62 (1H, d, J = 14.6 Hz), 4.46 (2H, dt, J = 47.2, 5.6 Hz), 9.77 (1H, bs).

 N- {5,6-dimethyl-8-[(5fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene }-2,1,3-benzothiadiazol-5-sulfonamide

To a suspension of sodium hydride (50.7 mg, 1.27 aging ₀ 1) (60% oil) in tetrahydrofuran (2.00 ml) was added the ί-amino-5,6-dimethyl-8-methyl obtained in Example 6-23. [(5-Fluoropentyl) sulfanyl] -3Η-imidazo [5, tric] A solution of [1,4] thiazin-3-one (200 mg, 0.634nimol) in tetrahydrofuran (1.00 ml) was added, and the mixture was cooled on ice. Stir for 5 minutes. To this was added a solution of 2,1,3-benzothiadiazole-5-sulfonyl chloride (268 mg, 1.14 mmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred at room temperature for 2 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), solvent was obtained as a dark red crystalline title compound was distilled off (236 mg, 73%) under reduced pressure. Recrystallized from ethyl acetate-getyl ether, dark red with melting point 165-167 ° C Color crystals were obtained.

IR (KBr) V:. 3223 , 3071, 2936, 2861, 1742, 1663, 1615, 1557, 1520 cm "1 'HN R (CDC1 3): δ 1.44-1.85 (6H, m), 1.80 (3H, s ), 2.28 (3H, d, J = 0.8 Hz), 2.98 (2H, t, J = 7.0 Hz), 4.45 (2H, dt, J = 47.2, 5.6 Hz), 8.12 (2H, d, J = 0.8 Hz) ), 8.68 (1H, s), 9.69 (1H, bs).

Elemental analysis: C ₁₉ H _2. N ₅ 0 ₃ S ₄ F

Calculated value (%): C, 44.43; H, 3.92; N, 13.63; S, 24.97.

Found (¾): C, 44.50; H, 3.74; N, 13.66; S, 24.76.

Example 7-156

N- {5,6-dimethyl_8 _ [(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydric mouth-1H-imidazo [5,1-c] [1,4] thiazine-triylidene}- 2,1,3-Benzoxaziazol-4-sulfonamide

To a suspension of sodium hydride (50.7 mg, 1.27 band01) (60 oily) in tetrahydrofuran (2.00 ml) was added 1-amino-5,6-dimethyl_8 _ [(5 -Fluoro mouth pentyl) sulfanyl] -3H-imidazo [5, tric] [1,4] thiazine-3-one (200 mg, 0.634 acetyl) in tetrahydrofuran (1.00 ml), and add ice-cooling Stir for 5 minutes. To this was added a solution of 2,1,3-benzoxadiazole-4-sulfonyl chloride (250 mg, 1.14 mmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred at room temperature for 18.5 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure to give the title compound (159 mg, 51¾) as a dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 179-181 ° C.

IR (KBr): 3260, 3094, 2930, 2861, 1744, 1661, 1617, 1557 cm " ¹ .

Ή-NMR (CDCI3): 51.20-1.78 (6H, m), 1.80 (3H, s), 2.33 (3H, s), 2.90 (2H, t, J = 7.0 Hz), 4.43 (2H, dt, J = 47.2, 6.0 Hz), 7.54 (1H, dd, J-9.2, 6.6 Hz), 8.06 (1H, d, J = 9.2 Hz), 8.13 (1H, d, J = 6.6 Hz), 9.87 (1H, bs) .

Elementary analysis: as _{C 19 H 2Q N 5 0 4} S 3 F

Calculated value (%): C, 43.86; H, 4.05; N, 14.07; S, 19.33.

Found (): C, 45.87; H, 4.13; N, 13.98; S, 19.12. Example 7-157

 N- {5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-tri Ylidene} [1,1'-biphenyl] _4-sulfonamide

To a suspension of sodium hydride (25.4 mg, 0.63411111101) (60% oily) in tetrahydrofuran (2.00 ml) was added 1-amino-5,6-dimethyl 8- [5-fluoro obtained in Example 6-23. A solution of [pentyl] sulfanyl] -3H-imidazo [5, tric] [1,4] thiazin-3-one (100 mg, 0.317 mmol) in tetrahydrofuran (1.00 ml) was added, and the mixture was stirred under ice-cooling for 5 minutes. . To this was added a solution of biphenylsulfonyl chloride (134 mg, 0.476 mmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 20 minutes. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was evaporated reduced pressure to give the title compound (153 mg, 91%) as a dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 181-183.

IR (KBr): 3210, 3061, 2934, 1740, 1663, 1615, 1557 cm—

_{Ή-NMR (CDC1 3):} 51. 8-1.62 (4H, m), 1.62-1.82 (2H, m), 1.79 (3H, s), 2.28 (3H, s), 2.97 (2H, t, J = 6.9 Hz), 4.44 (2H, dt, J = 47.1, 5.7 Hz), 7.37-7.53 (3H, m), 7.60 (2H, d, J-7.2 Hz), 7.70 (2H, d, J = 8.7 Hz) , 8.03 (2H, d, J = 8.1 Hz), 9.66 (1H, bs).

Elementary analysis: as _{C 25 H 26 N 3 0 3} S 3 F

Calculated value (%): C, 56.47; H, 4.93; N, 7.90; S, 18.09.

Found (¾): C, 56.70; H, 5.02; N, 7.69; S, 18.39.

Example 7-158

N- {5,6-Dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dialdehyde Mouth-1H-imidazo [5,1-c] [1,4] thiazine-1- Ylidene} sulfonamide A suspension of sodium hydride (25.4 mg, 0.634 mmol) (60% oil) in tetrahydrofuran (2.00 ml) was added to the triamino-5,6 obtained in Example 6-23. -Dimethyl 8- [5-fluoropentyl] sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-o> (100 mg, 0.317 mmol) in tetrahydrofuran (1.00 ml) was added. The mixture was stirred for 5 minutes under ice cooling. To this was added n-octanesulfonyl chloride (0.0931 ml, 0.476 A solution of lahydrofuran (1.00 ml) was added, and the mixture was further stirred for 45 minutes. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to give the title compound was evaporated Solvent under vacuum (97.5 mg, 62¾) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a point 1'21_123 ° C. IR (KBr) V: 3196, 2924, 2857, 1755, 1665, 1626, 1570 cm—

_{'H-NMR (CDC1 3)} : 50.882 (3H, t, J = 6.4 Hz), 1.15-2.00 (18H, m), 1.81 (3H, s), 2.28 (3H, s), 2.99 (2H, t, J = 7.4 Hz), 3.11 (2H, t, J = 7.8 Hz), 4.46 (2H, dt, J = 46.8, 6.4 Hz), 9.46 (1H, bs).

Elementary analysis: as _{C 21 H 34 N 3 0 3} S 3 F

Calculated (%): C, 51.30; H, 6.97; N, 8.55; S, 19.56.

Observed (: C, 51.27; H, 7.19; N, 8.31; S, 19.64.

Example 7-159

 4-tert-butyl-N- {5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro_1H-imidazo [5, tric] [1,4 ] Thiazine-1-ylidene} benzen's sulfonamide

To a suspension of sodium hydride (50.7 mg, 1.27 t ol) (60% oil) in tetrahydrofuran (2.00 ml) was added the triamino-5,6-dimethyl 8- [5- Add a solution of fluoropentyl] sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (200 mg, 0.634 mmol) in tetrahydrofuran (2.00 ml) and stir under ice-cooling for 5 minutes. I did. To this was added a solution of 4-tert-butylbenzenesulfonyl chloride (226 mg, 0.951 mmoi) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (289fflg, 89¾) as a dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 199-201. IR (KBr) level: 3260, 2963, 1742, 1728, 1663, 1626, 1561 cm- ¹ .

_{Ή-NMR (CDC1 3):} δ 1.33 (9Η, s), 1.50-1.62 (2H, m), 1.64-1.84 (4H, m), 1.79 (3H, s), 2.26 (3H, d, J = 0.9 Hz), 2.96 (2H, t, J = 7.5 Hz), 4.45 (2H, dt, J = 47.1, 5.7 Hz), 7.49 (2H, d, J = 8.1 Hz), 7.87 (2H, d, J = 8.4 Hz), 9.62 (1H, bs ) elemental analysis:. C ₂₃ H _3. N ₃ 0 ₃ S ₃ F Calculated (¾): C, 53.99; H, 5.91;, 8.21; S, 18.80.

Found (%): C, 53.98; H, 5.74; N, 8.23; S, 18.82.

Example 7-160

 (E) -N- {5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] Thiazine-triiden 2 -phenylethanesulfonamide

To a suspension of sodium hydride (50.7 mg, 1.27 mmol) (60% oily) in tetrahydrofuran (2.00 ml) was added the triamino-5,6-dimethyl 8- [5-fluoro obtained in Example 6-23. Add a solution of [pentyl] sulfanyl] -3H-imidazo [5, tric] [1,4] thiazin-3-one (200 mg, 0.634 benzyl) in tetrahydrofuran (2.00 ml) and stir under ice-cooling for 5 minutes. Was. To this was added a solution of trans_) 3-styrenesulfonesulfonyl chloride (199 mg, 0.951 ol) in tetrahydrofuran (1.00), and the mixture was stirred for 1 hour. 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. , dried (MgSO _4), to give the title compound (226 mg, 74%) as a dark red crystals and the solvent was distilled off under reduced pressure acetate Echiru -. mp recrystallization from Jeffrey chill ether 87.0-89. (A dark red crystal of TC was obtained.

IR (KBr) V 3260, 2932, 1736, 1663, 1611, 1557 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 1.46-1.68 (2Η, m), 1.68 - 1.88 (4H, m), 1.81 (3H, d, J = 1.2 Hz), 2.28 (3H, d, J = 1.2 Hz) , 2.99 (2H, t, J = 7.8 Hz), 4.44 (2H, dt, J = 47.2, 6.0 Hz), 6.94 (1H, d, J = 15.4 Hz), 7.36-7.44 (3H, m), 7.46- 7.54 (2H, m), 7.56 (1H, d, J = 15.4 Hz), 9.58 (1H, bs).

Elementary analysis: as _{C 21 H 24 N 3 0 3} S 3 F

Calculated value (¾): C, 52.37; H,, 5.02; N, 8.72; S, 19.97.

Found (¾): C, 52.11; H, 4.74; N, 8.72; S, 20.13.

Example 7-161

 N- {5, 6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydropenit-1H-imidazo [5,1-c] [1,4] thiazine- Trilidene}-4-phenoxybenzenesulfonamide

Sodium hydride (25.4 mg, 0.634 ol) (60% oily) in tetrahydrofuran (2.00 ml) of the suspension obtained in Example 6-23, the triamino-5,6-dimethyl 8_ [5-fluoropentyl] sulfanyl] -3H-imidazo [5,1-c] [1,4] ] A solution of thiazine-3-one (100 Dig, 0.317imol) in tetrahydrofuran (1.00 ml) was added, and the mixture was stirred under ice cooling for 5 minutes. To this was added a solution of 4-phenoxybenzenesulfonyl chloride (130 mg, 0.476 tmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 20 minutes. Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After the extract was washed with water and dried (Mgso ₄ ), the solvent was distilled off under reduced pressure to obtain the title compound (124 mg, 72%) as dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 152-154 ° C.

IR (KBr) V: 3240, 2936, 1740, 1665, 1615, 1563 cm ¹ .

_{ΐ-NMR (CDC1 3):} 51.45-1.85 (6H, m), 1.79 (3H, s), 2.27 (3H, s), 2.96 (2H, t, J = 7.4 Hz), 4.44 (2H, dt, J = 47.2, 5.8 Hz), 7.02 (2H, d, J = 8.8 Hz), 7.04 (2H, dd, J = 9.0, 1.0 Hz), 7.21 (1H, t, J = 7.6 Hz), 7.40 (2H, t , J = 8.0 Hz), 7.91 (2H, d, J = 8.8 Hz), 9.61 (1H, bs).

Elementary analysis: as _{C 25 H 26 N 3 0 4} S 3 F.

Calculated (%): C, 54.82; H, 4.78; N, 7.67; S, 17.56.

Found (%): C, 54.92; H, 4.84; N, 7.72; S, 17.60.

Example 7-162'ethyl 4-[({5,6-dimethyl-8-[(5fluoropentanyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-triylidene} amino) sulfonyl] benzoate

To a suspension of sodium hydride (76.1 mg, 1.90 ol) (60% oil) in tetrahydrofuran (4.00 ml) was added 1-amino-5,6-dimethyl 8- [5] obtained in Example 6-23. -Fluoropentyl] sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (300 mg, O.951mmol) in tetrahydrofuran (2.00 ml) was added, and the mixture was cooled on ice for 5 minutes. Stirred. To this was added a solution of ethyl (4-chlorosulfonyl) benzoate (284 mg, 1.14 mmol) in tetrahydrofuran (2.00 ml '), and the mixture was further stirred for 2 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure to give the title compound (360 mg, 75¾) as a dark red crystals. vinegar The crystals were recrystallized from acetic acid-ethyl ether to obtain dark red crystals having a melting point of 4-146. IR (KBr): 3227, 2926, 1759, 1723, 1663, 1622, 1559 cm " ¹ .

_{Ή-NMR (CDC1 3):} 61.41 (3H, t, J = 7.0 Hz), 1.48-1.84 (6H, m), 1.80 (3H, d, J = 1.0 Hz), 2.28 (3H, d, J = 1.0 Hz), 2.97 (2H, t, J = 7.Hz), 4.41 (2H, q, J = 7.0 Hz), 4.45 (2H, dt, J = 47.2, 5.8 Hz), 8.03 (2H, d, J = 8.8Hz), 8.15 (2H, d, J = 8.8 Hz), 9.61 (1H, bs).

Elementary analysis: as _{C 22 H 26 N 3 0 5} S 3 F

Calculated value (%): C, 50.08; H, 4.97; N, 7.96; S, 18.23.

Found (¾): C, 50.22; H, 5.10; N, 8.01; S, 18.32.

Example 7463 '

 N- {5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1- Ylidene}-4-morpholine sulfonamide,

A suspension of hydrogenated sodium (38.0 mg, 0.951 oi) (60 oily) in tetrahydrofuran (2.00 ml) was added to the triamino-5,6-dimethyl 8- [5-phenol) obtained in Example 6-23. Mouth Pentyl] sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (150 mg, 0.476 tmol) in tetrahydrofuran (1.00 ml) was added, and the mixture was stirred under ice cooling for 5 minutes. mixed. To this was added a solution of 4-morpholine sulfonyl chloride (106 mg, 0.571 ol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 25 minutes. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), followed by distilling off the solvent medium under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (41.7 mg, 19%) as dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 191-193.

IR (KBr) v: 3250, 2961, 2924, 2863, 1744, 1665, 1624, 1568 cm— ¹ .

 'H-NMR (CDCI3): δ 1.50-1.66 (2Η, m), 1.66-1.85 (4H, m), 1.81 (3H, s), 2.28 (3H, s), 3.00 (2H, t, J = 7.5 Hz), 3.10-3.18 (4H, m), 3.75-3.84 (4H, m), 4.46 (2H, dt, J = 46.8, 6.0 Hz), 9.23 (1H, bs).

Elemental analysis: as _{C 17 H 25 N 4 0S F} ? Calculated value (¾): C, 43.95; H, 5.42; N, 12.06; S, 20.70.

Found (%): C, 43.94; H, 5.49; N, 11.90; S, 20.42.

Example 7-164

Ethyl 2-[({5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5, toc] [1,4] thiazine -Triylidene} amino) sulfonyl] -1-cyclohexene-1

To a suspension of sodium hydride (52.8 mg, 1.32 thigh 01) (60% oily) in tetrahydrofuran (4.00 ml) was added the triamino-5,6-dimethyl 8- [5- [5- Fluoropentyl] sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (208 mg, 0.951 tmol) in tetrahydrofuran (1.00 ml) was added, and the mixture was stirred under ice cooling for 5 minutes. mixed. To this was added a solution of ethyl (2-chlorosulfonyl) cyclohexene-1-carboxylate (200 ig, 0.791 bandol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure to give the title compound (323 mg, 92¾) as a dark red crystals. Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 149-151 ° C.

IR (KBr): 2938, 2865, 1748, 1663, 1651, 1609, 1559 cm " ¹ .

¾ one _{NMR (CDC1 3): 51.34 (} 3H, t, J = 7.2 Hz), 1.50-1.64 (2H, m), 1.64-1.84 (4H, m), 1.81 (3H, d, J = 1.2 Hz), 2.29 (3H, d, J = 0.9 Hz), 2.38-2.44 (2H, m), 2.48-2.56 (2H, m), 2.98 (2H, t, J = 7.2 Hz), 4.32 (2H, q, J = 6.9 Hz), 4.46 (2H, dt, J = 46.8, 5.7 Hz), 9.99 (1H, bs).

Elemental analysis: C ₂₂ H _3. N ₃ 0 ₅ S ₃ F

Calculated value (¾): C, 49.70; H, 5.69; N, 7.90; S, 18.09.

Found (¾): C, 49.69; H, 5.57; N, 7.90; S, 18.30.

Example 7-165

N- {5,6-dimethyl_8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-triylidenepropane Sulfonamide Hydrogenated sodium (25.4 mg, 0.634 fraction 1) (60% oil) in tetrahydrofuran (2.00 ml) was added to a suspension of triamino-5,6-dimethyl 8- [obtained in Examples 6-23. 5-Fluoro Add a solution of [pentyl] sulfanyl] -3H-imidazo [5, tric] [1,4] thiazin-3-one (100 mg, 0.317 tmol) in tetrahydrofuran (1.00 ml), and stir under ice-cooling for 5 minutes. Was. To this was added a solution of 2-propanesulfonyl chloride (0.0503 ml, 0.476 ol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 25 minutes. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to give the title compound was evaporated Solvent under vacuum (75.2 mg, 56¾) as a dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 5-147 ° C. IR (KBr) V: 3200, 2973, 2938, 1753, 1665, 1624, 1568 cm " ¹ .

'Η-丽 R (CDCI ₃ ): άΐ.42 (6Η, d, J = 6.6 Hz), 1.50-1.64 (2H, m), 1.64-1.84 (4H, m), 1.81 (3H, s), 2.28 (3H, s), 2.99 (2H, t, J = 7.2 Hz), 3.22 (1H, quintet, J = 6.3 Hz), 4.45 (2H, dt, J = 47.1, 5.7 Hz), 9.46 (1H, bs) .

Elemental analysis: as C ₁₆ H ₂ 0 ₃ S ₃ F

Calculated value (%): C, 45.58; H, 5.74; N, 9.97; S, 22.82.

Found (%): C, 45.37; H, 5.84; N, 10.07; S, 22.58.

Example 7-166

 4-butoxy-N- {5,6-dimethyl-8-[(5-fluoropentyl) sulfael] -3-oxo-2,3-dihydrido-1H-imidazo [5,1-c] [1, 4] thiazine-triylidene} benzenesulfonamide

To a suspension of sodium hydride (25.4 mg, 0.634 ol) (60% oil) in tetrahydrofuran (2.00 ml) was added the triamino-5,6-dimethyl 8_ [5-fluoro obtained in Example 6-23. Pentyl] sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazine-3-one (100 rag, 0.317 t ol) in tetrahydrofuran (1.00 ml) was added, and the mixture was stirred under ice-cooling for 5 minutes. mixed. To this was added a solution of 4-butoxybenzenesulfonyl chloride (122 mg, 0.476 ol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 50 minutes. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure to give the title compound (121 mg, 73¾) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 140-142.

IR (KBr) V 3210, 2961, 1752, 1715, 1663, 1622, 1595, 1566 cm- ¹ . 'H-NMR (CDCI3): (50.978 (3H, t, J = 7.5 Hz), 1.-40-1.62 (4H, m), 1.62-1.75 (6H, m), 1.79 (3H, s), 2.26 (3H, d, J-0.9 Hz), 2.94. (2H, t, J = 7.5 Hz), 4.00 (2H, t, J = 6.3 Hz), 4.44 (2H, dt, J = 47.1, 5.7 Hz), 6.93 (2H, d, J = 8.7 Hz), 7.86 (2H, d, J = 9.3 Hz), 9.59 (1H, bs).

Elementary analysis: as _{C 23 H 3Q N 3 0 4} S 3 F

Calculated (%): C, 52.35; H, 5.73; N, 7.96; S, 18.23.

Found (¾): C, 52.05; H, 5.72; N, 7.79; S, 18.09.

Example 7-167

 (4-Promophenyl) -N- {5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-m-imidazo [5, tric] [1, 4 ] Thiazine-1-ylidene

 The compound was synthesized in the same manner as in Example 7-166, and recrystallized from ethyl acetate-getyl ether to obtain Δ red crystals having a melting point of 185-ISrC.

IR (KBr) V: 3225, 2938, 1742, 1665, 1617, 1564, 1487 cm— ¹ .

¾— NMR (CDCI3): 51.48-1.90 (6H, m), 1.80 (3H, d, J = 0.8 Hz), 2.24 (3H, d,

J = 1.0 Hz), 3.00 (2H, t, J = 7.2 Hz), 4.30 (2H, s), 4.49 (2H, dt, J = 47.2, 5.8

Hz), 7.31 (2H, d, J = 8 Hz), 7.48 (2H, d, J = 8.6 Hz), 9.21 (1H, bs).

Elemental analysis: C _2. H ₂₃ N ₃ 0 ₃ S _{3 As} BrF

Calculated value (¾): C, 43.79; H, 4.23; N, 7.66; S, 17.54.

Found (%): C, 43.81; H, 4.19; N, 7.64; S, 17.44.

Example 7-168

[(1R, 3S, 7R) -3-Bromo-1,7-dimethyl-2-oxobicyclo [2,2,1] hept-7-yl] -N- {5,6-dimethyl-3-oxo- 8-[(5-full-age pentyl) sulfanyl] -2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene} methanesulfonamide sodium hydride ( To a suspension of 39.5 mg, 0.987 benzyl) (60% oil) in tetrahydrofuran (2.00 ml) was added the triamino-5,6-dimethyl 8- [5-fluoropentyl] sulfanyl obtained in Example 6-23. ] -3H-Imidazo [5,1-c] [1,4] thiazin-3-one (150 mg, 0.49.3 tmol) in tetrahydrofuran (1.00 ml) was added, and the mixture was stirred under ice-cooling for 5 minutes. Was. However, D, (+)-3-bromo-campha-1-sulfonylc obtained in Reference Example 48 A solution of chloride in tetrahydrofuran (1.00 ml) was added, and the mixture was further stirred for 30 minutes. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to give the title compound solvent Te distilled off under reduced pressure (82.8 mg, 28%) as a dark red crystals. The crystals were recrystallized from ethyl acetate-getyl ether to give reddish crystals having a melting point of 161-163 ° C.

IR (Br): 3229, 2965, 2934, 1752, 1665, 1618, 1564 cm- ¹ .

_{Ή-NMR (CDC1 3):} (50.997 (3H, s), 1.29 (3H, s), 1.46-1.90 (8H, m), 1.82 (3H, s), 2.14-2.26 (2H, m), 2.29 ( 3H, s), 3.01 (2H, t, J = 7.8 Hz), 3.11 (IH, d, J = 14.7 Hz), 3.20-3.28 (IH, m), 3.48 (IH, d, J = 14.Hz) , 4.46 (2H, dt, J = 47.1, 5.7 Hz), 4.62 (IH, d, J = 3.0 Hz), 9.56 (IH, bs).

Elementary analysis: as _{C 23 H 31 N 3 0 4} S 3 BrF

Calculated value (¾): C, 45.39; H, 5.13; N, 6.90; S, 15.81.

Found (¾): C, 45.25; H, 5.04; N, 6.92; S, 16.06.

Example 7-169

N- {5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydrone-1H-imidazo [5,1-c] [1,4] thiazine-triylidene 2-phenylethanesulfonamide

 The compound was synthesized in the same manner as in Example 7-168, and recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 159-161 ^.

IR (KBr): 3175, 2963, 2942, 1755, 1665, 1622, 1568 cm—

_{Ή-NMR (CDC1 3):} 51.48-1.88 (6H, m), 1.82 (3H, s), 2.28 (3H, d, 1 = 1.2 Hz),

2.99 (2H, t, J = 7.5 Hz), 3.16-3.25 (2H, m), 3.38-3.48 (2H, m), 4.43. (2H, dt,

J = 47.1, 6.0 Hz), 7.18-7.35 (5H, m), 9.44 (IH, bs).

Elemental analysis: C ₂₁ H ₂₆ N ₃ 0 ₃ S ₃ F Ο · 7Η ₂₀

Calculated: C, 50.83; Η, 5.57; Ν, 8.47. '

Found (¾): C, 51.14; Η, 5.37; Ν, 8.62.

Example 7-170

C (1S, 4R) -7,7-dimethyl-2-oxovisic mouth [2,2,1] hept-1-yl] -N- {5,6-dimethyl-8-[(5-fluoro mouth Pentyl) sulfanyl] -3 -oxo-2,3-dihydrido-1H-imi Dazo [5,1-c] [1,4] thiazine-1-ylidene} methanesulfonamide

To a suspension of sodium hydride (25.4 mg, 0.634 mmol) (60% oily) in tetrahydrofuran (2.00 ml) was added the triamino-5,6-dimethyl 8- [5_fluoro obtained in Example 6-23. Add a solution of [pentyl] sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (100 mg, 0.317 mmol) in tetrahydrofuran (1.00 ml), and stir under ice-cooling for 5 minutes. Was. To this was added a solution of (+)-10-camphorsulfonyl chloride (122 mg, 0.476 tmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 30 minutes. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain a solvent Te distilled off under reduced pressure the title compound (151 mg, 90%) as a dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 157-159 ° C. IR (KBr) V: 3207, 2961, 1744, 1752, 1665, 1617, 1566 cm— ¹ .

_{ΐ-NMR (CDC1 3):} 50.867 (3H, s), 1.10 (3H, s), 1.43 (1H, ddd, J = 12.0, 8.7, 3.6 Hz), 1.50-2.14 (10H, m), 1.81 (3H , s), 2.29 (3H, s), 2.38 (1H, dt, J = 18.6, 3.6 Hz), 2.53 (1H, ddd, J = 14.7, 8.5, 3.9 Hz), 2.98 (2H, t, J = 7.5 Hz), 3.07 (1H, d, J = 15.0 Hz), 3.61 (1H, d, J = 14.7 Hz), 4.46 (2H, dt, J = 47.1, 5.7 Hz), 9.77 (1H, bs).

Elementary analysis: as _{C 23 H 32 N 3 0 4} S 3 F

Calculated (¾): C, 52.15; H, 6.09; N, 7.93; S, 18.16.

Found (%): C, 52.06; H, 6.39; N, 7.61; S, 18.51.

Example 7-171

 N- {5,6-dimethyl-8-[(5-fluoromethylpentyl) sulfanyl] -3-oxo-2,3-dihydrido-m-imidazo [5,1-c] [1,4] thiazine -1-ylidene} (4-fluorophenyl) methanesulfonamide 'Synthesized in the same manner as in Example 7-170, and recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 184_186 ° C.

IR (KBr) V: 3200, 2938, 2865, 1738, 1665, 1617, 1564, 1508 cm- ¹ .

'H-NMR (CDCI3): 51.52-1.66 (4H, m), 1.66-1.86 (4H, m), 1.80 (3H, s), 2.23 (3H, s), 3.00 (2H, t, J = 7.5 Hz) ), 4.31 (2H, s), 4.48 (2H, dt, J = 47.1, 5.4 Hz), 7.03 (2H, t, J-8.7 Hz), 7.40 (2H, dd, J = 8.4, 5.4 Hz), 9.19 (1H, bs). Elemental analysis: C _2. H ₂₃ N ₃ 0 _{3 As} S ₃ F ₂

Calculated (%): C, 49.26; H, 4.75; N, 8.62; S, 19.73.

Found (%): C, 49.03; H, 4.73; N, 8.44; S, 19.92.

Example 7-172

 (4-chlorophenyl) -N- {5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [ 1,4] thiazine-1-ylidene} methansulfonamide

 The compound was synthesized in the same manner as in Example 7-170, and recrystallized from ethyl acetate-getyl ether to obtain dark red crystals having a melting point of 182-183.

IR (KBr): 3210, 2960, 2940, 2860, 1742, 1665, 1617, 1564 cm— ¹ .

_{'H-NMR (CDC1 3)} : 51.50-1.68 (2H, m), 1.68-1.88 (4H, in), 1.80 (3H, s), 2.24 (3H, s), 2.99 (2H, t, J = 7.5 Hz), 4.31 (2H, s), 4.48 (2H, dt, J = 47.1, 5.7 Hz), 7.31 (2H, d, J = 8.7 Hz), 7.37 (2H, d, J = 8.4 Hz), 9.21 ( 1H, bs).

Elemental analysis: C _2. H ₂₃ N ₃ 0 ₃ S ₃ C1F

Calculated value (%): C, 47.66; Η, 4.60; Ν, 8.34; S, 19.08.

Found (%): C, 47.52; H, 4.55; N, 8.33; S, 18.83.

Example 7-173

 N- {5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydrone-1H-imidazo [5, tric] [1,4] thiazine_1-ylidene} (4-Methylphenyl) -methyl sulfonamide

 The compound was synthesized in the same manner as in Examples 7-170, and recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 188-190.

IR (KBr) V: 3250, 2936, 2865, 1740, 1665, 1617, 1566 cm " ¹ .

'H-NMR (CDCI3): δ 1.54-1.68 (2Η, m), 1.68-1.86 (4H, m), 1.80 (3H, d, J = 1.5 Hz), 2.21 (3H, d, J = 0.9 Hz) , 2.34 (3H, s), 3.01 (2H, t, J = 7.5 Hz), 4.31 (2H, s), 4.48 (2H, dt, J = 47.1, 6.0 Hz), 7.14 (2H, d, J = 7.8 Hz), 7.29 (2H, d, J = 8.1 Hz), 9.08 (1H, bs).

Elementary analysis: as _{C 21 H 26 N 3 0 3} S 3 F

Calculated (%): C, 52.15; H, 5.42; N, 8.69; S, 19.89. Found (%): C, 52.32; H, 5.38; N, 8.75; S, 20.19.

Example 7-174

 N- {5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1- Ylidene} -2-pyridinesulfonamide Synthesized in the same manner as in Examples 7-170, and recrystallized from ethyl acetate-getyl ether to obtain dark red crystals having a melting point of 151-153 ° C.

I (KBr) V: 3233, 2913, 1728, 1661, 1607, 1551 cm " ¹ .

_{Ή-NR (CDC1 3):} δ 1.46-1.60 (2Η, m), 1.60-1.84 (4H, m), 1.80 (3H, s), 2.30 (3H, s), 2.95 (2H, t, J = 7.5 Hz), 4.43 (2H, dt, J = 47.1, 6.0 Hz), 7.49 (IH, ddd, J = 7.5, 4.5, 0.6 Hz), 7.91 (IH, dt, J = 7.8, 1.5 Hz), 8.12 (1H , D, J = 7.8 Hz), 8.66 (IH, d, J-4.5 Hz), 10.26 (IH, bs).

Elementary analysis: as _{C 18 H 21 N 4 0 3} S 3 F

Calculated value (¾): C, 47.35; H, 4.64; N, 12.27; S, 21.07.

Found (%): C, 47.29; H, 4.61; N, 12.30; S, 21.06.

Example 7-175

 N- {5,6-Dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo_2,3-dihydrone-1H-imidazo [5, tric] [1,4] thiazine-trivden } (2-Ditrophenyl) methanesulfonamide

 The compound was synthesized in the same manner as in Example 7-170, and recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 143-1451 :.

IR (KBr) V: 3200, 2934, 1740, 1663, 1611, 1563, 1530 cm " ¹ .

Ή-NMR (CDCI3): δ 1.48-1.88 (6Η, m), 1.80 (3H, s), 2.25 (3H, s), 2.96 (2H, t, J = 7.5Hz), 4.48 (2H, dt, J = 47.4, 5.7 Hz), 4.96 (2H, s), 7.51 (IH, dt, J = 8.7, 1.4 Hz), 7.63 (IH, dt, J = 7.8, 0.9 Hz), 7.67 (IH, dd, J = 7.8, 1.5 Hz), 8.04 (IH, d, J = 7.8 Hz), 9.29 (1H, bs).

Elemental analysis: C _2. H ₂₃ N ₄ 0 ₅ S ₃ F

Calculated value (¾): C, 46.68; H, 4.50; N, 10.89; S, 18.69.

Found (¾): C, 46.49; H, 4.56; N, 10.87; S, 18.80.

Example 7-176 3-N- {5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4 ] Thiazine-1-ylidene} -propanesulfonamide

To a suspension of sodium hydride (25.4 mg, 0.634 tmol) (60% oil) in tetrahydrofuran (2.00 ml) was added 1-amino-5,6-dimethyl 8- [5 -Fluoropentyl] sulfanyl]-3H-imidazo [5, 1-c] [1, 4] thiazine-3-one (100 mg, 0.317 categoriz 01) in tetrahydrofuran (1.00 ml) was added, and the mixture was cooled on ice. Stir for 5 minutes. To this was added a solution of 3-chloropropanesulfonyl chloride (0.0472 ml, 0.380 marl) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 20 minutes. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (113 mg, 79%) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 140-142 ° C.

 IR (KBr) V: 3162, 2961, 2934, 1755, 1665, 1622, 1556 cm—

_{'H-NMR (CDC1 3)} : δ 1.50-1.84 (6H, m), 1.82 (3H, s), 2.29 (3H, s), 3.11 (2H, t, J = 7.6 Hz), 2.35-2.48 (2H , m), 3.01 (2H, t, J = 7.5 Hz), 3.30 (2H, t, J = 7.2 Hz), 3.72 (2H, t, J = 6.3 Hz), 4.47 (2H, dt, J-47. , 5.7 Hz), 9.43 (1H, bs). Elemental analysis: C ₁₆ H ₂₃ N ₃ 0 ₃ S ₃ C1F

Calculated value (%): C, 42.14; H, 5.08; N, 9.21; S, 21.09; C1, 7.77.

Obtained value (: C, 42.24; H, 4.91; N, 9.33; S, 20.92; Cl, 8.05.

Example 7-177

 N_ {5, 6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydrone-1H-imidazo [5,1-c] [1,4] thiazine_1-ylidene} -4- (methylsulfonyl) benzene sulphonamide

 The compound was synthesized in the same manner as in Examples 7-176, and recrystallized from ethyl acetate-getyl ether to obtain dark red crystals having a melting point of 195-197 ^.

IR (KBr) Re:. 3088, 3025, 2957, 2940, 2924, 1723, 1659, 1595, 1559 cm one _{^{1 Ή-NMR (CDCI 3)}} : 51.48-1.52 (2H, m), 1.52-1.84 (4H, m), 1.81 (3H, s), 2.29 (3H, s), 2.99 (2H, t, J = 7.2 Hz), 3.09 (3H, s), 4.47 (2H, dt, J-47.4, 5.7 Hz), 8.07 (2H, d, J = 8.7 Hz), 8.18 (2H, d, J = 8.7 Hz), 9.63 (1H, bs).

Elementary analysis: as _{C 20 H 24 N 3 0 5} S 4 F · 0 · 5E t OAc

Calculated value (%): C, 45.74; H, 4.89; N, 7.27; S, 22.20.

Found (%): C, 45.51; H, 4.89; N, 7.47; S, 21 92.

Example 7-178

 N- {5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydrone-1H-imidazo [5, tric] [1,4] thiazine-1-ylidene 3-Phenoxybenzenesulfonamide

 The compound was synthesized in the same manner as in Examples 7-176, and recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 178-180 ° C.

IR (KBr) V: 3250, 2921, 1732, 1663, 1620, 1584, 1559 cm " ¹ .

'H- Ran _{R (CDC1 3): (51.46-1.62} (2H, jn), 1.62-1.84 (4H, πι), 1.80 (3Η, s), 2.27 (3H, d, J = 0.9 Hz), 2.94 ( 2H, t, 1 = 7.8 Hz), 4.44 (2H, dt, J = 47.1, 5.7 Hz), 7.03 (2H, dd, J = 7.5, 1.2 Hz), 7.13-7.20 (2H, m), 7.37 (2H , t, J = 7.5 Hz), 7.44 (1H, t, J = 8.1 Hz), 7.61 (1H, t, J = 1.8 Hz), 7.68 (1H, dt, J = 3.0, 1.2 Hz), 9.57 (1H , bs).

Elementary analysis: as _{C 25 H 26 N 3 0 4} S 3 F

Calculated value (%): C, 54.82; H, 4.78; N, 7.67; S, 17.56.

Actual value (»: C, 54.55; H, 4.80; N, 7.59; S, 17.31.

Example 7-179

 (3,4-dichlorophenyl) -N- {5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c ] [1,4] thiazine-toylidene} methanesulfonamide

 The compound was synthesized in the same manner as in Examples 7-176, and recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 175-177 ° C.

IR (KBr) Re: 3189, 2940, 1736, 1665 , 1618, 1561 cm- Ή-NMR (CDC1 3): 51.46-1.68 (2H, m), 1.68-1.80 (4H, m), 1.81 (3H, s ), 2.25 (3H, s), 3.01 (2H, t, J = 7.2 Hz), 4.28 (2H, s), 4.47 (2H, dt, J = 47.1, 5.7 Hz), 7.29 (1H, dd, J = 8.1, 2.1 Hz), 7.43 (1H, d, J = 8. L Hz), 7.54 (1H, d, J = 1.8Hz), 9.23 (1H, bs).

Example 7-180

 N- {5,6-Dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-IH-imidazo [5,1-c] [1,4] thiazine-1- Ylidene} [4- (trifluoromethyl) phenyl] methanesulfonamide

 The compound was synthesized in the same manner as in Examples 7-176, and recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 177-179.

Infrared absorption spectrum (IR) (in KBr) Re: 3230, 2938, 1744, 1665 , 1615, 1564 cm- Ή-NMR (CDC1 3): δ 1.52-1.66 (2Η, m), 1.66-1.88 (4H, m), 1.80 (3H, d, J = 1.2 Hz), 2.23 (3H, d, J = 0.9 Hz), 2.99 (2H, t, J = 6.9 Hz), 4.40 (2H, s), 4.48 (2H, dt, 1 = 47.1, 6.0 Hz), 7.56 (2H, d, J = 9.0 Hz), 7.61 (2H, d, J = 8.7 Hz), 9.23 (IH, bs).

Elemental analysis: as C _2l H ₂₃ N ₃ 0 ₃ S ₃ F ₄

Calculated value (%): C, 46.92; H, 4.31; N, 7.82; S, 17.89.

Found (%): C, 46.53; H, 4.28; N, 7.92; S, 18.31.

Example 7-181

 [3,5-bis (trifluoromethyl) phenyl] -N- {5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] _3-oxo-2,3-dihydro-1H-imidazo [ 5,1-c] [1,4] thiazi Synthesized in the same manner as in Example 7-176, and recrystallized from ethyl acetate-getyl ether to obtain dark red crystals having a melting point of 160-162.

Infrared absorption spectrum (IR) (in KBr) V: 3281, 2934, 1730, 1667, 1617, 1561 cm- 'H-NMR (CDC1 3): δ 1.48-1.65 (2Η, m), 1.65-1.85 (4H , m), 1.80 (3H, s), 2.23 (3H, s), 2.99 (2H, t, J = 7.5 Hz), 4.45 (2H, s), 2.98 (2H, t, J-7.5 Hz), 4.47 (2H, di, J = 47.1, 6.0 Hz), 7.86 (1H, s), 7.92 (2H, s), 9.21 (ΪΗ, bs).

N- {5,6-Dimethyl-8-[(5-fluoromethylpentyl) sulfanyl] -3-oxo-2,3-dihydrido-1H-imidazo [5,1-c] [1,4] thiazine -Trilidene} [3- (trifluoromethyl) phenyl] methanesulfonamide The compound was synthesized in the same manner as in Example 7-176, and recrystallized from ethyl acetate-getyl ether to obtain dark red crystals having a melting point of 180-182 ° C.

Infrared absorption spectrum (IR) (in KBr) V:. 3220, 2942 , 1742, 1667, 1615, 1564 cm "1 Ή-NMR (CDC1 3): δ 1.40-1.84 (6Η, m), 1.80 (3H, s), 2.21 (3H, s), 3.01 (2H, t, J = 7.2 Hz), 4.40 (2H, s), 4.48 (2H, dt, J = 47.2, 5.8 Hz), 7.45-7.72 (4H, m ), 9.17 (1H, bs).

Elemental analysis: as C ₂₁ H ₂₃ N ₃ 0 ₃ S ₃ F ₄

Calculated (%): C, 46.92; H, 4.31;, 7.82; S, 17.89.

Found (%): C, 46.70; H, 4.26; N, 7.63; S, 17.84.

Example 7-183

 N- {5,6-Dimethyl-8-[(5-fluoromethylpentyl) sulfanyl] -3-oxo-2,3-dihydric-m-imidazo [5, lc] [1,4] thiazine-1 -Ylidene} [1,1'-biphenyl]-3-sulfonamide

 The compound was synthesized in the same manner as in Examples 7-176, and recrystallized from ethyl acetate-getyl ether to obtain dark red crystals having a melting point of 152-154T :.

IR (KBr) V 3202, 3071, 2963, 2942, 1752, 1663, 1620, 1559 cm " ¹ .

E - belly _{(CDC1 3): (51.40-1.84 (} 6H, m), 1.79 (3H, s), 2.27 (3H, s), 2.95 (2H, t, J-7.4 Hz), 4.41 (2H, dt, J = 46.8, 6.0 Hz), 7.38-7.54 (3H, m), 7.54-7.66

(3H, in), 7.78 (1H, d, J = 7.0 Hz), 7.94 (1H, d, J = 8.0 Hz), 8.22 (1H, s), 9.63 (1H, bs).

Elementary analysis: as _{C 25 H 26 N 3 O 3} S 3 F'0.3H 2 O

Calculated (¾): C, 55.91; H, 4.99; N, 7.82; S, 17.91.

Found (%): C, 55.88; H, 4.77; N, 7.70; S, 18.13.

Example 7-184

N- {5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydric mouth-1H-imidazo [5, lc] [1,4] thiazine-1-ylidene} -2,2-diphenylethanesulfonamide

The compound was synthesized in the same manner as in Example 7-176, and recrystallized from ethyl acetate-getyl ether to obtain dark red crystals having a melting point of 181-183. IR (KBr) v: 3220, 2934, 1740, 1665, 1622, 1566 cm one ^1.

_{Ή-NMR (CDC1 3):} 01.46-1.88 (6H, m), 1.81 (3H, d, J = 1.2 Hz), 2.24 (3H, d, J = 1.0Hz), 2.97 (2H, t, J = 7.2 Hz), 3.97 (2H, d, J = 7.4Hz), 4.48 (2H, dt, J = 47.2, 5.8 Hz), 4.64 (IH, t, J = 8.0 Hz), 7.14-7.36 (10H, m), 9.25 (IH, bs).

Elemental analysis: C _27. N ₃ 0 ₃ S ₃ F

Calculated value (%): C, 57.94; H, 5.40; N, 7.51; S, 17.19.

Found (%): C, 57.59; Η, 5.46; Ν, 7.38; S, 17.10.

Example 7-185

 Ν- (8-{[2- (Tudamantyl) ethyl] sulfanyl} -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, tri c] [1,4] Thiazine-triylidene) -4-bromobenzenesulfonamide

 To a suspension of the compound obtained in Example 6-40 (126 mg, 0.323 t) in THF (3.0 ml) was added sodium hydride (60% oil, 32.3 mg, 0.809 ol) at room temperature. After stirring for 1 minute, Shiojiri 4-bromobenzenesulfonyl (90.9 mg, 0.356 ol) was added, and the mixture was further stirred for 2 hours. Methanol (1 ml) and IN hydrochloric acid (0.7 ml) were added to the reaction solution, and methanol water (2: 1, 5 ml) was added for dilution. The precipitate was collected by filtration, washed with methanol water, methanol and diethyl ether, and dried to give the title compound (95 mg, 0.156 mol, 48.3%) as a red powder.

_{Ή-NMR (200MHz, CDC1 3} ): 51.43 (2H, m), 1.50 (6H, d, J = 2.6 Hz), 1.65 (3H, brd, J = 12 Hz), 1.71 (3H, brd, J = 12 Hz), 1.80 (3H, q, J = 1.2 Hz), 1.98 (3H, brs), 2.28 (3H, q, J = 1.0 Hz), 2.92 (2H, m), 7.63 (2H, dt, J = 8.4 , 2.2 Hz), 7.83 (2H, dt, J = 8.8, 2.2 Hz), 9.60 (1H, brs).

Elemental _{analysis: C 26 H 30 N 3 0} 3 S 3 Br Calculated: C, 51.31; H, 4.97 ; N, 6.90; S, 15.81; Br, 13.13 (%), Found: C, 51.38; H , 5.13; N, 6.64; S, 15.72; Br, 13.23 ().

Immediately. 199.5-201.0 ° C

Example 7-186

N- {8-[(1-adamantylmethyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine- 1-ylidene}-4-bromobenzenesul Honamide

To a suspension of the compound obtained in Example 6-41 (98 mg, 0.261 tmol) in THF (3.0 ml) was added sodium hydride (purity 60% oil, 26.1 mg, 0.652 bandol) at room temperature, and the mixture was added for 15 minutes. After stirring, 4-bromobenzenesulfonyl chloride (73.3 rag, 0.287 mol) was added, and the mixture was further stirred for 1 hour. Methanol (4 ml) and IN hydrochloric acid (OL 0 ml) were added to the reaction solution. The precipitate was collected by filtration, washed with methanol-water (1: 1), methanol and getyl ether, and dried to give the title compound (124 mg, 0.208 bandol, 79.9%) as a red powder. _{Ή-NMR (200MHz, CDC1 3} ): 51.55 (6H, d, J = 2.2 Hz), 1.61 (3H, brd, J = 12 Hz), 1.71 (3H, brd, J = 12 Hz), 1.80 (3H, q, J = 1.2 Hz), 2.01 (3H, brs), 2.27 (3H, q, J- 1.2 Hz), 2.77 (2H, s), 7.60 (2H, dt, J = 8.8, 2.2 Hz), 7.87 ( 2H, dt, J = 8.8, 2.2 Hz), 9.54 (1H, brs).

Elemental _{analysis: C 25 8 N 3 0 3} S 3 Br Calculated: C, 50.50; H, 4.75 ; N, 7.07; S, 16.18; Br, 13.44 (%), Found: C, 50.40; H, 4.56; N, 6.79; S, 15.91; Br, 13.56 (%).

mp. 227.0-228.Ot: ¹ Example 7-187

 4-bromoΝ- {8-[(cyclooctylmethyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1Η-imidazo [5, tric] [1,4] Thiazine-1-ylidene} benzenesulfonamide

 To a suspension of the compound (135 mg, 0.384 alcohol) obtained in Example 6-42 in THF (3.0 ml) was added sodium hydride (purity 60% oily, 38.4 mg, 0.960 mmol) at room temperature, and the mixture was added for 15 minutes. After stirring, 4-bromobenzenesulfonyl chloride (108 mg, 0.422 ol) was added, and the mixture was further stirred for 1 hour. Methanol (1 ml) and IN hydrochloric acid (1.0 ml) were added to the reaction solution, and aqueous methanol (2: 1, 5 ml) was added for dilution. The precipitate was collected by filtration, washed with methanol-water (1: 1), methanol and diethyl ether, and dried to give the title compound (217 mg, 0.380, ol, 99.0) as a red-orange powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.30-1.90 (15H, m), 1.79 (3H, s), 2.27 (3H, s), 2.83 (2H, d, J = 6.6 Hz), 7.61 (2H, d, J = 8.8 Hz), 7.84 (2H, d, J-8.4 Hz), 9.57 (1H, brs). Elemental _{analysis: C 23 H 28 N 3 0} 3 S 3 Br Calculated: C, 48.41; H, 4.95 ; N, 7.36; S, 16.86; Br, 14.00 (%), Found: C, 48.27; H , 4.98; N, 7.12; S, 16.76; Br, 14.14

(%).

mp. 199.0-200. O

Example 7-188

 N- {5,6-Dimethyl-8-[(5-fluoroopentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5, lc] [1,4] thiazine-1 -Ylidene} cyclopropanesulfonamide

 It was synthesized in the same manner as in Examples 7-176, and recrystallized from ethyl acetate-getyl ether to give dark red crystals having a melting point of 160-162 ° C.

IR (KBr) V: 3206, 2926, 1748, 1732, 1665, 1630, 1570 cm " ¹ .

_{Ή-NMR (CDC1 3):} (50.960-1.08 (2H, m), 1.20-1.32 (2H, m), 1.46-1.86 (6H, m),

1.81 (3H, s), 2.28 (3H, d, J = 0.8 Hz), 2.54-2.71 (1H, m), 2.99 (2H, t, J = 7.2

Hz), 4.46 (2H, dt, J = 47.4, 5.8 Hz), 9.43 (1H, bs).

Elemental analysis: C ₁₆ H ₂₂ N ₃ 0 ₃ S ₃ F'0.2H ₂₀

Calculated (%): C, 45.41; H, 5.34; N, 9.93; S, 22.73.

Found (%): C, 45.42; H, 5.34; N, 9.80; S, 22.96.

Example 7-189

 8,9-dimethyl-1 [[5-fluoropentyl) sulfanyl] -3,4-dihydro [1,4] thiazino [4,, 3 ': 3,4] imidazo [5,1-c] [1 , 2,4] thiadiazine _6-one 2,2-dioxide,

To a suspension of sodium hydride (25.4 mg, 0.634 ol) (60 oily) in tetrahydrofuran (2.00 ml) was added 1-amino-5,6-dimethyl 8- [5- Add a solution of fluoropentyl] sulfanyl] -3H-imidazo [5, tric] [1,4] thiazin-3-one (100 mg, 0.317 thigh 01) in tetrahydrofuran (1.00 ml), and stir under ice-cooling for 5 minutes. I did. To this was added a solution of ethanesulfonyl chloride 2-tetrachloride in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 22 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract washed with water to give after drying (MgSO _4), the solvent the title compound Te evaporated under reduced pressure (52.0mg, 41¾) as a dark red crystals. Ethyl acetate-Jechlether To give dark red crystals with a melting point of uo-urc.

IR (KBr) V: 2940, 2861, 1738, 1663, 1603, 1564 cm ¹

- thigh _{R (CDC1 3): 51.50-1.64 (} 2H,), 1.64-1.86 (4H, m), 1.83 (3H, d, J = 0.6 Hz), 2.29 (3H, d, J = 1.2 Hz), 3.00 (2H, t, J = 7.8 Hz), 3.26 (2H, t, J = 6.3 Hz), 4.21 (2H, i, J = 6.3 Hz), 4.45 (2H, di, J = 47.1, 5.7 Hz).

Elementary analysis: as _{C 15 0 N 3 O 3 S} 3 F -0.3¾0

Calculated values): C, 43.84; H, 5.05; N, 10.23.

Measured value (¾: C, 43.86; H, 4.75; N, 10.18.

Example 7-190

4-bromo--{1,6-dioxo-4-[(5-fluoropentyl) sulfanyl] -1,2,6,7,8,9-hexahydro-3H-imidazo [5,1-c ] [1,4] Benzothiazine-4-di • To a suspension of sodium hydride (37.7 mg, 0.942 mmol) (60W free) in tetrahydrofuran (1.00 ml) was added the suspension obtained in Example 6-47. Amino-4-[(5-fluoropentyl) sulfanyl]-8,9_dihydric mouth-1H-imidazo [5,1-c] [1,4] thiazine-1,6 (7H) -dione (167 mg, 0.471 mmol) in tetrahydrofuran (2.00 ml) was added, and the mixture was stirred under ice cooling for 5 minutes. To this was added a solution of 4-bromobenzenesulfonyl chloride (246 mg, 0.942 mmol) in tetrahydrofuran (1.00 ral), and the mixture was further stirred for 2.5 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried (after MgSO 4), and the solvent was distilled off under reduced pressure to obtain the title compound (175 mg, 65) as dark red crystals, which were recrystallized from ethyl acetate-ethyl ether to give a melting point of 245-247. ° C dark red crystals were obtained.

IR (KBr) V: 3169, 2967, 2940, 1736, 1649; 1605, 1582, 1541 cm— ¹ .

Ή Ichikaku _{R (CDC1 3): ά 1.50-1.90} (6Η, m), 1.98-2.14 (2H, m), 2.52 (2Η, ί, ] = 7.0 Hz), 3.07 (2Η , t, J = 7.4 Hz ), 3.22 (2H, t, J = 6.2 Hz), 4.46 (2H, dt, J = 47., 5.8 Hz), 7.64 (2H, d, J-8.8 Hz), 7.82 (2H, d, J = 8 . Hz), 9.83 (1H, bs) Elementary analysis:. a _{C 2i N 3 0 4 S 3} BrF

Calculated value (%): C, 43.90; H, 3.68; N, 7.31; S, 16.74.

Found (%): C, 44.06; Η, 3.59; Ν, 7.24; S, 16.59. Example 7-191

 4-Cyano-N- {5,6-dimethyl-8 _ [(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine- 1-ylidene} benzenesulfonamide

 The compound was synthesized in the same manner as in Example 7-176, and recrystallized from ethyl acetate-getyl ether to obtain dark red crystals having a melting point of 171-173 ° C.

 IR (KBr) V 3225, 2934, 2232, 1757, 1663, 1620, 1557 cm—

_{lH-NMR (CDC1 3):} δ 1.48-1.62 (4Η, m), 1.64-1.84 (2H, m), 1.80 (3H, d, J = 1.2 Hz), 2.28 (3H, d, J = 0.9 Hz) , 2.98 (2H, t, J = 7.2 Hz), 4.46 (2H, dt, J = 47., 5.7 Hz), 7.78 (2H, d, J = 8.4 Hz), 8.07 (2H, d, J = 8. Hz), 9.58 (1H, bs ) elemental analysis:. C _2. H ₂₁ N ₄ 0 _{3 As} S ₃ F

Calculated (¾): C, 49.98; H, 4.40; N, 11.66; S, 20.02.

Found (¾): C, 49.81; H, 4.39; N, 11.54; S, 19.99.

Example 7-192

N- {5,6-Dimethyl-8-[(5-fluoroopentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine -Trilidene} (3-methylphenyl) methanesulfonamide

 It was synthesized in the same manner as in Examples 7-176, and recrystallized from ethyl acetate-jetil ether to obtain dark red crystals having a melting point of 151-153 ° C.

IR (KBr) v: 3204, 2934, 1742, 1663, 1622, 1564 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 1.50-1.66 (2Η, m), 1.66-1.86 (4H, m), 1.80 (3H, s), 2.20

(3H, s), 2.35 (3H, s), 3.01 (2H, t, J = 7.5 Hz), 4.31 (2H, s), 4.47 (2H, dt,

? J = 47.1, 5.7 Hz) , 7.11-7.17 (1H, m), 7.18 7.24 (3H, m), 9.08 (1H, bs) Elementary analysis:. As _{C 21 H 24 N 3 0 3} S 3 F

Calculated value (%): C, 52.37; H, 5.02; N, 8.72; S, 19.97.

Found (%): C, 52.04; H, 5.36; N, 8.75; S, 19.74.

Example 7-193

4-bromo [5,6-dimethyl-3-oxo-8-({[(2S) -5-oxopyrrolidinyl] methyl} sulfael) -2,3-dihydro-1H-imidazo [5,1-c ] [1,] thiazine-toylidene] Nzensulfonamide

 Sodium hydride (purity 60% oil, 43.3 mg, 1.08 mL) was added to a suspension of the compound obtained in Example 6-44 (117 mg, 0.361 tmol) (D THF-DMF (3: 1, 4 ml)) Was added at room temperature, and the mixture was stirred for 15 minutes, 4-bromobenzenesulfonyl chloride (111 mg, 0.433 mL) was added, and the mixture was further stirred for 1.5 hours.The reaction solution was methanol (1 ml) and IN hydrochloric acid (1.1 ml). Then, the mixture was extracted with ethyl acetate, dehydrated and dried, and concentrated to obtain a red oily substance.Ethyl acetate and getyl ether were added thereto, and the precipitate was collected by filtration. 1: 4) and washed with getyl ether, and dried to give the title compound (134 mg, 0.247 ol, 68.3%) as a dark purple powder.

Ή one _{NMR (300MHz, CDC1 3):} 51.80 (3H, s), 1.84 (1H, dd, J = 14.1, 4.5 Hz), 2.27 (3H, s), 2.35 (1H, m), 2.36 (2H, brs ), 2.99 (1H, dd, J = 13.5, 7.5 Hz), 3.13 (1H, dd, J = 13.8, 5.1 Hz), 3.90 (1H, brquint, J = 5.6 Hz), 5.86 (1H, brs), 7.65 (2H, d, J = 8.4 Hz), 7.81 (2H, d, J = 8.4 Hz), 9.63 (1H, brs).

Elemental _{analysis: C 19 H 19 N 4 0} 4 S 3 Br Calculated: C, 41.99; H, 3.52 ; N, 10.31; S, 17.70; Br, 14.70 (%), Found: C, 42.02; H , 3.60; N, 10.28; S, 17.46; Br, 14.95

(%)

rap. 182.0-185. Ot:

Example 7-194

 3-{[(1-{[(4-bromophenyl) sulfonyl] imino}-5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] Thiazine-8-yl) sulfanyl] methyl} -1-butylpiperidinecarboxylate

To a suspension of the compound obtained in Example 6-45 (100 ig, 0.235 bandol) in THF (3 ml) was added sodium hydride (purity 60% oily, 23.5 mg, 0.589 mmol) at room temperature, and the mixture was added for 30 minutes.攪拌後, 4-bromobenzenesulfonyl chloride (72.2 mg, 0.283 mmol) was extracted with added an additional 24 hours攙拌the _p reaction solution are added a 1N hydrochloric acid (1.0 ml) acetic Echiru, dehydrated and dried, and concentrated And diluted with methanol. The precipitate was collected by filtration, washed with methanol, and dried to give the title compound (66 mg, 0.103 t, 43.6) as a gray-violet powder.

'H-NMR (300MHz, CDC1 3): 51.46 (9H, s), 1.40-1.52 (3H, m), 1.65 (1H, dt, J = 8.4, 4.8 Hz), 1.79 (3H, q, J = 0.9 Hz), 1.91 (1H, brd, J = 9.0 Hz), 2.27 (3H, q, J = 1.2 Hz), 2.60-2.80 (1H, br), 2.81 (1H, dd, J = 13.2, 7.2 Hz), 2.90 (1H, dd, J = 12.9, 6.6 Hz), 2.90 (1H, br ), 3.77 (1H, m), 3.80-4.14 (1H, br), 7.64 (2H, d, J = 8.4 Hz), 7.83 (2H, d, J = 8.4 Hz), 9.55 (1H, brs).

Elemental _{analysis: C 25 H 31 N 4 0} 5 S 3 Br Calculated: C, 46.65; H, 4.84 ; N, 8.70; S, 14.95; Br, 12.41 (%), Found: C, 47.29; H , 4.90; N, 8.57; S, 14.72; Br, 12.78 (%).

mp.158.5-160.0 ° C

Example 7-195 '

 (2S, 4R)-2 {[(1-{[(4-bromophenyl) sulfonyl] imino}-5, 6-dimethyl-3-oxo-2,3-dihydrido-1H-imidazo [5,1- c] [1,] thiazin-8-yl) sulfanyl] methylyl} -tert-butyl 4-hydroxy-topyrrolidinecarboxylate

 To a suspension of the crude compound (120 mg, 0.197 mmol) obtained in Example 6-46 in THF (3 ml) was added sodium hydride (purity: 60¾, 23.6 mg, 0.591 orchid ol) at room temperature for 10 minutes. After stirring, 4-chlorobenzenesulfonyl chloride (65.4 mg, 0.256 mmol) was added, and the mixture was further stirred for 2 hours. Methanol (1 ml) and IN hydrochloric acid (1.0 ml) were added to the reaction solution, extracted with ethyl acetate, dried, dried and concentrated to obtain a red oil. This was purified by chromatography on silica gel (7.5 g) (ethyl acetate-hexane, 3: 7-7: 3) and crystallized from ethyl acetate and getyl ether to give the title compound (30 mg, 0.046 mmol, 23.6 mg). ) Was obtained as a purple powder.

! H-NMR (300MHz, CDC1 3): δ 1.48 (9H, s), 1.74 (1Η, d, J = 3.6 Hz), 1.79 (3H, s), 1.94 (1H, ddd, J = 13.5, 7.5, 4.5 Hz), 2.11 (1H, ra), 2.26 (3H, q, J = 0.6 Hz), 3.14 (1H, br), 3.35 (1H, dd, J = 12.3, 4.2 Hz), 3.42 (1H, dd, J = 12.3, 4.2 Hz), 3.64 (1H, br), 4.25 (1H, m), 4.41 (1H, brs), 7.63 (2H, d, J = 8.1 Hz), 7.81 (2H, d, J = 8.4 Hz), 9.60 (1H, brs).

 p. 173.0-174.5 ° C

Example 7-196

N- {5,6-Dimethyl-8-C (5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine -1- To a solution of cyclohexylmercaptan (167 mg, 1.36 mmol) in acetonitrile (13.6 ml) was added potassium nitrate (348 mg, 3.41 mmol), followed by sodium chloride sulfuryl (0.279 ml, 3.41 wakeup), and the mixture was cooled on ice for 2 hours. Stirred. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure to give a hexane sulfonyl chloride cyclohexane as an oil. To a suspension of sodium hydride (25.4 mg, 0.634 tmol) (60% oil) in tetrahydrofuran (2.00 ml) was added the triamino-5,6-dimethyl-8- [obtained in Example 6-23. (5-Fluoropentyl) sulfanyl] -3H-imidazo [5, tric] [1,4] thiazin-3-one (100 mg, 0.317 mmol) in tetrahydrofuran (1.00 ml) was added, and the mixture was cooled under ice-cooling. Stir for a minute. To this was added a solution of cyclohexanesulfonyl chloride obtained above in tetravidrofuran (1.00 ml), and the mixture was further stirred at room temperature for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (44.7 mg, 31%) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 138-140 ° C. Infrared absorption spectrum (IR) (in KBr): 3158, 2936, 2857, 1755, 1665, 1626, 1572, 1375, 1094 cnr ¹ .

_{Ή-NMR (CDC1 3):} δ 1.14-1.38 (4Η, m), 1.48-1.65 (4H, m), 1.65-1.84 (4H, m), 1.81 (3H, d, J = 1.2 Hz), 1.86- 1.95 (2H, m), 2.18-2.30 (2H, m), 2.28 (3H, d, J = 1.2 Hz), 2.92 (1H, dt, J = 8.0, 3.3 Hz), 3.00 (2H, i, J = 7.5 Hz), 4.46 (2H, dt, J = 47.4, 6.0 Hz), 9.50 (1H, bs).

