WO1998009967A1 - Pyrrolocarbazole derivatives - Google Patents

Abstract

Pyrrolocarbazole derivatives represented by general formula (I) or pharmacologically acceptable salts thereof, wherein the ring (C) represents a benzene or cyclohexene ring; X and Y are the same or different and each represents carbonyl or methylene; R1 represents lower alkyl or aralkyl; R2 represents hydrogen, optionally substituted lower alkyl, lower alkenyl, or optionally substituted aralkyl; and R?3, R4, R5, R6, R7, R8, R9, R10 and R11¿ are the same or different and each represents hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, halogeno, nitro, optionally substituted lower alkanoyl, NR?12R13, OR14¿, NHCONHR16, or COR17. These compounds have the effect of promoting thrombopoiesis, which makes them useful in the treatment of thrombopenia.

Description

 Specification

 Pyrrolocarbazole derivatives

Technical field

 The present invention relates to a novel pyrrolocarbazolyl derivative or a pharmaceutically acceptable salt thereof useful for treating thrombocytopenia.

Background technology

 Platelet depletion due to various hematopoietic disorders, such as in chemotherapy and radiation therapy for cancer patients and autoimmune diseases such as aplastic anemia, causes severe symptoms such as bleeding tendency. At present, platelet transfusion is the dominant tool, but there is no sufficient platelet supply and there is no marketed drug that directly restores platelet loss. In addition to platelet transfusion, other compounds that promote the production of platelets include proteinaceous hematopoietic factors such as inuichi-leukin (IL) -16, IL-11, c-Mpl ligand, or indolorubazol compounds, conagenin , 2-Viranone derivative, FK5

65, Low molecular weight compounds such as α-galactosylceramide derivatives, pyrazolipid pyridine compounds, condensed virazole compounds, thioglycerol derivatives, and ketimine derivatives are known. [Blood, 75, 1602 (1990); Blood, 81, 901 (1993); Nature, 369, 533 (1994) International publication W〇94 / 06799, JP-A-7-285870, EP-0672668A, EP-067055A5A; JP-A-5-229939; JP-A-5-2 1337 58, JP-A-5-221867; WO93 / 23066; W094 / 02168; JP-A-6-32734; JP-A-6-206872;

7-126243, JP-A-7-247265, JP-A-7-252166, EP-0623343 A].

 It is known that pyrrolocarbazole derivatives have inhibitory activity against protein kinase C, antitumor activity and neurotrophic factor activity [Japanese Patent Laid-Open Nos. 2-142791, 4-178387, and 4-1] 230 385, JP-A-8-59666: Bioorganic & Medicinal Chemistry Letters, Vol. 5, pp. 1167 (1995)].

However, all of the pyrrolocarbazole derivatives have the effect of promoting platelet production. It is not known that there is any use.

 The pyrrolocarbazole derivative disclosed in Japanese Patent Application Laid-Open No. 2-142971 is characterized in that R ′ in the general formula (I) described below is hydrogen.

 In the pyrrolocarbazole derivative, as the compound in which R ′ in the general formula (I) described later is not hydrogen, compounds (A) disclosed in JP-A-4-178387 and JP-A-4-230385, Compounds (B) and Hetercrocycles, 27 described in Bioorganic & Medicinal Chemistry Letters), Vol. 5, pp. 1167 (1995), 27 The compound (C) described in Vol. 2, pp. 253 (1988) is known.

(D) However, as compound (A), JP-A-4-178387 or JP-A-4-1230

Specifically disclosed in Examples 385 is a compound in which a substituted phenyl group is bonded to the 5-position of a pyrazole rubazole skeleton and ^RA is 2- (dimethylamino) ethyl. Is limited to Furthermore, in these cases: (1) when X ¹ and Y ¹ are carbonyl, R ^B is hydrogen, 9-hydroxy or 9-methoxy, R ^c is hydrogen, and R ^D is hydrogen or or 2,4-difluoro. (2) When X ¹ is methylene and Y ′ is carbonyl, R ^B is hydrogen, R ^c is methyl, and R ^D is restricted to hydrogen.

Further, Compound R ^A moiety is a lower alkyl or Ararukiru is only described compounds (D) and the compound (E) is known as a raw material of the compound (B) and the compound (A). Compound (A) is known to have antitumor activity, but is not known to have a platelet production promoting effect. There is no report on the platelet production promoting effect of compound (B).

Disclosure of the invention

 The present invention provides a compound represented by the general formula (I):

(I)

Wherein ring C is a benzene ring or cyclohexene ring, X and Y are the same or different and are carbonyl or methylene, R ¹ is lower alkyl or aralkyl, R ^z is hydrogen, A substituted or unsubstituted lower alkyl, lower alkenyl or substituted or unsubstituted aralkyl, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ^ie and R ¹¹ are the same or different and each represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, halogen, nitro, substituted or unsubstituted lower alkanol, NR ¹² R ¹³ (wherein, R ¹² and R ′ ³ are the same or different and each represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkanoyl, aryloyl, lower alkoxycarbonyl, aralkyloxycarbonyl or amino acid A residue excluding the hydroxyl group of the carboxylic acid (the amino group of the amino acid may be protected by a protecting group)}, OR ¹⁴ (wherein, is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted of Arukanoiru, Aroiru, substituted or unsubstituted Ararukiru, substituted or unsubstituted heterocyclic group, CONHR ^'5 (in the formula R ¹⁵ is hydrogen, lower alkyl or Ariru) or tri-lower alkylsilyl}, NHCONHR ^'6 (wherein, R ^lfc is hydrogen, lower alkyl or Ariru), or COR' ⁷ {wherein, R ¹⁷ hydroxy, 'of ⁹ (wherein, R' lower alkoxy, NR ^l8 R ⁸ and R are the same or different, hydrogen, hydroxy, Ararukiru, substituted or unsubstituted lower alkyl, or N together are Or SR ^2e (where R ^2e is a lower alkyl, aryl or heterocyclic group).

However, (1) when X and Y are carbonyl at the same time, the ring C is a benzene ring, and R ^s , R ⁷ , R ⁸ and R ¹⁰ are simultaneously hydrogen, R ³ , R ⁴ , R ⁶ , At least one of R ⁹ and R ¹¹ is OR ²¹ (where R ²¹ is a higher alkanol, a substituted or unsubstituted heterocyclic group, a lower alkyl substituted with a substituted or unsubstituted heterocyclic group, CONHR ¹⁵ Wherein R ¹⁵ is as defined above, or tri-loweralkylsilyl; NHCONHR ¹⁶ (where R ' ⁶ is as defined above), substituted or unsubstituted lower alkyl, substituted or unsubstituted A substituted lower alkenyl or COR ¹⁷ wherein R ¹¹ is as defined above; (2) X and Y are carbonyl, R ^{1 is} benzyl, R ² is hydrogen when R ³ and R ⁵ are simultaneously black ^{opening, R 4, R 6, R} 7, R 8, R 9, R '° Oyo R ¹¹ is not hydrogen simultaneously, (3) X is carbonyl, Y is methylene, when R ¹ and R ² is ^{methyl, R 3, R 4, R} 5, R fc, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are not hydrogen at the same time. Or a pharmaceutically acceptable salt thereof.

 Hereinafter, the compound represented by the formula (I) is referred to as compound (I). The same applies to compounds of other formula numbers.

 In the definition of each group of compound (I), lower alkyl is straight-chain or branched having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, ter. Represents t-butyl, pentyl, neopentyl, hexyl, etc.

 Lower alkenyl represents a group having 2 to 6 carbon atoms, for example, vinyl, aryl, butenyl, pentenyl, hexenyl, pentenyl, hexenyl, and the like.

 The aralkyl moiety in aralkyl and aralkyloxycarbonyl represents a carbon number of 7 to 15, for example, benzyl, phenethyl, benzhydryl, naphthylmethyl and the like.

 Lower alkanoyl represents a straight or branched chain having 1 to 6 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, vivaloyl, hexanoyl and the like.

 The alkanol is the lower alkanol, and the carbon number? Represents up to 20 straight-chain or branched higher alkanols, for example, octanoyl, nanonoyl, palmitoyl, stearoyl and the like.

 The aryl and the aryl portion of the aryl represent, for example, phenyl, naphthyl and the like.

 The lower alkyl moiety in lower alkoxycarbonyl, lower alkoxy and tri-lower alkylsilyl has the same meaning as the lower alkyl, and the three lower alkyls in tri-lower alkyl may be the same or different.

 The heterocyclic group represents an aliphatic heterocyclic group such as pyrrolidinyl, piberidinyl, morpholinyl and the like, and an aromatic heterocyclic group such as furyl, phenyl, pyrrolyl, pyridyl, imidazolyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl and quinazolinyl.

A heterocyclic group formed by sandwiching N (the heterocyclic group may contain an oxygen atom, a sulfur atom, or another nitrogen atom) is pyrrolidinyl, morpholino, thiomorpholino, N-methylbiperazinyl, birazolidinyl , Piperidino, piperazinyl, homopi Represents perazinyl, indolyl, isoindolyl, etc.

 Halogen represents each atom of fluorine, chlorine, bromine or iodine.

 Amino acids represent natural amino acids such as glycine, alanine, proline, glutamic acid, lysine, serine, cysteine, phenylalanine, and tyrosine. Amino protecting groups for amino acids are those usually used in peptide synthesis, and include, for example, benzyloxycarbonyl, t-butoxycarbonyl and the like.

Substituents in the substituted lower alkyl may be the same or different and have 1 to 3 substituents, for example, hydroxy, halogen, oxo, lower alkoxy, carboxy, lower alkoxycarbonyl, lower alkanoyloxy, aroyloxy, p-toluenesulfonyloxy , Methanesulfonyloxy, aryl, heterocyclic group, NR ²⁷ R ²⁸ (wherein R ²⁷ and R ²⁸ are the same or different and are hydrogen, lower alkyl, cycloalkyl, aralkyloxycarbonyl, or A heterocyclic group formed by sandwiching N (the heterocyclic group may contain an oxygen atom, a sulfur atom or another nitrogen atom)}, CONR ²⁹ R ³⁰ (wherein R ²⁹ and R ³ ° Are the same or different and are hydrogen, hydroxy, aralkyl, lower alkyl, or a heterocyclic group formed together by N (The heterocyclic group may contain an oxygen atom, a sulfur atom or another nitrogen atom.) NR ³ ′ R ³² R ³³ Ha 1 (wherein R ³ ′ and R ³² are the same or different R ³³ is lower alkyl, aralkyl, or a heterocyclic group formed together by N (the heterocyclic group may contain an oxygen atom, a sulfur atom, or another nitrogen atom); Ha is a chlorine, bromine or iodine atom or represents trimethylsilylethoxy, etc. The lower alkyl moiety in the lower alkyl, lower alkoxy and lower alkoxycarbonyl has the same meaning as the lower alkyl described above. The lower alkanoyl moiety in the lower alkanoyloxy has the same meaning as the lower alkanoyl.The cycloalkyl has 3 to 6 carbon atoms, for example, cyclopropyl, Represents aryl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The aryl moiety in the aryl and the aryloxy has the same meaning as the aryl, and the aralkyl moiety in the aralkyl and the aralkyloxycarbonyl has the same meaning as the above aralkyl. The heterocyclic group has the same meaning as the above heterocyclic group, and the heterocyclic group formed by sandwiching N is a heterocyclic group formed by sandwiching N. Synonymous with ring group.

 The substituent in the substituted lower alkenyl has the same meaning as the substituent in the substituted lower alkyl.

 The substituents in the substituted aralkyl are the same or different and have 1 to 3 substituents, for example, halogen, nitro, amino, lower alkylamino, di-lower alkylamino and the like. The lower alkyl moiety in the lower alkylamino or di-lower alkylamino has the same meaning as the lower alkyl. The halogen has the same meaning as the halogen.

The substituted lower Arukanoiru are the same or different number of substituted 1 to 3, for example in a halogen or NR ^27A R ^{Z 8A} (formula as defined above, R ^27A and R ^28A are the same meanings as defined above R ^{2 7} and R ²⁸ , Etc.).

 Substituents in the substituted heterocyclic group are the same or different and represent lower alkyl, aralkyl and the like having 1 to 3 substituents. The lower alkyl has the same meaning as the lower alkyl, and the aralkyl has the same meaning as the aralkyl.

 In the lower alkyl substituted with a substituted or unsubstituted heterocyclic group, the lower alkyl moiety has the same meaning as the lower alkyl, the heterocyclic group has the same meaning as the heterocyclic group, and the substituted heterocyclic group has the same meaning. Has the same meaning as the above-mentioned substituted heterocyclic group.

 The pharmaceutically acceptable salts of compound (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. Examples of acid addition salts include inorganic acid salts such as hydrochloride, sulfate, phosphate, etc., acetate, maleate, fumarate, tartrate, citrate, lactate, aspartate, glutamate, etc. Organic acid salts, such as sodium salts, potassium salts, etc .; alkaline earth metal salts, such as alkali metal salts, magnesium salts, calcium salts, etc .; aluminum salts, zinc salts, etc .; and ammonium salts. Salts include salts such as ammonium and tetramethylammonium; organic amine addition salts include addition salts such as morpholine and piperidine; and amino acid addition salts include addition salts such as lysine, glycine, and phenylalanine. Can be

 Next, a method for producing the compound (I) will be described.

In the reaction steps, structural formulas, tables and the like described below, Me, Et, n—Pr, n—Bu, t—Bu, Bn, Ac, Ph, Ts, Ms, TBS, Bz are methyl, ethyl, n-propyl, n-butyl, t-butyl, benzyl, acetyl, phenyl, p — Means toluenesulfonyl, methanesulfonyl, t-butyldimethylsilyl, benzoyl. Further, the ring C including a dotted line in the structural formula represents a benzene or cyclohexene ring. The definition of each group in each step is synonymous with each of the above groups unless otherwise specified.

 Compound (I) can be produced according to the following reaction steps.

 In the following production methods, if the defined groups change or are unsuitable for carrying out the method, the methods for introducing and removing protecting groups commonly used in organic synthetic chemistry [ For example, Protective Groups in Organic Synthesis, by TW Greene, John Wiley and Sons Inc. ) (1981)] can be used to obtain the desired compound. In addition, the order of reaction steps such as introduction of a substituent can be changed as necessary.

Manufacturing method 1

 Compound (Ia) in which ring C is a cyclohexene ring and X and Y are carbonyl in compound (I) can be produced by the following steps.

(G) (Wherein, R ′, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are as defined above)

Process 1

 Compound (Ia) can be obtained by reacting compound (F) with compound (G) in a solvent such as xylene, toluene, dichlorobenzene or the like or without solvent.

 Compound (G) is used in an amount of 1 to 20 equivalents based on compound (F). The reaction is carried out between 60 and 200 and ends between 1 minute and 48 hours.

Compound (F) may be substituted or unsubstituted benzaldehyde in a known manner [eg, Canadian Journal of Chemistry (Can. J. Cem.), 51, 792 (1973)]. By a Wittig reaction with a substituted or unsubstituted halogenated indole-2-methyltriphenylphosphonium salt obtained in the same manner (the halogen is as defined above for Ha1) or by a known method [for example, · Substituted or unsubstituted 2-fluoro-2-carboxaldehyde and substituted or unsubstituted compounds obtained according to Journal of Organic Chemistry (j org. Chem.), 52, 104 (1987)]. Wittig reaction with substituted halogenated benzyltriphenylphosphonium salts (wherein the halogen is synonymous with Ha 1 above) [eg Canadian's Journal Ob. Chem. (Can. J. Chem.), 51, 792 (1973); Synthesis, 743 (1992)]. The functional groups contained in the substituents of R ³ , R ⁴ , R ^s , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹ ′ of the compound (F) are as described in the following production method 3 Can be converted to other desired functional groups.

Manufacturing method 2

Compound (Ic) in which ring C is a benzene ring in compound (I) can be produced from compound (Ib) in which ring C is a cyclohexene ring by the following steps.

 (lb) (lc)

Wherein X, Y, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^fc , R ⁷ , R ⁸ , R ⁹ , R ′ and R ¹¹ are as defined above.

Process 2

 The compound (lb) obtained by the above-mentioned production method 1 or the following production method 4 is converted to 2,3-dichloro-1,5,6 in a single or mixed solvent such as methylene chloride, ethyl acetate (AcOEt), toluene and dioxane. Compound (Ic) can be obtained by reacting with a dehydrogenating agent such as -dicyanor-1,4-benzoquinone (DDQ), 10% PdZC.

 The dehydrogenating agent is used in an amount of 2 to 10 equivalents based on compound (lb). The reaction is carried out at a temperature of 120 to 180 ° C. and is completed in 1 minute to 24 hours.

Manufacturing method 3

Among the compounds (I), the compound (Ie) having a functional group at the R ³ , R ⁴ , R ⁵ , R ^fc , R *, R ^fl , R ⁹ , R ¹⁰ or R ′ ¹ site is represented by R ^{3 , R 4, R 5, R} , R 7, R B, R 9 , or compounds having other functional groups in R ¹¹ sites, from (I d), can be prepared by the following Symbol steps.

(Id) (le) (Wherein, X, Y, R ¹ and R ² are as defined above, and R ^3a , R ^4a , R ^5a , R ^fca ,

R 7 & R ^8A > 10a Rl) ^a ^ 3b 4 b 5b 6 b 7b 8b R

^9b , R ^{, 0b} and R ^{l lb} follow the definition in each step below)

Process 3-1

{Wherein R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ′. ^a and R ' ^la are at least one carboxy, and at least one of R ^3b , R ^4b , R ^Sb , R ^6b , R ^7b , R ^8b , R ^9b , R ^{, 0} and R ^lb is CONR ¹⁸ R ' ⁹ (wherein, R ^ie and R ¹⁹ are as defined above) or C〇SR ^2C (wherein, R ^2C is as defined above)

 Compound (Id) can be obtained by converting thionyl chloride, phosphoryl chloride, pentachloride in the presence or absence of a base such as triethylamine, pyridine, or the like, alone or in a mixed solvent such as methylene chloride, tetrahydrofuran (THF) or a solvent. Reaction with a halogenating agent such as phosphorus or phosphorus trichloride, and then in a solvent such as methylene chloride, THF, or dimethylformamide (DMF) alone or in the presence or absence of a salt such as triethylamine or pyridine. Next formula

^{HNR 1B R 19 (1 1)} , or

R ^Z0 SH (III)

(In each formula, R ′ ^e , R ¹⁹ and R ² ° are as defined above.)

Compound (Ie) can be obtained by reacting with compound (II) or compound (III) represented by

 Based on the compound (Id), the base is used in an amount of 0 to 100 equivalents, the halogenating agent is used in an amount of 1 to 200 equivalents or a solvent, and the compound (II) or the compound (III) is used in an amount of 1 to 100 equivalents, respectively. The reactions are each performed at between 80 and 120 and are completed within 1 minute to 24 hours.

Process 3-2

{Wherein a ^{R 3a, R 4a, R 5a} , R 6a, R 7a, R 8a, R, a, is one even R ^IOa and R ^{l la} is no less ^{carboxy, R 3b, R 4b, R} 5b ^{, R tb, R 7b, R} 8b, R 9b, R, ob and R ^{l lb} is at least one of C_〇_NR ¹⁸ R ¹⁹ (wherein, R ^'8 and R ¹⁹ are the same as defined above) or COS R ² ° (wherein R ^2C is as defined above) }

 Compound (Id) is used alone or in a mixed solvent such as THF, DMF, methylene chloride, etc., in 4-dimethylaminopyridine (DMAP), 1-hydroxybenzotriazol hydrate (HOB t), p-nitrophenol 1- (3-dimethylaminopropyl) _3-ethylcarbodiimide hydrochloride (WS C · HC 1), N, N'-dicyclohexylcarpoimimid in the presence or absence of additives such as triethylamine and triethylamine Compound (Ie) is obtained by reacting with Compound (II) or Compound (III) in the presence of a condensing agent such as amide (DCC), 2-chloro-1-methylpyridium iodide, diphenylphosphoryl azide, etc. Can be.

 The additive is used in an amount of 0 to 10 equivalents to the compound (Id), and the condensing agent and the compound (II) or the compound (III) are each used in an amount of 1 to 50 equivalents. The reaction is carried out at —80 to 200: and is completed in 5 minutes to 120 hours.

Process 3-3

^{(Wherein, R 3a, R 4a, R} 5a, R fca, R 7 a, R 8a, R, a, R, 0a and R 'lower ^{of la} was one is lower alk force Noiru or hydroxy-substituted even without least Alkyl, wherein R ^3b , R ^4b , R ^5b , R ^6b , R ^7b , R ^8b , R ^{, b} , R ^10b and R ^lb are at least one hydroxy-substituted lower alkyl or lower alkyl)

 Compound (Id) is reacted with a reducing agent alone or in a mixture of THF, dioxane, methylene chloride, chloroform, DMF, methanol, water, trifluoroacetic acid, hydrochloric acid, acetic acid, etc., or 10% PdZC Compound (Ie) can be obtained by performing catalytic reduction in the presence of such a catalyst.

 As the reducing agent, sodium borohydride, sodium cyanoborohydride, triethylsilane and the like are used. For compound (Id), the reducing agent is 1 to 10

0 equivalents, the reduction catalyst is used 10 to 100% (weight). The reaction is — 80-12

Done at 0 and ends in 5 minutes to 24 hours.

Step 3-4

Wherein R ^3a , R ^4a , R ^5a , R ^ba , R ^{7a .R ea} , R ^9a , R ^10a and R ^la are at least one formyl or a lower alkyl substituted with formyl, and R ^3b , R ^4b , R ^5b , R ^6b , R ^7b , R ^eb , R ^9b , R ^{, 0} and ^R'lb are at least one NR ^{2 a} R ^z8a (wherein, R ^27a and R ^28a are groups other than the definition of R ²⁷ and R ²⁸ except for aralkyloxycarbonyl) are substituted lower alkyls}

 Compound (Id) is treated with a reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride in a solvent alone or in a mixed solvent such as chloroform, THF, methanol, acetonitrile, water, acetic acid and hydrochloric acid. Next formula

HNR ^27a R ^28a (IV)

( ^Wherein , R ^z7a and R ^28a are as defined above)

Compound (Ie) can be obtained by performing a reductive amination reaction using compound (IV) represented by

 The reducing agent and the compound (IV) are each used in an amount of 1 to 200 equivalents relative to the compound (Id). The reaction is carried out at a temperature of 120 to 100 ° C. and is completed in 5 minutes to 24 hours.

Process 3 _ 5

(Wherein, R ^3a , R ^4a , R ^sa , R ^6a , R ^7a , R ^8a , R ^9a , R ′. At least one of ^a and R ^lla is formyl, and R ^3b , R ^4b , R ^{5 \ R fcb, R 7b,} R 8b, R 9b, R 10b and R ^'lb at least one is a lower alkenyl substituted or unsubstituted)

 Compound (Id) in a single or mixed solvent such as methylene chloride, THF and DMF, in the presence or absence of a phase transfer catalyst such as 18-crown-16, potassium carbonate, n-butyllithium, sodium hydride Reaction with a substituted or unsubstituted halogenated lower alkyltriphenylphosphonium salt (the halogen is as defined above for Ha 1) or a substituted or unsubstituted lower alkyl diphosphoryl dialkyl lower ester in the presence of a base such as By doing so, compound (Ie) can be obtained.

For compound (Id), a base and a substituted or unsubstituted halogenated lower alkyltriphenylphosphonium salt (the halogen is as defined above for Ha 1) or a substituted or unsubstituted lower alkyl The lower alkyl phosphite is used in an amount of 1 to 20 equivalents, and the phase transfer catalyst is used in an amount of 0 to 1 equivalent. The reaction is performed at —80 to 120 and ends in 5 minutes to 24 hours. Process 3-6

(Wherein a ^{R 3a, R 4a, R Sa} , R 6a, R 7a, R 8a, R, R 10a and R '' ^a lower alkenyl one substituted or unsubstituted even without less, R ^3b, At least one of R ^4b , R ^Sb , R ^6b , R ^7b , R ^Bb , R ^9b , R ^{, 0} and R ^llb is a substituted or unsubstituted lower alkyl)

 Catalytic reduction of compound (Id) in AcOEt, DMF, etc., alone or in a mixed solvent, in the presence or absence of a base such as sodium bicarbonate, 丄 0% PdZC or other catalyst As a result, the compound (Ie) can be obtained.

 Based on the compound (Id), the reduction catalyst is used in an amount of 10 to 500% (by weight) and the base is used in an amount of 0 to 10 equivalents. The reaction is carried out at a temperature of 20 to 120 ° C and is completed in 5 minutes to 24 hours.

Process 3-7

^{(Wherein, R 3a, R 4a, R} 5a, R ba, R 7a, a ^{R 8a, R 9 a, R} , 0a and R ^{l la} one is lower alkoxycarbonyl Biel even without less, R ^3b, R ^4b , R ^5b , R ^6b , R ^7b , R ^8b , R ^9b , R ^{, 0b} and R ' ^lb are at least one of formylmethyl.) Compound (Id) is dissolved in a solvent such as acetonitrile in a solvent such as acetonitrile. Compound (Ie) can be obtained by reacting with trimethylsilane in the presence of silane or sodium iodide in the presence of trimethylsilane.

 Iodotrimethylsilane or sodium iodide and chlorotrimethylsilane are each used in an amount of 1 to 10 equivalents to the compound (Id). The reaction is carried out between 180 and 100 and ends in 5 minutes to 24 hours.

Process 3-8

(Wherein R ^3a , R ^a , R ^5a , R ^fca , R ^7a , R ^8a , R ^9a , R ^{, 0a} and R ′ ^la are at least one hydrogen, R ^3b , R ^4b , R ^5b R ^6b , R \ R ^8b , R ^9b , R ′ ° ^b and R ^{l lb} are methyl substituted with at least one of NR ^27a R ^28a , wherein R ^27a and R ^28a are as defined above. is there }

 Compound (Id) is reacted with formalin and compound (IV) in a solvent such as DMF, or

CH ₂ (NR ^27a R ^28a ) ₂ (V) (Wherein, R ^21a and R ^28a are as defined above)

Compound (Ie) can be obtained by reacting with compound (V) represented by

 Formalin and compound (IV) or compound (V) are each used in an amount of 1 to 100 equivalents based on compound (Id). The reaction is performed at 0-180 and ends in 5 minutes to 24 hours.

Process 3-9

{Wherein, R ^3a, is ^{R 4a, R 5a, R fca} , R 7a, R 8a, R 9a, R, 0a and R ^{l la} one hydroxy or carboxy even without less, R ^3b, R ^4b, At least one of R ^5b , R ^6b , R, ^b , R ⁸ \ R ⁹ R ^10b and R ' ^lb is OR' ^4a (where R

^{, 4a} is substituted or unsubstituted lower alkyl, substituted or unsubstituted aralkyl, heteroaralkyl, substituted or unsubstituted heterocyclic group or substituted or unsubstituted heterocyclic group substituted lower alkyl) or lower alkoxycarbonyl is there }

 Compound (Id) is dissolved in a single or mixed solvent such as DMF, THF and toluene in the presence of a base by the following formula:

R ' ^4a Ha 1 (VI), or

R ^{, 4a} OR 36 (VII), or

R ³⁷ H a 1 (VIII)

(In each formula, R ′ ″ and Ha 1 are as defined above, R ³⁶ is T s or M s, and R ³⁷ is lower alkyl.)

The compound (Ie) can be obtained by reacting with the compound (VI) or the compound (VIII) represented by the following or with the compound (VIII).

 As the base, sodium hydride, potassium carbonate, potassium t-butoxy, N, N-diisopropylethylamine and the like are used. The compound (VI) or the compound (VII), or the compound (VIII) and the base are each used in an amount of 1 to 20 equivalents based on the compound (Id). The reaction is carried out at —20-120 ^ and ends in 5 minutes-24 hours.

Process 3—10 (Wherein, at least one of R ^3a , R ^4a , R ^5a , ^{ba .R 7a} , R ^Ba , R ^{, a} , R ¹⁰³ and R ^lla is at least one of NR ³¹ R ^3Z (where R ³ ′ and R ^3Z is the same as defined above, wherein R ^3b , R ^4b , R ^5b , R ^6b , R ^7b , R ^8b , R ^9b , R ′ ° ^b and R ^Mb are at least one of NR ³¹ R ³² R ³³ H a 1 (wherein, R ³ ′, R ³² , R ³³ and Ha 1 have the same meanings as defined above). The compound (Id) is DMF, In a solvent such as form, the following formula

R ³³ Ha 1 (IX)

(Wherein, R ³³ and H a 1 are as defined above)

Compound (Ie) can be obtained by reacting with compound (I X) represented by

 The compound (IX) is used in an amount of 1 to 20 equivalents based on the compound (Id). The reaction is carried out between 0 and 180 and ends in 5 minutes to 24 hours.

Process 3— 1 1

^{{Wherein, R 3a, R 4a, R} 5a, R 6a, R 7a, R ea, R 9a, R, 0a and R ^{l la} One is NR ³ even without least ^{'R 3Z R 33 H a 1} ( formula Wherein R ³ R ^3Z , R ³³ and HaI are the same as defined above, and R ^3b , R ⁴ , R ^Sb , R ^6b , R ^7b , R ^8b , R ^9b , R ^10b and R ^{l lb} are at least one lower alkanoyloxy-substituted lower alkyl}

 Compound (Id) is represented by the following formula:

R CO _z H (X)

(Wherein, R ³⁷ is as defined above)

Using a compound (X) represented by the following formula as a solvent:

R ³⁷ C〇 ₂ (XI)

(Wherein R ³⁷ has the same meaning as described above, and M is potassium or sodium), whereby compound (Ie) can be obtained by reacting with compound (XI).

 The compound (XI) is used in an amount of 1 to 100 equivalents based on the compound (Id). The reaction is carried out between 0 and 200 and is completed between 5 minutes and 48 hours.

Process 3— 1 2 ^{{Wherein, R 3a, R 4a, R} 5a, in ^{R 6a, R 7a, R ea} , R 9a, R, 0a and R ^{l la} is even no less one is 〇_R ^14b (wherein, R ^14b is substituted or R ^3b , R ^4b , R ^5b , R ^6b , R ⁷ \ R ^8b , R ^9b , R ^10b and R ′ ^lb, which are unsubstituted lower alkanoyl) or lower alkanoyloxy-substituted lower alkyl. Is at least one hydroxy or hydroxy-substituted lower alkyl.

 The compound (Ie) can be obtained by reacting the compound (Id) with an acid or a base in a single or mixed solvent such as methylene chloride, THF, methanol, dioxane, and water.

 As the acid, hydrochloric acid, sulfuric acid or the like is used, and as the base, sodium methoxide, sodium hydrogen carbonate, potassium carbonate, aqueous ammonia, dimethylamine or the like is used. The acid or the base is used in the amount of 0.1 to 200 equivalents to the compound (Id), respectively. The reaction is carried out in 20 to 120 hours and is completed in 1 minute to 24 hours. Process 3—1 3

^{{Wherein, R 3a, R 4a, R} 5a, R 6a, R 7a, R 8a, R, a, R, 0a and R ^{l la} One is NR ^3l even without least R ³² R ³³ Ha 1 (wherein , R ³¹ , R ³² , R ³³ and H a1 have the same meanings as defined above, or a lower alkyl or halogen substituted with a halogen (the halogen has the same definition as the above Ha 1); And R ^3b , R ^4b , R ^5b , R ^6b , R ^7b , R ^8b , R ^9b , R ^{, 0b} and R ″ ^b are at least one of lower alkyl or hydrogen.

 Compound (Ie) can be obtained from compound (Id) by the same steps as in Steps 3-6.

Process 3-14

{Wherein, R ^3a, is ^{R 4a, R Sa, R fca} , R 7a, R ea, R 9a, R 10a and R '' ^a is the one even without least Amino or hydroxy, R ^3b, R ^4b, At least one of R ^5b , R ⁶ R ^7b , R ^8b , R ^9b , R ^{, 0b} and R ′ ^lb is NHCONHR ¹⁶ (wherein R ′ ⁶ is as defined above) or OCONHR ′ ⁵ (wherein R ¹⁵ is as defined above.)

Compound (Id) can be prepared by reacting compound (Id) alone or in a mixed solvent such as methylene chloride, DMF or THF in the presence or absence of a base such as triethylamine or pyridine, with the following formula R ³⁸ NCO (XII)

(Wherein, R ^3B has the same meaning as R ^1S or R ^lb )

Compound (Ie) can be obtained by reacting with compound (XII) represented by

 Compound (XII) is used in 1 to 20 equivalents and base is used in 0 to 20 equivalents with respect to compound (Id). The reaction is carried out in 20 to 120 hours and is completed in 5 minutes to 24 hours.

Step 3-1 5

^{{Wherein, R 3a, R 4a, R} sa, R fca, in ^{R 7a, R ea, R,} R, 0a and R ^{l la} is even no less one is lower alkoxycarbonyl or OR ¹ "(wherein, R ¹ "Is lower alkoxycarbonyl-substituted lower alkyl), and R ^3b , R ^4b , R ^5b , R ^6b , R ^7b , R ^eb , R ^9b , R ^{, ob} and R ^lb are at least one of carboxy or 〇lb. R ^{14d wherein} R ′ ^4d is carboxy-substituted lower alkyl.

 Compound (Ie) can be obtained by reacting compound (Id) with an acid such as hydrochloric acid or sulfuric acid in a single or mixed solvent such as methylene chloride, dioxane and THF.

 The acid is used in 0.1 to 100 equivalents relative to compound (Id). The reaction is carried out at 0 to 120 and ends in 5 minutes to 120 hours.

Process 3-16

(Wherein a ^{R 3a, R 4a, R 5a} , R 6a, R 7a, R ea, R, a, R, is one even ^oa and R ^{l la} is no less hydrogen, R ^3b, R \ R ^Sb , R ^6b , R ^7b , R ^8b , R ⁹ R ′ ° ^b and R ¹ are at least one octalogene (the halogen is as defined above for Ha 1)}

Compound (Id) is used alone or in a mixed solvent such as chloroform, methylene chloride, methanol, and THF, in the presence or absence of a base such as t-butylamine, in the presence or absence of sulfuryl chloride, tetra-n-butylammonium salt. The compound (Ie) can be obtained by reacting with an octalogizing agent such as a rib mouth mid, N-bromosuccinimide, λ'-succinimide and the like. The base is used in an amount of 0 to 10 equivalents, and the halogenating agent is used in an amount of 1 to 10 equivalents based on compound (Id). The reaction is performed at —20 to 100 and ends in 5 minutes to 24 hours. Process 3-1 7

{Wherein R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ′. ^at least one of ^a and R ' ^la is carboxy, OR " ^d (where R" ^d is as defined above) or CONR ¹⁸ R ¹⁹ (where R' ⁸ and R ¹⁹ are as defined above) a is ^{a), R 3b, R 4b,} R 5b, R 6b, R 7b, R 8b, R 9b, R, 0b and R ^{l lb} at least one hydroxymethyl, during oR ^L4E (wherein, R ¹ is Methyl substituted with hydroxy-substituted lower alkyl) or NR ^18a R ^{, 9a} (where R ' ^ea and R ^19a are the same or different and are hydrogen or substituted or unsubstituted lower alkyl) Is)

 Compound (Ie) can be obtained by reacting compound (Id) with a reducing agent such as borane Z dimethyl sulfide complex or borane ZT HF complex in a solvent such as THF.

 The reducing agent is used in an amount of 0.3 to 50 equivalents based on compound (Id). The reaction is performed at between 20 and 10 Ot: and is completed in 5 minutes to 24 hours.

Process 3—18

(Wherein, at least one of R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ′ ° ^a and R ^lla is OR ^14d (where R ^14d is as defined above) At least one of R ^3b , R ^4b , R ^Sb , R ^6b , R ^7b , R ^8b , R, R ^10b and R ^llb is OR ^{, 4e} (wherein, R ^14e is as defined above) Is) is}

 The compound (Id) is reacted with a halogenating agent such as thionyl chloride, phosphoryl chloride, phosphorus pentachloride, phosphorus trichloride in a solvent alone or in a mixed solvent such as methylene chloride and THF, and then dioxane and methylene chloride. Compound (Ie) can be obtained by reacting with a reducing agent such as sodium borohydride alone or in a mixed solvent such as methanol and methanol.

The compound (Id) is used in an amount of 1 to 200 equivalents of the halogenating agent or as a solvent, and 1 to 100 equivalents of the reducing agent. Each reaction is carried out at a temperature of 120 to 120 ° C and is completed in 5 minutes to 24 hours. Process 3-19

(Wherein, R ^3a , R ^a , R ^5a , R ^6a , R ^7a , R ^8a , R ^{, a} , R ^{, 0a} and R ^la are at least one hydroxy-substituted lower alkyl, R ^3b , ^{R 4b, R 5, R 6b} , R 7b, R 8b, R,, R 10b and R '' ^b is at least one is black port substituted lower alkyl)

 Compound (Id) is reacted with a halogenating agent such as thionyl chloride, phosphoryl chloride, phosphorus pentachloride, phosphorus trichloride or the like in a solvent alone or in a mixed solvent such as methylene chloride, THF or the like, to give compound (Id). e) can be obtained.

 The halogenating agent is used in an amount of 1 to 200 equivalents or a solvent with respect to the compound (Id). The reaction is carried out at —20 to 120 and ends in 5 minutes to 24 hours. Process 3-20

(Wherein a ^{R 3a, R 4a, R 5a} , R 6a, R 7a, R 8a, R 9a, is one even R ^IOa and R ^{l la} is no less ^{hydroxy, R 3b, R 4b, R} 5b, R ^6b , R ^7b , R ^eb , R ^9b , R ^{, 0b} and R ^lb are at least one of tri-lower-alkylsilyloxy) Compound (Id) in a solvent such as DMF, imidazole, triethylamine, etc. By reacting with tri-lower alkylsilane in the presence of a base, the compound

(I e) can be obtained.

 For the compound (Id), the base and the tri-lower alkylsilane are each used in an amount of 1 to 20 equivalents. The reaction is carried out in a period of 20-100, and is completed in 5 minutes to 24 hours.

Process 3-2 1

{Wherein, at least one of R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ^IOa and R ′ ^la is OR ^14f (where R ¹⁴ⁱ is aralkyl, N— R ^3b , R ^4b , R ^Sb , R ^6b , R ^7b , R ^Bb , R ^9b , R ^{, 0b} and R ′ ^{lb ,} which are lower alkyl substituted with an aralkyl heterocyclic group or an N-aralkyl heterocyclic group. Is at least one of OR ¹⁴⁹ , where is hydrogen, a heterocyclic group or a heteroalkyl-substituted lower alkyl.

Compound (Ie) can be obtained from compound (Id) by the same steps as in Steps 3-6. {Wherein R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ′. ^a and R ^{l la} is one hydroxy even without ^{less, R 3b, R 4b, R} 5b, R 6b, R 7b, R 8b, R 9b, R, ob and R ^'lb is at least one of OR ^14h ( Wherein R ^14h is a substituted or unsubstituted lower or higher alkanoyl)

 The compound (Id) can be prepared by adding the compound (Id) in a solvent such as THF, DMF, or methylene chloride, alone or in a mixed solvent, in the presence or absence of DMAP, in the presence of a base such as pyridine, triethylamine, or the like.

R ^14h Ha 1 (XIII), or

(R ^{, 4h} ) a O (XIV)

(In each formula, R ' ^4h and H a 1 are as defined above.)

Compound (Ie) can be obtained by reacting with compound (XIII) or compound (XIV) represented by

 Based on the compound (Id), the base and the compound (XII) or the compound (XIV) are each used in an amount of 1 to 50 equivalents, and DMAP is used in an amount of 0 to 1 equivalent. The reaction is carried out in 20 to 120 hours and is completed in 5 minutes to 24 hours.

Process 3-23

(Wherein a ^{R 3a, R 4a, R 5a} , R 6a, R 7a, R 8a, R, a, R l0a and R ^{l la} one hydroxymethyl even without less, R ^3b, R ^4b, R ^At least one of ^5b , ^Rbb , ^R7b , ^R8b , ^R9b , ^R10b and ^Rlb is formyl)

 Compound (Ie) can be obtained by reacting compound (Id) with an oxidizing agent such as manganese dioxide in a single or mixed solvent such as methylene chloride, toluene and DMF.

 The oxidizing agent is used in an amount of 100 to 2000% (by weight) based on the compound (Id). The reaction is carried out at about 20 to 12 O: and is completed in 30 minutes to 120 hours.

Process 3-24

(Wherein R ^3a , R ^4a , R ^sa , R ^6a , R ^7a , R ^8a , R ^9a , R ^{, 0a} and R ′ ^la are at least one carboxy, and R ^3b , R ^4b , R ^5b , R ^6b , R ^7b , R ^8b , R ^9b , R ^{, 0b} and R ^lb are at least one lower alkoxycarbonyl) The compound (Id) is reacted with a lower alkyl alcohol in the presence or absence of an acid catalyst such as p-toluenesulfonic acid or sulfuric acid in a solvent alone or in a mixed solvent such as methylene chloride, 1,2-dichloroethane or the like or without solvent. As a result, compound (Ie) can be obtained.

 The acid is used in an amount of 0.01 to 1 equivalent, and the lower alkyl alcohol is used in an amount of 1 to 100 equivalents or a solvent, based on the compound (Id). The reaction is carried out between 0 and 120 and ends in between 5 minutes and 120 hours.

Process 3—2 5

(Wherein, R ^3a , R ^4a , R ^5a , R ^fca , R ^7a , R ^ea , R ^9a , R ′ ° ^a and R ^lla are at least one of carboxy or hydroxy, and R ^3b , R ^4b , R ^Sb , R ^6b , R ^7b , R ^8b , R ^q R ' ⁰ and R ^llb are at least one methoxycarbonyl or methoxy)

 The compound (Id) is reacted with diazomethane in a single or mixed solvent such as methylene chloride, methanol, acetate nitrile, and ether, or in the presence or absence of a base such as diisopropylethylamine in the presence or absence of (trimethylsilyl) diazometa. Compound (Ie) can be obtained by reacting with

 Diazomethane or (trimethylsilyl) diazomethane is used in an amount of 1 to 50 equivalents and the base is used in an amount of 0 to 50 equivalents based on compound (Id). The reaction is carried out between 120 and 80 and ends between 1 minute and 24 hours.

Process 3-2 6

^{{Wherein, R 3a, R 4a, R} 5a, in ^{R 6a, R 7a, R 8a} , R 9a, R, 0a and R ^{l la} one is OR ^14e even without least is (wherein, R ^14e is defined as above a is ^{a), R 3b, R 4 b} , R 5b, in ^{R fcb, R \ R 8b,} R 9b, R, 0b and R '' ^b is at least one of 〇 R ^"1 (wherein, R ¹⁴ⁱ is Methanesulfonyloxy, p-toluenesulfonyloxy or cycloalkyl-substituted lower alkyl)}

Compound (Id) is reacted with methanesulfonyl chloride or p-toluenesulfonyl chloride in a solvent such as methylene chloride or 1,2-dichlorobenzene in the presence of a base such as pyridin or triethylamine to give the compound. (Ie) can be obtained. For compound (Id), methanesulfonyl chloride or p-toluenesulfate Honyl is used in an amount of 120 equivalents and a base is used in an amount of 120 equivalents or as a solvent. The reaction takes place in one hundred twenty-one and ends in five minutes to 48 hours.

Process 3-27

Wherein an ^{R 3a R 4a R 5a R 6a} R 7a R ea R 9a R 103 and R ^{l la} has one even without least OR ^L4i (wherein, R ^L4i is as defined above), R ^3b R ^4b R ^Sb R ^fcb R ^7b R ^8b R ^9b R ^10b and at least one of R ' ^lb are O R' ^4j (wherein, R ^14j is NR ^27a R ^28a (wherein, R ^27a and R ^28a are as defined above) Is lower alkyl substituted with})

 Compound (Id) is reacted with compound (IV) in the presence or absence of sodium iodide or potassium iodide, alone or in a mixed solvent of DMF, methylene chloride, etc., or DMF, methylene chloride, etc. By reacting with sodium iodide or potassium iodide in a single or mixed solvent of the above, and then reacting with compound (IV) alone or in a mixed solvent of DMF, methylene chloride, etc. to obtain compound (I e) be able to.

 To the compound (Id), 0200 equivalents of sodium iodide or potassium iodide is used, and 1,200 equivalents of the compound (IV) are used, respectively. Each reaction is performed at —20 120 ”and completes in 5 minutes to 24 hours.

Process 3—28

^{{Wherein, R 3a R 4a R Sa R} fca R 7a R 8a R 9a, R, 0a and R ^{l la} is one nitro even without ^{less, R 3b R 4b R 5b R} tb R 7b R eb RR 10b and R '' ^b is (wherein, R at least one of NR l2a ^{R, 3a '2a} and R ^{13 a} are the same or different, hydrogen, a substituted or unsubstituted lower alkyl)}

 The compound (Id) is subjected to catalytic reduction using a catalyst such as 10% Pd ZC in a single or mixed solvent such as DMF or ethanol, or under the catalytic reduction, to perform a reductive amination reaction using the corresponding aldehyde. By doing so, compound (Ie) can be obtained.

Based on the compound (Id), the reduction catalyst is used at 100% by weight, and the aldehyde is used at 1,200 equivalents. The reaction takes place between 20 and 120 minutes, 5 minutes to 48 hours Ends in between.

Process 3—29

(Wherein, R ^3a, is ^{R 4a, R 5a, R 6a} , R 7a, R ea, R 9a, R, oa and R ^{l la} has one even without least ^{formyl, R 3b, R 4b, R} 5b , R ^6b , R ^7b , R ^Bb , R ^9b , R ^10b and R ^llb are at least one carboxy)

 Compound (Id) was treated with sodium chlorite, [bis (trifluorofluoride) in a solvent alone or in a mixture of chloroform, methylene chloride, DMF, dimethyl sulfoxide (DMSO), methanol, water, phosphate buffer, etc. Acetoxy) eodo] benzene, [bis

(Trifluoroacetoxy) chloride] Compound (Ie) can be obtained by reacting with an oxidizing agent such as pentafluorobenzene.

 The oxidizing agent is used in an amount of 1 to 100 equivalents based on compound (Id). The reaction is carried out between 120 and 100 and ends in 5 minutes to 24 hours.

Process 3-30

{Wherein, R ^3a, R ^4a, in ^{R 5a, R 6a, R 7a} , R 8a, R 9a, R, 0a and R ^{l la} has one even without least OR ^"k (wherein, R ^'4k is pyrrolidinyl R ^3b , R ^4b , R ^5b , R ^6b , R ^7b , R ^8b , R ^9b , R ^{, ob} and R ′ ^lb are at least one of the following: piperidinyl or pyridinyl or piperidinyl-substituted lower alkyl. 〇 R ^{, 4n} (where R ' ^4m is N-lower alkylpyridinyl, N-lower alkylpiperidinyl or N-lower alkylpyridinyl or N-lower alkylpiperidinyl-substituted lower alkyl) is there)

 Compound (Id) was treated with sodium cyanoborohydride, sodium triacetoxyborohydride, hydrogen, in a solvent alone or in a mixed solvent such as chloroform, THF, methanol, acetate, water, acetic acid and hydrochloric acid. The compound (Ie) can be obtained by performing a reductive amination reaction using an aldehyde in the presence of a reducing agent such as sodium borohydride.

 The reducing agent and the aldehyde are each used in an amount of 1 to 200 equivalents based on compound (Id). The reaction is performed at —20-10 Ot: and ends in 5 minutes to 24 hours. Process 3-31

( ^Where R ^3a , R ^4a , R ^5a , R ^fca , R ^7a , R ^8a , R ^9a , R ^10a and R ^lla are small At least one is COS R ²⁰ (where R ^z is as defined above), and R ^3b , R ^4b , R ^5b , R ^6b , R ^7b , R ^8b , R ^9b , R ^10b and R ^{l lb} is at least one of the holmills}

 Reduction of compound (Id) in a single or mixed solvent such as DMF and methylene chloride in the presence of triethylsilane or a hydrogen stream in the presence of a catalyst such as 10% Pd / C yields compound (Id). e) can be obtained.

 Based on the compound (Id), the reduction catalyst is used in an amount of 10 to 500% (by weight), and triethylsilane is used in an amount of 1 to 20 equivalents. The reaction is carried out at -20 to 120, and is completed in 5 minutes to 24 hours.

Manufacturing method 4

 Among the compounds (I), the compound (Ig) in which at least one of X and Y is methylene can be produced from the compound (If) in which at least one of X and Y is carbonyl by the following steps. it can.

 (If) (ig)

(Wherein, R ′, R ² , R ³ , R ⁴ , R ^s , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ′ ° and R ¹ ′ are as defined above, X ^a and Y ^a is at least one carbonyl, X ^b and Y ^b are at least one methylene)

Process 4

The compound (If) is reacted with a reducing agent such as borane-dimethylsulfide complex or borane.THF complex in a solvent such as THF, and then in a solvent such as hydrochloric acid, sulfuric acid or the like alone or in a mixed solvent of THF, dioxane, water or the like. The compound (Ig) can be obtained by reacting with an acid. Based on the compound (If), the reducing agent is used in an amount of 0.3 to: L00 equivalent, and the acid is used in an amount of 0.1 to 100 equivalents. Each reaction is carried out at —80 to 12 O: and is completed in 5 minutes to 24 hours.

The conversion of the functional group contained in the substituent of R ³ , R ⁴ , R ⁵ , R ^fc , R ⁷ , R ⁸ , R ⁹ , R ^1G or R ′ ^{1 in} the compound (I) and the starting compound is not described above. And other known methods [eg, Comprehensive Organic Transformations, R. C., Larock, (1989)]. it can.

 The compound (I) having a desired functional group at a desired position can be obtained by appropriately combining and carrying out the above methods.

 The isolation and purification of the product in the above production method can be carried out by appropriately combining methods used in ordinary organic synthesis, for example, filtration, extraction, washing, drying, concentration, crystallization, various types of chromatography, and the like. In addition, the intermediate can be subjected to the next reaction without purification.

 The compound (I) may exist as isomers such as positional isomers, geometric isomers or optical isomers, but the possible isomers and mixtures of the isomers in any ratio are also included in the present invention.

 When it is desired to obtain a salt of compound (I), the compound (I) may be purified as it is when the salt is obtained, or may be dissolved or suspended in an appropriate solvent when obtained in a free form, An acid or a base may be added to form a salt.

Compound (I) or a pharmaceutically acceptable salt thereof may be present in the form of an adduct with water or various solvents, and such adducts are also included in the present invention. Specific examples of the compound (I) are shown in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, and Table 10. In the table, (E: Z) and (diastereomeric ratio) represent the geometric isomer ratio and diastereomeric ratio, respectively. LZ

u n H H HO ε

H H H HO zv mo H H H HO

 H H H. V0 0

H ^z oo HH. V0 6

HH ^Z 0N H. VO 8

HHH ^z 00 H OVO L

H H uao H. V0 9

H H H OVO 9

HH VO ^z H0 H OVO

H H HO'HO H uao ε

H 10 H 3 OQ HO z

HHHHH ²⁰⁰

₉ y

€ SieO / i6 ^ / 3d 9660/86 OW

Compound

R ³

20 C0 ₂ H

21 CONH (CH ₂ ) ₂ NMe ₂ HCI

22 CONMe (CH ₂ ) ₂ NMe ₂

 23 CO N ^, NMe HCI

24 cos-¾

 25 COSEt

26 CH ₂ OH

27 CH ₂ NMe ₂

28 CH ₂ ) ₂ fights e ₂ (E: 8: 1)

29 = ^ CH ₂ ) ₂ NMe ₂ (E Λ: 18)

30 ^ (CH ₂ ) ₂ NEt ₂ HCI 2:)

31 (CH ₂ ) ₂ NEt ₂ HCI (E 1: 8) 32 (CH ₂ ) ₄ NMe ₂ Table 3 (1

Compound

畨 "H R H H 4 ^

33 then H = CH then H ₂ NMe ₂ Π Π Π

34 (CH ₂ ) ₃ NMe ₂ HHH

 35 CH = CHOMe H H H

36 CH ₂ CHO HHH

37 (CH ₂ ) ₂ NMe ₂ HHH

38 CONH (CH ₂ ) ₂ NEt ₂ HHH HCI

39 OH CH ₂ NMe ₂ H Br

40 OH CH ₂ NMe ₂ HH

41 0 (CH ₂ ) ₂ NMe ₂ CH ₂ NMe ₂ HH 2HCI

42 OH CH ₂ Awake e ₃ l HH

43 OH CH ₂ OAc HH

44 OH CH ₂ OH HH

 45 OH Me H H

46 0 (CH ₂ ) ₂ NMe ₂ Me HH

47 OH C0 ₂ Me CI H

Table 3 (2

Compound

R ³ R ⁴ R ⁶ R ⁹ Inn

48 0 (CH ₂ ) ₂ NMe ₂ C0 ₂ Me CI H HCI

49 0 (CH ₂ ) ₂ NMe ₂ NHCONHPh HH HCI

50 0 (CH ₂ ) ₂ NMe ₂ C0 ₂ Me HH HC!