Elementary analysis: as _{C 19 H 2S N 3 0 3} S 3 F

Calculated (%): C, 49.43; H, 6.11; N, 9.10; S, 20.84.

Found (¾): C, 49.27; H, 6.16; N, 9.28; S, 21.10.

Example 7-197

(2S) -2-{[(1-{[(4-bromophenyl) sulfonyl] iminoto 5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4 ] Thiazine-8-yl) sulfanyl] methyl} -topyrrolidinecarboxylic acid tert-butyl

To a suspension of the crude compound obtained in Examples 6-48 (purity 70%, 140 mg, 0.24 mmol) in THF (3 ml) was added sodium hydride (purity 60%, oily, 33.4 mg, 0.835 mmol) at room temperature. In addition, After stirring for 10 minutes, 4-bromobenzenesulfonyl chloride (91 mg, 0.358 mmol) was added, and the mixture was further stirred for 2 hours. 1N Hydrochloric acid (1.0 ml) was added to the reaction solution, extracted with ethyl acetate, dehydrated and dried, and concentrated to obtain a red oil. This was purified by chromatography on silica gel (7.5 g) (ethyl acetate-hexane, 2: 8-4: 6) and crystallized from getyl ether to give the title compound (92 mg, 0.146 mmol, 60.9%) as a purple-red color. Obtained as a powder.

_{Ή-NMR (300MHz, CDC1 3} ): <5 1.47 (9H, s), 1.79 (3H, s), 1.84 (2H, HI), 1.95 (2H, m), 2.27 (3H, s), 2.90-3.15 (1H, br), 3.34 (2H, m), 3.40 (1H, m), 4.04 (1H, m), 7.63 (2¾ d, J = 8.4 Hz), 7.83 (2H, d, J = 8.4 Hz), . 9.59 (1H, brs) elemental _{analysis: C 24 H 29 N 4 0} 5 S 3 Br calculated: C, 45.78; H, 4.64 ; N, 8.90; S, 15.28; Br, 12.69 (%), measured Values: C, 45.87; H, 4.69; N, 8.84; S, 15.01; Br, 12.83 (%).

Melting point: 182.5-184. O

Example 7-198

 4-bromo-N- {8- [(5,5-difluorocyclooctylmethyl) sulfanyl] _5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1- c] [1, 4] thiazine-triylidene} benzenesulfonamide

 Sodium hydride (purity 60% oily, 39.4 mg, 0.984 mmol) was added to a suspension of the compound obtained in Example 6-49 (147 mg, 0.394 tmol) in THF (3 ml) at room temperature, and stirred for 15 minutes. After stirring, 4-bromobenzenesulfonyl (111 mg, 0.433 mmol) was added, and the mixture was further stirred for 3.5 hours. The reaction mixture was added with 1N hydrochloric acid (1.0 ml), extracted with ethyl acetate (30 ml), dried, dried and concentrated to obtain a red oil. This was dissolved in ethyl acetate, and the precipitate was collected by filtration, washed with getyl ether, dried, and dried to give the title compound (209 mg, 0.353 mmol,

89.5%) as a purple powder.

_{Ή-NMR (200MHz, CDC1 3} ): 51.76 (6H, m), 1.82 (3H, s), 2.09 (6H, m), 2.28 (3H, s), 3.54 (1H, m), 7.63 (2H, d , J = 8.8 Hz), 7.83 (2H, d, J = 8.8 Hz), 9.63 (1H, brs).

Elemental _{analysis: C 22 H 24 N 3 0} 3 S 3 BrF 2 Calculated: C, 44.59; H, 4.08 ; N, 7.09; S, 16.23; Br, 13.48; F, 6.41 (%), Found: C, 44.68; H, 4.12; N, 7.06; S, 16.03; Br, 13.24; F, 6.24 (%). Melting point: 197.0-199.5 ° C

Example 7-199 l) -5,6-Dimethyl-3-oxo-2,3-dihydrogen-1H-imidazo [5,1-c] [1,4] thiazine Crude obtained in Example 6-50 Sodium hydride (purity 60% oily, 81.2 mg, 2.03 band01) was added to a suspension of the above compound (purity 70%, 297 mg, 0.58 mmol) in THF (6 ml) at room temperature. After stirring for 15 minutes, chloride was added. 4-Bromobenzenesulfonyl (193 mg, 0.754 mmol) was added, and the mixture was further stirred for 2 hours. Methanol (1 m 1) and 1 N hydrochloric acid (2.0 m 1) were added to the reaction solution, and the mixture was stirred for 1 hour. The precipitate is collected by filtration, washed with methanol-water (3: 1 and 1: 1) and methanol, dried, and dried to give the title compound (3: 1 isomer mixture, 209 mg, 0.364 cellulose, 62.7%) Was obtained as a red-orange powder.

¾- testimony _{(300MHz, CDC1 3, major /} minor): δ 0.94 / 0.75 (2Η, m / q, J = 12.3Hz), 1.32 (2H, m), 1.48-1.70 (3H, in), 1.80 (3H , q, J = 0.9 Hz), 1.76-1.97 (4H, m), 2.27 (3H, q, J = 1.2 Hz), 2.85 / 2.95 (2H, d / dd, J = 6.6 / 7.2, 1.8 Hz), 4.22 (1H, ddd, J = 47.4, 8.7, 6.0 Hz, major), 4.26 (1H, ddd, J = 47.4, 8.7, 5.1 Hz, major), 4.30 (2H, ddd, J = 47.4, 6.3, 0.9 Hz) , minor), 7.61 (2H, dt, J = 9.0, 2.2 Hz), 7.83 (2H, dt, J = 8.7, 1.6 Hz), 9.61 (1H, brs).

Elemental _{analysis: C 22 H 25 N 3 0} 3 S 3 Calculated BrF: C, 45.99; H, 4.39; N, 7.31; S, 16.74; Br, 13.91; F, 3.31 (), Found: C "45.96; H, 4.32; N, 7.20; S, 16.61; Br, 13.68; F, 3.46 (%).

Melting point: 195.0- 197.

Example 7-200

 4-bromo-N- (5,6-dimethyl-8-{[(trimethylcyclohexyl) methyl] sulfanyl} -3_oxo_2,3-dihydro-1H-imidazo [5,1-c] [ [1, 4] thiazine-1-ylidene) benzenesulfonamide

To a suspension of the compound obtained in Example 6-51 (120 mg, 0.355 bandol) in THF (3 ml) was added sodium hydride (purity 60% oil, 35.6 mg, 0.889 bandol) at room temperature, and the mixture was added for 15 minutes. After stirring, 4-bromobenzenesulfonyl chloride (100 mg, 0.391 tmol) was added, and one more portion was added. Stirred for hours. Methanol (lml) and IN hydrochloric acid (1.0 ml) were added to the reaction solution, and the mixture was diluted with water (2 ml). The precipitate was collected by filtration, washed with methanol (1: 1), methanol and getyl ether, and dried to give the title compound α (80 mg, 0.324 mmol, 91.1%) as a purple powder.

'H-NMR (300MHz, CDC1 3): 1.00 (3H, s), 1.38 (5H, br), 1.47 (5H, br), 1.80 (3H, q, J = 0.6 Hz), 2.27 (3H, brs) , 2.94 (2H, s), 7.60 (2H, d, J = 8.2 Hz), 7.86 (2H, d, J = 8.4 Hz), 9.58 (1H, brs).

Elemental _{analysis: C 22 H 26 N 3 0} 3 S 3 Br Calculated: C, 47.48; H, 4.71 ; N, 7.55; S, 17.28; Br, 14.36 (%), Found: C, 47.35; H , 4.62; N, 7.46; S, 17.00; Br, 14.63 (%).

Example 7-201

 N- (3 _ {[1-({[4_ (acetylamino) phenyl] sulfonyl} imino) -5,6-dimethyl-3-oxo-2,3-dihydro-m-imidazo [5,1-c] [1,4] Thiazine-8-yl] sulfani Sodium hydride (purity 60% oil, 48.0 rag) was added to a suspension of the compound obtained in Example 6-39 (153 mg, 0.400 mmol) in THF (5 ml). , 1.20 bandol) at room temperature and stirred for 10 minutes, and then Shio-Dai 4-acetamidobenzenesulfonyl (116 mg, 0.480 liter) was added, and the mixture was further stirred for 2 hours. Then, IN hydrochloric acid (1.5 ml) and water (20 ml) were added, and the mixture was extracted with ethyl acetate (30 ml) .The organic layer was washed with 0.1N hydrochloric acid, water and saturated saline, dried over sodium sulfate, and concentrated. The precipitate was collected by filtration, washed with ethyl acetate and getyl ether, and dried to give the title compound (161 mg, 0.278 mol, 69.4%) as a gray-red powder.

'H-NMR (200MHz, CDCl ₃ -DMSO-d ₆ = 9: 1): (50.89 (3H, t, J = 6.6 Hz), 1.30 (4H, m), 1.62 (2H, brquint, J = 7.5 Hz) ), 1.79 (3H, s), 1.86 (2H, quint, J = 6.3 Hz), 2.16 (2H, t, J = 7.7 Hz), 2.17 (3H, s), 2.26 (3H, s), 2.97 (2H , t, J = 7.5 Hz), 3.27 (2H, q, J = 6.2 Hz), 6.84 (1H, brt, J = 6 Hz), 7.74 (2H, d, J = 8.8 Hz), 7.87 (2H, d , J = 9.0 Hz), 9.68 (1H, brs), 10.23 (1H, br).

Elemental analysis: C ₂₅ H ₃₃ N ₅ 0 ₅ S ₃ O.5¾0 Calculated: C, 51.00; H, 5.82; N, 11.90; S, 16.33 (%), found: C, 50.82; H, 5.90 ; N, 11.80; S, 16.54 (). mp.187-189 ° C

Example 7-202

 4-chloro-N- [8- (cycloheptylsulfanyl) -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1 -Ylidene] benzenesulfonamide

 To a suspension of the compound obtained in Example 6-15 (207 mg, 0.640 mol) in THF (4 ml) was added sodium hydride (purity 60% oily, 56.3 mg, 1.41 mol) at room temperature, and the mixture was added for 10 minutes. After stirring, 4-benzene benzenesulfonyl chloride (149 mg, 0.704 mol) was added, and the mixture was further stirred for 40 minutes. 1N Hydrochloric acid (0.77 ml) was added to the reaction solution, and ethyl acetate was added for extraction, washed with 0.1 hydrochloric acid and saturated saline, dried and concentrated. Getyl ether was added to the residue, the precipitate was collected by filtration, washed with getyl ether, and dried to give the title compound (234 mg, 0.470 mmol) as a purple powder.

_{Ή-NMR (200MHz ,, CDC1 3} ): (51.50-1.80 (10H, m), 1.80 (3H, q, J = 1.2 Hz), 2.05 (2H, DI), 2.27 (3H, q, J = 1.2 Hz ), 3.52 (1H, dt, J = 4.0, 9.2 Hz), 7.46 (2H, dt, J = 8.8, 2.2 Hz), 7.92 (2H, dt, J = 8.8, 2.2 Hz), 9.60 (1H, brs) .

Elemental _{analysis: C 21 H 24 N 3 0} 3 S 3 C1 Calculated: C, 50.64; H, 4.86 ;, 8.44; S, 19.31; CI, 7.12 (%), Found: C, 50.52; H, 4.76 ; N, 8.40; S, 19.44; CI, 7.05 (¾).

Melting point: 178.0-179.0 ° C

Example 7-203

4-Chloro-N- {5,6-dimethyl-8-[(4-methylpentyl) sulfanyl] -3-oxo-2,3-dihydric-1H-imidazo [5,1-c] [1, ] Thiazine-1-ylidene} benzenesulfonamide

To a suspension of the compound obtained in Example 6-17 (203 mg, 0.628 mraol) in THF (4.0 ml) was added sodium hydride (purity 60% oil, 62.8 mg, 1.57 acetyl) at room temperature, and the mixture was added for 30 minutes. After stirring, 4-chlorobenzenebenzenesulfonyl chloride (146 mg, 0.690 liter) was added, and the mixture was further stirred for 3.5 hours. The reaction solution was diluted with ethyl acetate, washed with 0.1N hydrochloric acid and saturated saline, dried and concentrated. Methanol was added to the residue, and the precipitate was collected by filtration, washed with methanol, and dried to give the title compound (268 mg, 0.539 bandol) as a red powder. _{^ - MR (300MHz, CDC1 3} ): δ 0.96 (2Η, brq, J = 11.9 Hz), 1.22 (3H, m), 1.54 (1H, quint, J- 3.7 Hz), 1.67-1.87 (5H, m), 1.80 (3H, q, J = 0.9 Hz), 2.27 (3H, q, J = 0.9 Hz), 2.83 (2H, d, J = 6.9) Hz), 7.45 (2H, dt, J = 9.0, 2.4 Hz), 7.92 (2H, dt, J = 8.7, 2.1 Hz), 9.60 (1H, brs).

Elemental _{analysis: C 21 H 24 N 3 0} 3 S 3 C1 Calculated: C, 50.64; H, 4.86 ; N, 8.44; S, 19.31; CI, 7.12 (%), Found: C, 50.60; H , 4.75; N, 8.62; S, 19.18; CI, 7.08 (¾). Melting point: 198.5-199.5 ° C

Example 7-204

 4- ク 口 口 -N- {5,6-dimethyl-8-[(4-methylpentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1, 4] thiazine-1-ylidene} benzenesulfonamide

Sodium hydride (purity 60% oily, 46.6 mg, 1.17 t) was added to a suspension of the compound obtained in Example 6-16 (165 mg, 0.530 t) in THF (3.5 ml) at room temperature. After stirring for one minute, 4-chlorobenzenebenzenesulfonyl chloride (123 mg, 0.583 ol) was added and the mixture was further stirred for 2.5 hours. The reaction solution was diluted with ethyl acetate, washed with 0.1N hydrochloric acid and saturated saline, dried and concentrated. Methanol was added to the residue, the precipitate was collected by filtration, washed with methanol, and dried to give the title compound (154 mg, 0.317 mmol) as a purple powder. 'H-NMR (200MHz, CDC1 3): 50.90 (6H, d, J = 6.6 Hz), 1.28 (2H, brq, J = 7.7 Hz), 1.59 (1H, quint, J = 6.4 Hz), 1.68 (2H , m), 1.79 (3H, brs), 2.28 (3H, brs), 2.93 (2H, brt, J = 7.5 Hz), 7.46 (2H, d, J = 8.4 Hz), 7.91 (2H, d, J = 8.4 Hz), 9.62 (1H, brs).

Elemental _{analysis: C 2fl H 24 N 3 0} 3 S 3 Calculated Cl: C, 49.42; H, 4.98; N, 8.64; S, 19.79; CI, 7.29 (¾), Found: C, 49.44; H , 5.03; N, 8.70; S, 19.76; CI, 7.28 (¾). Melting point: 163.0-163.5 ° C

Example 7-205

4-Promo-N- [8- (cycloheptylsulfaninole) -5,6-dimethisole-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine -1-ylidene] benzenesulfonami K

To a suspension of the compound obtained in Example 6-15 (175 mg, 0.562 benzyl) in THF (3.5 ml) was added sodium hydride (purity 60%, oily, 56.2 mg) at room temperature, and the mixture was stirred for 10 minutes. chloride 4-Bromobenzenesulfonyl (222 mg, 0.850 mol) was added, and the mixture was further stirred for 50 minutes. The reaction mixture was diluted with ethyl acetate, washed with 0.1N hydrochloric acid, water, and saturated saline, dried and concentrated. Methanol was added to the residue, and the precipitate was collected by filtration, washed with methanol, and dried to give the title compound (234 mg, 0.470 bandol) as a purple powder. 'H-NMR (200 MHz, double-mouthed form): δ 1.50-1.75 (10H, m), 1.80 (3H, q, J = 0.8 Hz), 2.05 (2H, m), 2.27 (3H, q, J = 1.2 Hz), 3.59 (1H, sept, J = 4.4 Hz), 7.62 (2H, dt, J = 8.8, 2.2 Hz), 7.84 (2H, dt, J = 8.8, 2.2 Hz), 9.66 (1H, brs) . elemental _{analysis: C 21 H 24 N 3 0} 3 S 3 Br calculated: C, 46.49; H, 4.46 ; N, 7.75; S, 17.73; Br, 14.73 (), Found; C, 46.55; H , 4.57; N, 7.81; S, 17.73; Br, 14.40 (%).

 Melting point: 190.0-191.5 ° C

 Example 7-206

 4-Bromo-N- {5,6-dimethyl-8-[(4-methylpentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] Thiazine-1-ylidene} benzenesulfonamide,

 To a suspension of the compound obtained in Example 6-16 (175 mg, 0.562 t ol) in THF (3.5 ml) was added sodium hydride (purity 60% oily, 56.2 mg, 1.41 t ol) at room temperature. After stirring for 4 minutes, 4-bromobenzenesulfonyl chloride (mg, 0.618 ml) was added, and the mixture was further stirred for 45 minutes. 1N Hydrochloric acid (1.41 ml) and methanol-water (1: 1) were added to the reaction solution, and the mixture was stirred for 10 minutes. The precipitate was collected by filtration, washed with methanol-water (1: 1) and methanol, and dried to give the title compound (165 mg, 0.311 bandol) as a red-purple powder. 'H-NMR (300 MHz, double-mouthed form): δ 0.90 (6Η, d, J = 6.6 Hz), 1.26 (1H, brt, J = 6.9 Hz), 1.29 (1H, brt, J = 6.6 Hz), 1.56 (1H, m), 1.67 (1H, m), 1.68 (1H, quint, J = 7.7Hz), 1.80 (3H, q, J = 0.9 Hz), 2.28 (3H, q, J = 0.9 Hz), 2.93 (2H, t, J = 7.5 Hz), 7.63 (2H, dt, J = 9.0, 2.1 Hz), 7.84 (2H, dt, J = 8.7, 2.1 Hz), 9.60 (1H, brs).

Elemental _{analysis: C 20 H 24 N 3 0} 3 S 3 Br Calculated: C, 45.28; H, 4.56 ; N, 7.92; S, 18.13

(%), Found; C, 45.16; H, 4.42; N, 7.68; S, 18.01 (%).

Melting point: 184.5-185. (TC Example 8-1

 N- [5,6-Dimethyl-3-oxo-8- (pentylsulfanyl) -2,3-dihydro-1H-imida'azo [5, l_c] [1,4] thiazine-1-ylidene] -4-Methylbenzoic acid amide

 Method A.

Triamino-5,6-dimethyl 8- (pentylsulfanyl) -3H-imidazo [5, tric] [1,4] thiazin-3_one obtained in Example 6-1 (150 mg, 0.504 ol Was dissolved in pyridine (3.00 ml), and 4-methylbenzoyl chloride (0.102 ml, 0.756 ol) was added. After stirring the reaction mixture at room temperature for 18 hours, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (82.9 mg, 40%) as dark red crystals. Recrystallization from ethyl acetate-ethyl ether gave dark red crystals.

 Method B

Triamino-5,6-dimethyl-8- (pentylsulfanyl) -3H-imidazo [5,1-c] [1,4] thiazin-3-one obtained in Example 6-1 (150 mg, 0.504 Ol) was dissolved in tetrahydrofuran (3.00 ml), and 4-methylbenzoyl chloride (0.102 ml, 0.756 t ol) and triethylan (0.141 ml, 1.01 t ol) were sequentially added. After stirring the reaction mixture at room temperature for 18 hours, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (74.3 mg, 36%) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 196-198 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3285, 2071, 2955, 2936, 2861, 1736, 1661, 1603, 1549, 1508 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 0.949 (3Η, t, J = 7.0Hz), 1.30-1.58 (4H, m), 1.70-1.88 (2H, m), 1.83 (3H, d, J = 1.0 Hz) , 2.34 (3H, d, J = l. Hz), 2.41 (3H, s), 3.06 (2H, t, J = 7.4 Hz), 7.24 (2H, d, J-8.0 Hz), 8.23 (2H, d , J = 8.4 Hz), 11.09 (1H, bs). Elemental analysis: C ₂₁ H ₂₅ N ₃ 0 ₂ S ₂

 Calculated value (%): C, 60.69; H, 6.06; N, 10.11; S, 15.43.

Found (%): C, 60.64; H, 5.90; N, 10.02; S, 15.50. Example 8-2

 N- [5,6-Dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene] 2-phenylacetic acid amide

 Example 8-1 In the same manner as in Method B, except that phenylacetyl chloride (0.0504 ml, 0.363 t ol) was used instead of 4-methylbenzoyl chloride, 1-7 mino-5 obtained in Example 6-2 was used. 6-Dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5,1-c] [1,4] thiazin-3-one (90.0 mg, 0.303 t.1) from the title compound (59.1 rag, 47%). The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 152-153 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3196, 2955, 2928, 2868, 1746, 1620, 1599, 1541, 1495 cm- ¹ .

_{NMR (CDC1 3): δ 0.968} (6Η, d, J = 6.4 Hz), 1.38-1.74 (3H, m), 1.80 (3H, s), 2.30 (3H, s), 2.88-3.05 (2H, m) , 3.83 (2H, s), 7.29-7.40 (5H, m), 10.81 (1H, bs)

Elementary analysis: as _{C 21 H 25 N 3 0 2} S 2

Calculated value (%): C, 60.69; H, 6.06; N, 10.11; S, 15.43.

Found (%): C, 60.60; H, 5.99; N, 9.99; S, 15.35.

Example 8-3

 N- [5,6-Dimethyl-3-oxo-8- (pentylsulfanyl) -2,3-dihydrido-1H-imidazo [5,1-c] [1,4] thiazine-triylidene] -4-Trifluoromethylbenzoylamide Example 8-1 By the same method as in Method B, 4-trifluoromethylbenzoyl chloride (71.6 mg, 0.333 t) was used in place of 4-methylbenzoyl chloride. Thus, 1-amino-5,6-dimethyl-8- (isopentylsulfanyl) -3H-imidazo [5, tric] [1,4] thiazine-3--obtained in Example 6-2. The title compound (82.0 mg, 57%) was synthesized from ON (90.0 mg, 0.303 mmol). The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 186-188 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3272, 3071, 2967, 2963, 2921, 2878, 1732 cm " ¹ .

Ή— NMR (CDCL): δ 1.00 (6Η, d, J = 6.4 Hz), 1.62-1.84 (3H, m), 1.85 (3H, s), 2.36 (3H, s), 3.09 (2H, t, J = 7.6 Hz), 7.70 (2H, d, J = 8.4 Hz), 8.43 (2H, d,

J = 8.2 Hz), 11.11 (1H, bs).

Elemental analysis: C ₂₁ H ₂₂ N ₃ 0 ₂ S ₂ F ₃ -0.4¾0

Calculated (%): C, 52.91; H, 4.82; N, 8.81; S, 13.45.

Found (¾): C, 52.90; H, 4.72; N, 8.60; S, 13.47.

The following is a list of compounds synthesized in Examples 8-1 to 8-3 and compounds synthesized in the same manner.

(Table 9 1)

Replacement paper (ΜΜ2β) (Table 9 2)

For replacement (Rule 26) (Table 93)

Replacement form (rules) The data of the compounds synthesized in Examples 8-4 to 8-31 are shown below.

Example 8-4

_{¾-NMR (CDC1 3, 300} MHz): δ 2.84 (2H, t, J = 7.3 Hz), 3.35 (2H, t, J = 7.3 Hz), 3.74 (3H, s), 5.11 (1H, d, J = 8.0 Hz), 6.78 (1H, d, J = 8.0 Hz), 7.46 (2H, brt, J = 7.4 Hz), 7.55 (1H, brt, J = 7.2 Hz), 8.31 (2H, brd, J = 7.2) Hz), 11.22 (1H, brs).

Elemental _{analysis: C 17 H 15 N 3 0} 4 S 2 Calculated: C, 52.43; H, 3.88 ; N, 10.79; S, 16.47

(%), Found: C, 52.51; H, 3.91;, 10.89; S, 16.43 (%).

Example 8-5

Ethyl 5-({5,6-dimethyl-1- [4- (methylbenzoyl) imino] -3_oxo-2,3-dihydro-1H-imidazo [5, l_c] [1,4] thiazine-8 {Sulfanyl) pentyl 5- [1-amino-5,6-dimethyl-3-oxo-311-imidazo [5,1-c] [l, 4] obtained in Example 6-24. [Thiazine-8_yl] sulfanyl] pennoate (600 mg, 1.49 t) and riethylamine (0.312 ml, 2.24 t) in tetrahydrofuran (6.00 ml), p-tolyl chloride (0.224 ml, 1.64 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 22 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. Washed with water extract exudates, dried (MgSO _4), the solvent was evaporated under reduced pressure to give the title compound (430 mg, 61¾) was synthesized. The crystals were recrystallized from ethyl acetate-getyl ether to obtain dark red crystals having a melting point of 163-165 ° C.

IR (KBr) ν: 3275, 306, 2980, 2905, 1738, 1603, 1547, 1508 cm " ¹ .

_{¾-NMR (CDC1 3):} (51.27 (3H, d, J-7.2 Hz), 1.76-1.88 (4H, m), 1.84 (3H, s), 2.34 (3H, d, J = 1.2 Hz), 2.36 -2.44 (2H, m), 2.41 (3H, s), 3.02-3.12 (2H, m), 4.15 (2H, q, J = 7.2 Hz), 7.25 (2H, d, J = 7.2 Hz), 8.22 ( 2H, d, J = 8.1 Hz), 11.08 (1H, bs).

Elemental analysis f straight: as _{C 23 H 27 N 3 0 4} S 2

Calculated value (¾): C, 58.33; H, 5.75;, 8.87; S, 13.54.

Found (¾): C, 57.95; H, 5.86;, 8.75; S, 13.68.

Example 8-6

5,6-dimethyl _1 ._ [({[(4-methylphenyl) sulfonyl] amino} carbonyl) imi [No] -3-oxo-8-[(5,5,6,6,6-pentylfluorohexyl) sulfanyl] -2,3-dihydro-1H-imidazo [5, tric] [1, 4] thiazine

 To a suspension of the compound obtained in Example 6-6 (223 mg, 0.556 mmol) in THF (4.0 ml) was added P-toluenesulfonyl isocyanate (123 mg, 0.611 mmol) at room temperature, and the mixture was stirred for 20 minutes. did. To the reaction mixture was added getyl ether (10 ml), and the precipitate was collected by filtration, washed with getyl ether, and dried to obtain the title compound (227 mg, 0.379 marl, 68.2%) as a brown-purple powder. Was. ,

_{lH- NMR (300MHz, CDC1 3)} : δ 1.78 (4Η, m), 1.80 (3H, q, J = 1.2 Hz), 2.08 (2H, m), 2.28 (3H, q, J = 0.9 Hz), 2.44 (3H, s), 3.00 (2H, t, J = 7.1 Hz), 7.33 (2H, d, J = 8.4 Hz), 7.97 (2H, d, J = 8.1 Hz), about 10.3 (1H, br).

Elemental _{analysis: C 22 l N 4 0 4} S 3 F 5 Calculated: C, 44.14; H, 3.87 ; N, 9.36; S, 16.07; F, 15.87 (%), Found: C, 43.90; H , 3.77; N, 9.38; S, 16.34 (%).

mp.132.5-135.5 ° C

Example 8-7

8-[(5-Fluoropentyl) sulfanyl] _5,6-dimethyl -1 _ [({[(4_methylphenyl) sulfonyl] amino} capillonyl) imino] -3-oxo-2,3-dihydro-1H-imida Zo [5, u c] [1,4] thiazine ''

 To a suspension of the compound (212 mg, 0.625 alcohol) obtained in Example 6-23 in THF (4.0 ml) was added P-toluenesulfonyl isocyanate (139 mg, 0.688 mol) at room temperature, and the mixture was stirred for 20 minutes. did. To the reaction mixture was added getyl ether (10 ml), and the precipitate was collected by filtration, washed with getyl ether, and dried to obtain the title compound (196 mg, 0.382 band-oI, 61.2%) as a purple powder.

_{NMR (300MHz, CDC1 3):} 51.59 (2H, m), 1.73 (4H, m), 1.79 (3H, s), 2.28 (3H, s), 2.44 (3H, s), 3.00 (2H, t, J = 7.2 Hz), 4.47 (2H, dt, J = 47.4, 5.7 Hz), 7.33 (2H, d, J = 8.4 Hz), 7.97 (2H, d, J = 8.1 Hz), about 10.3 (1H, br) .

Elemental analysis: Calculated for C ₂₁ H ₂₅ N ₄ 0 ₄ S ₃ F: C, 49.20; H, 4.92; N, 10.93; S, 18.76

(), Found: C, 48.89; H, 4.93; N, 11.12; S, 18.96 (%).

Immediately.116.0-118.0 ° C.

Example 8-8 5, 6-dimethyl-1-[({[(4-methylphenyl) sulfonyl] amino} aminopropionyl) imino] -3-oxo-8-[(4,4,5,5,5- Fluoropentyl) sulfanyl] -2,3-dihydro-1H-imidazo [5, l_c] [1,4] thiazine

 To a suspension of the compound obtained in Example 6-3 (209 mg, 0.540 mol) in THF (4.0 ml) was added P-toluenesulfonyl isocyanate (119 mg, 0.593 mol) at room temperature, and the mixture was stirred for 40 minutes. Stirred. To the reaction solution was added getyl ether (10 ml), and the precipitate was collected by filtration, washed with getyl ether, and dried to obtain the title compound (255 mg, 0.436 mmol, 80.8%) as a purple powder. .

'H-NMR (300MHz, CDC1 3): δ 1.80 (3Η, s), 2.05 (2H, q, J = 7.2 Hz), 2.20 (2H, m), 2.28 (3H, s), 2.44 (3H, s ), 3.06 (2H, t, J = 7.4 Hz), 7.33 (2H, d, J = 8.1 Hz), 7.97 (2H, d, J = 8.1 Hz), 10.27 (1H, br).

Elemental _{analysis: C 21 H 2l N 4 0} 4 S 3 F 5 Calculated: C, 43.14; H, 3.62 ;, 9.58; S, 16.45

(%), Found: C, 43.00; H, 3.51; N, 9.50; S, 16.54 (%).

mp.143.5-145.5 ° C

Examples 8-9

 N- {5,6-Dimethyl-3-oxo-8-[(5,5,6,6,6-pentylfluorohexyl) sulfanyl] -2,3-dihydro-1H-imidazo [5, 1-c] [1,4] thiazine-1-ylidene} -Ν '-(4-methylphenyl) ゥ rea

 Sodium hydride (purity 60% oily, 49.8 mg, 1.25 mmol) was added to a suspension of the compound (200 mg, 0.498 mmol) obtained in Example 6-6 in THF (4.0 ml) at room temperature, and the mixture was stirred for 10 minutes. A solution of P-tolyl isocyanate (77 mg, 0.548 mmol) in THF (1 ml) was added dropwise over 1 hour, and the mixture was further stirred for 30 minutes. The reaction solution was diluted with ethyl acetate (35 ml), washed with 0.1N hydrochloric acid, water and saturated saline, and dried over sodium sulfate. After concentration to dryness, the residue was diluted with methanol. The precipitate was collected by filtration, washed with methanol, and dried to give the title compound (227 mg, 0.425%, 85.3%) as a dark purple powder.

'H-NMR (200MHz, CDC1 3): δ 1.79 / 1.81 (3H, s), about 1.8 (4H, m), 2.10 (2H, m), 2.32 / 2.29 (3H, s), 2.34 / 2.32 (3H , s), 3.03 (2H, t, J = 7.2 Hz), 7.14 (2H, d, J = 7.8 Hz), 7.43 (2H, d, J = 7.8 Hz), 9.37 / 7.39 (1H, brs), 10.86 /10.69 (1H, brs). Elemental _{analysis: C 22 H 23 N 4 0} 2 S 2 F 5 Calculated: C, 49.43; H, 4.34 ; N, 10.48; S, 12.00; F, 17.77 (), Found: C, 49.66; H , 4.10; N, 10.52; S, 11.91; F, 17.56

(%). '

mp. 122.0-123.O:

Example 8-10

 N- {8-[(5-Fluoropentyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1- Ylidene} -Ν '-(4-methylphenyl) urea

 To a suspension of the compound obtained in Example 6-23 (210 mg, 0.666 mmol) in THF (4.0 ml) was added sodium hydride (purity 60% oil, 66.6 mg, 1.66 mol) at room temperature. After stirring for 1 minute, a solution of P-tolyl isocyanate (103 mg, 0.732 ranol) in THF (1 ml) was added dropwise over 30 minutes, and the mixture was further stirred for 30 minutes. Ethyl acetate (35 ml) and 0.2N hydrochloric acid (20 ml) were added to the reaction solution, and the organic layer was washed with 0.1N hydrochloric acid, water and saturated saline, and then dried over sodium sulfate. After concentration to dryness, the residue was diluted with methanol. The precipitate was collected by filtration, washed with methanol, and dried to give the title compound (239 mg, 0.533 mol, 80.0%) as a red-brown powder.

_{lH-NMR (200MHz, CDC1 3} ): δ 1.60 (2Η, m), 1.79 (3H, s), 1.80 (4H, i), 2.32 / 2.29

(3H, s), 2.39 / 2.43 (3H, s), 3.02 (2H, t, J = 7.4 Hz), 4.47 (2H, dt, J = 47.2,

5.6 Hz), 7.14 (2H, d, J- 8.0 Hz), 7.44 / 7.41 (2H, d, J = 8.4 / 8.0 Hz), 9.41 / 7.36 (1H, brs), 10.89 / 10.71 (1H, ¾rs).

Elemental _{analysis: C 21 H 25 N 4 0} 2 S 2 F.0.5H 2 0 Calculated: C, 55.12; H, 5.73 ;, 12.24;

S, 14.02; F, 4.15 (%), Found: C, 55.12; H, 5.78; N, 12.21; S, 13.97; F,

4.03 ().

Immediately. 99.5-101.5 ° C

Examples 8-11

 N- {5,6-Dimethyl-3-oxo_8-[(4,4,5,5,5-pentanofluoropentyl) sulfanyl] -2,3-dihydro-1H-imidazo [5, tric] [ 1,4] thiazine-1-ylidene} -Ν '_ (4-methylphenyl) ゥ rea

Hydrogen was added to a suspension of the compound obtained in Example 6-3 (210 mg, 0.542 acetyl) in THF (4.0 ml). Add sodium iodide (purity 60% oily, 54.2 mg, 1.36 t) at room temperature, stir for 10 minutes, and add a solution of P-tolyl isocyanate (84 mg, 0.596 b) in THF (1 nil) for 60 minutes. The mixture was added dropwise and stirred for another 30 minutes. Ethyl acetate (35 ml) and 0.2N hydrochloric acid (20 ml) were added to the reaction solution, and the organic layer was washed with 0.1N hydrochloric acid, water and saturated saline, and then dried over sodium sulfate. After concentration to dryness, the residue was diluted with methanol. The precipitate was collected by filtration, washed with methanol, and dried to give the title compound (205 mg, 0.394 mmol, 72.7%) as a purple powder.

Ή one _{NMR (200MHz, CDC1 3):} δ 1.80 / 1.81 (. 3Η, s), 2.11 (2Η, m), 2.20 (2Η, m), 2.32 / 2.29 (3H, S), 2.33 / 2.34 (3H, s), 3.09 / 3.06 (2H, t, J = 7.0 / 5.8 Hz), 7.14 / 7.13 (2H, d, J = 8.0 / 8.2 Hz), 7.44 / 7.41 (2H, d, J = 8.2 / 8.0 Hz) , 9.30 / 7.34 (1H, brs), 10.86 / 10.69 (1H, brs).

Elemental analysis: C ₂₁ N ₄ 0 ₂ S ₂ F ₅ Calculated: C, 48.45; H, 4.07; N, 10.76; S, 12.32; F, 18.25 (%), found: C, 48.57; H, 3.91; N, 10.84; S, 12.36; F, 18.22 (%).

 mp.127.0-128.5 ° C

 Example 8-12

 N- (4-bromophenyl) -N '-{8-[(5-fluoropentyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydric -1H-imidazo [5,1-c ] [1,] thiazine-1-ylidene

 To a suspension of the compound (176 mg, 0.558 mmol) obtained in Example 6-23 in THF (3.5 ml) was added sodium hydride (purity 60% oily, 55.8 mg, 1.39 acetyl) at room temperature, and the mixture was stirred for 10 minutes. Thereafter, 4_bromophenyl isocyanate (125 mg, 0.614 mmol) was added, and the mixture was further stirred for 60 minutes. Methanol (1 ml) and 1N hydrochloric acid (2.0 ml) were added to the reaction solution, and the mixture was diluted with methanol-one water (1: 1, 15 ml) and stirred for 10 minutes. The precipitate was collected by filtration, washed with methanol-water (1: 1) and methanol, and dried to give the title compound (274 mg, 0.534 bandol, 95.7%) as a red powder.

'H-NMR (200MHz, CDC1 3): 51.64 (2H, m), 1.80 (3H, s), 1.80 (4Η, m), 2.34 / 2.29 (3Η, s), 3.03 (2H, t, J = 7.5 Hz), 4.47 (2H, dt, J = 46.8, 5.4 Hz), 7.45 (4H, m), 9.44 (1H, brs), 11.07 / 10.66 (1H, brs). mp. 150-152 ^

Examples 8-13

N- {5,6-Dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydroxy mouth _ m -imidazo [5, tric] [1,4] thiazine-triidendent 4-Methylbenzamide To a suspension of sodium hydride (25.4 mg, 0.634 ol) (60% oil) in tetrahydrofuran (2.00 ml) was added triamino-5,6-dimethyl 8 obtained in Example 6-23. -[5-Fluoropentyl] sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (100 mg, 0.317 mmol) in tetrahydrofuran (1.00 ml) was added, and the mixture was cooled on ice. Stir for 5 minutes. To this was added a solution of p-toluyl chloride (0.0475 ml, 0.349 hall) in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 30 minutes. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (117 mg, 85%) as a dark red crystals. Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 195-197 ° C.

IR (KBr) V: 3247, 2961, 1732, 1603, 1547, 1507 cm " ¹ .

_{Ή-NMR (CDC1 3):} (51.50-1.92 (6H, m), 1.84 (3H, d, J = 0.6 Hz), 2.34 (3H, d, J = 0.6 Hz), 2.42 (3H, s), 3.08 (2H, t, J = 7.5 Hz), 4.49 (2H, dt, J-47.1, 5.7 Hz), 7.24 (2H, d, J-8.1 Hz), 8.22 (2H, d, J = 8.1 Hz), 11.09 (1H, bs). Elemental analysis: C ₂₁ H ₂₄ N ₃ 0 ₂ S ₂ F

Calculated (%): C, 58.17; H, 5.58; N, 9.69; S, 14.79.

Found (%): C, 58.30; H, 5.66; N, 9.76; S, 14.80.

Example 8-14

 4-Bromo-2-[({5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4 ] Thazin-1-ylidene} amino] phenyl] phenyl acetate

 The compound was synthesized in the same manner as in Examples 8 to 13, and recrystallized from ethyl acetate-getyl ether to obtain dark red crystals having a melting point of 220 to 222 ° C.

IR (KBr): 3241, 2957, 2938, 2859, 1757, 1736, 1638, 1603, 1557 cm— ^1. 'H-NMR (CDCI3): δ 1.62-1.78 (4Η, m), 1.78-1.92 (2H , m), 1.81 (3H, s), 2.35 (3H, s), 2.37 (3H, s), 3.09 (2H, t, J = 7.2 Hz), 4.47 (2H, dt, J = 47.4, 6.3 Hz) / 6.95 (1H, d, J = 7.8Hz), 7.60 (1H, dd, J = 8.1, 1.8 Hz), 8.76 (1H, d, J-2.7 Hz), 10.92 (1H, bs).

Elementary analysis: as _{C 22 H 23 N 3 0 4} S 2 BrF

Calculated value (%): C, 47.48; H, 4.17; N, 7.55; S, 11.52.

Found (%): C, 47.45; H, 4.07; N, 7.52; S, 11.37.

Example 8-15

 4-Buguchimo-N- {5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1, 4] Thiazine-1-ylidene} -2-hydroxybenzamide

 The compound was synthesized in the same manner as in Example 8-13, and recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 224-226 ° C.

IR (KBr) V: 3700-2700, 3303, 2922, 1742, 1601, 1541 cm " ¹ .

_{Ή-NMR (CDC1 3):} δΐ.58-1.96 (6Η, m), 1.86 (3H, d, J = 0.9 Hz), 2.36 (3H, d,

J = 1.2 Hz), 3.14 (2H, t, J = 7.2 Hz), 4.48 (2H, dt, J = 47.1, 6.0 Hz), 6.83 (1H, d, J = 8.7 Hz), 7.47 (1H, dd, J = 9.0, 3.0 Hz), 8.37 (1H, s), 12.20 (1H, bs). Elemental analysis: C _2fl H ₂₁ N ₃ 0 ₃ S ₂ BrF 3 0

Calculated value (%): C, 46.21; H, 4.19; N, 8.08; S, 12.34.

Found (%): C, 46.17; H, 4.10; N, 8.07; S, 12.18.

Example 8-16

 N- {5,6-Dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihido mouth-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene } Nicotinamide

 It was synthesized in the same manner as in Examples 8-13, and recrystallized from ethyl acetate-getyl ether to obtain dark red crystals having a melting point of 187-189 ° C.

IR (KBr) Re: 2936, 1728, 1661, 1622 , 1572, 1547 cm one ^1.

! H-NMR (CDCI3): 51.58-1.94 (6H, m), 1.86 (3H, s), 2.36 (3H, s), 3.09 (2H, t, J = 6.9 Hz), 4.48 (2H, dt, J = 47.1, 5.7 Hz), 7.38 (1H, dd, J = 7.2, 5.4 Hz), 8.49 (1H, dd, J = 9.9, 1.2 Hz), 8.73 (1H, d, J = 4.8 Hz), 9.56 (1H , s), 11.13 (1H, bs).

Elemental analysis: as C ₁₉ H ₂₁ N _{40 2} S ₂ FO.4H ₂₀ Calculated (): C, 53.35; H, 5.14; N, 13.10; S, 14.99.

Found (%): C, 53.54; H, 4.96; N, 13.17; S, 14.72.

Example 8-17

N- {5,6-Dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydrido-1H-imidazo [5,1-c] [1,4] thiazine -Triylidene}-2-Pyridyl lipoxamide 2-picolyl chloride hydrochloride (67.4 mg, 0.352) To a solution of tetrahydrofuran (1.00 ml) in maraudal oU was added triethylamine (0.0736 ml, 0.528 mmol), and the reaction mixture was heated at room temperature for 5 minutes. To a suspension of sodium hydride (25.4 mg, 0.634 mmol) (60% oil) in tetrahydrofuran (2.00 ml) was added the toamino-5,6-dimethyl 8- [5 obtained in Example 6-23. -Fluoropentyl] sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (100 mg, 0.317 mmol) in tetrahydrofuran (1.00 ml) was added, and the mixture was cooled on ice for 5 minutes. To this was added the 2-picolyl chloride solution obtained above in tetrahydrofuran, and the mixture was further stirred for 3 hours. It was. The reaction mixture 1N hydrochloric acid was added and extracted with acetic acid Echiru in the. The extract was washed with water, dried (MgSO ₄₎ After the solvent was distilled off under reduced pressure to give the title compound (83.2 mg, 56%) dark red crystals Recrystallization from ethyl acetate-ethyl ether yielded dark red crystals, mp 161-163 ° C.

IR (KBr) V: 2936, 2861, 1715, 1557, 1539, 1505 cm— ¹ .

_{^ -NMR (CDC1 3): δ} 1.50-1.70 (2Η, ι), 1.70-1.92 (4H, m), 1.79 (3H, d, J = 0.9 Hz), 2.38 (3H, d, 0.9 Hz), 3.08 (2H, t, J = 7.5 Hz), 4.37 (2H, dt, J = 47.4, 5.4 Hz), 7.54 (1H, dd, J = 6.6, 4.8 Hz), 7.94 (1H, dt, J = 7.8, 1.8 Hz), 8.34 (1H, d, J = 7.8 Hz), 8.59 (1H, d, J = 4.5 Hz).

Elemental analysis: C ₁₉ H _2l N ₄ 0 ₂ S ₂ F'0.3H ₂₀

Calculated value (%): C, 53.58; H, 5.11;, 13.15; S, 15.06.

Found (%): C, 53.46; H, 5.04; N, 13.03; S, 15.33.

Example 8-18 '

N- {5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-C] [1,4] thiazine- Ilidene} -6-methylnicotinamide triamino-5,6-dimethyl 8- [5-fluoroopentyl] sulfanyl] -3H-imidazo [5,1-c] obtained in Example 6-23 1,4] thiazin-3-one (100 mg, 0.317 rol) and 6- To a solution of methylditinic acid (43.4 mg, 0.349 ol) in N, N-dimethylformamide (3.00 ml) was added getyl cyanophosphate (0.0564 ml, 0.349 t), followed by triethylamine (0.0486 ml, 0.349 ml). Ol). After stirring the reaction mixture at room temperature for 15 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure to give the title compound (72.1 mg, 52¾) as a dark red crystals. Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 200-202 ° C. IR (KBr) V:. 3289 , 3071, 2921, 2861, 1736, 1665, 1615, 1599, 1547 cm "1 Ή-NMR (CDC1 3):« 51.50-1.94 (6H, m), 1.85 (3H, s ), 2.35 (3H, d, J = 1.0 Hz), 2.63 (3H, s), 3.07 (2H, t, J = 7.8 Hz), 4.48 (2H, dt, J-47.2, 5.8 Hz), 7.24 (1H , d, J = 8.0Hz), 8.37 (1H, dd, J = 8.0, 2.2 Hz), 9.47 (1H, d, J = 1.8Hz), 11.08 (1H, bs).

Elemental analysis: C 2 _Q H ₂₃ N ₄ 0 ₂ S ₂ F · 0.3¾0

Calculated (¾): C, 54.60; H, 5.41; N, 12.73; S, 14.58.

Found (¾): C, 54.63; H, 5.31; N, 12.50; S, 14.56.

Example 8-19

 N- {5,6-Dimethyl-8-[(5-fluoropentyl) sulfanylyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1- Ylidene} isonicotinamide

Triamino-5,6-dimethyl 8- [5-fluoropentyl] sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one obtained in Example 6-23 (100 mg, 0.317 recitation1) and isonicotinic acid (43.4 mg, 0.349 mmol) in N, N-dimethylformamide (3.00 ml) solution, getyl cyanophosphate (0.0564 ml, 0.349 mmol), and then triethylamine (0.0486 ml) , 0.349 bandits ol). After stirring the reaction mixture at room temperature for 15 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (8.7 m _g, 6.5¾) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 203-205 ° C. IR (KBr) S: 2934, 2863, 1732, 1661, 1626, 1595, 1553 cm " ¹ .

¾-NMR (CDCI3): ά 1.45-1.94 (6Η, m), 1.86 (3H, s), 2.37 (3H, s), 3.11 (2H, t, J = 7.5 Hz), 4.48 (2H, dt, J = 47.1, 5.7 Hz), 8.09 (2H, d, J = 5.7 Hz), 8.75 (2H, d, J = 6.0 Hz), 11.08 (1H, bs). Example 8-20

N- {5,6-Dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3_dihidid-1H-imidazo [5, tric] [1,4] thiazine- Trident 6_cloniconicotinamide 1-amino-5,6-dimethyl8_ [5-fluoropentyl] sulfanyl] _3H-imidazo [5, tric] [1, obtained in Example 6-23 4] To a solution of thiazin _3-one (100 mg, 0.317 mmol) and 6_ cyclonicotinic acid (56. lmg, 0.349 mmol) in N, N-dimethylformamide (3.00 ml) was added getyl cyanophosphate (0.0564 ml, 0.349 mmol). mmol), followed by triethylamine (0.0486 ml, 0.349 ol). After stirring the reaction mixture at room temperature for 16 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure to give the title compound (70.5 mg, 49¾) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 198'-200 ° C. IR (KBr) V:. 3285 , 3063, 2940, 2863, 1738, 1601, 1582, 1559, 1539 cnf 1 ¾-NMR (CDC1 3): δ 1.48-1.68 (2Η, m), 1.68-1.92 (4H, m), 1.85 (3H, d, J = 1.2 Hz), 2.36 (3H, d, J = 0.9 Hz), 3.07 (2H, t, J-7.2 Hz), 4.48 (2H, dt, J = 47.1, 6.0 Hz), 7.39 (1H, d, J = 8.4 Hz), 8.42 (1H, dd, J = 8.4, 2.4 Hz), 9.34 (1H, dd, J = 2.4, 0.3 Hz), 11.04 (1H, bs).

Elemental analysis: as C ₁₉ H ₂₀ N _{40 2} S ₂ C1F-0.5H ₂₀

Calculated (¾): C, 49.19; H, 4.56; N, 12.08; S, 13.82.

Found (¾): C, 49.20; H, 4.27; N, 11.74; S, 13.62.

Examples 8-21

 N- {5,6-Dimethyl-8-[(5-fluoropentyl) sulfanylyl] -3-oxo-2,3-dihydrone-1H-imidazo [5,1-c] [1,] thiazine-toylidene}- 6- (trifluoromethyl) cotinamide

1-Amino-5,6-dimethyl 8- [5-7-chloropentyl] sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazine-3 obtained in Example 6-23 To a solution of 1-one (100 mg, 0.317 mmol) and 6- (trifluoromethyl) nicotinic acid (66.6 mg, 0.349 mmol) in N, N-dimethylformamide (3.00 ml) was added getyl cyanophosphate (0.0564 ml, 0.349 mmol). mmol) Then, triethylamine (0.0486 ml, 0.349 mmol) was added. After stirring the reaction mixture at room temperature for 18 hours, water was added, and the mixture was extracted with ethyl acetate. Wash the extract with water and dry (MgSO ₄₎ After the solvent was distilled off under reduced pressure to give the title compound (51.8mg, 33¾) and the obtained as dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 183-185 ° C.

IR (KBr) V: 3262, 2936, 1732, 1661, 1626, 1599, 1549 cm " ¹ .

_{¾-NMR (CDC1 3):} δ 1.46-1.70 (2Η, m), 1.70 - 1,96 (4H, m), 1.87 (3H, s), 2.37 (3H, s), 3.09 (2H, t, J = 7.5 Hz), 4.48 (2H; dt, J = 47.1, 5.7 Hz), 7.76 (1H, d, J = 8.1 Hz), 8.65 (1H, dd, J = 7.5, 0.6 Hz), 9.65 (1H, d , J = 0.6 Hz), 11.06 (1H, bs).

Elemental analysis: C _2. H _2. N ₄ 0 ₂ S ₂ F ₄ '0.5H ₂ 0

Calculated (%): C, 48.28; H, 4.25; N, 11.26; S, 12.89.

Found (¾): C, 48.59; H, 4.14; N, 11.39; S, 12.65.

Examples 8 to 22

 N- {5,6-dimethyl-8-[(5-fluoroopentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5, lc] [1,4] thiazine-1 -Ylidene}-6_ (1H pyrazolyl) nicotinamide

Triamino-5,6-dimethyl 8- [5-fluoropentyl] sulfanyl] -3H-imidazo [5, tric] [1,4] thiazin-3-one obtained in Example 6-23 (100 mg , 0.317 mmol) and 6- (1H-pyrazole-tolyl) nicotinic acid (75.0 mg, 0.349 mmol) in N, N-dimethylformamide (3.00 ml) were mixed with getyl cyanophosphate (0.0564 ml, 0.349 t ) Subsequently, triethylamine (0.0486 ml, 0.349 alcohol) was added. After the reaction mixture was stirred at room temperature for 20 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO ₄₎ after solvent was obtained as a distilled to give the title compound (20.6 nig, 13%) dark red crystals under reduced pressure. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 203-205.

IR (KBr) V: 3270, 2924, 1740, 1603, 1591, 1545 cm— ¹ .

^-M (CDCI3): δ 1.42-1.98 (6Η, m), 1.86 (3H, d, J = 1.0 Hz), 2.36 (3H, d, J = 1.2 Hz), 3.11 (2H, t, J = 7.6 Hz), 4.50 (2H, dt, J = 47.2, 6.2 Hz), 6.50 (1H, dd, J = 2.6, 1.6 Hz), 7.78 (1H, d, J = 1.8Hz), 8.04 (1H, d, J = 8.8 Hz), 8.58-8.67 (2H, m), 9.35 (1H, dd, J = 2.2, 0.6 Hz), 11.09 (1H, bs). Elementary analysis: as _{C 22 H 23 N 6 0 2} S 2 F · 0.5H 2 0

Calculated (¾): C, 53.32; H, 4.88; N, 16.96; S, 12.94.

Found (¾): C, 53.14; H, 4.60; N, 16.77; S, 13.25.

Examples 8-23

N- {5,6-dimethyl _8_ [(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydrone-1H-imidazo [5, l-c] [1,4] thiazine-1-ylidene} acrylamide

To a suspension of sodium hydride (20.3 mg, 0.507 marl ol) (60% oil) in tetrahydrofuran (2.00 ml) was added 1-amino-5,6-dimethyl-8- [obtained in Example 6-23. Add a solution of 5-fluoropentyl] sulfanyl] -3H-imidazo [5, tric] [1,4] thiazin-3-one (80.0 mg, 0.254 mmol ol) in tetrahydrofuran (1.00 ml) and cool on ice for 5 minutes Stirred. To this was added 3-pilot propionyl chloride (0.0353 ml, 0.349 awake ol), and the mixture was further stirred for 23 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure to give the title compound (84.1 mg, 81%) as a dark red crystals. The crystals were recrystallized from ethyl acetate-getyl ether to give dark red crystals having a melting point of 154-156T :.

Infrared absorption spectrum (IR) (in KBr): 3208, 2917, 1734, 1663, 1634, 1607, 1543 cm ^-1 .

One _{NMR (CDC1 3): δ 1.46-1.88} (6Η, m), 1.82 (3H, s), 2.32 (3H, s), 2.59 (3H, s), 3.02 (2H, t, J = 7.2Hz), 4.46 (2H, dt, J = 47.1, 5.7 Hz), 5.87 (1H, dd, J = 9.9, 0.3 Hz), 6.34 (1H, dd, J = 17.1, 10.5 Hz), 6.65 (1H, d, J = 15.9 Hz), 10.90 (1H, bs).

Elemental analysis: C ₁₆ H ₂₀ N ₃ O ₂ S ₂ F-0.1H ₂₀

Calculated value (%): C, 51.76; H, 5.48; N, 11.32; S, 17.27.

Found (¾): C, 51.95; H, 5.33; N, 11.29; S, 16.80.

Examples 8-24

 N- {5,6-Dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydrone-1H-imidazo [5, lc] [1,4] thiazine-1-ylidene} -6-methyl-2-pyridine

Triamino_5,6-dimethyl-8- [5-fluoropentyl] sulfur obtained in Example 6-23 Fanyl] -3H-imidazo [5, tric] [1,4] thiazin-3-one (100 mg, 0.317 mmol) and 6-methyl-2-pyridinecarboxylic acid (66.5 mg, 0.476 mmol) Ν, Ν To a solution of -dimethylformamide (5.00 ml) was added getyl cyanophosphate (0.0769 ml, 0.476 mmol), followed by triethylamine (0.0663 ml, 0.476 mmol). After stirring the reaction mixture at room temperature for 15.5 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (120 mg, 87%) 'and the obtained as dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 160-162 ° C.

Infrared absorption spectrum (IR) (in KBr): 3206, 2942, 2911, 2861, 1713, 1655, 1578, 1549, 1514 cm- ¹ .

_{Ή- NMR (CDC1 3): δ} 1.52-1.92 (6H, m), 1.80 (3H, s), 2.38 (3H, d, J = 0.6 Hz),

2.59 (3H, s), 3.06 (2H, t, J = 7.2 Hz), 4.35 (2H, dt, J = 47.1, 5.7 Hz), 7.39

(1H, d, J = 7.8 Hz), 7.82 (1H, t, J = 7.8 Hz), 8.14 (1H, d, J = 7.5 Hz).

Elementary analysis: as _{C 2Q H 23 N 4 0 2} S 2 F

Calculated (¾): C, 55.28; H, 5.33; N, 12.89; S, 14.76.

Found (%): C, 55.42; H, 5.36; N, 12.65; S, 14.49.

Example 8-25

 3-chloro-N- {5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydric-1H-imidazo [5,1-c] [1 , 4] Thiazine-1-ylident 2,2-dimethylpropaneamide

To a suspension of sodium hydride (38.0 mg, 0.951 ol) (60 oily) in tetrahydrofuran (2.00 ml) was added 1-amino-5,6-dimethyl-8- [5] obtained in Example 6-23. -Fluoropentyl] sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazine-3-one (150 mg, 0.476 marl) in tetrahydrofuran (1.00 ml) was added and the mixture was cooled under ice. Stir for a minute. To this was added 3-chloropivaloyl chloride (0.0766 ml, 0.571 ol ol) and stirred for an additional 23 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (103 mg, 50%) as a dark red crystals. Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 137-139 ° C. Infrared absorption spectrum (IR) (in KBr) ν: 3247, 2967, 2940, 2870, 1750, 1613, 1599, 1537 cm " ¹ .

 Ή-NMR (CDC "): (51.32 (6H, s), 1.50-1.86 (6H, m), 1.81 (3H, d, J = 0.9 Hz), 2.31 (3H, d, J = 0.9 Hz), 3.01 (2H, t, J = 7.5 Hz), 3.80 (2H, s), 4.46 (2H, dt, J = 47.1, 6.0 Hz), 10.70 (1H, bs).

Elemental analysis: as C ^ H ^ NAS ^ IF

Calculated (%): C, 49.81; H, 5.81;, 9.68; S, 14.78.

Found (%): C, 49.70; H, 5.71;, 9.70; S, 14.67.

Example 8-26

N- {5, 6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydrone-1H-imidazo [5,1-c] [1,4] thiazine-1- Ilidene} -3-Methyl 2-pyridine lipoxamide

1-Amino-5,6-dimethyl-8- [5-fluoropentyl] sulfanyl] -3H-imidazo [5, tric] [1,4] thiazin-3-one obtained in Example 6-23 ( To a solution of 100 mg, 0.317 mmol) and 3-methyl_2_pyridinecarbonic acid (68.6 mg, 0.476 mmol) in N, N-dimethylformamide (5.00 ml) was added getyl cyanophosphate (0.0769 ml, 0.476 mmol). Then, triethylamine (0.0663 ml, 0.476 mmol) was added. After stirring the reaction mixture at room temperature for 15.5 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), solvent was obtained as a dark red crystalline title compound was distilled off (106 mg, 77%) under reduced pressure. The crystals were recrystallized from ethyl acetate-ethyl ether to give dark red crystals having a melting point of 148-150.

Infrared absorption spectrum (IR) (in KBr) V 3196, 2934, 2861, 1715, 1651, 1549, 1505 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 1.50-1.90 (6L m), 1.79 (3H, s), 2.37 (3H, d, J = 1.2 Hz), 2.82 (3H, s), 3.06 (2H, t, 1 = 1.2 Hz), 4.38 (2H, dt, J-47.7, 5.7 Hz), 7.43 (1H, dd, J-7.5, 4.5 Hz), 7.70 (1H, d, J = 8.4 Hz), 8.44 (1H, d , J = 3.9 Hz) elemental analysis:. C _2. H ₂₃ N ₄ 0 ₂ S ₂ F

Calculated (¾): C, 55.28; H, 5.33; N, 12.89; S, 14.76.

Found (%): C, 55.12; H, 5.42; N, 12.86; S, 14.49. Example 8-27

 4-Cross-N- {5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] Thiazine-1-ylidene pyridinecarboxamide

1-Amino-5,6-dimethyl-8- [5-fluoropentyl] sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazine-3- obtained in Example 6-23 To a solution of ON (100 mg, 0.317 marl ol) and 4-chloro-2-pyridinepyridine (77.2 mg, 0.476 mmol) in Ν, Ν-dimethylformamide (5.00 ml) was added getyl cyanophosphate (0.0769 ml). , 0.476 mmol) followed by triethylamine (0.0663 ml, 0.476 bandol). After stirring the reaction mixture at room temperature for 21 hours, water was added, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water, a dry (MgSO ₄₎ After the solvent was distilled off under reduced pressure to give the title compound (56.4 mg, 39%) of two or isomer mixture.

Infrared absorption spectrum (IR) (in KBr) V: 2940, 2867, 1732, 1597, 1549, 1514 cm ¹ .

_{Ή-NMR (CDC1 3):} δ 1.50-1.94 (6Η, m), 1.80 (3HX0.57, s), 1.86 (3HX0.43, s), 2.38 (3H, s), 3.07 (2HX0.57, t , J = 7.5 Hz), 3.13 (2HX0.43, t, J = 7.8Hz),

4.39 (2HX0.57, dt, J-46.8, 5.7 Hz), 4.48 (2HX0.43, dt, J = 47.1, 6.3 Hz),

7.41 (1HX0.43, dd, J = 5.1, 2.1 Hz), 7.54 (1HX0.57, dd, J = 5.4, 2.1 Hz), 8.32

(1HX0.57, t, J = 2.1 Hz), 8.50 (1HX0.57, t, J = 5.1 Hz), 8.57 (1HX0.43, d,

J = 2.1 Hz), 8.68 (1HX0.43, d, J = 5.4 Hz), 11.12 (1HX0.43, bs), 12.38 (1H X0.57, bs).

Elemental analysis: C ₁₉ H _{2 Q} N ₄ 0 ₂ S ₂ C1F

Calculated value (%): C, 50.16; H, 4.43; N, 12.31; S, 14.10.

Found (%): C, 50.24; H, 4.30; N, 12.36; S, 13.87.

Example 8-28

6_Black-N- {5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5, 1-c] [1, 4] Thiazine-1 -ylidene}-2-pyridinecarboxamide

1-Amino-5,6-dimethyl-8- [5-fluoropentyl] sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one obtained in Example 6-23 (80.0 mg, 0.254 mmol) and 6-Chloro-2-pyridinepyridine (59.9 mg, 0.380 ol) in N, N-dimethylformamide (4.00 ml), getyl cyanophosphate (0.0615 ml, 0.380 ol), and then triethylamine (0.0530 ml, 0.380 t). After stirring the reaction mixture at room temperature for 21 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (64.7 mg, 56%) was obtained as a dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 198-200 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3204, 3127, 2938, 2865, 1717, 1653, 1624, 1595, 1545, 1516 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 1.48-1.96 (6Η, m), 1.80 (3H, s), 2.38 (3H, s), 3.09 (2H, t, J = 6.9 Hz), 4.39 (2H, dt, J = 46.8, 5.1 Hz), 7.58 (1H, d, J = 7.8 Hz), 7.92

(1H, t, J = 7 Hz), 8.26 (1H, d, J = 4.8 Hz), 12.40 (1H, bs).

Elemental analysis: C _19. N ₄ 0 ₂ S ₂ C1F

Calculated value (%): C, 50.16; H, 4.43; N, 12.31; S, 14.10.

Found (%): C, 50.30; H, 4.34; N, 12.53; S, 14.02.

Example 8-29

 N- {5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-1-ylidene Isoquinoline carboxamide,

1-Amino-5,6-dimethyl-8- [5-fluoropentyl] sulfanyl] _3H-imidazo [5, l_c] [1,4] thiazin-3-one obtained in Example 6-23 (80.0 mg , 0.254 recitation ol) and triisoquinoline carboxylic acid (66.5 mg, 0.380 SUBSTITLE) in Ν, Ν-dimethylformamide (4.00 ml) solution, getyl cyanophosphate (0.0615 ral, 0.380 mmol), followed by triethylamine (0.0530 ml, 0.380 mmol). After stirring the reaction mixture at room temperature for 22.5 hours, water was added and extracted with ether acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure to give the title compound (19.0 mg, 16¾) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 198-200 ° C.

Infrared absorption spectrum (IR) (in KBr): 3169, 2940, 1709, 1653, 1580, 1549, 1507 CUT ¹ .

ΐ-NMR (CDClg): δ 1.50-1.98 (6H, m), 1.80 (3H, s), 2.39 (3H, d, J = 0.8 Hz), 3.10 (2H, t ,, J = 7.0 Hz), 4.37 (2H, dt, J = 47.2, 5.8 Hz), 7.70-7.84 (2H, m), 7.84-7.97 (2H, m), 8.51 (1H, d, J = 5.4 Hz), 9.70 (1H, dd, J -6.8, 3.4 Hz). Elemental analysis: C ₂₃ H ₂₃ N _{40 2} S ₂ F

Calculated (%): C, 58.70; H, 4.93; N, 11.91; S, 13.63.

Found (%): C, 58.74; H, 4.90; N, 12.09; S, 13.56.

Example 8-30

 N- {5,6-Dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihidido-1H-imidazo [5, tric] [1,4] thiazine- Triylidene}-2-furamide

To a suspension of sodium hydride (20.3 mg, 0.507 mmol) (60% oil) in tetrahydrofuran (2.00 ml) was added the triamino-5,6-dimethyl-8- [5-] obtained in Example 6-23. Add a solution of fluoropentyl] sulfanyl] -3H-imidazo [5,1-c] [1,] thiazin-3-one (80.0 mg, 0.254 bandol) in tetrahydrofuran (1.00 ml), and stir under ice-cooling for 5 minutes. I did. To this was added a solution of 2-furoyl chloride (0.0279 mg, 0.279 marl) in tetrahydrofuran, and the mixture was further stirred for 30 minutes. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (84. ling, 81¾) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 199-201 ° C.

Infrared absorption spectrum (IR) (in KBr) So: 3239, 3119, 2961, 2944, 2868, 1713, 1663, 1628, 1607, 1576, 1541 cm- ¹ .

Ή—NMR (CDCI3): δ 1.56-1.90 (6Η, m), 1.81 (3H, s), 2.33 (3H, d, J = 0.9 Hz), 3.06 (2H, t, J = 7.5 Hz), 4.48 ( 2H, dt, J = 47.1, 6.0 Hz), 6.51 (1H, dd, J = 3.6, 1.8 Hz), 7.34 (1H, d, J = 3.3 Hz), 7.61 (1H, d, J = 0.9 Hz), 10.88 (1H, bs) elemental analysis:. C ₁₈ H _2. N ₃ 0 ₃ S ₂ F

Calculated (¾): C, 52.79; H, 4.92; N, 10.26; S, 15.66.

Found (%): C, 52.76; H, 4.88; N, 10.14; S, 15.42.

Example 8-31

N- {5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydride Mouth-m-imidazo [5, .1 -c] [1,4] thiazine-triylidene 2-thiophenecarboxamide.

To a suspension of sodium hydride (20.3 mg, 0.507 mmol) (60% oil) in tetrahydrofuran (2.00 ml) was added 1-amino-5,6-dimethyl-8- [5] obtained in Example 6-23. -Fluoropentyl] sulfanyl] -3H-imidazo [5, tric] [1,4] thiazin-3-one (80.0 mg, 0.254 mmol) in tetrahydrofuran (1.00 ml) was added, and the mixture was stirred under ice cooling for 5 minutes. I did. To this was added a solution of 2-thenoyl chloride (0.0299 mg, 0.279 t ol) in tetrahydrofuran, and the mixture was further stirred for 1.5 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (80.6mg, 75¾) as a dark red crystals. Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 193-195 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3229, 3083, 2965, 2938, 2915, 2863, 1736, 1661, 1609, 1597, 1553, 1520 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 1.54-1.90 (6Η, m), 1.83 (3H, d, J = 0.9 Hz), 2.33 (3H, d, J = 0.9 Hz), 3.07 (2H, t, J = 7.5 Hz), 4.48 (2H, dt, J-47.1, 5.4 Hz), 7.11 (1H, dd, J = 4.8, 3.9 Hz), 7.54 (1H, dd, J = 4.8, 0.9 Hz), 7.91 (1H, dd, J = 3.6, 1.2 Hz), 10.91 (1H, bs).

Elemental analysis: C ₁₈ H _2. N ₃ 0 ₂ S ₃ F

Calculated value (%): C, 50.80; H, 4.74; N, 9.87; S, 22.60.

Found (¾): C, 50.77; H, 4.74; N, 9.78; S, 22.62.

Example 9-1

In the formula (XXI), R ² is a 2- (ethoxycarbonyl) ethyl group, R ⁵ is an n-butyl group, one of R ⁸ and R ⁹ is an n-butyl group, the other is a hydrogen atom, and Z is S 0 ₂ Of compounds in which R ¹⁵ is a P-tolyl group

 The compound (305 Big, 0.510 oifflol) synthesized in Example 1-14 was dissolved in toluene (10 ml) and acetic anhydride (0.05 ml, 0.51 mmol), and D-potassin-1-10-sulfonic acid (119 mg, (0.510 mL) was added and the mixture was heated under reflux for 2 hours. The reaction solution was diluted with ethyl acetate (20 ml), washed with water, a 2% aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over sodium sulfate, and concentrated to dryness under reduced pressure. The residue is dissolved in methanol and subjected to reverse phase preparative HPLC (Carrier: 0DS, YMC-Pack, S-363-1-15, ID 30 mm, length 250 mm, manufactured by Y'M'C, mobile phase : Elute with 0.05 (v / v)% trifluoroacetic acid Z77 ~ 90 (v / v)% 7 acetonitrile water, collect fractions with elution volume of 1060 ~ 1180ml, concentrate and concentrate the remaining aqueous layer to ethyl acetate (40ml) ). The organic layer was washed with 0.05N hydrochloric acid, water and a saline solution, dried over sodium sulfate, and concentrated to dryness under reduced pressure. Ether was added to the residue, and the resulting precipitate was collected by filtration, washed with ether, and dried to give a yellow powder of the title compound (176 mg, 0.304 mmol).

 -Thigh (300 MHz, in double-mouthed holm): δ 0.89 (3Η, t, J = 7.2 Hz), 0.91 (3H, t, J = 7.2 Hz), 1.26 (3H, t, J = 7.2 Hz), 1.33 (4H, m), 1.41 (4H, m), 1.63 (2H, m), 2.17 (2H, brquint, J = 7.3 Hz), 2.42 (3H, s), 2.66 (2H, i, J = 7.5 Hz ), 3.22 (2H, di, J2 3.4, 7.5 Hz), 4.15 (2H, q, J = 7.2 Hz), 4.03 (1H, t, J = 7.9 Hz), 5.92 (1H, t, J = 7.9 Hz) ), 7.02 (1H, s), 7.30 (2H, brd, J- 8.3 Hz), 7.88 (2H, d, J = 8.3 Hz), 9.63 (1H, br).

Elemental _{analysis: C 27 H 37 N 3 0} 5 S 3 Calculated: C, 55.93; H, 6.43 ; N, 7.25; S, 16.59 (%), Found; C, 56.19; H, 6.40 ; N, 7.13; S, 16.80 (%).

 Further, fractions having an elution volume of 1360 to U00 ml were collected in the reverse phase preparative HPLC and treated in the same manner to obtain a red powder (18 mg, 0.030 mmol) of the compound synthesized in Example 2-19.

The following is a list of compounds synthesized in Example 9-1 and compounds synthesized in the same manner. (Table 94)

Replacement paper (M; (Table 95)

Replacement form (Rule 2β) (Table 96)

ぇ用弒 m ) 以下に実施例 9- 2〜9- 27で合成した化合物のデータを示す。

ぇ m) The data of the compounds synthesized in Examples 9-2 to 9-27 are shown below.

Example 9-2

_{^ -NM (300MHz, CDC1 3)} : δ 0.86 (3Η, t, J = 6.8 Hz), 1.23 (3H, t, J = 7.1 Hz), 1.26 (2H, brs), 1.30 (2H, m), 1.37 (2H, m), 1.64 (2H, m), 2.38 (3H, s), 2.64 (2H, t, J = 7.3 Hz), 3.19 (2H, m), 3.51 (1H, brt, J = 7.3 Hz) , 4.13 (2H, q, J = 7.1 Hz), 4.83 (1H, brs), 5.46 (1H, brs), 7.23 (2H, brd, J = 8.2 Hz), 7.88 (2H, d, J = 8.2 Hz) .

Elemental analysis: C ₂₄ H ₃₁ N ₃ 0 ₅ S ₃ · 0.60 Calculated: C, 52.55; H, 5.92; N, 7.66; S, 17.53 (%). Found: C, 52.44; H, 5.67 ; N, 7.63; S, 17.46 (%).

Example 9-3

'H-NMR (300MHz, CDC1 3): <5 0.89 (3H, t, J = 6.9 Hz), 1.26 (3H, t, J = 7.1 Hz), 1.31 (2H, m), 1.31 (2H, m) , 1.45 (2H, brquint, J = 7.0 Hz), 2.18 (2H, brq, J = 7.5 Hz), 2.42 (3H, s), 2.67 (2H, t, J-7.4 Hz), 3.24 (2H, t, J = 7.3 Hz), 3.60 (2H, s), 4.15 (2H, q, J = 7.1.Hz), 6.08 (1H, t, J = 7.9 Hz), 7.30 (2H, brd, J = 8.3 Hz), . 7.87 (2H, d, J = 8.3 Hz), 9.68 (1H, brs), elemental analysis: calculated _{C 24 H 31 N 3 0 5} S 3: C, 53.61; H, 5.81; N, 7.81; S, 17.89

Found: C, 53.46; H, 5.53; N, 7.83; S, 18.10 (%).

Example 9-4

匪 -band R (300MHz, CDC): δ 0.87 (3H, t, J = 7.2 Hz), 1.25 (3H, t, J = 7.2 Hz), 1.42 (2H, m), 1.72 (2H, m), 2.43 (3H, s), 2.66 (2H, dt, J = 6.8, 7.9 Hz), 3.23 (2H, dt, J = 2.3, 7.5 Hz), 4.15 (2H, q, J = 7.2 Hz), 4.31 (1H, dd, J- 8.7, 6.8 Hz), 7.02 (1H, s), 7.21 (2H, d, J = 8.3 Hz), 7.31 (1H, m), 7.32 (2H, brd, J = 8.3 Hz), 7.38 ( 2H, brt, J = 7.5 Hz ), 7.90 (2H, d, J- 8.3 Hz), 9.73 (1H, br) elemental _{analysis:. C 28 H 31 N 3} 0 5 S 3 calculated: C, 57.41 H, 5.33;, 7.17; S, 16.42 (%). Found: C, 57.31; H, 5.18;, 7.17; S, 16.46 (%).

Example 9-5

_{Ή-NMR (300MHz, CDC1 3} ): δ 1.27 (3H, t, J = 7.2 Hz), 2.40 (3H, s), 4.16 (2H, q, J = 7.2 Hz), 4.21 (2H, s), 4.35 (2H, s), 6.57 (1H, s), 7.23 (2H, d, J = 8.3 Hz), 7.28 (5H, s), 7.89 (2H, d, J = 8.3 Hz). Example 9-6

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.95 (3H, t, J = 7.2 Hz), 1.26 (3H, t, J = 7.2 Hz), 1.52 (2H, dq, J = 3.0, 7.2 Hz), 2.23 (1H, dt, J = 13.2, 7.2 Hz), 2.26 (1H, dt, J = 13.2, 7.2 Hz), 2.40 (3H, s), 2.58 (2H, dt, J = 3.8, 7.9 Hz), 3.21 ( 1H, dt, J = 13.6, 7.2 Hz), 3.25 (1H, dt, J = 13.6, 7.2 Hz), 4.15 (2H, q, J = 7.2 Hz), 5.36 (1H, s), 6.16 (1H, t , J = 7.9 Hz), 7.27 (2H, d, J = 8.3 Hz), 7.31 (5H, s), 7.82 (2H, d, J = 8.3 Hz), 9.63 (1H, br).

Elemental analysis: C ₂₈ H ₃₁ N ₃ 0 ₅ S ₃ · 0.4H ₂ 0 Calculated: C, 56.72; H, 5.41; N, 7.09; S, 16.22 (). Observed: C, 56.75; H, 5.28; N, 6.92; S, 16.48 (%).

Examples 9-7

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.86 (3H, t, J = 7.2 Hz), 1.42 (2H, m), 1.71 (2H, m), 2.42 (3H, s), 2.73 (2H, t, J = 7.5 Hz), 3.22 (2H, q, J- 7.2 Hz), 4.31 (1H, dd, J = 8.3, 6.8 Hz), 7.01 (1H, s), 7.21 (2H, brd, J = 7.2 Hz) , 7.31 (1H, m), 7.32 (2H, brd, J = 8.3 Hz), 7.38 (2H, brt, J = 7.5 Hz), 7.90 (2H, d, 1 = 8.3 Hz), 9.87 (1H, br) .

Example 9-8

_{-NMR (300MHz, CDC1 3):} δ 0.82 (3H, t, J = 7.5 Hz), 1.33 (2H, m), 1.57 (1H, m), 1.62 (1H, m), 2.43 (3H, s), 4.20 (2H, s), 4.23 (1H, dd, J = 8.7, 6.4 Hz), 6.97 (1H, s), 7.19 (2H, d, J = 7.2 Hz), 7.29 (1H, m), 7.29 (5H , s), 7.30 (2H, d, J = 8.3 Hz), 7.36 (2H, t, J = 7.5 Hz), 7.90 (2H, d, J = 8.3 Hz), 9.75 (1H, br).

Elemental analysis: C _3. Calculated for H ₂₉ N ₃ 0 ₃ S ₃ : C, 62.58; H, 5.08; N, 7.30; S, 16.71

(). Found: C, 62.34; H, 5.12; N, 7.19; S, 16.56 (%).

Example 9-9

_{Ή-NMR (300MHz, CDC1 3} ): δ 0.85 (3Η, t, J = 7.5 Hz), 1.41 (2H, m), 1.69 (2H, m), 2.42 (3H, s), 2.56 (2H, brt, J = 7.2 Hz), 3.30 (2H, m), 4.29 (1H, dd, J = 8.3, 6.8 Hz), 4.43 (2H, brd, J = 5.7 Hz), '5.90 (1H, m), 7.00 (1H , S), 7.21 (2H, brd, J = 7.5 Hz), 7.29 (6H, m), 7.36 (2H, brt, J = 7.5 Hz), 7.88 (2H, d, J = 8.3 Hz), 9.7 (1H , br). Elemental _{analysis: C 33 H 34 N 4 0} 4 S 3 · 0.8 0 Calculated:. C, 59.94; H, 5.43; N, 8.47 (%) Found: C, 60.02; H, 5.42 ; N, 8.09 (%).

Example 9-10

'H-NMR (300MHz, CDC1 3): δ 0.90 (3Η, brt, J = 7.1 Hz), 1.26 (3H, t, J = 7.1 Hz), 1.34 (2H, m), 1.42 (2H, m), 2.19 (2H, brq, J = 7.5 Hz), 2.41 (3H, s), 2.67 (2H, t, J = 7.4 Hz), 3.23 (2H, t, J = 7.4 Hz), 3.60 (2H, s), 4.15 (2H, q, J = 7.1 Hz), 6.08 (1H, t, J = 7.9 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.87 (2H, d, J = 8.3 Hz), 9.74 ( 1H, br).

Examples 9 to 11

'H-NMR (300MHz, CDC1 3): δ 0.88 (3H, brt, J = 6.9 Hz), 1.26 (3H, t, J = 7.1 Hz), 1.28 (4H, brs), 1.31 (2H, m), 1.44 (2H, brqiuni, J = 7.3 Hz), 2.18 (2H, q, J = 7.4 Hz), 2.41 (3H, s), 2.67 (2H, t, J- 7.4 Hz), 3.23 (2H, t, J = 7.4 Hz), 3.60 (2H, s), 4.15 (2H, q, J = 7.1 Hz), 6.08 (1H, t, J = 7.9 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.87 ( 2H, d, J = 8.3 Hz), 9.74 (1H, br).

Examples 9-12

'H-NMR (300MHz, CDC1 3): δ 0.90 (3H, t, J = 7.1 Hz), 1.33 (2H, m), 1.41 (2H, m), 2.16 (2H, q, J = 7.4 Hz), 2.41 (3H, s), 3.53 (2H, s), 4.20 (2H, s), 6.04 (1H, t, J = 7.9 Hz), 7.27 (2H, d, J = 8.3 Hz), 7.29 (5H, s) ), 7.86 (2H, d, J = 8.3 Hz), 9.67 (1H, brs).

Elemental _{analysis: C 25 H 27 N 3 0} 5 S 3 Calculated:. C, 58.45; H, 5.30; N, 8.18; S, 18.73 (%) Found: C, 58.45; H, 5.26 ; N, 8.20; S, 18.80 (%).

Example 9-13.

_{Ή-NR (300MHz, CDC1 3} ): δ 0.88 (3Η, t, J = 6.9 Hz), 1.27 (4H, m), 1.33 (2H, m), 1.43 (2H, brquint, J = 7.1 Hz), 2.15 (2H, q, J- 7.4 Hz), 2.41 (3H, s), 3.53 (2H, s), 4.21 (2H, s)., 6.04 (1H, t, J = 7.9 Hz), 7.27 (2H, d , J = 8.3 Hz), 7.29 (5H, s), 7.86 (2H, d, J = 8.3 Hz), 9.66 (1H, brs).

Elemental _{analysis: C 27 H 31 N 3 0} 5 S 3 Calculated:. C, 59.86; H, 5.77; N, 7.76; S, 17.76 (%) Found: C, 59.72; H, 5.70 ; N, 7.79; S, 17.68 (%).

Examples 9-14 'H-NMR (300MHz, CDC1 3): δ 0.88 (3H, t, J = 7.0 Hz), 1.26 (4H, m), 1.32 (2H, m), 1.59 (2H, m), 2.42 (3H, s ), 3.51 (1H, t, J = 7.5 Hz), 4.20 (2H, s), 4.90 (1H, brs), 5.50 (1H, brs), 7.28 (2H, d, J = 8.3 Hz), 7.29 (5H , s), 7.87 (2H, d, J = 8.3 Hz), 9.69 (1H, brs).

Elemental _{analysis: C 26 H 29 N 3 0} 3 S 3 Calculated: C, 59.18; H, 5.54 ; N, 7.96; S, 18.23

(%), Found: C, 59.06; H, 5.31; N, 7.94; S, 18.46 (%).

Example 9-15

_{¾-NMR (300MHz, CDC1 3} ): δ 0.88 (3H, t, J = 6.8 Hz), 1.28 (4H, m), 1.43 (2H, m), 2.15 (2H, q, J = 7.5 Hz), 2.41 (3H, s), 3.53 (2H, s), 4.21 (2H, s), 6.04 (1H, t, J-7.9 Hz), 7.27 (2H, d, J = 8.3 Hz), 7.29 (5H, s) , 7.86 (2H, d, J = 8.3 Hz), 9.66 (1H, brs).

Elemental _{analysis: C 26 H 29 N 3 0} 3 S 3 Calculated: C, 59.18; H, 5.54 ; N, 7.96; S, 18.23

(%), Found: C, 59.09; H, 5.31; N, 8.07; S, 18.21 (%).

Example 9-16

_{Ή-NMR (300MHz, CDC1 3} ): δ 1.26 (3H, t, J = 7.2 Hz), 2.42 (3H, s), 2.68 (2H, t, J = 7.1 Hz), 3.26 (2H, t, J = 7.1 Hz), 3.81 (2H, s), 4.16 (2H, q, J- 7.2 Hz), 6.90 (1H, s), 7.31 (2H, d, J = 8.3 Hz), 7.87 (2H, d, J = 8.3 Hz), 9.76 (1H, brs) elemental analysis:. C ₁₉ H _2. Calculated for N ₃ 0 ₅ S ₃ C1: C, 45.46; H, 4.02; N, 8.37; S, 19.16; Cl, 7.06 (%), found: C, 45.41; H, 3.81; N, 8.31; S , 19.15; Cl, 7.23 (%). Example 9_17

_{NMR (300 MHz, CDC1 3)} : (31.30 (3H, t, J = 7.2Hz), 2.70 (2H, t, J = 7.3Hz), 3.27 (2H, t, J = 7.3Hz), 3.70 (3H, s), 4.19 (2H, q, J = 7.2Hz), 4.67 (2H, s), 6.61 (1H, s), 7.48-7.62 (3H, m), 7.96-8.02 (2H, m).

Examples 9-18

'H-NMR (300 MHz, CDC1 3): 61.29 (3H, t, J = 6.9Hz), 4.18 (2H, q, J = 6.9Hz), 4.25 (2H, s), 4.41 (2H, s), 6.69 (1H, s), 7.27-7.34 (5H, ID), 7.44-7.62 (3H, m), 7.94-8.01 (2H, m), 9.50-10.0 (1H, m).

Example 9-19

Ή-NMR (200 MHz, CDCl ₃ -DMS0-d ₆ = 9: 1): δ 2.42 (3H, s), 2.93 (3H, m), 3.22 (2H, m), 4.39 (1H, brs), 5.06 (1H, brs), 5.60 (1H, brs), 7.14-7.29 (7H, m), 7.86 (2H, d, J = 8.4 Hz).

Elemental _{analysis: C 23 H 21 N 3 0} 5 S 3 -H 2 0 Calculated: C, 51.77; H, 4.34 ; N, 7.87; S, 18.03 (%), Found; C, 51.46; H, 4.33; N, 7.87; S, 17.79 ().

Example 9-20

'H-NMR (200MHz,' CDC1 3): δ 1.26 (3H, t, J = 7.1 Hz), 1.43 (3H, d, J = 7.0 Hz), 1.80 (3H, d, J = 7.0 Hz), 2.42 (3H, s), 2.66 (2H, t, J = 7.3 Hz), 3.21 (2H, t, J = 7.3 Hz), 4.15 (2H, q, J = 7.2 Hz), 4.27 (1H, q, J = 6.9 Hz), 5.94 (1H, q, J = 7.2 Hz), 7.31 (2H, d, J = 8.2 Hz), 7.89 (2H, d, J = 8.6 Hz), 9.70 (1H, brs). : C ₂₁ H ₂₅ N ₃ 0 ₅ S ₃ Calculated: C, 50.89; H, 5.08;, 8.48; S, 19.41 (), Found: C, 50.74; H, 5.17; N, 8.48; S, 19.39 {%).

141.5- 142.0 ° C

Example 9-21

_{Ή- NMR (200MHz, CDC1 3)} : δ 1.03 (3H, t, J = 7.3 Hz), 1.26 (3H, t, J = 7.2 Hz), 1.76 (2H, dquint, J = 7.7, 4.0 Hz), 2.43 (3H, s), 2.67 (2H, t, J = 7.4 Hz), 3.24 (2H, t, J = 7.2 Hz), 3.52 (1H, i, J = 7.6 Hz), 4.16 (2H, q, J = 7.1 Hz), 4.95 (1H, d, J = 1.0 Hz), 5.55 (1H, brs), 7.31 (2H, d, J = 8.2 Hz), 7.88 (2H, d, J = 8.4 Hz), 9.71 (1H , brs).

Elemental analysis: Calculated for C ₂₁ H ₂₅ N ₃ 0 ₅ S ₃ : C, 50.89; H, 5.08; N, 8.48; S, 19.41 (%), found: C, 50.78; H, 5.01; N, 8.43; S, 19.40 (%).

Melting point.122.5-123.0 ° C

Examples 9 to 22

_{Ή-NMR (200MHz, CDC1 3} ): δ 0.91 (6Η, d, J- 6.2 Hz), 1.43 (3H, d, J = 7.0 Hz), 1.58 (2H, m), 1.63 (1H, quint, J = 6.6 Hz), 1.80 (3H, d, J = 7.2 Hz), 2.43 (3H, s), 2.94 (2H, brt, J = 7.9 Hz), 4.26 (1H, q, J = 7.1 Hz), 5.94 (1H , q, J- 7.1 Hz), 7.30 (2H, d, J = 8.4 Hz), 7.89 (2H, d, J = 8.4 Hz), 9.68 (1H, brs). Elemental analysis: C ₂₁ H ₂₇ N ₃ 0 ₃ S ₃ calculated: C, 54.17; H, 5.84 ;, 9.02; S, 20.66

(), Found: C, 54.18; H, 5.85; N, 9.03; S, 20.60 (%).

Melting point.168.5-171.0 ° C Examples 9 to 23

_{¾-NR (200MHz, CDC1 3} ): δ 1.26 (3H, t, J = 7.1 Hz), 1.34 (3H, d, J = 6.8 Hz), 1.67 (3H, d, J = 7.3 Hz), 2.44 (3H , s), 2.56 (2H, t, J = 7.0 Hz), 3.19 (2H, t, J-6.8 Hz), 4.14 (2H, q, J = 7.1 Hz), 4.47 (1H, q, J = 7.1 Hz) ), 5.15 (1H, q, J = 7.3 Hz), 7.34 (2H, d, J = 8.0 Hz), 7.89 (2H, d, J = 8.4 Hz), 9.86 (1H, brs). Elemental analysis: C ₂₁ H ₂₅ N ₃ 0 ₅ S ₃ · Calculated as ¾0: C, 49.11; H, 5.30; N, 8.18; S, 18.73

(%), Found: C, 49.35; H, 4.96; N, 8.18; S, 18.99 (%).

 85.5-87.0 ° C

 Example 9-24

_{Ή- NMR (200MHz, CDC1 3)} : δ 1.02 (3Η, t, J- 7.4 Hz), 1.75 (2H, m), 2.43 (3H, s), 2.48 (3H, s), 3.53 (1H, t, J = 7.5 Hz), 4.94 (1H, d, J = 1.2 Hz), 5.56 (1H, d, J = 1.2 Hz), 7.31 (2H, d, J = 8.0 Hz), 7.88 (2H, d, J = 8.4 Hz), 9.64 (1H, br).

'Elemental _{analysis: C 17 H 19 N 3 0} 3 S 3 Calculated: C, 49.86; H, 4.86 ; N, 10.26; S, 23.49

(%), Found: C, 49.68; H, 4.63; N, 10.14; S, 23.41 (%).

 Melting point. 163.0-165. Ot:

 Example 9-25

The crystals were recrystallized from ethyl acetate-ethyl ether to obtain orange crystals.

 Melting point: 185-187 ° C.

Infrared absorption spectrum (IR) '(in KBr): 3438, 3310, 3179, 3065, 2959, 2928, 2857, 1732, 1669, 1645, 1620, 1557, 1497 cm ^-1 .

_{- NMR (CDC1 3): δ} 0.840-0.942 (3Η, m), 1.26-1.42 (4H, m), 1.60-1.76 (2H, m), 2.43 (3H, s), 3.00 (2H, t, J = 7.0 Hz), 4.38 (1H, s), 5.15 (1H, d, J = 1.4 Hz), 5.53 (1H, bs), 5.80 (1H, d, J = 1.6 Hz), 6.04 (1H, bs), 7.31 (2H, d, J = 8.8 Hz), 7.88 (2H, d, J = 8.0 Hz), 9.74 (1H, bs).

Elemental analysis: C _2. H ₂₄ N ₄ 0 ₄ S ₃ Calculated: C, 49.98; H, 5.03 ; N, 11.66; S, 20.00

(%), Found: C, 49.72; H, 4.98; N, 11.60; S, 19.76 (%).

Example 9-26

The crystals were recrystallized from ethyl acetate-ethyl ether to obtain orange crystals. Melting point: 154-156 ° C.

Infrared absorption spectrum (IR) (in KBr) V: 3250, 2961, 2930, 2863, 2243, 2209, 1763, 1642, 1628, 1561 cm " ¹ .

'H-NMR (CDCI ₃ ): δ 0.890 (3Η, t, J = 7.0 Hz), 1.24-1.44 (4H, m), 1.58-1.74 (2H, m), 2.44 (3H, s), 2.86-3.02 , (2H, m), 4.53 (1H, s), 5.24 (1H, d, 1 = 2.2 Hz), 5.84 (1H, d, J = 2.2 Hz), 7.33 (2H, d, 7 = 8.Hz) , 7.89 (2H, d, J = 8.0 Hz), 9.82 (1H, bs).

Elemental analysis: C _2. H ₂₂ N ₄ 0 ₃ S ₃ Calculated: C, 51.93; H, 4.79 ; N, 12.11; S, 20.79 (%), Found: C, 51.63; H, 4.93 ; N, 11.95; S, 20.50 ( %).

Example 9-27

 N- {8- (Isopentylsulfanyl) -6-methyl-3-oxo-5-[(Z) -propylidene] -2,3,5,6-tetrahydrid-1H imidazo [5,1-c [1,4] thiazine-1-ylidentate 4- The compound of Example -467 was subjected to the silylation gel chromatography of Example 4-467. The red fraction following the fraction was concentrated to dryness to give the compound (44 mg, 0.092 IMOI) was obtained as a dark red oil.

_{Ή-NMR (200MHz, CDC1 3} ): δ 0.90 (6H, d, J = 6.6 Hz), 1.03 (3H, t, J = 7.5 Hz), 1.49 (3H, d, J = 7.0 Hz), 1.54 (2H , m), 1.66 (1H, quint, J = 6.2 Hz), 2.10 (2H, btt, J = 7.0 Hz), 2.43 (3H, s), 2.95 (2H, t, J = 7.7 Hz), 3.81 (1H , q, J = 5.8 Hz), 5.30 (1H, t, J- 6.9 Hz), 7.31 (2H, d, J = 8.4 Hz), 7.90 (2H, d, J = 8.0 Hz), 9.65 (1H, brs ).

Example 10-1

Synthesis of a compound of the formula (XX IV) wherein R ² is a 2- (methoxycarbonyl) ethyl group, R ⁵ is an n-hexyl group, Z is S〇 ₂ , and R ¹⁵ is a P-tolyl group

The compound synthesized in Reference Example 3-2 (739 mg, 1.72 mol) and carbonated carbonate (476 mg, 3.4 mmol) were mixed with DMF (15 ml), and ethyl 2-bromooctanoate (0.493 ml, 2.06 ml) was added at room temperature. And the mixture was stirred for 1 hour. After further stirring at 80 ° C for 13 hours, the mixture was again left at room temperature for 5 days. The reaction mixture is concentrated to dryness, mixed with ethyl acetate (25 ml), washed with 0.3N hydrochloric acid, water and saturated saline, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. Evaporated. Ether was added to the residue and mixed, and the resulting precipitate was collected by filtration, washed with ether, and dried to give a yellow powder of the title compound (484 mg, 0.874 mmol). Ή-NMR (300 MHz, in double-mouthed form): δ 1.27 (3Η, t, J- 7.1 Hz), 2.43 (3H, s), 2.73 (2H, t, J = 7.4 Hz), 3.24 (2H, t, J = 7.4 Hz), 4.17 (2H, q, J = 7.1 Hz), 4.98 (1H, s), 7.20 (2H, dd, J = 8.3, 1.5 Hz), 7.32 (2H, d, J = 8.3) Hz), 7.37 (3H, m), 7.87 (2H, d, J = 8.3 Hz), 9.69 (1H, brs).

Elemental _{analysis: C 24 H 23 N 3 0} 5 S 3 Calculated: C, 54.42; H, 4.38 ; N, 7.93; S, 18.16

(%), Found; C, 54.23; H, 4.46; N, 8.00; S, 18.45 (%).

Example 10-2

R ² Gabe Njiru group in the formula (XX IV), R ⁵ is 2-hydroxy E butyl group, the synthesis of Z is S 0 _2, compound R ¹⁵ is P- Bok Ruiru group

 The compound synthesized in Reference Example 11 (117 mg, 0.279 tmol) and potassium carbonate (77 mg, 0.558 imol) were mixed with DMF (2 ml), and 2-bromobutyltyl lactone (0.033 ml, 0.335 mmol) was added at room temperature. After stirring for 2 hours, the mixture was further stirred at 80 ° C for 4 hours. The reaction solution was mixed with ethyl acetate (25 ml), washed with 0.3 N hydrochloric acid, water and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was mixed with ethyl acetate and ether, and the resulting precipitate was collected by filtration, washed with ether, and dried to give a yellow powder (64 mg). This was recrystallized from methanol to give the title compound as a yellow powder (42 mg, 0.083 mmol).

'H-NMR (300 MHz, double-mouthed form-deuterated dimethyl sulfoxide in 9: 1): δ 1.81 (1H, m), 2.20 (1H, dq, J = 13.6, 6.4 Hz), 2.43 (3H, s) , 3.67 (2H, brq, J = 4.9 Hz), 3.92 (1H, t, J = 7.2 Hz), 4.19 (1H, brt, J = 4.9 Hz), 4.26 (2H, brs), 7.28 (2H, d, J = 8.3 Hz), 7.31 ( 5H, s), 7.87 (2H, d, J = 8.3 Hz), 11.05 (1H, br) elemental _{analysis:. C 22 H 21 N 3} 0 5 S 3 calculated: C, 52.47; H, 4.20; N, 8.34; S, 19.10 (%), found; C, 52.41; H, 4.19; N, 8.13; S, 19.10 (%). ' A list of compounds synthesized in 10-2 and compounds synthesized in the same manner is shown below. (Table 9 7)

ぇ 甩 弒 (Table 98)

Replacement ^ 弒 (fine (? ² 6) The data of the compounds synthesized in Examples 10-3 to 10-22 are shown below.

Example 10-3

 'H-NMR (300 MHz, in double-mouthed form): δ 1.28 (3Η, t, J = 7.1 Hz), 2.43 (3H, s), 3.60 (2H, s), 3.81 (2H, s), 4.21 (2H, q, J = 7.1 Hz), 7.32 (2H, brd, J = 8.3 Hz), 7.86 (2H, d, J = 8.3 Hz), 9.89 (1H, br).

Elemental _{analysis: C 17 H 17 N 3 0} 6 S 3 Calculated: C, 44.82; H, 3.76 ; N, 9.22; S, 21.12

(%), Found; C, 45.17; H, 4.04; N, 8.97; S, 21.16 (%).

Implementation 10-4

 Ή-NMR (300 MHz, in heavy dimethyl sulfoxide): δ 2.39 (3Η, s), 3.75 (2H, s), 3.98 (2H, s), 7.41 (2H, d, J = 8.1 Hz), 7.88 (2H , d, J = 8.1 Hz), 12.01 (1H, br), 13.07 (1H, br).

Elemental analysis: Calculated as _{C 15 H 13 N 3 0 6} S 3; C, 42.15; H, 3.07;, 9.83; S, 22.50

(%), Found; C, 42.19; H, 3.05; N, 9.92; S, 22.47 (%).

Example 10-5

 Ή-NMR (300 MHz, in double-mouthed form): δ 0.88 (3Η, t, J = 6.9 Hz), 1.26 (26H, brs), 1.64 (2H, brquint, J = 7 Hz), 2.44 (3H, s), 3.59 (2H, s), 3.81 (2H, s), 4.14 (2H, t, J = 6.8 Hz), 7.33 (2H, brd, J = 8.3 Hz), 7.87 (2H, d, J = 8.3) Hz), 9.86 (1H, br).

Example 10-6

 ¾-thigh (300 MHz, in a double-mouthed form): δ 2.44 (3Η, s), 3.61 (2H, s), 3.82 (2H, s), 3.77 (3H, s), 7.33 (2H, brd, J = 8.3 Hz), 7.87 (2H, d, J = 8.3 Hz), 9.82 (1H, br).

Example 10-7

 'H-NMR (300 MHz, in double-mouthed form): δ 0.88 (3Η, t, J = 6.9 Hz), 1.26 (16H, brs), 1.33 (2H, m), 1.64 (2H, brquint, J = 6.9 Hz), 2.44 (3H, s), 3.59 (2H, s), 3.81 (2H, s), 4.14 (2H, t, J = 6.8 Hz), 7.33 (2H, brd, J = 8.3 Hz), 7.87 (2H, d, J = 8.3 Hz), 9.77 (1H, br).

Example 10-8

'H-NMR (300 MHz, in double chromatographic form): δ 0.88 (3Η, t, J = 6.9 Hz), 1.26 (12H, brs), 1.33 (2H, m), 1.64 (2H, brquint, J = 6.9 Hz), 2.44 (3H, s), 3.59 (2H, s), 3.81 (2H, s), 4.14 (2H, i, J = 6.8 Hz), 7.33 (2H, brd, J = 8.2 Hz), 7.87 (2H, d, J = 8.2 Hz), 9.76 (1H, br).

Example 10-9

^ -NMR (300 MHz, double-mouthed form-deuterated dimethyl sulfoxide in 3: 1): δ 2.41 (3Η, s), 3.55 (2H, s), 3.92 (2H, s), 5.21 (2H, s), 7.31 (2H, d, J = 8.1 Hz), 7.36 (1H, m), 7.44 (2H, d, J = 8.1 Hz), 7.45 (2H, t, J = 7.3 Hz), 7.59 (4H, brd, J = 8.0 Hz), 7.91 (2H, d, J = 8.1 Hz), 11.73 (1H, br).

Example 10-10

'H-NMR (300 MHz, in double-mouthed form): δ 1.99 (2Η, it, J = 7.6, 6.5 Hz), 2.41 (3H, s), 2.68 (2H, t, J = 7.6 Hz), 3.58 (2H, s), 3.79 (2H, s), 4.18 (2H, t, J = 6.5 Hz), 7.15 (2H, brd, J = 7.0 Hz), 7.20 (1H, m), 7.29 (2H, t, J = 8.0 Hz), 7.31 (2H, d, J- 8.3 Hz), 7.86 (2H, d, J = 8.3 Hz), 9.87 (1H, br).

Elemental _{analysis: C 24 H 23 N 3 0} 6 S 3 Calculated: C, 52.83; H, 4.25 ; N, 7.70; S, 17.63 (%), Found; C, 52.67; H, 4.24 ; N, 7.89; S, 17.94 (%).

Example 10-11

 'H-NMR (300 MHz, in double-mouthed form): δ 1.60 (3Η, s), 1.60 (3H, s), 1.68 (3H, s), 1.71 (3H, s), 1.99 (4H, m) , 2.07 (6H, m), 2.43 (3H, s), 3.59 (2H, s), 3.81 (2H, s), 4.67 (2H, d, J = 7.2 Hz), 5.08 (2H, t, J = 5.6) Hz), 5.33 (1H, brt, J = 7.2 Hz), 7.33 (2H, d, J = 8.3 Hz), 7.86 (2H, d, J- 8.3 Hz), 9.89 (1H, br).

Elemental analysis: C _3. H ₃₇ N ₃ 0 ₆ S ₃ · 0.8H ₂ 0 Calculated: C, 55.76; H, 6.02; N, 6.50; S, 14.88 (%), found; C, 55.50; H, 5.58; N, 6.70 ; S, 15.14 (%).

Examples 10-12

Ή-NMR (300 MHz, in double-mouthed form): δ 1.60 (3Η, s), 1.68 (3H, s), 1.71 (3H, s), 2.07 (4H, m), 2.44 (3H, s), 3.58 (2H, s), 3.81 (2H, s), 4.67 (2H, d, J- 7.2 Hz), 5.07 (1H, m), 5.33 (1H, brt, J = 7.2 Hz), 7.33 (2H, d , J = 8.3 Hz), 7.86 (2H, d, J = 8.3 Hz), 9.87 (1H, brs).

Elemental analysis: C ₂₅ H ₂₉ N ₃ O _s S ₃ Calculated: C, 53.27; H, 5.19; N, 7.45 (%), Found: C, 52.88; H, 4.93; N, 7.54 (%).

Example 10-13

 'H-NMR (300 MHz, heavy duty in P-holm): δ 1.26 (3Η, t, J- 7.1 Hz), 2.43 (3H, s), 2.70 (2H, t, J = 7.2 Hz), 3.30 ( 2H, t, J = 7.2 Hz), 3.65 (2H, s), 4.16 (2H, q, J = 7.1 Hz), 7.32 (2H, d, J = 8.3 Hz), 7.86 (2H, d, J = 8.3) Hz), 9.8 (1H, br).

Elemental _{analysis: C 18 H 19 N 3 0} 6 S 3 - 0.3H 2 0 Calculated: C, 45.52; H, 4.16 ; N, 8.85; S, 20.25 (%), Found; C, 45.41; H , 3.90; N, 8.94; S, 20.41 ().

Example 10-14

4-isomer mixture

 -Fiber (300 MHz, in double-holed holm): 6 1.54 / 1.55 (3H, d, J = 7.2 / 6.6 Hz), 1.58 / 1.59 (3H, .d, J-6.9 / 7.4 Hz), 2.43 (3H , s), 3.72 / 3.83 (1H, q, J = 7.0 Hz), 4.16 (1H, q, J = 7.3 Hz), 7.33 (2H, d, J = 8.2 Hz), 7.86 / 7.87 (2H, d, J = 8.2 Hz).

Example 10-15

 4-isomer mixture

 Ή-Image R (300 MHz, in double-mouthed form): δ 0.88 (3Η, t, J = 6.9 Hz), 1.26 (24H, brs), 1.29 (2H, m), 1.51 / 1.58 (3H, d, J = 7.0 / 7.2 Hz), 1.57 (3H, d, J = 7.1 Hz), 1.62 (2H, m), 2.44 (3H, s), 3.71 / 3.73 (1H, q, J- 7.0 Hz), 4.11 ( 2H, dt, J = 5.2, 6.7 Hz), 4.17 / 4.20 (1H, q, J = 7.3 / 7.4 Hz), 7.33 (2H, d, J = 8.2 Hz), 7.88 (2H, d, J = 8: 2 Hz), 9.6 (1H, br).

Example 10-16

'H-NMR (300MHz, CDC1 3): δ 0.88 (3H, t, J = 6.4 Hz), 1.26 (6H, br), 1.30 (2H, m), 1.64 (1H, m), 1,95 (1H , m), 2.42 (3H, s), 3.51 (1H, dd, J = 7.5, 6.4 Hz), 4.25 (2H, s), 7.30 (2H, brd,, J = 8.3 Hz), 7.31 (5H , s), 7.86 (2H, d, J = 8.3 Hz), 9.86 (1H, brs).

Elemental _{analysis: C 2S H 29 N 3 0} 4 S 3 '0.4H 2 0 Calculated: C, 56.68; H, 5.45 ; N, 7.62 (), Found: C, 56.51; H, 5.24 ;, 7.67 (%).

Examples 10-17 _{¾-NMR (300MHz, CDC1 3} ): δ 1.27 (3H, t, J = 7.2 Hz), 1.61 (3H, d, J = 6.8 Hz), 2.44 (3H, s), 2.69 (2H, t, J = 7.4 Hz), 3.29 (2H, dt, J-2.3, 7.2 Hz), 3.76 (1H, q, J = 7.2 Hz), 4.17 (2H, q, J = 7.2 Hz), 7.32 (2H, brd, J = 7.9 Hz), 7.86 (2H, d, J = 8.3 Hz), 9.66 (1H, br).

Elemental _{analysis: C i9 H 21 N 3 O} s S 3 Calculated: C, 47.19; H, 4.38 ; N, 8.69; S, 19.89 (%), Found: C, 47.32; H, 4.38 ; N, 8.73; S, 19.66 (%).

Example 10-18

¾ chromatography Awakening: _{R (300MHz, CDC1 3):} δ 0.90 (3H, t, J = 7.0 Hz), 1.33 (4H, m), 1.64 (1H, m), 1.95 (1H, m), 2.43 (3H, s ), 3.50 (1H, dd, J = 7.9, 6.4 Hz), 4.26 (2H, s), 7.31 (2H, d, J = 8.3 Hz), 7.31 (5H, s), 7.86 (2H, d, J = . 8.3 Hz), 9.81 (1H , brs) elemental _{analysis: C 24 H 25 N 3 0} 4 S 3 calculated:. C, 55.90; H, 4.89; N, 8.15; S, 18.65 (%), measured Values: C, 55.84; H, 4.88; N, 8.02; S, 18.58 (%).

Example 10-19,

_{¾-NMR (300MHz, CDC1 3} ): δ 1.23 (3Η, t,] = 7.0 Hz), 2.43 (3H, s), 4.19 (1H, dq, J = 12.5, 7.2 Hz), 4.24 (1H, dq, J = 12.5, 7.2 Hz), 4.26 (1H, d, J = 13.6

Hz), 4.28 (1H, d, J = 13.6 Hz), 4.31 (1H, s), 7.31 (2H, d, J- 8.3 Hz), 7.32

(5H, s), 7.85 (2H, d, 'J = 8.3 Hz), 9.86 (1H, brs).

Elemental analysis: Calculated as _{C 23 H 21 N 4 0 6} S 3: C, 51.96; H, 3.98; N, 7.90; S, 18.10 (%), Found: C, 51.74; H, 3.99 ; N, 7.78; S, 18.07 (%).

Example 10 20

'H-NMR (300MHz, CDC1 3): δ 2.43 (3Η, s), 4.28 (2H, s), 4.77 (1H, s), 7.26 (3H, m), 7.29 (2H, d, J = 8.3 Hz ), 7.32 (5H, s), 7.38 (2H, dd, J- 5.3, 2.3 Hz), 7.85 (2H, d, J = 8.3 Hz), 9.80 (1H, br).

Elemental _{analysis: C 26 H 21 N 3 0} 4 S 3 Calculated: C, 58.30; H, 3.95 ; N, 7.84; S, 17.96 (), Found: C, 58.26; H, 3.80 ; N, 8.09 S, 17.83 ().

Example 10-21

_{Ή-NMR (300MHz, CDC1 3} ): <5 0.88 (3H, t, J = 6.6 Hz), 1.25 (18H, brs), 1.40 (2H, m), 1.64 (1H, m), 1.95 (1H, m ), 2.43 (3H, s), 3.50 (1H, dd, J = 7.9, 6.4 Hz), 4.26 (2H, s), 7.30 (2H, d, J = 8.3 Hz), 7.31 (5H, s), 7.86 (2H, d, J = 8.3 Hz), 9.80 (1H, brs).

Elemental _{analysis: C 32 H 41 N 3 0} 4 S 3 Calculated: C, 61.21; H, 6.58 ; N, 6.69; S, 15.32

(%), Found: C, 61.29; H, 6.58; N, 6.83; S, 15.27 (%).

Example 10-22

N- [3,5-Dioxo-8_ (isobutylsulfanyl) -6-methyl-2,3,5,6-tetrahydro-1H-imidazo [5, lc] [1,4] thiazine-triylidene ] _4-Methylbenzenesulfonamide

To a suspension of sodium hydride (346 mg, 8.65 thigh 01) (60% oily) in tetrahydrofuran (15.0 ml) was added 2-{[(isobutylsulfanyl) (5- { A solution of [(4-methylphenyl) sulfonyl] imino} -2-oxo-4-imidazolidinylidene) methyl] sulfanyl} ethyl propionate (3.50 g, 7.21 mmol) in tetrahydrofuran (15.0 ml) was added. After the reaction mixture was heated to reflux for 30 minutes, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), and the solvent was distilled off under reduced pressure to give the title compound (1.66 g, 52%) as a dark red crystals. Recrystallization from ethyl acetate-ethyl acetate gave dark red crystals with a melting point of 163-165.

Infrared absorption spectrum (IR) (in KBr): 3260, 2959, 2930, 2872, 1802, 1713, 1632, 1557, 1495 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 1.03 (6Η, d, J = 6.6 Hz), 1.60 (3H, t, J = 7.0 Hz), 1.81-1.96 (1H, in), 2.43 (3H, s), 2.90 (2H, d, J = 6.6 Hz), 3.73 (1H, q, J-7.0 Hz), 7.32 (2H, d, J = 8.0 Hz), 7.88 (2H, d, J = 8.Hz), 9.83 ( 1H, bs).

Elementary analysis: as _{C 18 H 21 N 3 0 4} S 3

Computing Shari (¾): C, 49.18; H, 4.82; N, 9.56; S, 21.88.

Found (¾): C, 48.98; H, 4.95; N, 9.49; S, 21.71.

Example 11-1

Formula (XV I) in a hexyl group R ¹ is the n-, synthesis of R ⁵ and R ⁵ are both methyl groups, Z is S 0 _2, R ¹⁵ is p- tolyl group compound

The compound synthesized in Example 4-96 (247 mg, 0.624 mmol) was mixed with THF (5 ml), n-butylmagnesium bromide (1.31 ml, 1.0 M, THF solution) was added at room temperature, and the mixture was stirred for 46 hours. . During this time, add the above n-butylmagnesium bromide (0.187 ml) to the reaction mixture. Was added. 0.1 IN hydrochloric acid (15 ml) and ethyl acetate (15 ml) were added to the reaction solution and mixed. After the organic layer was washed with 0.1N hydrochloric acid, water and saturated saline, insolubles were removed, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography on silica gel 60 (10 g), and the fraction eluted with ethyl acetate: hexane (20:80) was concentrated to dryness under reduced pressure to give the title compound as an orange oil (19 mg, 0.044 mmol) ). 'H-NMR (200 MHz, in double-mouthed form): δ 0.85 (3Η, t, J = 6.7 Hz), 1.17 (6H, m), 1.41 (2H, m), 1.73 (3H, q, J- 0.8 Hz), 2.25 (3H, brs), 2.43 (3H, s), 2.68 (2H, t, J = 7.6 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.79 (2H, d, J = 8.4 Hz), 9.74 (1H, brs).

Elemental analysis: Calculated for C _{2 17} N ₃ 0 ₃ S ₂ : C, 58.17; H, 6.28; N, 9.69; S, 14.79 (%) found; C, 57.96; H, 6.21; N, 9.86; S, 14.82 ().

Melting point: 171.0-174.0 ° C

Example 11-2

Synthesis of a compound of the formula (XVI) in which R ¹ is a benzoylmethyl group, R ⁵ is an ethyl group, R ⁶ is a methyl group, Z is S 0 ₂ , and R ¹⁵ is a P-tolyl group

 The compound synthesized in Example 4-376 (166 mg, 0.323 orchid oi) was mixed with THF (4 ml), and methylmagnesium bromide (0.237 ml, 3.0′Μ, THF solution) was added at −78 ° C. to give 1 Stirred for hours. After returning the reaction solution to room temperature, it was stirred at room temperature for 18 hours. 0.1N hydrochloric acid (0.81 ml) and ethyl acetate (25 ml) were added to the reaction solution and mixed. The organic layer was washed with 0.1N hydrochloric acid, water and a saturated saline solution, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Methanol was added to the residue, and the precipitated powder was collected by filtration to obtain a red powder. This was subjected to column chromatography on silica gel 60 (5 g), and the fraction eluted with ethyl acetate: hexane (3: 7 to 4: 6) was concentrated to dryness under reduced pressure. Ether was added to the residue, and the precipitated powder was collected by filtration, washed with ether, and dried to give a red powder of the title compound (69 mg, 0.143 tU).

Ή-NMR (300 MHz, in double-mouthed form): 6 1.07 (3H, t, J = 7.5 Hz), 2.09 (2H, q, J-7.6 Hz), 2.28 (3H, s), 2.33 (3H, s), 4.36 (2H, s), 6.98 (2H, d, J = 8.0 Hz), 7.34 (2H, d, J = 8.2 Hz), 7.43 (2H, brt, J = 7.3 Hz), 7.60 (1H, tt, J = 7.4, 1.2 Hz), 7.78 (2H, dm, J = 8.0 Hz), 9.68 (1H, brs). Elemental _{analysis: C 24 H 23 N 3 0} 4 S 2 Calculated: C, 59.86; H, 4.81 ; N, 8.73; S, 13.32

(%), Found; C, 59.47; H, 4.82; N, 8.62; S, 13.48 (%).

Mass spec (FAB-MS): 482 (M + H).

Example 11-3

Synthesis of a compound of the formula (XVI), wherein R ¹ is a benzoylmethyl group, R ⁵ and R ⁶ are methyl groups, Z is S〇 ₂ , and R ¹⁵ is a p-tolyl group.

 (Method 1) Using the compound (524 mg, 1.05 mmol) obtained in Example 4-75 as a starting material, a red powder (39 mg, 0.083 ol) of the title compound was obtained in the same manner as in Example 11-2.

Ή-Image R (300 MHz, in double-mouthed form): δ 1.73 (3Η, q, J = .2 Hz), 2.28 (3H, q, J = 1.0 Hz), 2.32 (3H, s), 4.35 ( 2H, s), 6.98 (2H, brd, J = 7.6 Hz), 7.36 (2H, d, J = 8.2 Hz), 7.44 (2H, brt, J = 7.2 Hz), 7.60 (1H, brt, J = 7.4) Hz), 7.78 (2H, d, J = 8 Hz), 9.66 (1H, brs).

Elemental _{analysis: C 23 H 21 N 3 0} 4 S 2 - 0.5H 2 0 Calculated: C, 57.97; H, 4.65 ; N, 8.82; S, 13.46 (%), Found; C, 58.09; H , 4.43; N, 8.81; S, 13.48 (%).

 (Method 2) To a solution of the compound obtained in Example 4-75 (262 rag, 0.52 acetyl) and triphenylphosphine (567 mg, 2.10 mmol) in THF (5.0 ml) was added n-butyllithium (to 1.6 M). A hexane solution (0.754 ml, 1.21 mmol) was added, and the mixture was stirred at room temperature for 21 hours. 1N Hydrochloric acid (1.21 ml) and water were added to the reaction solution, and the mixture was extracted with ethyl acetate (30 ml). The organic layer was washed with 0.1N hydrochloric acid, water and saturated saline, dried and concentrated. The residue was subjected to chromatography on silica gel (10 g) (ethyl acetate-hexane, 1: 9-), and the ethyl acetate-hexane (4: 6) fraction was concentrated and crystallized from methanol. The title compound (46 rag, 0.098 ol) was obtained as a red powder.

Melting point: 137.0-137.5 ° C.

The following is a list of compounds synthesized in Examples 11-1 to 11_3 and compounds synthesized in the same manner. (Table 9 9)

麄 Replacement form (Rule 26) The data of the compounds synthesized in Examples 11-4 to 11-8 are shown below.

Example 11-4

'H-NMR (200MHz, CDC1 3): 6 1.08 (3H, t, J = 7.3 Hz), 1.73 (3H, q, J = 0.6 Hz), 2.25 (3H, q, J = 1.2 Hz), 2.43 ( 3H, s), 2.74 (2H, q, J = 7.5 Hz), 7.30 (2H, d, J = 8.2 Hz), 7.80 (2H, d, J = 8.2 Hz), 9.75 (1H, brs).

Elemental _{analysis: C 17 H 19 N 3 0} 3 S 2 Calculated: C, 54.09; H, 5.07 ;, 11.13; S, 16.99

(%), Found: C, 54.09; H, 4.91; N, 10.86; S, 16.83 (%).

Melting point. 202.5-203.5 ° C

Example 11-5

_{¾-NMR (200MHz, CDC1 3} ): δ 1.07 (3H, t, J = 7.5 Hz), 1.09 (3H, t, J = 7.5 Hz), 2.09 (2H, q, J = 7.5 Hz), 2.25 (3H , s), 2.43 (3H, s), 2.76 (2H, q, J = 7.5 Hz), 7.30 (2H, d, J = 8.1 Hz), 7.80 (2H, d, J = 7.0 Hz), 9.75 (1H , Brs).

Elemental _{analysis: C 18 H 21 N 3 0} 3 S 2 Calculated: C, 55.22; H, 5.41 ; N, 10.73; S, 16.38 (%), Found: C, 54.82; H, 5.42 ; N, 10.62; S, 16.35 (%).

Melting point. 184.0- 185.0 ° C

Example 11-6

'H-NMR (300MHz, CDC1 3): δ 1.77 (3H, s), 2.08 (3Η, s), 2.24 (3H, s), 2.37 (3H, s), 6.87 (1H, s), 7.11 (2H , d, J = 8.0 Hz), 7.40 (2H, t, J = 7.6 Hz), 7.45 (2H, d, J = 8.4 Hz), 7.59 (1H, t, J = 7.4 Hz), 7.93 (2H, d , J = 7.5 Hz), 9.82 (1H, brs).

^{13 C-NMR (75MHz, CDC1} 3): d 14.67 (C¾), 15.69 (CH 3), 17.39 (CH 3), 21.56 (CH 3), 49.79 (CH), 106.47 (Q), 124.00 (Q), 126.46 (CH), 128.73 (2CH), 129.00 (2CH), 129.56 (2CH), 133.78 (CH), 134.58 (Q), 137.44 (Q), 138.23 (Q), 143.91 (Q), 147.18 (Q), 147.92 (Q), 191.97 (Q).

Mass spectrometry (FAB-MS): M + H = 514, M + K = 552

Melting point.169.0- 170.0 ° C

Example 11-7

'H-NMR (200MHz, CDC1 3): δ 1.36 (3H, d, J = 6.5 Hz), 1.76 (3H, q, J = 0.9 Hz), 2.25 (3H, q, J = 0, 9 Hz), 2.43 (3H, s), 3.30 (1H, d, J = 6.1 Hz), 5.23 (1H, quint, J = 6.4 Hz), 7.32 (2H, d, J = 8.3 Hz), 7.80 (2H, d, J = 8.3 Hz), 9.78 (1H, brs). [H-Awake R (200MHz, CDC1 ₃ + (Heavy water) <5 1.35 (3H, d, J = 6.5 Hz), 1.76 (3H, brs), 2.25 (3H, brq, J = 0.8 Hz), 2.43 (3H, s), 5.22 (1H, q, J = 6.4 Hz), 7.32 (2H, d, J = 8.1 Hz), 7.80 (2H, d, J = 8.3 Hz).

Elemental _{analysis: C 17 H 19 N 3 0} 4 S 2 Calculated: C, 51.89; H, 4.87 ;, 10.68 (%), actual Hakachi: C, 51.70; H, 4.96 ; N, 10.41 (%) Melting point: 192.0-193.0 ° C

Mass Spectrometry (FAB-MS) :: M + H = 393, M + K = 432

Example 11 8

_{¾-NMR (200MHz, CDC1 3} ): δ 1.69 (3Η, q, J = 1.2 Hz), 2.26 (3H, q, J = 1.6 Hz), 2.43 (3H, s), 6.70 (1H, s), 7.31 (2H, d, J = 8.8 Hz), 7.80 (2H, d, J = 8.0 Hz), 9.60 (1H, br).

Elemental _{analysis: C 15 H 15 N 3 0} 3 S 2 Calculated: C, 51.56; H, 4.33 ; N, 12.03; S, 18.35

(%), Found: C, 51.22; H, 4.39; N, 11.73; S, 18.14 ().

Example 12 1

Synthesis of a compound of the formula (XXV) wherein R ² is a 2- (methoxycarbonyl) ethyl group, R ⁵ is an n-hexyl group, and R ⁶ is a hydrogen atom

Triethylamine (3.8 ml) was added to a suspension of the compound synthesized in Reference Example 3-3 (3.27 g), 2-bromoctanal (2.5 ml) in THF (80 ml) and DMF (15 ml) at 0 ° C. The mixture was added dropwise and stirred at room temperature for 1 hour. Ethyl acetate (100 ml) was added, and the organic layer was washed sequentially with 0.05 M hydrochloric acid, water, and saturated saline, and then dried over magnesium sulfate. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography. From the hexane: ethyl acetate (1: 2) elution part, in the formula (XX), R ² was a 2- (methoxycarbonyl) ethyl group, hexyl group R ⁵ is the n-, R ⁶ is a hydrogen atom, Z is give CO, pale brown oil of the compound R ¹⁵ is phenyl group and (3.13 g). This was dissolved in toluene (50 ml), acetic anhydride (0.6 ml) and camphorsulfonic acid (0.9 g) were added, and the mixture was stirred for 4 hours at T. After cooling to room temperature, ethyl acetate (100 ml) was added to the reaction solution. In addition, the organic layer was washed with a saturated aqueous solution of sodium carbonate and saturated saline, dried over magnesium sulfate, and the solvent was distilled off.The residue obtained was subjected to silica gel column chromatography, and hexane: ethyl acetate (hexane) was added. 2: 1) The title compound (1.08 g, 46%) was obtained from the eluate. One _{NMR (300 MHz, CDC1 3)} : 60.90 (3H, t, J = 6.9Hz), 1.25-1.36 (6H, m), 1.43-1.53 (2H, m), 2.05 (2H, t, J = 7.1Hz ), 2.74 (2H, t, J = 7.5Hz), 3.23 (2H, t, J = 7.5Hz), 3.73 (3H, s), 6.50 (1H, brs), 8.46 (1H, brs).

Example 12-2

Synthesis of a compound of the formula (XXV) wherein R ^{2 is a} benzyl group, R ⁵ is an n-hexyl group, and R ⁶ is a hydrogen atom

 To a mixed solution of the compound synthesized in Example 10-1 (1.53 g) in THF (15 ml) and methanol (5 ml) was added dropwise a solution of potassium hydroxide (1.2 g) in methanol (10 ml), and the mixture was stirred for 30 minutes. Thereafter, benzyl bromide (0.59 ml) was added dropwise and stirred for 3 hours. After adding 0.1 M hydrochloric acid (40 ml) to the reaction solution and extracting with ethyl acetate, the extract was washed with water and saturated saline, and dried over magnesium sulfate. The solvent was distilled off to obtain the title compound (1.54 g, 99%).

¾-NMR (300 MHz, CDC1 3): d 0.90 (3H, t, J = 6.9Hz), 1.24-1.51 (8H, m), 2.03 (2H, t, J = 7.1Hz), 4.22 (2H, s ), 6.47 (1H, s), 7.24-7.40 (5H, m), 8.30 (1H, br s).

The compounds synthesized in Examples 12-1 and 12-2 are shown below.