51 0 (CH ₂ ) ₂ Ne ₂ C0 ₂ HHH HCI

52 0 (CH ₂ ) ₂ NMe ₂ CONEt ₂ HH HCI

53 0 (CH ₂ ) ₂ CI H CH ₂ OH H

54 0 (CH ₂ ) ₂ CI H Me H

55 0 (CH ₂ ) ₂ CI H Me Br

56 0 (CH ₂ ) ₂ NMe ₂ H CH ₂ OH H

57 0 (CH ₂ ) ₂ NMe ₂ H Me H

58 0 (CH ₂ ) ₂ NMe ₂ H Me Br

59 0 (CH ₂ ) ₂ NMe ₂ H CH ₂ NMe ₂ Br

60 0 (CH ₂ ) ₂ NMe ₂ H CH = CHPh H

61 0 (CH ₂ ) ₂ NMe ₂ H (CH ^ Ph H

62 0 (CH ₂ ) ₂ NMe ₂ H CH (OH) e Br

Table 3 (3

Compound

63 0 (CH ₂ ) ₂ NMe ₂ H CH (OH) e H

64 0 (CH ₂ ) ₂ NMe ₂ H Et Br

65 0 (CH ₂ ) ₂ NMe ₂ H Et H

66 0 (CH ₂ ) ₂ NMe ₂ H NHCONHMe H

67 0 (CH ₂ ) ₂ NMe ₂ H NHCONHn-Pr H

68 0 (CH ₂ ) ₂ NMe ₂ H NHCONHPh H

69 OAc H C0 ₂ Me H

70 OH H C0 ₂ Me H

71 0 (CH ₂ ) ₂ NMe ₂ H C0 ₂ Me H HCI

72 0 (CH ₂ ) ₂ NMe ₂ H C0 ₂ HH HCI

73 0 (CH ₂ ) ₂ NMe ₂ H CONH ₂ H HCI

74 0 (CH ₂ ) ₂ NMe ₂ H CONHMe H HCI

75 0 (CH ₂ ) ₂ NMe ₂ H CONMe ₂ H HCi

76 0 (CH ₂ ) ₂ NMe ₂ H CO 〇 H HCI

Compound

No.R ³ R ⁴ R ⁶ R ⁹

77 0 (CH ₂ ) ₂ NMe ₂ H CONH (CH ₂ ) ₂ OH H HCI

78 0 (CH ₂ ) ₂ Ne ₂ H CONHOH H

79 0 (CH ₂ ) ₂ diagram e ₂ H CONHBn H HC!

80 OH H C0 ₂ HH

81 OH H CH ₂ OH H

82 OTBS H C0 ₂ HH

83 OTBS H CH ₂ OH H

 84 OTBS H CHO H

85 0 (CH ₂ ) ₂ NMe ₂ H CH = CH ₂ H HCI

86 0 (CH ₂ ) ₂ e ₂ H CH = CHEt H HCI

87 0 (CH ₂ ) ₂ NMe ₂ H CH = CHC0 ₂ Et H HCI

_{88 0 (CH 2) 2 NMe} 2 H (CH 2) 2 C0 2 Et H HCI

89 0 (CH ₂ ) ₂ strokes e ₂ H CH = CHC0 ₂ HH HCI

90 OCHMeCH _{2 go} e ₂ H NHCONHMe H HCI

Compound

No.R ³ R ⁴ R ⁵ R '

91 OAc H C0 ₂ HH

 92 OAc H COSEt H

 93 OAc H CHO H

 94 OH H CHO H

95 0 (CH ₂ ) ₂ NMe ₂ H CHO H

96 0 (CH ₂ ) ₂ NMe ₂ H CH ₂ OH H

97 0 (CH ₂ ) ₂ NMe ₂ H CH ₂ NMe ₂ H

98 0 (CH ₂ ) ₂ CI H CHO H

99 0 (CH ₂ ) ₂ NMe ₂ H C0 ₂ Me H HCI

100 0 (CH ₂ ) ₂ NMe ₂ H C0 ₂ HH HCI

101 OAc H Me H

 102 OH H Me H

103 0 (CH ₂ ) ₂ NMe ₂ H Me H

104 OAc H OBn H

Table 4 (2

Compound

 + &

W u R ³ R ⁴ R ⁵ R ⁶

 105 OH H OBn H

106 0 (CH ₂ ) ₂ NMe ₂ H OBn H

107 0 (CH ₂ ) ₂ NMe ₂ H OH H

108 0 (CH ₂ ) ₂ NMe ₂ H OMe H

 109 OH H OH H

110 0 (CH ₂ ) ₂ NMe ₂ H OBn Br

111 0 (CH ₂ ) ₂ NMe ₂ H OH Br

1 120 (CH ₂ ) ₂ NMe ₂ Br OH Br

1 13 0 (CH ₂ ) ₂ NMe ₂ H OCONHMe H

114 0 (CH ₂ ) ₂ NMe ₂ H OCO (CH ₂ ) ₃ Me H HCI

1 150 (CH ₂ ) ₂ NMe ₂ H OCO (CH ₂ ) ₈ e H HCI

1 16 0 (CH ₂ ) ₂ NMe ₂ H OCO (CH ₂ ) ₁₄ Me H HCI

117 OAc H N0 ₂ H

118 OH H N0 ₂ H

Compound

货 R ³ R ⁴ R ⁵ R ⁶ 4fe

133 OCHMeCH ₂ OH H CONMe ₂ H

134 OCHMeCH ₂ OH H CH ₂ NMe ₂ H

135 OCHMeCH ₂ OMs H CONMe ₂ H

136 OCHMeCH ₂ NMe ₂ H CONMe ₂ H HCI

137 OCHMeCH ₂ OMs H CH ₂ NMe ₂ H

138 OCHMeCH ₂ NMe ₂ H CH ₂ NMe ₂ H

139 OCHMeCH ₂ NMe ₂ H NMe ₂ H 2HCI

Table 5 (1

Compound

# R ³ R ⁷

140 OAc C0 ₂ Me

141 0 (CH ₂ ) ₂ NMe ₂ C〇 ₂ Me

142 0 (CH ₂ ) ₂ NMe ₂ C0 ₂ H

_{143 0 (CH 2) 2 N} e 2 COSEt

144 OH C0 ₂ H

145 OH CH ₂ OH

 146 OH CHO

147 0 (CH ₂ ) ₂ NMe ₂ CHO

148 OH CH ₂ CI

 149 OH Me

150 0 (CH ₂ ) ₂ NMe ₂ Me

151 0 (CH ₂ ) ₂ NMe ₂ CH ₂ OH

 152 OH NHCOt-Bu

153 0 (CH ₂ ) ₂ NMe ₂ NHCOt-Bu HCI Table 5 (2

Compound

τττ mouth R ³ FT

 154 OH OMe

155 0 (CH ₂ ) ₂ NMe ₂ OMe HCI

156 OH OBn

157 0 (CH ₂ ) ₂ NMe ₂ OBn HCI

158 OH CONEt ₂

159 0 (CH ₂ ) ₂ NMe ₂ CONEt ₂ HCI

160 0 (CH ₂ ) ₂ Ne ₂ OH HCI

161 0 (CH ₂ ) ₂ NMe ₂ OAc HCI

162 OH n-Bu

163 0 (CH ₂ ) ₂ NMe ₂ n-Bu HCI

164 OH F

165 0 (CH ₂ ) ₂ NMe ₂ F HCI

166 OCHMeC0 ₂ Me Br

167 OCHMeC0 ₂ H Br

Compound

R ³ R ⁷

168 OCHMeCH ₂ OH Br

169 OCHMeCH ₂ OMs Br

170 OCHMeCH ₂ NMe ₂ Br HCI (Diastereomer ratio 1: 0)

171 OCHMeCH ₂ NMe ₂ Br HCI (Diastereomer ratio 2: 3)

172 OCHMeC0 ₂ Me OBn

173 OCHMeC0 ₂ H OBn

174 OCHMeCH ₂ OH OBn

175 OCHMeCH ₂ OMs OBn

176 OCHMeCH ₂ NMe ₂ OBn HCI (Diastereomer ratio 1: 0)

177 OCHMeCH ₂ NMe ₂ OBn HCI (Diastereomer ratio 0: 1)

178 OCHMeC0 ₂ Me OH

179 OCHMeC0 ₂ Me F

180 OCHMeC0 ₂ HF

181 OCHMeCH ₂ OH F

Compound

182 OCHMeCH ₂ OTs F

183 OCHMeCH ₂ NMe ₂ F HCI (Diastereomer ratio 1: 0)

184 OCHMeCH ₂ NMe ₂ F HCI (Diastereomer ratio 0: 1)

Compound

 R R H

185 0 (CH ₂ ) ₂ Ne ₂ Me H HCI

186 0 (CH ₂ ) ₂ NMe ₂ CH ₂ OH H

187 0 (CH ₂ ) ₂ Ne ₂ CH ₂ Ne ₂ H 2HCI

188 0 (CH ₂ ) ₂ NMe ₂ CH = CHPh H

189 0 (CH ₂ ) ₂ NMe ₂ CH = CHn-Pr H

190 0 (CH ₂ ) ₂ Ne ₂ Et H

191 OAc C0 ₂ HH

192 OAc C0 ₂ e H

193 OH C0 ₂ Me H

194 0 (CH ₂ ) ₂ NMe ₂ C0 ₂ Me H

 195 OAc Me H

 196 OH Me H

197 OCHMeCH ₂ NMe ₂ Me H HCI

Table 6 (2

Compound

R ³ R ⁹ R ¹¹

198 OCH ₂ CHMeNMe ₂ Me H HCI

199 0 (CH ₂ ) ₂ NMe ₂ H CH ₂ NMe ₂ 2HCI

200 0 (CH ₂ ) ₂ NMe ₂ H CH ₂ OH HCI

201 0 (CH ₂ ) ₂ NMe ₂ H Me HCI

202 ¾Bn H H

 203 H H HCI

204 H H HCI

205 H H

Bn

6 tables (3

Compound

3 R ^s R "

209 ⁰ HH HCI

H

Table 7

Compound

jaz. mouth

XYR ⁷ i

21 1 CH ₂ c = o H HCI

212 c = o CH ₂ H HCI

213 CH ₂ CH ₂ H ₂ HCI

214 CH ₂ C-〇 Br HCI

215 C-〇 CH ₂ Br HCI

Compound

217 Br (1: 0)

218 OBz Br (diastereomeric ratio 0: 1) 219 Br HCI (diastereomeric ratio 0) 220 Br HCI (diastereomeric ratio 0: 1) 221 Br HCI (diastereomeric ratio 1: 0) 222 Br HCI (diastereomeric ratio 0: 1) )

 Me Γ

223 ON Br HCI (Geostereo ratio 0: 1)

Compound

畨 R ⁴ R ⁷ jfem

 224 〇Me Br HCI (Diastereomer ratio 1 1)

225 H 1 HCI (diastereo — ratio 13)

226 H CHO HCI (1/3 stereo)

227 H CH ₂ 〇H HCI (1 to 3)

228 H Me HCI (1/3 stereo)

229 H CH ₂ Ne ₂ 2HCI 1 5)

Compound

The world "^ R ⁵ R ⁶ R ⁷ + s

230 OBn H H

 231 OH H H HCI

232 H OBn H

 233 H OH H HCI

234 H Me H HCI

235 H Br H HCI

236 H H Br HCI

237 HHH HCI

Compound (I) or a pharmacologically acceptable salt thereof can be used as it is or in various pharmaceutical forms depending on its pharmacological action and the purpose of administration. The pharmaceutical composition of the present invention can be produced by uniformly mixing an effective amount of compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient with a pharmaceutically acceptable carrier. The carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in a unit dosage form suitable for oral or parenteral administration such as ointment or injection.

 In preparing tablets, for example, excipients such as lactose, glucose, sucrose, mannitol, and methylcellulose; starch, sodium alginate, calcium carboxymethylcellulose, disintegrants such as crystalline cellulose, magnesium stearate, talc Lubricants such as gelatin, polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropylcellulose, methylcellulose, etc., and surfactants such as sucrose fatty acid ester, sorbitol fatty acid ester, etc. in accordance with ordinary methods. Good. Tablets containing 1 to 20 mg of active ingredient per tablet are preferred.

 In preparing the granules, for example, excipients such as lactose and sucrose, disintegrants such as starch, and binders such as gelatin may be used in a conventional manner. In preparing the powder, an excipient such as lactose and mannitol may be used in a conventional manner. In preparing capsules, for example, gelatin, water, sucrose, acacia, sorbitol, glycerin, crystalline cellulose, magnesium stearate, talc, and the like may be used in a conventional manner. Capsules containing 1-20 mg of active ingredient per capsule are preferred.

 In preparing the syrup, for example, sugars such as sucrose, water, ethanol and the like may be used in a conventional manner.

 When preparing an ointment, for example, ointment bases such as petrolatum, liquid paraffin, lanolin, and macgol, emulsifiers such as sodium lauryl lactate, benzalkonidum chloride, sorbitan monofatty acid ester, sodium carboxymethylcellulose, and gum arabic are used in the usual manner. May be used.

In preparing injections, plants such as water, saline, olive oil, peanut oil, etc. Oils, solvents such as ethyl oleate · propylene glycol, solubilizers such as sodium benzoate-sodium salicylate · urethane, salt tonicity agents such as sodium chloride, phenol, cresol · p-hydroxybenzoate · chlorobutanol And the like, and antioxidants such as ascorbic acid and sodium pyrosulfite may be used in a conventional manner.

 Compound (I) or a pharmacologically acceptable salt thereof can be administered orally, or as an ointment or parenterally as an injection. Usually, it is preferable to administer 0.1 to 50 mg / kg per day.

 Next, the toxicity and activity of compound (I) will be described with reference to test examples.

Test Example 1 Enhancement of megakaryocyte colony formation

After sacrifice of an 8-week-old Balb / c mouse, the femur and tibia were taken out and both ends were cut. Bone marrow cells were obtained from a cut piece of a femur and a tibia using an injector containing an IMDM (430-2200EA manufactured by Gibco) solution, and the marrow cells were blown into a test tube. After standing for 5 minutes, the supernatant was obtained using a pit. Bone marrow cells (50000 cells), bovine serum albumin (2%: Sigma A4508), transferrin (600 g / ml: Boehringer Mannheim 652202), IL-3 (100 U / ml), cholesterol (16 g / ml: A test compound of each type was added to a reaction composition comprising 036-0641) and agar (0.6%: 0142-02 manufactured by Difco), and lm 1 was added to a 35 圆 dish manufactured by Lux. placed at _{3 7, 5% C0 2,} 9 5% or more humidity conditions, and cultured for 7 days. A control obtained by adding IL-3 alone to bone marrow cells was used as a control. After completion of the culture, the agar was dried using a filter paper (100-55, manufactured by Whatman), fixed with 2.5% glutaraldehyde, and then stained with acetylcholinesterase (ACHE staining).

 In addition, ACHE staining was performed by the following method.

ACHE staining method: Acetylthiocholine iodide 0.67 mg / ml sodium citrate 2.94 mg / ml copper sulfate (U) 7.5 mg / ml and potassium ferricyanide 1.65 mg / ml are added to the sample, and the solution is added at room temperature in the dark for 4 to 4 days. Left for 6 hours. The number of colonies per dish was calculated with a microscope using 4 or more megakaryocyte cells stained red-brown as one colony, and the results are shown in Table 11 as relative values to the control. Table 11 shows the effect of compound (I) on megakaryocyte colony formation.

 Compound concentration (nM) Relative value Control 100

 57 1 146

 59 10 145

 72 1 121

 96 0.1 150

 115 1 123

Test Example 2 Acceleration of platelet-lowering recovery in mice

 BAL BZc mice (male, 7 weeks old, 4 mice / group) were irradiated with 300 X-rays on Day 1 and the test compound was subcutaneously administered once daily from Day 1 for 5 days. The control group received only X-ray irradiation. On Day 11, blood was collected from the fundus vein of each individual, and the platelet count was measured using a microcell counter (F800, manufactured by Toa Medical Electronics Co., Ltd.). The effect of the test compound is defined as the increase rate (%), as shown in the following formula, in which the platelet count of mice receiving the test compound at Day 11 is divided by the platelet count of the mice not receiving the test compound. expressed.

Trial !; Platelet count in mice treated with the avid compound

 Platelet increase rate X 100 (%)

 Platelet count in mice without test compound

The results are shown in Table 12. Table 12 Increase effect of compound ω on platelet count Test compound dose (mg / kg / day) Platelet increase rate (%)

 29 10 235

 90 10 210

 125 10 384

 150 10 226

 171 10 296

 197 10 225

 211 10 166

 235 10 292 Test Example 3 Acute toxicity test

 BALBZc mice (male, 7 weeks old, 4 mice per group) were irradiated with 300 X-rays, and the test compounds shown in Table 12 were subcutaneously administered at the doses shown in Table 12 and 24 hours later. Life or death was determined.

 As a result, none of the compounds shown in Table 12 showed lethal toxicity.

Examples will be described below. In the following _{description, brine, CHC 1 3> Me} OH represents their respective saturated brine, black hole Holm, methanol.

BEST MODE FOR CARRYING OUT THE INVENTION

Example 1 Compound 1

Process 1

 Hydroxyfluoride 1.46 g (9.69 mmo 1) was dissolved in DMF l O Om l, and iodide (1-methylindole-1-yl) methyl (triphenyl) phosphonium, 5. 70 g (10.7 mmol) and 6.75 g (48.8 mmol) of lithium carbonate were added, and the mixture was stirred at room temperature for 14 hours. After ice water and then a 10 N aqueous solution of sodium hydroxide were added to the reaction solution, the aqueous layer was washed with AcOEt. 6 N hydrochloric acid was added to adjust the pH to 3, and the resulting precipitate was collected by filtration to give 2- [2- (2-force lipoxyphenyl) vinyl] -1 -methylindole, 2 · 23 g (81%) Was obtained.

Ή NMR (DMS0-d ₆ ) δ; 3.86 (s.3H), 6.77 (s.1H) .7.03 (t, 1H, J = 7.3 Hz), 7.14 (ddd, 1H, J = l.0, 7.3, 8.3Hz), 7.35 (d, 1H.J = 16.4Hz), 7.40 (t, 1H, 7.8Hz), 7.45 (d, 1H, J = 8.3Hz) ), 7.53-7.62 (m, 210. 7.86 (dd, 1H, J = l.

2, 7.8Hz), 7.98 (d, 1H, J = 7.6Hz) .7.99 (d, 1H, J = 16.4Hz), 13.05 (br s, 1

H).

 FABMS (m / z); 277 [M] +.

Process 2

 2- [2- (2-Carboxyphenyl) vinyl] 1-methylindole, a mixture of 1.92 g (6.9 lmmo1) and N-methylmaleimide 2.29 g (20.6 mmo1) The mixture was stirred at 180 for 30 minutes. After cooling the reaction mixture to room temperature, it was triturated with AcOEt to obtain 1.45 g (54%) of Compound 1.

 Ή NMR (DMSO-dt) 6; 2.63 (s, 311), 3.06 (dd, 1H, J = 3.8, 15.6Hz). 3.23 (dd, 1H, J-12.8, 15.6Hz), 3.66 (s, 3H) , 3.96 (dd, 1H, J2 3.8, 7.6Hz), 4.2 2 (dt, 1H, J = 3.8, 12.8Hz), 4.32 (d, 1H, J = 7.6Hz), 7.06 (ddd, 1H, J = l.0. 7.0, 7.9Hz), 7.13 (ddd, 1H, J = l.2, 7.0, 8.2Hz), 7.38 — 7.41 (m, 2H), 7.60 (dt, 1H, J = l.5, 7.78 — 7.80 On, 2H), 7.88 (dd, 1H, J = l.5.7.9Hz), 12.99 (br s, 1H).

 FABMS (m / z); 388 [] +.

Example 2 Compound 2

Process 1

 5-7.3 g salicylic acid 17.3 g (100.Ommo 1) was dissolved in MeOH 200 ml, concentrated sulfuric acid 6.Oml (0.11 mmo 1) was added, and the mixture was heated under reflux for 24 hours. The reaction mixture was concentrated, and a saturated aqueous solution of sodium hydrogen carbonate was added to the residue. The mixture was extracted with AcOEt, washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. 7.5 g (94%) were obtained.

 Ή NMR (CDC) δ; 3.96 (s, 3H), 6.93 (d, 1H, J = 8.9Hz), 7.41 (dd, 1H, J = 2.5, 8.9Hz), 7.81 (d, 1H. J-2.5Hz) ), 10.67 (s, 1H).

Process 2

5-Methyl salicylate 5.61 g (30.0 mmo 1) The solution was dissolved in 25 ml of an acid, 8.40 g (60.0 mmo 1) of hexamethylenetetramamine was added, and the mixture was stirred at 9 Ot: for 6 hours. 90 ml of water and 6 ml of concentrated hydrochloric acid were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was extracted with AcOEt, washed with water and then brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (CHCl ₃ / Me〇H 40/1) to give 0.78 g (12%) of methyl 5-methyl-3-formylsalicylate.

 Ή NMR (CDC) δ; 4.01 (s, 3H), 7.97 (d, 1H, J = 3.OHz), 8.05 (d, 1H, J = 3.OHz), 10.45 (s, 1H), 11.40 (s , 1H).

Process 3

 According to Step 1 of Example 1, iodide (1-methylindole-2-yl) methyl (triphenyl) phosphonium 2.40 g (4.5 Ommo 1), 5-chloro-1,3 0.88 g (4.09 mmo 1) of methyl formylsalicylate, 1.24 g (9.0 Ommo 1) of carbonated lime and 18—crown—6, 0.10 g (0.41 mmo 1) ), 0.85 g (60%) of 2- [2- (5-chloro-2-hydroxy-3-methoxycarbonylphenyl) vinyl} 1-methylindole was obtained.

 'Η NMR (CDC) δ; 3.83 (s, 3H), 3.98 (s, 3H), 7.05 (m, 1H), 7.21 (dt, 1H.J = l.5, 7.7Hz), 7.26 (s, 1H ), 7.30 (d, 111, 7.9Hz), 7.32 (d.1H, J = l 6.3Hz), 7.42 (d, 1H, J = 16.3Hz), 7.59 (d, 1H, J = 7.4Hz), 7.68 (d, III, J = 2.5 Hz), 7.74 (d, 1H, or 2.5Hz), 11.40 (s, 1H).

Process 4

 According to Step 2 of Example 1, 829 mg (2.42 mmo 1) of 2- [2- (5- (2-chloro-2-hydroxy-3-methoxycarbonylphenyl) vinyl] -111-methylindole) and N-methylmaleimi Compound 806 mg (7.26 mmo 1) gave Compound 2, 1.13 g (quantitative).

 FABMS (m / z); 454 [M + 1] +.

Example 3 Compound 3

 Process 1

3.90 g of 3-hydroxy-4-methylbenzoic acid according to Step 1 of Example 2 (38.8 mmo 1), 20 ml of MeOH and 744 mg (3.91 mmo 1) of p-toluenesulfonic acid monohydrate gave 4.62 g (72%) of the methyl ester.

Process 2

 4.62 g (2.78 mmo 1) of the methyl ester was dissolved in 10 ml of pyridine, and 3.15 ml of acetic anhydride (33.4 mmo 1) and 66 mg of DMAP were dissolved.

(3.3.4 mmo 1) was added, and the mixture was stirred at room temperature for 2 hours. Ice water and ether were added to the reaction solution, and then 6N hydrochloric acid was added to make the reaction solution acidic. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and then brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 6.14 g (quantitative) of an acetyl derivative.

Process 3

 6.14 g (27.8 mmo 1) of the acetyl derivative was dissolved in 250 ml of carbon tetrachloride, and 12.40 g (69.66 mm o 1) of N-bromosuccinimide and peracid were dissolved. 66 mg (0.27 mmo 1) of benzoyl chloride was added, and the mixture was heated under reflux for 9 hours. After cooling the reaction mixture to O :, insolubles were filtered off and the filtrate was concentrated to give methyl 3-acetoxy-4-dibromomethyl benzoate.

_{Ή NMR (CDC1 3) δ;} . 2.43 (s, 3H), 3.94 (s, 3H), 6.82 (s, 1H), 7.79 (d, 1 H, J = l.2Hz), 7.93 (d, 1H J = 8.2Hz), 7.98 (dd, 1H, J = l.2, 8.2Hz).

 FABMS (m / z); 367 [M + l] +.

Process 4

 140 ml of water and 112 ml of sulfuric acid were added to the obtained methyl 3-acetoxy-4-dibromomethylbenzoate, and the mixture was refluxed for 5 hours. After the reaction mixture was cooled to 0, 400 ml of water was added, and the resulting precipitate was collected by filtration, purified by silica gel column chromatography (CHC 13 NO MeOH 10/1), and purified with 4-formyl-13-hydroxybenzoic acid. , 3.88 g (84%).

_{Ή NMR (CDC1 3) (5} ; 7.46 (dd, 1H, J = l.4, 8.0Hz), 7.56 (d, 1H, J = l.4Hz), 7.73 (d, 1H, 8.0Hz), 10.36 ( s, 1H), 10.95 (br s, 111).

FABMS (m / z); 167 [M + l] ⁺ .

Process 5 According to Step 1 of Example 1, (1 -methylindole-2-yl) methyl (triphenyl) phosphonium 13.71 g (25.70 mmo 1), 4-formyl 3- From 3.88 g (23.4 mmol) of hydroxybenzoic acid and 16.21 g (17.3 mmol) of potassium carbonate, 2- [2- (4-carboxy-2-hydroxyphenyl) Biel] 1-methylindole 4.38 g (64%) was obtained.

'Η NMR (DMS0-d _fc ) <5; 3.85 (s, 3H), 6.68 (s, 1H), 7.02 (ddd, 1H, J = 0.8, 7.0, 7.9 Hz), 7.13 (ddd, 1H, J = l.2, 7.0, 8.2Hz), 7.41 (dd, 1H, J = l.7, 8.2Hz), 7.44 (dd, 1H, J = 0.8, 8.2Hz), 7.49 (m, 2H) .7.52 (br d, 1H, J = 7.9Hz),

7.54 (d, 1H, J = 16.4Hz), 7.80 (d, 1H, J = 8.2Hz), 10.17 (s, 1H), 12.75 (br s, 1H).

FABMS (mIz); 293 [M] ⁺ .

Process 6

 2- [2- (4-Carboxy-2-hydroxyphenyl) vinyl] —1-methylindole, 2.45 g (8.35 mmo 1) was dissolved in 25 ml of DMF, and potassium carbonate 6.97 g (50.4 mmO 1) and Benzyl bromide 3.Oml (25 mmO 1) were added, and the mixture was stirred at room temperature for 10 hours. Ice water was added to the reaction solution, and the mixture was made alkaline with potassium carbonate. After extraction with ether, the extract was washed with water and then with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane ZAc OEt 10/1) to give 2- [2- (2-benzyloxy-4-benzyloxycarbonylphenyl) vinyl] -1-methylindole, 1.53 g (39%) were obtained.

 FABMS (in Iz); 473 [] +.

Process 7

2-33- [2- (2-benzyloxy-4-benzyloxycarbonylphenyl) vinyl] 111-methylindole 5 33mg (1.13mmo1) was dissolved in THF 10m1 and lithium aluminum hydride 86mg (2.3 mmo 1), and the mixture was stirred at room temperature for 15 minutes. A saturated aqueous solution of sodium sulfate was added to the reaction solution, which was filtered through Celite. The filtrate was concentrated, and the residue was subjected to silica gel column chromatography (hexane). / AcOEt 4/1) to give 138 mg (33%) of 2- [2- (2-benzyloxy-4-hydroxymethylphenyl) vinyl] -11-methylindole.

 FABMS (m / z); 369 [M] +.

Process 8

 According to step 2 of Example 1, 2- [2- (2-benzyloxy-4-hydroxymethylphenyl) vinyl] 1-1-methylindole 134 mg (0.362 mmol) and N-methylmaleimide 12 lmg ( 1. 12 mm (65%) of compound 3 was obtained from 1.09 mmo 1).

_{^{! H NMR (CDC1 3) δ}} ; 2.77 (s, 3H), 2.98 (dd, 1H, J = 3.9, 15.4Hz), 3.27 (dd, 1H, J = 13.1, 15.4Hz), 3.67 (s, 3H) 3.80 (dt.1H, J = 3.9, 13.1Hz), 3.94 (dd, 1H.3.9, 7.4Hz), 4.36 (d, 1H, J = 7.4Hz), 4.74 (s, 2H), 5.11 (d, 1H, J = ll.5Hz), 5.16 (d, HI, J-ll.5Hz), 7.08-7.10 (m, 2H), 7.18 (dt, 1H, J = 1.2, 7.1Hz), 7.23 (ddd. , Jl., 7.1, 8.1Hz), 7.28-7.39 (m, 6H), 7.58 (br d, 1H, J = 8.1Hz), 7.98 (dd, 1H, J = l.2, 7.1Hz).

 FABMS (m / z); 480 [M] +.

Example 4 Compound 4

Process 1

 According to Step 2 of Example 3, 2- [2-((4-carboxy-12-hydroxyphenyl) vinyl] -11-methylindole 2.63 g (8.97 mmo 1), anhydrous acetic acid 1. From 2-ml (10.8 mmo 1) and 60 mg of DMA P (0.49 mmo 1), 2- [2- (2-acetoxy-4-carboxyphenyl) vinyl] -111-methylindole 1.79 g (60%) were obtained.

 lH NMR (CDCI3) δ; 2.42 (s, 3H), 3.83 (s, 3H), 6.86 (s, 1H), 7.11 (ddd, 1H, J = 0.9, 7.0, 7.9Hz), 7.19 (d, 1H, J = 16.2Hz), 7.23 (ddd, 1H, J = l.2, 7.0.8.2Hz), 7.30 (d, 1H, J = 16.2Hz), 7.31 (dd, 1H, J = 0.9, 8.2Hz) ), 7.61 (dd, 1H, J = l., 7.9Hz), 7.79 (d, 1H, J = 8.2Hz), 7.84 (d, 1H, J = l.7Hz), 7.99 (dd, 1H, 1 = 1.7, 8.2Hz).

FABMS On / z); 335 [M] +. Process 2

 According to Step 6 of Example 3, 2- [2- (2-acetoxy-4-carboxyphenyl) vinyl] -1-methylindole 94 mg (0.28 mmo 1), potassium carbonate 47 mg (0.34 mmo 1 ) And methyl iodide from 0.02 1 ml (0.334 mmo 1), 2- [2- (2-acetoxy-4-methoxycarbonylphenyl) vinyl]-1-methylindole, 72 mg (74) I got

 FABMS (m / z); 350 [Mil] +.

Process 3

 According to Step 7 of Example 3, 2- [2- (2-acetoxy-4-methoxycarbonylcarbonylphenyl) vinyl] —1-methylindole 69 mg (0.2 Ommo 1) and lithium aluminum hydride 35 5 mg ( From 0.93 mmo 1), 38 mg (56%) of 2- [2- (2-hydroxy-1-hydroxymethylphenyl) vinyl] -1-methylindole was obtained.

 FABMS (m / z); 279 [M] +.

Process 4

 According to Step 2 of Example 3, 2- [2- (2-hydroxy-4-hydroxymethylphenyl) vinyl] -1-methylindole 38 mg (0.14 mmo 1), anhydrous anhydride 0.03 1 ml (0.33 mmo 1) and DMA P 12 mg (0.10 mmo 1), 2— [2- (2-acetoxy-1-4-acetoxymethylphenyl) vinyl] —1 —35 mg (71%) of methylindole were obtained.

 Ή NMR (CDC) 6; 2.12 (s, 3H), 2.38 (s, 3H), 3.81 (s, 3H), 5.11 (s, 2H). 6.79 (s, 1H), 7.08-7.26 (m, 9H ).

 FABMS (m / z); 363 [M] +.

Process 5

 According to Step 2 of Example 1, 2- [2- (2-acetoxy-4-acetoxymethylphenyl) vinyl] —1-methylindole 35 mg (0.097 mmo 1) and N-methylmaleimide 32 mg (0.29 mmo Compound 4 and 21 mg (45%) were obtained from 1).

Ή NMR (CDC) δ; 2.11 (s, 3H), 2.30 (s, 3H), 2.79 (s, 3H). 2.98 (dd, 1H, J = 4.2, 15.4Hz) .3.23-3.30 (m, 1H), 3.46 (dt.1H, 4.2. 12.2Hz), 3.66 (s, 3H), 3.72 (m, 1H), 4.45 (d , 1H,] = 7.8Hz), 5.13 (s, 2H), 7.11 (d, 1H, 1.8Hz), 7.20 (dt, 1H, J = l.2, 7.3Hz), 7.22-7.34 ( m, 3H), 7.76 (d,

1H, J = 8.2Hz), 7.99 (d, 1H, J = 7.3Hz).

FABMS (m I z); 474 [M] ⁺ .

Example 5 Compound 5

Process 1

 According to Step 1 of Example 2, 5.85 g (38.4 mmo 1) of 4-monomethylsalicylic acid, 20 ml of Me〇H 120 ml and p-toluenesulfonic acid monohydrate 1.4 From 7 g (7.71 mmo 1), 1.69 g (27%) of methyl 4-methylsalicylate was obtained.

_{Ή NMR (CDC1 3) δ 2.34} (s, 3H), 3.93 (s. 3H), 6.65 one 6.79 (m, 211). 7.7 1 (d, 1H, J = 8.0Hz), 10.71 (s, 1H).

FABMS (m / z); 167 [M + l] ⁺ .

Process 2

 According to Step 7 of Example 3, benzyl alcohol derivative 1 was obtained from 1.68 g (10.1 mmo 1) of methyl 4-methylsalicylate and 763 mg (20.1 mmo 1) of lithium aluminum hydride. 40 g (quantitative) were obtained.

Process 3

 1.40 g (10.1 mmo 1) of the benzyl alcohol compound was dissolved in 10 Om 1 of methylene chloride, 6.9.8 g of manganese dioxide was added, and the mixture was stirred at room temperature for 8.5 hours. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain 0.35 g (25%) of 4-methylsalicylaldehyde.

 Ή NMR (CDC) δ; 2.38 (s, 3H), 6.79 — 6.86 (m, 2H), 7.43 (d, 1H, J = 8.3Hz), 9.83 (d, 1H, J = 0.5Hz), II. 04 (s, 1H).

Process 4

According to Step 1 of Example 1, 0.35 g (2.57 mmo 1) of 4-methyl salicylaldehyde, iodide (1-methylindole-1-yl) methyl (triphenyl) phosphonium 1. 3 9 g (2.6 Ommo 1) and potassium carbonate 1.6 From 2 g (11.73 mmo 1), 580 mg (82%) of 2- [2- (2-hydroxy-14-methylphenyl) vinyl] -1-monomethylindole was obtained.

FABMS (m / z); 263 [M] ⁺ .

Process 5

 According to Step 2 of Example 3, 2- [2- (2-hydroxy-4-methylphenyl) vinyl] 1-1-methylindole 117 mg (0.444 mmo 1), acetic anhydride 0.50 ml (0.53 mmo 1) and DMAP 1 2 mg (0.10 mmo 1) show that 2- [2- (2-acetoxy-4-methylphenyl) vinyl] 1-methylindole 86 mg ( 6 4%).

 FABMS (m / z); 305 [M] +.

Process 6

 According to step 2 of Example 1, 2- [2- (2-acetoxy-4-methylphenyl) vinyl] 111-methylindole 84 mg (0.27 mmo 1) and N-methylmaleimide 91 mg ( From 0.82 mmo 1), the compound 5, 73 mg (64%) was obtained.

 Ή NMR (CDCU) δ; 2.28 (s, 3H), 2.37 (s, 3H), 2.78 (s, 3H), 2, 97 (dd.1H, J = 4.0, 15.6Hz). 3.24 (dd. 12.5, 15.6Hz), 3.42 (dt, 1H, J = 4.0, 12.5Hz), 3.66 (s, 3H), 3.71 (dd, 1H, J = 4.0, 7.6Hz), 4.44 (d, 1H, J = 7.6 Hz), 6.91 (d, 1H.J = l.0Hz), 7.15 (dd, 1H.J = l.0, 7.9Hz), 7.19 (ddd, III, J = 1.0, 7.0.7.9 Hz), 7.24 (ddd.1H, 1 = 1.2, 7.0, 8.2Hz), 7.29 (dd, 1H, J = l. 0, 8.2Hz), 7.62 (d, 1H, J = 7.9Hz), 7.99 (dd , 1H,) = 1.2, 7.9Hz).

 FABMS (m / z); 416 [M] +.

Example 6 Compound 6

Process 1

 According to Step 6 of Example 3, 1.39 g (10.Ommo 1) of 4-hydroxysalicylaldehyde, 1.53 g (1 1.Ommo 1) of potassium carbonate and benzyl chloride 1. From 31 mi (1 1. Ommo 1), 674-mg (29%) of 4-benzyloxysalicylaldehyde was obtained.

_{Ή NMR (CDC1 3) δ;} 5.18 (s, 2H), 6.57 (d, 1H, J = 2.2Hz), 6.65 (dd, 1H, 3 : 1.1 8.5Hz), 7.33-7.47 (m, 5H), 7.64 (d, 1H, J = 8.5Hz), 10.01 (s, 1H), 11.01 (s. 1H).

FABMS (mIz); 229 [M + l] ⁺ .

Process 2

 According to Step 1 of Example 1, 4 O-benzyloxysalicylaldehyde 63 Omg (2.76 mmo 1), iodide (1-methylindole-2-yl) methyl (tririfenyl) phosphonium 1.55 g (2.91 mmo 1) and 1.9 g (13.8 mmo 1) of carbonic acid rim, 2— [2— (4-benzyloxy-2-hydroxyphenyl) vinyl] 1-1— 0.68 g (66%) of methylindole was obtained.

 Ή NMR (CDC) (5; 3.79 (s, 3H), 5.06 (s, 2H). 5.50 (br s.1H), 6.25-7.57 (m, 15H).

FABMS (m I z); 355 [M] ⁺ .

Process 3

 According to Step 2 of Example 3, 2- [2- (4-benzyloxy-2-hydroxyphenyl) vinyl] -1-methylindole 0.67 g (l. 88 mmo 1), acetic anhydride 0.2 lm 1 (2.2 mmo 1) and 12 mg of DMA P (0.10 mmol) gave acetyl derivatives.

 Next, according to Step 2 of Example 1, the acetyl group was reacted with N-methylmaleimide (625 mg, 5.63 mmol) to obtain Compound 6, 791 mg (83%).

 'Η NMR (CDC) δ; 2.28 (s, 3H), 2.78 (s, 3H), 2.96 (dd, 1H,) = 4, 3, 15.6Hz), 3.22 (dd, 1H, 12.2, 15.6Hz) , 3.41 (dt, 1H, J = 4.3, 12.2Hz), 3.65 (s, 3H), 3.68 (dd, 1H, J = 4.3.7.6Hz), 4.43 (d, 1H, J = 7.6Hz) .5.06 ( d, 1H, J = ll.6Hz), 5.07 (d, 1H, J = ll.6Hz), 6.74 (d, 1H, J = 2.4Hz), 6.97 (dd, 1H.J = 2.4, 8.5Hz), 7.19 (ddd, 1H, J = l.2, 7.0, 7.6Hz), 7.24 (ddd, 1H, J = l.2, 7.0, 8.2Hz), 7.29 (br d.1H, J = 8.2Hz), 7.32 ― 7.44 (m, 5H), 7.66 (d, 1H, J = 8.5Hz), 7.99 (dd, 1H. J = l.2, 7.6Hz).

FABMS (m / z); 508 [M] ⁺ . Example 7 Compound 7

 According to Step 2 of Example 1, 2- [2- (2-acetoxy-1-carboxyphenyl) vinyl] -1-methylindole 1.78 g (5.31 mmo 1) and N —Compound 7, 1.88 g (79) was obtained from 1.75 g (15.8 mmo 1) of methylmaleimide.

 Ή NMR (CDCla) δ; 2.33 (s, 3H), 2.80 (s, 3H), 3.02 (dd, 1H, J = 4.0, 15.6Hz), 3.30 (dd, 1H, J = 12.5, 15.6Hz), 3.50 (dt, 1H, J = 4.0, 12.5Hz), 3.68 (s, 3H), 3.77 (dd, 1H, J = 4.0, 7.5Hz), 4.49 (d, III, J = 7.5Hz), 7.1 (ddd, 1H.J = l.1, 7.0, 7.9Hz), 7.25 (ddd, III, J = l.3, 7.0, 8.2Hz), 7.31 (br d, 1H, J = 8.2Hz), 7.83 (d, 1H, 1 = 1.7Hz), 7.88 (d, 1H, J = 8.2Hz), 8.00 (br d, 1H, 7.9Hz), 8.01 (dd, 1H, 1.7, 8.2Hz).

FAB S (m / z); 446 [M] ⁺ .

Example 8 Compound 8

Process 1

 According to Step 2 of Example 3, 2-methyl-5-ditrophenol 18.2 g (0.12mo1), acetic anhydride 17m1 (0.18mo1) and pyridine 17ml From (0.21 moI), 23.5 g (quantitative) of an acetyl derivative was obtained.

 'Η NMR (CDC) δ; 2.29 (s, 3H), 2.37 (s, 3H), 7.40 (d, 1H, J = 8.4Hz), 7.93 (d, 1H, 2.0Hz), 8.03 (dd, 1H, J = 2.0, 8.4Hz).

Process 2

 According to Step 3 of Example 3, 2.43 g (12.5 mmo 1) of the acetyl derivative, 5.58 g (31.3 mmo 1) of N-bromosuccinic acid imide and benzoperoxide 5.48 g (quantitative) of the dibromomethyl compound was obtained from 305 mg (0.88 mmo 1) of the compound.

 瞧 (CDC) δ; 2.46 (s, 3H), 6.81 (s, 1H), 8.05 (d, 111, J-2.5Hz), 7.93 (d, 1H, J = 8.9Hz), 8.17 (dd, 1H, J = 2.5, 8.9Hz).

 Process 3

According to Step 4 of Example 3, dihydroxymethyl form 5.48 g (12.5 mmo 1) and sulfuric acid 2 Oml were used to prepare 2-hydroxy-4-nitrobenzaldehyde 1. 47 g (70%) were obtained.

 Ή NMR (CDCla) δ; 7.71 (dd, 1H, J = 2.2, 8.7Hz), 7.79 (d, 1H, J-2.2Hz), 7.86 (d, 1H, J = 8.7Hz), 10.39 (s.1H ), 11.57 (s, 1H).

Process 4

 According to Step 1 of Example 1, 1.38 g (8.32 mmo 1) of 2-hydroxy-4-nitrobenzaldehyde, iodide (1-methylindole-1-yl) methyl (triphenyl) From phosphonium 4.04 g (7.58 mmo 1) and potassium carbonate 5.26 g (38.1 mmo 1), 2- [2- (2-hydroxy-14-nitrophenyl) vinyl] 1-1 One methyl indole was obtained.

Process 5

 According to Step 2 of Example 3, 2- [2- (2-hydroxy-4-nitrophenyl) vinyl] 1-methylindole and acetic anhydride 7.2 ml (76.3 mm 0

From 1) and pyridine 6.2 m1 (76.6 mmo 1), 2- [2- (2-a-Sethoxy-412-trophenyl) vinyl] 1-1-methylindole 1.62 g

(64%).

 Ή NMR (CDCU) 6; 2.46 (s, 3H), 3.90 (s, 3H), 7.04 (t, 1H, J = 8.0Hz), 7.12 (s, 1H), 7.29 (d, 1H, J = 16.3Hz), 7.46 (d, 1H, J = 8.0Hz), 7.55 (d, 1H, J = 6.9Hz), 7.75 (d, 1H, J = 16.3Hz), 8.13 (s, 1H), 8 .15 (d, 1H, J = 6.9Hz), 8.30 (d, 1H, J-8.0Hz).

 EIMS (m / z); 336 [M] +.

Process 6

 According to Step 2 of Example 1, 2- [2- (2-acetoxy-4-112-trophenyl) vinyl] -11-methylindole 3.01 g (8.97 mmol) —Compound 8, 3.67 g (92%) was obtained from 2.20 g (19.8 mmo 1) of methylmaleimide.

_{»H NMR (CDC1 3) (} 5;. 2.35 (s, 3H), 2.80 (s, 3H) 3.03 (m, 1H), 3.30 (dt, 1H, J = 2.0, 14.4Hz), 3.50 (m, 1H ), 3.63-3.76 (m, 2H), 3.69 (s, 3H), 4.50 (d, 1H.J = 7.9Hz), 7.15-7.33 (m, 3H), 7.96 (d, 1H, J = 8.6Hz), 8.00 (d, 1H, J = 6.9Hz), 8.02 (d, IH, J = 2.1Hz), 8.22 (dd, 1H, J = 2.1, 8.6Hz). EIMS (m / z); 447 [M] ⁺ .

Example 9 Compound 9

Process 1

 According to Step 2 of Example 2, 5.03 g (33.1 mmo 1) of methyl 4-hydroxybenzoate, 5.10 g (36.4 mmo 1) of hexamethylenetetramine and trifluoromethyl From 50. Oml of acetic acid (0.66 mol), 2.32 g (39%) of 3-formyl-4-methyl methyl hydroxybenzoate was obtained.

 Ή NMR (CDC) δ; 3.93 (s, 3H), 7.04 (d, 1H, 8.9Hz), 8.19 (dd, 1H, J = 2.0.8.9Hz), 8.32 (d, 1H, 2.0Hz), 9.96 ( s, 1H), 11.39 (s, 1H).

 EIMS (m I z); 180 [] +.

Process 2

 According to Step 1 of Example 1, 13.3 g (73.6 mmo 1) of 3-formyl-methyl 4-hydroxybenzoate, iodide (1-methylindole-1-yl) methyl (triphenyl) Phosphonium 30.1 g (56.4 mmo 1), Carbonated rim 10.2 g (73.7 mmo 1) and 18—crown 1.6, 1.53 g

From (5.71 mmo 1), 2- [2- (2-hydroxy-1-5-methoxycarbonylcarbonyl) vinyl] -111-methylindole was obtained.

_{Ή NMR (CDC1 3) δ;} 3.83 (s, 3H), 3.93 (s, 3H), 5.72 (s, 1H), 6.84 (d, 1 H, J = 8.4Hz), 6.85 (s, 1H), 7.09 (ddd, 1H, J = l.0, 6.9, 7.9Hz), 7.21 (ddd, 1H, J = 1.0, 6.9, 8.2Hz), 7.26 (d, 1H, J = 8.2Hz), 7.29 (d, 1H , J-16.3Hz), 7.45 (d, 1H, J = 16.3Hz), 7.59 (d, 1H, J = 7.9Hz), 7.85 (dd, 1H, J = 2.0, 8.4Hz), 8.26 (d, 1H, J = 2.0Hz).

EIMS (m / z); 307 [M] ⁺ .

 Process 3

According to Step 2 of Example 3, 2- [2- (2-hydroxy-5-methoxycarbonylphenyl) vinyl] -11-methylindole, acetic anhydride 8.Oml (84.8 mmo 1) and DMAP 13.0 g (66%) of 2_ [2_ (2-acetoxy-5-methoxycarbonylphenyl) vinyl] -11-methylindole was obtained from O.70 g (5.7 Omm 1). . Ή NMR (CDC) δ; 2.40 (s.3H), 3.82 (s, 311), 3.95 (s, 3H), 6.81 (s, 1H), 7.11 (ddd, 1H, J = l.5, 6.9, 7.9Hz), 7.14 (d, 1H, J- 16.8Hz), 7.21 (d, 1H, J = 8.4Hz), 7.22 (ddd, 1H, J = l.5, 6.9, 8.2Hz), 7.26 (d, 1H,] = 16.8Hz), 7.31 (d, 1H, J = 8.2Hz), 7.60 (d, 1H, J = 7.9Hz), 7.96 (dd, 1H, J = 2.0, 8.4Hz), 8.39 (d , 1H, J = 2.0Hz).

EIMS (m / z); 349 [M] ⁺ .

Process 4

 According to Step 2 of Example 1, 2- [2- (2-acetoxy-1-5-methoxycarbonylphenyl) vinyl] —1-methylindole 9.72 g (27.9 mmo 1) and N-methylmaleimide From 6.22 g (56. Ommo 1), compound 9 and 13.5 g (quantitative) were obtained.

 Ή NMR (CDC) (5; 2.31 (s, 3H), 2.79 (s, 3H), 3.02 (m, 1H), 3.36 (dt, 1H,) = 1.7, 13.4Hz), 3.47 (dl, 1H. J = 3.1, 13.4Hz), 3.68 (s, 3H), 3.76 (m, 1H), 3.96 (s, 3H), 4.48 (d, 1H, J = 7.4Hz), 7.19 (dt, 1H, J = l. 5, 6.4Hz), 7.20 (d, 1H, J = 8.4Hz), 7.23 (d, 1H, J = 6.4Hz). 7.29 (dt, 1H, J = l.5, 6.4Hz), 7.99 ( dd, 1H, J = l.5, 6.4Hz), 8.05 (dd, 1H, J = 2.0, 8.4Hz), 8.45 (d, 1H, J = 2.0Hz).

EIMS (m / z); 460 [M] ⁺ .

Example 10 Compound 10

Process 1

 According to Step 2 of Example 2, 10.09 g (66.32 mmo 1) of methyl 3-hydroxybenzoate, 9.33 g (66.6 mmo 1) of hexamethylenetetramine and 96.Om of trifluoroacetic acid 4.75 g (40%) of 2-formyl-3-methyl methyl hydroxybenzoate was obtained from l (1.25 m 1).

 Ή NMR (CDCU) <5; 3.96 (s, 3H). 7.17 (ddd, 1H, J = 0.6, 1.2, 8.5Hz), 7.48 (dd, 1H, J = l.2, 7.6Hz), 7.54 ( dd, 1H.J = 7.6, 8.5Hz), 10.64 (d, 1H, J = 0.6Hz), 12.19 (s, 1H).

FABMS (m / z); 180 [M + l] ⁺ .

Process 2 According to Step 1 of Example 1, 2-formyl-3-hydroxymethyl benzoate 4.70 g (26.1 mmo 1), iodide (1-methylindole-2-yl) methyl (triphenyl) ) From 14.56 g (27.3 Ommo 1) of phosphonium and 1 7.86 g (129.2 mmo 1) of potassium carbonate, 2- [2- (2-hydroxy-6-methoxycarbonyl) Enyl) vinyl] -1-methylindole 7.24 g (90%) was obtained.

_{Ή NMR (CDC1 3) 6;} 3.80 (s, 3H), 3.88 (s, 3H), 5.80 (s, 1H), 6.89 (s, 1 H), 7.01 (d, 1H, J = 16.6Hz), 7.10 (ddd, 1H, J = l.0, 7.0, 7.8Hz), 7.14 (dd, 1H.J = l.1.8.1Hz), 7.22 (ddd, 1H.J = l.2, 7.0, 8.2Hz) , 7.24 (t, 1H, J = 8.1 Hz), 7.30 (dd, 1H, J = l.0, 8.2Hz), 7.53 (d, 1H,] = 16.6Hz), 7.54 (dd, 1H, J = l.2, 7.8Hz), 7.60 (dd.1H, J = l.1, 8.1Hz).

 FABMS (m / z); 308 [M + l] +.

Process 3

 According to Step 2 of Example 3, 2 _ [2- (2-hydroxy-6-methoxycarbonylphenyl) vinyl] — 1-methylindole 7.23 g (23.5 mmo 1), acetic anhydride 2.33 m An acetyl derivative was obtained from l (24.7 mmo 1) and 0.14 g (1.2 mmo 1) of DMAP.

 Then, according to Step 2 of Example 1, the compound was reacted with 7.70 g (69.3 mmol) of N-methylmaleimide to give 9.64 g (89%) of compound 12. Obtained.

 FABMS (m / z); 460 [M] +.