(Table 100)

Substitution (Rule 26) Example 13-1

Synthesis of a compound of the formula (XXVI) wherein R ^{2 is a} benzyl group, R ⁵ is an n-hexyl group, R ⁶ is a hydrogen atom, and R ¹⁴ is a t-butoxycarbonylmethyl group

To a solution of the compound synthesized in Example 12-2 (51. Omg) in DMF (1 ml) was added tributyl bromoacetate (0.024 ml) and carbonated carbonate (37.5 mg), and the mixture was stirred for 21 hours. After dilution with ethyl acetate, the organic solvent was washed with 0.05M hydrochloric acid and saturated saline, and then dried over magnesium sulfate. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography, and the title compound (64.2 mg, 97%) was obtained from a fraction eluted with hexane: ethyl acetate (2: 1). 'H-NMR (300 MHz, CDC1 3): 50.91 (3H, i, J = 7.1Hz), 1.20-1.55 (8H,), 1.46 (9H, s), 2.00-2.07 (2H, m), 4.19 ( 2H, s), 4.22 (2H, s), 6.50 (1H, br s), 7.20-7.40 (5H, m).

Example 13-2

Synthesis of a compound of the formula (XXV I) wherein R ^{2 is a} benzyl group, R ⁵ is an n-hexyl group, R ⁶ is a hydrogen atom, and R ¹⁴ is a carboxymethyl group

 Trifluoroacetic acid (0.5 ml) was added to the compound (32.1 mg) synthesized in Example 13-1, and the mixture was stirred for 15 minutes. Ether was added to adjust the pH to 4 with a 1N aqueous sodium hydroxide solution, and the organic layer was extracted with a 1N aqueous sodium hydroxide solution (10 ml). The combined aqueous layer was adjusted to pH 2 with 1N hydrochloric acid and extracted with ethyl acetate. After the extract was dried over magnesium sulfate, the solvent was distilled off to obtain the title compound (7.5 mg, 26). .

Ή-NMR (300 MHz, CDC1 3):. Δ 0.91 (3Η, t, J-6.9Hz), 1.00-1.80 (8H, m), 2.00-2.09 (2H, m), 4.23 (2H, s), 4.35 (2H, s), 6.52 (1H, brs), 7.23-7.39 (5H, m). Example 13-3

Synthesis of a compound of the formula (XXVI) wherein R ^{2 is a} benzyl group, R ⁵ is an n-hexyl group, R ⁶ is a hydrogen atom, and R ¹⁴ is a 4-methoxybenzyl group

To a solution of the compound (30.5 mg) synthesized in Example 12-2 in DMF (0.6 ml) was added 4-methoxybenzyl chloride (0.017 ml) and potassium carbonate (22.5 mg), and the mixture was stirred for 19.5 hours. Ether and water (2 ml each) were added, and the mixture was stirred for 1 hour, added with 0.05 M hydrochloric acid (1 ml), and extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. Evaporate the solvent The resulting residue was subjected to silica gel column chromatography to give the title compound (26.3 mg, 67%) from a fraction eluted with hexane: ethyl acetate (6: 1).

'HN R (300 MHz, CDC1 3): (50.89 (3H, t, J = 6.9Hz), 1.20-1.50 (8H, m), 1.96-2.06 (2H, m), 3.78 (3H, s), 4.20 (2H, s), 4.63 (2H, s), 6.46 (1H, br s), 6.82 (2H, d, J = 8.4Hz), 7.24-7.38 (7H, m).

Example 13-4

Synthesis of a compound of the formula (XXVI) wherein R ^{2 is a} benzyl group, R ⁵ is an n-hexyl group, R ⁶ is a hydrogen atom, and R ¹⁴ is a P-toluenesulfonyl group

 To a solution of the compound (31.9 mg) synthesized in Example 12-2 in dichloromethane (11), p-toluenesulfonyl chloride (17.lmg) and triethylamine (0.0143 ml) were added, and the mixture was stirred for 15.5 hours. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over magnesium sulfate. The residue obtained by distilling off the solvent was collected by filtration and washed with hexane to obtain the title compound (26. Omg, 61%).

¾-NMR (300 MHz, CDC1 3): 50.89 (3H, t, J = 6.9Hz), 1.22-1.48 (8H, m), 2.00 (2H, t, J-7.2Hz), 2.44 (3H, s) , 4.20 (2H, s), 6.42 (1H, s), 7.27-7.37 (7H, m), 8.03 (2H, d, J = 8.3Hz).

Example 13-5

Synthesis of a compound of the formula (XXVI) wherein R ^{2 is a} benzyl group, R ⁵ is an n-hexyl group, R ⁶ is a hydrogen atom, and R ¹⁴ is an n-butylsulfonyl group

 The title compound was obtained in the same manner as in Example 13-4 from the compound synthesized in Example 12-2 (22.4 mg) and 1-butanesulfonyl chloride (0.009 ml). Yield 75%.

[H-NMR (200 MHz, CDC1 3): 50.91 (3H, t, J = 7.0Hz), 0.95 (3H, t, J = 7.3Hz), 1.25-1.55 ( Yuzuru, i), 1.79-1.91 (2H , m), 2.01-2.10 (2H, m), 3.46-3.54 (2H, m), 4.24 (2H, s), 6.49 (1H, s), 7.27-7.40 (5H, m).

Example 13-6

Synthesis of a compound of the formula (XXVI) wherein R ^{2 is a} benzyl group, R ⁵ is an n-hexyl group, R ⁶ is a hydrogen atom, and R ¹⁴ is a dimethylaminomethyl group

The title compound was obtained from the compound (29.8 mg) synthesized in Example 12-2 and 2-chloroethyldimethylamine hydrochloride (11.5 nig) in the same manner as in Example 13-3. Yield 53%. 'H-NMR (300 MHz, CDC1 3): 50.90 (3H, t, J-6.9Hz), 1.24-1.38 (8H, m), 1.39-1.51 (2H, m), 2.03 (2H, t, J = 7.0Hz), 2.26 (6H, s), 2.54 (2H, t, J = 6.7Hz), 3.67 (2H, t, J = 6.7Hz), 4.21 (2H, s), 6.49 (1H, s), 7.24 -7.40 (5H, m).

The following is a list of compounds synthesized in Examples 13-1 to 13-6 and compounds synthesized in the same manner.

(Table 101)

Custom paper »U26) (Table 1.02)

差替え用紙（規則 26) 以下に実施例 13-7〜13- 22で合成した化合物のデータを示す。

Replacement form (Rule 26) The data of the compounds synthesized in Examples 13-7 to 13-22 are shown below.

Example 13-7

_{Ή-NMR (CDC1 3):} (50.85-0.93 (6H, m), 1.20-1.70 (14H, m), 2.00-2.07 (2H, m), 3.53 (2H, t, J = 7.3Hz), 4.21 ( 2H, s), 6.50 (1H, br s), 7.22-7.40 (5H, m).

-Marauder R (CDC1 ₃ ): 50.87 (3H, t, J = 6.8Hz), 1.20-1.47 (8H, m), 2.11 (2H, t, J = 6.7Hz), 3.97 (2H, s), 4.29 ( 2H, s), 6.66 (1H, s), 7.20-7.43 (6H, m), 7.60 (1H, br s).

Example 13-9

_{H-NMR (CDC1 3):} δ 0.90 (3H, t, J = 6.8Hz), 1.10-1.50 (8H, m), 2.03 (2H, t, J = 7.0Hz), 4.21 (2H, s), 4.63 (2H, s), 6.48 (1H, s), 7.20-7.50 (9H, m) .Example 13-10

 'Η—Awake R (CDCI3): 50.90 (3H, t, J-7.0Hz), 1.22-1.35 (6H, m), 1.24 (3H, t, J = 7.2Hz), 1.38-1.50 (2H, m) , 2.04 (2H, t, J = 7.7Hz), 2.65 (2H, t, J = 7.2Hz), 3.85 (2H, t, J = 7.2Hz), 4.13 (2H, q, J = 7.2Hz), 4.21 (2H, s), 6.49 (1H, s), 7.25-7.40, (5H, m).

Examples 13-11

 ¾-NMR (CDCI3): ά 0.90 (3H, t, J = 6.1Hz), 1.38 (3H, t, J = 7.1Hz), 1.25-1.50 (8H, m), 2.03 (2H, t, J = 7.6) Hz), 4.21 (2H, 's), 4.36 (2H, q, J = 7.1Hz), 4.74 (2H, s), 6.49 (1H, s), 7.27-7.39 (5H, m), 7.44 (2H, d, J = 7.3Hz), 7.98 (2H, d, J = 7.3Hz).

Example 13-12

 'H-NMR (CDCI3): 50.90 (3H, t, J = 6.9Hz), 1.25 (3H, t, J = 7.1Hz), 1.27-1.37 (6H, m), 1.41-1.50 (2H, m), 1.93 (1H, tt, J = 7.5, 6.8Hz), 1.96 (1H, tt, J = 7.5, 6.8Hz), 2.04 (2H, t, J = 7.1Hz), 2.31 (2H, t, J = 7.5Hz) ), 3.61 (2H, t, J-6.8Hz), 4.13 (2H, q, J = 7.1Hz), 4.22 (2H, s), 6.49 (1H, s), 7.25-7.40 (5H, m) Example 13-13

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 91-Sip Toshiki

• (in ¾9) QfL- ^ Z'L '(s ¾l) 09' 9 '(s' ΕΖ) ΙΖ' ('' 9 = Γ '1' ΕΖ) Οΐ · ε Ί 'ΗΖ) 88' (ΖΗ “= ί '1' ΗΖ) fO'Z '(ω ¾f) Wi_SS'I' (ω 'ΕΖ) ZS't-Of Ί' (πι 'Η9) 68 * l- Z'l' (ζΗ8 · 9 = ί Ί 'Η8) 06 Ό Ρ: (' ΙΟΟΟ) Ν-Η, ΐ-2ΐ m

 '(ιπ)

^ ■ 1-111 '(s'Ηΐ)'(s' Μ) 8f '(s'ΗΖ)' (ΖΗΓ ί '' ΗΖ) ίΟ '(ω S' Μ) Ζ9ΐ ΐ-0 ^ * ΐ ^£ (ιπ 'Η9) 6Γΐ-SZ'I' (ΖΗ6 · 9 = ί 'Ηδ) Ϊ6.0 ·: ( ^ε ΐ3α3) picture-

(In ¾S) ^ · ί-Π-ί '(s' Ηΐ) 6 9' (s' ΗΖ) ΐΖ '(ΖΗΓΑ = ί' b 'ΗΖ) Wf' (ΖΗΓ9 = 1) 99 Έ 'W9 = r Ί 'ΗΖ)

68 mu

0t9t0 / Z0dr / lDd 909Ζ60 / Ζ0 OAV (5H, m).

Examples 13-21

_{lH - NMR (CDC1 3):} δ 0.89 (3Η, t, J = 6.9Hz), 1.24-1.48 (8H, m), 2.01 (2H, br t, J = 7.5Hz), 2.30 (3H, s), 2.67 (6H, s), 4.20 (2H, s), 6.42 (1H, br s), 6.97 (2H, s), 7.28-7.34 (5H, m).

Example 13-22

 — Bandit R (CDCI3): 50.90 (3H, t, J = 6.9Hz), 1.23-1.51 (8H,), 2.04 (2H, dt, J = 7.0, 1.1Hz), 2.64 (1H, dd, J = 4.5 , 2.5Hz), 2.77 (1H, dd, J = 4.5, 4.2Hz), 3.13-3.20 (1H, m), 3.61 (1H, dd, J = 14.3, 5.3Hz), 3.84 (1H, dd, J = 14.3, 5.0Hz), 4.22 (2H, s), 6.51 (1H, s), 7.27-7.40 (5H, m).

Example 14-1

In the formula (XXX), synthesis of a compound wherein R ⁵ is an ethoxydicarbonyl group, R ⁶ is a methyl group, R ¹⁴ is a tert-butoxycarboylmethyl group, and R is a methyl group

 The compound synthesized in Reference Example 14 (2.07 g, 5.50 tmol) was dissolved in THF (45 ml), and ethyl 2-chloroacetoacetate (0.84 ml, 6.05 mmol) and triethylamine (1.91 ml, 13.7 ramol) were added. For 1 hour. After concentration of the reaction solution, the residue was diluted with ethyl acetate (130 ml), washed with water and saturated saline, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel 60 (25) column chromatography. The eluted fraction of ethyl acetate: hexane (30:70) was concentrated under reduced pressure to dryness. A yellow oil (2.57 g, 5.09 mmol) of the title compound was obtained as a mixture of four isomers. '

 -麵 R (300 MHz, in double-holed form): 6 1.27 / 1.30 (3Η, t, J = 7.1 Hz), 1.47 (9H, s), 1.84 / 2.04 (3H, s), 2.69 / 2.71 (2H , T, J = 7.3 Hz), 3.05-3.35 (2H, m), 3.70 / 3.70 (3H, s), 3.76 / 3.90 (1H, s), 4.19 / 4.19 (2H, s). 4.20 / 4.24 (2H , q, J = 7.1 Hz), 4.77 / 6.00 (1H, s / brs).

Elemental analysis: C _2. Calculated for H ₂₈ N ₂ 0 ₉ S ₂ : C, 47.61; H, 5.59; N, 5.55; S, 12.71 (%), found; C, 47.65; H, 5.66; N, 5.47; S, 12.61 ( %)

The following is a list of compounds synthesized in Example 14-1 and compounds synthesized in the same manner. (Table 103)

差替え用紙（規則 26) 以下に実施例 14-2〜14 - 10で合成した化合物のデータを示す。

Replacement form (Rule 26) The data of the compounds synthesized in Examples 14-2 to 14-10 are shown below.

Example 14-2

 (Η-wake R (300 MHz, in double-mouthed form)): δ 0.90 (3Η, t, J = 6.9 Hz), 0.93 (3H, ί, J = 7.3 Hz), 1.30 (8H, brs), 1.37 ( 2H, brq, J = 7.4 Hz), 1.48 (2H, m), 1.62 (2H, quint, J = 7.0 Hz), 1.72 (1H, m), 1.81 (1H, m), 2.73 (2H, t, J = 7.3 Hz), 3.23 (1H, dt, J = 13.8, 7.1 Hz), 3.27 (1H, m), 3.33 (1H, dt, J = 13.7, 7.3 Hz), 3.54 (1H, brd, J = 8.0 Hz) ), 3.71 (3H, s), 4.16 (2H, t, J = 6.7 Hz), 4.31 (2H, s), 5.85 (1H, brdd, J = 7.8, 1.3 Hz).

Elemental _{analysis: C 22 H 34 N 2 0} 7 S 2 Calculated: C, 52.57; H, 6.82 ; N, 5.57; S, 12.76 (%) Found; C, 52.64; H, 6.86 ; N, 5.63 ; S, 12.74 (%).

Example 14-3

 Ή-Thigh (300 MHz, in double-mouthed form): δ 0.93 (3H, t, J- 7.3 Hz), 1.27 / 1.30 (3H, t, J = 7.1 Hz), 1.37 (2H, sixtet, J 7.5) Hz), 1.63 (2H, quint, J = 7.3 Hz), 1.84 / 2.05 (3H, s), 2.69 / 2.72 (2H, t, J = 7.4 / 7.2 Hz), 3.10-3.35 (2H, m), 3.70 /3.71 (3H, s), 3.77 / 3.89 (1H, s), 4.17 (2H, t, J = 6.7 Hz), 4.24 (2H, q, J = 7.1 Hz), 4.9 / 4.30 (2H, s ), 4.75 / 5.96 (1H, s).

Elemental _{analysis: C 20 H 28 N 2 O} g S 2 Calculated: C, 47.61; H, 5.59 ; N, 5.55; S, 12.71 (%), Found; C, 47.40; H, 5.54 ; N, 5.62; S, 12.65 (%).

Example 14-4

-NMR (300 MHz, in heavy-duty form): δ 0.93 (3Η, t, J = 7.4 Hz), 1.37 (2H, sixtet, J = 7.6 Hz), 1.62 (2H, m), 2.74 (2H, t) , J = 7.3 Hz), 3.09 (1H, dd, J = 13.2, 1.7 Hz), 3.16 (1H, dd, J = 13.2, 3.0 Hz), 3.24 (1H, dt, J = 13.8, 7.3 Hz), 3.36 (1H, dt, J = 13.8, 7.3 Hz), 3.71 (3H, s), 3.79 (1H, brd, J = 7.1 Hz), 4.17 (2H, 6.7 Hz), 4.32 (2H, s), 6.11 (1H , brddd, J = 7.1, 3.0, 1.7 Hz). Elemental analysis: Calculated for C ₁₆ H ₂₂ N ₂ 0 ₇ S ₂ : C, 45.92; H, 5.30; N, 6.69; S, 15.32 (%), Found: C, 46.02; H, 5.16; N, 7.06; S, 15.12 (%).

Example 14-5

Ή-丽 R (300 MHz, in double-hole form): <5 0.93 (3H, t, J = 7.3 Hz), 1.37 (2H, sixtet, J = 7.6 Hz), 1.63 (2H, quint, J = 7.5) Hz), 1.91 (3H, s), 2.73 (2H, t, J = 7.4 Hz), 3.03 (1H, d, J = 13.3 Hz), 3.17 (1H, d, J = 13.4 Hz), 3.26 (1H, dt, J = 13.6, 7.1 Hz), 3.30 (1H, dt, J = 13.6, 7.2 Hz), 3.71 (3H, s), 4.17 (2H, i, J = 6.7 Hz), 4.28 (2H, s), 5.12 (1H, s).

Elemental _{analysis: C 17 H 24 N 2 0} 7 S 2 Calculated: C, 47.21; H, 5.59 ; N, 6.48; S, 14.83 (%), Found; C, 47.08; H, 5.60 ; N, 6.80; S, 14.47 (%).

Example 14-6

 ¾-NMR (300 MHz, in double-mouthed form): δ 1.90 (3Η, s), 2.54 (3H, s), 3.03 (1H, d, J = 13.3 Hz), 3.18 (1H, d, J = 13.3) Hz), 3.77 (3H, s), 4.31 (2H, s), 5.08 (1H, s).

_!. Elemental _{analysis: C H H 2 N 2 0} 4 S 2 H 2 0 Calculated: C, 41.50; H, 4.43 ; N, 8.80; S, 20.14 (%), Found; C, 41.80; H , 4.41; N, 8.72; S, 19.93 (%).

Example 14-7

 Ή-NMR (300 MHz, in double-mouthed form): δ 2.74 (2Η, t, J = 7.3 Hz), 3.05 (1H, dd, J- 13.3, 1.8 Hz), 3.09 (3H, s), 3.15 ( 1H, dd, J = 13.4, 3.0 Hz), 3.23 (1H, dt, J- 13.9, 7.4 Hz), 3.35 (1H, dt, J = 13.8, 7.3 Hz), 3.66 (1H, brd, J = 7.6 Hz) ), 3.71 (3H, s), 6.09 (1H, ddd, J = 7.6, 3.0, 1.9 Hz).

Elemental _{analysis: C H H 14 N 2 0} 5 S 2 Calculated: C, 41.50; H, 4.43 ; N, 8.80; S, 20.14

(%), Found; C, 41.59; H, 4.30; N, 8.87; S, 20.09 (%).

Example 14-8

Ή-Awake R (300 MHz, in double-mouthed form): 6 1.29 (3H, t, J = 7.1 Hz), 1.91 (3H, s), 2.73 (2H, t, J = 7.4 Hz), 3.02 (1H) , d, J = 13.3 Hz), 3.18 (1H, brd, J-13.2 Hz), 3.26 (1H, di, J = 13.8, 7.3 Hz), 3.30 (1H, dt, J = 13.8, 7.5 Hz), 3.71 (3H, s), 4.23 (2H, q, J = 7.1 Hz), 4.28 (2H, s), 5.09 (1H, s).

Elemental _{analysis: C 15 H 20 N 2 0} 7 S 2 Calculated: C, 44.54; H, 4.98 ; N, 6.93; S, 15.86 (%), Found; C, 44.75; H, 5.07 ; N, 6.70; S, 15.80 (%).

Example 14-9

lH-NMR (300 MHz, in a double-mouthed form): δ 1.27 / 1.30 (3Η, t, J = 7.1 Hz), 1.81 / 2.03 (3H, s), 2.69 / 2.71 (2H, t, J = 7.5 / 7.3 Hz), 3.07 / 3.07 (3H, s), 3.11 / 3.24 (2H, m), 3.70 / 3.70 (3H, s), 3.74 / 3.87 (1H, s), 4.20 / 4.25 (2H, q, J = 7.1 Hz), 4.66 / 6.07 (1H, s / brs).

Example 14-10

 Ή-NMR (300 MHz, in double-mouthed form): δ 1.32 (3Η, t, J = 7.1 Hz), 1.47 (9H, s), 2.03 (3H, s), 4.22 (2H, s), 4.29 / 4.30 (2H, q, J = 7.1 Hz), 4.55 (1H, s), 4.82 (1H, br), 7.64 (1H, s).

Elemental analysis: C ₁₆ H ₂₂ N ₂ 0 ₇ S ₂ · 0.3 H ₂ 0 Calculated: C, 45.34; H, 5.37; N, 6.61; S, 15.13 (%), found; C, 45.35; H , 5.17;, 6.64; S, 15.23 ().

Example 15-1

Synthesis of a compound of the formula (XXXI) wherein R ⁵ is an ethoxycarbonyl group, R ⁶ is a methyl group, R ¹⁴ is a tert-butoxycarbonylmethyl group, and R is a methyl group

 The compound synthesized in Example 14-1 (0.75 g, 1.49 t ol) was dissolved in toluene (25 ml) and acetic anhydride (0.215 ml, 2.23 mmol), and D-potassium 10-sulfonic acid ( 173 mg, 0.743 mmol) and stirred at 60 ° C for 3 hours. The reaction solution was diluted with ethyl acetate (80 nil), washed with water, a 2% aqueous sodium hydrogen carbonate solution, water and saturated saline, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography on silica gel 60 (1 Og). The eluted fraction of ethyl acetate: hexane (20:80) containing 0.1% formic acid was reduced in pressure. The residue was concentrated to dryness to give a red oily substance (300 mg, 0.616, fraction 1) of the title compound.

 'H-NMR (300 MHz, in double-mouthed form): δ 1.33 (3Η, t, J = 7.1 Hz), 1.47 (9H, s), 2.75 (2H, t, J = 7.3 Hz), 2.77 (3H , s), 3.28 (2H, t, J = 7.3 Hz), 3.72 (3H, s), 4.19 (2H, s). 4.26 (2H, q, J = 7.1 Hz).

Elemental analysis: C _2. H ₂₆ N ₂ 0 ₈ S ₂ Calculated: C, 49.37; H, 5.39 ; N, 5.76; S, 13.18 (%), Found; C, 49.16; H, 5.38 ; N, 5.47; S, 13.25 ( %)

The following is a list of compounds synthesized in Example 15-1 'and compounds synthesized in the same manner. (Table 104)

For Goze (mm) The data of the compounds synthesized in Examples 15-2 to 15-12 are shown below.

Example 15-2

 Ή-NMR (300 MHz, in double-mouthed form): δ 0.90 (3Η, brt, J = 7.1 Hz), 0.93 (3H, t, J = 7.3 Hz), 1.30 (6H, brs), 1.37 (2H, brq, J- 7.4 Hz), 1.47 (2H, brquint, J- 6.9 Hz), 1.62 (2H, brquint, J = 6.9 Hz), 2.06 (2H, brt, J = 7.1 Hz), 2.74 (2H, t, J = 7.6 Hz), 3.23 (2H, t, J = 7.6 Hz), 3.72 (3H, s), 4.16 (2H, t, J = 6.7 Hz), 4.30 (2H, s), 5.64 (1H, brt, J = 1.0 Hz).

Elemental _{analysis: C 22 H 32 N 2 0} 6 S 2, Calculated: C, 54.52; H, 6.66 ; N, 5.78; S, 13.23 (%), Found; C, 54.65; H, 6.49 ; N , 5.93; S, 13.20 (%)

Example 15-3

 Ή-NMR (300 MHz, in double-mouthed form): 6 0.93 (3H, t, J = 7.4 Hz), 1.33 (3H, t, J = 7.1 Hz), 1.37 (2H, sixtet, J- 7.5 Hz) , 1.62 (2H, m), 2.75 (2H, t, J = 7.4 Hz), 2.77 (3H, s), 3.28 (2H, t, J = 7. Hz), 3.72 (3H, s), 4.17 (2H , t, J = 6.7 Hz), 4.27 (2H, q, J- 7.1 Hz), 4.29 (2H, s).

Elemental _{analysis: C 20 H 26 N 2 0} 8 S 2 Calculated: C, 49.37; H, 5.39 ; N, 5.76; S, 13.18 (%), Found; C, 49.45; H, 5.25 ; N, 5.94; S, 13.19 (%).

Example 15-4

 Ή-NMR (300 MHz, in double-mouthed form): δ 0.93 (3Η, ί, J = 7.3 Hz), 1.37 (2H, sixtet, J = 7.6 Hz), 1.63 (2H, quint, J = 7.0 Hz) , 2.74 (2H, t, J = 7.4 Hz), 3.21 (2H, t, J = 7.4 Hz), 3.72 (3H, s), 4.16 (2H, t, J- 6.7 Hz), 4.30 (2H, s) , 4.98 (1H, d, J = 8.0 Hz), 6.69 (1H, d, J = 8.0 Hz).

Elemental analysis: C ₁₆ H ₂₀ N ₂ O ₆ S ₂ Calculated: C, 47.99; H, 5.03; N, 7.00; S, 16.01 (%), found; C, 47.89; H, 5.20; N, 7.00; S, 15.75 (%).

Example 15-5

Ή-NMR (300 MHz, in double-mouthed form): δ 0.93 (3Η, t, J = 7.3 Hz), 1.37 (2H, sixtet, J = 7.6 Hz), 1.63 (2H, quint, J = 7.1 Hz) , 2.28 (3H, d, J = 1.2 Hz), 2.73 (2H, t, J = 7.4 Hz), 3.20 (2H, t, J = 7.4 Hz), 3.72 (3H, s), 4.16 (2H, t, J = 6.7 Hz), 4.28 (2H, s), 4.59 (1H, d, J = 1.2 Hz).

Elemental analysis: C ₁₇と し て₂ N ₂ 0 ₆ S ₂ Calculated: C, 49.26; H, 5.35; N, 6.76; S, 15.47 (%), Found; C, 49.34; H, 5.25; N, 7.00; S, 15.43 (%).

 Ή-麵 R (300 MHz, in the double-mouthed form): δ 2.74 (2Η, t, J = 7.3 Hz), 3.08 (3H, s), 3.21 (2H, t, J = 7.3 Hz), 3.72 (3H , s), 4.96 (1H, d, J = 8.0 Hz), 6.70 (1H, d, J = 8.0 Hz).

Elemental _{analysis: C n H 12 N 2 0} 4 S 2 Calculated: C, 43.99; H, 4.03 ; N, 9.33; S, 21.35 (%), Found; C, 44.03; H, 4.15 ; N, 9.41; S, 21.35 (%).

Example 15-7,

 Ή-Thigh (300 MHz, in double-mouthed form): δ 1.29 (3Η, t, J = 7.1 Hz), 2.28 (3H, s), 2.73 (2H, t, J-7.4 Hz), 3.20 (2H, t, J = 7.4 Hz), 3.72 (3H, s), 4.22 (2H, q, J = 7.1 Hz), 4.28 (2H, s), 4.59 (1H, brs).

Elemental _{analysis: C 15 H 18 N 2 0} 6 S 2 Calculated: C, 46.62; H, 4.69 ; N, 7.25; S, 16.60 (%), Found; C, 46.38; H, 4.65 ; N, 7.43; S, 16.60 ().

Examples 15-8

Ή-Awake (300 MHz, in the middle of the double mouth): δ 1.33 (3Η, t, J = 7.1 Hz), 2.75 (2H, t, J = 7.3 Hz), 2.78 (3H, s), 3.07 (3H, s), 3.28 (2H, t, J = 7.3 Hz), 3.72 (3H, s), 4.26 (2H, q, J = 7.1 Hz).

Elemental _{analysis: C 15 H 18 N 2 0} 6 S 2 - 0.5H 2 0 Calculated: C, 45.56; H, 4.84 ; N, 7.08; S, 16.22 (%), Found; C, 45.74; H , 4.78; N, 6.86; S, 16.38 (%).

Example 15-9'-NMR (300 MHz, in double-mouthed form): δ 1.33 (3Η, i, J-7.1.1 Hz), 2.76 (2H, t, J = 7.4 Hz), 2.77 (3H , s), 3.28 (2H, t, J = 7.3 Hz), 3.72 (3H, s), 4.27 (2H, q, J = 7.1 Hz), 4.35 (2H, s).

Elemental _{analysis: C 16 H 18 N 2 0} 8 S 2 Calculated: C, 44.64; H, 4.21 ; N, 6.51; S, 14.90 (%), Found; C, 45.00; H, 4.37 ; N, 6.44; S, 14.67 (%).

Example 15-10

'H-NMR (300 MHz, in double-mouthed form): δ 1.29 (3Η, t, J = 7.2 Hz), 1.33 (3H, t, J = 7.1 Hz), 2.75 (2H, t, J = 7.4 Hz) ), 2.77 (3H, s), 3.28 (2H, t, J = 7.3 Hz), 3.72 (3H, s), 4.22 (2H, q, J = 7.1 Hz), 4.26 (2H, q, J = 7.2 Hz) ), 4.28 (2H, s).,

Elemental _{analysis: C 18 H 22 N 2 0} 8 S 2 Calculated: C, 47.15; H, 4.84 ; N, 6.11; S, 13.99

(%), Found; C, 47.38; H, 4.77; N, 6.10; S, 13.97 (%).

Example 15-11 '

Ή-NMR (300 MHz, in double-mouthed form): δ 1.33 (3Η, t, J = 7.1 Hz), 2.75 (2H, t, J = 7.3 Hz), 2.77 (3H, s), 22.84 (3H, d, J = 4.8 Hz), 3.28 (2H, t, J = 7.3 Hz), 3.72 (3H, s), 4.19 (2H, s), 4.27 (2H, q, J = 7.1 Hz), 5.75 (1H, m). Examples 15-12

 ¾-NMR (300 MHz, in double-mouthed form): δ 1.33 (3Η, t, J = 7.1 Hz), 2.75 (2H, t, J = 7.3 Hz), 2.77 (3H, s), 3.28 (2H, t, J- 7.3 Hz), 3.72 (3H, s), 3.77 (3H, s), 4.27 (2H, q, J = 7.1 Hz), 4.30 (2H, s).

Elemental _{analysis: C 17 H 20 N 2 0} 8 S 2 Calculated: C, 45.94; H, 4.54 ; N, 6.30 (%), actual Hakachi; C, 46.02; H, 4.73 ; N, 6.16 (% ).

Example 16-1

Synthesis of Compound of Formula (XXXIII) wherein R ² is an isobutyl group, R ⁵ is an ethoxycarbonyl group, R ⁶ is a methyl group, and R ¹⁴ is a tert-butoxycarbonylmethyl group Compound (430) synthesized in Example 15-1 mg, 0.88 mmol) was dissolved in tert-butanol (8 ml), potassium tert-butoxide (140 mg, 1.06 mmol) was added, and the mixture was stirred at room temperature for 1 hour. 1N Hydrochloric acid (1.06 ml) was added to the reaction solution, mixed, and stirred at room temperature for 30 minutes. The reaction mixture was concentrated, diluted with ethyl acetate (30 ml), washed with 0.05N hydrochloric acid, water and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to give a brown oil (380 mg). ). This was dissolved in THF (8 ml), to which triethylamine (0.31 ml, 2.21 mniol) and benzyl bromide (0.117 ml, 1.06 mmol) were added, followed by stirring at room temperature for 30 minutes. Further, the reaction solution was stirred at 70 ° C for 18 hours. During this time, 1,8-diazabicyclo [5,4,0] -7-indene (O.Uml, 0.884 mmol) and sodium iodide (133 mg, 0.884 t) were added to the reaction mixture. Dilute the reaction mixture with ethyl acetate (30 ml), wash with 0.1N hydrochloric acid, water and saturated saline, dry over sodium sulfate, evaporate the solvent under reduced pressure, and concentrate the residue on a silica gel 60 (1 Og) column. The fraction eluted with ethyl acetate: hexane (10:90) containing 0.1% formic acid was concentrated to dryness under reduced pressure. An orange oil (112 mg, 0.245 ol) of the title compound was obtained.

 'H-NMR (300 MHz, in double-mouthed form): δ 1.05 (6Η, d, J = 6.7 Hz), 1.33 (3H, t, J = 7.1 Hz), 1.47 (9H, s), 1.93 (1H , Sept, J = 6.7 Hz), 2.77 (3H, s), 2.89 '(2H, d, J = 6.8 Hz), 4.20 (2H, s), 4.26 (2H, q, J- 7.1 Hz).

Elemental analysis: C _2. H _2S N ₂ 0 ₆ S ₂ Calculated: C, 52.61; H, 6.18 ; N, 6.14; S, 14.05 (%), Found; C, 52.38; H, 6.12 ; N, 6.24; S, 13.90 ( %)

 Example 16-2

In the formula (XXXIII), R ² is a 2-phenethyl group, R ⁵ is an ethoxycarbonyl group, R ⁶ is a methyl group, and R ¹⁴ is a tert-butoxycarbonylmethyl group. Synthesis in Example 15-1 The resulting compound (0.56 g, 1.15 bandol) was dissolved in tert-butanol (12 ml) and 2-phenethyl bromide (0.213 ml, 1.50 mmol) and tert-butoxycalide (182 mg, 1.38 mmol) were added. Stirred at room temperature for 80 minutes. The mixture was heated under reflux for about 7 hours. Potassium carbonate (79 mg, 0.58 mmol) was added to the reaction solution, and the mixture was further stirred at 6 for about 15 hours. The reaction solution was diluted with ethyl acetate (40 ml), washed with 0.1N hydrochloric acid, 2% aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. ml) and mixed. The resulting precipitate was collected by filtration, washed with methanol, and dried to give the title compound as an orange powder (169 mg, 0.335 mmol).

-NMR (300 MHz, in double-mouthed form): 3 1.35 (3H, t, J = 7.1 Hz), 1.47 (9H, s), 2.78 (3H, s), 3.00 (2H, brdd, J = 8.6, 7.2 Hz), 3.24 (2H, brdd, J = 8.6, 7.2 Hz), 4.20 (2H, s), 4.27 (2H, q, J = 7.1 Hz), 7.25 (3H, m), 7.30 (2H, m) . elemental _{analysis: C 24 H 28 N 2 0} 6 S 2 calculated: C, 57.12; H, 5.59 ; N, 5.55; S, 12.71

(), Found; C, 57.25; H, 5.54; N, 5.74; S, 12.73 (%).

Example 16-3

Synthesis of a compound of the formula (XXXIII) wherein R ² is a 2-phenethyl group, R ⁵ is an ethoxycarbonyl group, R ⁶ is a methyl group, and R ¹⁴ is a carboxymethyl group

The compound (32 mg, 0.063 bandol) synthesized in Example 16-2 was dissolved in trifluoroacetic acid (0.5 ml) and left at room temperature for 70 minutes. The reaction solution was diluted with toluene (15 ml), concentrated to dryness, ether (2 ml) was added to the residue, and the mixture was mixed. The resulting precipitate was collected by filtration. After washing with ether, drying was performed to obtain an orange powder of the title compound (22 mg, 0.049 mol). ^l H-Awake R (300 MHz, in double-mouthed form): 6 1.34 (3Η, t, J = 7.1 Hz), 2.78 (3H, s), 3.00 (2H, brdd, J = 8.5, 7.2 Hz), 3.24 (2H, brdd, J = 9.6, 7.2 Hz), 4.27 (2H, q, J = 7.1 Hz), 4.36 (2H, brs), 7.24 (3H, m), 7.31 (2H, m).

Elemental analysis: C _2. ¾. N ₂ 0 ₆ S ₂ Calculated: C, 53.56; H, 4.49 ; N, 6.25; S, 14.30 (%), Found; C, 53.32; H, 4.26 ; N, 6.28; S, 14.13 (%) .

Example 16-4

In the formula (XXXIII), R ^{2 is a} benzyl group, R ⁵ is an ethoxycarbonyl group, R ⁶ is a methyl group, and R ¹⁴ is a tert-butoxycarbonylmethyl group. Synthesis of the compound obtained in Example 15-1 ( 420 mg, 0.863 mmol) was dissolved in THF-ethanol (1: 1, 8 ml), benzyl bromide (0.126 ml, 1.03 mmol) was added, and 20% sodium ethoxide (ethanol solution, (0.372 ml, 0.950 mmol) was added dropwise, followed by stirring at room temperature for 4 hours. Dilute the reaction solution with ethyl acetate (30 ml), wash with 0.1N hydrochloric acid, water, 2% aqueous sodium hydrogen carbonate solution, water and saturated saline, dry over sodium sulfate, and evaporate the solvent under reduced pressure to red. An oil was obtained. This was subjected to column chromatography on silica gel 60 (1 Og), the fraction eluted with ethyl acetate: hexane (10:90) · was concentrated to dryness under reduced pressure, and the residue was diluted with methanol. The precipitate was collected by filtration, washed with methanol, and dried to give a red-orange powder (30 mg, 0.061 mmol) of the title compound.

'H-NMR (300 MHz, in double-mouthed form): (51.33 (3H, t, J = 7.1 Hz), 1.46 (9H, s), 2.76 (3H, s), 4.18 (2H, s). 4.25 (2H, q, J = 7.1 Hz), 4.26 (2H, s), 7.27-7.39 (5H, m).

Elemental _{analysis: C 23 H 26 N 2 0} 6 S 2 Calculated: C, 56.31; H, 5.34 ; N, 5.71; S, 13.07 (%;), Found; C, 56.10; H, 5.15 ; N , 5.97; S, 13.07 ().

The methanol wash of the crystal mother solution was collected and concentrated to obtain an orange oily substance (180 mg, 0.335 mmol) of the following compound.

 'H-NMR (300 MHz, in double-mouthed form): 01.10 (3H, t, J = 7.0 Hz), 1.22 (3H, t, J- 7.1 Hz), 1.46 (9H, s), 2.04 (3H, s), 3.25 (1H, dq, J = 8.7, 7.0 Hz), 3.64 (1H, dq, J = 8.8, 7.0 Hz), 3.66 / 3.67 (1H, s), 4.12 (2H, q, J = 7.1Hz) ), 4.13 / 4.19 (2H, s), 4.20 (1H, d, J = 12.9 Hz), 4.29 (1H, d, J = 12.9 Hz), 7.24-7.37 (5H, i).

Elemental analysis: C ₂₅ H ₃₂ N ₂ 0 ₇ S ₂ Calculated: C, 55.95; H, 6.01; N, 5.22; S, 11.95 (%), found; C, 56.17; H, 6.12; N, 5.30; S, 11.70 (%).

The following is a list of compounds synthesized in Examples 16-1 to 16-4 and compounds synthesized in the same manner.

(Table 105)

、ノ —个= 人

, ノ —person = person

XYRI ¹⁴ Example Ri R5 R6 R14

16-1 -SCH ₂ CH (CH3) 2 -COsEt -CHs -CH ₂ C02C (CH3) 3

_{16-2 -S (CH 2) 2 Ph} -G0 2 Et ■ CH 3 -CH 2 C0 2 C (CH 3) 3

16-3 -S (CH ₂ ) ₂ Ph -C0 ₂ EtCH ₃ -CH2CO2H

16-4 -SGH2PI1C0 ₂ EtCHa -CH ₂ C0 ₂ C (CH ₃ ) ₃

16-5 -SCH2C0 ₂ C (CH ₃ ) 3-(CH ₂ ) ₇ CH ₃ -H -CH2PI1

16-6 -SCH2PI1-(CH ₂ ) ₅ CH3 -H -CH ₂ C0 ₂ C (CH ₃ ) ₃

16-7 -SCH3 -HCHsCH2CO2H

16-8 -SCH2PI1 -C0 ₂ EtCHs -CH2CO2H

16-9 -SCH ₂ PhCOsEt -CH ₃ -CH2CO2CH2CH3

16-10 -SCH2PI1 -CO2H -CHs -CH2CO2H

_{16-11 -SCH 2 CH (CH 3)} 2 -COsEt • CH 3 ■ GH2CO2H

16-12 -S (CH ₂ ) ₃ COPli -C0 ₂ EtCH ₃ -CH ₂ C0 ₂ C (CH ₃ ) ₃

16-13 -S (CH ₂ ) 3COPhC0 ₂ Et -CH ₃ -CH2CO2H

For replacement (Rule 26) The data of the compounds synthesized in Examples 16-5 to 16-13 are shown below.

Example 16-5

 'H-NMR (300 MHz, in double-mouthed form): δ 0.88 (3Η, brt, J = 6.8 Hz), 1.26 (12H, brs), 1.46 (9H, s), 2.03 (2H, brdd, J = 7.2, 6.8 Hz), 3.64 (2H, s), 4.71 (2H, s), 6.50 (1H, brs), 7.30 (3H, m), 7.41 (2H, dd, J = 7.9, 1.5 Hz).

Mass spectrometry (SIMS): 517 (M + H)

Example 16 6

 Ή-NMR (300 MHz, in double-mouthed form): 50.90 (3H, brt, J = 6.6 Hz), 0.93 (3H, t, J = 7.3 Hz), 1.30 (6H, brs), 1.37 (2H, brq , J = 7.6 Hz), 1.46 (2H, m), 1.62 (2H, quint, J = 6.9 Hz), 2.05 (2H, t, J = 7.6 Hz), 4.16 (2H, t, J = 6.7 Hz), 4.23 (2H, s), 4.29 (2H, s), 6.51 (1H, s), 7.34 (5H, m).

Elemental _{analysis: C 25 H 32 N 2 0} 4 S 2 Calculated: C, 61.45; H, 6.60 ; N, 5.73; S, 13.12

(%), Found; C, 61.14; H, 6.45; N, 5.94; S, 13.11 (%).

Example 16-7

¾-NMR (300 MHz, in heavy dimethyl sulfoxide): 52.18 (3H, d, J = 1.0 Hz), 2.46 (3H, s), 4.12 (2H, s), 5.09 (1H, d, J = 1.0 Hz) , 13.1 (1H, br).

1 ³ C-NMR (in 75 MHz, deuterated dimethyl _{sulfoxide): 6 13.03 (CH 3)} , 19.20 (CH 3), 39.14 (CH 2), 92.77 (CH), 116.31 (Q), 132.07 (Q), 132.90 (Q), 148.16 (Q), 155.01 (Q), 168.39 (Q).

Elemental _{analysis: C 10 H 10 N 2 0} 4 S 2 Calculated: C, 41.95; H, 3.52 ; N, 9.78; S, 22.40 (%), Found; C, 41.90; H, 3.68 ; N, 9.57; S, 22.35 (%).

Example 16-8

-Thigh (300 MHz, in double-mouthed holm): (51.34 (3H, t, J = 7.1 Hz), 2.76 (3H, s), 4.26 (2H, q, J = 7.1 Hz), 4.27 (2H, s) ), 4.34 (2H, s) , 7.27-7.38 (5H, m) elemental _{analysis: C 19 H 18 N 2 0} 6 S 2 calculated:. C, 52.52; H, 4.18; N, 6.45; S, 14.76 found; C, 52.63; H, 4.28; N, 6.41; S, 14.66 (%).

Example 16-9

'H-NMR (300 MHz, in double-mouthed form): 51.28 (3H, t, J = 7.2 Hz), 1.34 (3H, t, J = 7.1 Hz), 2.76 (3H, s), 4.22 (2H, q, J = 7.2 Hz), 4.26 (2H, q, J = 7.1 Hz), 4.27 (2H, s), 4.28 (2H, s), 7.28-40 (5H, m).

Elemental _{analysis: C 21 H 22 N 2 0} 6 S 2 Calculated: C, 54.53; H, 4.79 ; N, 6.06; S, 13.87

(%), Found; C, 54.65; H, 4.84; N, 6.09; S, 13.85 (%).

Example 16-10

lH-NMR (300 MHz, double-mouthed form-deuterated dimethyl sulfoxide in 9: 1): δ 2.77 (3Η, s), 4.23 (2H, s), 4.28 (2H, s), 7.34 (5H, m).

Elemental _{analysis: C 17 H 14 N 2 0} 6 S 2 -0.6Et 2 0 Calculated: C, 51.68; H, 4.47 ; N, 6.21

(%), Found; C, 52.05; H, 4.43; N, 6.41 (%).

Example 16-11

 ^-MR (300 MHz, in double-hole form): δ 1.05 (6Η, d, J = 6.6 Hz), 1.34 (3H, t, J = 7.1 Hz), 1.94 (1H, sept, J = 6.7 Hz) , 2.77 (3H, s), 2.90 (2H, d, J = 6.8 Hz), 4.27 (2H, q, J = 7.1 Hz), 4.36 (2H, brs).

Elemental analysis: C ₁₆ H ₂₀ N ₂ 0 ₆ S ₂ Calculated: C, 47.99; H, 5.03; N, 7.00; S, 16.01 (%), found; C, 48.20; H, 4.95; N, 7.27; S, 15.77 (%).

Examples 16-12

^[ H-NMR (300 MHz, in double-mouthed form): 51.33 (3H, t, J = 7.1 Hz), 1.47 (9H, s), 2.18 (2H, quint, J = 6.9 Hz), 2.77 (3H, s), 3.16 (2H, t, J = 6.9 Hz), 3.18 (2H, t, J = 6.9 Hz), 4.20 (2H, s), 4.25 (2H, q, J = 7.1 Hz), 7.47 (2H, brt, J = 7.8 Hz), 7.57 (1H, tt, J = 7.4, 2.1 Hz), 7.96 (2H, d, J = 7.9 Hz).

Elemental _{analysis: C 26 H 30 N 2 O} 7 S 2 Calculated: C, 57.13; H, 5.53 ; N, 5.12; S, 11.73

(%), Found; C, 57.18; H, 5.52; N, 5.00; S, 11.71 ()

Example 16-13

 'H-NMR (300 MHz, in deuterated chloroform): 51.33 (3H, t, J = 7.1 Hz), 2.18 (2Η, quint, J = 6.8 Hz), 2.76 (3H, s), 3.16 (2H, t, J = 6.9 Hz), 3.18 (2H, t, J = 6.9 Hz), 4.26 (2H, q, J = 7.1 Hz), 4.35 (2H, brs), 7.47 (2H, brt, J = 7.5 Hz), 7.58 (1H, brt, J = 7.1 Hz), 7.96 (2H, brd, J = 7.3 Hz).

Elemental analysis: C ₂₂ H ₂₂ N ₂ O ₇ S ₂ -0.2 S0 Calculated: C, 53.47; H, 4.57; N, 5.67; S, 12.98 (%), found; C, 53.44; H, 4.54 ; N, 5.78; S, 12.76 (). Example 18-1

 N- {8-[(6-Fluorohexyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,] thiazine -1-ylidene}-4-methylbenzenesulfonamide ''

 The compound obtained in Example 4-64 (1.15 g, 2.39 bandol) in dichloromethane (10 ml) was stirred in a solution of DAST (0.50 g, 3.10 mmol) in dichloromethane (10 ml) at -78 ° C. The solution was added dropwise over 40 minutes, and after heating, the reaction solution was stirred at room temperature for 1.5 hours. The reaction solution was diluted with ethyl acetate (100 ml), washed with 0.1N hydrochloric acid, water and saturated saline, dried over sodium sulfate, and concentrated to obtain a dark red solid. The solids obtained in the same manner from the compound obtained in Example 4-64 (207 mg, 0.430 mmol) were combined and subjected to chromatography on silica gel (15 g) (ethyl acetate-hexane and ethyl acetate-toluene). Purification gave the title compound (516 mg, 1.07 imnol) as a purple powder.

_{ΐ-NMR (300MHz, CDC1 3} ): δ 1.45 (4Η, m), 1.70 (4H, m), 1.79 (3H, q, J = 0.8 Hz), 2.26 (3H, q, J = 1.0 Hz), 2.42 (3H, s), 2.94 (2H, t, J = 7.5 Hz), 4.51 (2H, dt, J = 47.2, 5.9 Hz), 7.29 (2H, d,} = 8.4 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.62 (1H, brs).

Elemental analysis: calculated as C ₂₁ H ₂₆ N ₃ 0 ₃ S ₃ F: C, 52.15; H, 5.42; N, 8.69 (%), found: C, 52.02; H, 5.26; N, 8.58 (% ).

mp.157.0-159.0 ° C

The following is a list of compounds synthesized in Example 18-1 and compounds synthesized in the same manner.

(Table 106)

Hairpin paper (Rule ²⁶ (Table 107)

Replacement form (Rule 2β) (Table 108)

Pig iron (Rule 26) (Table 10)

羞 (Rule 26) (Table 110)

Left 赘 & (Fiber (Table 1 1 1)

褰 for replacement 鈹 (i¾l! L26) (Table 1 1 2)

For replacement (Rule 2 The data of the compounds synthesized in Examples 18-2 to 18-80 are shown below.

Example 18-2

 4-bromo-N- {8-[(6-fluorohexyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydrido-1H-imidazo [5,1-c] [1 ,] Thiazine-1-ylidene} benzenesulfonamide

 The compound obtained in Example 4-505 (0.85 g, 1.56 mmol) in dichloromethane (5 ml) was stirred in a solution of DAST (335 mg, 1.87 ol) in dichloromethane (6 ml) at −78 ° C. The solution was added dropwise over 10 minutes, and after heating, the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was worked up, purified and crystallized from methanol in the same manner as in Example 18-1 to give the title compound (315 mg, 0.57 in dish 01) as a dark purple powder.

¾ one _{NMR (200MHz, CDC1 3):} δ 1.45 (4Η, m), 1.71 (4Η, m), 1.80 (3Η, q, J = 1.2 Hz), 2.28 (3H, q, J = 0.6 Hz), 2.96 (2H, t, J = 7.3 Hz), 4.46 (2H, dt, J = 47.2, 5.8 Hz), 7.63 (2H, dt, J = 8.8, 2.2 Hz), 7.83 (2H, di, J = 8.8, 2.2 Hz), 9.63 (lH, brs).

Elemental _{analysis: C 2Q H 23 N 3 0} 3 S 3 BrF Calculated: C, 43.79; H, 4.23 ; N, 7.66; S, 17.54; Br, 14.57; F, 3.46 (%), Found: C , 43.86; H, 4.05; N, 7.55; S, 17.28; Br, 14.51; F, 2.98 (%).

mp.171.0-171.5 ° C

Example 18-3

N- {8-[(7-Fluoroheptyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine -1 -ylidene} -4-methylbenzenesulfonamide

 To a solution of the compound (807 mg, 1.63 mmol) obtained in Example 4-507 in dichloromethane (7 mi) was added a solution of DAST (583 mg, 3.26 alcohol) in dichloromethane (3 ml) while stirring at 0 ° C. The mixture was added dropwise over 40 minutes, and after heating, the reaction solution was stirred at room temperature for 22 hours. The reaction solution was worked up, purified and crystallized from methanol in the same manner as in Example 18-1 to give the title compound (343 nig, 0.689 bandol) as a red powder.

_{Ή-NMR (200MHz, CDC1 3} ): δΐ.38 (6Η, m), 1.68 (4H, m), 1.79 (3H, q, J = 1.0 Hz), 2.26 (3H, q, J = 1.0 Hz), 2.42 (3H, s), 2.94 (2H, t, J = 7.4 Hz), 4.45 (2H, dt, J = 47.4, 6.1 Hz), 7.29 (2H, d, J-8.4 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.62 (1H, brs).

Elemental _{analysis: C 22 H 28 N 3 0} 3 S 3 F Calculated: C, 53.09; H, 5.67 ; N, 8.44; S, 19.33; F, 3.82 (), Found: C, 53.04; H, 5.47; N, 8.40; S, 19.37; F, 3.45 (%) .nip. 169.0-169.5 ° C

Example 18-4

 N- {5-[(5,6-dimethyl-tri {[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo [5, tri c] [1,4] Thiazine-8-yl) sulfanyl] pentyl} hexaneamide

 The fraction of ethyl acetate-toluene (4: 6-5: 5) was concentrated to dryness by silica gel chromatography in Example 18-6 and crystallized from getyl ether to give the title compound (158 mg, 0.280 mmol) as a red powder. As obtained.

_{Ή-NM (300MHz, CDC1 3} ): 50.89 (3H, t, J- 6.9 Hz), 1.31 (4H, m), 1.46 (2H, m), 1.54 (2H, m), 1.60 (2H, m), 1.71 (2H, quint, J = 7.2 Hz), 1.79 (3H, brs), 2.15 (2H, t, 'J = 7.6 Hz), 2.26 (3H, brs), 2.42 (3H, s), 2.94 (2H, t, J = 7.5 Hz), 3.25 (2H, brq, J = 6.6 Hz), 5.51 (1H, m), 7.29 (2H, d, J = 8.4 Hz), 7.84 (2H, d, J = 8.4 Hz) , 9.64 (1H, brs).

Elemental _{analysis: C 26 H 36 N 4 0} 4 S 3 Calculated: C, 55.29; H, 6.42 ;, 9.92; S, 17.03 (%), Found: C, 55.37; H, 6.56 ;, 9.90; S, 16.82 (%). '

mp.154.5-155.5 ° C

Example 18-5

 N- {8-[(5-Aminopentyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydrone-1H-imidazo [5,1-c] [1,4] thiazine-ί- Ylidene} -4-methylbenzenesulfonamide trifluoroacetate

 The compound (1.07 g, 1.89 mmol) obtained in Example 4-512 was dissolved in TFA (2.0 ml) and left at room temperature for 40 minutes. The reaction solution was diluted with toluene (50 ml) and concentrated to dryness. Ethyl acetate was added to the residue to obtain a red suspension. The precipitate was collected by filtration, washed with ethyl acetate, and dried to give the title compound (1.01 g, 1.74 mmol) as a red-purple powder.

_{¾-NMR (300MHz, CDC1 3} ): δ 1.49 (2Η, m), 1.69 (4H, m), 1.76 (3H, q, J- 0.9 Hz), 2.24 (3H, q, J = 0.9 Hz), 2.40 (3H, s), 2.93 (2H, t, J = 6.9 Hz), 2.98 (2H, t, J = 7.2 Hz), 7.29 (2H, d, J = 8.1 Hz), 7.82 (2H, d, J = 8.1 Hz), 8.13 (3H, brs).

Elemental _{analysis: C 22 H 27 N 4 0} 5 S 3 F 3 -0.3¾0 Calculated: C, 45.09; H, 4.75 ; N, 9.56; S, 16.41; F, 9.73 (), Found: C, 45.14; H, 4.83; N, 9.62; S, 16.38 ().

 N- {5-[(5,6-Dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1, 4] Thiazine-8-yl) sulfanyl] pentyl} -2,2,2-trifluoroacetamide

 To a suspension of the compound (290 mg, 0.499 mmol) obtained in Example 18-5 and DMF (4.0 ml) of Shii-dani hexanoyl (80.7 mg, 0.599 t) was added triethylamine (0.208 ml, 1.50 ol). At room temperature, the reaction was stirred at room temperature for 18 hours. Hexanoyl chloride (39 mg, 0.289 mmol) was added three times every two hours during the reaction. The reaction solution was extracted with ethyl acetate, dried, dried and concentrated to obtain a dark red solid. This was combined with the dark red solid (0.45 g) similarly obtained from the compound (0.79 g, 1.36 mmol) obtained in Example 18-5, and suspended in THF to remove insolubles. Chromatography on silica gel (15 g) (ethyl acetate-toluene, 1: 9-5: 5). The fraction of ethyl acetate-toluene (2: 8-3: 7) was concentrated to dryness and crystallized from getyl ether to give the title compound (140 mg, 0.248 mmol) as an orange powder.

_{- NMR (300MHz, CDC1 3)} : δ 1.47 (4Η, m), 1.61 (2H, m), 1.73 (2H, quint, J = 7.2 Hz), 1.79 (3H, s), 2.26 (3H, s), 2.42 (3H, s), 2.95 (2H, t, J = 7.2 Hz), 3.38 (2H, brq, J = 7.2 Hz), 6.44 (1H, m), 7.29 (2H, d, J = 8.1 Hz), 7.84 (2H, d, J = 7.8 Hz), 9.64 (1H, brs).

Elemental _{analysis: C 22 H 25 N 4 0} 4 S 3 F 3 • O toluene Calculated: C, 49.69; H, 4.74 ; N, 9.34; S, 16.05; F, 9.51 (), Found: C, 49.60; H, 4.74; N, 9.37; S, 15.94; F, 9.24 (%).

mp. 168.5-169.5

Example 18-7

N- {8-[(6-aminohexyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydrido B-lH-imidazo [5, lc] [1,4] thiazine-1-ylidene} -4-methylbenzenesulfonamide trifluoroacetate

 The compound obtained in Example -513 (2.40 g, 4.13 bandol) was dissolved in TFA (5.0 ml) and left at room temperature for 50 minutes. The reaction solution was diluted with toluene (50 ml) and concentrated to dryness. Ethyl acetate was added to the residue to obtain a red suspension. The precipitate was collected by filtration, washed with ethyl acetate, and dried to give the title compound (2.41 g, 4.05 l) as a red-purple powder.

¾-NMR (300MHz, DMSO— d ₆ ): (51.34 (4H, m), 1.52 (2H, brquint, J = 6.9 Hz), 1.59 (2H, brq, J = 8 Hz), 1.76 (3H, brs) , 2.17 (3H, q, J = 0.9 Hz), 2.39 (3H, s), 2.78 (2H, brq, J = 7 Hz), 2.97 (2H, t, J = 7.2 Hz), 7.37 (2H, d, J = 7.8 Hz), 7.67 (3H, brs), 7.84 (2H, d, J- 8.1 Hz), 11.70 (1H, brs).

Elemental _{analysis: C 23 H 29 N 4 0} 5 Calculated _{S 3 F 3: C, 46.45} ; H, 4.92; N, 9.42; S, 16.18; F, 9.58 (%) Found: C, 46.35; H , 4.91; N, 9.41; S, 16.10 ().

mp. 169.0-171.5 ° C

Example 18-8

 Ν- {6-[(5,6-Dimethyl-{[(4-methylphenyl) sulfonyl] imino 3-oxo-2,3-dihydro-1H-imidazo [5, lc] [1,4] thiazine- 8-yl) sulfanyl] hexyl}-2,2,2-trifluoroacetamide

Hexanoyl chloride (104 mg, 0.513 mmol) was added to a suspension of the compound obtained in Example 18-7 (305 mg, 0.513 mmol) and triethylamine (0.213 ml, 1.54 mmol) in DMF-THF (1: 3, 8.0 ml). (0.769 mmol) in THF (1.0 ml) was added dropwise at room temperature, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate, dried, dried and concentrated to obtain a crude substance. This was chromatographed on silica gel (15 g) (ethyl acetate-toluene, 1: 9-4: 6). The fraction of ethyl ethyl acetate (15: 85-2: 8) was concentrated to dryness and crystallized from geethyl ether to give the title compound (115 mg, 0.199 acetyl) as a red-purple powder. 'H-NMR (300MHz, CDC1 3): <51.43 (4H, m), 1.60 (2H, m), 1.70 (2H, quint, J = 7.0 Hz), 1.79 (3H, brs), 2.26 (3H, q , J = 0.9 Hz), 2.42 (3H, s), 2.94 (2H, t, J = 7.4 Hz), 3.37 (2H, q, J = 6.7 Hz), 6.45 (1H, br), 7.29 (2H, d , J = 8.1 Hz), 7.84 (2H, d, J = 8.1 Hz), 9.64 (1H, brs).

Elemental _{analysis: C 23 H 27 N 4 0} 4 S 3 F 3 Calculated: C, 47.90; H, 4.72 ; N, 9.72; S, 16.68; F, 9.88 (%), Found: C, 47.95; H, 4.65; N, 9.71; S, 16.69; F, 9.71 (%) · nip. 150.0-150.5:

Example 18-9

 N- [5,6-dimethyl-8-({[1- (methylsulfonyl) -4-pyridinyl] methyl} sulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5, c] [1, 4] thiazine-1-ylide 0% was added to a solution of the compound obtained in Example 4-116 (450 rag, 0.874 ol) and methanesulfonyl chloride (121 mg, 1.05 IMOI) in DMF (9.0 ml). While stirring at ° C, triethylamine (0.363 ml, 2.62 ol) was added dropwise. The reaction was stirred at 0 ° C. for 7 hours. The reaction solution was diluted with ethyl acetate, washed successively with 0.05N hydrochloric acid, water and saturated saline, dried and concentrated. The precipitate was collected by filtration, washed with ethyl acetate, and dried to give the title compound (145 mg, 0.260 minol) as a purple powder.

_{Ή-NMR (300MHz, CDC1 3} ): 51.36 (2H, dq, J = 3.0, 13.8 Hz), 1.62 (4H, m), 1.79 (3H, s), 1.95 (2H, brd, J = 13.5 Hz), 2.27 (3H, s), 2.43 (3H, s), 2.64 (2H, brt, J = 11.4 Hz), 2.79 (3H, s), 2.88 (2H, d, J = 6.6 Hz), 3.83 (2H, brd , J = 11.4 Hz), 7.29 (2H, d, J = 8.1 Hz), 7.84 (2H, d, J = 8.1 Hz), 9.66 (1H, brs). Elemental analysis: C ₂₂ H ₂₈ N ₄ 0 ₅ calculated _{S 4: C, 47.46; H} , 5.07; N, 10.06 (%), Found: C, 47.80; H, 5.14 ; N, 9.84 (%).

Example 18-10

N- (4-{[(5,6-dimethyl-to {[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1 , 4] Thiazine-8-yl) sulfanyl] methyl} phenyl) hexaneamide

N- (5,6-Dimethyl-3-oxo-8-sulfanyl-2,3-dihydrone-1H-imidazo [5,1-c] [1,4] thiazine- obtained in Example 3-4 A 1-ylidene) -4-methylbenzenesulfonamide (200 mg, 0.524 t ol) and potassium carbonate (109 mg, 0.786 benzyl) suspension in N, N-dimethylformamide (2.00 ml) A solution of hexanoic acid (4-chloromethylphenyl) amide (188 mg, 0.780 ol) in N, N-dimethylformamide (2.00 ml) obtained in 68 was added. After heating the reaction mixture at 80 ° C. for 30 minutes, 1N hydrochloric acid was added and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent under reduced pressure Was distilled off. The residue was subjected to silica gel column chromatography, and eluted with II-hexane-ethyl acetate (10: 1, v / v) to give the title compound (48.6 mg, 16%) as dark red crystals. The crystal was recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 212-214 ° C.

IR (KBr) V: 3248, 3046, 2957, 2930, 2859, 1748, 1725, 1663, 1603, 1559, 1539 cm— ¹ .

_{'H-NMR (CDC1 3)} : 50.916 (3H, t, J = 6.6Hz), 1.28-1.44 (4H, m), 1.64-1.82 (2H, m), 1.76 (3H, s), 2.24 (3H, d, J = 1.0 Hz), 2.36 (2H, t, J = 7.8 Hz), 2.41 (3H, s), 4.15 (2H, s), 7.19 (1H, bs), 7.26 (4H, d, J = 8.6 Hz), 7.50 (2H, d, J = 8 Hz), 7.80 (2H, d, J = 8.2 Hz), 9.59 (1H, bs).