Example 11 1 Compound 11

Process 1

Dissolve 1.72 g (10.4 mmol) of 2,6-dimethoxybenzaldehyde in methylene chloride 4 Om 1, and add 1 M boron tribromide Z methylene chloride solution 12 m 1 (1 2. Ommo 1) was added, and the mixture was stirred at room temperature for 9.5 hours. Water was added to the reaction solution, extracted with getyl ether, washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane / AcOEt 3/1) to give 2-hydroxy-6-methoxybenzaldehyde. 0.87 g (55%) of hide were obtained.

_{Ή NMR (CDC1 3) δ;} 3.89 (s, 3H), 6.38 (d, 1H, J = 8.4Hz), 6.53 (d, 1H, J = 8.4Hz), 7.41 (t, 1H, J = 8.4Hz) , 10.34 (s, 1H), 11.97 (s, 1H).

Process 2

 According to Step 1 of Example 1, (1 monomethylindole-2-yl) methyl (triphenyl) phosphonium 1.76 g (3.3 Ommo 1), 2-hydroxy-6-methoxy From 0.46 g (3.0 mmo 1) of benzaldehyde, 0.91 g (6.6 Ommo 1) of potassium carbonate and 18-crown 6, 0.07 g (0.3 Ommo 1) There was obtained 0.60 g (72%) of 2- [2- (2-hydroxy-6-methoxyphenyl) vinyl] -111-methylindole.

 Ή NMR (CDC) δ; 3.78 (s, 3H), 3.88 (s, 3H), 5.34 (s, 1H), 6.51 (d, 1 H. J = 8.3 Hz), 6.53 (d. 1H, 1 = 7.9 Hz), 6.84 (s, 1H), 7.00-7.40 (m. 3H), 7.09 (t, 1H, J = 8.3Hz), 7.40 (d, 1H, J = 17.2Hz), 7.47 (d, 1H) , J = 17.2Hz), 7.5 9 (d, 1H, J = 7.6Hz).

 FABMS (m / z); 280 [M + l] +.

Process 3

 According to Step 2 of Example 1, 2- [2- (2-hydroxy-6-methoxyphenyl) vinyl] -1-methylindole 59 Omg (2.11 mm 01) and N-methylmaleimide 7 Compounds 11 and 42 mg (50%) were obtained from 07 mg (6.33 mm 01).

_{Ή NMR (CDC1 3) δ;} 2.82 (dd, 1H, J = 4.5, 16.7Hz), 2.88 (. S 3H), 3.61 (s, 3H), 3.67 (m, 1H), 3.79 (s, 3H), 3.79 (m, 1H), 4.16 (m, 1H), 4.59 (d, 1 H. J = 7.3 Hz), 6.57 (d, 1H, J = 8.3 Hz), 6.77 (d, 1H, J = 8.2 Hz), 7.13-7.34 On, 4H), 7.97 (dd, 1H, J = l.7, 7.8Hz), 8.65 (s, 1H).

Example 1 2 Compound 1 2

Process 1

Resorcinol 11.0 g (10 Ommo 1) was dissolved in methylene chloride 300 m 1, and 3,4-dihydro-2H-pyran 27 ml (30 Ommo 1) and d 1-10 Add 0.70 g (2.99 mmo 1) of camphorsulfonic acid and add at room temperature. Stir for 1 hour. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and extracted with CHC 1 _3, after brine washed, dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane / AcOEt 9/1) to obtain 27.1 g (97%) of a ditetrahydropyrael compound.

 Ή NMR (CDC) δ; 1.50-2.10 (m, 12H), 3.50-3.70 (m, 2H), 3.90 (m, 2H), 5.40 (m, 2H), 6.60-6.80 (m, 3H), 7.16 (t, 1H, J = 8.2Hz).

Process 2

 13.9 g (50.Ommo 1) of the ditetrahydroviranyl compound was dissolved in 180 ml of THF, and the solution was diluted with 0 to 1.6 M n-butyllithium Zn—hexane solution 4 1 m 1 (6 5.6 mmo 1) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with Ac〇Et, washed with water and then brine, dried over anhydrous sodium sulfate, and the solvent was distilled off to give 2,6-ditetrahydroviranyloxybenzaldehyde 1 5.7 g (quantitative) were obtained.

 FABMS (m / z); 307 [M + 1] +.

Process 3

 Dissolve 2,5.7-ditetrahydroviranyloxybenzaldehyde (15.7 g, 51.3 mmo 1) in THF (200 ml), and add 6N hydrochloric acid (2,1 m 1 (0.13 mmo 1)). The mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with AcOEt, washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane / AcOEt 2/1) to obtain 4.56 g (64) of 2,6-dihydroxybenzaldehyde.

EIMS (m / z); 138 [] ⁺ .

Process 4

 According to Step 6 of Example 3, 2.76 g (20. Ommo 1) of 2,6-dihydroxybenzaldehyde, 2.65 ml (22.Ommo 1) of benzylbenzene and potassium carbonate 2.65 g (58%) of 2-hydroxy-6-benzyloxybenzaldehyde was obtained from 2.76 g (20. Ommo 1).

EIMS (m / z); 228 [M] +. Process 5

 According to Step 1 of Example 1, iodide (1-methylindole-2-yl) methyl (triphenyl) phosphonium 5.86 g (1 1.Ommo 1), 2-hydroxy-6- From benzyloxybenzaldehyde 2.28 g (10. Ommo 1), potassium carbonate 1.66 g (1 2. Ommo 1) and 18—crown 1.6, 0.26 g (1.0 Ommo 1) 1.48 g (42%) of 2- [2- (6-benzyloxy-2-hydroxyphenyl) vinyl] -111-methylindole were obtained.

_{Ή NMR (CDC1 3) δ;} 3.53 (s, 3H), 5.13 (s, 2H), 5.29 (s, 1Η), 6.52 (d, 1 H, J = 8.3Hz), 6.62 (d, 1H, J = 8.2Hz), 6.80 (s, 1H). 7.48 (d, 1H, J = 16.6Hz), 7.54 (d, 1H, J = 16.6Hz), 7.00-7.60 (m, 10H).

FABMS (m / z); 356 [M + l] ⁺ .

Process 6

 According to Step 2 of Example 1, 2- [2- (6-benzyloxy-2-hydroxyphenyl) vinyl] -1-methylindole 14.2 g (40. Ommo 1) and N-methylmaleimide 1 Compound 3.3 and 16.7 g (89%) were obtained from 3.3 g (19.8 mmol).

 FABMS On / z); 467 [M + 1] +.

Example 13 Compound 13

Process 1

 Example 11 According to step 1 of 1, 476 mg (2.03 mmo 1) of N, N-getyl-2-formyl-13-methoxybenzamide and 1 M of boron tribromide in methylene chloride 4.10 ml From (4.1 Ommo 1), 324 mg (72%) of N, N-getyl-2-formyl-3-hydroxybenzamide was obtained.

 EIMS (m / z); 221 [M] +.

Process 2

According to Step 1 of Example 1, iodide (1-methylindole-2-yl) methyl (triphenyl) phosphonium 1.76 g (3.3 Ommo 1),, N-diethyl-2- Formyl 3-hydroxybenzamide 0.46 g (3.0 Ommo1), potassium carbonate 0.91 g (6.60 mmol) and 18-crown From 6, 0.08 g (0.3 Ommo 1), 2- [2- (2-Jetylcarbamoyl 6-hydroxyphenyl) vinyl] 1.1-methylindole 0.64 g

(76%).

 Ή NR (CDC) δ; 0.99 (t, 3H, J = 7.3Hz), 1.25 (t, 3H, J = 7.3Hz), 3.12 (q, 2H, J = 7.3Hz), 3.40 (m, 1H), 3.70 (m, 1H), 3.57 (s.3H), 6.68 (s, 1H), 6.70 (d, 1H, J = 7.6Hz), 6.73 (d, 1H, J = 7.6Hz), 6.95 (t, 1H , J = 7.6Hz), 7.

07 (d, 1H, J = 16.2Hz), 7.10 (m, 2H), 7.50 (m, 2H), 7.42 (d, 1H, J = 16.2Hz).

 FABMS (m / z); 349 [M + l] *.

Process 3

 According to Step 2 of Example 1, 2_ [2- (2-getylcarbamoyl-6-hydroxyphenyl) vinyl] -111-methylindole 299 mg (0.86 mmo 1) and N-methylmaleimide From 480 mg (4.3 Ommo 1), 376 mg (95%) of the compound 13 was obtained.

 FABMS (m / z); 460 [M + l] +.

Example 14 Compound 14

Process 1

 According to the step 2 of Example 12, 3-fluoroanisole 2.28 ml (20.Ommol), 1.6 M n-butyllithium Zn-hexane solution 16 ml (26- Om 1) and DMF 3.1 ml (40. Om 1) gave 3.05 g (99%) of 6-fluoro-2-methoxybenzaldehyde.

 Ή NMR (CDC) δ; 3.94 (s, 3H), 6.77 (m, 2H), 7.49 (m, 1H), 10.44 (d, 1H, 0.7Hz).

Process 2

 Example 54 1.54 g (10. Ommo 1) of 6-fluoro-2-methoxybenzaldehyde and LM boron tribromide Z methylene chloride solution 12.0 ml (1 2. Ommo) From 1), 1.18 g (84%) of 6-fluoro-2-hydroxybenzaldehyde was obtained.

 FABMS (m / z); 141 [M + l] +.

O Process 3

 According to Step 1 of Example 1, iodide (1-methylindole-2-yl) methyl (triphenyl) phosphonium 1.77 g (3.32 mmo 1), 6-fluoro 2- From 0.42 g (3.01 mmo 1) of hydroxybenzaldehyde, 0.92 g (6.63 mmo 1) of potassium carbonate and 18—crown 6, 0.085 g (0.32 mmo 1) 0.90 g (96%) of 2- [2- (6-fluoro-2-hydroxyphenyl) vinyl] -1-methylindole was obtained.

FABMS (m / z); 268 [Mil] ⁺ .

Process 4

 According to Step 2 of Example 1, 2- [2- (6-fluoro-2-hydroxyphenyl) vinyl] -1 monomethylindole 902 mg (3.38 mmo1) and N-methylmaleimide 1.1 From 2 g (10.1 mmo 1), compound 14, 1.12 g (88%) was obtained.

 Ή NMR (CDC) δ; 2.89 (s, 3H), 2.90 (m, 1H), 3.62 (s, 3H), 3.77 (m.2H), 3.95 (m, 1H), 4.60 (m, 1H), 6.50 On, 2H), 6.95 ― 7.35 (m, 4H), 7.97 (d, 1H, J = 7.8Hz), 8.53 (s, 1H).

Example 15 Compound 15

Process 1

 6-Promo 2-methoxybenzoic acid 6.93 g (30.Ommo 1) was dissolved in THF 10 Om 1, and PORAN'dimethylsulfuric acid complex 14.3 m 1 (150.00 mmo 1) was added. 1. Heated to reflux for 5 hours. After cooling, water was added to the reaction solution, extracted with getyl ether, washed with water and then brine, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 5.70 g (88%) of a benzyl alcohol compound. Was.

 FABMS (m I z); 216 [M + 1] +.

Process 2

 According to Step 3 of Example 5, 6-bromo-2-methoxybenzaldehyde was obtained from 5.70 g (26.3 mmol) of the benzyl alcohol compound and 23.0 g (264 mmol) of manganese dioxide. 4.33 g (77%) were obtained.

FABMS (m / z); 215 [M + 1] ⁺ . Process 3

 Example 11 According to Step 1 of 1, 4.33 g (20.2 mmo 1) of 6-promo 2-methoxybenzaldehyde and 1 M boron tribromide / methylene chloride solution 2 4.Oml (24. Ommol), 2.05 g (50%) of 6-bromo-2-hydroxybenzaldehyde was obtained.

 FABMS (m / z); 199 [M].

Process 4

 According to Step 1 of Example 1, (1-methylindole-2-yl) methyl (triphenyl) phosphonium 2.93 g (5.5 Ommo 1), 6-bromo-2-hydroxybenzaldehyde 1.0 1 g (5.02 mmo 1), potassium carbonate 1.52 g (1 1.Ommo 1) and 18—crown 6, 0.13 g (0.50 mmo 1) From 1), 1.59 g (96%) of 2- [2- (6-bromo-1-hydroxyphenyl) vinyl] -1-monomethylindole was obtained.

 FABMS (m I z); 328 [M] +.

Process 5

 According to Step 2 of Example 1, 2- [2- (6-promo-2-hydroxyphenyl) vinyl] 1-1-methylindole 1.56 g (4.82 mmo 1) and N-methyl Compound 1.15 and 1.63 g (77%) were obtained from maleimide (1.60 g, 14.41 mmo 1).

 Ή NMR (CDCla) δ; 2.90 (s, 3H), 2.90 (m. 1H), 3.63 (s, 3H), 3.81 (m, 2H), 4.13 (m, 1H), 4.62 (m, 1H ), 6.60 ― 7.35 (m, 6H), 7.97 (dd, 1H, J = l.7, 7.3Hz), 8.90 (s, 1H).

 FABMS (m / z); 439 [M] +.

Example 16 Compound 16

Process 1

According to Step 2 of Example 12, 2.5-ml (20.0 mmol) of 3-chlorodisole, 1.6 M n-butyllithium / n-hexane solution 16 m 1 ( 2.35 g (35%) of 6-n-butyl-2-methoxybenzaldehyde was obtained from 26 ml of Oml and DMF 3.1 ml (40 ml of Oml). Ή NMR (CDCla) δ; 0.92 (t, 3H, J = 7.4Hz), 1.40-1.70 (m, 4H), 2.94 (t, 2H, J-7.4Hz), 3.88 (s, 3H). 6.82 (d , 2H, 1 = 7.9Hz), 7.39 (t, 1H.7.9Hz), 10.60 (s, 1H).

 FABMS (m / z); 193 [M] + ·

Process 2

 Example 11 According to Step 1 of 1, 1.34 g (6.98 mmo 1) of 6-n-butyl-2-methoxybenzaldehyde and 8.4 ml of a 1 M boron tribromide Z methylene chloride solution ( 8. 40 mm 01) gave 94 g (76%) of 6-n-butyl-2-hydroxybenzaldehyde.

FABMS (m / z);] 79 [M] ⁺ .

Process 3

 According to Step 1 of Example 1, iodide (1-methylindole-2-yl) methyl (triphenyl) phosphonium 1.8 1 g (3.4 Ommo 1), 6-n-butyl-2 —From 0.55 g (3.1 Ommo 1) of hydroxybenzaldehyde, 0.95 g (6.88 mmo 1) of potassium carbonate and 18—crown 6, 0.08 g (0.31 mmo 1) There was obtained 0.73 g (77%) of 2- [2- (6-n-butyl-2-hydroxyphenyl) vinyl] -11-methylindole.

 FABMS (m / z); 306 [M] +.

Process 4

 According to Step 2 of Example 1, 2- [2- (6-n-butyl-2-hydroxyphenyl) vinyl] -1-methylindole 72 Omg (2.36 mm 01) and N- Compounds 16 and 8 16 mg (83%) were obtained from 800 mg (7.08 mmol) of methyl maleimide.

 FABMS (m / z); 417 [M + l] +.

Example 17 Compound 1

Process 1

According to Step 1 of Example 1, (1-methylindole-2-yl) methyl (triphenyl) phosphonium 3.20 g (6.0 Ommo 1), 2-hydroxy 6-bivaloylaminobenz Aldehyde 1.llg (5.0 2mmo 1), From 2.42 g (17.5 mmo 1) and 18—crown 6, 0.14 g (0.5 Ommo 1) of potassium carbonate, 2-— 2-(2-hydroxy-1-6-pivaloy) Laminophenyl) vinyl] —1.02 g (49%) of 1-methylindole.

FABMS (m / z); 349 [] ⁺ .

Process 2

 According to Step 2 of Example 1, 2_ [2- (2-hydroxy-6-bivaloylaminophenyl) vinyl] —1-methylindole 726 mg (2.09 mmo 1) and N-methylmaleimide 69 7 mg (6 Compounds 17 and 91 mg (95%) were obtained from .28 mmo1).

FABMS (m / z); 460 [Mil] ⁺ .

Example 18 Compound 18

Process 1

 According to Step 6 of Example 3, 2.78 g (19.9 mmo 1) of 6-fluoro-2-hydroxybenzaldehyde, 3.4 ml of methyl 2-bromopropionate

(30.5 mmo 1) and 4.14 g (30. Ommo 1) of potassium carbonate gave 2.51 g (56%) of 6-fluoro-2- (1-methoxycarbonylethoxy) benzaldehyde. Was.

 Ή NMR (CDC) δ; 1.70 (d, 3H, J = 6.7Hz), 3.77 (s, 3H), 4.88 (q, 1H, J = 6.7Hz). 6.62 (d, 1H, J = 8.7Hz), 6.77 (dt, 1H, J = 9.4, 8.7Hz), 7.43 (dt, 1H,

J = 6.4, 8.7Hz), 10.51 (s, 1H).

EIMS (m / z); 226 [M] +.

Process 2

According to Step 1 of Example 1, 2.39 g (10.6 mmo 1) of 6-fluoro-2- (1-methoxycarbonylethoxy) benzaldehyde, iodide (1-methylindole-2-yl) ) Methyl (triphenyl) phosphonium 6.76 g (12.7 mmo 1), potassium carbonate 4.38 g (3.1.7 mmo 1) and 18—crown 1.6, 0.δ8 g (2.2 From 1 mmo 1), 2- {2- [6-Fluoro-2- (1-methoxycarbonyldioxy) phenyl] vinyl} 3.45 g (93%) of indole were obtained.

 Ή NMR (CDCls) δ; 1.72 (d, 3H, J = 6.6 Hz), 2.17 (s, 3H), 3.82 (s, 311), 4.

88 (q, 1H, J = 6.6Hz), 6.57 (d, 1H, J-8.3Hz), 6.77 (dd, III. J = 8.3, 11.2Hz), 6.86 (s, 1H), 7.06 — 7.15 On, 2H), 7.19 (dt, 1H, J = l.3, 8.1 Hz), 7.30 (d, 1H, J = 8.1 Hz), 7.42 (d, 1H, J-16.6Hz), 7.60 (d , 1H, J = 8.1 Hz), 7.69 (d, 1

(H, J = 16.6Hz).

Process 3

 According to Step 2 of Example 1, 2- {2- [6-fluoro-2- (1-methoxycarbonylethoxy) phenyl] vinyl} 1-11-methylindole 3.31 g (9.37 mmo 1) and N —Methylmaleimide Compound 3.18 and 3.14 g (72%) were obtained from 3.13 g (28.2 mm 01).

 Ή NMR (CDC) δ; 1.58 (d, 3H, J = 6.9Hz), 2.84 (s, 3H), 3.10 (m, 1H), 3.62 ― 3.82 (m, 2H), 3.67 (s, 3H), 3.75 (s, 3H), 4.07 (m, 1H). 4.49 (t, 1H, J = 7.2Hz), 4.88 (m, 1H), 6.52 (d, 1H, 8.2Hz), 6.82 (dd, 1H, 1 = 8.2, 11.4Hz), 7.15 — 7.31 On, 4H), 7.99 (dt, 1H, J = 2.3, 8.2Hz).

EIMS (m / z); 464 [] ⁺ .

Example 19 Compound 19

Process 1

 According to Step 6 of Example 3, 6-promo 2-hydroxybenzaldehyde 201 mg (1.0 Ommo 1), methyl 2-bromopropionate 0.23 ml (2.0 2 mmo 1) and potassium carbonate 0.27 g (93%) of 6-bromo-2- (1-methoxycarbonylethoxy) benzaldehyde was obtained from 0.21 g (1.5 Ommo 1).

FABMS (m I z); 287 [M] ⁺ .

Process 2

According to Step 1 of Example 1, (1 monomethylindole-2-yl) methyl (triphenyl) phosphonium (267 mg, 0.93 mm 01), 6-bromo—2- (1- —Methoxycarbonylethoxy) benzaldehyde 597 mg (1.12 mmo 1), potassium carbonate 193 mg (1.4 Ommo 1) and 18- Round — From 26 mg (0.10 mmo 1), 2- {2- [6-bromo-2- (1-methoxycarbonyl-2-ethoxy) phenyl] vinyl} 1-methylindole 29 Omg (75%).

 FABMS (m / z); 414 [M] +.

Process 3

 According to Step 2 of Example 1, 2- {2 -— [6-promo 2- (1-methoxy propylonylethoxy) phenyl] vinyl} 11-methylindole 10.25 g

(19.23 mmo 1) and N-methylmaleimide (4.60 g, 16.03 mmol) gave Compound 19, 5.84 g (88%).

FABMS (m / z); 526 [M + 1] ⁺ .

Example 20 Compound 20

 1.45 g (3.72 mmo 1) of Compound 1 was dissolved in 100 ml of dioxane, and 1.77 g (7.79 mmo 1) of DDQ was added thereto, followed by stirring at room temperature for 20 minutes. The resulting precipitate was filtered off, the filtrate was concentrated, and the residue was triturated with ethyl acetate to obtain 20.1.30 g (91%) of a compound.

 'Η NMR (DMSO-dt) <5; 3.08 (s, 3H). 4.03 (s, 3H), 7.44 (ddd, 1H, J = 0.9, 7.1, 7.8Hz). 7.49 (dd, 1H, J = l .2, 7.6Hz), 7.62 (dt, 1H, J = l.2, 7.6Hz), 7.70 (ddd, 1H, J = l.2, 7.1, 8.3Hz), 7.72 (dt, 1H, J = l.2, 7.6Hz), 7.79 (br d, 1H, J = 8.3Hz), 7.81 (s, 1H), 8, 08 (dd, 1H, 1.2, 7.6Hz), 8.99 (br d, 1H, J = 7.8Hz).

 FABMS (m / z); 385 [M + 1] ^.

Example 21 Compound 21

Process 1

Compound 20, 64 mg (0.17 mmol) was suspended in 5. Oml of thionyl chloride and stirred at room temperature for 30 minutes. Thionyl chloride was distilled off under reduced pressure to obtain an acid chloride. The acid chloride was dissolved in 5 ml of methylene chloride, 0.14 ml (1.28 mmol) of N, N-dimethylethylenediamine was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with methylene chloride. The organic layer was washed with water and then brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. Preparative thin layer chromatography of the residue (CHC13 / UeOH10 / 1) to give 70 mg (93%) of compound 21 free base.

Process 2

Compound 2 1 free base 7 Omg the (0. 1 6 mm ol) was dissolved in a mixed solvent of CHC 1 ₃ 5 m 1 and A c OE t 1 Om 1, 0. 8 8 4N hydrogen chloride A c OE t soluble liquid 0 35 ml (0.31 mmo 1) was added, and the mixture was stirred at room temperature for 12 hours. The resulting precipitate was collected by filtration to give Compound 21 (5 mg, 59%).

Ή NMR (DMS0-d _fc ) δ; 2.70 (s, 6H), 2.95-3.07 (m, 2H), 3.05 (s, 3H), 3.28-3.37 (m, 2H), 3.97 (s, 3H) , 7.40 (dd, 1H, J = 7.1, 7.8Hz), 7.49 (dd, 1H, J = l.7, 7.1Hz), 7.55 ― 7.60 (m, 2H), 7.65-1 7.81 (m, 4H ), 8.45 (m, 1 H), 8.95 (d, 111, J: 7.8 Hz), 7.87 (br s, 1H).

 FABMS (m / z); 455 [M + l] +.

Example 22 Compound 22

 Example 21 According to Step 1 of 1, from 20 and 62 mg (0.16 mmol) of compound 20 and 2.0 ml of thionyl chloride, an acid chloride was obtained. The compound 22 was reacted with 0.10 ml (0.79 mmo 1) of N′-trimethylethylenediamine to obtain 64 mg (85%) of compound 22.

_{Ή NMR (CDC1 3) δ;} 1.77 - 2.23 On, 2H), 1.84 and 2.00 (2s, 6H), 2.62 an d 2.71 (2s, 3H), 3. 16 - 3.60 (m, 2H), 3. 19 and 3.20 (2s, 3H), 3.88 and 3.89 (2s, 3H), 7.37-7.67 (m, 8H). 9.10 (m. 1H).

 FABMS (m / z); 469 [M + l] +.

Example 23 Compound 23

Process 1

 Example 21 An acid chloride was obtained from compound 64, 64 mg (0.17 mmol) and thionyl chloride 5.0 ml according to Step 1 of Example 1 and then converted the acid chloride to N-methylbiperazine 0 By reacting with 18 ml (1.6 mmo 1), compound 23 free base, 38 mg (49%) was obtained.

Process 2

According to step 2 of Example 2 1, compound 23 free base 38 mg (0.081 mm 0 1) Compound 0.87N Hydrogen chloride ZAc OEt solution 0.13 ml (0.17 mmol) of compound 23 gave 17 mg (42%) of compound 23.

 Ή NMR (DMSO-dfc) δ; 3.07 (s.3H), 3.96 (s, 3H), 7.41 (dd, 1H, J = 7. 1.7.8 Hz) .7.50-1.60 (m, 4H), 7.66 One 7.70 (m, 2H), 7.77 (d, 1H.J = 8.3Hz), 8.96 (d, 1H, J = 7.8Hz).

 FABMS (m / z); 467 [M + l] +.

Example 24 Compound 24

 Example 21 An acid chloride was obtained from compound 20, 19 Omg (0.494 mmo 1) and thionyl chloride lm 1 according to Step 1 of Example 1, and then the acid chloride was converted to 2-pi By reacting with 55 mg (0.5 Ommo 1) of lysine thiol and 0.069 m 1 (0.5 Ommo 1) of triethylamine, compounds 24 and 38 mg (33%) were obtained.

 Ή NMR (CDC) δ; 3.17 (s, 3H), 3.88 (s, 3H), 7.18 (ddd, 1H, J = l.2, 4.9, 7.3Hz), 7.38 (ddd, 1H, J = 0.9, 7.0, 7.9Hz), 7.42 (s.1H), 7.43 — 7.48 (m, 3H), 7.59 — 7.63 (m, 3H), 7.67 (dt, 1H, J = l.4, 7.5Hz), 8.16 (dd, 1H, J = l.4, 7.5Hz), 8.52 (ddd, 1H, J = 0.9, 1.5, 4.9Hz), 9.07 (dd, 1H, J = l. 1, 7.9Hz).

FABMS (m / z); 478 [M + l] ⁺ .

Example 25 Compound 25

 Compound 20 and 1.20 g (3.13 mmo 1) were suspended in methylene chloride 9 Om 1, and DMAP 4 2 mg (0.34 mmo 1) and ethanethiol O. 92 ml

(12 mmo 1) was added, and WS C′HCl, 72 mg (3.77 mmo 1) was added with Ot: and the mixture was stirred at room temperature for 17 hours. Ice water was added to the reaction solution, extracted with methylene chloride, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was triturated with MeOH to obtain Compound 25 (1.07 g, 80%).

Ή NMR (CDC) δ; 1.13 (t, 3H, J = 7.3Hz), 2.81 (m, 2H). 3.16 (s, 3H), 3.89 (s, 3H), 7.40 On, 2H), 7.43 ( dd, 1H, J = l.3, 7.6Hz), 7.45 (br d, 1H, J = 8.4Hz), 7.54 (dt, 1H, J = l.3, 7.6Hz), 7.61 (dt, 111, 1.3 , 7.6Hz), 7.62 (ddd, 1H, 1.2, 7.0, 8.4Hz), 8.00 (dd, 1H, J = l.3, 7.6Hz), 9.09 (dd, 1H, J = 1.2, 7.9Hz).

 FABMS (m / z); 429 [M + l] +.

Example 26 Compound 26

 According to Step 1 of Example 15 from Compound 20 and 25 mg (0.066 mmo 1) and borane-dimethylsulfide complex 0.4 ml (4.2 2 mmo 1), Compound 26 16 mg (65%) were obtained.

Ή NMR (CDC) δ; 2.22 (br s, 1H), 3.18 (s, 3H). 3.91 (s, 3H), 4.42-4.51 (m, 2H), 7.29 (dd, 1H, J = l.2, 7.5Hz), 7.40-7.44 (m, 2H), 7.43 (s, 1H), 7.48 (br d, 1H, J = 8.3Hz), 7.52 (dt, 1H, J = l., 7.5Hz), 7.65 ( ddd.1H, J = l.2, 7.5, 8.3Hz) _; 7.66 (br d.1H, J = 7.5Hz), 9.11 (br d, 1H, J = 7.5Hz).

FABMS (m I z); 370 [M] ⁺ .

Example 27 Compound 27

Process 1

 Dissolve Compound 25, 1.07 g (2.5 Ommo 1) in methylene chloride, 300 m 1, and use 0 at 10% PdZC, 2.67 g, and triethylsilane 2.4. 0 ml (1 5. Ommo 1) was added and the mixture was stirred at 0 for 30 minutes. After the reaction mixture was filtered through celite, the filtrate was concentrated, and the residue was triturated with diisopropyl ether to give 1,3-dioxo41- (2-formylphenyl) -12,6-dimethyl-1,2,3,6. —643 mg (70%) of tetrahydropyro [3,4-l-c] yl rubazole was obtained.

 Ή NMR (CDC) 6; 3.17 (s, 3H), 3.93 (s, 3H), 7.43 (dd, 1H, J = 7.1, 7.8 Hz), 7.45 (s, 1H), 7.49 (m, 2H) , 7.63 (t, 1H, J = 7.6Hz), 7.66 (ddd, 1H, J = 1.2, 7.1, 8.3Hz), 7.71 (dt, 1H.J = l.5, 7.6Hz), 8.08 (dd , 1H, J = l.5, 7.6 Hz), 9.13 (br d, 1H, 7.8Hz), 9.93 (s, 1H).

 FABMS (m / z); 369 [M + l] +.

Process 2

1, 3-Dioxo 4- (2-formylphenyl) 1,2,6-dimethyl-1- 1, Dissolve 23 mg (0.061 mmo 1) of 2,3,6-tetrahydropyro [3,4-c] potassium in a mixed solvent of 4 m 1 of THF and 4 m 1 of MeOH Then, add 0.llmi (1.2 mmo 1) and 43 mg (0.68 mmo 1) of sodium cyanoborohydride in 50% dimethylamine aqueous solution at 0, adjust the pH to about 5 with acetic acid, and add Stirred for hours. To the reaction solution, ice water was added, and § alkali resistance added potassium carbonate, and collected by filtration the resulting precipitate was purified by preparative thin layer chromatography _{(CHC 1 3 ZMe OH 1 0} /1), compound 27, 1 8 mg (72%).

 Ή NMR (CDC) δ; 2.07 (s, 6H), 3.17 (s, 3H), 3.19 (d, 1H, J: 13.3Hz),

3.32 (d, 1H, 13.3Hz), 3.91 (s, 3H), 7.30 (dd, 111, J = l.3, 7.6Hz), 7.36 (dt, 1H, J = l.3, 7.6Hz), 7.42 (ddd, 1H, J = 0.9, 7.0, 7.9Hz), 7.46 (dt, 1H,

J = l.4, 7.6Hz), 7.48 (br d, 1H, J = 8.2Hz), 7.64 (ddd, 1H, J = l., 7.0, 8.2 Hz), 9.12 (dd, 111, 1.2, 7.9Hz) ).

FABMS (m / z); 398 [M + l] ⁺ .

Example 28 8 Compound 28 and Compound 29

 (3-dimethylaminopropyl) bromide triphenylphosphonium 119 mg

(0. 278 mmo 1) was suspended in THF 1 Om 1 and 0.16 ml (0.27 mmol) of 1.661 ^ of 1-butyllithium-hexane solution was added at 0, and room temperature was added. For 15 minutes. Then, 1,3-dioxo-41- (2-formylphenyl) -1,2,6-dimethyl-1,2,3,6-tetrahydropyrro [3,4-c] potassium 7.3 mg (0.2 Ommo 1) was added and the mixture was stirred for 1.5 hours. To the reaction mixture was added a phosphate buffer of pH 7 and the mixture was extracted with methylene chloride, washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by preparative thin layer chroma Bok graph I over _{(CHC l 3 / Me OH 1} 0/1), Compound 2 8 (E: Z = 8 :

1), 12 mg (10%) and compound 29 (E: Z = 1: 18), 42 mg

(35%).

 Compound 28

_{lH NMR (CDC1 3) δ;} 2.14 (s, 6H), 2.16 - 2.19 (m, 2H), 2.23 - 2.29 (m, 2 H), 3.17 (s, 310, 3.90 (s, 3H), 6.11 (dt l! l, J = 6.1. 15.7Hz), 6.18 (d, 1H, J = 15.7Hz), 7.29-7.44 (m, 4H), 7.41 (s.1H), 7.48 (d, 1H, J = 8.1Hz), 7.61-7.66 (m, 2H), 9.13 (d, 1H, J = 7.8Hz).

FABMS (m / z); 438 [M + l] ⁺ .

Compound 29

_{Ή NMR (CDC 1 3) δ} ; 2.17 (s, 6H), 2.21 - 2.28 (m, 210, 2.34 - 2.40 (m, 2 H), 3.16 (s, 3H), 3.89 (s, 3H), 5.44 ( dt, 1H, J = 7.0, 11.7Hz), 6.18 (d, 1H, J = ll.7Hz), 7.36 — 7.44 (m, 5H), 7.40 (s, 1H), 7.46 (d, 1H, 1 = 8.3Hz), 7.63 (ddd, 1H, J = l.0, 7.3, 8.3Hz), 9.11 (br d, 1H, J = 8.1Hz).

 FABMS (m / z); 438 [M + l] *.

Example 29 Compound 30 and Compound 31

Process 1

Dissolve 5.03 g (10.8 mmo 1) of bromide (3-bromopropyl) triphenylphosphonium and 22 ml (21.0 mmo 1) of getylamine in 2 ml of DMF and add 2 ml at room temperature. Stirred for days. Ice water was added to the reaction solution, and a 10 N aqueous solution of sodium hydroxide was added to make the reaction solution alkaline. Then, the solvent was distilled off. Water was added to the residue, and extracted with CH C l _3, dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was triturated with AcOEt to give 587 mg (12%) of (3-ethylethylaminopropyl) bromide triphosphonium bromide.

 Ή NMR (CDC) δ; 0.95 (t, 6H, J-7.1Hz), I.78 (m, 2H). 2.45 (q, 4H, J = 7.1Hz), 2.71 (t, 2H, J = 6.2Hz) ), 3.92 (m, 2H), 7.68-7.88 (m, 15H).

 FABMS (m / z); 376 [M-79] +.

Process 2

 According to Example 28, 583 mg (1.39 mmo 1) of (3-methylethylaminopropyl) triphenylphosphonium bromide, 1.63 M n-butyllithium Zn-hexane solution 1.Oml ( 1.6 mmol) and 1,3-dioxo-41- (2-formylphenyl) — 2,6-dimethyl-1,2,3,6-tetrahydropyrro [3,4-c] Power rubazole 346 mg (0.939 mm) ol), a mixture of 30 free bases of the compound and 31 free bases of the compound (E: Z = 2.5: 1) was obtained in a yield of 42 mg (98%).

Process 3 Mixture of compound 30 free base and compound 31 free base 4 19 mg (0.899 mmol) and 0.88 N hydrogen chloride / Ac〇Et solution 2.0 m 1 (1.8 mmo 1) The precipitate was collected by filtration, and the resulting precipitate was filtered to obtain 244 mg (54%) of compound 31 (E: Z = 1: 8). Diisopropyl ether was added to the filtrate, and the formed precipitate was filtered. Thus, compound 30 (E: Z = 2: 1), 127 mg (27%) was obtained. Compound 30

Ή NMR (DMSO-d ₆ ) 6; 1.11 (t, 3H, J = 7.2 Hz), 1.12 (t, 3H. J = 7.2 Hz), 2.33-2.51 (m, 2H), 2.95-3.15 (m , 6H), 3.05 (s, 3H), 3.98 (s, 3H), 6.15 (dt, 1H, J = 6.8, 15.9Hz), 6.29 (d, 1H, J = 15.9Hz), 7.32-7.74 ( m, 7H), 7.72 (s, 1H), 8.97 (d, 1H, 1 = 7.6Hz), 9.70 (br s, 1H).

 FABMS (m / z); 466 [M + l] +.

Compound 3 1

lH NMR (DMS0-d ₆ ) δ; 1.17 (t, 6H, 7.2 Hz), 2.51 (m, 2H), 2.98 (m, 6H), 3.04 (s, 3H), 3.98 (s, 3H), 5.40 ( dt, 1H, J = 7.1, 11.5Hz), 6.27 (d, 1H, J = ll.5Hz), 7.33-7.76 (m, 7H), 7.76 (s, 1H), 8.95 (d, 1H, J = 7.8Hz).

Example 30 Compound 3 2

Dissolve 104 mg (0.238 mm o 1) of a mixture of compound 28 and compound 29 in 5 ml of DMF, add 10% Pd / C, 55 mg, and add hydrogen atmosphere at room temperature and atmospheric pressure For 14 hours. The reaction solution Celite separated by filtration, concentrated the filtrate and purify the residue by preparative thin layer chromatography _{(CHC 1 3 XM e OH 1} 0/1), compound 3 2, 8 Omg (7 7%) Obtained.

 Ή NMR (CDC) δ; 1.34-1.54 (m, 4H), 1.78-2.37 (m, 2H), 2.20 (s, 6H), 2.43-2.62 (m.2H), 3.17 (s, 3H) , 3.92 (s, 3H), 7.23-7.43 (m, 5H), 7.41 (s.1H), 7.48 (d, 1H, J = 8.3 Hz), 7.64 (ddd, 1H, J = l.2, 7.3, 8.3Hz). 9.12 (br d, 1H, J = 7.8Hz).

 FABMS On Iz); 440 [M + l] +.

 Example 3 1 Compound 3 3

According to Example 28, 1,3-dioxo-41- (2-formylphenyl) -1,2,6-dimethyl-1,2,3,6-tetrahydropyrro [3,4-c] carbazo 198 mg (0.536 mmo 1), (2-dimethylaminoethyl) triphenylphosphonium bromide 339 mg (0.88 mmo 1) and 1.66 M n-butyl From 1.0 ml (1.7 mmol) of a lithium Zn—hexane solution, 197 mg (87%) of a compound 33 (E: Z = 28: 72) was obtained.

'Η Oki (CDC1 ₃ ) δ; 2.14 and 2.23 (2s, 6H), 2.87 (d, 0.56H, J = 6.3Hz), 3.15 (m, 1.44H), 3.15 and 3.16 (2s , 3H), 3.88 and 3.89 (2s, 3H), 5.58 (dt, 0.72H, 6.3, 11.7Hz), 6.17 (dt, 0.28H, J = 6.3, 15.6Hz), 6.22 — 6.28 (m, 1H ), 7.32 ― 7.69 (m, 8H), 9.12 (m, 1H).

FABMS (m I z); 424 [M + l] ⁺ .

Example 3 2 Compound 34

 According to Example 30, Compounds 34 and 67 mg (78%) were obtained from Compounds 33 and 86 mg (0.2 Ommo 1) and 10% PdZC and 46 mg, respectively.

Ή NMR (CDC1 ₃ ) δ; 1.61-1.71 (m, 2H), 2,000-2.20 (m, 2H), 2.14 (s, 6H), 2.45-2.62 (m, 2H), 3.17 (s , 3H), 3.91 (s, 3H), 7.23-7.44 On, 5H), 7.42 (s, 1H), 7.48 (d, 1H, J = 8.3Hz), 7.64 (ddd, 1H, J = l.2, 7.1, 8.3Hz), 9.12 (dd, 1H, J = l.2, 8.1Hz).

FABMS (m / z); 426 [M + l] ⁺ .

Example 3 3 Compound 35

 According to Example 28, 1,3-dioxo-1- (2-formylphenyl) -1,2,6-dimethyl-1,2,3,6-tetrahydropyrro [3,4-c] carbazole, 18 1 mg (0.49 Ommo 1), (methoxymethyl) triphenylphenyl bromide 26 Omg (0.758 mmo 1) and 1.66 M n-butyl lithium Zn-hexane solution 0 From 46 ml (0.76 mmo 1), compound 35 (E: Z = 4: 5), 144 mg (77%) was obtained.

_{Ή NMR (CDC 1 3) δ} ; 3. 17 and 3.18 (2s, 3H), 3.42 and 3.71 (2s, 3H), 3.89 and 3.90 (2s, 3H), 4.91 (d, 0.56H, J = 7.2Hz) , 5.53 (d, 0.44H, J = 12.8Hz), 5.96 (d.0.56H, J = 7.2Hz), 6.90 (d, 0.4411, J = 12.8Hz), 7.24-8.20 (m, 8H). 9 .12 (m, IH).

FABMS (m / z); 397 [M + l] +. Example 34 Compound 36

 Compound 35, 118 mg (0.297 mmo 1) was dissolved in 60 ml of acetonitrile, and 57 mg (0.38 mmo 1) of sodium iodide and 0.04 1 ml (0.32 mmo) of chlorotrimethylsilane were dissolved. 1) was added, and the mixture was stirred at room temperature for 15 minutes. The solvent was distilled off, water was added to the residue, extracted with methylene chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by preparative thin layer chromatography (CHC 13 / MeOH 100/1) to give 109 mg (96%) of compound 36.

 Ή NMR (CDCU) δ; 3.17 (s, 3H), 3.54 (dd.1H, J = 2.1, 17.0Hz), 3.61 (dd, 1H, 2.1, 17.0Hz), 3.89 (s, 3H), 7.36 (s , 1H), 7.36 ― 7.52 (m, 6H), 7.64 (ddd, 1H, J = l.2, 7.3, 8.3Hz), 9.10 (dd, 1H. Jl.2. 7.8Hz).

FAB S (m / z); 383 [M + l] ⁺ .

Example 3 5 Compound 37

 According to Step 2 of Example 27, compound 36, 109 mg (0.284 mmol), 50% aqueous dimethylamine solution 0.26 ml (2.9 mmol) and sodium cyanoborohydride 96 mg (1.5 mmol) From 1), 37, 94 mg (54%) of the compound were obtained.

 Ή NMR (CDC) <5; 2.05 (s, 6H), 2.40-2.45 (m, 2H), 2.61-2.77 (m, 2H), 3.17 (s.3H), 3.91 (s, 3H), 7.25- 7.44 (m, 5H), 7.42 (s, 1H), 7.48 (d, 1H, J = 8.2Hz), 7.64 (ddd, 1H, J = l.2, 7.1, 8.3Hz), 9.12 (br d, 1H , 3 = 8.1 Hz).

 FABMS (m / z); 412 [M + l] +.

 Example 36 Compound 38

 Process 1

 Example 21 According to step 1 of 1, from 25,1 mg (0.846 mmol) of compound 20, 325 mg and 25 ml of thionyl chloride, an acid chloride was obtained, and then N, N-getyl ethylenediamine 1.2 ml (8 By reacting with 5 mmol 1), 33 Omg (81%) of the compound 38 free base was obtained.

 Process 2

Example 38 Compound 38 free base 33 Omg (0.684 m 1110 1) Compound 38, 297 mg (84%) were obtained from 1.55 ml (1.4 mmol) of a 0.98 N hydrogen chloride / AcOEt solution.

 Ή NMR (DMSO-dfc) δ; 1.08 (t, 6H, J = 7.2Hz), 2.89 (br s, 2H) .3.00 (m, 4H), 3.06 (s, 3H), 3.37 (br s, 2H ), 3.97 (s, 3H), 7.39 (ddd, 1H, J = l.0, 7.1, 7.8Hz), 7.48-7.80 (m, 6H), 7.72 (s. 1H), 8.94 (d, 1H) , 7.8Hz), 10.08 (br s, 1H).

FABMS (m / z); 483 [M + l] ⁺ .

Example 3 7 Compound 39

Process 1

 According to Step 1 of Example 1, iodide (1-methylindole-2-yl) methyl (triphenyl) phosphonium 8.91 g (16.7 mmo 1), salicylaldehyde 2.00 g (16.4 mmo 1), potassium carbonate 3.40 g (24.6 mmo 1) and 18—crown 6, 0.04 g (0.16 mmo 1), 2-[2-( 2.60 g (88%) of 2-hydroxyphenyl) vinyl] 111-methylindole were obtained.

 FABMS (m / z); 250 [M] +.

Process 2

 According to Step 2 of Example 3, 2- [2- (2-hydroxyphenyl) vinyl] -111-methylindole 3.02 g (1.2.13 mmo 1), DMAP 25 mg (0. 1 2 mmo 1), triethylamine 3.4 m 1 (24.26 mmo 1) and acetic anhydride 2. Oml (1 8.20 mmo 1), 2— [2— (2-acetoxyphenyl) Vinyl] —1 -methylindole 3.21 g (91%) was obtained.

 FABMS (mIz); 292 [M] +.

Process 3

According to Step 2 of Example 1, 2- [2- (2-acetoxyphenyl) vinyl] -1-methylindole, 6.07 g (20.86 mmo 1) and N-methyl maleimide 4.64 g (41.72 mmo 1), 4— (2-acetoxoxyphenyl) -1-1,3-dioxo-1,6-dimethyl-1,2,3,3a, 4,5,6,10 Quinol hydropyro [3,4-c] carbazole, 6.97 g (83 %).

 lH NMR (CDCla) 6; 2.30 (s 3H), 2.78 (s, 3H), 2.99 (m 1H). 3.27 On, 1H). 3.48 (m 1H), 3.67 (s, 310, 3.74 (dd, 1H, J = 3.4, 7.6Hz), 4.45 (d, 1H, J = 7.6Hz), 7.09 (m, 1H), 7.16-7.35 (m, 5H), 7.76 (m, 1H), 7.99 (m, 1H).

FABMS (m / z); 402 [M + l] +.

Process 4

 According to Example 20, 4- (2-acetoxoxyphenyl) 1-1,3-dioxo-2,6-dimethyl-1,2,3,3a, 4,5,6,10c From the hydropyrro [3,4-c] hydrorubazole 6.97 g (17.32 mm 01) and DDQ 7.88 g (34.7 Ommo 1), 4 Cetoxyphenyl) 1,1,3-dioxo-2,6-dimethyl-1,1,2,3,6-tetrahydropyrro [3,4-c] potassium 6.78 g (98%) Was.

 Ή NMR (CDC) δ; 1.89 (s, 3H), 3.21 (s, 3H), 3.91 (s, 3H), 7.25 (m. 1H). 7.41 (m, 2H), 7.46 (s. 1H), 7.48 (m, 2H), 7.51 (dt, 1H, J = l.8, 7.8Hz). 7.65 (ddd, 1H, J = l.2, 7.2, 8.3Hz), 9.12 (d, 1H, J = 7.9Hz).

FABMS (m / z); 399 [M + l] ⁺ .

Process 5

4- (2-Acetoxyphenyl) 1-1,3-Dioxo-2,6-dimethyl-1,2,3,6-tetrahydropyrro [3,4-c] caproluvazole 1.0 g (2.51 mmo 1) was dissolved in 25 ml of THF, 0.49 g (2.76 mmo 1) of N-bromosuccinic acid imide was added, and the mixture was stirred at room temperature for 4.5 hours. 1 0% C I mud monkey sulphite aqueous sodium was added to the reaction solution, and extracted with CHC 1 _3, after brine washed, dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was triturated with MeOH to give 4 _ (2-acetoxyphenyl) — 9-bromo-1,3, -dioxo-1,2,6-dimethyl-1,1,2,3,6-tetrahydropyrrolate [3 , 4—c] bolazole 1.13 g (94%) was obtained.

Ή NMR (CDC) δ; 1.90 (s, 3H), 3.20 (s, 3H), 3.89 (s, 3H). 7.25 (m, 1H), 7.35 (d, 1H, J = 8.6Hz), 7.39 ( dt.1H, J = l.2, 7.4Hz), 7.50 (m, 1H), 7.46 (s, 1H), 7.52 (ddd, 111, J = 2.0, 7.4, 8.1Hz). 7.72 (dd , 1H, 2.0, 8.6H z), 9.27 (d, 1H, J = 2. OHz).

 FABMS (m / z); 477 [M + l] +.

Process 6

 4- (2-acetoxyphenyl) —9-bromo-13-dioxo-2,6-dimethyl-1,2,3,6-tetrahydropyrro [3 4 -c] lipazole 1 13 g (2.36 mmo 1) was dissolved in a mixed solvent of methylene chloride 10 OmI and 50 mL of Me〇H, 0.39 g (2.82 mmol) of potassium carbonate was added, and the mixture was stirred at room temperature for 40 minutes. To the reaction solution was added 2 ml of a 3.95 N hydrogen chloride ZMeOH solution, and the solvent was distilled off. Water was added to the residue, and the resulting precipitate was collected by filtration, washed with water and then with MeOH, and washed with 9-bromo-1,3-dioxo-4- (2-hydroxyphenyl) -1,2,6-dimethyl- There was obtained 0.99 g (96%) of 1,2,3,6-tetrahydropyro [3,4-c] carbazole.

 Ή NMR (D SO-dt) «5; 3.05 (s, 3H), 3.96 (s, 3H), 6.90 (dt, 1H, J = l.0, 7.6Hz), 6.93 (d, 1H, J = 8.5Hz), 7.27 (m, 2H), 7.72 (d, 1H, J = 8.8Hz), 7.77 (dd, 1H,) = 2.1, 8.8Hz), 7.80 (s.1H) .9.07 (d, 1H, J = 2.1Hz), 9.43 (s, 1 H).

 FABMS (m I z) 435 [M + l] +.

Process 7

9-bromo-13-dioxo-1- (2-hydroxyphenyl) -1,2,6-dimethyl-1,2,3,6-tetrahydropyrro [3,4-c] carbazol, 1.00 g (2. Dissolve 3 Ommo 1) in DMF 10 Om I and add 5 O% aqueous dimethylamine solution 1.O Oml (9.54 mmo 1) and 35% formalin 0.8 Oml (9.4 Ommo 1) , 8 5 "C 5 h and stirred. the ice water to the reaction solution added, and extracted with CHC 1 _3, after brine washed, dried over anhydrous sodium sulfate, the solvent was distilled off. residue to silica gel column chromatography (CHC after purification 1 _3), and Bok Richiyureshiyon in Me_〇_H to give compound 3 9, 0. 38 g (33%).

Ή NMR (CDC) 6; 2.36 (s, 6H), 3.18 (s, 3H), 3.75 (s, 2H), 3.88 (s, 3H), 6.91 (t, 1H, J = 7.6Hz), 7.09 ( dd, 1H, Jl.6, 7.6Hz), 7.26 (dd, 1H, J = 1.6, 7.6Hz), 7.30 (d, 1H, J = 8.8IIz), 7.54 (s, 1H), 7.67 (dd, 1H.J = 2.1, 8.8Hz), 9.2 (d, 1H, 2.1Hz) .

 FABMS (m / z); 492 [Mil] +.

Example 3 8 Compound 40

Process 1

 According to Step 6 of Example 37, 4- (2-acetoxyphenyl) -1,1,3-dioxo-1,2,6-dimethyl_1,2,3,6-tetrahydropyrro [3,4- c] From 2.50 g (6.28 mmo 1) of potassium hydroxide and 1.74 g (12.6 mmo 1) of potassium carbonate, 1,3-dioxo-1- (2-hydroxyphenyl) 1.83 g (82%) of 2,6-dimethyl-1- (1,2,3,6-tetrahydropyrro [3,4-c] caproluvazole) was obtained.

Ή NMR (DMS0-d ₆ ) δ; 3.05 (s, 3H), 3.97 (s, 3H), 6.90 (dt, 1H, J = l. 1, 7.5 Hz), 6.93 (dd, 1H. J = l .1, 8.2Hz), 7.26 (ddd, 1H, J = l.8, 7.5, 8.2Hz), 7.29 (dd, 1H, J = l.8, 7.5Hz), 7.38 (t, 1H, J = 7.5Hz), 7.65 (ddd, 1H, J = l.2, 7.1, 8.3Hz), 7.73 (d.1H, J = 8.3Hz) .7.77 (s, 1H), 8.95 (d, 1H. J = 7.8Hz), 9.38 (s, 1H).

 FABMS (m / z); 357 [M + l] +.

Process 2

 According to Step 7 of Example 37, 1,3-dioxo-4- (2-hydroxyphenyl) -1,2,6-dimethyl-1,2,3,6-tetrahydropyrro [3,4-c] From 3.56 g (1 Ommo 1) and ル, Ν, Ν ', Ν'—tetramethyldiaminomethane 13.6 m 1 (10 Ommo 1), compound 40, 2.59 g (63%) were obtained.