Elemental analysis: C ₂₈ H ₃₂ N ₄ 0 ₄ S ₃ 0.4 H ₂ 0

Calculated (¾): C, 56.81; H, 5.58; N, 9.46; S, 16.25.

Found (¾): C, 56.74; H, 5.50; N, 9.39; S, 16.00.

Example 18-11

tert-butyl 3-{[(8- (isopentylsulfanyl) -6-methyl-1-{[(4-methylphenyl) sulfonyl] imino} _3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazin-5-yl) carbonyl] amino} propyl carbamate

The compound obtained in Example 4-462 (573 mg, 1.19 mmol), trihydroxybenzotriazole (hereinafter sometimes abbreviated as H0BT) (177 mg, 1.31 thigh ol) and triethyl-3- A suspension of (3-mg-dimethylaminopropyl) carbodiimide hydrochloride (WSC) (hereinafter sometimes abbreviated as WSC) (251 mg, 1.31 bandol) in THF (12 id) was stirred at room temperature for 5 hours. . During the reaction, WSC (46 mg, 0.238 mmol) was added twice. The reaction solution was diluted with ethyl acetate, washed successively with 0.05N hydrochloric acid, water and saturated saline, dried and concentrated. The precipitate is collected by filtration, washed with ethyl acetate, dried and dried to give 8- (isopentylsulfanyl) -6-methyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3 The H0BT ester of 0.6-dihydro-1H-imidazo [5, tric] [1,4] thiazine-5-carboxylic acid (0.68 g) was obtained as a purple powder. This was dissolved in THF (12 ml), N-Boc-propanediamine (254 mg, 1.43 ol) was added, the mixture was stirred at room temperature for 20 minutes, and triethylamine (0.412 ml, 2.98 ol) was added. For 90 minutes. Reaction solution with ethyl acetate The mixture was diluted, washed sequentially with 0.05N hydrochloric acid, water and saturated saline, dried, concentrated, and diluted with ethyl acetate and ethyl acetate. The precipitate was collected by filtration, washed with ethyl acetate-ethyl ether (1: 2) and getyl ether, and dried to give the title compound (607 mg, 0.952 mol) as a red-purple powder.

_{Ή-NMR (300MHz, CDC1 3} ): 50.93 (6H, d, J = 6.3 Hz), 1.44 (9H, s), 1.57 (2H, quint, J = 7.4 Hz), 1.66 (1H, m), 1.73 ( 2H, m), 1.90 (3H, s), 2.42 (3H, s), 2.96 (2H, t, J = 7.7 Hz), 3.25 (2H, brq, "J = 6.3 Hz), 3.41 (2H, brq, J = 6.3 Hz), 4.91 (1H, brt, J = 6.3 Hz), 6.99 (1H, brt, J = 5.5 Hz), 7.29 (2H, d, J 8.4 Hz), 7.83 (2H, d, J = 8.1 Hz), 9.76 (1H, br).

Elemental _{analysis: C 28 H 39 N 5 0} 6 S 3 -0.2H 2 0 Calculated: C, 52.43; H, 6.19 ; N, 10.92; S, 15.00 (%), Found: C, 52.33; H , 6.14; N, 10.75; S, 14.99 (%).

 mp.165.0-166.0 ° C

 Example 18-12

 N- {8-[(3-Aminopropyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydrone-1H-imidazo [5,1-c] [1,4] thiazine-1 Ylidene}-4-methylbenzenesulfonamide hydrochloride

 The compound (883 mg, 1.55 mmol) obtained in Example 4-106 was dissolved in TFA (2 ml) and left at room temperature for 1 hour. The reaction solution was diluted with toluene and concentrated to dryness. The residue was dissolved in THF and methanol (1: 2, 60 ml), and concentrated by adding 6N hydrochloric acid (0.39 ml). The residue was suspended in THF, and the precipitate was collected by filtration, washed with THF and ethyl acetate, and dried to give the title compound (350 mg, 0.737 mmol) as a red-purple powder.

Ή-NMR (300MHz, DMSO-d ₆ ): 51.80 (3H, s), '1.90 (2H, quint, J = 7.5 Hz), 2.17 (3H, s), 2.39 (3H, s), 2.86 (2H, s) m), 3.06 (2H, i, J = 7.2 Hz), 7.39 (2H, d, J = 8.1 Hz), 7.85 (2H, d, J- 8.1 Hz), 7.92 (3H, brs), 11.71 (1H, brs). Elemental analysis: Calculated for C ₁₈ H ₂₂ N ₄ 0 ₃ S ₃ CI Ό.5¾0: C, 44.66; Η, 5.00; Ν, 11.57; S, 19.87; C1, 7.32 (%), actual : C, 44.56; Η, 5.00; Ν, 11.66; S, 19.84; C1, 7.18 (%).

 Example 18-13

Ν- {3-[(5,6-dimethyl_1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo -2,3-Dihydro-1H-imidazo [5,1-c] [1,4] thiazin-8-yl) sulfanyl] propyl} hexaneamide

 Hexanoyl chloride was added to a suspension of the compound obtained in Example 18-12 (0.43 g, 0.81 r. Ol) and triethylamine (0.338 ml, 2.44 alcohol01) in 1¾ «?-11 ^ (1: 2, 9.0 ml). (164 mg, 1.22 fflmol) was added dropwise at room temperature, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was extracted with ether acetate, dehydrated and dried, concentrated, and then diluted with getyl ether. The precipitate was collected by filtration, washed with petroleum ether, and crystallized from ethyl acetate and getyl ether to give the title compound (207 mg, 0.386 orchid ol) as a red-purple powder.

_{Ή-NMR (300MHz, CDC1 3} ): 50.89 (3H, t, J = 6.9 Hz), 1.30 (4H, m), 1.63 (2H, quint, J = 7.8 Hz), 1.79 (3H, q, J = 0.9 Hz), 1.90 (2H, quint, J = 7.4 Hz), 2.17 (2H, t, J = 7.7 Hz), 2.26 (3H, q, J = 0.9 Hz), 2.42 (3H, s), 2.97 (2H, t, J = 7.4 Hz), 3.34 (2H, q, J = 6.5 Hz), 5.77 (1H, brt, J = 5 Hz), 7.30 (2H, d, J = 8.1 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.66 (1H, brs).

Elemental analysis: C ₂₄ H ₃₂ N ₄ 0 ₄ S ₃ 0.5H ₂₀ Calculated: C, 52.82; H, 6.09; N, 10.27; S, 17.63 (%), found: C, 52.62; H, 5.79; N, 10.36; S, 17.59 (%).

mp. 140.0-141.0 ° C '' Example 18-14

 N- {8-[(2-Aminoethyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro_1 イ -imidazo [5,1-c] [1,4] thiazine-1-ylidene }-4-methylbenzenesulfonamide hydrochloride

 The compound (1.33 g, 2.53 mmol) obtained in Example 4-114 was dissolved in TFA (2 ml) and left at room temperature for 30 minutes. The reaction solution was diluted with toluene and concentrated to dryness. The residue was dissolved in THF and methanol (2: 3, 50 ml), and concentrated by adding 6N hydrochloric acid (0.63 ml, 3.80%). The residue was suspended by adding THF and methanol, and the precipitate was collected by filtration, washed with THF and ethyl acetate, and dried to give the title compound (0.92 g, 1.99 tmol) as a red-brown powder.

Ή- NMR (300MHz, DMS0-d 6): δ 1.80 (3H, q, J = 0.9 Hz), 2.17 (3H, q, J = 1.2 Hz), 2.39 (3H, s), 3.06 (2H, m) , 3.21 (2H, t, J = 6.9 Hz), 7.39 (2H, d, J = 8.1 Hz), 7.86 (2H, d, J = 8.1 Hz), 8.09 (3H, brs), 11.74 (1H, br) . Elemental analysis: Calculated as _{C 17 H 2Q N 4 0 3} S 3 iiCl 0: C, 42.62; H, 4.84; N, 11.70; S, 20.08; Cl, 7.40 (), Found: C, 42.75; H , 4.85; N, 11.66; S, 20.26; C1, 7.32 (%).

Examples 18-15

N- [3- (Hexanoylamino) propyl] -8- (isopentylsulfanyl) -6-methyl-1-({[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H -Imidazo [5,1-c] [1,4] Thiazine-5-Dolpoxamide

 N- (3-Aminopropyl) -8- (isopentylsulfane) obtained by treating the compound (0.23 g, 0.24 fraction 1) obtained in Example 18-11 in the same manner as in Example 18-17 ) -6-methyl-1-{[((4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-5 -Carboxamide hydrochloride crude red-brown powder was suspended in THF (4 ml) and triethylamine (0.28 ml, 2.0 Aging 01), hexanoyl chloride (108 mg, 0.80 mmol) was added, and the reaction solution was stirred at room temperature for 3 hours. Stirred. The reaction solution was extracted with ethyl acetate, dehydrated and dried, concentrated, and then diluted with diethyl ether. The precipitate was collected by filtration, washed with getyl ether, and dried to give the title compound (59 mg, 0.093 mol) as a red-brown powder.

Ή one _{NMR (300MHz, CDC1 3):} 50.89 (3H, t, J = 7.2 Hz), 0.93 (6H, d, J = 6.6 Hz), 1.31 (4H, in), 1.57 (2H, quint, J = 7.4 Hz), 1.60 (2H, m), 1.75 (2H, m), 1.90 (3H, s), 2.19 (2H, t, J = 7.5 Hz), 2.43 (3H, s), 2.96 (2H, t, J = 7.8 Hz), 3.38 (2H, brq, J = 6.3 Hz), 6.04 (1H, t, J = 5 Hz), 7.14 (1H, brt, J = 5 Hz), 7.29 (2H,, d, J = 7.8 Hz), 7.83 (2H, d, J = 8.1 Hz), 9.77 (1H, br).

Elemental _{analysis: C 29 H 41 N 5 0} 5 S 3 -0.6¾0 Calculated: C, 53.86; H, 6.58 ; N, 10.83; S, 14.88 (%), Found: C, 53.84; H, 6.43 ; N, 10.92; S, 15.10 ().

mp. 154.5-155.5

Example 18-16

 N- {3-[(5,6-dimethyl_1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4 ] Thiazine-8-yl) sulfanyl] propyl} -2,2,2-trifluoroacetamide

The crude material obtained by combining the mother liquor and the washing solution in Examples 18-13 was treated with silica gel. (lOg) was subjected to chromatography (ethyl acetate-hexane, 3: 7-8: 2). The ethyl acetate-hexane (5: 5) fraction was concentrated to dryness and then crystallized from ethyl acetate to give the title compound (20 mg, 0.037 ol) as a red-brown powder.

_{Ή-NMR (300MHz, CDC1 3} ): δ 1.78 (3Η, s), 2.00 (2H, quint, J = 7.1 Hz), 2.26 (3H, s), 2.42 (3H, s), 2.98 (2H, i, J = 7.4 Hz), 3.47 (2H, brq, J = 6.6 Hz), 6.83 (, m), 7.30 (2H, d, J = 8.1 Hz), 7.83 (2H, d, J = 8.1 Hz), 9.66 ( 1H, brs).

Elemental analysis: C _2. Calculated for H ₂₁ N ₄ 0 ₄ S ₃ F ₃ : C, 44.93; H, 3.69; N, 10.48; S, 17.99 (%), found: C, 45.04; H, 4.02; N, 10.42; S, 18.00 (%)

mp.167.0-168.0 ° C

Example 18-17

 N- (3-Aminopropyl) -8- (isopentylsulfanyl) -6-methyl-1-{[((4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydrogen- 1H-imidazo [5, tric] [l, 4] thiazine-5-carboxamide hydrochloride

 The compound obtained in Example 18-11 (327 mg, 0.513 tmol) was dissolved in TFA (0.5 ml) and left at room temperature for 30 minutes. The reaction solution was treated in the same manner as in Example 18-11 to give the title compound (232 mg, 0.404 mmol) as a dark red powder.

Ή one _{NMR (300MHz, DMS0-d 6} ): δθ.88 (6Η, d, J = 6.6 Hz), 1.49 (2H, brq, J = 7.0 Hz), 1.62 (1H, sept, J = 6.9 Hz), 1.75 (2H, brquint, J = 7 Hz), 1.83 (3H, s), 2.39 (3H, s), 2.83 (2H, brq, J = 5 Hz), 3.01 (2H, t, J = 7.5 Hz) , 3.21 (2H, brq, J = 6.0 Hz), 7.39 (2H, d, J = 8.1 Hz), 7.84 (2H, d, J = 8.4 Hz), 7.86 (3H, brs), 11.86 (1H, br) .

Elemental _{analysis: C 23 H 31 N 5 0} 4 S 3 flCl -0.8H 2 0 Calculated: C, 46.93; H, 5.75 ; N, 11.90; S, 16.34; CI, 6.02 (%), Found: C, 46.98; H, 5.75; N, 11.90; S, 16.40; CI, 5.57 (%).

mp.154.5-155.5 ° C

Examples 18-18

N- {2-[(5,6-dimethyl-1-[[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1, 4] thiazine-8-yl) sulfanyl] eti } Hexanamide

 The compound (300 mg, 0.651 mmol) obtained in Examples 18 to 14 was suspended in THF (6.0 ml) and triethylamine (0.271 ml, 1.95 ol), and hexanoyl chloride (131 mg, 0.976 ol) was added. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate, dried with water, concentrated and diluted with ethyl acetate and getyl ether. The precipitate was collected by filtration, washed with diethyl ether, and dried to give the title compound (188 mg, 0.360 mmol) as a red-brown powder.

'H-NMR (200MHz, CDC1 3): 50.89 (3H, t, J = 6.6 Hz), 1.30 (4H, brquint, J = 3.7 Hz), 1.63 (2H, quint, J = 7.2 Hz), 1.78 (3H , q, J = 1.2 Hz), 2.19, (2H, t, J = 7.7 Hz), 2.26 (3H, q, J = 1.0 Hz), 2.43 (3H, s), 3.12 (2H, t, J = 6.1 Hz), 3.52 (2H, q, J = 6.3 Hz), 6.09 (1H, brt, J; 6 Hz), 7.30 (2H, d, J = 8.0 Hz), 7.84 (2H, d, J- 8.0 Hz) , 9.69 (1H, brs).

Elemental analysis: C ₂₃ H ₃₀ N ₄ 0 ₄ S ₃ 0.2¾0 Calculated: C, 52.49; H, 5.82; N, 10.65; S, 18.28 (%), found: C, 52.50; H, 5.84; N, 10.71; S, 18.35.

 mp.137.5-138.5 ° C

 Example 18-19

 2- [5,6-Dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydrido-1H-imidazo [5,1-c] [1,4] Thiazine-8-yl] sulfanyl] -N-hexylacetoamide

2- [5,6-Dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo obtained in Example 4-30 [5,1 -c] [1,4] Thiazin-8-yl] sulfanyl] acetic acid (30.7 mg, 0.0698 mmol) and 1-hexylamine (0.0102 ml, 0.0768 mmol) in N, N-dimethylformamide (3,00 To the solution, getyl cyanophosphate (0.0124 ml, 0.0768 v) and triethylamine (0.0107 ml, 0.0768 v) were added. After stirring the reaction mixture at room temperature for 15 hours, water was added, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (18.5 'mg, 51¾) as a dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 160-162 ° C.

IR (KBr) V: 3254, 2957, 2930, 2859, 1752, 1719, 1661, 1622, 1559 cm- ¹ . Ή-NMR (CDCI3): δ 0.883 (3Η, t, J = 6.3Hz), 1.24-1.38 (6H, m), 1.46-1.66 (2H, m), 1.76 (3H, d, J = 0.9 Hz), 2.25 (3H, d, J = 1.2 Hz), 2.43 (3H, s), 3.27 (2H, q. J = 6.3 Hz), 3.62 (2H, s), 6.56 (1H, bs), 7.32 (2H, d , J = 8.1 Hz), 7.84 (2H, d, J = 8.7 Hz), 9.66 (1H, bs).

Elemental analysis: C ₂₃ H _{3 ()} N ₄ 0 ₄ S ₃ · 0 · 40

Calculated (¾): C, 52.13; Η, 5.86; Ν, 10.57; S, 18.15.

Found (%) C, 52.04; Η, 6.03; Ν, 10.64 '; S, 18.13.

Example 18-20

 6-[(5,6-Dimethyl-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo [5, tri-c] [1,4] thiazine-8 -Yl) sulfanyl]-N-hexylhexanamide

6- [5,6-Dimethyl-tolu [[(4-methylphenyl) sulfonyl] iminoto 3-oxo-2,3-dihydro-1H-imidazo [5,1-c] obtained in Example 4-37 N, N-dimethylformamide (10.0 ml) solution of [1,4] thiazine-8-yl] sulfanyl] hexanoic acid (103 mg, 0.210 ol) and trihexylamine (0.0305 ml, 0.231 ol) To this was added diethyl cyanophosphate (0.0373 ml, 0.231 ol), followed by triethylamine (0.0321 ml, 0.231 t ol). After stirring the reaction mixture at room temperature for 15 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO ₄₎ After the solvent was distilled off under reduced pressure to give the title compound (78.8 mg, 65¾) was synthesized. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 118-120 ° C.

IR (KBr) V: 3260, 2928, 2859, 1723, 1645, 1620, 1559 cm " ¹ .

lH- thigh _{(CDC1 3): (50.884 (} 3H, t, J = 6.9Hz), 1.24-1.36 (6H, HI), 1.41-1.76 (8H, m), 1.78 (3H, d, J = 0.9 Hz) , 2.17 (2H, t, J = 7.5 Hz), 2.26 (3H, d, J = 0.9 Hz), 2.42 (3H, s), 2.94 (2H, t, J = 7.2 Hz), 3.24 (2H, q. J = 6.0 Hz), 5.44 (1H, bs), 7.29 (2H, d, J = 7.8 Hz), 7.84 (2H, d, J = 8.Hz), 9.57 (1H, bs).

Elemental analysis: as C ₂₇ H ₃₈ N ₄ 0 ₄ S ₃ -0.6H ₂₀

Calculated value (%): C, 55.00; H, 6.70;, 9.50.

Found (%) C, 55.00; H, 6.58; N, 9.63.

Example 18-21 5-[(5,6-Dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine -8-yl) sulfanyl] valeric acid Ethyl 5-[(5,6-dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2 obtained in Example 4-522 , 3-Dihydro-1H-imidazo [5,1-c] [1,4] thiazin-8-yl) sulfanyl] pentanoate (400 mg, 0.785 mmol) in ethanol (10.0 ml) and tetrahydrofuran (10.0 ml) 1) To the solution was added a 1N aqueous sodium hydroxide solution (2.35 ml). After stirring the reaction mixture at room temperature for 3 hours, the solvent was distilled off under reduced pressure. 1N Hydrochloric acid was added to the residue, and the resulting precipitate was collected by filtration, washed with water, and dried to synthesize the title compound (334 mg, 88%). Recrystallization from ethyl acetate-methanol-tetrahydrofuran gave dark red crystals with a melting point of 208-210 ° C.

IR (KBr) V: 3600-2780, 2951, 1732, 1663, 1611, 1557 cm " ¹ .

_{¾-NMR (CDC1 3):} δ 1.72-1.82 (4Η, m), 1.79 (3H, d, J = 0.6 Hz), 2.26 (3H, d, J = 1.2 Hz), 2.38-2.46 (2H, m) , 2.42 (3H, s), 2.92-3.00 (2H, m), 7.29 (2H, d, J = 8.4 Hz), 7.85 (2H, d, J = 8.1 Hz), 9.63 (1H, bs).

Elemental analysis: C _2. H ₂₃ N ₃ 0 ₅ S ₃

Calculated (%): C, 49.88; H, 4.81;, 8.72; S, 19.97.

Found (¾): C, 50.05; H, 4.73; N, 8.35; S, 19.60.

Example 18-22

 4-[(5,6-dimethyl-tolu [[(4-methylphenyl) sulfonyl] imino 3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-8- Yl) sulfanyl] butyric acid

 Ethyl 4-[(5,6-dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} obtained in Example 4-523} -3_oxo-2,3-dihydrido-1H-imidazo [ To a solution of [5, 1-c] [1,4] thiazin-8-yl) sulfanyl] butanoet (169 mg, 0.745 mmol) in ethanol (10.0 ml) and tetrahydrofuran (10.0 ml) was added an aqueous solution of sodium hydroxide. (2.23 ml) was added. After stirring the reaction mixture at room temperature for 2 hours, the solvent was distilled off under reduced pressure. 1N Hydrochloric acid was added to the residue, and the resulting precipitate was collected by filtration, washed with water, and dried to give the title compound (321 mg, 92%) as dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 183-185 ° C.

IR (KBr) Seo: 3700-2800, 2930, 1726, 1661, 1615, 1557 cm " ¹ . Ή- thigh _{(CDC1 3): (51.78 (} 3H, d, J = 1.2 Hz), 2.03 (2H, quint, J = 6.9 Hz), 2.26 (3H, d, J = 1.2 Hz), 2.42 (3H, s ), 2.50 (2H, t, J = 6.9 Hz), 3.03 (2H, t, J = 7.2 Hz), 7.30 (2H, d, J = 8.1 Hz), 7.85 (2H, d, J = 8.1 Hz), 9.67 (1H, bs).

Elemental analysis: as C ₁₉ H ₂₁ N ₃ 0 ₅ S ₃

Calculated (¾): C, 48.80; H, 4.53; N, 8.99; S, 20.57.

Found (%): C, 48.58; H, 4.90; N, 9.11; S, 20.35.

Example 18-23

 5-[(5,6-Dimethyl-{[(4-methylphenyl) sulfonyl] imino 3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-8 -Yl) sulfanyl]-N-hexyl pentanamide

5-[(5,6-dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} _3-oxo-2,3-dihydro-1H-imidazo [5, obtained in Example 18-21 1-c] [1,4] Thiazin-8-yl) sulfanyl] valeric acid (150 mg, 0.311 bandol) and trihexylamine (0.0454 ml, 0.343 mniol) in N, N-dimethylformamide (5.00 ml) To the solution was added getyl cyanophosphate (0.0554 ml, 0.343 mmol), followed by triethylamine (0.0478 ml, 0.343 bandol). After stirring the reaction mixture at room temperature for 23 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), was synthesized solvent was distilled off under reduced pressure the title compound (101 mg, 57%). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 133-135 ° C.

IR (KBr) Seo:. 3280, 2957, 2928, 2859, 1750, 1717, 1642, 1622, 1557 cm "1 Ή-NMR (CDC1 3): 50.880 (3H, t, J = 6.6Hz), 1.24-1.36 (6H, m), 1.43-1.56 (2H, m), 1.66-1.82 (4H, m), 1.78 (3H, s), 2.19 (2H, t, J = 6.9 Hz), 2.25 (3H, s), 2.42 (3H, s), 2.95 (2H, t, J = 7.2 Hz), 3.24 (2H, q, J = 6.3 Hz), 5.49 (1H, bs), 7.29 (2H, d, J = 8.7 Hz), 7.84 (2H, d, J = 8.1 Hz).

Elemental analysis: as C ₂₆ H ₃₆ N ₄ 0 ₄ S ₃

Calculated value (¾): C, 55.29; H, 6.42; N, 9.92; S, 17.03.

Found (%): C, 54.95; H, 6.42; N, 9.64; S, 16.92.

Example 18-24 '

4 _ [(5,6-Dimethyl-1 _ {[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3- Dihydro-imidazo [5,1-c] [1,4] thiazin-8-yl) sulfanyl] hexyl butanamide

4-[(5,6-Dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo obtained in Example 18-22 1, Ν-Dimethylformamide (5.00 ml) of 1,1-c] [1,4] thiazin-8-ylsulfanyl) butyric acid (150 mg, 0.321 t ol) and trihexylamine (0.0467 ml, 0.353 t ol) To the solution was added getyl cyanophosphate (0.0571 ml, 0.353 mmol) followed by triethylamine (0.0492 ml, 0.353 mmol). After stirring the reaction mixture at room temperature for 23 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure to give the title compound (100 ig, 57¾) as a dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 151-153 ° C.

IR (KBr) V:. 3300 , 2955, 2930, 2857, 1748, 1723, 1659, 1644, 1622, '1564 cm "1 Ή-NMR (CDC1 3): 50.882 (3H, t, J = 6.9Hz), 1.24-1.38 (6H, m), 1.44-1.60 (2H, m), 1.78 (3H, s), 2.03 (3H, quint, J = 6.9Hz), 2.26 (3H, s), 2.32 '(2H, t , J = 6.6 Hz), 2.43 (3H, s), 3.02 (2H, t, J = 6.9 Hz), 3.24 (2H, q.J = 6.0 Hz), 5.65 (1H, bs), 7.30 (2H, d , J = 8.4 Hz), 7.84 (2H, d, J = 8.1 Hz).

Example 18-25

 5-methyl-1-[[(4-methylphenyl) sulfonyl] imino}-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl]- 2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-6-carboxylic acid

Ethyl 5_methyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-8-[(5,5,6,6,6-pentanfluo obtained in Example -521 Hexyl) sulfanyl] -2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-6-carboxylate (500 mg, 0.815 mmol) in ethanol (10.0 ml) and tetrahydrofuran To the (10.0 ml) solution was added a 1N aqueous solution of sodium hydroxide (2.44 ml). After stirring the reaction mixture at room temperature for 3 hours, the solvent was distilled off under reduced pressure. 1N Hydrochloric acid was added to the residue, and the resulting precipitate was collected by filtration, washed with water, and dried to give the title compound (85.3 mg, 18%) as dark red crystals. Recrystallization from ethyl acetate-jetelether gave dark red crystals with a melting point of ZZS-Z? ^. IR (KBr) Re:. 3400-2200, 3183, 2926, 2541, 1755, 1705, 1686, 1630, 1557 cm "1 Ή-NMR (CDC1 3): (51.66-1.85 (4H, m), 1.96-2.16 (2H, m), 2.42 (3H, s), 2.77 (3H, s), 3.03 (2H, t, J = 6.9 Hz), 7.29 (2H, d, J = 7.8 Hz), 7.85 (2H, d, J = 8.1 Hz), 10.41 (1H, bs).

Elemental analysis: C _2l H _2. N ₃ 0 ₅ S ₃ F ₅

Calculated value (: C, 43.07; H, 3.44;, 7.18; S, 16.43.

Found: C, 43.05; H, 3.4; N, 7.40; S, 16.48.

Examples 18-26

 N-hexyl-5-methyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-8-[(5,5,6,6,6-pentahexylhexyl) sulfanyl] -2,3-Dihydro-1H-imidazo [5,1-c] [1,4] thiazine-6-caproleptamide

5-methyl (4-methylphenyl) sulfonyl] imino} -3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -2 obtained in Example 18-25 , 3-Dihydro-1H-imidazo [5, tric] [1,4] thiazine-6-carburonic acid (50.0 mg, 0.0854 acetylol) and trihexylamine (0.0124 ml, 0.0939 mmo 1) N, To a solution of N-dimethylformamide (5.00 ml) was added getyl cyanophosphate (0.0152 ml, 0.0939 mmol), followed by triethylamine (0.0131 ml, 0.0939 bandol). After stirring the reaction mixture at room temperature for 15 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure to give the title compound (12.6 mg, 22¾) as a dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 160-162 ° C.

IR (KBr) Re:. 3382, 3260, 3150, 2934, 2859, 1763, 1742, 1628, 1595, 1539 cm one _{^{1 Ή-NMR (CDC1 3)}} : 50.885 (3H, t, J = 7.0Hz), 1.24 -1.43 (6H, m), 1.44-1.66 (2H, HI), 1.66-1.84 (4H, m), 1.88-2.18 (2H, m), 2.42 (3H, s), 2.47 (3H, s), 2.99 (2H, t, J = 7.6 Hz), 3.31 (2H, q.J = 6.6 Hz), 5.79 (1H, bs), 7.30 (2H, d, J = 8.0 Hz), 7.84 (2H, d, J- 8.Hz), 9.70 (1H, bs).

Examples 18-27

N- {6-Hydroxymethyl-5-methyl-3-oxo-8-[(5,5,6,6,6-pentylfluorohexyl) sulfanyl] -2,3-dihydrid-1H- Imidazo [5, 1-c] [1, 4] thiazine-1-ylide In a suspension of lithium aluminum hydride (116 mg, 2.44 mmol) in tetrahydrofuran (40.0 ml) was added ethyl 5-methyl-1-{[(4-methylphenyl) sulfonyl] imino} -3 obtained in Example 4-521. -Oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine A solution of -6-carboxylate (l.OOg, 1.63 mol) in tetrahydrofuran (10.0 ml) was added under ice cooling. After stirring the reaction mixture at room temperature for 30 minutes, a small amount of water was added to decompose excess lithium aluminum hydride. The resulting precipitate was collected by filtration, and the filtrate was evaporated under reduced pressure to give the title compound (648 mg, 70%) as dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 169-171 ° C.

I (KBr) V: 3700-2800, 3202, 2928, 1723, 1651, 1607, 1551 cm " ¹ .

¾ one _{NMR (CDC1 3): δ 1.60-1.68} (1H, m), 1.68-1.84 (4H, m), 1.96-2.16 (4H, m), 2.34 (3H, s), 2.42 (3H, s), 3.01 (2H, t, J = 7.2 Hz), 4.26 (2H, d, J = 5.4 Hz), 7.29 (2H, d, J = 7.8 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.68 ( 1H, bs).

Elementary analysis: as _{C 21 H 22 N 3 0 4} S. 3 F 5

Calculated (%): C, 44.13; H, 3.88; N, 7.35; S, 16.83.

Found (%): C, 44.14; H, 3.66; N, 7.35; S, 16.97.

Example 18-28

Methanesulfonic acid 2-[(5,6-dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3_oxo-2,3-dihydro-1H-imidazo [5,1-c] [ 1 ,, 4] thiazine-8-yl) sulfanyl] ethyl

Triethylamine (2.16 ml) was added to a solution of the compound obtained in Example 4-524 (5.10 g, 12.0 bandol) and methanesulfonyl chloride (1.53 g, 13.2 bandol) in THF (100 ml) while stirring at 0 ° C. , 15.6 mmol) was added and the reaction was stirred at 0 for 4 hours. Methanesulfonyl chloride (139 mg, 1.20 mmol) and triethylamine (0.83 ml, 6.00 mmol) were added to the reaction solution, and the mixture was further stirred for 1.5 hours. After the reaction solution was concentrated, it was diluted with ethyl acetate (200 ml) and 0.1N hydrochloric acid (200 ml). The precipitate was collected by filtration, washed with methanol-water (1: 1) and methanol, and dried to give the title compound (3.42 g, 6.80 mmol, 56.6%) as a purple powder. _{Ή-NMR (300MHz, CDC1 3} ): 51.80 (3H, s), 2.26 (3H, s), 2.43 (3H, s), 3.03 (3H, s), 3.28 (2H, t, J = 6.8 Hz), 4.38 (2H, t, J = 6.9 Hz), 7.31 (2H, d, J = 8.1 Hz), 7.84 (2H, d, J = 8.1 Hz), 9.67 (1H, brs).

Elemental _{analysis: C 18 H 21 N 3 0} 6 S 4 Calculated: C, 42.93; H, 4.20 ;, 8.34; S, 25.47 (%), Found: C, 43.22; H, 4.30 ; N, 8.53 ; S, 25.30 (%).

mp.147.5-149.0 ° C

Examples 18-29

 N- (8-{[(4-hydroxycyclohexyl) methyl] sulfanyl} -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4 ] Thiazine-1-ylidene) -4-methylbutylsulfonamide

 Example 4-A suspension of the compound (1.15 g, 1.99 mmol) obtained in 538 in methanol (20 ml) and THF (6 ml) was mixed with D-camphor-10-sulfonic acid (46 mg, 0.199 mol). The mixture was stirred at room temperature for 13 hours. The reaction solution was concentrated, diluted with ethyl acetate (200 ml), washed with water and saturated saline, dried over sodium sulfate and concentrated. The residue was subjected to ethyl hexane acetate, 2: 8-4: 6), diluted with ethyl acetate and ethyl ether, the precipitate was collected by filtration, washed with ethyl ether, dried and dried to give the title compound. (747 mg, 1.51 mmol, 76.0 »was obtained as a dark purple powder.

_{Ή-NMR (300MHz, CDC1 3} ): 61.32 (1H, brs), 1.46 (2H, brq, J = 10.8 Hz),

1.50-1.70 (5H, m), 1.74 (2H, ra), 1.79 (3H, brq, J = 0.9 Hz), 2.26 (3H, brq, J = 0.6 Hz), 2.42 (3H, s), 2.87 (2H , d, J = 6.0 Hz), 4.02 (1H, brs), 7.27 (2H, d, J = 8.4 Hz), 7.86 (2H, d, J = 8.4 Hz), 9.65 (1H, brs).

Elemental analysis: Calculated as _{C 22 H 27 N 3 0 4} S 3: C, 53.53; H, 5.51;, 8.51; S, 19.49 (), Found: C, 53.63; H, 5.84 ; N, 8.46; S, 18.70.

mp. 191.0-193.0 ° C

Example 18-30

 N- {8-[(3-cyclohexene-toylmethyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, lc] [1,4] thiazine -Triylidene} _4-Methylbenzene benzenesulfonamide

Compound (191 mg, 0.387 ol) of the compound obtained in Examples 18-29 in dichloromethane (3 ml) Deoxo-Fluor ™ (121 mg, 0.547 tmol) was added to the solution at room temperature, and the mixture was stirred for 16 hours. Further, Deoxo-Fluor ™ (46 mg, 0.232 ol) was added and stirred for 9 hours. Methanol (1 ml) and saturated sodium hydrogen carbonate (5 ml) were added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml). The organic layer was washed with a 2% aqueous sodium hydrogen carbonate solution, 0.1 N hydrochloric acid, water and saturated saline, dried over sodium sulfate, and concentrated. The residue obtained by diluting the residue with methanol was chromatographed on silica gel (10 g) (ethyl acetate-hexane, 2: 8-3: 7) to give ethyl acetate-hexane (1: 3--3). : 7) was concentrated to dryness and then diluted with methanol. The precipitate was collected by filtration, washed with methanol, and dried to give the title compound (94 mg, 0.204 mmol, 53.7%) as a red powder.

_{Ή-NMR (200MHz, CDC1 3} ): 1.32 (2H, m), 1.79 (3H, brq, J = 1.2 Hz), 1.84 (2H, m), 2.08 (2H, m), 2.18 (1H, m), 2.26 (3H, brq, J = 0.6 Hz), 2.42 (3H, s), 2.90 (2H, dd, J = 6.6, 2.2 Hz), 5.66 (2H, m), 7.28 (2H, d, J = 8.4 Hz ), 7.86 (2H, d, J = 8.4 Hz), 9.62 (1H, brs).

Elemental _{analysis: C 22 H 25 N 3 0} 3 S 3 Calculated: C, 55.55; H, 5.30 ; N, 8.83; S, 20.22 (%), Found: C, 55.36; H, 5.34 ; N, 8.92; S, 20.22 (%).

mp. 184.0-185.5 ° C

Example 18-31

 5-{[5,6-dimethyl-({[4- (acetylamino) phenyl] sulfonyl} imino) -3-oxo-2,3-dihydrido-1H-imidazo [5,1-c] [1, 4] thiazin-8-yl] sulfanyl} -N-hexylpentanamide

To a suspension of sodium hydride (9.74 mg, 0.243 marl ol) (60% oil) in tetrahydrofuran (0.50 ml) was added 5- [1-amino-5,6-dimethyl-methyl obtained in Example 6-35. A solution of 3-oxo-3H-imidazo [5, tric] [1,4] thiazine-8-yl] sulfanyl] -N-hexylpentanamide (50.0 mg, 0.121 mmol) in tetrahydrofuran (0.50 ml) was prepared. Then, the mixture was stirred for 5 minutes under ice cooling. To this was added a solution of 4_ (acetylamino) benzenesulfonyl chloride (42.7 mg, 0.183 bandol) in tetrahydrofuran (0.50 ml), and the mixture was further stirred at room temperature for 16 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure to give the title compound (48.9 mg, 66%) as a dark red crystals. Recrystallized from ethyl acetate-getyl ether and melted Dark red crystals at a point 148-150 ° C were obtained.

IR (KBr) V: 3270, 3108, 2955, 2928, 2863, 1755, 1728, 1645, 1593, 1557, 1539, 1505 cur ¹ .

_{Ή-NMR (CDC1 3):} δ 0.882 (3Η, t, J = 6.9Hz), 1.24-1.36 (6H, m), 1.44-1.56 (2H, m), 1.65-1.74 (4H, m), 1.78 ( 3H, d, J = 1.2 Hz), 2.14-2.22 (2H, m), 2.21 (3H, s), 2.26 (3H, d, J = 0.9 Hz), 2.94 (2H, t, J-6.3 Hz), 3.24 (2H, q, J = 5.7 Hz), 5.66 (1H, bs), 7.67 (2H, d, J = 9.0 Hz), 7.90 (2H, d, J = 8.7 Hz), 8.00 (1H, bs), 9.54 (1H, bs).

Elementary analysis: as _{C 27 H 37 N 5 0 5} S 3

Calculated value (%): C, 53.35; H, 6.14; N, 11.52; S, 15.83.

Found (%): C, 53.03; H, 6.17 '; N, 11.43; S, 15.58.

Examples 18-32

 5-[(6-hexyl-5-methyl- (4-methylphenyl) sulfonyl] imino} _3-oxo-3H-imidazo [5, tric] [1,4] thiazin-8-yl) sulfanyl ] Valeric acid

Ethyl 5-[(6-hexyl-5-methyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-inosimidazo [5,1-c] [obtained in Example -542 To a solution of 1,4] thiazin-8-yl) sulfanyl] pentanoate (500 mg, 0.862 mol) in ethanol (10.0 ml) and tetrahydrofuran (10.0 ml) was added a 1N aqueous sodium hydroxide solution (2.59 ml). After stirring the reaction mixture at room temperature for 2.5 hours, the solvent was distilled off under reduced pressure. IN hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure to give the title compound (472 mg, 99¾) as a dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 181-183 ° C.

IR (KBr) V: 3400-2400, 2926, 2859, 1725, 1657, 1603, 1559 cm- ¹ .

-謹_{(CDC1 3): (50.892 (} 3H, t, J = 6.9Hz), 1.24-1.36 (6H, m), 1.38-1.52 (2H, m), 1.72-1.80 (4H, in), 2.11 (2H , t, J = 8.1 Hz), 2.26 (3H, s), 2.38-2.44 (2H, m), 2.42 (3H, s), 2.96 (2H, t, J = 6.6 Hz), 7.29 (2H, d, J = 8.7 Hz), 7.85 (2H, d, J = 8.1 Hz), 9.66 (1H, bs).

Elemental analysis: as C ₂₅ H ₃₃ N ₃ 0 ₅ S ₃ Calculated value (¾): C, 54.42; H, 6.03; N, 7.62; S, 17.43.

 Found (¾): C, 54.33; H, 5.82;, 7.61; S, 17.57.

 Example 18-33

 5-[(6-benzyl-5-methyl-{{((4-methylphenyl) sulfonyl] imino} -3-oxo-3H-imidazo [5, 1-c] [1, 4] thiazine-8 Yl) sulfanyl] valeric acid

Ethyl 5-[(6-benzyl-5-methyl-{{((4-methylphenyl) sulfonyl] imino} -3-oxo-3H-imidazo [5,1-c] obtained in Example 4-543 To a solution of [1,4] thiazin-8-yl) sulfanyl] pentanoate (500 mg, 0.854 mmol) in ethanol (10.0 ml) and tetrahydrofuran (10.0 ml) was added aqueous sodium hydroxide solution (2.56 ml). After stirring the reaction mixture at room temperature for 2.5 hours, the solvent was distilled off under reduced pressure. 1N Hydrochloric acid was added to the residue, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO ₄₎ after solvent was obtained as title compound was evaporated under reduced pressure (478 mg, ca. 100%) of dark red crystals. Recrystallization from ethyl acetate-getyl ether gave a dark red crystal with a melting point of 182-184 ° C.

IR (KBr) v: 3400-2800, 2926, 1734, 1655, 1618, 1561, 1493 cm— ¹ .

_{¾-NMR (CDC1 3):} δ 1.60-1.72 (4Η, m), 2.32 (2H, t, J-6.9 Hz), 2.37 (3H, s),

2.42 (3H, s), 2.85 (2H, t, J = 6.9 Hz), 3.50 (2H, s), 7.18-7.38 (7H, m), 7.85

(2H, d, J-8.4 Hz), 9.68 (1H, bs).

, Elemental analysis: as C ₂₆ H ₂₇ N ₃ 0 ₅ S ₃

 Calculated (¾): C, 55.99; H, 4.88; N, 7.53; S, 17.25.

 Found (%): C, 55.91; H, 5.03; N, 7.62; S, 17.36.

 Example 18-34

 N- {8-[(5-bdroxycyclooctyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,] thiazine -1-ylidene} -4-methylbenzenesulfonamide

To a suspension of the compound (291 mg, 0.529 mol) obtained in Example 4-540 in THF-methanol (1: 1.5 ml) was added IN aqueous sodium hydroxide solution (2.38 ml, 2.38 thigh 01). The mixture was stirred at room temperature for 4 hours. 1N Hydrochloric acid (2.38 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 4 hours. The precipitate is collected by filtration, washed with methanol (1: 1) and methanol, dried, and dried. The compound (261 mg, 0.514 ol, 97.2%) was obtained as a gray-red powder.

_{Ή-NR (200MHz, CDC1 3} ): δ 1.34 (1Η, brs), 1.60-1.80 (8H, m), 1.80 (3H, s), 1.85 (2H, m), 1.96 (2H, m), 2.26 ( 3H, q, J = 1.2 Hz), 2.42 (3H, s), 3.52 (1H, br), 3.82 (1H, br), 7.28 (2H, d, J = 8.4 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.63 (1H, brs).

Elemental _{analysis: C 23 H 29 N 3 0} 4 S 3 · 0.5Η 2 0 Calculated: C, 53.46; Η, 5.85 ; Ν, 8.13; S, 18.62 (%), Found: C, 53.39; Η , 5.83; Ν, 8.00; S, 18.92 (%).

mp. 191.5-192.5 ° C

Example 18-35

5-[(6-hexyl-5-methyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-3H-imidazo [5,1-c] [1,4] thiazine- 8-yl) sulfanyl] -N-hexylpentanamide

 5-[(6-Hexyl-5-methyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-3H-imidazo [5, tric] obtained in Examples 18-32. [1,4] Thiazin-8-yl) sulfanyl] valeric acid (100 nig, 0.181 mmol) and trihexylamine (0.0264 ml, 0.199 tmol) in N, N-dimethylformamide (5.00 ml) solution Getyl cyanophosphate (hereinafter sometimes abbreviated as DEPC) (0.0322 ml, 0.199 mmol) followed by triethylamine

(0.0278 ml, 0.199 mmol) was added. After stirring the reaction mixture at room temperature for 18 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to give the title compound and the solvent was distilled off under reduced pressure (54.8 mg, 48) as a dark red crystals. The crystals were recrystallized from ethyl acetate-deethyl ether to obtain dark red crystals having a melting point of 98.0-100 ° C.

IR (KBr): 3260, 2955, 2928, 2859, 1734, 1653, 1615, 1559 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 0.840 - 0.940 (6Η, m), 1.-1.38 (14H, m), 1.38-1.56 (4H, m), 1.68-1.84 (4H, m), 2.10 (2H, t, J = 8.1 Hz), 2.20 (2H, t, J = 7.21 Hz), 2.25 (3H, s), 2.42 (3H, s), 2.96 (2H, t, 1 = 1.2 Hz), 3.24 (2H, q, J = 5.4 Hz), 5.48 (1H, bs), 7.29 (2H, d, J-8.Hz), 7.84 (2H, d, J-8.1 Hz), 9.62 (1H, bs).

Elemental analysis: as C ₃₁ H ₄₆ N ₄ 0 ₄ S ₃

Calculated value (%): C, 58.64; H, 7.30; N, 8.82; S, 15.15.

Found (%): C, 58.57; H, 7.41; N, 8.81; S, 15.30. Examples 18-36

 5-[(6-benzyl-5-methyl-1 _ {[((4-methylphenyl) sulfonyl] imino} -3-oxo-3H-imidazo [5,1-c] [1,4] thiazine-8 -Yl) sulfanyl] -N-hexylpentanamide

5-[(6-benzyl-5-methyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-3H-imidazo [5,1-c] obtained in Example 18-33 N, N-Dimethylformamide (5.00ml) solution of [1,4] thiazin-8-yl) sulfanyl] valeric acid (100 mg, 0.179 t ol) and 1-hexylamine (0.0261 ml, 0.197 marl ol) To the mixture was added getyl cyanophosphate (0.0322 ml, 0.199 t), followed by triethylamine (0.0275 ml, 0.197 mmol). After stirring the reaction mixture at room temperature for 18 hours, water was added and extracted with ethyl acetate. Washed with water extract exudates, dried (MgSO _4), and the solvent was evaporated under reduced pressure to give the title compound (60.2 mg, 53%) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 107-109.

IR (KBr) V: 3250, 2928, 2857, 1742, 1655, 1615, 1557, 1495 cnf ¹ .

_{'H-NMR (CDC1 3)} : (50.879 (3H, t, J = 6.2 Hz), 1.24-1.38 (6H, m), 1.38-1.55 (2H,

1), 1.55-1.80 (4H, m), 2.12 (2H, t, J = 6.6 Hz), 2.36 (3H, s), 2.42 (3H, s),

2.87 (2H, t, J = 7.0 Hz), 3.22 (2H, q, J = 6.8 Hz), 3.49 (2H, s), 5.482 (1H, bs),

7.16-7.40 (7H, m), 7.84 (2H, d, J = 8.4 Hz).

Elemental analysis: C ₃₂ H _4. N ₄ 0 ₄ S ₃ '0.2H ₂₀

Calculated value (%): C, 59.63; H, 6.32; N, 8.69.

Found (¾): C, 59.53; H, 6.27; N, 8.83.

Examples 18-37

 N- [8-({[(2S, 4R) -4-hydroxypyrrolidinyl] methyl} sulfanyl) -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1 -c] [1,4] thiazine-trilidene] -4-methylbenzenesulfonamide hydrochloride

The powder (416 mg, 0.716 bandol) of the compound obtained in Example 4-555 was dissolved in TFA (1.0 ml) and left at room temperature for 90 minutes. The reaction solution was diluted with toluene (20 ml) and concentrated to dryness. Toluene (20 ml) was added to the residue and concentrated. The obtained residue was dissolved in THF-ethanol (1: 1, 20 ml), 1N hydrochloric acid (1.43 ml) was added, and the mixture was concentrated. Lil was added and concentrated to give a red suspension. This was diluted with THF and ethyl acetate. The precipitate was collected by filtration, washed with ethyl acetate, and dried to give the title compound (298 mg, 0.576 mmol, 80.5%) as a red powder.

Ή-NMR (200 MHz, DMSO— d ₆ ): άΐ.78 (1Η, m), 1.81 (3H, s), 2.06 (1H, m), 2.18 (3H, q, J = 0.8 Hz), 2.39 (3H , s), 3.08 (1H, m), 3.20-3.40 (3H, m), 3.85 (1H, m), 4.4K1H, brs), 5.44 (1H, br), 7.39 (2H, d, J = 8.2 Hz ), 7.87 (2H, d, J = 8.0 Hz), 9.24 (1H, m), 9.59 (1H, m), 11.76 (1H, m).

Elemental _{analysis: C 20 H 24 N 4 0} 4 S 3 .HC1.0.5H 2 0 Calculated: C, 45.66; H, 4.98 ; N, 10.65; S, 18.29; C1, 6.74 (%), Found : C, 45.66; H, 4.90; N, 10.67; S, 17.90; C1, 6.60 (%).

mp.188.0-191.0 ° C

Examples 18-38

 (2S) -4-[(5,6-Dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} _3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1, 4] Thiazine-8-yl) sulfanyl] -2-pimethyl lysinecarboxylate hydrochloride

 The powder (776 mg, 1.27 mmol) of the compound obtained in Example 4-545 was dissolved in TFA (1.0 ml) and left at room temperature for 2 hours. The reaction solution was diluted with toluene (20 ml), concentrated to dryness, and the residue was concentrated by adding toluene (20 ml). The obtained residue was dissolved in THF-ethanol (1: 1, 20 ml), concentrated by adding 1 hydrochloric acid (1.5 ml), and concentrated by adding THF and ethyl acetate to the residue. A liquid was obtained. The precipitate was collected by filtration, washed with THF-ethyl acetate (1: 1) and ethyl acetate, and dried to give the title compound (518 mg, 0.950 mmol, 74.8%) as a red-purple powder.

Ή-NMR (200 MHz, DMSO—d ₆ ): (51.80 (3H, s), 2.10 (1Η, m), 2.17 (3H, s), 2.39 (3H, s), 2.80 (1H, dt, J = 13.6) , 6.8 Hz), 3.24 (1H, m), 3.75 (1H, m), 3.76 / 3.78 (3H, s), 4.13 (1H, brq, J = 7.2 Hz), 4.54 (1H, t, J = 8.2 Hz) ), 7.39 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.0 Hz), 10.41 (3H, br).

Elemental _{analysis: C 2I H 24 N 4 0} 5 S 3 .HC1.0.3H 2 0 Calculated: C, 45.82; H, 4.69 ; N, 10.18; S, 17.47; CI, 6.44 (%), Found : C, 45.82; H, 4.71 ;, 10.21; S, 17.46; CI, 6.61 (%). Immediate. 188.0-191.0 ° C

Examples 18-39

 (2S, 4R) -1- (tert-Butoxycarbonyl) -4-[(5,6-dimethyl-1-{{((4-methylphenyl) sulfonyl] imino} -3-oxo-3,2-oxo Dihydro-1H-imidazo [5,1-c] [1,4] thiazin-8-yl) sulfanyl] -2-pyrrolidine

 Potassium hydroxide (85%, 172 mg) was added to a suspension of the compound obtained in Example 4-545 (317 mg, 0.52 mmol) in THF-methanol-water (1: 1: 1, 9 ml) at room temperature with stirring. , 2.60 mmol) was added and the reaction was stirred for 1 hour. 1N Hydrochloric acid (2.6 ml) was added to the reaction solution, and extracted with ethyl acetate (40 ml). The organic layer was washed successively with a main solution and saturated saline, dried over sodium sulfate, and concentrated to obtain a dark red oil. This was subjected to silica gel (10 g) chromatography (ethyl acetate-hexane, 4: 6, 5: 5), and the ethyl acetate-hexane (5: 5) fraction was concentrated to dryness. Diluted with Jettlether. The precipitate was collected by filtration, washed with diethyl ether, and dried to give the title compound (108 mg, 0.182 mmol, 35.1¾) as a red powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.47 (6Η, s), 1.50 (3H, s), 1.77 (3H, s), 2.25 (3H, s), 2.43 (3H, s), 3.47 (1H, m), 3,96 (1H, m), 3.98 (1H, m), 4.46 (1H, m), 7.32 (2H, d, J = 8.4 Hz), 7.87 (2H, d, J = 8.4 Hz), 9.69 (1H, br).

Elemental analysis: C ₂₅ H _3. N ₄ 0 ₇ S ₃ Calculated: C, 50.49; H, 5.08 ; N, 9.42; S, 16.17 (%), Found: C, 50.29; H, 5.31 ; N, 9.29; S, 16.03 (%) .

mp. 152.0-155.0 ° C (decomposition)

Examples 18-40

 N- [8-({[(2S, 4R) -1-acetyl-4-hydroxypyrrolidinyl] methyl} sulfanyl) -5,6-dimethyl-3-oxo-2,3-dihydro-1H- Imidazo [5,1-c] [1,4] thiazine The compound obtained in Example 18-37 (214 mg, 0.41 ol) and acetic anhydride (0.12 ml,

To a suspension of 1.4 mmol) in THF (5 ml) was added triethylamine (0.115 ml, 0.828 mmol) with stirring at room temperature, and the reaction solution was stirred for 3 hours. The reaction mixture was diluted with ethyl acetate (40 ml), washed successively with 0.2N hydrochloric acid—5% brine and saturated brine, dried over sodium sulfate, concentrated, and methanol was added to the resulting dark red oil. Was. Precipitate is collected by filtration After washing with methanol and drying, the title compound (179 rag, 0.342 mmol, 82.7) was obtained as a red powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.79 (3Η, s), 2.04 (3H, s), 2.12 (2H, m), 2.25 (3H, s), 2.43 (3H, s), 3.32 (1H, dd, J = 13.0, 6.8 Hz), 3.42 (1H, m), 3.46 (1H, m), 3.55 (1H, dd, J = 11.0, 4.4 Hz), 4.47 (1H, dd, J = 6.6, 4.0 Hz ), 4.54 (1H, m), 7.30 (2H, d, J = 8.0 Hz), 7.83 (2H, d, J = 8.0 Hz), 9.67 (1H, br). Elemental analysis: 'C ₂₂ H ₂₆ N ₄ 0 ₅ S ₃ calculated: C, 50.56; H, 5.01 ;, 10.72; S, 18.40

(%), Found: C, 50.61; H, 5.14; N, 10.76; S, 18.45 (%).

Immediately. 208.5-209.5 ° C

Example 18-41

Maleic sulfonic acid 5-[(5,6-dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazin-8-yl) sulfanyl] cyclooctyl

 To a solution of the compound (286 mg, 0.563 mmol) obtained in Example 18-34 and methanesulfonyl chloride (72.3 mg, 0.620 mmol) in THF (6 ml) was stirred at 0T while stirring triethylamine (0.204 ml, 1.46%). ol) in THF (1 ml) was added dropwise over 20 minutes. The reaction solution was stirred at 0 ° C for 2.5 hours. The reaction mixture was diluted with ethyl acetate (30 ml), washed sequentially with 0.05N hydrochloric acid, water and saturated saline, dried over sodium sulfate, and concentrated to dryness to give the title compound (330 mg, 0.563 mmol, quant. ) Was obtained as a purple powder.

_{Ή- NMR (200MHz, CDC1 3)} : δ 1.12 (4H, m), 1.80 (3H, s), 2.01 (8H, m), 2.26 (3H, s), 2.42 (3H, s), 3.01 / 3.02 ( 3H, s), 3.47 (1H, m), 4.86 (1H, m), 7.29 (2H, d, J = 8.4 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.64 (1H, brs).

Elemental _{analysis: C 24 H 31 N 3 0} 6 S 4 Calculated: C, 49.21; H, 5.33 ; N, 7.17; S, 21.90 (%), Found: C, 49.05; H, 5.31 ; N, 7.27; S, 22.03 (%).

mp.126.0-129.0 ° C

Example 1842

N- [8- (4-Cyclooctene-1-ylsulfanyl) -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine- 1-ylidene] _4-methylbenzenesulfonamide. To a solution of the compound obtained in Examples 18-41 (168 mg, 0.287 mmol) in acetonitrile (1 ml) was added tetrabutylammonium fluoride hydrate (150 mg, 0.574 t) while stirring at room temperature. The reaction solution was stirred at room temperature for 2 hours, at 50 ° C for 16 hours, and at 60 ° C for 7.5 hours. Ethyl acetate (30 ml) was added to the reaction solution, which was washed sequentially with 0.1 N hydrochloric acid, water and saturated saline, dried over sodium sulfate, and concentrated to obtain a dark red oil. This was subjected to silica gel (10 g) chromatography (ethyl acetate-hexane, 2: 8-3: 7), and the ethyl acetate-hexane (3: 7) fraction was concentrated to dryness and diluted with methanol. did. The precipitate was collected by filtration, washed with methanol, and dried to give the title compound (68 mg, 0.139 marl, 48.4%) as a red powder.

_{Ή-NMR (200MHz, CDC1 3} ): (51.5-1.8 (6H, m), 1.80 (3H, q, J = 1.2 Hz), 1.93 (2H, m), 2.16 (2H, brq, J = 6.6 Hz) , 2.18 (1H,), 2.26 (3H, q, J = 1.0 Hz), 2.40 (1H, m), 2.41 (3H, s), 3.46 (1H, m), 5.66 (1H, m), 5.71 (1H , m), 7.28 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.0 Hz), 9.64 (1H, brs).

Elemental _{analysis: C 23 H 27 N 3 0} 3 S 3 Calculated: C, 56.41; H, 5.56 ; N, 8.58; S, 19.64 (), Found: C, 56.39; H, 5.48 ; N, 8.62 ; S, 19.53 (%).

mp. 177.5-178.5 ° C

Example 18-43

 (2S, 4R) -2-{[(5,6-dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3--year-old oxo-2,3-dihydro-1H-imidazo [5,1 -c] [1,4] thiazine-8-yl) sulfanyl] methyl} -tert-butyl 4-fluoro-topyrrolidinecarbonate

To a solution of the compound obtained in Example 4-555 (250 mg, 0.430 mol) in dichloromethane (3 ml) was added Deoxo-Fluor ™ (114 mg, 0.517 mmol) in dichloromethane (1 ml) while stirring at 0 ° C. ) The solution was added dropwise over 60 minutes, and the reaction solution was stirred at room temperature for 2.5 hours. Methanol (1 ml) and saturated sodium bicarbonate (aoml) were sequentially added to the reaction solution, and the mixture was extracted with ethyl acetate-ethyl ether (5: 1, 60 ml). The organic layer was washed successively with 0.1N hydrochloric acid-5% brine, 5 brine and saturated brine, dried over sodium sulfate, and concentrated to give a dark red oil. This was subjected to chromatography on silica gel (10 g) (ethyl acetate-hexane, 2: 8-5: 5), and the ethyl acetate-hexane (4: 6) fraction was concentrated to dryness. Diluted with ether. The precipitate is collected by filtration and washed with getyl ether. After drying, the title compound (19 mg, 0.033 ramol, 7.6%) was obtained as a red powder. Ή-NMR (200MHz, CDC): 1.48 (9H, s), 1.78 (3H, s), 2.26 (3H, s), 2.43 (3H, s), 3.29 (1H, dd, J = 13.3, 3.1 Hz) , 3.41 (2H, m), 3.60-4.20 (2H, m), 4.35 (1H, m), 5.05 (1H, brd, J = 53 Hz), 7.30 (2H, d, J = 8.2 Hz), 7.83 ( 2H, d, J = 8.4 Hz), 9.62 (1H, brs).

Example 18-44

 N- (tert-butyl) -5-[(5,6-dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo [5, c] [1,4] thiazin-8-yl) sulfanyl] pentanamide

Example 18-21 5-{[2,3-dihydro-5,6-dimethyl-3-oxo-1-({[4- (trifluoromethyl) phenyl] sulfonyl} imino obtained in ' )-1H-imidazo [5, tric] [1,4] thiazin-8-yl] sulfanyl} N, N- of valeric acid (100 mg, 0.208 mmol) and tert-butylamine (0.0247 ml, 0.228 mmol) To a dimethylformamide (4.00 ml) solution was added getyl cyanophosphate (0.165 ml, 10.2 benzyl), followed by triethylamine (0.0369 ml, 0.228 dandelion). After stirring the reaction mixture at room temperature for 16 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to give the title compound was evaporated Solvent under reduced pressure (23.6 mg, 4.6%) as a dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 187-189 ° C. IR (KBr): 3198, 2967, 2924, 1752, 1721, 1645, 1618, 1561 cm " ¹ .

_{¾-NMR (CDC1 3):} 51.35 (9H, s), 1.54-1.82 (4H, m), 1.78 (3H, s), 2.08-2.18 (2H, m), 2.26 (3H, s), 2.42 (3H , s), 2.88-3.02 (2H, m), 5.27 (1H, bs), 7.29 (2H, d, J = 8.0 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.61 (1H, bs) .

Elemental analysis: as C ₂₄ H ₃₂ N ₄ 0 ₄ S ₃

Calculated value (¾): C, 53.71; H, 6.01;, 10.44; S, 17.92.

Obtained value (): C, 53.50; H, 5.76; N, 10.36; S, 18.05.

Example 18-45

N-{3 _ [(5,6-dimethyl-1--[[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4 ] Thiazine-8-yl) sulfanyl] propyl} -2,2-dimethylpropanamide To a suspension of the compound obtained in Example 18-12 (0.49 g, 0.79 mmol) and pivaloyl chloride (0151 mg, 1.19 IMOI) in THF (10 ml) was added triethylamine (0.33 ml, 2.37 IMOI) with stirring at room temperature. The reaction was stirred for 24 hours. The reaction mixture was diluted with ethyl acetate (50 ml), washed successively with 2% aqueous sodium hydrogen carbonate, 0.1N hydrochloric acid, water and brine, dried over sodium sulfate, and concentrated to give a dark red oil. Was. This was purified by chromatography on silica gel (10 g) (ethyl acetate-hexane, 2: 8-6: 4), and the obtained red oil was crystallized from getyl ether to give the title compound (269 nig, 0.515 miol, 65.1%) as a red powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.20 (9Η, s), 1.78 (3H, s), 1.90 (2H, quint, J = 7.1 Hz), 2.26 (3H, s), 2.42 (3H, s) , 2.95 (2H, t, J = 7.5 Hz), 3.34 (2H, q, J = 6.2 Hz), 5.84 (1H, br), 7.29 (2H, d, J = 8.4 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.64 (1H, brs).

Elemental _{analysis: C 23 H 30 N 4 0} 4 S 3 .0.3H 2 0 Calculated: C, 52.49; H, 5.86 ; N, 10.65; S, 18.28 (%), Found: C, 52.37; H , 5.84; N, 10.67; S, 18.38 (%)

mp. 172.0-174. Ot

Example 18-46

 N- [8-({[(2S, 4S) -4-fluoro-pyro'J-dinyl] methyl} sulfanyl) -5,6-dimethyl-3-oxo-2,3-dihydro- 1H-imidazo [5 , 1-c] [1,] thiazine-triylidene] + methylbenzenesulfonamide hydrochloride

 The powder of the compound obtained in Example 4-546 (purity 80 '%, 526 mg, 0.722 alcohol) was added to TFA

(1.0 ml) and left at room temperature for 3 hours. The reaction solution was diluted with toluene (50 ml) and concentrated to dryness. Toluene (50 ml) was added to the residue and concentrated. The obtained residue was dissolved in methano-ruacetonitrile (1: 9, 50 ml), concentrated by adding 1N hydrochloric acid (1.08 ml), and concentrated by adding methanol-acetonitrile α: ι) to the residue. And diluted with ethanol. The precipitate was collected by filtration, washed with acetonitrile and ethyl acetate, and dried to give the title compound (148 mg, 0.285 w / w, 39.5%) as a dark purple powder.

Ή-NMR (200MHz, DMS0- d 6): <51.81 (3H, s), 2.06 (2H, m), 2.17 (3H, s) ', 2.39 (3H, s), 3.30-3.60 (4H, m) , 3.88 (1H, m), 5.42 (1H, brd, J = 51.6 Hz), 7.40 (2H, d, J = 8.2 Hz), 7.87 (2H, d, J = 8.4 Hz), 9.54 (1H, br) , 9.89 (1H, br), 11.79 (1H, br).

Elemental analysis: C _2. H ₂₃ N _{4 3} S ₃ F. Calculated as HC 1.0.5¾0: C, 45.49; H, 4.77; N, 10.61; S, 18.22; CI, 6.71 (%), found: C, 45.40; H, 4.87; N, 10.42; S, 18.48; CI, 6.53 (%).

Example 18-47 '

 N- [8-({[(5R, 7S) -3- (Hydroxymethyl) tris-capped [3.3.1.1-3,7-] dec-1-yl] methyl} sulfanyl) -5,6-dimethyl- 3-oxo_2,3-dihydro-m-imidazo [5,1-c] [1,4] thiazine-triylidene] -4-methylbenzenesulfonamide

 To a suspension of the compound obtained in Example 4-549 (495 mg, 0.822 mol) in THF-methanol (1: 1, 6 ml) was added an aqueous IN sodium hydroxide solution (3.0 ml, 3.0 mmol), and the mixture was heated at 65 ° The mixture was stirred at C for 30 minutes. The reaction solution was returned to room temperature, 1N hydrochloric acid (3.0 ml) was added, and the mixture was stirred for 30 minutes. The precipitate was collected by filtration, washed with water and methanol-water (1: 1), and dried to give the title compound (432 mg, 0.772 bandol, 93.9%) as a purple powder.

_{-NMR (200MHz, CDC1 3):} 51.34 (1H, s), 1.45 (2H, m), 1.50-1.58 (8H, m), 1.61 (2H, m), 1.78 (3H, q, J = 1.2 Hz) , 2.12 (2H, m), 2.26 (3H, q, J = 0.8 Hz), 2.41 (3H, s), 2.81 (2H, s), 3.25 (2H, d, J = 5.6 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.88 (2H, d, J = 8.4 Hz), 9.57 (1H, brs).

Elemental analysis: Calculated as _{C 27 H 33 N 3 0 4} S 3: C, 57.93; H, 5.94; N, 7.51 (%), actual Hakachi: C, 57.94; H, 6.11 ;, 7.28 (%) .

Immediately. 197.5-198.0 ° C

Example 18-48 tyl-3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-1-ylidene] -4-methylbenzenesulfonamide

To a suspension of the compound obtained in Example 4-550 (1.67 g, 3.04 mol) in THF-methanol (1: 1, 20 ml) was added IN aqueous sodium hydroxide solution (9.12 ml, 9.12 mol), and the mixture was stirred at room temperature. For 2.5 hours. The mixture was returned to the reaction solution, IN hydrochloric acid (10 ml) was added, and the mixture was stirred for 30 minutes. The precipitate was collected by filtration, washed with water and methanol / water (1: 1), and dried to give the title compound (1.17 g, 2.30 fraction ol, 75.8) as a red-purple powder. _{¾-NR (200MHz, CDC1 3} ): δ 0.89 / 0.69 (2H, qm / q, J = 13 / 12.2 Hz), 1.32 (2H, m), 1.40-1.65 (4H, m), 1.79 (3H, s ), 1.90 (2H, brq, J = 11.8 Hz), 2.26 (3H, q, J = 0.8 Hz), 2.42 (3H, s), 2.84 / 2.92 (2H, d, J = 6.6 / 7.0 Hz), 3.49 (2H, m), 7.28 (2H, d, J = 8.4 Hz), 7.86 (2H, d, J = 8.4 Hz), 9.62 (1H, brs).

Elemental analysis: Calculated as _{C 23 H 29 N 3 0 4} S 3: C, 54. 1; H, 5.76; N, 8.28; S, 18.95 (%), Found: C, 54.26; H, 5.50 ; N, 8.25; S, 18.98 (%).

mp. 156.5-157.0. C

Example 18-49

 N- {8 _ [(5-hydroxy-3,3-dimethylpentyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4 ] Thiazine-1-ylidene}-4-methylbenzenesulfonamide

 To a suspension of the compound (1.64 3.05 mmol) obtained in Example 4-552 in THF-methanol (1: 1, 24 ml) was added IN NaOH (12.2 ml, 12.2 SUB01), and the mixture was stirred at room temperature for 90 minutes. 1N Hydrochloric acid (12.2 ml) was added to the reaction solution, and the mixture was stirred for 30 minutes. The precipitate was collected by filtration, washed with water, methanol-one water (1: 1) and methanol, and dried to give the title compound (1.48 g, 2.98 ol, 97.8%) as a red-purple powder.

'H-NMR (300MHz, CDC1 3): 50.96 (6H, s), 1.22 (1H, br), 1.55 (2H, t, J- 7.5 Hz), 1.60 (2H, m), 1.79 (3H, q, J = 0.9 Hz), 2.26 (3H, q, J = 0.9 Hz), 2.42 (3H, s), 2.92 (2H, m), 3.71 (2H, brt, J = 7.5 Hz), 7.28 (2H, d, J = 7.8 Hz), 7.83 (2H, d, J = 7.8 Hz), 9.61 (1H, brs).

Elemental analysis: Calculated as _{C 22 H 29 N 3 0 4} S 3: C, 53.31; H, 5.90;, 8.48; S, 19.41

(%), Found: C, 53.11; H, 5.79; N, 8.53; S, 19.58 (%).

mp. 193.0-195.5 ° C

Example 18-50

N- [8-({[l- (2,2-Dimethylpropanoyl) -4-piperidinyl] methyl} sulfanyl) -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, 1-c] [1,4] thiazine A suspension of the compound obtained in Example 4-116 (266 mg, 0.516 mmol) and triethylamine (0.215 ml, 1.55 mmol) in THF (5 ml) was salted. Dani Pivaloyl (0.080 ml, 0.620 mmol) at room temperature and the reaction was stirred at room temperature for 12 hours. The reaction mixture was diluted with 1N hydrochloric acid (1.6 ml), diluted with water (aOml) and ethyl acetate (15 ml), and stirred at room temperature. The precipitate was collected by filtration, washed with methanol-water (1: 1) and methanol, and dried to give the title compound (251 mg, 0.446 mmol, 86.4%) as an orange powder.

_{- NMR (200MHz, CDC1 3)} : 51.16 (2H, brq, J = 11.2 Hz), 1.28 (9H, s), 1.79 (3H, q, J = 1.0 Hz), 1.85 (1H, m), 1.87 (2H , brd, J- 11.0 Hz), 2.26 (3H, q, J = 1.2 Hz), 2.43 (3H, s), 2.75 (2H, brt, J = 11.0 Hz), 2.85 (2H, d, J = 6.6 Hz) ), 4.44 (2H, brd, J = 13.2 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.84 (2H, d, J = 8.4 Hz), 9.63 (1H, brs).

Elemental _{analysis: C 26 H 34 N 4 0} 4 S 3 Calculated: C, 55.49; H, 6.09 ; N, 9.96; S, 17.09 (), Found: C, 55.47; H, 5.90 ; N, 9.95 ; S, 16.98 (%).

mp.221.0-223.0 ° C

Example 18-51

 N- (8-{[(Tracetyl-4-piberidinyl) methyl] sulfanyl} -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4 ] Thiazine-triylidene) -4-methylbenzenesulfonamide

 Compound obtained in Example 4-116 (303 mg, 0.588 awake ol) and triethylamine

Acetic anhydride (0.113 ml, 1.18 mmol) was added to a suspension of (0.244 ml, 1.76 mmol) in THF (6 ml) at room temperature, and the reaction solution was stirred at room temperature for 12 hours. Ethyl acetate (15 ml), IN hydrochloric acid (1.8 ml) and water (10 ml) were added to the reaction solution, and the mixture was stirred at room temperature. The resulting suspension was dissolved by adding methanol and THF, and concentrated to about 15 ml. The precipitate was collected by filtration, washed with methanol / water (1: 1) and methanol, and dried to give the title compound (283 mg, 0.543 mmol, 92.4%) as an orange powder.

_{Ή-NMR (200MHz, CDC1 3} , mixture of isomers): 51.16 (2H, m) , 1.79 (3H, q, J = 1.0 Hz), 1.79 (1H, m), 1.92 (2H, brd, J = 15.0 Hz ), 2.10 (3H, s), 2.26 (3H, q, J = 1.2 Hz), 2.43 (3H, s), 2.51 (2 / 2H, brt, J = 12.8 Hz), 2.82 (2 / 2H, d, J = 6.2 Hz), 2.87 (2 / 2H, d, J = 6.6 Hz), 3.02 (2 / 2H, dt, J = 2.6, 12.4 Hz), 3.83 (2 / 2H, brd, J = 13.6 Hz), 4.64 (2 / 2H, brd, J = 13.0 Hz), 7.29 (2H, d, J = 8.2 Hz), 7.84 (2H, d, J = 8.2 Hz), 9.64 (1H, brs). Elemental _{analysis: C 23 H 28 N 4 0} 4 S 3 Calculated: C, 53.05; H, 5.42 ; N, 10.76; S, 18.47

(), Found: C, 52.82; H, 5.34; N, 10.75; S, 18.35.

mp. 216.0-217.O:

Example 18-52

N- [8-({'[1,2-trans-2- (hydroxymethyl) cyclohexyl] methyl} sulfanyl) -5,6-dimethyl-3-oxo-2,3-dihydrido-1H- Imidazo [5,1-c] [1,4] thiazine 1N sodium hydroxide was added to a suspension of the compound obtained in Example 4-556 (1.90 g, 3.46 tD in THF-methanol (1: 1, 26 ml)). An aqueous solution (13.8 ml, 13.8 mol) was added, and the mixture was stirred for 30 minutes at 60 ° C. The reaction solution was returned to room temperature, 1N hydrochloric acid (13.8 ml) was added, and the mixture was stirred for 30 minutes. After washing with water and methanol-water (1: 1), drying was performed to obtain the title compound (1.55 g, 3.05 mmol, 88.1%) as a red-purple powder.

Ή one _{NMR (200MHz, CDC1 3):} δ \ .18 (2Η, in), 1.25 (2H, m), 1.36 (2H, m), 1.60 (2H, m), 1.74 (2H, brs), 1.78 ( 3H, q, J = 0.8 Hz), 2.02 (1H, brd, J = 12.0 Hz), 2.26 (3H, q, J = 1.2 Hz), 2.42 (3H, s), 2.84 (1H, dd, J = 12.8 , 7.6 Hz), 3.28 (1H, dd, J = 12.6, 4.2 Hz), 3.64 (2H, brd, J = 3.5 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.86 (2H, d, J = 8.4 Hz), 9.60 (1H, brs).

Elemental _{analysis: C 23 N 3 0 4 S} 3 Calculated: C, 54.41; H, 5.76 ; N, 8.28; S, 18.95 '(%), Found: C, 54.26; H, 5.56 ; N, 8.03 ; S, 19.23 (%)

mp. 183.0-183.5 ° C

Example 18-53

Methyl (5, 6-dimethyl - 1- {[(4 - methylphenyl) sulfonyl] Imino Bok ₃ - Okiso - 8 - [(5, 5, 6, 6, 6-pen evening cyclohexyl Furuo port) sulfanyl] - IH -Imidazo [5, 1-c] [1, 4] thiazine-2 (3H) -yl) acetate ''

N- {5,6-Dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] obtained in Example 4-35 -2,3 -Dihide mouth- 1H-imidazo [5, 1-c] [1, 4] thiazine-triidentyl 4-methylbenzenesulfonamide (816 mg, 1.47 mmol) and potassium carbonate (305 mg, 2.21 thigh 01) Methyl bromoacetate (0.214 ml, 2.21 oi) was added to a suspension of N, N-dimethylformamide (16.0 ml). Reaction mixture at room temperature After stirring for 15 hours, IN hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, after Drying (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexan-ethyl acetate (10: 1, v / v) to give the title compound (167 mg, 18%) as dark red crystals.

 IR (KBr) V: 3013, 2955, 2863, 1746, 1665, 1617, 1557 cm—

_{'H-NMR (CDC1 3)} : 51.54-1.64 (4H, m), 1.80 (3H, d, J = 0.6Hz), 1.84-2.14 (2H, m), 2.29 (3H, d, J = 1.2 Hz) , 2.39 (3H, s), 2.84 (2H, t, J-6.6 Hz), 3.82 (3H, s), 5.08 (2H, s), 7.24 (2H, d, J = 8.0 Hz), 7.88 (2H, d, J = 8.4 Hz).

Elemental analysis: C ₂₄ H ₂₆ N ₃ 0 ₅ S ₃ F ₅ -0.3 H ₂ 0

Calculated (¾): C, 45.53; H, 4.24; N, 6.64; S, 15.20.

Found (%): C, 45.53; H, 4.35; Ν ,, 6.62; S, 15.13.

Example 18-54

Ethyl 5-[(1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,5,6-trimethyl-2,3-dihydro-1H-imidazo [5,1-c] [1 , 4] Thiazine-8-yl) sulfanyl] pentanoate

Ethyl 5-[(5,6-dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo obtained in Example 4-522 1-c] [1,4] thiazine-8-yl) sulfanyl] pentanoate (l.OOg, 1.96 ol) and potassium carbonate (407 mg, 2.94 ol)), Ν-dimethylformamide (20.0 ml) of suspension was added to potassium methoxide (336 mg, 2.35 thigh 01). After stirring the reaction mixture at room temperature for 15 hours, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (940 mg, 92%) as a dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 128-130 ° C. IR (KBr): 2926, 1738, 1661, 1615, 1557 cm " ¹ .

_{Ή-NMR (CDC1 3):} (51.27 (3H, t, J = 7.2 Hz), 1.44-1.66 (4H, m), 1.79 (3H, d, J = l.2 Hz), 2.26 (2H, t, J = 6.8 Hz), 2.29 (3H, d, J = 0.8 Hz), 2.41 (3H, s), 2.81 (2H, t, J = 6.6 Hz), 3.70 (3H, s), 4.14 (2H, q, J = 7.2 Hz), 7.27 (2H, d, J = 8.2 Hz), 7.91 (2H, d, J = 8.0 Hz).

Elementary analysis: as _{C 23 H 29 N 3 0 5} S 3 Calculated value (¾) ': C, 52.75; H, 5.58; N, 8.02; S, 18.37

Found (%): C, 52.85; H, 5.67;, 8.01; S, 18.30.

Example 18-55

tert-Butyl 5-[(l-{[(4-methylphenyl) sulfonyl] imino 3-oxo-2,5,6-trimethyl_2,3-dihydro-1H-imidazo [5,1-c] [1, 4] Thiazine-8-yl) sulfanyl] pen

Tert-Butyl 5-[(5,6-dimethyl_1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydrido-1H- obtained in Examples 18-72 N, N of imidazo [5, 1-c] [1,4] thiazin-8-yl) sulfanyl] pentanoate (424 mg, 0.789 marl ol) and carbonated lithium (164 mg, 1.18 mmol) To a suspension of -dimethylformamide (9.00 ml) was added methane (135 mg, 0.947 mmol). After stirring the reaction mixture at room temperature for 22 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (285 mg, 66¾) as dark red crystals. Recrystallization from ethyl acetate-ethyl ether gave dark red crystals, mp 147-149 ° C.

IR (KBr) V: 2978, 2928, 1736, 1663, 1617, 1561 cm " ¹ .

_{'H- R (CDC1 3):} (51.45 (9H, s), 1.51-1.58 (4H, in), 1.79 (3H, d, J = 0.9 Hz), 2.18 (2H, t, J = 7.2 Hz), 2.29 (3H, d, J-1.2 Hz), 2.42 (3H, s), 2.81 (2H, t, J = 6.6 Hz), 3.70 (3H, s), 7.26 (2H, d, J = 8.1 Hz), 7.91 (2H, d, J = 8.1 Hz). Elemental analysis: C ₂₅ H ₃₃ N ₃ 0 ₅ S ₃

Calculated value (¾): C, 54.42; H, 6.03;, 7.62; S, 17.43.

Found (¾): C, 54.33; H, 6.02; N, 7.64; S, 17.48.

Example 18-56

tert-butyl (5,6-dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-8-[(5,5,6,6,6-pentahexylhexyl) Sulfanyl] -1Η-imidazo [5,1-c] [1,4] thiazine-2 (3H) -yl) acetate

N- {5,6-Dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] obtained in Example 4-35] -2,3 -Dihide mouth-1H-imidazo [5,1-c] [1,4] thiazine -Triylidene}-To a suspension of 4-methylbenzenesulfonamide (1.00 g, 1.80 mmol) and potassium carbonate (373 mg, 2.70 01) in N, N-dimethylformamide (20.0 ml) was added tert-bromoacetic acid. -Butyl ester (0.377 ml, 2.70 mmol) was added. After stirring the reaction mixture at room temperature for 18 hours, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. Washed with water extract exudates, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (940 mg, 92%) as dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 162-164 ° C.

IR (KBr) V 2982, 2934, 2876, 1742, 1665, 1617, 1557 cm- ¹ .

_{'H-NMR (CDC1 3)} : (51.51 (9H, s), 1.46-1.64 (4H, m), 1.79 (3H, s), 1.84-2.12

(2H, m), 2.29 (3H, s), 2.39 (3H, s), 2.80-2.88 (2H, m), 3.70 (3H, s), 4.98

(2H, s), 7.24 (2H, d, J = 8.0 Hz), 7.90 (2H, d, J = 8.2 Hz).

Elemental analysis: as C ₂₇ H ₃₂ N ₃ 0 ₅ S ₃ F ₅

Calculated (¾): C, 48.42; H, 4.82; N, 6.27; S, 14.36.

Found (%): C, 48.36; H, 4.66; N, 6.31; S, 14.18.

Example 18-57

 5- [α _ {[(4-Methylphenyl) sulfonyl] imino} -3-oxo-2,5,6-trimethyl-2,3-dihydro-1H-imidazo [5, l_c] [1,4] thiazine-8 -Yl) sulfanyl] valeric acid tert-butyl 5-[(1-{[(4-methylphenyl) sulfonyl] imino} obtained in Example 18-55} -3-oxo-2,5,6_ Dissolve trimethyl-2,3-dihydro-1H-imidazo [5, l-c] [1,4] thiazine-8-yl) sulfanyl] pentanoate (177 nig, 0.322 mmol) in trifluoroacetic acid (1.00 ml). It was left at room temperature for 1 hour. After dilution with ethyl acetate, the solvent was distilled off under reduced pressure to obtain the title compound (132 mg, 83%) as dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 189-19 C.

IR (KBr) V: 3400-2400, 2909, 1736, 1661, 1615, 1559 cm " ¹ .

Ή-NMR (CDCI3): 51.40-1.68 (4H, m), 1.80 (3H, s), 2.30 (3H, s), 2.33 (2H, t, J = 6.9 Hz), 2.41 (3H, s), 2.82 (2H, t, J = 6.6 Hz), 3.70 (3H, s), 7.27 (2H, d, J = 8.1 Hz), 7.91 (2H, d, J = 8.1 Hz). Elemental analysis: as C ₂₁ H ₂₅ N ₃ 0 ₅ S ₃

Calculated value (¾): C, 50.89; H, 5.08; N, 8.48; S, 19.41.

Found (¾): C, 50.90; H, 5.04; N, 8.60; S, 19.14.

Example 18-58

5-[(1-{[(4-Methylphenyl) sulfonyl] imino} -3-oxo-2,5,6-trimethyl-2,3-dihydrido-1H-imidazo [5,1-c] [1, 4] Thiazine-8-yl) sulfanyl] -N-hexylpentanamide

5-[(1-{[(4-Methylphenyl) sulfonyl] imino} -3-oxo-2,5,6-trimethyl-2,3-dihydro-1H-imidazo obtained in Example 18-57 , 1-c] [1,] Thiazine-8-yl) sulfanyl] valeric acid (31.5 mg, 0.0636 mmol) and trihexylamine (0.0096 ml, 0.0699 mmol) in Ν, Ν-dimethylformamide (1.00 ml) To this was added getyl cyanophosphate (0.0113 ml, 0.0699 ol) and then triethylamine (0.0097 ml, 0.0699 thigh). After stirring the reaction mixture at room temperature for 17 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title of compound a (16.4 mg, 45) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 115-117 ° C.

IR (KBr): 3291, 2955, 2930, 2859, 1738, 1645, 1611, 1557 cm " ¹ .

_{Ή-NMR (CDC1 3):} 50.886 (3H, t, J = 6.2 Hz), 1.20-1.40 (6H, m), 1.40-1.72 (6H, m), 1.80 (3H, s), 2.11 (2H, t , J = 7.0 Hz), 2.29 (3H, s), 2.42 (3H, s), 2.82 (2H, t, J = 7.0 Hz), 3.24 (2H, q, J = 7.0 Hz), 3.70 (3H, s) ), 5.37 (1H, bs), 7.28 (2H, d, J = 8.0 Hz), 7.91 (2H, d, J = 8.4 Hz).

Examples 18-59

 5,6-Dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-8-[(5,5,6,6,6-pentylfluorohexyl) sulfanyl] -1H- Imidazo [5, 1-c] [1,4] thiazine_2 (311) -yl) acetic acid

Tert-Butyl (5,6-dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-ino} -8-oxo- (5,5,6,6 obtained in Examples 18-56 Hexyl) sulfanyl]-1H-imidazo [5,1-c] [1,4] thiazine-2 (3H) -yl) acetate (665 mg, 0.993 t) It was dissolved in acetic acid (1.00 ml) and left at room temperature for 3 hours. After dilution with ethyl acetate, the solvent was distilled off under reduced pressure to obtain the title compound (153 mg, 25%) as dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 203-205 ° C.

IR (KBr) V: 3400-2400, 2949, 1750, 1725, 1667, 1613, 1551 cm one ^1.

_{¾-NMR (CDC1 3):} (51.52-1.66 (4H, m), 1.80 (3H, d, J = 1.2 Hz), 1.88-2.08 (2H, m), 2.29 (3H, d, J = 1.2 Hz) , 2.40 (3H, s), 2.85 (2H, t, J = 6.6 Hz), 5.15 (2H, s), 7.25 (2H, d, J = 8.1 Hz), 7.89 (2H, d, J = 8.1 Hz) .

Elemental analysis: as C ₂₃ H ₂₄ N ₃ 0 ₅ S ₃ F ₅

Calculated (¾): C, 45.02; H, 3.94; Ν, '6.85; S, 15.68.

Observed value (%): C, 45.02; Η, 4.11;, 6.92; S, 15.61.

Examples 18-60

 6-[(Ζ) -Hydroxymethylidene] -tri {[(4-methylphenylenyl) sulfonyl] imino} -3-oxo-8-[(5,5,6,6,6-pentaphenol Methylhexyl) sulfanyl] -2,3,5,6-tetrahydro-IH-imidazo [5,1-c] [1,4] thiazine-5-carboxylic acid

 To a solution of the crude compound obtained in Example 4-571 (914 mg, 1.39 hall) in methanol (10 ml) was added ^ sodium hydroxide (10 ml) with stirring at room temperature, and the reaction solution was stirred for 10 minutes. . 1N Hydrochloric acid (14 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (60 ml). The organic layer was washed successively with 10¾ and saturated saline, dried over sodium sulfate, concentrated, and getyl ether was added to the residue. The precipitate was collected by filtration, washed with getyl ether, and dried to give the title compound (390 mg, 0.619 bandol, 44.6%) as an orange powder.

¾- thigh _{(300MHz, CDC1 3 - DMSO- d} 6 = 19: 1, endo / exo isomeric mixture): δ 1.67 (4Η, m ), 2.02 (2H, m), 2.42 (3H, s), 2.99 ( 2H, q, J = 7.2 Hz), 3.42 (2H, s, for exo), 5.47 (1H, s, for exo), 6.34 (IH, s, for exo), 7.31 (2H, d, J = 8.4 Hz) ), 7.88 (2H, d, J = 8.4 Hz), 10.27 (IH, br).

Elemental _{analysis: C 22 H 2D N 3 0} 7 S 3 F 5 Calculated: C, 41.97; H, 3.20 ; N, 6.67; S, 15.28; F, 15.09 (%), Found: C, 41.63; H, 3.29; N, 6.65; S, 15.20 (%).

Example 18-61

N- {5,6-Dimethyl-3-oxo-8-[(3-piridinylmethyl) sulfanyl] -2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine- 1-ylidene}-4-methylbenzenesul Honamide

 The compound (0.20 g, 0.345 mmol) obtained in Example 4-558 was dissolved in TFA (1.0 ml) and left at room temperature for 18 hours. The reaction solution was diluted with toluene and concentrated to dryness. The residue was dissolved in methanol, and concentrated by adding 1N hydrochloric acid (1.0 ml). The residue was suspended in THF, and the precipitate was collected by filtration, washed with THF and ethyl acetate, and dried to give the title compound (120 mg, 0.233 mmol, 67.0%) as a red-purple powder.

NMR-NMR (200 MHz, DMS0-d ₆ + TFA): δ 1.21 (2Η, brq, J = 13 Hz), 1.60 (2H, brq, J = 10 Hz), 1.80 (3H, s), 1.97 (1H, m), 2.17 (3H, s), 2.39 (3H, s), 2.64 (1H, brd, J = 7.4 Hz), 2.72 (1H, m), 2.96 (2H, d, J = 6.6 Hz), 3.24 ( 2H, brt, J = 10 Hz), 7.39 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.4 Hz), 8.59 (1H, br), 8.87 (1H, m), 1.1. 74 (1H, br).

Elemental analysis: C ₂₁ H ₂₆ N ₄ 0 ₃ S ₃ flCl Ό.5H ₂ 0 Calculated: C, 48.12; H, 5.38; N, 10.69; S, 18.35; C1, 6.76 (%), found: C, 48.34; H, 5.33; N, 10.38; S, 18.55; Cl, 6.76 ()

mp. 211.5-213. O

Example 18-62

 N- (5,6-dimethyl-3-oxo-8-{[(2S) -pyrrolidinylmethyl] sulfanyl} -2,3_dihydro-1H-imidazo [5,1-c] [1,4 ] Thiazine-1-ylidene) -4-methylbenzenesulfonamide

 The crude compound (0.38 g, 0.54 tmol) obtained in the same manner as in Example 4-559 was dissolved in TFA (1.0 ml) and left at room temperature for 16 hours. The reaction solution was diluted with toluene and concentrated to dryness. The residue was dissolved in methanol, 1N hydrochloric acid (1.0 ml) was added, and the mixture was diluted with acetonitrile and concentrated. The residue was suspended in THF, and the precipitate was collected by filtration, washed with THF and ethyl acetate, and dried to give the title compound (152 mg, 0.303 mmol, 56.2%) as a gray-violet powder.

lH - NMR (300MHz, DMS0 - d 6): δΐ.65 (1H, m), 1.81 (3H, s), 1.88 (1H, m), 1.91 (1H, m), 2.11 (1H,), 2.17 ( 3H, s), 2.39 (3H, s), 3.17 (2H, m), 3.66 (1H, m), 7.39 (2H, brd, J- 8.7 Hz), 7.85 (2H, d, J = 7.8 Hz), 9.06 (1H, br), 9.39 (1H, br). Ή-NMR (200 MHz, DMS0-d ₆ + TFA): δ 1.66 (1H, m), 1.81 (3H, s), 1.90 (2H, brq, J = 7.6 Hz), 2.10 (1H, m), 2.17 ( 3H, s), 2.39 (3H, s), 3.17 (2H, m), 3.35 (2H, d, J = 6.8 Hz), 3.67 (1H, brquint, J = 6.8 Hz), 7.39 (2H, d, J = 8.0 Hz), 7.87 (2H, d, 'J = 8.0 Hz), 9.12 (1H, br), 9.45 (1H, br), 11.73 (1H, br).

Elemental analysis: C _2. H ₂₄ N ₄ 0 ₃ S ₃ i! Cl 0.5H ₂ 0 Calculated: C, 47.09; H, 5.14;, 10.98; S, 18.86; CI, 6.95 (%), Found: C, 47.14; H, 5.10; N, 10.86; S, 18.85; CI, 7.01 (%).

Example 18-63

 N- [8- ({[(2S, 4R) -1-hexanoyl-4_hydroxypyrrolidinyl] methyl} sulfanyl) -5,6-dimethyl-3-oxo-2,3-dihydro-1H -Imidazo [5, tric] [1,4] thiazine_1-ylidene] -4-methylbenzenesulfonamide

 Triethylamine (0.148 ml, 1.07 mmol) was added to a suspension of the compound obtained in Examples 18-37 (184 mg, 0.356 tmol) and hexaneyl chloride (0.060 ml, 0.427 mmol) in THF (3.7 ml) at room temperature. The reaction was stirred at room temperature for 1.5 hours. The reaction solution was extracted with ethyl acetate, dehydrated, dried and concentrated, and crystallized from ethyl acetate and getyl ether to give the title compound (176 mg, 0.304 mmol, 85.4%) as a red powder.

'H-NMR (200MHz, CDC1 3): 50.89 (3H, brt, J = 6.8 Hz), 1.31 (4H, m), 1.62 (2H, brquint, J = 6.5 Hz), 1.78 (3H, s), 2.02 (1H, di, J = 14.1, 6.0 Hz), 2.12 (1H, m), 2.20 (1H, d, J = 8.1 Hz), 2.24 (3H, s), 2.26 (1H, m), 2.42 (3H, s), 3.33 (1H, dd, J = 13.2, 7.2 Hz), 3.44 (1H, dd, J = 13.2, 2.7 Hz), 3.44 (1H, brd, J = 11 Hz), 3.52 (1H, dd, J = 11.1, 4.5 Hz), 4.47 (1H, dq, J = 3.0, 7.2 Hz), 4.53 (1H, m), 7.28 (2H, d, J = 8.1 Hz), 7.81 (2H, d, J = 8.4 Hz) ), 9.66 (1H, brs).

Elemental _{analysis: C 26 H 34 N 4 0} 5 S 3 Calculated: C, 53.96; H, 5.92 ; N, 9.68; S, 16.62 (), Found: C, 53.91; H, 5.86 ; N, 9.86 ; S, 16.40 (%).

mp. 153-159 ° C

Example 18-64

N- {6-Hydroxy-8-methyl-1_oxo-4-[(5,5,6,6,6-pentylfluorohexyl) sulfanyl] -1,2,6,7,8,9 -Hexahydro-3H-imidazo [5, 1-c] [1, 4] benzothia Zin-3-ylidene} -4-methylbenzenesulfonamide

A suspension of lithium aluminum hydride (509 mg, 10.7 mmol) in tetrahydrofuran (100 ml) was added to the suspension of N- {1,6-dioxo-8-methyl-4-[(5 , 5,6,6,6-Pentafluorohexyl) sulfanyl] -1,2,6,7,8,9-Hexahydro-3H-imidazo [5, tric] [1,4] benzothiazine A solution of 4-ylidene} -4-methylbenzenesulfonamide (4.36 g, 7.15 bandol) in tetrahydrofuran (100 ml) was added under ice-cooling. After stirring the reaction mixture at room temperature for 5 minutes, excess lithium hydride was decomposed with water, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (1.32 g, 30¾) as a dark red crystals. Recrystallization from ethyl acetate-n-hexane gave dark red crystals with a melting point of 190-192.

IR (KBr) V: 3700-2800, 3440, 3300,2953, 2930, 1750, 1732, 1655, 1617, 1557 cm " ¹ .

_{Ή-NMR (CDC1 3):} 51.06 (3HX0.80, d, J = 6.6 Hz), 1.20 (3HX0.2, d, J = 6.6Hz), 1.22-1.36 (1H, m), 1.58-1.84 (6H , m), 1.94-2.20 (2H, m), 2.38-2.50 (1H, m),

2.42 (3H, s), 2.71 (1H, dd, J = 18.3, 5.4 Hz), 3.02 (2H, dt, J = 7., 1.2 Hz),

4.14-4.25 (1H, m), 7.29 (2H, d, J = 9.0Hz), 7.84 (2HX0.8, d, J = 8.4Hz), 7.87

(2HX0.2, d, J = 8.4 Hz), 9.56 (1HX0.2, bs), 9.66 (1HX0.8, bs).

Elementary analysis: as _{C 24 H 26 N 3 0 4} S 3 F 3

Calculated (%): C, 47.13; H, 4.28; N, 6.87; S, 15.73.

Found (¾): C, 47.13; H, 4.51;, 6.69; S, 15.95.

Example 18-65

 N- {8-methyl-1-oxo-4-[(5,5,6,6,6-pentylfluorohexyl) sulfanyl] -1,2-dihydro-3H-imidazo [5, tric ] [1,4] Benzothiazine-3-ylidene} -4-methylbenzenesulfonamide

N- {6-hydroxy-8-methyl-1-oxo-4-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] obtained in Examples 18-64-1,2 6,7,8,9_Hexahydro-3H-imidazo [5, tric] [1,4] benzothiazine-3-ylidene} -4-methylbenzenesulfonamide (l.OOg, 1.63 t) (10.0 ml) and acetic anhydride (0.463 ml, 4.90 fraction 01) Then, p-toluenesulfonic acid monohydrate (262 mg, 1.31 ol) was added, and the mixture was heated and stirred with lOOt: for 10 minutes. The reaction mixture was concentrated, the residue was diluted with acetic acid Echiru, washed with water, after Drying (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (175 mg, 18%) and the obtained as dark red crystals . Recrystallization from ethyl acetate gave orange crystals with a melting point of 203-205 ° C.

IR (KBr): 3200, 3050, 2932, 1728, 1626, 1597, 1557, 1493 cm " ¹ .

_{Ή- NMR (CDC1 3): (} 51.66-1.88 (4H, m), 1.98-2.16 (2H, m), 2.31 (3H, s), 2.42

(3H, s), 3.03 (2H, i, J = 7.2 Hz), 6.83 (1H, d, J = 8.1 Hz), 6.90 (1H, dd, J-8.7,

0.6 Hz), 7.30 (2H, d, J = 8.1 Hz), 7.86 (2H, d, J = 8.4 Hz), 8.30 (1H, d, J = 0.6

Hz), 9.75 (1H, bs).

Elemental analysis: as C ₂₄ H ₂₂ N ₃ 0 ₃ S ₃ F ₅

Calculated value (¾): C, 48.72; H, 3.75; N, 7.10; S, 16.26.

Found (%): C, 48.58; H, 3.72; N, 7.12; S, 16.32.

Example 18-66

Acetic acid (i, 4-cis-4-([(5,6-Dimethyl-1 _ {[(4-methylphenyl) sulfonyl] imino)} _ 3-oxo-2,3-dihydrido-1H-imidazo [5 , 1-c] [1,4] thiazine-8-yl) sulfenyl] methyl} cyclohexylmethyl) methyl

 A solution of the crude compound (0.62 g, 0.70 ol) obtained in Example 4-573 and acetic anhydride (2 ml) in pyridine (4 ml) was stirred at room temperature for 16 hours. The reaction solution was concentrated to dryness; dissolved in ethyl acetate (35 ml), washed with 0.1N hydrochloric acid, water and saturated saline, dried over sodium sulfate, and concentrated to obtain a crude oil. This was subjected to chromatography on silica gel (10 g) (ethyl acetate-hexane, 2: 8-4: 6), and the red fraction was concentrated and then diluted with ethyl acetate and methanol. The precipitate was collected by filtration, washed with methanol, and dried to give the title compound (86 mg, 0.156 mol, 22.3) as a red powder.

_{^ -NMR (300MHz, CDC1 3)} : 51.42 (4H, m), 1.54 (2H, m), 1.62 (2H, m), 1.79 (3H, q, J = 1.2 Hz), 1.85 (2H, m), 2.07 (3H, s), 2.26 (3H, q, J- 0.9 Hz), 2.41 (3H, s), 2.89 (2H, d, J = 7.5 Hz), 3.98 (2H, d, J = 6.9 Hz), 7.27 (2H, d, J = 8.1 Hz), 7.84 (2H, d, J = 8.1 Hz), 9.61 (1H, brs) '.

Elemental _{analysis: C 25 H 31 N 3 0} 5 S 3 Calculated: C, 54.62; H, 5.68 ; N, 7.64; S, 17.50 (%), Found: C, 54.74; H, 5.67; N, 7.73; S, 17.36 (%). Examples 18-67

Methanesulfonic acid (4-{[(5,6-dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oki) -3-oxo V-2,3-dihydro-1H-imidazo [5, 1-c] [1,4] thiazin-8-yl) sul The compound obtained in Example 4-573 (660 mg, 1.30 fraction 1, cis / t fraction: 92: 8 mixture) and methanesulfonyl chloride (0.112 Triethylamine (0.216 ml, 1.56 mL) was added to a THF (13 ml) solution of 0.1 ml, 1.43 bandol) at 0 ° C with stirring, and the reaction solution was stirred at 0 ° C or 10 ° C for 2 hours. The reaction solution was diluted with ethyl acetate (45 m), washed with 0.1 N hydrochloric acid, water and saturated saline, dried over sodium sulfate, and concentrated to obtain a red oily substance. after washing the precipitate was濾琅by Jeffrey chill ether, dried to give the title compound (355 mg, 0.606 negation ol, 46.6%) was obtained as a red-brown powder 'H-NMR (300MHz, CDC1 3):. 51.46 (4H, m), 1.63 (4H, m), 1.79 (3H, s), 1.83 (1H, m), 1.96 (1H, m), 2.26 (3H, s), 2.42 (3H, s), 2.90 (2H, d, J = 7.2 Hz), 3.02 (3H, s), 4.13 (2H , d, J = 7.2 Hz), 7.27 (2H, d, J = 8.4 Hz), 7.83 (2H, d, J = 8.4 Hz), 9.62 (1H, brs).

Melting point: 177.5-178.5 ° C

Example 18-68

Acetic acid (l, 4_trans-4-{[(5,6_dimethyltolu [[(4-methylphenyl) sulfonyl] imino} _3_oxo_2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazin-8-yl) sulfanyl] methyl} cyclohexylmethyl) methyl

 A solution of the compound obtained in Example 4-574 (220 mg, 0.433 mol) and acetic anhydride (0.6 ml) in pyridine (2 ml) was stirred at room temperature for 2.5 days. The reaction was concentrated to dryness and diluted with methanol. The precipitate was collected by filtration, washed with methanol, and dried to give the title compound (207 mg, 0.376 ol, 87.0 »as a red-purple powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 1.00 (4Η, brquint, J = 10.2 Hz), 1.59 (2H, m), 1.79 (3H, s), 1.83 (2H, m), 1.93 (2H, brd, J = 7.4 Hz), 2.07 (3H, s), 2.27 (3H, s), 2.42 (3H, s), 2.83 (2H, d, J = 6.8 Hz), 3.90 (2H, d, J = 6.2 Hz) , 7.28 (2H, d, J = 8.4 Hz), 7.86 (2H, d, J = 8.4 Hz), 9.65 (1H, brs). Elemental _{analysis: C 25 H 31 N 3 0} 5 S 3 Calculated: C, 54.62; H, 5.68 ; N, 7.64; S, 17.50

(%), Found: C, 54.46; H, 5.54; N, 7.50; S, 17.28 (%).

Melting point: 183.5-184.0 ° C

Example 18-69

N- [8-({[4- (Fluoromethyl) cyclohexyl] methyl} sulfanyl) -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [ 1,4] thiazine-1-ylidene] -4-methylbenzenesulfonamide

 Crude compound obtained in Examples 18-67 (purity 80%, 270 mg, 0.370 bandages, 1, cis / trans = 92: 8 mixture), tetrabutylammonium fluoride (TBAF, 300 mg, 0.926 holol) ) And water (0.025 ml, 1.39 tmol) in acetonitrile (0.5 ml) were stirred at 80 ° C for 3 hours. TBAF (300 mg, 0.926 finol) was added to the reaction mixture, and the mixture was further stirred for 8 hours (3.5 hours at T.) The reaction mixture was concentrated and extracted with ethyl acetate (80 ml). After washing with water and saturated saline, drying over sodium sulfate and concentration to dryness gave a dark purple oil which was chromatographed on silica gel (10 g) (ethyl acetate monohexane, 2: 8- 4: 6) and crystallized from methanol to give the title compound (cis / trans = 4: 1, 72 mg, 0.141 ol, 38.2%) as a grey-purple powder.

_{Ή-NMR (300MHz, CDC1 3} , major cis-isomer): δ 1.46 (4Η, m), 1.59 (4Η, m), 1.79 (3Η, q, J = 0.9 Hz), 1.84 (1H, m), 1.93 (1H, m), 2.26 (3H, q, J = 1.2 Hz), 2.41 (3H, s), 2.91 (2H, d, J = 7.5 Hz), 4.33 (2H, dd, J = 47.4, 6.6 Hz) , 7.27 (2H, d, J = 8.4 Hz), 7.84 (2H, dt, J = 8.4, 2.0 Hz), 9.61 (1H, brs).

Elemental _{analysis: C 23 H 28 N 3 0} 3 S 3 F Calculated: C, 54.20; H, 5.54 ; N, 8.24; S, 18.87; F, 3.73 (%), Found: C, 54.50; H , 5.47; N, 8.13; S, 18.83; F, 3.54 (%). Melting point: 186.0-187.5 ° C

Example 18-70

N- {8-[(5-Hydroxy-2,2-dimethylpentyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c ] [1, 4] thiazine-triylidene} -4-methylbenzenesulfonamide

To a suspension of the compound obtained in Example 4-575 (418 mg, 0.681 mmol) in THF-methanol (1: 1, 6 ml) was added an aqueous solution of sodium hydroxide IN (3.4 ml, 3.4 mol) at room temperature. , 3 hours Stirred. IN hydrochloric acid (3.4 ml) was added to the reaction solution, and the mixture was stirred for 30 minutes. The precipitate was collected by filtration, washed with methanol-one water (1: 1) and methanol, and dried to give the title compound (275 mg, 0.555 mL, 81.5%) as a purple powder.

'H-NMR (200MHz, CDC1 3): δ 1.01 (6Η, s), 1.38 (2H, m), 1.41 (1H, br), 1.52 (2H, m), 1.79 (3H, q, J = 1.2 Hz ), 2.26 (3H, q, J = 1.2 Hz), 2.41 (3H, s), 2.90 (2H, s), 3.63 (2H, t, J = 6.2 Hz), 7.28 (2H, d, J = 8.4 Hz) ), 7.87 (2H, d, J = 8.4 Hz), 9.60 (1H, brs).

Elemental _{analysis: C 22 H 29 N 3 0} 4 Calculated _{S 3: C, 53.31; H} , 5.90;, 8.48; S, 19.41 (%), Found: C, 53.43; H, 5.91 ; N, 8.22 S, 19.13 (%).

Melting point: 159.0-159.5 ° C

Examples 18-71

 N- {6-[(5,6-Dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydrido-1H-imidazo [5,1-c] [1 , 4] Thiazine-8-yl) sulfanyl] hexyl} hexaneamide

 The fraction of ethyl acetate (4: 6) was concentrated to dryness by silica gel chromatography in Example 18-8 and crystallized from getyl ether to give the title compound (149 mg, 0.257 mol) as a red powder.

_{¾-NMR (300MHz, CDC1 3} ): (50.89 (3H, t, J = 6.9 Hz), 1.31 (4H, m), 1.43 (4H, m), 1.45 (2H, m), 1.51 (2H, quint, J = 7.4 Hz), 1.63 (2H, quint, J = 7.1 Hz), 1.79 (3H, q, J = 0.9 Hz), 2.16 (2H, t, J = 7.5 Hz), 2.26 (3H, s), 2.42 (3H, s), 2.93 (2H, t, J = 7.4 Hz), 3.25 (2H, q, J-6.7 Hz), 5.49 (1H, m), 7.29 (2H, d, J = 8.7 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.64 (1H, brs).

Elemental _{analysis: C 27 H 38 N 4 0} 4 S 3 O.3H 2 0 Calculated: C, 55.51; H, 6.66 ;, 9.59; S, 16.47 (%), Found: C, 55.49; H, 6.59; N, 9.52; S, 16.49 (%).

mp.121.0-122.0 ° C

Examples 18-72

tert-butyl 5-[(5,6-dimethyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [ 1,4] thiazine-8-yl) sulfanyl] pentanoate 5-[(5,6-Dimethyl-1-{[(4-methylphenyl) sulfonyl] iminoto 3_oxo-2,3-dihydro-1H-imidazo [5, 1-c] [1,4] Thiazin-8-yl) sulfanyl] valeric acid (560 mg, 1.16 ol) and triethylamine (0.162 ml, 1.16 ol) in tetrahydrofuran (2.00 ml) , 4,6-Triclo benzoyl chloride (0.187 ml, 1.16 marl ol) was added. After stirring the reaction mixture at room temperature for 3 hours, triethylamine hydrochloride was removed by filtration. The filtrate was concentrated, and a solution of the residue in toluene (3.00 ml) was added to a solution of tert-butanol (174 mg, 2.33 mol) and 4-dimethylaminopyridine (287 mg, 2.33 ml) in toluene (2.00 ml). ) Solution was added. After stirring the reaction mixture at room temperature for 16 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (190 mg, 30¾) as dark red crystals. Recrystallization from ethyl acetate-jetil ether gave dark red crystals with a melting point of 124-126 ° C.

IR (KBr): 3220, 2980, 2934, 1726, 1661, 1620, 1563 cm— ¹ .

_{Ή-NMR (CDC1 3):} (51.45 (9H, s), 1.64-1.76 (4H, m), 1.78 (3H, s), 2.20-2.30 (2H, m), 2. 6 (3H, s), 2.42 (3H, s), 2.89-2.98 (2H, ni), 7.29 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.4 Hz), 9.61 (1H, bs).

Elemental analysis: as C ₂₄ H ₃₁ N ₃ 0 ₅ S ₃

Calculated value (%): C, 53.61; H, 5.81;, 7.81; S, 17.89.

Found (%): C, 53.33; H, 5.55; N, 7.86; S, 17.77.

Example 18-73

 8- (isopentylsulfanyl) -1-{[(4-methylphenyl) sulfonyl] iminoto 3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine- 5-carboxylic acid

In a suspension of the compound obtained in Example 4-416 (169 mg, 0.341 mol) in THF-methanol (1: 1, 2.0 ml) was added 1N sodium hydroxide (1.02 ml, 1.02 ml) while stirring at room temperature. ) Was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction mixture was added with 0.1 N hydrochloric acid (20 ml) and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over sodium sulfate, and concentrated. The residue was mixed with diethyl ether, and the precipitate was collected by filtration, washed with diethyl ether, and dried to give the title compound (131 mg, 0.281 讓) as a red powder. Obtained.

One _{NMR (200MHz, CDC1 3 - DMSO-} d 19: 1): δ 0.91 (6H, d, J = 6.2 Hz), 1.56 (2H, brquint, J = 7.4 Hz), 1.65 (1H, sixtet, J = 6.6 Hz), 2.43 (3H, s), 2.95 (2H, t, J- 7.7 Hz), 6.02 (1H, s), 7.30 (2H, d, J = 8.4 Hz), 7.85 (2H, d, J = 8.4 Hz) Hz), 10.01 (1H, br).

Elemental _{analysis: C 19 H 21 N 3 0} 5 S 3 Calculated: C, 48.80; H, 4.53 ; N, 8.99; S, 20.57

(%), Found: C, 48.87; H, 4.57; N, 8.77; S, 20.32 (%).

Melting point. 211- 216 ° C

Example 18-74

8- (Isopentylsulfanyl) -1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine- 5-forceluxamide A solution of the compound obtained in Example 18-73 (201 mg, 0.430 ol), H0BT (70 mg, 0.516 fraction 1) and WSC (99 mg, 0.519 ol) in a THF (4.0 ml) solution was added to the solution. Aqueous ammonia (0.049 ml, 0.645 mmol) was added at room temperature. The mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate, washed with a 2% aqueous sodium hydrogen carbonate solution, diluted hydrochloric acid, water and saturated saline, dried over sodium sulfate, and concentrated. A powder (173 mg) obtained by crystallizing the residue from geethylether was recrystallized from methanol to give the title compound (84 mg, 0.180 mol) as a red powder. ,.

_{¾-NMR (200MHz, CDC1 3} _DMS0- d 6 = 9: 1): δ 0.92 (6Η, d, J = 6.2 Hz), 1.56 (2H, brquint, J = 7.6 Hz), 1.65 (1H, sixtet, J = 7 Hz), 2.43 (3H, s), 2.95 (2H, t, J = 7.5 Hz), 5.75 (1H, s), 6.33 (2H, m), 7.30 (2H, d, J = 8.0 Hz), 7.85 (2H, d, J = 8.4 Hz), 10.30 (1H, br).

Elemental analysis: Calculated as _{C 19 H 22 N 4 0 4} S 3: C, 48.91; H, 4.75;, 12.01 (%), actual Hakachi: C, 49.02; H, 4.51 ; N, 12.34 (%) .

Melting point. 197.5-204.0

Example 18-75

N-ethyl-8- (isopentylsulfanyl) -1-{[(4-methylphenyl) sulfonyl] imino} -3_oxo-2,3_dihydro-1H-imidazo [5,1-c] [ 1, 4] thiazine-5-carboxamide A 70% aqueous solution of getylamine (0.052) was added to a solution of the compound obtained in Example 18-73 (248 mg, 0.530 ol), H0BT (86 mg, 0.636 mmol) and WSC (122 mg, 0.636 mmol) in THF (5.0 ml). ml, 0.636 mmol) at room temperature. The mixture was stirred at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate, washed with a 2% aqueous sodium hydrogen carbonate solution, diluted hydrochloric acid, water and saturated saline, dried over sodium sulfate, and concentrated. The residue was crystallized from getyl ether to give the title compound (182 mg, 0.368 ol) as a red powder.

_{Ή-NMR (200MHz, CDC1 3} ): δ 0.92 (6Η, d, J = 6.6 Hz), 1.18 (3H, t, J = 7.2 Hz), 1.53 (2H, brq, J = 7.2 Hz), 1.67 (1H , sixtet, J = 6.6 Hz), 2.43 (3H, s), 2.95 (2H, brt, J = 7.7 Hz), 3.35 (2H, brquint, J = 7.2 Hz), 5.56 (1H, s), 6.57 (1H , brt, J = 4.8 Hz), 7.30 (2H, d, J = 8.0 Hz), 7.84 (2H, d, J = 8.0 Hz), 9.70 (1H, brs).

Elemental analysis: Calculated for C ₂₁ H ₂₆ N ₄ 0 ₄ S ₃ : C, 50.99; H, 5.30; N, 11.33; S, 19.45

(%), Found: C, 50.90; H, 5.52; N, 11.12; S, 19.24 (). 'Melting point. 222.5-225.0 ° C

Example 18-76

 N- [5- (Hydroxymethyl) -8- (isopentylsulfanyl) -6-methyl-3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine- 1-ylidene] -4-methylbenzensulfonamide

To a solution of the compound obtained in Example 4-462 (300 mg, 0.623 t ol) and thionyl chloride (0.052 ml, 0.685 dandelion oi) in chloroform (5 ml) was added chloroform (0.060 ml, 0.747 rol) in chloroform. (1 ml) solution was added dropwise at 0 over 3 minutes and the mixture was stirred for 3 hours. During this time, thionyl chloride (0.019 ml, 0.249 ol) and pyridine (0.020 ml, 0.249 ol) were added to the reaction solution. The reaction solution was returned to room temperature over 1 hour and stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate (38 ml) and hexane (12 ml), washed with 2% sodium hydrogen carbonate, water and saturated saline, dried over sodium sulfate, and concentrated. The acid chloride of the compound obtained in 462 (233 mg, 0.466 t) was obtained as a dark red solid. _{Ή-NMR (200MHz, CDC1 3} ): δ 0.93 (6Η, d, J = 6.6 Hz), 1.56 (2H, brq, J = 7.1 Hz), 1.68 (1H, quint, J = 6.6 Hz), 2.00 (3H _{? s), 2.43 (3H,} s), 2.98 (2H, brt, J = 7.7 Hz), 7.31 (2H, d, J = 8.0 Hz), 7.45 (1H, brt, J- 5.9 Hz), 7.86 (2H , d, J = 8.4 Hz), 8.68 (1H, br).

 To a solution of this dark red solid (230 mg, 0.460 mmol) in THF (5 ml) was added sodium borohydride (19.3 mg, 0.460 mmol) at room temperature, and the mixture was stirred for 1 hour. 0.1 hydrochloric acid (10 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 2% aqueous sodium hydrogen carbonate solution, water and saturated saline, dried over sodium sulfate, and concentrated. The residual solid was crystallized from getyl ether to give the title compound (32 mg, 0.068 ol) as a red powder.

Dang _{R (200MHz, CDC1 3):} δ 0.93 (6Η, d, J = 6.2 Hz), 1.56 (2H, brq, J = 7.3 Hz), 1.69 (m, quint, J = 6.4 Hz), 1.91 (3H, s), 2.42 (3H, s), 2.95 (2H, t, J = 7.7 Hz), 3.97 (1H, m), 4.43 (2H, brd, J = 5.8 Hz), 7.29 (2H, d, J = 8.4) Hz), 7.85 (2H, d, J = 8.4 Hz), 9.86 (1H, br).

Elemental analysis: C _{2. H 25 N 3 0 4 S 3} · 1 / 3H 2 0 Calculated: C, 50.72; 'H, 5.46; N, 8.87; S, 20.31 (%), Found: C, 50.73; H, 5.62 ; N , 8.77; S, 20.08 (%).

Melting point. 184-188. C

Examples 18-77

 N-Ethyl-8- (isopentylsulfanyl) -6-methyl-1-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydric mouth-1H-imidazo [5 , 1-c] [1,4] thiazine-5-potrolupoxamide

 A 70% aqueous getylamine solution (0.099 ml, 70%) was added to a solution of the compound obtained in Example 4-462 (585 mg;), H0BT (164 mg, 1.22 ol) and WSC (233 mg, 1.22 t) in THF (11.5 ml). 1.22 Maraudal ol) was added at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction solution was treated in the same manner as in Examples 18-75, and crystallized from getyl ether to give the title compound (29 mg, 0.057 mmol) as a red powder.

¾ one _{NMR (200MHz, CDC1 3):} δ 0.93 (6Η, d, J = 6.6 Hz), 1.23 (3H, t, J = 7.1 Hz), 1.56 (2H, brq, J = 6.2 Hz), 1.65 (1H , septet, J = 6.6 Hz), 1.89 (3H, s), 2.43 (3H, s), 2.96 (2H, brt, J = 7.7 Hz), 3.43 (2H, dq, J = 5.8, 7.2 Hz), 5.99 (1H, brt, J = 5.8 Hz), 7.29 (2H, d, J = 8.2 Hz), 7.82 (2H, d, J = 8.2 Hz), 9.71 (1H, brs).

Melting point.190.0-197.0 ° C Example 18-78

N- [5- (1-hydroxypropyl) -8- (isopentylsulfanyl) -6-methyl-3-oxo-2,3-dihydrido-1H-imidazo [5,1-c] [1,] Thiazine-1-ylidene] -4-methylbenzenesulfonamide. (Method 1) The compound obtained in Example 4-469 (1.03 g, 2.08 pt) and cerium chloride heptahydrate (514 mg, 2.08 pt) To a suspension of THF (20 ml) was added sodium borohydride (438 mg, 10.4 mol) at room temperature. To the mixture was added dropwise a solution of methanol (1.0 ml) in THF (5 ml) over 2.5 hours, and the mixture was stirred for 1.5 hours. 1N Hydrochloric acid (13.4 ml) and water (30 ml) were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.1N hydrochloric acid, water and saturated saline, dried over sodium sulfate and concentrated.The residue obtained was crystallized from getyl ether to give the title compound (590 mg, 1.19 mmol) as a red-orange powder. Was. ¾ one _{NMR (200MHz, CDC1 3):} δ 0.93 (6Η, d, J = 6.2 Hz), 0.95 (3H, t, J = 7 Hz), 1.55 (2H, brq, J = 6.4 Hz), 1.65 (1H , m), 1.82 (2H, m), 1.95 (3H, s), 2.43 (3H, s), 2.96 (2H, brt, J = 7.7 Hz), 4.58 (1H, dt, J = 11.8, 7.6 Hz) , 5.28 (1H, d, J = 12.2 Hz), 7.30 (2H, d, J = 8.4 Hz), 7.86 (2H, d, J = 8.4 Hz), 9.84 (1H, brs) elemental analysis:. C _{22 9} N ₃ 0 ₄ S ₃ calculated: C, 53.31; H, 5.90 ; N, 8.48 (%), Found: C, 53.34; H, 5.91 ; N, 8.41 (%).

mp. 170.0-171.5:

 (Method 2) To a solution of the compound obtained in Example 4-469 (216 mg, 0.438 mol) in THF (4.3 ml) was added sodium borohydride (19.3 mg, 0.60 mmol) at room temperature. Stirred for hours. A solution of methanol (0.19 ml) in THF (1.0 ml) was added dropwise to the reaction solution, and sodium borohydride (10 mg, 0.24 mmol) was added three times every hour at room temperature, and the mixture was stirred for 15 hours. 1N Hydrochloric acid (10 ml) was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with 0.1N hydrochloric acid, water and saturated saline, dried over sodium sulfate, and concentrated. The residue was chromatographed on silica gel (10 g) (ethyl acetate-hexane, 2: 8-4: 6), and the ethyl acetate-hexane (3: 7) fraction was crystallized from ethyl acetate to give the title. The compound (20 mg, 0.040 t) was obtained as a red-orange powder.

Examples 18-79

N- [8- (Isopentylsulfanyl) -6-methyl-3-oxo + propyl-2,3-dihydride Mouth-1H-imidazo [5, 1-c] [1,4] thiazine-triylidene] -4-methylbenzenesulfon amide

 To a solution of the compound obtained in Examples 18-78 (146 mg, 0.295 nimol) in chloroform (1.0 ml) was added TFA (0.5 ml) with stirring at room temperature, and then triethylsilane (42 nig, 0.354 ol). ) Was added and the reaction solution was stirred at room temperature for 15 hours. The reaction solution was added with toluene (10 ml), concentrated, diluted with ethyl acetate, washed with water and saturated saline, dried over sodium sulfate, and concentrated. The residue was purified by chromatography on silica gel (5 g) (ethyl acetate-hexane, 2: 8-5: 5), and the red fraction of ethyl acetate-hexane (2: 8) was crystallized from getyl ether. The title compound (3.8 mg, 0.008 alcohol) was obtained as a dark red powder.

_{ΐ-NMR (200MHz, CDC1 3} ): <5 0.93 (6H, d, J = 6.2 Hz), 0.94 (3H, t, J = 7.0 Hz), 1.48 (2H, q, J = 7.7 Hz), 1.60 ( 1H, m), 1.70 (2H, m), 1.82 (3H, s), 2.42 (3H, s), 2.74 (2H, brt, J = 7.7 Hz), 2.94 (2H, t, J = 7.7 Hz), 7.28 (2H, d, J = 8.0 Hz), 7.86 (2H, d, J = 8.0 Hz), 9.60 (1H, brs).

Example 18-80

 0- [l- (8- (Isopentylsulfanyl) -6-methyl-l-{[(4-methylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo [ 5,1-c] [1,4] Thiazine-5-yl) propyl] 1H-imidazole-1-carpothioate

 A solution of the compound obtained in Examples 18-78 (228 mg, 0.460 mmol) and 1, Γ-thiocarbonyl diimidazole (109 mg, 0.552 mol) in toluene (10 ml) was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate, washed with 0.1N hydrochloric acid, water, sodium bicarbonate, and saturated saline, dried over sodium sulfate, and concentrated. The residue was purified by chromatography on silica gel (10 g) (ethyl acetate-hexane, 1: 9-5: 5), and the red fraction of ethyl acetate-hexane (4: 6) was crystallized from getyl ether. To give the title compound (28 mg, 0.046 mmol) as a red-orange powder.

賺_{(200MHz, CDC1 3): δ} 0.93 (6H, d, J = 6.2 Hz), 1.07 (3H, t, J = 7.3 Hz), 1.55 (2H, brq, J- 7.4 Hz), 1.61 (1H, m )> 2.08 (2H, s), 2.08 (2H, m), 2.42 (3H, s), 2.95 (2H, t, J = 7.7 Hz), 5.17 (1H, m), 7.10 (1H, brs), 7.29 (2H, d, J = 8.4 Hz), 7.49 (1H, brs), 7.86 (2H, d, J = 8.4 Hz), 8.23 (1H, brs), 9.83 (1H, brs)

Elemental _{analysis: C 26 H 31 N 5 0} 4 S 4 · 0.3EtOAc Calculated: C, 51.67; H, 5.32 ; N, 11.07; S, 20. 8 (%), Found: C, 52.04; H , 5.33; N, 11.11; S, 20.21 (%) mp.171.0-172.0 ° C

Example 19

 5-[(E) -Holepoxymethylidene] -buta [[(4-methylphenyl) sulfonyl] iminoto 3-oxo- 8-[(5,5,6,6,6-penoxyfluorhexyl ) Sulfanyl] -2,3,5,6-tetrahydro-1H-imidazo [5, tric] [1,4] thiazine-6-carboxylic acid

 5,5,6 Iodide was added to a suspension of the crude compound obtained in Examples 3-40 (0.74 g, 1.28 ol) and carbonated lime (0.30 g, 2.17 dl) in DMF (10 ml). Hexyl (0.44 g, 1.44 mmol) was added dropwise at 60 ° C. and stirred for 1.5 hours. 1N Hydrochloric acid (3.2 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 ml). The obtained organic layer was washed with a 7% and 15% saline solution adjusted to be acidic, then with a saturated saline solution, dried over sodium sulfate, and concentrated to dryness. The residue was chromatographed on silica gel (10 g) (ethyl acetate-hexane, 3: 7), and the orange fraction was concentrated to dryness to give a red oil (0.68 g). This was dissolved in methanol (8 ml) and THF (3 ml), 1N sodium hydroxide (8 ml) was added while stirring at room temperature, and the reaction solution was stirred for 30 minutes. 1N Hydrochloric acid (10 ml) was added to the reaction solution, extracted with ethyl acetate (40 ml), and purified to obtain a crude organism (375 mg). This was dissolved in methanol (8 ml) and 1N sodium hydroxide (8 ml) and stirred at room temperature for 3 hours. 1N Hydrochloric acid (9 ml) was added to the reaction solution, and the mixture was stirred for 30 minutes. The precipitate was collected by filtration, washed with methanol-water (1: 1), and dried to give the title compound (311 mg, 0.494 mmol, 38.6%) as a grey-orange powder.

'H-NMR (200MHz, CDC1,-DMS0-d ₆ = 2: 1, mixture of endo / exo isomers): δ 1.72 (4Η, m), 2.19 (2H, m), 2.36 (3H, s), 2.98 / 3.06 (2H, t, J = 6.9 / 7.1 Hz), 6.53 (1H, s), 6.58 (1H, s), 7.33 (2H, d, J = 8.1 Hz), 7.90 (2H, d, J = 8.4 Hz), ca.12.0 (1H, br).

Elemental analysis: calculated as C ₂₂ H ₂₀ N ₃ 0 ₇ S ₃ F ₅計算 0: C, 40.80; H, 3.42; N, 6.49; S, 14.85; F, 14.67 (%), found: C, 40.69; H, 3.20; N, 6.41; S, 14.85; F, 14.76

(%).