_{Ή NMR (CDC1 3) δ;} 3.19 (s, 3H), 3.75 (s, 2H), 3.91 (s, 3H), 6.91 (t, 1 H, J = 7.5Hz), 7.09 (d, 1H, J = 7.5Hz), 7.27 (m, 1H), 7.38 (t, 1H, J = 7.7Hz), 7.45 (d, 1H, J = 8.2Hz), 7.55 (s, 1H), 7.61 (m, 1H), 9 . 1 [(d, 1H, J = 7.7H z).

 FABMS (m / z); 414 [M + l] +.

Example 3 9 Compound 4 1 Process 1

 According to Step 6 of Example 3, compound 40, 30 Omg (0.73 mmo1), 2-dimethylaminoethyl chloride hydrochloride 127 mg (0.87 mmo1) and potassium carbonate 224 mg (1.62 mmo 1), Compound 41 Free base 54 mg

(15%).

Process 2

 According to Step 2 of Example 2 54, compound 41 free base 54 mg (0.11 mm o 1) and 4N hydrogen chloride / Ac〇Et solution 0.062 ml (0.25 mm o 1) As a result, 74 mg (quantitative) of compound 41 was obtained.

'Η NOTE (D S0-d ₆ ) δ; 2.50 (s, 6H), 2.82 (br, 2H), 2.96 (br, 6H), 3.06 (s, 3H), 3.50-3.90 (m, 2H), 4.40 -4.60 (m, 2H), 4.02 (s, 3H) .7.30-7.50 (m, 2H), 7.60-7.80 (m, 3H), 7.78 (d.1H, J = 8.3Hz), 7.98 (s, 1H) ), 8.98 (d, 1H, J = 8.3Hz).

 FABMS (m / z); 485 [+ l] +.

Example 40 Compound 42

1.00 g (2.42 mmo 1) of Compound 40 was dissolved in 50 ml of DMF, 0.23 ml (3.69 mmo 1) of methyl chloride was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was Torichu Les one Chillon with a mixed solvent of CHC 1 ₃ and Ac OE, compound 42, was obtained 1. 30 g (97%).

FABMS (m / z); 428 (M-127) ⁺ .

Example 4 1 Compound 43

3.30 g (5.94 mmo 1) of compound 42 was suspended in 60 ml of acetic acid, 1.95 g (23.777 mmo I) of sodium acetate was added, and the mixture was stirred at 110 for 6 hours. Ice water was added to the reaction solution, and extracted with CHC 1 _3, after brine washed, dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography (CHCl ₃ ZMe〇H 100/1) and triturated with MeOH to obtain Compound 43, 1.41 g (55%).

_{Ή NMR (CDC1 3) (5} ;. 2.14 (s, 3H), 3.19 (s, 3H), 3.90 (s 3H), 5.25 (s, 2 H), 7.06 (t, 1H, J = 7.6Hz), 7.40 (m, 3H), 7.45 (d.1H, J = 8.9Hz), 7.52 (s, 1H). 7.62 (ddd, III,): 1.1, 7.2, 8.9 Hz), 9.09 (dd, 111,) = 1.1, 7.9 Hz).

FABMS (m / z); 429 [M + l] ⁺ .

Example 4 2 Compound 44

 According to Step 6 of Example 37, Compound 43, 1.54 g (3.59 mmo 1) and 29% ammonia water 20 ml 1 gave Compound 44, 0.69 g (50% %).

'Η NMR (CDC1 ₃ ) (5; 3.18 (s, 3H), 3.90 (s, 3H), 4.23 (s, 2H), 6.91 (t, 1 H, 1 = 7.6 Hz), 7.10 (d, 1H, J = 7.6Hz), 7.27 (dd, 1H, J = 7.6Hz), 7.38 (t, 1H, J = 7.8Hz) .7.44 (d, 1H, J = 8.3Hz), 7.56 (s, 1H) , 7.61 (m, 1H), 9.11 (d, 1H, J = 7.8Hz).

 FABMS (m / z); 386 [M] +.

Example 4 3 Compound 4 5

 According to Example 30, Compounds 42, 0.26 g (4.68 mmo 1) and 10% Pd / C, 0.1 lg gave Compounds 45, 0.12 g ( 70%).

FABMS (m / z); 371 [M + l] ⁺ .

Example 44 Compound 4 6

 According to Step 6 of Example 3, compound 45, 10 Omg (0.27 mmol), 2-dimethylaminoethyl chloride hydrochloride 78 mg (0.54 mmol) and potassium carbonate 149 mg From (1.08 mmo 1), compound 46, 114 mg (96%) was obtained.

_{Ή NMR (CDC1 3) δ;} 1.94 (s, 6H), 2.23 (m, 2H), 2.41 (s, 3H), 3.20 (s, 3 H), 3.53 (m, 2H), 3.91 (s, 3H) , 7.12 (d.1H, 1 = 7.5Hz), 7.23 (dd, 1H, J = 2.0, 7.5Hz), 7.29 (dd, 1H.J = 2.0, 7.5Hz), 7.41 (dd, 1H, J = 7.3, 7.9Hz), 7.4 7 (d, 1H, J = 8.2Hz), 7.64 (s.1H), 7.64 (ddd, 1H, J = l.3.7.3, 8.2Hz), 9.13 ( (dd, 1H, J = l.3, 7.9Hz).

 FABMS (m / z); 442 [M] +.

 Example 4 5 Compound 4 7

According to Example 20, Compound 4, 1.83 g (2.42 mmo 1) and DDQ 1.19 g (4.84 mmo 1) gave Compounds 47, 83, 2 mg (77 %) Obtained.

Ή NMR (DMSO-d ₆ ) δ; 3.06 (s, 3H), 3.97 (s, 3H), 3.99 (s, 3H), 7.30-7.50 (m, 1H), 7.60-7.70 (m.1H), 7.72 (d, 1H, J = 2.5Hz), 7.75 (d, 1H, J = 8.4Hz), 7.80 (d, 1H, J = 3.0Hz), 7.93 (s, 1H), 8.95 (d, 1H, J = 7.4Hz), 10.80 (br, 1H).

 EIMS (m / z); 448 [M + l] +

Example 46 Compound 48

Process 1

 According to Step 6 of Example 3, compound 47, 815 mg (1.82 mmol), 2-dimethylaminoethyl hydrochloride 524 mg (3.64 mmol) and potassium carbonate 753 mg (5.46 mmol) As a result, Compound 48 free base (510 mg, 54%) was obtained.

Process 2

 According to Step 2 of Example 2 1, the compound 48 was obtained from 73 mg (0.14 mmo 1) of free base and 4 N hydrogen chloride ZA c OEt solution 0.039 ml (0.16 mmo 1). 48, 76 mg (97%) were obtained.

Ή NMR (DMS0-d _t ) δ; 2.47 (d, 6H, J = 3.3 Hz), 3.02 (br, 2H), 3.08 (s, 3H), 3.80-4.00 (m, 2H), 3.94 (s, 3H ), 4.02 (s, 3H), 7.30-7.50 (m, 1H), 7.60-7.90 (in, 3H), 7.90-8.00 (m, 2H), 8.97 (d, 1H, J = 7.9Hz), 9.89 ( br, 1H).

FABMS (m / z); 520 [M + l] +.

Example 47 Compound 49

Process 1

1,3-dioxo-41- (2-hydroxyphenyl) -1,2,6-dimethyl-1,2,3,6-tetrahydropyrro [3,4-c] carbazole, 2.00 g (5.6 1 was dissolved mmo 1) a mixed solvent of CHC 1 ₃ 2 50 m l and DMF 2 5 m l, min fuming nitric 7. 20m l (1 68. 3 mmo 1) three times every 1 hour at 0 And stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with CHC13. The organic layer was washed with saturated sodium hydrogen carbonate and then with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue is subjected to silica gel column chromatography (CH C 1 a / MeOH 100/1), and purified by 1,3-dioxo-1- (2-hydroxy-5-ditrophenyl) -1,2,6-dimethyl-1,2,3,6- Tetrahydropyrro [3,4-c] potassium 1.12 g (50%) and 1,3-dioxo-4- (2-hydroxy-3-nitrophenyl) 1-2,6-dimethyl-1 There was obtained 0.55 g (24%) of 2,3,6-tetratetrahydropyrazole [3,4-c] potassazole.

 1,3-dioxo-1,4- (2-hydroxy-15-nitrophenyl) -1,2,6-dimethyl-1,2,3,6-tetrahydropyrro [3,4-c] caproluvazole

• H NMR (D S0-d ₆ ) δ; 3.02 (s, 3H), 3.94 (s, 3H), 6.11 (br s, 1H), 7.14 (d, 1H, J = 9.8 Hz), 7.43 ( dt, 1H, J = 0.8, 7.9Hz). 7.47 (d, 1H, J = 8.3Hz) .7.52 (s, 1H), 7.67 (ddd, 1H, J = l.2, 7.2, 8.3Hz) , 8.29 (d, 1H, J-2.6Hz), 8.29 (dd, 1H, J = 2.6, 9.8Hz), 9.04 (d, 1H. 7.9Hz).

 FABMS (m / z); 402 [M + l] +.

 1,3-Doxoxo 4- (2-hydroxy-3-nitrophenyl) _2,6-dimethyl-1,2,3,6-tetrahydropyrro [3,4-c]

 Ή NMR (DMSO-de) δ; 3.20 (s, 3H), 3.94 (s, 3H), 7.73 (dd, 1H, J = 7.4, 8.6 Hz), 7.42 (ddd.1H, J = 0.9, 7.3, 8.0Hz), 7.48 (d, 1H, J = 8.3Hz), 7.52 (s, 1H), 7.65 (ddd, 1H, J = l.2, 7.3, 8.3Hz), 7.70 (dd, 1H, J = l .7, 7.4Hz), 8.26 (dd, 1H, J = l.7, 8.6Hz), 9.12 (ddd, 1H, J = 0.7, 1.2, 8.0Hz), 11.00 (s, 1H).

FABMS (mIz); 402 [M + l] ⁺ .

Process 2

 According to Step 6 of Example 3, 1,3-dioxo-4- (2-hydroxy-3-nitrophenyl) -1,2,6-dimethyl-1,2,3,6-tetrahydropyro

[3,4-c] potassium hydroxide 240 mg (0.6 Ommo 1), 2-dimethylaminoethyl chloride hydrochloride 26 Omg (1.8 Ommo 1) and potassium carbonate 58 Omg (4. 2 Ommo 1) shows that 1,3-dioxo-1- [2- (2-dimethylaminoethoxy) -13-nitrophenyl] -1,2,6-dimethyl-1- 1,2,3,6-tetrahydropyrro [ 3, 4-c] bolazole 1 75 mg (62%) Was.

 Ή NMR (CDC) δ; 1.91 (s, 6H), 2.27 (m, 2H), 3.22 (s, 3H), 3.64 (m, 1H), 3.81 (m, 1H), 3.93 (s, 3H), 7.31 (t, 1H, J = 8.OHz), 7.44 (dt, 1H, 1.0, 7.5Hz), 7.51 (d, 1H, J = 8.3Hz), 7.66 n, 2H), 7.67 (s, 1H) ), 7.91 (dd, 1H, 1 = 1.7, 8. OHz), 9.13 (m 1H).

FABMS (m / z); 473 [M + l] ⁺ .

Process 3

 According to Example 30, 1,3-dioxo-1-4- [2- (2-dimethylaminoethoxy) -3--3-trophenyl] -12,6-dimethyl-1,2,3,6-tetra Hydropyrrole [3,4-c] sorbazole From 1.15 g (2.43mmo I) and 10% PdZC, 0.30g, 4- [3-amino-2- (2- Dimethylaminoethoxy) phenyl] 1,1,3-dioxo-1,2,6-dimethyl-1,2,3,6-tetrahydropyrrole [3,4-c] -caproluvazole 0.97 g (90%) Was.

 Ή NMR (CDC) (5; 2.11 (s, 6H), 2.28 (t. 2H, 5. OHz), 3.20 (s, 3H). 3.48 (m. 2H), 3.91 (s, 3H), 6.73 (dd, 1H.J = l.6, 7.5Hz), 6.83 (dd, 1H, J = l. 6, 7.9Hz), 7.01 (t, 1H, J = 7.8Hz), 7.40 (ddd, 1H, J = 0.9, 7.4, 7.9Hz) .7.4 7 (d.1H, 8.3Hz). 7.62 (s, 1H), 7.63 (ddd, 1H, 1 = 1.1, 7.4, 8.3Hz), 9.1 2 (dd, 1H. J = l.1, 7.9Hz).

 FABMS (m / z); 443 [M + l] +.

Process 4

 4- [3-Amino-2- (2-dimethylaminoethoxy) phenyl] —1,3, dioxo-1,2,6-dimethyl-1,2,3,6-tetrahydropyrro [3,4-1c] Was dissolved in 5 ml of methylene chloride, and 0.04 ml of phenyl isocyanate (0.37 mol) was added, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (CHC1a / MeOH30 / 1), followed by trituration with diisopropyl ether to obtain compound 49 free base, 94 mg (55%). Was.

Process 5 According to Step 2 of Example 2 1, from compound 49 free base 9 Omg (0.16 moI) and 4N hydrogen chloride / AcOEt solution 0.044 ml (0.18 mmo 1) Compounds 49 and 85 mg (88%) were obtained.

Ή NR (DMS0-d ₆ ) δ; 2.20-2.60 (m, 2H), 2.50 (s, 6H), 3.08 (s, 3H), 3.60 (m.2H), 4.01 (s, 3H), 6.97 ( t, 1H, J = 7.6Hz), 7.02 (dd.1H, J = 7.6, 1.3 Hz), 7.20 (t, 1H, J = 7.6Hz), 7.29 (t, 2H, J = 7.6Hz), 7.41 ( t, 1H, J = 7.6Hz), 7.57 (d, 2H, J = 7.6Hz), 7.68 (t, 1H, J = 7.3Hz), 7.77 (d, 1H, J = 8.3Hz), 7.92 ( s, 1H), 8.30 (d, 1H, J = 7.6Hz), 8.98 (d, 1H, J = 7.6Hz).

FABMS (m / z); 562 [M + l] ⁺ .

Example 4 8 Compound 50

Process 1

 According to Example 30, Compound 48 free base 545 mg (1.05 mmol) and 10% Pd / C (50 wt%), 276 mg, Compound 50 free base 41 6 mg (82%) were obtained.

Process 2

 Example 2 According to Step 2 of 1, from Compound 50 free base 82 mg (0.17 mmo 1) and 4N hydrogen chloride ZAc OEt solution 0.04 7 ml (0.19 mmo 1), Compound 50, 79 mg (90%) was obtained.

Ή NMR (DMS0-d ₆ ) δ; 2.48 (s, 6H), 3.07 (s, 3H), 2.90-3.20 (m.2H), 3.70-4.00 (m, 2H), 3.92 (s, 3H), 4.01 (s, 3H), 7.40 (m, 1H), 7.40 (t, 1H, J = 7.6Hz), 7.65 (dd, 1H, J = l.6, 7.6Hz), 7.70 (m, 1H), 7.77 (d, 1H, J = 8.3H z). 7.90 (m, 1H), 7.91 (s, 1H), 8.97 (d, 1H, J-7.6Hz), 9.90 (br, 1H).

FABMS (m / z); 486 [M + l] +.

Example 4 9 Compound 5 1

 Process 1

The compound 50 free base (318 mg, 0.66 mmo 1) was dissolved in dioxane (1 Om 1), 2N hydrochloric acid (1 Om 1) was added, and the mixture was heated under reflux for 15 hours. The reaction mixture was neutralized by adding 10N aqueous sodium hydroxide solution, and the resulting precipitate was collected by filtration and triturated with AcOEt to give Compound 51 free base, 19 Omg (62%). Obtained. Process 2

 Example 5 According to Step 2 of Example 1, Compound 5 was obtained from 8 Omg (0.17 mmo 1) of free base and 4 N hydrogen chloride ZA c OEt solution 0.047 ml (0.19 mmo 1) to obtain Compound 5 1, 83 mg (96%) were obtained.

Ή NMR (DMS0-d ₆ ) δ; 2.51 (s, 6H), 3.01 (br, 2H), 3.07 (s, 3H), 3.87 (br, 2H), 4.01 (s, 3H). 7.40 (m, 1H ), 7.37 (t, 1H, J = 7.6Hz), 7.60 (m, 2H), 7.77 (d, 1H, 8.3Hz), 7.90 (m, III), 7.91 (s, 1H), 8.97 (d, 1H) , J = 7.9Hz), 9.90 (br, 1H).

FABMS (m / z); 472 [+ l] ⁺ .

Example 50 Compound 52

Process 1

 According to Example 25, compound 51 1 free base 1 24 mg (0.26 mmo 1), WSC'HC and 15 1 mg (0.79 mmo 1) and getylamine 0.05 5 ml (0. From 53 mmol), 68 mg (49%) of compound 52 free base was obtained.

Process 2

 Example 2 According to step 2 of 1, from compound 52 free base, 64 mg (0.12 mmo 1) and 4N hydrogen chloride ZA c〇Et solution 0.033 ml (0.13 mmo l) Compound 52, 65 mg (95%) was obtained.

 Ή NMR (DMSO-dfc) δ; 1.12 (t, 3H, J = 6.9Hz), 1.22 (t, 3H, J = 6.9Hz), 2.49 (s, 6H), 2.95 (m, 2H), 3.06 (s , 3H), 3.25 (m.2H), 3.55 (m, 2H), 3.95 (m, 2H), 4.02 (s, 3H), 7.40 (m, 4H), 7.65 (m, 1H), 7.77 (t. 1H, J = 8.4Hz), 7.95 (s, 1H), 8.98 (d, 1H, J = 7.9Hz), 9.84 (br,! H).

 FABMS (m / z); 527 [+ l] +.

Example 5 1 Compound 53 and Compound 54

Process 1

According to Step 6 of Example 3, 1,3-dioxo 41- (2-hydroxyphenyl) -1,2,6-dimethyl-1,2,3,6-tetrahydropyrro [3,4-c ] Potassium 5 53 mg (1.55 mmo 1), 60% sodium hydride 93 m g (2.33 mmo 1) and p-toluenesulfonic acid 2-chloroethyl (0.56 m1) (3.1 Ommo 1), give 4- [2- (2-chloroethoxy) phenyl] — 1,5-Dioxo-1,2,6-dimethyl-1,2,3,6-tetrahydropyrrolo [3,4-c] potassium 505 mg (78%) was obtained.

_{Ή NMR (CDC1 3) δ;} . 3.17 (s, 3H), 3.59 (t, 2H, J = 5.6Hz), 3.89 (s, 3H) 4. 23 (I. 2H, 5.6Hz), 6.90 - 7.80 ( m, 7H) 7.54 (s, 1H), 9.10 (dd, 1H, J = l. 0, 7.6Hz).

FABMS (m / z); 419 [Mil] ⁺ .

Process 2

 According to Step 5 of Example 37, 4- [2- (2-chloroethoxy) phenyl] —1,3-dioxo-1,2,6-dimethyl-1,2,3,6-tetrahydropyro-

[3,4-c] sorbazole 505 mg (1.21 mmo 1) and tetra-n-butylammonium tribromide 64 Omg (1.33 mmo 1) gave 9-bromo-4- (2 — (2-chloroethoxy) phenyl] — 1,3-dioxo-2,6-dimethyl-1,2,3,6-tetrahydropyro [3,4-c] carbazol 585 mg (99%) I got

Ή NMR (DMS0-d ₆ ) δ; 3.04 (s, 3H), 3.73 (t, 2H, J = 5.OHz), 3.98 (s, 3H),

4.21 (m, 2H), 7.11 (dt, 1H, J = l.0, 7.5Hz), 7.15 (d, 1H.J = 8.OHz), 7.42 (dd, 1H, 1.8, 7.5Hz) ), 7.44 (ddd, 1H. J = l.8, 7.2, 8.OHz), 7.75 (d, 1H, J = 8.8Hz), 7.79 (dd, 1H, J-2.1, 8.8Hz), 7.86 (s, 1H), 9.09 (d, 1H, J = 2.1Hz).

 FABMS (m / z); 497 [M + l] +.

Process 3

9-bromo-4- [2- (2-chloroethoxy) phenyl] — 1,3-dioxo-1,6-dimethyl-1,2,3,6-tetrahydropyro [3,4-c] 5 85 mg (1.18 mmo 1) was suspended in 100 ml of methylene chloride, and titanium tetrachloride dissolved in 4 ml of methylene chloride under ice-cooling 1.29 ml (1 1.76 mmo 1) ) And 1.06 ml (10.17 mmo 1) of dichloromethyl methyl ether dissolved in 4 ml of methylene chloride, and the mixture was stirred at room temperature for 3 hours. To the reaction solution Ice water and concentrated hydrochloric acid 0. 7m l was added, and extracted with CHC 1 _3, after washing with water was distilled off the solvent. The residue was triturated with water and then with MeOH to give compound 9-bromo-4-1 [2- (2-chloroethoxy) -1-5-formylphenyl] -1,3-dioxo-1,2,6-dimethyl-1, 593 mg (96%) of 2,3,6-tetrahydropyro [3,4-c] potassium were obtained.

 Ή NMR (DMSO-de) δ; 3.05 (s, 3H), 3.77 (t, 2H, J = 5.OHz), 4.00 (s, 3H), 4.34 (m, 2H), 7.37 (d, 1H. 1 = 8.5Hz), 7.76 (d, 1H, J = 8.7Hz), 7.81 (dd, 1H, J = 2.0, 8.7Hz), 7.96 (s, 1H), 7.97 (d, 1H, J-2.1Hz) , 8.05 (dd.1H, J = 2.1, 8.5Hz), 9.08 (d, 1H, 2.OHz), 9.98 (s, 1H).

 FABMS (m / z); 525 [M + l] +.

Process 4

 According to Example 30, 9-promo 4- [2- (2-chloroethoxy) -15-formylphenyl] -1,3-dioxo-2,6-dimethyl-1,2,3,6-tetrahydropyro [ [3, 4-c] Potassium 554 mg (1.05 mmo 1) and 250 mg of lOP dZC gave Compound 53, 62 mg (13%) and Compound 54, 278 mg (61%).

Compound 53

_{Ή NMR (CDC1 3) 6;} 1.68 (t, 1H, ] = 6. OHz), 3.18 (s , 3H), 3.59 (I, 2H, J = 5.7Hz), 3.92 (s, 3H), 4.23 (t , 2H, J = 5.7Hz), 4.73 (d, 2H, J = 6.OHz), 6.97

(m, 1H), 7.40 (dd.IH, J = 7.2, 8.OHz), 7.43 On, 2H), 7.6 (d, 1H, 1 = 8.3Hz), 7.55 (s, 1H), 7.63 (ddd, 1H, J = l.2, 7.2, 8.3Hz), 9.12 (dd, 1H, 1.2,

9.0Hz).

 FABMS (m / z); 449 [M + l] +.

Compound 54

 Ή NMR (CDC) δ; 2.41 (s, 3H), 3.19 (s, 3H), 3.58 (t, 2H, J = 5.8Hz), 3.92 (s, 3H), 4.20 (t, 2H, J = 5.8Hz), 6.92 (d, 1H,] = 8.OHz), 7.22 (m, 2H), 7.40 (dd, 1H, J = 7.3, 8.1Hz), 7.47 (d, 1H, J = 8.3Hz), 7.53 (s, 1H), 7.63 (dd, 1H, J = 7.3, 8.3Hz), 9.13 (d, 1H, J = 8.1Hz).

FABMS (m / z); 433 [M + l] Example 5 2 Compound 55

 Compound 54, 75 mg (0.13 mmo 1) and 95 mg (0.2 Ommo 1) of tetra-n-butylammonium tribromide were obtained from Compound 54, 75 mg (0.2 Ommo 1) according to Step 5 of Example 37. 55, 57 mg (64%) were obtained.

 Ή NMR (CDC) δ; 2.38 (s, 3H), 3.18 (s, 3H), 3.58 (t, 2H, J = 5.7Hz), 3.90 (s, 3H), 4.19 (t, 2H, J = 5.7Hz), 6.91 (d.1H, J = 8.3Hz), 7.19 (d, 1H, J = 2.3Hz), 7.23 (dd, 1H, 2.3, 8.3Hz), 7.33 (d, 1H, J = 8.8Hz), 7.53 (s, 1H), 7.70 (dd, 1H, 1 = 2.2, 8.8Hz), 9.27 (d, 1H, J = 2.2Hz).

FABMS (m / z); 511 [M + l] ⁺ .

Example 5 3 Compound 5 6

Compounds 51 and 51 mg (0.11 mmo 1) were dissolved in 6 ml of DMF, sodium iodide 688.9 mg (1.54 mmo 1) was added, and the mixture was stirred at 100: 5 for 5 hours. Water was added to the reaction solution, and extracted with CHC 1 _3, after brine washing, the solvent was distilled off under reduced pressure. Next, the residue was dissolved in 6 ml of DMF, 0.2 ml of a 50% aqueous dimethylamine solution (30.8 Ommo 1) was added, and the mixture was stirred at room temperature for 10 hours. Water was added to the reaction solution, and extracted with CHC 1 _3, after brine washing, the solvent was distilled off under reduced pressure. The residue was purified by preparative thin-layer chromatography (CHC la ZMeOH 10/1) to obtain 56 and 33 mg (63%) of the compound.

 Ή NMR (CDC) δ; 2.12 (s, 6H), 2.47 (t, 2H, J-6. OHz), 3.18 (s, 3H), 3.91 (s, 3H), 4.07 (t, 2H) , 6.OHz), 4.71 (s, 2H), 7.01 (d, 1H, J = 8.3Hz),

7.40 (m, 3H), 7.46 (d, 1H, 1 = 8.3Hz), 7.50 (s, 1H), 7.63 (dd, 1H. 1 = 7.3.

8.3Hz), 9.11 (d, 1H, J = 7.8Hz).

 FABMS (m / z); 458 [M + l] + ·

 Example 5 4 Compound 5 7

 According to Example 53, compound 54, 2775 mg (0.64 mmo 1), sodium iodide 3.80 g (2 5.35 mmo 1) and 50% dimethylamine aqueous solution Compounds 57 and 167 mg (60%) were obtained from 1.0 ml (11.11 mmo 1).