Example 20

 N- {5-Hydroxy-5,6-dimethyl-3-oxo-8-[(5,5,6,6,6-pentylfluorohexyl) sulfanyl] _2,3,5,6-tetrahydro -1H-imidazo [5, tric] [1, 4] thiazine-1_ ylidene} -4-methylbenzenesulfonamide

実施例 4-35で得られた N - {5, 6 -ジメチル -3-ォキソ -8 - [(5， 5, 6， 6, 6-ペン夕フル ォ口へキシル）スルファニル ]-2, 3 -ジヒドロ- 1H-イミダゾ [5，卜 c] [1,4]チアジン -卜イリデン }- 4-メチルベンゼンスルホンアミド （600 mg, 1.08 mmol) と濃塩酸 (0.200 ml) のエタノール （10.0 ml) 懸濁液を 100 で 3時間かき混ぜた。 反応 混合物を室温まで冷やした後、 酢酸ェチルで希釈し、 水洗、 乾燥 （MgS0₄) 後、 溶 媒を減圧下に留去した。 残留物をシリカゲルカラムクロマトグラフィーに付し、 n -へキサン -酢酸ェチル （10:1， v/v) で溶出して題記化合物 （83.3 mg, 13¾) を 暗赤色結晶として得た。

N- {5,6-Dimethyl-3-oxo-8-[(5,5,6,6,6-pentylfluorohexyl) sulfanyl] -2,3 obtained in Example 4-35 -Dihydro-1H-imidazo [5, tric] [1,4] thiazine-triylidene} -4-Hydrogenbenzenesulfonamide (600 mg, 1.08 mmol) and concentrated hydrochloric acid (0.200 ml) suspended in ethanol (10.0 ml) The suspension was stirred with 100 for 3 hours. After cooling the reaction mixture to room temperature, diluted with acetic acid Echiru, washed with water, dried (MgSO _4), followed by distilling off the solvent medium under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (83.3 mg, 13¾) as dark red crystals.

IR (KBr) v: 3600-2800, 2944, 1732, 1622, 1557 cm- ¹ .

_{Ή-NR (CDC1 3):} 51.42 (3H, d, J = 7.0 Hz), 1.71 (3H, s), 1.60-1.86 (4H, m), 1.90-2.20 (2H, m), 2.42 (3H, s ), 3.01 (2H, t, J = 7.0 Hz), 3.42 (2H, q, J = 7.0 Hz), 5.50 (1H, s), 7.30 (2H, d, J = 8.4 Hz), 7.87 (2H, d , J = 8.4 Hz), 9.61 (1H, bs). Elementary analysis: as _{C 21 H 24 N 3 0 4} S 3 F 5

Calculated value (¾): C, 43.97; H, 4.22; N, 7.33; S, 16.77.

Found (¾): C, 44.00; H, 4.34; N, 7.47; S, 16.72.

Example 21-1

3-({[5,6-Dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1 -Ylidene] amino} sulfonyl) -N-hexylbenzamide

The 3-({[5,6-dimethyl-8- (isopentylsulfanyl) -3-oxo-2,3-dihydrido-1H-imidazo [5,1--) obtained in Example 7-80 c] 1,, Ν-dimethylformamide (6.00 ml) of [1,4] thiazine-1-ylidene] amino} sulfonyl) benzoic acid (150 mg, 0.311 mol) and trihexylamine (0.0454 ml, 0, 343 mmol) To the solution was added getyl cyanophosphate (0.554 ml, 0.343 mmol), followed by triethylamine (0.0478 ml, 0.343 mmol). After stirring the reaction mixture at room temperature for 19.5 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), and the solvent was evaporated under reduced pressure to synthesize the title compound (18. lmg, 10%). Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 181-183 ° C.

IR (KBr) V:. 3272 , 2955, 2930, 2868, 1732, 1715, 1661, 1615, 1605, 1545 cm- 1 Ή-NMR (CDC1 3): (5, 0.844 (3H, t, J = 7.2Hz ), 0.993 (6H, d, J = 6.6Hz), 1.14-1.34 (6H, m), 1.38-1.52 (2H, in), 1.68-1.90 (3H, m), 1.85 (3H, s), 2.37 ( 3H, s), 2.95 (2H, q.J = 7.2 Hz), 3.09 (2H, t, J = 8.4 Hz), 4.34 (1H, bs), 7.60 (1H, t, J = 8.1 Hz), 7.99 ( 1H, dt, J = 7.5, 3.3 Hz), 8.47 (1H, dt, J = 6.3, 0.6 Hz), 8.93 (1H, t, J = 1.5 Hz), 11.07 · (1H, bs).

Elemental analysis: as C ₂₆ H ₃₆ N ₄ 0 ₄ S ₃

Calculated value (¾): C, 55.29; H, 6.42; N, 9.92; S, 17.06.

Found (%): C, 55.15; H, 6.19; N, 9.76; S, 16.99.

The following is a list of compounds synthesized in Example 21-1 and compounds synthesized in the same manner. (Table 1 1 3)

Replacement form (rules) (Table 1 14)

Bun hairstyle paper OT ^{1 6} ' (Table 1 15)

# IS Britain («26) The following shows the results of the compounds synthesized in Examples 21_2 to 21-25.

Example 21-2

 4-[({5,6-dimethyl-3-oxo-8-[(5,5,6,6,6-pentylfluorohexyl) sulfanyl] -l, 3-dihydro-1H-imidazo [ 5, 1-c] [1,] thiazine-tolylidene} amino) sulfonyl] benzamide

4-cyano-N- [5,6_dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfael] -2, obtained in Example 7-8 3-Dihydrid-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene] benzenesulfonamide (515 nig, 1.63 mmol) is dissolved in concentrated sulfuric acid (1.50 ml) and left at room temperature for 5.5 hours. Stirred. The reaction mixture was added to ice water and extracted with ethyl acetate. The extract was washed with water, dried (MgSO ₄₎ after, to obtain a solvent the title compound was evaporated under pressure (12.5 mg, 8.1%) as a dark red crystals. The crystals were recrystallized from ethyl acetate-diethyl ether to obtain reddish crystals having a melting point of 206-208 ° C.

IR (KBr) V: 3428, 3160, 1736, 1682, 1665, 1613, 1557 cm " ¹ .

_{NMR (CDC1 3): δ 1.68-1.84} (4Η, m), 1.80 (3H, s), 1.92-2.22 (2H, m), 2.28 (3H, s), 2.98 (2H, t, J = 7.0 Hz) , 7.91 (2H, d, J = 8.4 Hz), 8.05 (2H, d, J-8. Hz), 9.65 (1H, bs).

Example 21-3

 4-amino-N- {5,6-dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -2,3-dihydro-1H-imidazo [5 , 1-c] [1,4] thiazine-1-ylidene} benzenesulfonamide

 (Method 1) A suspension of the compound (219 mg, 0.329 mmol) obtained in Example 7-86 in dioxane / aqueous solution (9: 1, 7 ml) was added in the presence of tosylate hydrate (75 mg, 0.39511111101) for 5.5 min. The mixture was heated under reflux for an hour. After extraction with ethyl acetate, washing with water, drying and concentration, the mixture was diluted with getyl ether. The precipitate was collected by filtration, washed with getyl ether, and dried to give the title compound (37 mg, 0.066 ol) as a red powder.

 — Band R (200MHz, CDCI3): δΐ.75 (4Η, m), 1.78 (3H, brs), 2.04 (2H, m), 2.26 (3H, brs), 2.97 (2H, q, J = 8.2 Hz) , 4.10 (2H, brs), 6.66 (2H, d, J = 8.8 Hz), 7.72 (2H, d, J = 8.8 Hz), 9.60 (1H, br).

Elemental analysis: C _2. Calculated for H ₂₁ N ₄ 0 ₃ S ₃ F ₅ : C, 43.16; H, 3.80; N, 10.07; S, 17.28 (%), Found: C, 42.88; H, 3.55;, 9.94; S, 17.44 (%) .mp. 172.5-176.5 ° C

(Method 2) A solution of the compound obtained in Example 7-86 (3.36 g, 5.61 mmol) and p-toluenesulfonic acid hydrate (1.28 g, 6.73 删 01) in dioxane-water (9: 1, 70 ml) Was stirred at 80 for 4.5 hours. The reaction mixture was concentrated to dryness, diluted with ethanol (80 ml), concentrated, diluted with acetonitrile (80 ml), and concentrated to about 30 ml. The precipitate was collected by filtration, washed with acetonitrile, and dried to give the title compound P-toluenesulfonate (905 ing, 1.24 mmol, 22.1) as a red-brown powder. After the mother liquor was concentrated to dryness, it was dissolved in toluene (60 ml) and stirred at 80 ^DC for 1 hour. The reaction solution was concentrated to about 30 ml, diluted with acetonitrile (20 ml), and the precipitate was collected by filtration, washed with acetonitrile, dried, and dried to give the title compound P-toluenesulfonate (2.27 g, 3.11 ol, 55.5%) as a red-brown powder.

Example 21_4

 N- {4-[({5,6-dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-1-ylidene} amino) sulfonyl] phenyl} hexaneamide

 Example 21-3 4-amino-N- {5,6-dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) obtained in the same manner as in (Method 1) ) Sulfanyl] -2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-triylidene} Crude benzenesulfonamide (purity 60, 0.60 g, 0.62 mmol, hydrate To a solution of hexanoyl chloride (125 mg, 0.93 t) in THF (10 ml) while stirring at room temperature was added triethylamine (0.34 ml, 2.5 n-ol). The reaction solution was stirred for 1 hour, diluted with ethyl acetate (30 ml), washed with 0.2N hydrochloric acid, water and saturated saline, dried over sodium sulfate, and concentrated. The residue was dissolved in toluene (10 ml) and stirred at 80 ° C for 1 hour in the presence of acetic anhydride (0.18 ml) and P-toluenesulfonic acid hydrate (118 mg, 0.62 mmol). The reaction solution was diluted with ethyl acetate (30 ml), washed with water and saturated saline, dried over sodium sulfate and concentrated, and methanol was added to the residue. The precipitate was collected by filtration, washed with methanol, and dried to give the title compound (125 mg, 0.191 mmol, 30.9%) as a red-brown powder.

Ή one _{NMR (300MHz, CDC1 3):} δθ.91 (3Η, brt, J = 6.6 Hz), 1.36 (4H, m), 1.74 (6H, m), 1.79 (3H, brs), 2.06 (2H, in), 2.27 (3H, brs), 2.38 (2H, t, J = 7.5 Hz), 2.96 (2H, t, J = 6.9 Hz), 7.39 ( 1H, brs), 7.65 (2H, d, J = 8.7 Hz), 7.89 (2H, d, J = 8.4 Hz), 9.63 (1H, br).

Elemental analysis: C ₂₆ H ₃₁ N ₄ 0 ₄ S ₃ F ₅ -0.4H ₂ 0 Calculated: C, 47.18; H, 4.84; N, 8.46; S, 14.53; F, 14.35 (%), actual : C, 47.20; H, 4.78;, 8.53; S, 14.74; F, 14.54 ().

 mp. 165.5-170.0 ° C

 ■ Example 21-5

 4- [Bis (methylsulfonyl) amino] -N- {5,6-dimethyl-3-oxo-8-[(5,5,6,6,6-pentanofluorohexyl) sulfanyl] -2 , 3-Dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidene} benzenesulfonamide

 To a solution of the compound obtained in Example 21-3 (Method 1) (175 mg, 0.31 bandol) and methanesulfonyl chloride (43.6 mg, 0.377 mraol) in THF (3.5 ml) was stirred triethylamine (0 ° C) at 0 ° C. 0.065 ml, 0.471 mniol) was added and the reaction solution was stirred at 0 for 4.5 hours. The same amounts of methanesulfonyl chloride and triethylamine were added, and the mixture was further stirred for 3 hours. The reaction solution was diluted with ethyl acetate (30 ml), washed with water and saturated saline, dried over sodium sulfate and concentrated, and getyl ether was added to the residue. The precipitate was collected by filtration, washed with diethyl ether, and dried to give the title compound (188 mg, 0.264 mmol, 84.0%) as a purple powder.

_{LH-NMR (200MHz, CDC1 3} ): 1.74 (4H, m), 1.81 (3H, q, J = 0.8 Hz), 2.06 (2H, m), 2.29 (3H, q, J- 0.8 Hz), 3.00 ( 2H, t, J = 7.0 Hz), 3.41 (6H, s), 7.48 (2H, d, J = 8.8 Hz), 8.06 (2H, d, J = 8.8 Hz), 9.63 (1H, br).

Elemental _{analysis: C 22 H 25 N 4 0} 7 S 5 F 5 Calculated: C, 37.07; H, 3.54 ; N, 7.87; F, 13.33 (%), Found: C, 37.38; H, 3.34 ; N, 8.02; F, 13.62 (%).

 mp.180.5-182.0 ° C

 Example 21-6 (1)

-{5,6-Dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -2,3-dihydro-1H-imidazo [5,1-c ] [1,4] thiazine-1 -ylidene}-4 -formyld, Example 21-6 (2)

 N- {5,6-Dimethyl-3-oxo-8-[(5,5,6,6,6-pentylfluorohexyl) sulfanyl] -2,3-dihydro-1H-imidazo [5, lc] [1,4] thiazine-1-ylidene} -4- (hydroxymethyl) benzenesulfonamide

4-Cyano-N- {2,3-dihydro-5,6-dimethyl-3-oxo-3-8-[(5,5,6,6,6-pentenfluorene) obtained in Example 7-84 [Hexyl) sulfanyl] -1H-imidazo [5, lc] [1,4] thiazine-1-ylidene} To a solution of benzenesulfonamide (251 mg, 0.442, fraction 1) in dichloromethane (200 ml) was added diisobutylaluminum hydride. A 1.5 mol / 1 toluene solution (0.590 ml, 0.884 leak 1) was added at -70 ° C. The reaction mixture was stirred at _70 ° C under a stream of argon for 7 hours. A saturated aqueous solution of ammonium chloride (250 ml) was added, the reaction mixture was stirred at room temperature for 30 minutes, and 1N hydrochloric acid was added, followed by extraction with dichloromethane. The extract was washed with water, dried (MgSO _4), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound 21-6 (1) (15.7 mg, 6.2¾) and 21-6 (2) (26.0 mg, 10%) was obtained as dark red crystals.

The title compound 21-6 (1) was recrystallized from ethyl acetate to give dark red crystals having a melting point of 174-175.

IR (KBr): 3240, 2934, 1748, 1711, 1663, 1597, 1557 cm- ¹ .

_{Ή-NMR (CDC1 3):} δ 1.67-1.88 (4Η, m), 1.80 (3H, d, J = 1.2 Hz), 1.92-2.22 (2H, 111), 2.28 (3H, d, J = l.2 Hz), 2.99 (2H, t, J = 6.6 Hz), 8.00 (2H, d, J = 8.4 Hz),

8.14 (2H, d, J = 8.6 Hz), 9.58 (1H, bs), 10.09 (1H, s).

Elementary analysis: as _{C 21 H 2Q N 3 0 4} S 3 F 5

Calculated (%): C, 44.28; H, 3.54; N, 7.38; S, 16.89.

Found (¾): C, 44.39; H, 3.44; N, 7.73; S, 16.94.

The title compound 21-6 (2) was recrystallized from ethyl acetate-jetether to give dark red crystals with a melting point of 180-181.

IR (KBr) V: 3700-2600, 3472, 1748, 1661, 1615, 1557 cm " ¹ .

—Awake R (CDC1 ₃ ): 51.64-1.90 (4H, m), 1.79 (3H, d, J = 1.2 Hz), 1.90-2.22 (2H, m), 2.27 (3H, d, J = l.2 Hz) ), 2.97 (2H, t, J = 7.4 Hz), 4.78 (2H, d, J = 6.2 Hz), 7.49 (2H, d, J = 8.4 Hz), 7.95 (2H, d, J = 8.Hz), 9.63 (1H, bs).

Elementary analysis: as _{C 21 H 22 N 3 0 4} S 3 F 5

Calculated)): C, 44.13; H, 3.88; N, 7.35; S, 16.83.

Found (¾): C, 43.75; H, 3.90; N, 7.42; S, 16.95.

Example 21-7

 4- (dimethylamino) -N- {5,6-dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorofluorohexyl) sulfanyl] -2,3-dihydro-1H- Imidazo [5, l_c] [1, 4] thiazine-1- Example 2 A suspension of the compound obtained in Step 3 (Method 1) (195 mg, 0.350 mmol) in acetonitrile (4.0 ml) and THF (0.5 ml) To the mixture was added formalin (purity 37% aqueous solution, 0.105 ml, 1.40 dragonol) at room temperature, and after stirring for 30 minutes, sodium cyanoborohydride (23.2 mg, 0.350 liter) was added, and the mixture was further stirred for 30 minutes. Formalin (0.053 ml, 0.70 mmol) and sodium cyanoborohydride (12 mg, 0.18 ol) were added to the reaction solution, and the mixture was further stirred for 30 minutes. The reaction solution was diluted with ethyl acetate (30 ml), washed with 0.1N hydrochloric acid, water and saturated saline, and dried over sodium sulfate. After concentration to dryness, the residue was diluted with methanol. The precipitate was collected by filtration, washed with methanol, and crystallized from ethyl acetate to give the title compound (100 mg, 0.171 tmol, 48.9%) as a red powder.

_{Ή-NMR (300MHz, CDC1 3} ): (51.74 (4H, m), 1.78 (3H, brs), 2.04 (2H, m), 2.25 (3H, brs), 2.95 (2H, t, J = 6.8 Hz) , 3.04 (6H, s), 6.66 (2H, d, J- 9.0 Hz), 7.77 (2H, d, J = 9.0 Hz), 9.63 (1H, br).

Elemental _{analysis: C 22 H 25 N 4 0} 3 S 3 F 5 Calculated: C, 45.20; H, 4.31 ;, 9.58; S, 16.45; F, 16.25 (), Found: C, 44.85; H, 4.34; N, 9.66; S, 16.66; F, 16.24 (%). Immediately. 197.5-199. O

Example 21-8

N- {5,6-Dimethyl-3-oxo-8-[(5,5,6,6,6-pentylfluorohexyl) sulfanyl] -2,3-dihydrido-1H-imidazo [5 , 1-c] [1,4] thiazine toylidene} -4-[(methyl) P-toluenesulfonate (487 mg, 0.668 mmol) of the compound obtained in Example 21-3 (Method 2) in THF (3.5 pyridine (0.132 ml, 1.63 ml) at room temperature with stirring. After adding thigh ol) and stirring for 20 minutes, methanesulfonic anhydride (129 mg, 0.717 ol) was added, and the mixture was further stirred for 13 hours. The reaction solution was diluted with ethyl acetate (30 ml), washed with 0.1N hydrochloric acid, and extracted with a 2% aqueous sodium carbonate solution. The aqueous extraction layer was adjusted to be acidic and extracted with ethyl acetate. Similarly, the organic layers obtained from the raw materials (254 mg, 0.348 mol) were combined, washed with 0.1 N hydrochloric acid, water and saturated saline, dried over sodium sulfate and concentrated, and methanol was added to the residue. The precipitate was removed, the mother liquor and the methanol wash were concentrated, and diluted with geethyl ether. The precipitate was washed with geetyl ether and dried to give the title compound (104 mg, 0.164 ol, 16.1%) as a purple powder.

Ή-NMR (300MHz, DMS0- d 6): 51.62 (2H, brq, J = 6.9 Hz), 1.70 (2H, brq, J = 7.2 Hz), 1.79 (3H, brs), 2.17 (3H, brs), 2.23 (2H, m), 3.03 (2H, t, J = 7.1 Hz), 3.11 (3H, s), 7.31 (2H, d, J = 9.0 Hz), 7.90 (2H, d, J = 9.0 Hz), 10.36 (1H, s), 11.64 (1H, brs).

Elemental analysis: Calculated for C ₂₁ H ₂₃ N ₄ 0 ₅ S ₄ F ₅ : C, 39.74; H, 3.65; N, 8.83; S, 20.21; F, 14.97 (%), found: C, 40.07; H, 3.65; N, 8.85; S, 20.08; F, 14.32 (%). Mp. 186.5-188.0 ° C

Example 21-9

 N- {5,6-dimethyl-3-oxo- 8-[(5,5,6,6,6_pentafluorohexyl) sulfanyl]-2,3-dihydro-1H-imidazo [5,1- c] [1,4] thiazine_1-ylidene}-4-{[(4-methylphenyl) sulfonyl] amino} benzenesulfonamide

Example 21-3 Pyridine (0.092 ml, 1.14) was added to a suspension of the compound obtained in (Method 2) in P-toluenesulfonic acid salt (340 mg, 0.467 mol) in THF (7 ml) at room temperature with stirring. ol), followed by P-toluenesulfonyl chloride (hereinafter sometimes abbreviated as p-TsCi, 107 mg, 0.546 ol), and the mixture was further stirred for 2 hours. Triethylamine (0.063 ml, 0.455 mmol) was added to the reaction solution, and the mixture was further stirred for 2 hours. N, N-Dimethylaminopyridine (hereinafter abbreviated as DMAP, 11 mg, 0.091 tmol) was added to the reaction solution, and the mixture was further stirred for 4 hours. Triethylamine (0.063 ml, 0.455 mmol) and p-TsCl (53.5 mg, 0.273 mmol) were added to the reaction solution, and the mixture was further stirred for 60 hours. 1N Hydrochloric acid (2.0 ml) was added to the reaction solution, and the mixture was diluted with methanol-water (1: 1, 10 ml). The precipitate was washed with methanol-water (1: 1) and methanol, dried and dried to give the title compound (259 mg, 0.364 bandol ol, 78. ID was obtained as a purple powder.

Ή-NMR (300 MHz, DMS0-d ₆ ): 51.61 (2H, brq, J = 6.6 Hz), 1.68 (2H, brq, J = 7.2 Hz), 1.77 (3H, brs), 2.16 (3H, brs), 2.22 (2H, m), 2.34 (3H, s), 3.00 (2H, t, J = 7.1 Hz), 7.23 (2H, d, J = 8.8 Hz), 7.36 (2H, d, J = 8.1 Hz), 7.72 (2H, d, J = 7.8 Hz), 7.79 (2H, d, J = 8.7 Hz), 10.84 (1H, s), 11.59 (1H, brs). Elemental analysis: C ₂₇ H ₂₇ N ₄ 0 ₅ S ₄ F ₅ calculated: C, 45.62; H, 3.83 ; N, 7.88; S, 18.04; F, 13.36 (), Found: C, 45.58; H, 4.03 ; N, 7.94; S, 18.19; F , 13.35 (%). Immediately. 225.5-226.5 ° C,

Example 21-10

5-{[5,6-Dimethyl-3-oxo-({[4- (trifluoromethyl) phenyl] sulfonyl} imino) -2,3-dihydro-1H-imidazo [5,1-c [1,4] Thiazine-8-yl] sulfanyl} valeric acid

Ethyl 5-{[5,6-dimethyl-3-oxo-1 _ ({[4_ (trifluoromethyl) phenyl] sulfonyl} imino) -2,3-dihydro-1H- obtained in Example 7-105 To a solution of imidazo [5, 1-c] [1,4] thiazine-8-yl] sulfanyl} pentanoate (1.05 g, 1.86 ol) in ethanol (10.0 ml) and tetrahydrofuran (10.0 ml) was added 1N aqueous solution. An aqueous solution of sodium oxide (5.59 ml) was added. After stirring the reaction mixture at room temperature for 1 hour, the solvent was distilled off under reduced pressure. 1N Hydrochloric acid was added to the residue, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (747 mg, 75%) as a dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 191 to 193 ° C.

IR (KBr) V: 3700-2400, 3125, 2928, 1725, 1663, 1599, 1557 cm " ¹ .

_{Ή-NMR (CDC1 3):} (51.70-1.83 (4H, m), 1.80 (3H, d, J = 1.2 Hz), 2.28 (3H, d, J = 1.2Hz), 2.37-2.45 (2H, m) , 2.94-3.02 (2H, m), 7.77 (2H, d, J = 8.1 Hz), 8.11 (2H, d, J = 8.4 Hz), 9.69 (1H, bs).

Elementary analysis: as _{C 20 H 20 N 3 0 5} S 3 F 3 -0.3H 2 O

Calculated value (%): C, 44.40; H, 3.83; N, 7.77; S, 17.78.

Found (¾): C, 44.39; H, 4.04; N, 7.83; S, 17.66.

Example 21-11 5-{[5,6-dimethyl-3-oxo-butanol ({[4- (trifluoromethyl) phenyl] sulfonyl} imino) -2,3-dihydro-1H-imidazo [5,1-c ] [1,4] thiazin-8-yl] sulfanyl nitrate N-hexylpentanamide

Example 2 5-{[5,6-Dimethyl-3-oxo-({[4- (trifluoromethyl) phenyl] sulfonyl} imino) -2,3-dihydro-1H- N, N of imidazo [5,1-c] [1,4] thiazin-8-yl] sulfanyl} valeric acid (442 mg, 8.27 marl ol) and trihexylamine (0.135 ml, 10.2 marl. 1) To a solution of -dimethylformamide (5.00 ml) was added getyl cyanophosphate (0.165 ml, 10.2 mol), followed by triethylamine (0.142 ml, 10.2 mmol). After stirring the reaction mixture at room temperature for 21.5 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain a solvent the title compound was evaporated under reduced pressure (23.6 mg, 4.6%) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether yielded dark red crystals with a melting point of 117-119 ° C.

IR (KBr) V: 3252, 2932, 2860, 1748, 1622, 1557 cm- ¹ .

_{Ή-NM (CDC1 3):} 50.881 (3H, t, J = 6.9 Hz), 1.24-1.38 (6H, in), 1.42-1.54 (2H, m), 1.68-1.84 (4H, m), 1.80 (3H , d, J = 0.9 Hz), 2.19 (2H, t, J = 6.6 Hz), 2.28

(3H, d, J = 0.9Hz), 2.98 (2H, t, J = 6.9 Hz), 3.24 (2H, q, J = 7.2 Hz), 5.45 (1H, bs), 7.77 (2H, d, J = 8.1 Hz), 8.10 (2H, d, J = 8.1 Hz), 9.63 (1H, bs).

Examples 21-12

 N- {5,6-dimethyl_3-oxo_8 _ [(5,5,6,6,6-pentafluorohexyl) sulfanyl] -2,3-dihydro-1H-imidazo [5,1-c ] [1,4] thiazine-1-yl 4- (2-oxo

-Topyrrolidinyl) benzenesulfonamide

 To a suspension of the compound obtained in Examples 21-23 (0.33 g, 0.42 mol) in DMF (5 ml) was added sodium hydride (purity 60% oily, 68 nig, 1.70 mol) at room temperature. Sodium chloride (10 nig) was added and the mixture was stirred for 60 minutes. The reaction mixture was diluted with 1N hydrochloric acid (2.0 ml), diluted with ethyl acetate (30 ml), washed with 0.1N hydrochloric acid, water and saturated saline, and then dried over sodium sulfate. After concentration to dryness, the residue was diluted with ethyl acetate and getyl ether. The precipitate was collected by filtration, washed with diethyl ether, and dried to give the title compound (173 mg, 0.277 mol, 65.3%) as a red powder.

lH- negation _{R (300MHz, CDC1 3):} δΐ.75 (4Η, m), 1.80 (3H, s), 2.05 (2H, tt, J = 17.4, 7.5 Hz), 2.20 (2H, t, J = 7.7 Hz), 2.27 (3H, q, J- 0.6 Hz), 2.65 (2H, t, J = 8.3 Hz), 2.96 (2H, t, J = 6.9 Hz) ), 3.89 (2H, t, J = 6.9 Hz), 7.78 (2H, d, J = 9.0 Hz), 7.95 (2H, d, J = 8.7 Hz), 9.63 (1H, brs).

Elemental _{analysis: C 24 H 24 N 4 0} 4 S 3 F 5 Calculated: C, 46.15; H, 4.03 ; N, 8.97; S, 15.40; F, 15.21 (%), Found: C, 45.85; H, 3.99; N, 8.94; S, 15.40; F, 14.99 (%). Mp. 179.0-181.5 ° C

Examples 21-13

 5 _ {[1-({[4- (Acetylamino) phenyl] sulfonyl} imino) -5,6-dimethyl-3-oxo-2,3 dihydro-1H-imidazo [5,1-c] [1, 4] thiazine-8-yl] sulfanyl} valeric acid

Ethyl 5-{[1-({[4- (acetylamino) phenyl] sulfonyl} imino) -5,6_dimethyl-3-oxo-2,3-dihydro-1H obtained in Examples 7-141 To a solution of -imidazo [5,1-c] [1,4] thiazin-8-yl] sulfanyl} pentanoate (200 mg, 0.361 mmol) in ethanol (5.00 ml) and tetrahydrofuran (5.00 ml) was added 1N aqueous solution. An aqueous solution of sodium oxide (1.08 ml) was added. After stirring the reaction mixture at room temperature for 1 hour, the solvent was distilled off under reduced pressure. 1N Hydrochloric acid was added to the residue, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (167 mg, 88%) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 226-228 ° C.

IR (KBr): 3700-2700, 3314, 2930, 1742, 1667, 1591, 1549 cm— ¹ .

_{Ή-NMR (CDC1 3):} (51.50-1.70 (4H, m), 1.79 (3H, s), 2.08 (3H, s), 2.17 (3H, s), 2.18-2.28 (2H, m), 2.90- 3.00 (2H, m), 7.73 (2H, d, J = 8.4 Hz), 7.87 (2H, d, J = 8.4 Hz), 10.30 (1H, bs), 11.61 (1H, bs).

Elemental analysis: C ₂₁ ¾ ₄ N _{40 s} S ₃ 0.7H ₂₀

Calculated value (%): C, 46.95; H, 4.77; N, 10.43; S, 17:91.

Found (%): C, 46.87; H, 4.74; N, 10.33; S, 18.23.

Example 21-15

4-bromo-N- [5,6-dimethyl-8-[(5-fluoroopentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1, ] Thiazine-1-ylidene] benzenesulfo Amide sodium salt

To a suspension of the compound obtained in Example 7-72 (2.17 g, 4.06 mmol) in THF-methanol (1: 1, 100 ml) was added IN aqueous sodium hydroxide solution (4.00 ml, .00 mmol), and the mixture was treated with about 50%. Heated to ° C to dissolve. Water (50 ml) was added to the obtained solution, and the mixture was concentrated under reduced pressure to remove THF and methanol. The precipitate was collected by filtration, washed with water and methanol-water (1: 1), and dried to give the title compound (1.92 g, 3.45 band01, 85.0) as a purple-brown powder. _{Ή-NMR (200MHz, CDC1 3} ): 51.47 (2H, m), 1.60 - 1.75 (4H, m), 1.65 (3H, s), 2.02 (3H, s), 2.87 (2H, t, J = 7.2 Hz ), 4.42 (2H, dt, 1 = 47.4, 5.9 Hz), 7.41 (2H, d, J = 8.6 Hz), 7.80 (2H, d, J = 8.0 Hz).

Elemental analysis: C ₁₉ H _2. Calculated for N ₃ 0 ₃ S ₃ BrFNa: C, 41.01; H, 3.62; N, 7.55; S, 17.29; Br, 14.36; F, 3.41 (%), found: C, 40.66; H, 3.66;, 7.57; S, 17.41; Br, 14.28; F, 3.50 (%).

Example 21-16

 5-[(5,6-dimethyl-1-{[(4-acetylphenyl) sulfonyl] imino} -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine -8-yl) sulfanyl] -N-hexylpentanamide

To a suspension of sodium hydride (9.74 mg, 0.243 mmol) (60% oil) in tetrahydrofuran (0.50 ml) was added the 5- [1-amino-5,6-dimethyl-3 obtained in Example 6-33. -Oxo-3H-imidazo [5,1-c] [1,4] thiazin-8-yl] sulfanyl] -N-hexylpentanamide (50.0 mg, 0.121 bandol) in tetrahydrofuran (0.50 ml) And stirred under ice cooling for 5 minutes. To this was added a solution of 4-acetylbenzenesulfonyl chloride (41.2 mg, 0.183 mol) in tetrahydrofuran (0.50 il), and the mixture was further stirred at room temperature for 21 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was water washed, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (23.8 mg, 33%) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 103-105 ^.

IR (KBr) V:. 3266 , 3073, 2955, 2930, 2859, 1752, 1692, 1645, 1615, 1557 cm "1 ¾-NMR (CDC1 3): (50.881 (3H, t, J = 7.0 Hz), 1.24-1.38 (6H, m), 1.42-1.56 (2H, m), 1.68-1.84 (4H, m), 1.79 (3H, d, J = 1.2 Hz), 2.19 (2H, t, J = 6.2 Hz) , 2.28 (3H, d, J = 1.2 Hz), 2.65 (3H, s), '2.97 (2H, t, J = 7.0 Hz), 3.24 (2H, q, J = 5.8 Hz), 5.49 (1H, bs), 8.06 (4H, s), 9.63 (1H, bs).

Example 21-17

 N- {4-[({8-[(3-Aminopropyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, lc] [1,4] thiazine -Trilidene} amino) sulfonyl] phenyl} acetamide hydrochloride

 The compound powder (purity 95%, 255 mg, 0.416 mmol) obtained in Example 7-152 was added to TFA

(1.0 ml) and left at room temperature for 80 minutes. The reaction solution was diluted with toluene (25 ml), concentrated to dryness, and the residue was concentrated by adding toluene (25 ml). The obtained residue was dissolved in THF-ethanol (1: 1, 50 ml), and concentrated by adding 1N hydrochloric acid (0.50 ml).

THF-methanol (1: 1) was added and concentrated to give a red suspension. This was diluted with THF and ethyl acetate. The precipitate was collected by filtration, washed with ethyl acetate, and dried to give the title compound (200 mg, 0.386 mmol, 92.8%) as a gray-red powder.

Ή-NMR (200 MHz, DMS0-d ₆ ): δ 1.80 (3Η, s), 1.89 (2H, quint, J = 7.2 Hz), 2.09 (3H, s), 2.17 (3H, s), 2.86 (2H, brq, J = 7 Hz), 3.05 (2H, t, J = 6.6 Hz), 7.76

(2H, d, J = 9.2 Hz), 7.86 (3H, brs), 7.87 (2H, d, J = 8.8 Hz), 10.41 (1H, s),

11.65 (1H, brs).

Elemental _{analysis: C 19 H 24 N 5 0} 4 S 3 C1 · 1.2Η 2 0 Calculated: C, 42.28; Η, 4.93 ; Ν, 12.98; S, 17.82; C1, 6.57 (%), Found: C, 42.11; Η, 5.01;, 12.90; S, 18.23; C1, 6.47 (%).

mp. 192-195 ° C (deco immediately)

Examples 21-18

 5-({5,6-dimethyl-1-[(n-octylsulfonyl) imino] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine- 8-yl} sulfanyl) hexylpentane amide

To a suspension of sodium hydride (9.74 mg, 0.243 tmol) (60% oil) in tetrahydrofuran (0.50 ml) was added the 5- [triamino-5,6-dimethyl-3) obtained in Example 6-33. -Oxo-3H-imidazo [5, 1-c] [1,4] thiazine-8-yl] sulfanyl] -N-hexylpentene amide (50.0 mg, 0.121 bandol) in tetrahydrofuran (0.50 ml) Add ice-cold Stir for 5 minutes below. To this was added a solution of n-octanesulfonyl chloride (0.0337 ml, 0.183 mmol) in tetrahydrofuran (0.50 ml), and the mixture was further stirred at room temperature for 21 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, Drying (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (23.4 mg, 33%) was obtained as a dark red crystals of. The crystals were recrystallized from ethyl acetate-getyl ether to obtain dark red crystals having a melting point of 128-13 (TC).

IR (KBr) V:. 3179 , 3086, 2928, 2857, 1755, 1740, 1665, 1640, 1574 cm "1 one _{NMR (CDC1 3): (50.884} (6H, t, J = 6.9 Hz), 1.20-1.36 (14H, m), 1.36-1.54 (4H, m), 1.67-1.82 (4H, m), 1.81 (3H, d, J = 0.6 Hz), 1.82-1.92 (2H, m), 2.20 (2H, t , J = 6.9 Hz), 2.27 (3H, d, J = 0.6 Hz), 2.98 (2H, t, J = 6.9 Hz), 3.11 (2H, t, J = 7.8 Hz), 3.24 (2H, q, J = 6.0 Hz), 5.47 (1H, bs), 9.48 (1H, bs).

Examples 21-19

 4-Bumo-N- [5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [ 1,4] thiazine-1-ylidene] benzenesulfonamide calcium salt

 To a suspension of the compound obtained in Examples 7-72 (1.00 g, 1.87 mmol) in THF-methanol (1: 1, 60 ml) was added an aqueous solution (40 ml) of calcium hydroxide (70.0 mg, 0.898 mmol). Was. The mixture was heated to about 5 (TC and dissolved by further addition of THF and methanol. The obtained solution was concentrated to about 50 ml under reduced pressure, and the obtained precipitate was collected by filtration, and washed with water and methanol. —Washed with water (1: 1) and dried to give the title compound (813 mg, 1.47 mmol, 78.5%) as a purple-brown powder.

Ή- negation _{R (200MHz, CDC1 3):} d 1.55 (2H, m), 1.60-1.80 (4H, m), 1.73 (3H, s), 2.11 (3H, s), 2.91 (1H, t, J = 7.4Hz), 4.40 (2H, dt, J- 46.8, 5.7 Hz), 7.48 (2H, brd, J = 7.8 Hz), 7.80 (2H, d, J = 8.0 Hz), 9.62 (1H, brs).

Elemental _{analysis: C 19 H 2Q N 3 O} 3 S 3 BrF.0.5Ca.0.5¾O Calculated: C, 40.57; H, 3.76 ; N, 7.47; S, 17.10 (%), Found: C, 40.73 ; H, 3.80; N, 7.50; S, 17.12 (%). Examples 21-20

4-[({5,6-Dimethyl-8-[(5-fluoroopentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4 ] Thiazine-triylidene} amino) sulfonyl] benzoic Etyl 4 _ [({5,6-dimethyl-3_oxo-8 _ [(5-fluoropentyl) sulfanyl] -2,3-dihydro-1H-imidazo [5,1-c] obtained in Example 7-162 A solution of [1,4] thiazine-trilidene} amino) sulfonyl] benzoate (260 mg, 0.514 mmol) in ethanol (5.00 ml) and tetrahydrofuran (5.00 ml) was added IN aqueous sodium hydroxide solution (1.54 ml). Was added. After stirring the reaction mixture at room temperature for 1.5 hours, the solvent was distilled off under reduced pressure. 1N Hydrochloric acid was added to the residue, and the resulting precipitate was collected by filtration, washed with water, and dried to give the title compound (241 mg, 94%) as dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 4-146 ° C.

. IR (KBr) V 3700-2300, 3208, 2936, 1759, 1696, 1663, 1620, 1559 cm 1 Ή-NMR (CDC1 3 + DMS0-d 6): 51.46-1.60 (2H, m), 1:65 -1.82 (4H, m), 1.80 (3H, d, J = 1.2 Hz), 2.27 (3H, d, J = 0.9 Hz), 2.96 (2H, t, J = 7.2 Hz), 4.44 (2H, dt, J = 47.4, 5.7 Hz), 8.03 (2H, d, J = 8.7 Hz), 8.14 (2H, d, J = 8.7 Hz), 10.45 (1H, bs).

Elemental analysis: as C _2Q H ₂₂ N ₃ 0 ₅ S ₃ F

Calculated (%): C, 48.08; H, 4.44; N, 8.41; S, 19.25.

Found (%): C, 48.00; H, 4.54; N, 8.31; S, 19.31.

Example 21-21

 N- (tert-butyl) -4-[({5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c ] [ί, 4] thiazine-ylidene} amino) sulfonyl] benzamide

4-[({5,6-dimethyl-3-oxo-8-[(5-fluoropentyl) sulfanyl] -2,3-dihydro-1H-imidazo [5, tric] obtained in Example 21-20 ] N, N-dimethylformamide (5.00 ml) of [1,4] thiazine-1-ylidene} amino) sulfonyl] benzoic acid (150 mg, 0.300 benzylol) and tert-butylylamine (0.0357 ml, 0.330 dandelionol) To the solution was added getyl cyanophosphate (0.0534 ml, 0.330 tmol) followed by triethylamine (0.0460 ml, 0.330 mmol), and the mixture was stirred at room temperature for 16 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained extract was washed with water, dried (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (73.1mg, 44¾) as a dark red crystals. Ethyl acetate-Jetil Recrystallization from ether gave dark red crystals, mp 169-171 ° C.

IR (KBr): 2969, 2936, 1742, 1661, 1615, 1559 cm " ¹ .

_{'H-NMR (CDC1 3)} : δ 1.47 (9Η, s), 1.45-1.62 (2H, m), 1.62-1.82 (4H, m), 1.79 (3H, d, J = 0.9 Hz), 2.27 (3H , d, J = 1.2 Hz), 2.96 (2H, t, = Ί Hz), 4.45 (2H, dt, J = 47.1, 5.7 Hz), 5.96 (1H, bs), 7.80 (2H, d, J = 8.4) Hz), 8.00 (2H, d, J = 8.7 Hz), 9.58 (1H, bs).

Elementary analysis: as _{C 24 H 3I N 4 0 4} S 3 F 0.5EiOAc

Calculated value (¾): C, 52.15; H, 5.89; K, 9.36; S, 16.07.

Found (%): C, 52.00; H, 5.63; N, 9.40; S, 16.04.

Examples 21 to 22

 9,10-dimethyl-11 _ [(5_fluoropentyl) sulfanyl] -4,5-dihydrogen _3H_ [1,4] thiazino [4,, 3,: 3,4] imidazo [5, tric] [1, [2,4] thiazepine-7-one 2,2-dioxide

3-mouth DN- {5,6-dimethyl-3-oxo-8-[(5-fluoropentyl) sulfanyl] -2,3-dihydro-1H-imidazo obtained in Example 7-176 [5, 1-c] [1,4] Thiazine-1-ylidene} -topropanesulfonamide (145 mg, 0.317 mmol) and potassium carbonate (65.7 mg, 0.476 mmol) in N, N-dimethylformamide (5.00 ml) Was stirred at room temperature for 22 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was water washed, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (28.8 mg, 22%) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 109-110 ° C.

IR (KBr): 2938, 1738, 1663, 1601, 1557 cm " ¹ .

Ή one _{NMR (CDC1 3):? Δ} 1.46-1.70 (2Η, m), 1.70-1.88 (4H, in), 1.83 (3H, s), 2.20 2.35 (2H, m), 2.30 (3H, s), 2.99 (2H, t, J-7.8 Hz), 3.63 (2H, t, J = 7.0 Hz), 4.16-4.28 (2H, m), 4.46 (2H, dt, J = 47.2, 6.0 Hz).

Elementary analysis: as _{C 16 H 22 N 3 0 3} S 3 F

Calculated value (¾): C, 45.80; H, 5.29; N, 10.02; S, 22.91.

Found (%): C, 45.61; H, 5.07; N, 9.66; S, 23.07.

Examples 21-23 4- ク 口 口-N-{4-[({5,6_dimethyl-3-oxo-8-[(5,5,6,6,6,6-pentylfluorohexyl) sulfanyl] -2 , 3-Dihydrido-1H-imidazo [5,1-c] [1,4] thiazine-trilidene} amino) sulfonyl] phenyl} butanamide

 Example 2 To a suspension of the compound obtained in Part 3 in p-toluenesulfonic acid salt (295 mg, 0.405 fflinol) in THF (6 ml) was added pyridine (0.080 ml, 0.988 mmol) with stirring at room temperature. Then, 4-chlorobutyryl chloride (67 nig, 0.474 mmol) was added, and the mixture was further stirred for 2 hours. Triethylamine (0.055 ml, '0.395 tmol) was added to the reaction solution, and the mixture was further stirred for 1 hour. MAP (10 rag, 0.082 bandol) was added to the reaction solution, and the mixture was further stirred for 3 hours. The same amount of triethylamine and 4-chlorobutyryl chloride were added to the reaction solution, and the mixture was further stirred for 20 minutes. The reaction solution was diluted with ethyl acetate (30 ml), washed with 0.1N hydrochloric acid, water and saturated saline, dried over sodium sulfate and concentrated, and getyl ether was added to the residue. The precipitate was washed with getyl ether and dried to give the title compound (227 mg, 0.343 mmol, 84.8%) as a purple powder.

_{Ή- NMR (300MHz, CDC1 3)} : 51.74 (4H, m), 1.80 (3H, brs), 2.05 (2H, m), 2.21 (2H, quint, J = 6.5 Hz), 2.27 (3H, s), 2.61 (2H, t, J = 7.1 Hz), 2.96 (2H, t, J = 6.9 Hz), 3.67 (2H, t, J = 6.0 Hz), 7.52 (1H, brs), 7.64 (2H, d, J = 8.7 Hz), 7.90 (2H, d, J = 9.0 Hz), 9.62 (1H, brs).

Elemental _{analysis: C 24 H 26 N 4 0} 4 S 3 C1F 5 Calculated: C, 43.60; H, 3.96 ; N, 8.47; S, 14.55; CI, 5.36; F, 14.37 (%), Found: C, 43.60; H, 3.96; N, 8.47; S, 14.55; CI, 5.36; F, 14.37 (%).. 'Mp. 137-1411:

Example 21-24

N- {5,6-Dimethyl-3-oxo-8 _ [(5,5,6,6,6-pentafluorohexyl) sulfanyl] -2,3-dihydro-1H-imidazo [5, -c] [1,] thiazine-toylidene} -4- (1-pyrroli) Acetonitrile of the compound obtained in Example 21-3 (206 mg, 0.370 alcohol) and 2,5-dimethoxytetrahydrofuran (0.245 ml, 1.85 alcohol) Sodium cyanoborohydride (36.7 mg, 0.555 mmol) was added to the suspension of THF (1:18 ml), and the mixture was stirred for another 23 hours, during which the same amount of sodium cyanoborohydride was added to the suspension five times. And 2,5-dimethoxytetrahydrofuran (0.245 ml, 1.85 mmol) were added. The reaction solution was diluted with ethyl acetate-THF (2: 1, 40 ml), washed with 0.1N hydrochloric acid, 10% sodium bicarbonate, water and saturated saline, and dried over sodium sulfate. After concentration to dryness, the residue was diluted with ethyl acetate. The precipitate was removed and washed with ethyl acetate and ethyl acetate. The mother liquor and washings were concentrated and diluted with methanol. The precipitate was washed with methanol, and dried to give the title compound (51 mg, 0.058 mol) as a red-brown powder. _{¾-NMR (300MHz, CDC1 3} ): 61.14: (4H, m), 1.78 (3H, s), 2.03 (4H, m), 2.05 (2H, m), 2.25 (3H, s), 2.61 (2H, t, J = 7.1 Hz), 2.94 (2H, t, J = 6.6 Hz), 3.33 (4H, brt, J = 6.6 Hz), 6.52 (2H, d, J = 8.7 Hz), 7.75 (2H, d, J = 8.7 Hz), 9.63 (1H, brs).

Elemental _{analysis: C 24 H 27 N 4 0} 3 S 3 F 5 Calculated: C, 47.20; H, 4.46 ; N, 9.17; S, 15.75; F, 15.56 (%), Found: C, 47.23; H, 4.19; N, 9.15; S, 15.97; F, 15.53 (%). Mp.190.0-191.5

Example 21-25

N- {5,6-dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl]-2,3-dihydro-1H-imidazo [5,1- c] [1,4] thiazine-1-ylidene} _4- (1H-pyro p-toluenesulfonate (390 mg, 0.535 methylol) of the compound obtained in Example 3 and 2,5-dimethoxy A suspension of tetrahydrofuran (0.707 ml, 5.35 ml) in THF (10 ml) was stirred at room temperature for 30 minutes and at 50 ° C. for 10 minutes The reaction solution was diluted with ethyl acetate (40 ml), and 0.1N hydrochloric acid was added. The residue was diluted with methanoic acid, washed with methanol, dried, and dried to give the title compound (Π5 mg, 0.288 mg). . negation ol, 53.9 »was obtained as a red-purple powder _{Ή-NMR (300MHz, CDC1 3} ): 51.75 (4H, m), 1.80 (3H, s), 2.06 (2H, m), 2.28 (3H, s) , 2.98 (2H, t, J = 7.2 Hz), 6.40 (2H, t, J = 2.1 Hz), 7.14 (2H, t, J = 2.3 Hz) Hz), 7.49 (2H, d, J = 8.7 Hz), 8.02 (2H, d, J = 8.7 Hz), 9.67 (1H, brs). Elemental analysis value C _M H ₂₃ N ₄ 0 ₃ S ₃ F ₅ Calculated: C, 47.52; H, 3.82;, 9.24; S, 15.86; F, 15.66 (%), found: C, 47.32; H, 4.00; N, 9.18; S, 15.89; F, 15.40 (). mp.183.0-187.0 ° C Example 22-1

 5-({5,6-Dimethyl-tri [4- (methylbenzoyl) imino] -3-oxo-2,3-dihydro-1H-imidazo [5, tri-c] [1,4] thiazine-8 Yl} sulfanyl) valeric acid

Ethyl 5-({5,6-dimethyl- [4- (methylpentzyl) imino] -3-oxo-2,3-dihydro-1H-imidazo [5, tric] obtained in Example 8-5 To a solution of [1,4] thiazine-8-yl} sulfanyl) pentanoate (400 mg, 0.845 mmol) in ethanol (10.0 ml) and tetrahydrofuran (10.0 ml) was added a 1N aqueous sodium hydroxide solution (2.53 ml). added. After stirring the reaction mixture at room temperature for 5.5 hours, the solvent was distilled off under reduced pressure. IN hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO ₄₎ After the solvent was distilled off under reduced pressure to give the title compound (314 mg, 84¾) was synthesized. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 239-241 ° C.

IR (KBr) V: 3500-2700, 1732, 1719, 1653, 1597, 1537, 1505 cm- ¹ .

_{Ή- NMR (CDC1 3): δ} 1.27 (3Η, d, J = 7.2 Hz), 1.76-1.88 (4H, 111), 1.84 (3H, s), 2.34 (3H, d, J = 1.2 Hz), 2.36 -2.44 (2H, m), 2.41 (3H, s), 3.02-3.12 (2H, m), 4.15 (2H, q, J = 7.2 Hz), 7.25 (2H, d, J = 7.2 Hz), 8.22 ( 2H, d, J = 8.1 Hz), 11.08

(m, bs).

Elementary analysis: as _{C 21 N 3 0 4 S 2} 0.3H 2 0

Calculated: C, 55.93; H, 5.27; N, 9.32; S, 14.22.

Found (¾): C, 55.80; H, 4.97; N, 9.26; S, 14.29.

The following is a list of compounds synthesized in Example 22-1 and compounds synthesized in the same manner.

(Table 1 16)

摹 蒈 ぇ § 弒 «§2 Example 22-2

 N- (5,6-dimethyl-8-{[5- (hexylamino) -5-oxopentyl] sulfanyl} -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [ 1,4] thiazine-8-ylidene) -4-methylbenzamide

5-({5,6-dimethyl-1- [4- (methylbenzoyl) imino] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] obtained in Example 22-1 ] [1,4] thiazin-8-yl} sulfanyl) valeric acid (100 mg, 0.224 ol) and trihexylamine (0.0327 ml, 0.242 marl ol) in N, N-dimethylformamide (2.00 ml) To this was added getyl cyanophosphate (0.0399 ml, 0.247 mmol) and then triethylamine (0.0344 ml, 0.247 uimol). After stirring the reaction mixture at room temperature for 21 hours, water was added, and the mixture was extracted with ethyl acetate. Washed with water extract exudates, dried (MgSO _4), was synthesized solvent was distilled off under reduced pressure the title compound (24.0mg, 20%). The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 128-130 ° C.

IR (KBr): 3268, 2955, 2928, 2861, 1717, 1607, 1549, 1505 cm " ¹ .

_{Ή-NMR (CDC1 3):} 50.873 (3H, t, J = 6.9 Hz), 1.24-1.36 (6H, m), 1.42-1.54 (2H, m), 1.78-1.90 (4H, m), 1.83 (3H , d, J = 1.2 Hz), 2.20-2.28 (2H, m), 2.33 (3H, d, J = 0.9Hz), 2.41 (3H, s), 3.04-3.12 (2H, m), 3.23 (2H, q, J = 6.3 Hz), 7.25

(2H, d, J = 8.0 Hz), 8.22 (2H, d, J = 8 Hz), 11.09 (1H, bs)

Elementary analysis: as _{C 27 H 36 N 4 0 3} S 2 · 0.3Η 2 0

Calculated value (%): C, 60.71; Η, 6.91; Ν, 10.49; S, 12.01.

Found (¾): C, 60.57; Η, 6.69; Ν, 10.48; S, 12.31.

Example 22-3

 -(4-Bromophenyl) -N '-{8- [(5-fluoropentyl) sulfanyl] -5, 6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-1-ylidene}-{-methyl} rea

To a suspension of the compound obtained in Example 8-12 (106 mg, 0.206 ol) in THF (3.0 ml) was added sodium hydride (purity 60% oily, 20.6 mg, 0.516 ol) at room temperature. After stirring for 1 minute, a solution of methyl iodide (0.017 ml, 0.268 mol) in THF (0.17 ml) was added to the reaction solution, and the mixture was stirred for 24 hours. Obtained similarly from compound (136 mg) obtained in Example 8-12 The reaction solutions were combined, diluted with ethyl acetate (30 ml), washed with 0.1 N hydrochloric acid, water and saturated saline, and dried over sodium sulfate. After concentration to dryness, the residue was diluted with methanol. The precipitate was collected by filtration, subjected to silica gel chromatography (elution solvent, ethyl acetate-hexane, 2: 8-4: 6), and the ethyl acetate-hexane (4: 6) fraction was concentrated to dryness. Diluted with ethyl acetate. The precipitates are collected by filtration, washed with acetic acid Echiru and Jefferies chill ether and dried to give the title compound (127 mg, 0.241 thigh OI, 51.1 »was obtained as a red powder _{- NMR (200MHz, CDC1 3)} :. Δ 1.50 (2H, m), 1.74 (3H, s), 1.75 (2H, m), 1.80 (2H, m), 2.25 (3H, s), 2.72 / 3.03 (2H, brs / m), 3.31 / 3.56 (3H , s / brs), 4.48 (2H, dt, J = 47.4, 5.7 Hz), 7.21 (2H, brd, J = 7.8 Hz), 7.45 (2H, brd, J = 8.4 Hz), 10.60 / 10.63 (1H, brs).

Elemental _{analysis: C 21 H 24 N 4 0} 2 S 2 BrF Calculated: C, 47.82; H, 4.59 ; N, 10.62; S, 12.16; Br, 15.15; F, 3.60 (%), Found: C , 47.84; H, 4.65; N, 10.51; S, 12.03; Br, 14.93; F, 3.61 ().

mp. 153.0-155.5 ° C

Example 23

 N- {5,6-dimethyl-3-oxo_8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -2,3-dihydro-lri-imidazo [5,1-c ] [1,4] thiazine-1-ylidene} -P, P-diphenylphosphinic amine

To a suspension of sodium hydride (29.9 mg, 0.747 ol) (60% oily) in tetrahydrofuran (1.00 ml) was added 1-amino-5,6-dimethyl-8 _ [(obtained in Example 6-6. 5,5,6,6,6-pentafluorohexyl) sulfanyl] -3H-imidazo [5, tric] [1,4] thiazin-3-one (150 mg, 0.374 mmol) in tetrahydrofuran (1.00 ml), and the mixture was stirred under ice-cooling for 5 minutes. To this was added a solution of diphenylphosphinic chloride (108 mg, 0.448 tmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred at room temperature for 17 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, Drying (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (170 mg, 76%) and the obtained as dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 214-216 ° C.

IR (KBr) V: 2917, 2685, 1734, 1672, 1640, 1574 cm— ¹ . ^l H-NMR (CDCI3): (51.78 (3H, d, J = 0.6 Hz), 1.74-1.92 (4H, m), 2.00-2.20 (2H, m), 2.23 (3H, d, J = 0.9 Hz) , 3.05 (2H, t, J = 6.9 Hz), 7.37-7.50 (6H, m), 7.92 (4H, ddd, J = 12.0, 7.8, 1.5 Hz), 9.85 (1H, bs).

Elemental analysis: as C ₂₆ H ₂₅ N ₃ 0 ₂ S ₂ F ₅ P

Calculated (¾): C, 51.91; H, 4.19; N, 6.98; S, 10.66.

Found (%): C, 51.92; H, 4.20; N, 7.03; S, 10.45.

Example 24

Diphenyl 5,6-dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -2,3-dihydro-1H-imidazo [5, c] [1 , 4] Thazine-1_ylideneamide phosphate

To a suspension of sodium hydride (29.9 nig, 0.747 mmol) (60 oily) in tetrahydrofuran (1.00 ml) was added 1-amino-5,6-dimethyl-8-[(5 , 5,6,6,6-Penyu fluor-hexyl) sulfanyl] -3H-imidazo [5, tric] [1,4] thiazin-3-one (150 mg, 0.374 tmol) of tetrahydrofuran (1.00 mi) The solution was added, and the mixture was stirred for 5 minutes under ice cooling. To this was added a solution of diphenyl chloroformate phosphate (120 mg, 0.448 ol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred at room temperature for 30 minutes. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO ₄₎ after; solvent was evaporated under reduced pressure to give the title compound (185 mg, 78¾) was obtained as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 100-102 ° C.

IR (KBr): 3071, 2942, 2735, 1746, 1667, 1635, 1572 cm— ¹ .

(CDC1 ₃ ): «51.68-1.82 (4H, m), 1.77 (3H, d, J = 1.2 Hz), 1.92-2.18 (2H, m), 2.25 (3H, d, J = 1.0 Hz), 2.94 (2H, t, J = 7.0 Hz), 7.10-7.37 (10H, m), 9.60 (1H, bs).

Elementary analysis: as _{C 26 H 25 N 3 0 4} S 2 F 5 P

Calculated value (%): C, 49.29; H, 3.98; N, 6.63; S, 10.12.

Found (¾): C, 49.20; H, 3.85; N, 6.64; S, 9.97.

Example 25

Getyl 5, 6-dimethyl-3-oxo _8-[(5, 5, 6, 6, 6- ぺ: Fanyl] -2,3-dihydro-1H-imidazo [5, 1-c] [1,4] thiazine-1-ylidenamide phosphite

To a suspension of sodium hydride (29.9 mg, 0.747 tmol) (60% oil) in tetrahydrofuran (1.00 ml) was added 1-amino-5,6-dimethyl-8- [ (5,5,6,6,6-Pentafluorohexyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (150 mg, 0.374 tmol) A tetrahydrofuran (1.00 ml) solution was added, and the mixture was stirred for 5 minutes under ice cooling. To this was added a solution of getyl chloroformate (0.0835 ml, 0.561 mmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred at room temperature for 19 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, Drying (MgSO _4), solvent was evaporated under reduced pressure to give the title compound (138 mg, 69%) and the obtained as dark red crystals. Recrystallization from ethyl acetate-ethyl ether gave dark red crystals with a melting point of 154-156 ° C.

IR (KBr): 2986, 1750, 1672, 1651, 1576 cm " ¹ .

_{lH-NMR (CDC1 3):} d 1.34 (6H, d, J = 6.9 Hz), 1.68-1.88 (4H, in), 1.79 (3H, d, J = 1.2Hz), 1.98-2.16 (2H, m) , 2.26 (3H, d, J = 0.9 Hz), 4.00-4.15 (4H, m), 9.68 (1H, bs).

Elementary analysis: as _{C 18 H 25 N 3 0 4} S 2 F 5 P

Calculated (%): C, 40.22; H, 4.69; N, 7.82; S, 11.93.

Found (%): C, 40.09; H, 4.79; N, 7.58; S, 11.84.

Example 26

 N- {5,6-dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -2,3-dihydro-1H-imidazo [5, 1-c] [1,4] thiazine-1-ylidene} -P-methyl-P-phenylphosphinic amide

To a suspension of sodium hydride (29.9 mg, 0.747 mmol) (60% oil) in tetrahydrofuran (2.00 ml) was added 1_amino-5,6-dimethyl 8-[(5 , 5,6,6,6-Pentafluorohexyl) sulfanyl] -3H-imidazo [5, tric] [1,4] thiazin-3-one (150 mg, 0.574 mmol) in tetrahydrofuran (1.00 ml) And stirred under ice cooling for 5 minutes. To this was added a solution of methylphenylphosphinic chloride (80.7 mg, 0.448 acetyl) in tetrahydrofuran (1.00 ml), and the mixture was stirred for another 30 minutes. mixed. IN hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, Drying (MgSO _4), solvent was obtained as a distilled off the dark red crystals of the title compound (145 mg, 47%) and under reduced pressure. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 188-190 ° C.

IR (KBr): 3058, 2915, 2691, 1744, 1671, 1644, 1582 cm— ¹ .

_{Ή-NMR (CDC1 3):} 6 1.78 (6H, s), 1.74-1.92 (4H, m), 1.94-2.20 (2H, m), 2.23 (3H, d, J = l.2 Hz), 2.30 ( 2H, t, J = 6.6Hz), 7.40-7.53 (3H, m), 7.84-7.96 (2H, m), 9.84 (1H, bs).

Elemental analysis: C ₂ iH ₂₃ N ₃ 0 ₂ S ₂ F ₅ P,

Calculated value (¾): C, 46.75; Η, 4.30; Ν, 7.79; S, 11.89.

Found (¾): C, 46.47; H, 4.20; N, 7.84; S, 11.82.

Example 27

 N- {5,6-Dimethyl-3-oxo-8-[(5,5,6,6,6-pentafluorohexyl) sulfanyl] -2,3_dihydro-1H-imidazo [5, 1-c] [1,4] thiazine_1-ylidene}-4_methylbenzenesulfinamide

To a suspension of sodium hydride (39.9 mg, 0.996 ethanol) (60% oil) in tetrahydrofuran (2.00 ml) was added 1_amino-5,6-dimethyl 8-[(obtained in Example 6-6. 5,5,6,6,6-pentylfluorohexyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazine-3-one (200 mg, 0.498 tmol) of tetrahydrofuran (1.00 ml) solution was added and stirred for 5 minutes under ice-cooling. To this was added a solution of p_toluenesulfinyl chloride (80.7 mg, 0.448 mmol) obtained in Reference Example 47 in tetrahydrofuran (1.00 ml), and the mixture was further stirred for 19 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure to give the title compound (133 mg, 50¾) as a dark red crystals. Recrystallization from ethyl acetate gave dark red crystals with a melting point of 147-149 ° C.

IR (KBr) V: 2934, 2689, 1755, 1684, 1597, 1198 cm " ¹ .

Ή one _{NMR (CDC1 3):??} Δ1.62 1.85 (4Η, m), 1.76 (3H, d, J = 1.2 Hz), 1.92 2.11 (2H, in), 2.24 (3H, d, J = 1.2 Hz ), 2.36 (3HX0.51, s), 2.40 (3HX0.49, s), 3.00 (2H, t, J = 7.8 Hz), 7.19 (2HX0.42, d, J = 8.1 Hz) ', 7.27 (2HX0 .58, d, J = 8.4 Hz), 7.61 (2HX0.58, d, J = 8.4 Hz), 7.77 (2HX0.42, d, J = 8.1 Hz), 8.20 (1H, bs). Elemental analysis: C ₂₁ H ₂₂ N ₃ 0 ₂ S ₃ F ₅・ 1 ・ 2H ₂ 0

Calculated value (%): C, 44.94; H, 4.38; N, 7.49.

Found (¾): C, 44.96; H, 4.30; N, 7.56.

Example 28

 N- {5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine -1 -ylidene} -P-methyl-P-phenylphosphinic amide

A suspension of sodium hydride (25.4 mg, 0.654 ol) (60% oil) in tetrahydrofuran (1.00 ml) was added to the suspension of 1-amino-5,6-dimethyl-8- [obtained in Example 6-23. (5_Fluoro-pentyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazin-3-one (100 mg, 0.317 mmol ol) in tetrahydrofuran (1.00 ml) and ice-cooled Stir for 5 minutes below. To this was added a solution of methylphenylphosphinic chloride (68.5 mg, 0.380 tmol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred at room temperature for 40 minutes. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (99.4 mg, 69%) as a dark red crystals. Recrystallization from ethyl acetate-ethyl ether yielded dark red crystals with a melting point of 158-160 ° C.

Infrared absorption spectrum (IR) (in KBr) Seo:. 2905, 2699, 1740, 1669, 1644, 1580 cm one _{^{1 ¾-NMR (CDC1 3)}} : δ 1.48-1.89 (6H, m), 1.78 (6H, s), 2.23 (3H, s), 2.99 (3H, s), 2.99 (2H, t, J = 6.8 Hz), .4.47 (2H, dt, J = 47.0, 5.8 Hz), 7.39-7.56 (3H, m), 7.84-7.98 (2H, m), 9.82 (1H, bs).

Elemental analysis: C _2. N ₃ 0 ₂ S ₂ FP

Calculated value (%): C, 52.96; H, 5.56; N, 9.27; S, 14.14.

Found (%): C, 52.68; H, 5.41; N, 9.36; S, 14.23.

Example 29

Getyl 5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1-ylidenamide Phosphate Sodium hydride (25.4 mg, 0.654 mol) (60% oil) in tetrahydrofuran (1.00 of the 1-amino-5,6-dimethyl-8 _ [(5-fluoropentyl) sulfanyl] -3H-imidazo [5, tric] [1 , 4] Thiazin-3-one (100 mg, 0.317-oi) in tetrahydrofuran a.OOml) was added, and the mixture was stirred under ice-cooling for 5 minutes. To this was added a solution of getyl chloride mouth phosphate (0.0436 ml, 0.476 bandol) in tetrahydrofuran (1.00 ml), and the mixture was further stirred at room temperature for 40 minutes. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (74.3 mg, 56%) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 125-127.

Infrared absorption spectrum (IR) (in KBr) V: 2978, 2930, 2708, 1740, 1671, 1649, 1582 cm " ¹ .

Awakening: _{R (CDC1 3): δ 1.34} (6H, dt, J = 7.0, 0.8 Hz), 1.46-1.85 (6H, m), 1.79 (3H, d, J = 0.6Hz), 2.26 (3H, d, J = 1.Hz), 3.98-4.20 (2H, m), 4.46 (2H, dt, J = 47.2, 5.6 Hz), '9.66 (1H, bs).

Elementary analysis: as _{C I7 ¾ 7 N 3 0 4} S 2 FP

Calculated (¾): C, 45.22; H, 6.03; N, 9.31; S, 14.20.

Found (¾): C, 45.00; H, 5.93; N, 9.08; S, 14.24.

Example 30

Ethyl P-benzyl-N- {5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1, 4] thiazine-1-ylidene} phosphonamide ester

A suspension of sodium hydride (38. Omg, 0.951 ol) (60% oil) in tetrahydrofuran (1.00 ml) was added to a suspension of 1-amino-5,6-dimethyl-8- obtained in Example 6-23. Add [(5-fluoropentyl) sulfanyl] -3H imidazo [5,1-c] [1,4] thiazin-3-one (150 mg, 0.476 ol) to tetrahydrofuran (1.00 ml) and add ice Stir for 5 minutes below. To this was added the ethyl benzyl clonal phosphonate (2.00 ml) obtained in Reference Example, and the mixture was further stirred at room temperature for 2 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title of compound a (25.7 mg, 11%) as a dark red crystals. Ethyl acetate Recrystallization from the solution gave dark red crystals with a melting point of 132-134 ° C.

Infrared absorption spectrum (IR) (in KBr) V 2938, 2905, 2691, 1732, 1671, 1638, 1578 cm- ¹ .

_{Ή-NMR (CDC1 3):} δ 1.28 (3Η, t, J = 6.9 Hz), 1.50-1.86 (6H, m), 1.77 (3H, s),

2.21 (3H, s), 2.95 (2H, t, J = 7.5Hz), 3.20 (2H, d, J = 20.7Hz), 3.90-4.16 (2H, m), 4.47 (2H, dt, J = 47.1, 6.0 Hz), 7.16-7.34 (5H, m), 9.58 (1H, bs). Elemental analysis: C ₂₂ H ₂₉ N ₃ O ₃ S ₂ FP-0.7H ₂ O.

Calculated value (¾): C, 51.79; H, 6.01; N, 8.24; S, 12.57.

Observed value (C): C, 51.64; H, 5.95; N, 8.36; S, 12.85. A list of compounds synthesized in Examples 23 to 30 is shown below.

(Table 11)

麄赘ぇ用紙（siは 実施例 31

麄 赘 ぇ Paper (si Example 31

 8-[(5-Fluoropentyl) sulfanyl] -5,6-dimethyl-1H-imidazo [5,1-c] [1,4] thiazine-1,3 (2H) -dione

 To a suspension of the compound obtained in Example Ί-ΊΪ (purity 90%, 2.70 g, 4.55 mmol) in THF-methanol (3: 5, 80 ml) was added IN sodium hydroxide aqueous solution (4.55 ml, 4.55 liter). In addition, it dissolved. Ethanol (50 ml) was added to the obtained solution and concentrated. Ethanol (50 ml) was added to the residue, and the mixture was concentrated and diluted with ethyl acetate and getyl ether. The precipitate is collected by filtration, washed with ethyl acetate and ethyl acetate, and dried.

The title compound represented by the formula (433 mg, 匪 .37 Marl ol, 30.) was obtained as a brown powder.

_{- NMR (200MHz, CDC1 3)} : δ 1.58 (2Η, m), 1.62 (2H, m), 1.74 (2H, m), 1.78 (3H, q, J = 1.2 Hz), 2.27 (3H, q, J = 1.2 Hz), 2.97 (2H, t, J = 7.2 Hz), 4.45 (2H, di, J = 47.0, 5.7 Hz).

Elemental _{analysis: C 13 H 17 N 2 0} 2 S 2 F Calculated: C, 49.35; H, 5.42 ;, 8.85; F, 6.00

(%), Found: C, 49.20; H, 5.38; N, 8.76; F, 5.97 (%).

mp. 174.0-175.0 ° C

Example 32

Ethyl N_ {5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-m-imidazo [5, He] [1,4] thiazine-1-ylidene P -Phenylphosphonamide ester. 0CH ₂ CH ₃

One drop of N, N-dimethylformamide was added to a solution of getyl phenylphosphonate (0.371ini, 1.90mmol) in thionyl chloride (3.00ml), and the mixture was refluxed for 3 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, eluting with n-hexane-ethyl acetate (10: 1, v / v) to remove ethyl phenylphosphonate as an oil. And used directly in the next reaction. To a suspension of sodium hydride (38.0 rag, 0.951 mmol) (60 oily) in tetrahydrofuran (1.00 ml) was added the triamino-5,6-dimethyl-8-[(5- Fluoropentyl) sulfanyl] -3H-imidazo [5, tric] [1,4] thiazin-3-one (150 mg, 0.476 mmol) in tetrahydrofuran (1.00 ml) was added. Stir for a minute. To the mixture was added the ethyl phenyl phosphonate obtained above, and the mixture was further stirred at room temperature for 19.5 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title compound (40.2 mg, 18%) as a dark red crystals. The crystals were recrystallized from ethyl acetate-ethyl ether to obtain dark red crystals having a melting point of 153-155.

Infrared absorption spectrum (IR) (in KBr) V:. 2934, 2697 , 1738, 1671, 1644, 1574 cm "1 Ή-NMR (CDC1 3): δ 1.30 (3Η, t, J = 6.9 Hz), 1.50 -1.66 (2H, m), 1.66-1.92 (4H, m), 1.78 (3H, s), 2.25 (3H, s), 2.98 (2H, t, J = 7.5 Hz), 3.96-4.10 (2H, m ), 4.46 (2H, dt, J = 47.1, 6.0 Hz), 7.40-7.54 (3H, m), 7.93 (2H, dd, J = 12.6, 7.2 Hz), 9.88 (1H, bs).

Example 33

Ethyl N- {5,6-dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-triylidene U-P- (4-methoxyphenyl) phosphonamide

One drop of N, N-dimethylformamide was added to a solution of getyl (4-methoxyphenyl) phosphonate (479 mg, 1.90 mmol) in thionyl chloride (3.00 ml), and the mixture was heated under reflux for 3 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted with n-hexane-ethyl acetate (10: 1, v / v), and ethyl chloride (4-methoxyphenyl). The phonate was obtained as an oil and was used directly in the next reaction. A suspension of sodium hydride (38.0 nig, 0.951 ol) (60% oil) in tetrahydrofuran (1.00 ml) was added to the suspension of 1-amino-5,6-dimethyl-8_ [obtained in Example 6-23. (5-Fluoropentyl) sulfanyl] -3H-imidazo [5, tric] [1,4] thiazin-3-one (150 mg, 0.476 mmol) in tetrahydrofuran (1.00 ml) was added, and the mixture was cooled on ice for 5 minutes. Stirred. To this was added the ethyl clo-mouth (4-methoxyphenyl) phosphate obtained above, and the mixture was further stirred at room temperature for 24 hours. 1N Hydrochloric acid was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure to give the title compound (116 mg, 48¾) as a dark red crystals. Recrystallization from ethyl acetate-jetil ether gave dark red crystals with a melting point of 173-175.

Infrared absorption spectrum (IR) (in KBr) V: 2940, 2905, 2693, 1734, 1671, 1642, 1601, 1580, 1507 cnr ¹ .

Testimony _{(CDC1 3): 6 1.29 (} 3H, t, J = 6.9 Hz), 1.54-1.65 (2H, m), 1.65-1.84 (4H, ill), 1.78 (3H, d, J = 0.9 Hz), 2.24 (3H, d, J = 0.9 Hz), 2.98 (2H, t, J = 7.5 Hz), 3.84 (3H, s), 3.95-4.08 (2H, m), 4.47 (2H, dt, J = 47.4, 6.0 Hz), 6.95 (2H, dd, J = 8.7, 3.0 Hz), 7.85 (2H, dd, J = 12.3, 8.7 Hz), 9.88 (1H, bs).

Elementary analysis: as _{C 22 H 29 N 3 0 4} S 2 FP

Calculated value (%): C, 51.45; H, 5.69; N, 8.18; S, 12.49.

Found (%): C, 51.19; H, 5.66; N, 7.99; S, 12.35. Example 34

Bis (2-chlorophenyl) 5,6-dimethyl-8-[(5-fluoro1Fal) .- 3-oxo-2,3-dihydro-1H-imidazo [5, 1-c] [1, 4] Thiazine-1-ylideneamide phosphate

To a suspension of hydrogenated sodium (25.3 mg, 0.634 mmol) (60 g oily) in tetrahydrofuran (2.00 ml) was added the triamino_5,6-dimethyl-8 _ [(5-fluorinated) obtained in Example 6-23. [Pentyl) sulfanyl] -3H-imidazo [5, tric] [1,4] thiazine-3-100-mg (0.317 mL) in tetrahydrofuran (1.00 ml), and shake under ice-cooling for 5 minutes. mixed. To this was added bis (2-chlorophenyl) phosphorochloridate (165 mg, 0.476 mmol), and the mixture was further stirred at room temperature for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure to give the title compound (153 mg, 78¾) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 114-116 ° C.

Infrared absorption spectrum (IR) (in KBr) v: 3069, 2936, 2865, 1744, 1667, 1634, 1566 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 1.46-1.58 (2Η, m), 1.60-1.82 (4H, m), 1.77 (3H, d, J = 0.9 Hz), 2.26 (3H, d, J = 1.2 Hz) , 2.89 (2H, t, J = 7.5 Hz), 4.47 (2H, dt, J = 47.4, 5.7 Hz), 7.10 (2H, tt, J = 7.5, 1.5 Hz), 7.22 (2H, dt, J = 7 > 8, 2.1 Hz), 7.40 (2H, td, J = 8.1, 1.2 Hz), 7.57 (2H, td, J = 8.1, 1.5 Hz), 9.50 (1H, bs). Elemental analysis: C ₂₅ H ₂₅ N ₃ 0 ₄ S ₂ C1 ₂ FP

Calculated (¾): C, 48.71; H, 4.09; N, 6.82; S, 10.40.

Found (%): C, 48.67; H, 3.91; N, 6.79; S, 10.42. Example 35

 N,-{5,6-Dimethyl-8-[(5-fluoropentyl) sulfanyl] -3-oxo-2,3-dihydro-1H-imidazo [5,1-c] [1,4] thiazine-1 -Irident Ν, Ν, Ν ', Ν'-Tetramethylphosphoric triamide

水素化ナトリウム（12.7 mg， 0.317歷01) (60油性）のテトラヒドロフラン（2.00 ml) の懸濁液に、 実施例 6- 23で得られた 1-ァミノ- 5,6-ジメチル-8-[(5-フルォ 口ペンチル）スルファニル] - 3H -イミダゾ [5, 1-c] [1,4]チアジン- 3 オン (50.0 nig, 0.159腿 ol) のテトラヒドロフラン （1.00ml) 溶液を加え、 氷冷下 5分間かき混 ぜた。 これにビス（ジメチルァミノ）ホスホリルクロリド (0.0370 ml, 0.238睡 1) を加え、 さらに室温で 1時間かき混ぜた。'反応混合物に 1N塩酸を加えて酢酸ェチ ルで抽出した。 抽出液を水洗、 乾燥 (MgS0₄) 後、 溶媒を減圧下に留去して題記化 合物 （27.3mg, 38%) を暗赤色結晶として得た。 酢酸ェチル -ジェチルエーテルか ら再結晶して融点 150-152°Cの暗赤色結晶を得た。

To a suspension of sodium hydride (12.7 mg, 0.317-01) (60 oily) in tetrahydrofuran (2.00 ml) was added 1-amino-5,6-dimethyl-8-[(obtained in Example 6-23. 5-Fluoro-pentyl) sulfanyl] -3H-imidazo [5,1-c] [1,4] thiazine-3-one (50.0 nig, 0.159 tmol) in tetrahydrofuran (1.00 ml) Stir for a minute. Bis (dimethylamino) phosphoryl chloride (0.0370 ml, 0.238 sleep 1) was added thereto, and the mixture was further stirred at room temperature for 1 hour. '1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), to obtain solvent was distilled off under reduced pressure the title of compound (27.3 mg, 38%) as a dark red crystals. Recrystallization from ethyl acetate-getyl ether gave dark red crystals with a melting point of 150-152 ° C.

Infrared absorption spectrum (IR) (in KBr) So: 2932, 2845, 2807, 1746, 1672, 1645, 1586 cm " ¹ .

_{Ή-NMR (CDC1 3):} δ 1.48-1.84 (6Η, m), 1.78 (3H, d, J = 0.9 Hz), 2.24 (3H, d, J = 0.9 Hz), 2.63 (6H, s), 2.66 (6H, s), 2.94 (2H, 1, J = 7.5 Hz), 4.45 (2H, dt, J = 47.1, 6.0 Hz), 9.87 (1H, bs).

Elementary analysis: as _{C 17 H 29 N 5 0 2} S 2 FP

Calculated (%): C, 45.42; H, 6.50; N, 15.58; S, 14.27.

Found (%): C, 45.13; H, 6.47; N, 15.19; S, 14.51.

Example 36-1

N- [8- (benzylsulfinyl) -5-methyl-7-oxide-3-oxo-6-pentyl-2,3- Dihydrid-1H-imidazo [5, 1-c] [1,] thiazin-1-ylidene] -4-methylbenzenesulfonamide

 The compound synthesized in Example 4-233 (101 mg, 0.191 ol) was dissolved in acetic acid-THF (1: 1, 3.0 ml), and 30% hydrogen peroxide solution (0.039 ml, 0.383 t ol) was added. The mixture was stirred at room temperature for 30 minutes and further at 60 ° C for 30 minutes. A 30% aqueous hydrogen peroxide solution (0.039 ml, 0.383 ol) was added to the reaction solution, and the mixture was further stirred at 60 ° C for 30 minutes. Dilute the reaction mixture with ethyl acetate (20 ml), wash with water, 2% aqueous sodium bicarbonate, 5% aqueous sodium sulfite, 0.1N hydrochloric acid, water and saturated saline, dry over sodium sulfate, and concentrate under reduced pressure It was dried. The residue is dissolved in methanol, and reversed-phase preparative HPLC (Carrier: 0DS, YMC-Pack, D-0DS-5, 20 mm ID x 250 mm long, manufactured by YMC Corporation, mobile phase : 0.05 (v / v)% trifluoroacetic acid / 60 (v / v)% acetonitrile water), collect the fractions with an elution volume of 205-240ml, and concentrate to dryness to give a yellow powder of the title compound (30%). mg, 0.054 mmol).

Ή-NMR (300 MHz, in double-mouthed form): δ 0.90 (3Η, t, J = 6.8 Hz), 1.36 (4H, m), 1.64 (2H, m), 2.44 (3H, s), 2.63 ( 3H, s), 2.70 (1H, ddd, J = 16.2, 9.0, 7.2 Hz), 2.85 (1H, ddd, J = 15.8, 8, 7, 7.1 Hz), 4.47 (1H, d, J = 12.4 Hz) , 4.52 (1H, d, J = 12.4 Hz), 7.32 (2H, d, J = 8.7 Hz), 7.35 (5H, s), 7.82 (2H, d, J- 8.2 Hz).

Elemental analysis: C ₂₆ H ₂₉ N ₃ 0 ₅ S ₃ O.4H ₂ 0 Calculated: C, 55.08; H, 5.30; N, 7.41; S, 16.97 (%), Found: C, 55.13; H , 5.30; N, 7.23; S, 16.8.0 (%).

Mass spectrometry (SIMS): 560 (M + H), 512 (M + H-SO), 421-SO-PhCH ₂ )

Example 36-2 '

N- [8- (benzylsulfonyl) -5-methyl-7-oxide-3-oxo-6-pentyl-2,3-dihydro-1H-imidazo [5, tric] [1,4] thiazine-1 -Ylidene] -4-methylbenzenesulfonamide

The compound synthesized in Example 4-233 (111 mg, 0.210 mol) was dissolved in chloroform (3.0 ml), m-mouth perbenzoic acid (130 rag, 0.526 alcohol) was added, and the mixture was added at room temperature. Stirred for 20 minutes. Dilute the reaction mixture with ethyl acetate (20 ml), wash with water, 2% aqueous sodium bicarbonate, 5% aqueous sodium sulfite, 0.1N hydrochloric acid, water and saturated saline, dry over sodium sulfate, and reduce pressure. Concentrated. Dissolve the residue in methanol and reverse phase Preparative HPLC (Carrier: 0DS, YMC-Pack, SH-343-5, Inner diameter 20 marauder x Length 250 cruises, manufactured by YMC Corp., Mobile phase: 0.05 (v / v)% trifluoroacetic acid / 60 (v / v)% acetonitrile water). Fractions with an elution volume of 245 to 290 ml were collected and concentrated, and 50% aqueous methanol was added to the residue. The precipitate was collected by filtration, washed with 50% aqueous methanol and dried to obtain a yellow powder of the title compound (44 mg, 0.076 mmol).

 'H-NMR (300 MHz, in double-mouthed form): δ 0.92 (3Η, t, J = 7.0 Hz), 1.39 (4H, m), 1.65 (2H, brquint, J = 7.2 Hz), 2.45 (3H , s), 2.50 (3H, s), 2.59 (2H, t, J = 8.3 Hz), 4.51 (1H, d, J = 12.1 Hz), 4.89 (1H, d, J = 12.1 Hz), 7.32 (2H , d, J = 8.3 Hz), 7.34 (5H, m), 7.76 (2H, d, J- 8.3 Hz).

Elemental _{analysis: C 26 H 29 N 3 0} 6 S 3 Calculated: C, 54.24; H, 5.08 ; N, 7.30; S, 16.71 (), Found: C, 54.19; H, 4.97 ; N, 7.38 ; S, 16.79 (%).

Mass spectrometry (SIMS): 576 (M + H), 598 (M + Na).

Example 36-3

 4-Methyl _N_ {5-methyl-8-[(5-methylhexyl) sulfonyl] -7-oxide-3-oxo-6-pentyl-2,3-dihydro-1H-imidazo [5,1- c] [1,4] thiazine-1-ylidene} benzenesulfonamide

 The compound synthesized in Example 4-225 (113 mg, 0.211 tmol) was dissolved in chloroform (3.0 ml), m-chloroperbenzoic acid (156 mg, 0.633 mmol) was added, and the mixture was added at room temperature for 60 minutes. Stirred. Dilute the reaction mixture with ethyl acetate (20 ml), wash with water, 2% aqueous sodium bicarbonate, 5% aqueous sodium sulfite, 0.1N hydrochloric acid, water and saturated saline, dry over sodium sulfate, and reduce pressure. Concentrated. The residue was dissolved in methanol and subjected to reversed-phase preparative HPLC (Carrier: 0DS, YMC-Pack, SH-343-5, ID: 20 t x 250 mm, manufactured by YMC), mobile phase: 0.05 (v / v)% trifluoroacetic acid / 60 (v / v)% acetonitrile water). Fractions having an elution volume of 345 to 375 ml were collected, concentrated, extracted with ethyl acetate, washed with water, dried, and concentrated to dryness to obtain a yellow powder of the title compound (38 mg, 0.065 mmol). ,

-NMR (300 MHz, in double-mouthed form): δ 0.87 (6Η, d, J = 6.4 Hz), 0.89 (3H, t, J = 6.8 Hz), 1.15 (2H, brdt, J = 8.7, 6.8 Hz) ), 1.36 (6H, m), 1.51 (1H, sept, J = 6.7 Hz), 1.62 (3H, m), 1.82 (1H, m), 2.46 (3H, s), 2.50 (3H, s), 2.54 (2H, brt, J = 8.5 Hz), 3.06 (1H, ddd, J = 12.4, 10.2, 6.8 Hz), 3.66 (1H, ddd, J = 12.4, 9.8, 4.5 Hz), 7.36 (2H, d, J = 8.3 Hz) .), 7.80 (2H, d , J = 8.3 Hz) elemental _{analysis: C 26 H 37 N 3 0} 6 S 3 calculated: C, 53.49; H, 6.39 ; N, 7.20; S, 16.48

(%), Found: C, 53.15; H, 6.28;, 7.44; S, 16.12 (%).

Mass spectrometry (SIMS): 584 (M + H), 606 (M + Na).

Formulation Example 1-1

 Mix all the components of the following formulation uniformly and fill into gelatin capsules to produce capsules containing 100 mg of the compound obtained in Example 4-2 per capsule.

 100 mg of the compound obtained in Example 4-2

 Lactose 100 mg

 Corn starch 40 mg

 Magnesium stearate 1 Omg

 1 capsule 25 Omg

Formulation example 2

 All the components of the following formulation are mixed uniformly, filled into a gelatin capsule, and a capsule is prepared containing 100 mg of the compound obtained in Example 4-6 per capsule.

 Compound obtained in Examples 4-6 100 mg

 Lactose 10 Omg

 Cornstarch 4 Omg

 Magnesium stearate 1 Omg

 250 kg of 1-strength pushel

Formulation example 3

 Mix all the components of the following formulation uniformly, fill into gelatin capsules, and produce capsules containing 100 mg of the compound obtained in Example 4-9 per capsule.

 100 mg of the compound obtained in Example 4-9

Lactose 10 Omg 40mg corn starch

 Magnesium stearate 10mg

 1 capsule 25 Omg

Formulation example 4

 All the components of the following formulation are mixed uniformly and filled into gelatin capsules to produce capsules containing 100 mg of the compound obtained in Examples 4-34 per capsule.

 100 mg of the compound obtained in Example 4-34

 Lactose 10 Omg

 Cornstarch 4 Omg

 Magnesium stearate 10mg

 1 capsule 25 Omg

Formulation Example 1-5

 Mix all the components of the following formulation uniformly and fill into gelatin capsules to produce capsules containing 100 mg of the compound obtained in Example 4-35 per capsule.

 Compound 10 Omg obtained in Example 4-35

 Lactose 10 Omg

 Cornstarch 4 Omg

 Magnesium stearate 10mg

 1 force 25 Omg

Formulation Example 2-1

 The compound obtained in Example 4-2 and magnesium stearate are granulated with an aqueous solution of soluble starch, dried, then mixed with lactose and corn starch, and the mixture is compression-molded to contain 100 mg of the compound per tablet. To make tablets.

 100 mg of the compound obtained in Example 4-2

 Lactose 65mg

 Cornstarch 3 Omg

35mg soluble starch Magnesium stearate 20mg

 1 tablet 25 Omg

Formulation example 2_2

 The compound obtained in Example 4-6 and magnesium stearate were granulated with an aqueous solution of soluble starch, dried, mixed with lactose and corn starch, and the mixture was compression-molded to contain 100 mg of the compound per tablet. To make tablets.

 100 mg of the compound obtained in Example 4-6

 Lactose '65mg

 Corn Yuichi 3 Omg

 35mg soluble starch

 Magnesium stearate 2 Omg

 1 tablet 25 Omg

Formulation example 2-3

 The compound obtained in Example 4-9 and magnesium stearate were granulated with an aqueous solution of soluble starch, dried, mixed with lactose and corn starch, and the mixture was compression-molded, containing 100 rag of the compound per tablet. To make tablets. '' 100 mg of compound obtained in Examples 4-9

 Lactose 65mg

 Cornstarch 3 Omg

 35mg soluble starch

 Magnesium stearate 2 Omg

 1 tablet 25 Omg

Formulation Example 2-4

 The compound obtained in Example 4-34 and magnesium stearate are granulated with an aqueous solution of soluble starch, dried, then mixed with lactose and corn starch, and the mixture is compression-molded, containing 10 Omg of the compound per tablet. Make tablets.

 100 mg of the compound obtained in Example 4-34

 Lactose 65mg

Cornstarch 3 Omg Soluble starch 3 5mg

 Magnesium stearate 20mg

 250mg / tablet

Formulation Example 2-5

 The compound obtained in Example 4-35 and magnesium stearate are granulated with an aqueous solution of soluble starch, dried, mixed with lactose and corn starch, and the mixture is compression-molded to contain 100 mg of the compound per tablet. Make tablets.

 Compound 10 Omg obtained in Example 4-35

 Lactose 65mg

 Cornstarch 3 Omg

 35mg soluble starch

 Magnesium stearate 2 Omg

 1 tablet 25 Omg

Formulation Example 3-1

 The compound obtained in Example 4-2 was dissolved in physiological saline containing 30% (w / v) polyethylene dalicol 400 to prepare a 0.05% solution of the compound.After sterile filtration, 30 ml of the compound was dispensed into vials. Inject and manufacture injections containing 15 mg of compound per vial. Formulation Example 3-2

 The compound obtained in Example 4-6 was dissolved in physiological saline containing 30 (w / v) polyethylene glycol 400 to prepare a 0.05 solution of the compound.After sterile filtration, 30 ml was dispensed into vials. Then, an injection containing 15 mg of the compound per vial is manufactured. Formulation Example 3-3

 The compound obtained in Example 4-9 was dissolved in physiological saline containing 30% (w / v) polyethylene glycol 400 to prepare a 0.05% solution of the compound.After sterile filtration, 30 ml was dispensed into vials. Then, an injection containing 15 mg of the compound per vial is manufactured. Formulation Example 3-4

The compound obtained in Example 4-34 was dissolved in physiological saline containing 30% (w / v) polyethylene glycol 400 to prepare a 0.05% solution of the compound.After sterile filtration, the solution was dispensed into vials at 30 ml each. Injections containing 15 mg of compound per vial are prepared. Formulation Example 3-5

 The compound obtained in Example 4-35 was dissolved in a physiological saline solution containing 30% (w / v) polyethylene glycol 400 to prepare a 0.05 solution of the compound. Dispense to produce injections containing 15 mg of compound per vial. Formulation Example 4-1

 The compound obtained in Example 4-2 and lipoxymethylcellulose sodium are uniformly mixed in a mortar, and a solution prepared by dissolving saccharin sodium in purified water is added little by little and mixed well. Add 1 ml of 10% aqueous sodium benzoate solution, make up to 100 ml with purified water, and prepare a suspension containing 10 mg of compound per 100 ml.

 Compound obtained in Example 4-2 1 O mg

 Carboxymethylcellulose sodium 2.0 g

 4 O mg

 Sodium benzoate 10 O mg

 1 0 0 ml

Formulation Example 4-2

 The compound obtained in Example 4-6 and carboxymethylcellulose sodium are uniformly mixed in a mortar, and a solution prepared by dissolving saccharin sodium in purified water is added little by little and mixed well. 10 Add 1 ml of an aqueous solution of sodium benzoate, make up to 100 ml with purified water, and prepare a suspension containing 10 mg of compound per 100 ml.

 Compound obtained in Example 4-6 10 mg

 Carboxymethylcell mouth sodium 2.0 g

 Saccharin sodium 4 O mg

 Sodium benzoate 10 O mg

 Total volume 100 m l

Formulation Example 4-3

The compound obtained in Example 9 and carboxymethylcellulose sodium are uniformly mixed in a mortar, and a solution prepared by dissolving saccharin sodium in purified water is added little by little and mixed well. Add 1 ml of 10% aqueous sodium benzoate solution, make up to 100 ml with purified water, and prepare a suspension containing 10 mg of compound per 100 ml. Compound obtained in Example 4-9 Omg carboxymethylcellulose sodium 2.0 g

 Saccharin sodium 4 Omg

 Sodium benzoate 10 Omg

 100ml

Formulation Example 4-4

 The compound obtained in Example 4-34 and carboxymethylcellulose sodium are uniformly mixed in a mortar, and a solution prepared by dissolving saccharin sodium in purified water is added little by little and mixed well. 10 ml of an aqueous solution of sodium benzoate is added, and the total volume is made up to 100 ml with purified water to prepare a suspension containing 10 mg of the compound per 100 ml.

 Compound 1 Omg obtained in Example 4-34

 Carboxymethylcell mouth-sunium 2.0 g

 4 Omg

 Sodium benzoate 10 Omg

 100ml

Formulation Examples 4-5

 The compound obtained in Example 4-35 and carboxymethylcellulose sodium are uniformly mixed in a mortar, and a solution obtained by dissolving saccharin sodium in purified water is added little by little and mixed well. Add 1 ml of 10% aqueous sodium benzoate solution, make up to 100 ml with purified water, and prepare a suspending agent containing 10 mg of compound per 100 ml.

 Compound 1 Omg obtained in Example 4-35

 Sodium carboxymethyl cellulose 2.0 g

 Saccharin sodium 4 Omg

 Sodium benzoate 10 Omg

 Total volume 100ml

Test example 1

 A method for measuring the activity of inhibiting the degradation of cartilage proteodarin

Aseptic removal of nasal cartilage from slaughtered cows, Dulbecco's modified serum containing 5% heat-inactivated fetal calf serum, 100 units of penicillin G Zml, and 100 units of streptomycin Zml Preculture was performed for 3 days in a 1: 1 mixed medium of Dull medium / Ham F12 medium at 37 ° C, 5% carbon dioxide, and 95% air. After completion of the preculture, a cartilage piece weighing about 2 mg was prepared, and transferred to a culture medium of IOOU containing human recombinant interleukin-li3 (IL-1: manufactured by Zenzym) and a test compound. Culture was continued for another 4 days. After completion of the culture, the proteodalican released into the culture medium and the sulfated glycosaminodalican contained in the proteodalican remaining in the cartilage fragments are each treated with 1,9-dimethylmethylene blue using the method of Farundel-Arl-Double et al. [Farndal e, RW, et al., Connective Tissue Research, Connect. Tissue Res., Volume 9, pp. 247-248, 1982] to determine the rate of proteodalican degradation. I asked. In addition, Z-DBH (debromohymenialdicine) was used as a control compound. The proteodalican degradation inhibitory activity of the test compound and the control compound was determined by the following formula. Proteodalican degradation inhibitory activity (%) = 100 X (Pi -Ps) / (Pi -Pc)

 Pc: Proteodalican degradation rate when neither IL-li3 nor test compound is contained

 Pi: Proteodalican degradation rate when IL-1) 3 is added

 Ps: Proteodalican degradation rate when both IL-l j3 and test compound were added Test Example 2

 Method for measuring cartilage collagen degradation inhibitory activity

Nasal cartilage is aseptically removed from the slaughtered cattle, and a Dulbecco's modified medium containing 5% heat-inactivated fetal bovine serum, 100 units of penicillin G Ziiil, and 100 units of streptomycin Zml, Zham F12 medium 1: (1) Pre-cultured for 3 days in a mixed medium at 37 ° (5% CO 2, 95% air) to produce a cartilage fragment weighing about 2 mg. After culturing for 7 days in a 100 1 culture medium supplemented with interleukin-1) 3 (IL-liS: manufactured by Zenzam) and human recombinant, Oncostatin M (0SM: manufactured by Zenzam), the medium was added to the medium. The material was renewed and cultured for another 7 days. After completion of the culture, the collagen released in the culture solution and the hydroxyloxyproline contained in the collagen remaining in the cartilage fragments were removed using chloramine-T and P-dimethylaminobenzaldehyde, respectively. The method of Gum-Ie et al. [Bergam, I. et al., Analytical Biochemistry (Anal. Biochem.) 35, 1961-1965, 1963] to determine the rate of collagen degradation. I asked. In addition, Z-DBH (debromohymenialdisine) was used as a control compound. The collagen decomposition inhibitory activity of the test compound was determined by the following equation. Collagen degradation inhibitory activity () = 100 X (Ci-Cs) / (Ci-Cc)

Cc: Collagen degradation rate when neither IL-1β, 0SM nor test compound is contained

Ci: Collagen degradation rate when IL-1β and 0SM are added

Cs: Collagen degradation rate when both IL-1β, 0SM and test compound were added Test Example 3

Method for Measuring the Activity of Inhibiting the Production of Matrix Medium Proteinase-13 (MMP-13) The activity of the test compound to inhibit the production of ΜΜΡ-13 was examined using normal human knee articular chondrocytes (Clonetics). Dulbecco's Buretsutokitto CGM (Clonetics Corp.) normal human knee articular chondrocytes to 1X10 ⁵ cells ZML become as 0.1% heat inactivated fetal bovine serum and cultured with, Beni cylindrical G100 units ZML, streptomycin 100 units ZML After suspension in a modified Eagle medium / ham F12 medium 1: 1 mixed medium, the cells were inoculated in 0.5 ml Z-wells in an 8-well plate and pre-cultured for 1 day under the conditions of 37, 5% carbon dioxide, and 95 air. After completion of the preculture, add 0.5 ml of the test compound dissolved in 0.5 ml of Dulbecco's modified idal medium, Noham F12 medium 1: 1 mixed medium and Ν, Ν-dimethyliormamide, to each well, pre-warmed to 37 ° C. Thirty minutes later, IL-liS (final concentration lOngZml) was added. After culturing the cells for 2 days at 37 ° C, 5% carbon dioxide, and 95% air, the MMP-13 produced in the culture solution was purified using the MMP-13 ERISA system (Amersham Biosciences). Quantified. The MMP-13 production inhibitory activity of the test compound was determined by the following formula.

MMP-13 production inhibitory activity (%) = 100 X (Mi -Ms) / (Mi-Mc) ''

Mc: MMP-13 production when neither IL-li3 nor test compound is contained

Mi: MMP-13 production when adding Ms: MMP-13 production amount when both IL-1 / 3 and test compound were added Test result

 The results in the above Test Examples 1, 2 and 3 are shown in% inhibition rate and are shown in the following table. % The higher the inhibition rate, the higher the proteodalican degradation inhibitory effect, collagen degradation inhibitory effect, and MMP-13 production inhibition effect.

 (Table 1 18)

Cartilage proteodalican degradation inhibitory activity (% inhibition rate)

 卖 ^ / hiruJUi Example 1 1 Li ^ 1 "thing ΎJ 10 // M VI 1 f〃Jj M V

 Λ.

 I Δ

 ■ ¾ 0 i 丄

 Λ-

4-7 100 56

 4-8 99

 4-9 96

 4-10 98

 4-26 81

 4-34 97

 4-35 98

 4-6l (a) 84

 4-62 87

 7-58 91

 7-72 90

Z-DBH 94 36 0 (Table 1 1 9)

 Cartilage collagen degradation inhibitory activity (% inhibition rate)

(Table 12)

 MMP-13 production inhibitory activity (% inhibition rate)

産業上の利用可能性

Industrial applicability

The compound represented by the general formula (I) or a salt thereof, for example, the compounds exemplified in the above Test Examples 12 and 3 are used for analyzing cartilage matrix caused by IL-13. Since it has an excellent inhibitory effect on cartilage destruction due to its ability to inhibit solution and inhibit MMP-13 production, it can be used for cartilage disorders (eg, joints in knee osteoarthritis, rheumatoid arthritis, and similar diseases). It can be used for the prevention and treatment of cartilage destruction, etc., and, in turn, can improve the quality of life of patients who are impaired in daily life due to pain caused by fatigue or destruction of articular cartilage.

Claims

The scope of the claims  1. General formula

[Wherein, R ¹ is — (S) _n —R ² or —NR ³ R ⁴ , n is an integer of 0 to 2, R ² is a hydrogen atom, an optionally substituted hydrocarbon group or substituted Wherein R ³ and R ⁴ are the same or different and are each a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or A nitrogen-containing heterocyclic ring formed together with a nitrogen atom, wherein R ⁵ is a hydrogen atom, an optionally substituted carbon hydride group, a cyano group, an acyl group, an esterified or amidated amino group; A xyl group or an optionally substituted heterocyclic group,

R ⁶ represents a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group, an acyl group, a carboxyl group which may be esterified or amidated, or a heterocyclic group which may be substituted, ⁷ is an optionally substituted hydroxyl group, R ⁸ and R ⁹ are each a hydrogen atom or an optionally substituted hydrocarbon group (R ⁵ and R ⁶ , R ⁵ and R ⁸ or R ^{8 9} may be taken together to form an optionally substituted cyclic hydrocarbon or heterocyclic ring),

The, R ¹⁰ is a hydrogen atom, -ZR ¹⁵ (Z one S0 ₂ -, -SO-, - C_〇_NR ¹⁸ S_〇 ₂ - (R ¹⁸ is - shows the ₆ alkyl), one CONR ¹⁹ - (R ¹⁹ ^ - ₆ an alkyl) or _C_〇-, R ¹⁵ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group) or a P (O) R ¹⁶ R ¹⁷ (R ¹⁶ and R ¹⁷ each represent an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group or an optionally substituted amino group), and R ¹¹ represents a hydrogen atom or a substituted R ¹ ° and R ¹¹ may be taken together to form a nitrogen-containing heterocyclic ring which may be substituted, and R ¹² and R ¹³ may each be a hydrogen atom or a substituted also be a hydrocarbon group or a connexion nitrogen-containing heterocyclic ring such together with the nitrogen atom to which they are attached,, R ¹⁴ is a hydrogen atom, Conversion is hydrocarbon group which may be substituted or a ZR ¹⁵ (Z and R ¹⁵ are as defined above) shows a. Where R ⁵ is a hydrogen atom,

In the formula, R ¹⁴ represents an optionally substituted hydrocarbon group or —ZR ¹⁵ (Z and R ¹⁵ have the same meanings as described above). Or a salt thereof or a sulfoxide thereof. 2. General formula

[Wherein, R ¹ is one (S) _n —R ² or —NR ³ R ⁴ , n is an integer of 0 to 2, R ² is a hydrogen atom, an optionally substituted hydrocarbon group or substituted Wherein R ³ and R ⁴ are the same or different and are each a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or A nitrogen-containing heterocyclic ring formed together with a nitrogen atom, wherein R ⁵ is a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group, an acyl group, a carboxyl group which may be esterified or amidated, or An optionally substituted heterocyclic group,

Is or  r, R R ⁶ represents a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group, an acyl group, an esterified or adoxylated propyloxyl group or an optionally substituted heterocyclic group. R ^{7 represents a} hydroxyl group which may be substituted; R ⁸ and R ^{9 each represent a} hydrogen atom or a hydrocarbon group which may be substituted (R ⁵ and R ⁶ , R ⁵ and R ⁸ or R ⁸ and R ⁹ may be taken together to form an optionally substituted cyclic hydrocarbon or heterocyclic ring),

A, R ^1. Is a hydrogen atom or one ZR ¹⁵ (Z is one S0 ₂ — or one CO—, R ¹⁵ Represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group), R ¹¹ represents a hydrogen atom or an optionally substituted hydrocarbon group, and R ¹² and R ¹³ represent A hydrogen atom or an optionally substituted hydrocarbon group, or a nitrogen-containing heterocyclic ring together with a nitrogen atom to which they are bonded; R ¹⁴ is a hydrogen atom, an optionally substituted hydrocarbon Or ZR ¹⁵ (Z and R ¹⁵ have the same meanings as described above). Where R ⁵ is a hydrogen atom,

In the formula, R ¹⁴ represents an optionally substituted hydrocarbon group or ZR ¹⁵ (Z and R ¹⁵ have the same meanings as described above). Or a salt thereof or a sulfoxide thereof. 3. R ⁵ is an optionally substituted hydrocarbon group, a cyano group, an acyl group, an esterified or amidated hydroxyl group or an optionally substituted complex ring group. Item 6. The compound according to item 1 or 2. Four.

[R ⁶ is a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group, an acyl group, an esterified or amidated alkoxyl group or an optionally substituted heterocyclic group, R ⁷ represents an optionally substituted hydroxyl group; R ⁸ and R ^{9 each} represent a hydrogen atom or an optionally substituted hydrocarbon group (R ⁵ and R ^s ; ⁵ and R ⁸ or R ⁸ And R ⁹ may be taken together to form a cyclic hydrocarbon or heterocyclic ring which may be substituted))]. Five.

[R ^1G is hydrogen atom, - ZR ¹⁵ (Z one SO SO CONR ¹⁸ SO, one ¹⁸ ^ -. Shows a ₆ alkyl), - CONR ¹⁹ - (R ¹⁹ is shows the C E _ ₆ alkyl) Or one CO—, and R ¹⁵ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group) or — P (0) R ¹⁶ R ¹⁷ (R ¹⁶ and R ¹⁷ represent R ¹¹ represents a hydrogen atom or an optionally substituted hydrocarbon group, which represents an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group or an optionally substituted amino group, respectively. R ^1Q and R ¹¹ may be taken together to form an optionally substituted nitrogen-containing complex ring), R ¹² and R ¹³ are each a hydrogen atom or an optionally substituted hydrocarbon group, or And a nitrogen-containing heterocycle together with the nitrogen atom to which they are attached.]. 6.

[R ^{1 ()} is a hydrogen atom or a ZR ¹⁵ (Z one S0 ₂ - or - a CO-, R ¹⁵ is a optionally substituted hydrocarbon group or an optionally substituted heterocyclic group R ¹¹ represents a hydrogen atom or an optionally substituted hydrocarbon group, and R ¹² and R ^{13 represent a} hydrogen atom or an optionally substituted hydrocarbon group, respectively, or a combination thereof. A nitrogen-containing heterocyclic ring together with a nitrogen atom that is present). 7. Compound (I) has the general formula ()

 [Wherein each symbol has the same meaning as described in claim 1.] The compound according to claim 1, which is a compound represented by the formula:  8. Compound (I) has the general formula 1  ()

 [Wherein each symbol has the same meaning as described in claim 2.] 3. The compound according to claim 2, which is a compound represented by the formula: 9. R ^{1Q is} —S0 ₂ R ¹⁵ (R ¹⁵ is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group), and R ⁵ and R ⁶ are each substituted Tei with an optionally substituted cyclic hydrocarbon or an optionally substituted heterocyclic hydrocarbon group, or they may be combined into a connexion formed compound of claim 8 wherein R ¹¹ is a hydrogen atom. 10. The compound according to claim 9, wherein R ¹ is one SR ² (R ² represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group). 11. The compound according to claim 10, wherein R ² is an optionally substituted hydrocarbon group. 12. The compound according to claim 9, wherein R ⁵ and R ⁶ are each an optionally substituted hydrocarbon group having 1 to 6 carbon atoms. ' 13. The compound according to claim 12, wherein R ⁶ is methyl or ethyl. 14. R ⁵ and R ⁶ together form an optionally substituted benzene ring 13. The compound according to claim 12. 15. The compound according to claim 9, wherein R ¹⁵ is an optionally substituted aryl group, an optionally substituted aralkyl group, or an optionally substituted heterocyclic group. 16. The compound according to claim ¹⁵ , wherein R ¹⁵ is an optionally substituted phenyl group, an optionally substituted benzyl group, or an optionally substituted phenyl group. 17.R ¹ is one of SR ² (R ² is an optionally substituted alkyl group having 1 to 8 carbon atoms, an alkenyl group optionally having 2 to 8 carbon atoms, and optionally substituted A cycloalkyl group having 3 to 8 carbon atoms or an aralkyl group having 7 or 10 carbon atoms which may be substituted), and R ¹⁵ is a phenyl group which may be substituted, a benzyl group which may be substituted 10. The compound according to claim 9, wherein the optionally substituted phenyl group, R ⁵ and R ⁶ are both methyl groups. 18. The compound according to claim 17, wherein R ² is an optionally substituted alkyl group having 1 to 8 carbon atoms. 19. The compound according to claim 18, wherein R ² is an alkyl group having 4 to 8 carbon atoms which may be substituted with a halogen atom. 20. When R ^1Q is —COR ¹⁵ (R ¹⁵ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group), and R ⁵ and R ⁶ are each independently substituted 9. The compound according to claim 8, wherein the compound is a good hydrocarbon group or an optionally substituted cyclic hydrocarbon or an optionally substituted heterocyclic ring formed together, and R ¹¹ is a hydrogen atom. 21. The compound according to claim 20, wherein R ¹ is one SR ² (R ² represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group). 22. The compound according to claim 21, wherein R ² is an optionally substituted hydrocarbon group. 23. The compound according to claims 20 to 22, wherein R ⁵ and R ⁶ are each an optionally substituted hydrocarbon group having 1 to 6 carbon atoms. 24. R ⁶ is The compound of claim 23, wherein methyl or Echiru. 25. R ⁵ and R ⁶ The compound of claim 23 wherein forming a benzene ring which may be substituted together. 26. The compound according to claim 20, wherein R ¹⁵ is an optionally substituted aryl group, an optionally substituted aralkyl group, or an optionally substituted heterocyclic group. 27. The compound according to claim 26, wherein R ¹⁵ is an optionally substituted pyridyl group. 28. 4-Bromo-N— {8-[(5-Fluoropentyl) sulfanyl] -5,6-dimethyl-3-oxo-2,3-dihydro-1H-imidazo [5, lc] [l, 4] thiazine-1— Ylidene} benzenesulfonamide, N- {5,6-dimethyl-13-oxo-18-[(4,4,4,5,5-fluorenepentyl) sulfanyl] -1,2,3-dihydro-1H-imidazo [5,1-1c] [l, 4] thiazine-1 1-ylidene} (phenyl) methanesulfonamide, N— {5,6-dimethyl-3—year-old xo 8— [(4,4,4,5,5 —Penfu fluoropentyl) sulfanyl] 1,2,3-dihydro-1H-imidazo [5,1—c] [l, 4] thiazine—11-ylidene} 1-4-methylbenzenesulfonamide, 4-bromo-N— [8— (Isopentylsulfanyl) 1,5,6-dimethyl-3-oxo-1,2,3-dihydro-1H-1 ^ f midazo [5,1—c] [l, 4 [Thiazine_1-Ilidene] benzenesulfonamide or salts thereof.  29. General formula

[Wherein, R ¹ represents one (S) _n _R ² or one NR ³ R ⁴ , n represents an integer of 0 to 2, R ² represents a hydrogen atom, an optionally substituted hydrocarbon group or a substituted R ³ and R ⁴ are the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or a nitrogen atom to which they are bonded. R ⁵ represents a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group, an acyl group, an optionally esterified or amidated nitrogen-containing heterocyclic ring formed together with an atom. A xyl group or an optionally substituted heterocyclic group,

R ⁶ represents a hydrogen atom, a hydrocarbon group which may be substituted, a cyano group, an acyl group, a propyloxyl group which may be esterified or amidated, or a heterocyclic group which may be substituted; R ⁷ is an optionally substituted hydroxyl group; R ⁸ and R ⁹ are each a hydrogen atom or an optionally substituted hydrocarbon group (R ⁵ and R ⁶ , R ⁵ and R ⁸ or R ⁸ And R ⁹ may be substituted together to form a cyclic hydrocarbon or heterocyclic ring,

., R ¹ . It is a hydrogen atom, one ZR ¹⁵ (Z - S_〇 ₂ -, -SO-, one CONR ¹⁸ S_〇 ₂ - (R ¹⁸ represents a CI- ₆ alkyl), -CONR ¹⁹ - (R ¹⁹ is (: ₆ represents an alkyl) or —CO—, and R ¹⁵ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group) or —P (O) R ¹⁶ R ¹⁷ (R ¹⁶ And R ¹⁷ each represent an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group or an optionally substituted amino group), and R ¹¹ represents a hydrogen atom or an optionally substituted hydrocarbon R ¹ ° and R ¹¹ may be taken together to form an optionally substituted nitrogen-containing heterocycle, and R ¹² and R ¹³ are each a hydrogen atom or an optionally substituted hydrocarbon R ¹⁴ is a hydrogen atom, a substituted or unsubstituted nitrogen-containing heterocyclic ring, Or a salt thereof, or a prodrug of the sulfoxide or a salt thereof, which represents a hydrocarbon group or ZR ¹⁵ (Z and R ¹⁵ have the same meanings as described above). 30. General formula

[Wherein, R ¹ represents one (S) _n —R ² or one NR ³ R ⁴ , n represents an integer of 0 to 2, R ² represents a hydrogen atom, an optionally substituted hydrocarbon group or substituted Wherein R ³ and R ⁴ are the same or different and are each a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or A nitrogen-containing heterocyclic ring formed together with a nitrogen atom, wherein R ⁵ is a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group, an acyl group, an esterified or amidated hydroxyl group; Or an optionally substituted heterocyclic group, Or

R ⁶ represents a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group, an acyl group, a carboxyl group which may be esterified or amidated, or a heterocyclic group which may be substituted, ⁷ is an optionally substituted hydroxyl group; R ⁸ and R ⁹ are each a hydrogen atom or an optionally substituted hydrocarbon group (R ⁵ and R ⁶ R ⁵ and R ⁸ or R ⁸ and R ^{8 9} may be taken together to form an optionally substituted cyclic hydrocarbon or heterocyclic ring),

A, R ^1. Is a hydrogen atom, _ZR ¹⁵ (Z is one S〇 ₂ —, one SO— -CONR ¹⁸ SO ₂ — (R ¹⁸ represents — 6 alkyl), one CONR ¹⁹ — (R ¹⁹ represents — ₆ alkyl) or one CO—, and R ¹⁵ represents an optionally substituted hydrocarbon group or substituted Or a P (O) R ¹⁶ R ¹⁷ (R ¹⁶ and R ¹⁷ are each an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, or an optionally substituted heterocyclic group) R ¹¹ represents a hydrogen atom or an optionally substituted hydrocarbon group (R ^{1 Q} and R ¹¹ are taken together to form an optionally substituted nitrogen-containing heterocyclic ring) R ¹² and R ¹³ each represent a hydrogen atom or a hydrocarbon group which may be substituted, or a nitrogen-containing heterocyclic ring together with a nitrogen atom to which they are bonded, and R ¹⁴ represents a hydrogen atom An optionally substituted hydrocarbon group or —ZR ¹⁵ (Z and R ¹⁵ are as defined above) Shows the same meaning). Or a salt thereof, a sulfoxide thereof, or a prodrug thereof represented by the formula (I):  31. The pharmaceutical composition according to claim 30, which is a cartilage matrix degrading enzyme production inhibitor.  32. The pharmaceutical composition according to claim 30, which is a proteodalican degradation inhibitor.  33. The pharmaceutical composition according to claim 30, which is an agent for preventing or treating osteoarthritis.  34. The pharmaceutical composition according to claim 30, which is an agent for preventing or treating a disease caused by cartilage destruction. 35. The pharmaceutical composition according to claim 30, which is a matrix meta-oral proteinase gene expression inhibitor.  36. The pharmaceutical composition according to claim 30, which is a matrix meta-oral proteinase-1 13 gene expression inhibitor.  37. A proteoglycan degradation inhibitor comprising a condensed imidazolidine derivative. .  38. A cartilage matrix degrading enzyme production inhibitor comprising a condensed imidazolidine derivative. 39. An agent for preventing or treating osteoarthritis, comprising a condensed imidazolidine derivative.  40. An agent for preventing and treating diseases caused by cartilage destruction, characterized by containing a condensed imidazolidine derivative. 41. General formula

[Wherein, R ¹ represents one (S) _n —R ² or one NR ³ R ⁴ , n represents an integer of 0 to 2, R ² represents a hydrogen atom, an optionally substituted hydrocarbon group or substituted Wherein R ³ and R ⁴ are the same or different and are each a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or A nitrogen-containing heterocyclic ring formed together with a nitrogen atom, wherein R ⁵ is a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group, an acyl group, an esterified or amidated hydroxyl group; Or an optionally substituted heterocyclic group, X Y is also

R ⁶ represents a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group, an acyl group, a carboxyl group which may be esterified or amidated, or a heterocyclic group which may be substituted, ⁷ is an optionally substituted hydroxyl group, R ⁸ and R ⁹ are each a hydrogen atom or an optionally substituted hydrocarbon group (R ⁵ and R ⁶ , R ⁵ and R ⁸ or R ⁸ R ⁹ may be taken together to form an optionally substituted cyclic hydrocarbon or heterocyclic ring),

, R ^{1 ()} is a hydrogen atom, one ZR ¹⁵ (Z is —SO, SO—, -CONR ¹⁸ SO ₂ - (R ¹⁸ is C ^ - shows the ₆ alkyl), one CONR ¹⁹ - (R ¹⁹ is C - shows the ₆ alkyl) or an CO-, R ¹⁵ may be substituted hydrocarbon group or Represents an optionally substituted heterocyclic group) or one of P ′ (O) R ¹⁶ R ¹⁷ (R ¹⁶ and R ¹⁷ are each an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group or a substituted R ¹¹ represents a hydrogen atom or an optionally substituted hydrocarbon group (R ^1Q and R ¹¹ together represent a nitrogen-containing heterocyclic ring which may be optionally substituted) R ¹² and R ¹³ are each a hydrogen atom or a hydrocarbon group which may be substituted, or a nitrogen-containing heterocycle together with the nitrogen atom to which they are bonded, and R ¹⁴ is a hydrogen atom, optionally substituted hydrocarbon group or - ZR ¹⁵ (Z and R ¹⁵ are, before Shows the the the same meaning). Or a salt thereof or a sulfoxide thereof or a prodrug thereof, which is administered to a mammal in an effective amount.  2. General formula

[Wherein, R ¹ represents one (S) _n —R ² or one NR ³ R ⁴ , n represents an integer of 0 to 2, R ² represents a hydrogen atom, an optionally substituted hydrocarbon group or substituted Wherein R ³ and R ⁴ are the same or different and are each a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or A nitrogen-containing heterocyclic ring formed together with a nitrogen atom, wherein R ⁵ is a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group, an acyl group, an esterified or amidated hydroxyl group; Or an optionally substituted heterocyclic group, Or

R ⁶ represents a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group, an acyl group, a carboxyl group which may be esterified or amidated, or a heterocyclic group which may be substituted, ⁷ is an optionally substituted hydroxyl group, R ⁸ and R ⁹ are each a hydrogen atom or an optionally substituted hydrocarbon group (R ⁵ and R ⁶ , R ⁵ and R ⁸ or R ⁸ R ⁹ may be taken together to form an optionally substituted cyclic hydrocarbon or heterocyclic ring), ― A  14 R  Is N

A, R ^1. Is a hydrogen atom, — ZR ¹⁵ (Z is — S0 ₂ —, —SO—, — CONR ¹⁸ S〇 ₂ — (R ¹⁸ is (: ₆ alkyl), one CONR ¹⁹ — (R ¹⁹ is (: ₆ R ¹⁵ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group) or one P (O) R ¹⁶ R ¹⁷ (R ¹⁶ and R ¹⁷ represents an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group or an optionally substituted amino group), and R ¹¹ represents a hydrogen atom or an optionally substituted hydrocarbon group (R ^1Q and R ¹¹ may be taken together to form an optionally substituted nitrogen-containing heterocyclic ring), R ¹² and R ¹³ are each a hydrogen atom or an optionally substituted hydrocarbon group, Alternatively, together with the nitrogen atom to which they are attached, form a nitrogen-containing heterocycle, R ¹⁴ is a chromium atom, Or a ZR ¹⁵ (Z and R ¹⁵ have the same meanings as described above).] An effective amount of the compound (I) or a salt thereof, a sulfoxide thereof or a prodrug thereof A method for preventing and treating a disease caused by cartilage destruction, which comprises administering to a mammal. 43. General formula for the manufacture of a 'osteoarthritis prevention' therapeutic agent

[Wherein, R ¹ represents one (S) _n —R ² or one NR ³ R ⁴ , n represents an integer of 0 to 2, R ² represents a hydrogen atom, an optionally substituted hydrocarbon group or substituted Wherein R ³ and R ⁴ are the same or different and are each a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or A nitrogen-containing heterocyclic ring formed together with a nitrogen atom, wherein R ⁵ is a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group, an acyl group, an esterified or amidated hydroxyl group; Or an optionally substituted heterocyclic group,

Is also  R ", R R ⁶ represents a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group, an acyl group, a carboxyl group which may be esterified or amidated, or a heterocyclic group which may be substituted, ⁷ is an optionally substituted hydroxyl group, R ⁸ and R ⁹ are each a hydrogen atom or an optionally substituted hydrocarbon group (R ⁵ and R ⁶ , R ⁵ and R ^s or R ⁸ and R ⁹ may be taken together to form an optionally substituted cyclic hydrocarbon or heterocyclic ring),

A, R ^1. Is a hydrogen atom, — ZR ¹⁵ (Z is one S0 ₂ —, one SO—, -CONR ¹⁸ SO ₂ — (R ¹⁸ represents Ci- ₆ alkyl), — CONR ¹⁹ — (R ¹⁹ represents (^ —6 alkyl) or one CO—, R ¹⁵ represents an optionally substituted hydrocarbon group or Or an optionally substituted heterocyclic group) or — P (〇) R ¹⁶ R ¹⁷ (R ¹⁶ and R ¹⁷ are each an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, or an optionally substituted R ¹¹ represents a hydrogen atom or an optionally substituted hydrocarbon group (R ¹ and R ¹¹ together form an optionally substituted nitrogen-containing heterocyclic ring). R ¹² and R ¹³ are each a hydrogen atom or a hydrocarbon group which may be substituted, or a nitrogen-containing heterocycle together with the nitrogen atom to which they are bonded, and R ¹⁴ is , A hydrogen atom, an optionally substituted hydrocarbon group or — ZR ¹⁵ (Z and R ¹⁵ are Which has the same meaning as described above). Or a salt thereof, a sulfoxide thereof or a prodrug thereof. 44. General formula for manufacturing preventive and therapeutic agents for diseases caused by cartilage destruction

[Wherein, R ¹ represents one (S) _n -R ² or —NR ³ R ⁴ , n represents an integer of 0 to 2, R ² represents a hydrogen atom, an optionally substituted hydrocarbon group or substituted Wherein R ³ and R ⁴ are the same or different and are each a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or A nitrogen-containing heterocyclic ring formed together with a nitrogen atom, wherein R ⁵ is a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group, an acyl group, a carboxyl group which may be esterified or amidated, or An optionally substituted heterocyclic group,

R ⁶ represents a hydrogen atom, a hydrocarbon group which may be substituted, a cyano group, an acyl group, a propyloxyl group which may be esterified or amidated, or a heterocyclic group which may be substituted. R ⁷ represents an optionally substituted hydroxyl group; R ⁸ and R ^{9 each} represent a hydrogen atom or an optionally substituted hydrocarbon group (R ⁵ and R ⁶ , R ⁵ and R ⁸ or R ⁸ and R ⁹ may be taken together to form an optionally substituted cyclic hydrocarbon or heterocyclic ring), One A  Is

A, R ^1. Is a hydrogen atom, one ZR ¹⁵ (Z one S_〇 ₂ - one _{^{SO-, - CONR 18 SO 2 -}} (R 18 represents a CI- ₆ alkyl), -CONR ¹⁹ - (R ¹⁹ is (: ₆ R ¹⁵ represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group) or one P (〇) R ¹⁶ R ¹⁷ (R ¹⁶ and R ¹⁷ represents an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group or an optionally substituted amino group), and R ¹¹ represents a hydrogen atom or an optionally substituted hydrocarbon group (R ^1Q and R ¹¹ may be taken together to form an optionally substituted nitrogen-containing heterocyclic ring), R ¹² and R ¹³ are each a hydrogen atom or an optionally substituted hydrocarbon group, Or a nitrogen-containing heterocyclic ring together with the nitrogen atom to which they are attached, R ¹⁴ is a hydrogen atom, Or a salt thereof, or ZR ¹⁵ (Z and R ¹⁵ have the same meanings as described above).] Or a salt thereof, a sulfoxide thereof or a prodrug thereof. 45. Expression

Wherein each symbol is as defined in claim 1] or a salt thereof;

Wherein L is a leaving group, R ⁵ and; ⁶ have the same meaning as described in claim 1, or a salt thereof, followed by a hydrolysis reaction, if desired. General formula characterized by performing a dehydration reaction, an alkylation reaction, a substitution reaction and / or an oxidation reaction

[Wherein the symbols have the same meanings as described in claim 1], a method for producing a compound (I) or a salt thereof or a sulfoxide thereof.