Ή NMR (CDC1 ₃ ) 6; 2.11 (s, 6H). 2.37 (s. 3H), 2.44 (t, 2H, J = 6. OHz), 3. 19 (s, 3H), 3.91 (s, 3H), 4.03 (t, 2H, 6.0Hz), 6.92 (d, 1H.J = 8.4Hz), 7.17 (d, 1H, 2.2Hz), 7.21 (dd, 1H, J-2.2, 8.4Hz), 7.40 (t, 1H, J = 7.5Hz), 7.46 (d, 1H, J: 8.3Hz), 7.48 (s, 111), 7.62 (ddd, 1H, J = l.0, 7.2, 8.3H z), 9.12 (dd, 1H,] = 1.0, 7.8Hz).

FABMS (m / z); 442 [M + l] ⁺ .

Example 55 Compound 58

 From compound 55, 55 mg (0.1 lmmo 1), sodium iodide 800 mg (5.34 mmol) and 50% aqueous dimethylamine solution 0.2 m1 (2.22 mmol 1), compound 58 was obtained according to Example 53. And 2 Omg (36%) were obtained.

Ή NMR (CDCl ₃ ) δ; 2.11 (s, 6H), 2.37 (s, 3H), 2.46 (t, 2H. 1 = 5.9 Hz), 3.19 (s, 3H), 3.89 (s, 3H). 4.04 (t, 2H, J = 5.9Hz), 6.92 (d, 1H, J = 8.4Hz), 7.16 (d, 1H, J = 2.2Hz), 7.22 (dd, 1H, J-2.2, 8.4Hz), 7.33 (d, 1H, J = 8.7Hz), 7.49 (s, 1H), 7.70 (dd, 1H, J = l.9, 8.7Hz), 9.27 (d.1H, J = l.9Hz).

FABMS (m / z); 520 [M + l] +.

Example 56 Compound 59

Process 1

 According to Example 53, 9-promo 4- [2- (2-chloroethoxy) -1-5-formylphenyl] -1,3-dioxo-2,6-dimethyl-1,2,3,6-tetrahydropyro [3, 4—c] sorbazole 224 mg (0.46 mmo 1), sodium iodide 1.40 g (9.34 mmo 1) and 50% aqueous dimethylamine solution 2. Oml (18.68 mmo 1) gave 9 —Promo 4- [2- (2-Dimethylaminoethoxy) -1-5-formylphenyl] -1,1,3-dioxo-2,6-dimethyl-1,2,3,6-tetrahydropyro [3,4-c] 165 mg (67%) of Lubasol were obtained.

'Η corrupt (CDC1 ₃ ) (5; 2.12 (s, 6H), 2.50 (t, 2H, J = 5.9Hz), 3.19 (s, 3H), 3.92 (s, 3H), 4.16 (t, 2H , J = 5.9Hz), 7.13 (d, 1H.J = 8.5Hz), 7.36 (d, 1H, J = 8.7Hz), 7.51 (s, 1H), 7.72 (dd, 1H, J = 2.0, 8.7Hz) ), 7.93 (d, 1H, J = 2.2Hz), 7.97 (dd, 1H, J = 2.2, 8.5Hz), 9.27 (d, 1H, J = 2.0Hz), 9.97 (s1H).

FABMS (m / z); 534 [M + l] Process 2

 According to Step 2 of Example 27, 9-bromo-4- [2- (2-dimethylaminoethoxy) -5-formylphenyl] -1, 3-dioxo-2,6-dimethyl-1,2,3 , 6-Tetrahydropyrro [3,4-c] sorbazole 155 mg (0.29mmol), 50% aqueous dimethylamine solution 0.94ml (10.11mmo1) and borocyanoborohydride Compounds 59 and 91 mg (56%) were obtained from sodium 267 mg (4.31 mmo 1).

 Ή NMR (CDC) δ; 2.12 (s, 3H), 2.31 (s, 3H), 2.47 (t, 2H, J = 6. OHz), 3.18 (s, 3H), 3.48 On, 2H), 3.90 (s, 3H), 4.06 (t, 2H, J = 6.OHz), 6.97 (d, 1H.J-8.9Hz), 7.33 (m, 3H), 7.54 (s, 1H), 7.70 (dd, 1H , 2.0, 8.7Hz) .9.27 (d, 1H, 1 = 2.0Hz).

 FABMS (m / z); 563 [M + l] +.

Example 5 7 Compound 60

Process 1

9-bromo-41 [2- (2-dimethylaminoethoxy) — 5-formylphenyl] — 1,3-dioxo_2,6-dimethyl-1,2,3,6-tetrahydropyrro [3,4- c) Dissolve 30 Omg (0.56 mmo 1) of sorbazole in 15 ml of DMF, and add 9 mg (0.58 mmo 1) of tetrakis (triphenylphosphine) palladium and 67 mg (0.5 mg of potassium acetate) of tetrakis (triphenylphosphine) palladium. Then, the mixture was stirred at normal pressure 100 under a hydrogen atmosphere for 3 hours. Ice water was added to the reaction solution, extracted with CHC 13, washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography _{(CHC l 3 / Me OH 3} 0/1), 4 one [2 - (2-dimethylaminoethoxy) over 5 Horumirufue sulfonyl] -1, 3-Jiokiso _ 2, 6 —Dimethyl-1,2,3,6-tetrahydropyrro [3,4-c] -caproluvazole 21.4 mg (84) was obtained.

_{Ή NMR (CDC1 3) δ;} 2. 12 (s, 6H), 2.50 (t, 2H, 5.7Hz), 3.19 (s, 3H), 3. 94 (s, 3H), 4. 17 (t, 2H , J-5.7Hz), 7.13 (d, III, J = 8.5Hz), 7.42 (ddd, 1H, J = 0.9, 7.3, 8.OHz), 7.49 (d, 1H.J = 8.3Hz), 7.50 ( s, 1H), 7.65 (ddd, 1H, 1 = 1.1 '7.3, 8.3Hz), 7.93 (d, 1H, J = 2.2Hz), 7.97 (dd, 1H, J = 2.2, 8.5Hz),

00 9.12 (dd.1H, 1.1, 8.OHz), 9.97 (s, 1H).

 FABMS (m / z); 456 [M + l] *.

Process 2

 According to Step 1 of Example 1, 4- [2- (2-dimethylaminoethoxy) -1 51-formylphenyl] —1,3-dioxo-1,2,6-dimethyl-1,2,3,6-te Trahydropyrro [3,4-c] sorbazole l O Omg (0.22 mmo 1), potassium carbonate 45 mg (0.37 mmo 1) and tribenzylphosphonium chloride (benzyl) 8 8 mg From (0.23 mmo 1), 102 mg (88%) of compound 60 (E: Z = 1-6: 1) was obtained.

E body:

 Ή NMR (CDC) δ; 2.11 (s, 6H), 2.46 (t, 2H, J = 6.1Hz), 3.18 (s, 3H), 3.86 (s, 3H), 4.05 (t, 2H, J-6.1Hz), 6.55 (d, 1H, 12.2Hz), 6.62 (d, 1H, J = 12.2Hz), 6.88 (d, 1H, J = 8.5Hz), 7.17-7.66 (m. 11H), 9.09 (dd, 1H, J = 1.2.7.8Hz).

 FABMS (m / z); 530 [M + l] +.

Example 5 8 Compound 6 1

 According to Example 30, Compounds 61 and 56 mg (79%) were obtained from Compounds 60 and 70 mg (0.13 mmol) and 25 mg of 10% PdZC.

_{Ή NMR (CDC1 3) δ;} 2. 11 (s, 6H), 2.46 (t, 2H, J = 6.1Hz), 2.96 (br s, 4H), 3. 19 (s, 3H), 3.91 (s, 3H), 4.04 (t, 2H, J = 6.1Hz), 6.94 (d, 1H. J = 8.3Hz), 7.11 (d, 1H, J = 2.2Hz), 7.17-7.32 (m, 6H), 7.40 (dd, 1H, 7.2, 8.2 Hz), 7.41 (s, 1H), 7.46 (d, 1H, J = 8.5Hz), 7.62 (ddd, 1H, J = l.3, 7.2, 8.5 Hz ), 9.11 (dd, 1H, J = l.3, 8.2Hz).

FABMS (m / z); 532 [M + l] ⁺ .

Example 5 9 Compound 6 2

Process 1

According to Step 6 of Example 3, 9-promo 1,3-dioxo-41- [2- (2-hydroxy) phenyl] -1,2,6-dimethyl-1,2,3,6-tetrahydropyro [3 4—c] Power base 20 Omg (0.46 mm 0 1), chloride 2— From 99.9 mg (2.0 mmo 1) of dimethylaminoethyl hydrochloride and 590 mg (4.27 mmo 1) of carbonated lithium, 9-bromo-4- [2- (2-dimethylaminoethoxy) ) [Phenyl] 1-1,3-dioxo-2,6-dimethyl-1,2,3,6-tetrahydropyrrole [3,4-c] carbazole 94 mg (40%) was obtained.

 Ή NMR (CDC) δ; 2.14 (s, 6H), 2.50 (t, 2H, J = 6.OHz), 3.20 (s, 3H), 3.90 (s, 3H), 4.09 (t, 2H, J = 6.OHz), 7.04 (d, 1H, J-8.3Hz), 7.10 (dt, 1H,) = 1.0, 7.6Hz), 7.35 (d, 1H.J = 8.8Hz), 7.37 (dd, 1H, then 7,7.6Hz), 7.45 (ddd, 1H, J = l.7, 7.3, 8.3Hz) .7.52 (s, 1H), 7.72 (dd.1H, J = l.9, 8.8Hz), 9.28 (d, 1H, J = l.9Hz).

 FAB S (m / z); 506 [M † l] +.

Process 2

 To 5.25 g (39.38 mmo 1) of aluminum chloride in 5 Om 1 of a methylene chloride suspension, add 1.40 ml (19.6 9 mmo 1) of acetyl chloride at 1 78 "C and add At the same temperature, 9-promo 4-1- [2- (2-dimethylaminoethoxy) phenyl] —1,3-dioxo-2,6-dimethyl-1 dissolved in 25 ml of methylene chloride at the same temperature , 2,3,6-Tetrahydropyrro [3,4-c] carbazole 1.0 g (1.97 mmo 1) was added, and the mixture was stirred for 2 hours with O: ice water and 2N. Hydrochloric acid was added, and the mixture was extracted with a mixed solvent of CHC 13 and MeOH, washed with an aqueous solution of sodium hydrogencarbonate and then brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. Tritiation with a mixed solvent of Et is performed, and 4- [5-acetyl-2- (2-dimethylaminoethoxy) phenyl] —9-bromo-1,3 0.76 g (70%) of -dioxo-2,6-dimethyl-1,2,3,6-tetrahydropyro [3,4-c] caproluvazole was obtained.

 Ή NMR (CDC) (5; 2.13 (s, 6H), 2.51 (1, 2H, J = 5.9 Hz), 2.61 (s, 3H), 3.18 (s, 3H), 3.91 (s, 3H), 4.15 (t, 2H, J-5.9Hz), 7.05 (d.1H, J = 8.8Hz), 7.34 (d, 1H, J = 8.7Hz), 7.50 (s, 1H), 7.71 (dd , 1H, J = 2.0, 8.7Hz), 8.02 (d,

1H, J-2.3Hz), 8.07 (dd, 1H, J = 2.3, 8.8Hz), 9.25 (m, 1H).

 FABMS (m / z); 548 [M + l] +.

02 Process 3

4- [5-Acetyl-2- (2-dimethylaminoethoxy) phenyl] 1-19-1Bromo-1,3-dioxo-2,6-dimethyl-1,2,3,6-tetrahydropyro [3,4-c Dissolve 488 mg (0.89 mmo 1) of sorbazole in a mixed solvent of THF 3 Om 1 and MeOH 1 Oml, add 400 mg (6.37 mmo 1) of sodium cyanoborohydride, and add 3.9 N The pH was adjusted to about 3 with a hydrogen chloride / MeOH solution, and the mixture was stirred at room temperature for 1 hour. Saturated sodium hydrogen carbonate aqueous solution was added to the reaction solution, and extracted with CHC 1 _3, after brine washed, dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography (CH C1a / MeOH 50/1) to give Compound 62, 291 mg (59%).

 Ή NMR (CDC) <5; 1.55 (d, 3H, J = 6.4 Hz), 2.12 (s, 6H), 2.48 (ί, 2H. I- 5.9 Hz), 3.16 (s, 3H), 3.85 (s. 3H), 4.06 (t, 2H. J = 5.9Hz), 4.93 (q, 1H, J = 6.4Hz), 6.98 (d, 1H, J = 8.3Hz), 7.29 (d, 1H, J = 8.7Hz) , 7.41 (m, 2H), 7.48 (s, 1H), 7.68 (dd, 1H, J = 2.1, 8.7Hz), 9.22 (d, 1H, J = 2.1Hz).

 FABMS (m / z); 550 [M + l] +.

Example 60 Compound 63

 According to Example 30, compound 63, 155 mg (62%) was obtained from compound 62, 29 lmg (0.65 mmo 1) and 10% Pd / C, lO Omg.

 Ή NMR (CDCU) δ; 1.52 (d, 3H, J = 6.4Hz), 2.08 (s, 6H), 2.44 (t, 2H, 6.0Hz), 3.15 (s, 3H), 3.80 (s, 3H), 4.02 (t.2H, J = 6.0Hz), 4.90 (q, 1H, J = 6.4Hz), 6.92 (d, 1H, J = 8.6Hz), 7.16-7.72 (m, 6H), 9.04 (d, 1H) , J = 8.3 Hz).

Example 6 1 Compound 64

Compound 62, 15 Omg (0.27 mmo 1) was dissolved in trifluoroacetic acid 3 m 1, and triethylsilane 0.065 ml (0.4 lmmo 1) was added, followed by stirring at room temperature for 2 hours. After concentrating the reaction solution, a saturated aqueous solution of sodium hydrogen carbonate was added thereto, extracted with CHC13, washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (CHCl ₃ ZMe〇H 50 / 1) to give Compound 64, 106 mg (73%).

 lH NMR (CDC) δ; 1.28 (t, 3H, J = 7.8Hz), 2.11 (s, 6H), 2.46 (t, 2H.3 = 6.0Hz), 2.68 (q, 2H, J = 7.8Hz), 3.19 (s, 3H), 3.89 (s, 3H) .4.04 (t.2H, J = 6.0Hz), 6.95 (d, 1H, J = 8.4Hz), 7.18 (d, 1H, J = 2.3Hz), 7.25 (dd, 1H, J = 2.3, 8.4Hz), 7.33 (d, 1H, J = 8.7Hz), 7.50 (s, 1H), 7.70 (dd, 1H, J = 2.0, 8.7Hz), 9.27 ( d, 1H, J = 2.0Hz).

 FABMS (m / z); 534 [M + l] *.

Example 62 Compound 65

 According to Example 30, Compound 65, 36 mg (64%) was obtained from Compound 64, 65 mg (0.12 mmo1) and 25 mg of 10% Pd / C.

 Ή NMR (CDC) δ; 1.28 (t, 3H, J = 7.6Hz), 2.11 (s, 6H), 2.45 (t, 2H, J = 6.0Hz), 2.68 (q, 2H, J = 7.6Hz), 3.19 (s, 3H), 3.91 (s, 3H), 4.04 (t, 2H, J = 6.0Hz), 6.95 (d, 1H, J = 8.5Hz), 7.20 (d, 1H, J = 2.3Hz), 7.24 (dd, 1H, J = 2.3, 8.5Hz), 7.40 (dd, 1H, J = 7.2, 8.0Hz), 7.46 (d, 1H, J = 8.3Hz), 7.50 (s.1H), 7.62 (ddd , 1H, J = l.2, 7.2, 8.3Hz), 9.12 (dd, 111, J = l.2.8.0Hz).

FABMS (m / z); 456 [Mil] ⁺ .

Example 63 Compound 66

Process 1

 According to Step 6 of Example 3, 1,3-dioxo-41- (2-hydroxy-5-nitrophenyl) _2,6-dimethyl-1,2,3,6-tetrahydropyro

[3,4—c] sorbazole 5 Omg (0.13 mmo 1), 2-dimethylaminoethyl chloride hydrochloride 36 mg (0.25 mmo 1) and potassium carbonate 69 mg

From (0.5 Ommo 1), 4- [2- (2-dimethylaminoethoxy) -1 5-nitrophenyl] —1,3-dioxo-2,6-dimethyl-1,2,3,6-tetra 22 mg (37%) of lahydropyro [3,4-c] potassium were obtained.

 Ή NMR (CDCh) δ; 2.13 (s, 6H), 2.52 (t, 2H, J = 5.9Hz), 3.21 (s, 3H), 3.97 (s, 3H), 4.18 (t, 2H, J = 5.9Hz), 7.09 (d, 1H, 9.0Hz), 7.45 (ddd, 1H,

J = l.0, 7.2, 8.1Hz), 7.51 (s, 1H), 7.51 (d, 1H, J = 8.3Hz), 7.68 (ddd, 1H,

J = l.2, 7.2, 8.3Hz). 8.32 (d.1H, J = 2.9Hz), 8.38 (dd, 1H, J = 2.9, 9.0Hz),

1 O 4 9.14 (ddd.1H, J = 0.7, 1.2, 8.1Hz).

 FABMS (m / z); 473 [MH] +.

Process 2

 According to Example 30, 41- [2- (2-dimethylaminoethoxy) -15-2-nitrophenyl) -1, 3-dioxo-1,2,6-dimethyl-1,2,3,6 —Tetrahydropyrrole [3,4-c] sorbazolone 1.58 g (3.34 mm o 1) and 10% Pd / C, 0.5 g Amino-2- (2-dimethylamino ethoxy) phenyl] -1,3-dioxo-2,6-dimethyl-1,2,3,6-tetrahydropyrro [3,4-c] power rubazole 1.36 g (92 %).

_{Ή NMR (CDC1 3) (5} ;.. 2.09 (s, 6H), 2.40 (t 2H, J = 6.1Hz), 3. 19 (s 3H), 3.

50 (br.2H), 3.90 (s, 3H), 3.94 (t, 2H.J = 6.1 Hz), 6.77 (m, 2H), 6.88 (m, 1H), 7.40 (ddd, 1H, 1 = 1.0 , 7.2, 8.1Hz), 7.46 (d, 1H, J = 8.4Hz), 7.50 (s, 1H). 7.62 (ddd, 1H, J = l.2, 7.2, 8.4Hz), 9.11 (ddd, 1H, J = 0.7, 1.2, 8.1Hz).

 FABMS (m / z); 443 [M + l] +.

Process 3

 Example 4 According to step 4 of 7, 4- [5-amino-2- (2-dimethylaminoethoxy) phenyl] -1,3-dioxo-2,6-dimethyl-1,2,3,6-tetrahydropyro [ 3, 4 c] From olevazole 5 Omg (0.11 mmo 1) and methyl isocyanate 0.024 ml (0.41 mmo 1), 66, 47 mg (84%) of the compound was obtained. Obtained.

 lH NMR (CDC) δ; 2.14 (s, 6H), 2.51 (t, 211, J = 5.9Hz), 2.86 (d, 3H, J = 4.9Hz), 3.19 (s, 3H), 3.91 (s , 3H), 4.05 (br t, 2H), 5.43 (br q, 1H), 6.08 (s, 1H), 7.01 (d, 1H, J = 8.7Hz), 7.19 (dd, 1H,] = 2.7 , 8.7Hz), 7.34 (d, 1H, J = 2.7Hz), 7.41 (m, 1H), 7.46 (d, 1H, 1 = 8.3Hz), 7.64 (s, 1H), 7.64 (dd, 1H, J = 7, 1, 8, 3Hz), 9.11 (d, 1H, J = 7.9Hz).

 FABMS (m / z); 500 [M + l] +.

Example 6 4 Compound 6 7

05 According to Step 4 of Example 47, 4- [5-amino-2- (2-dimethylaminoethoxy) phenyl] -1,3-dioxo-1,2,6-dimethyl-1,2,3,6-tetrahydropyrrolate [3,4-1c] Compound 67, 44 mg (74%) was obtained from 50 mg (0.11 mmo 1) sorbazole and n-propyl isocyanate 0.016 ml (0.17 mmo 1). Obtained.

 Ή NMR (CDCU) 6; 0.92 (t, 3H, J = 7.5 Hz), 1.58 (m, 2H), 2.14 (s, 6H), 2.50 (t, 2H, J = 5.8 Hz), 3.18 (s , 3H), 3.24 (dt, 2H, J = 5.9, 7.1Hz), 3.91 (s, 3H), 4.04 (t, 2H, J = 5.8Hz), 5.39 (t, 1H, J = 5.9Hz), 6.07 (s, 1H), 7.00 (d, 111, J = 8.8Hz). 7.20 (dd, 1H, 1 = 2.7, 8.8Hz), 7.34 (d, 1H, J = 2.7Hz), 7.41 (dd 1H , J = 7.4, 8.1Hz), 7.46 (d, 1H, J = 8.3Hz), 7.62 (s, 1H), 7.64 (ddd, 1H, 1.2, 7.4, 8.3Hz), 9.11 (dd, 1H, J = l.2, 8.1Hz).

 FABMS (m / z); 528 [Mil] +.

Example 6 Compound 68

 According to step 4 of Example 47, 4- [5-amino-2- (2-dimethylaminoethoxy) phenyl] -1,3-dioxo-2,6-dimethyl-1,2,3,6-tetrahydropyro [ 3, 4—c] Caproluvazole 5 Omg (0.11 mmo 1) and phenyl isocyanate 0.018 ml (0.17 mmo 1) gave 68, 53 mg (84%) of the compound Was.

 Ή NMR (CDC) δ; 2.12 (s, 6H), 2.47 (1, 2H, J = 6.OHz), 3.17 (s, 3H), 3.59 (s, 3H), 4.01 (t, 2H, 6 OHz), 6.48 (s, 1H), 6.99 (d, 1H, J = 8.8Hz), 7.04 (m, 1H), 7.17 (s, 1H), 7.22 (dd, 1H, J = 2.7, 8.8Hz) , 7.28 (m, 2H), 7.40 (dd, 1H, J = 7.2, 8.1Hz), 7.45 (d, 1H, J = 8.3Hz), 7.51 (m.3H), 7.59 (s, 1H), 7.63 (ddd, 1H, J = l.3, 7.2, 8.3Hz), 9.09 (dd, 1H, J = l.3, 8.1Hz).

 FABMS (m / z); 562 [M + l] +.

 Example 66 Compound 69

 Compound 69, 10.7 g (84%) was obtained from Compound 9, 13.5 g (29.3 mmol) and DDQ 14.5 g (58.7 mmol) according to Example 20. Was.

_{Ή NMR (CDC1 3) 6;} 1.91 (s, 3H), 3.20 (s, 3H), 3.92 (s, 3H), 3.93 (s, 3

06 H), 7.35 (d, III, J = 8.9 Hz), 7.43 (dt, 1H, J = l.3, 8.1 Hz), 7.46 (s, 1H), 7.49 (d, 1H, J = 8.1 Hz), 7.66 (dt, 1H, J = l.3, 8.1 Hz), 8.17 (d, 1H, J = 2.5Hz), 8.19 (dd, III, J = 2.5, 8.9Hz), 9. 11 (d, 1H, J = 8.1 Hz).

EI S (m / z); 456 [M] ⁺ .

Example 6 7 Compound Ί 0

 According to Step 6 of Example 37, Compound 69, 5.02 g (11.0 mmo 1) and 1.85 g (13.4 mmo 1) of potassium carbonate were used to obtain Compound 70. 4.55 g (quantitative) were obtained.

Ή NMR (DMS0-d ₆ ) δ; 3.06 (s, 3H). 3.82 (s, 3H), 3.98 (s, 3H), 7.03 (d, 1H, J = 9.1 Hz), 7.38 (t, 1H, J 2.7.6Hz), 7.64 (dt, 1H, J = l.0, 7.6Hz). 7.72 (d, 1H, J = 7.6Hz), 7.80 (s, 1H), 7.90 (m, 2H), 8.95 (d 1H. J = 7.6Hz).

EIMS (m / z); 414 [M] +.

Example 6 8 Compound 7 1

Process 1

 According to Step 6 of Example 3, compound 70, 1.33 g (3.21 mmo 1), 2-dimethylaminoethyl hydrochloride 0.65 g (4.53 mmo 1) and Compound 22 free base, 1.63 g (quantitative) was obtained from 2.22 g (16.1 mmo 1) of potassium carbonate.

Process 2

 Example 2 Compound 71 free base, 1.41 g (2.90mmo 1) and 4N hydrogen chloride / AcOEt solution 0.73 ml (2.9 From 2 mmo 1), 1.37 g (95%) of compound 71 was obtained.

 Ή NMR (DMS0-dJ δ; 2.51 (s, 6H), 2.40 (m, 2H), 3.06 (s, 3H), 3.85 (s, 3H), 3.99 (s, 3H), 4.09 (m, 2H), 7.24 (d, 1H.J = 8.7Hz), 7.39 (t, 1H, J = 7.5Hz), 7.66 (I, IH.J = 7.5Hz), 7.74 (d, 1H, J = 7.5Hz), 7.85 ( s, 1H), 7.97

(d, 1H,] = 2.0Hz). 8.05 (dd, 1H, J = 2.0, 8.7Hz), 8.95 (d, 1H, J-7.5Hz).

EIMS (m / z); 485 [M] +.

Example 6 9 Compound 7 2

According to Step 1 of Example 49, compound 7 1 free base 2.08 g (3.99 mm Compound 72, 1.55 g (76) was obtained from 6 Om 1 (0.12 mol) of 1N) and 4N hydrogen chloride ZAcOEt solutions.

 'Η NMR (DMSO-dt) δ; 2.45 (m, 2H), 2.54 (s, 6H), 3.07 (s, 3H), 4.00 (s, 3H). 7.29 (d, 1H, 8.4 Hz), 7.40 ( 7.67 (t, 1H, 1 = 8.OH z), 7.75 (d, 1H, J = 8.0Hz). 7.89 (s, 1H), 7.95 (s, 1H), 8.08 (d, 1H, J = 8.4Hz), 8.96 (d, 1H, J = 8.0Hz).

 EIMS (m / z); 507 [M] +.

Example Ί 0 Compound 73

Process 1

Compound 7 2 Free base 185 mg (0.37 mmo 1) was dissolved in DMF 5 ml, p-nitrophenol 88 mg (0.63 mmo 1), iodide 2-chloro-1-methylpyridinium 165 mg (0.63 mmo 1) and 0.23 ml (1.65 mmo 1) of triethylamine were added, and the mixture was refluxed for 6 hours. Then, at room temperature, 1.62 ml (11. Ommo 1) of a 6.8 N ammonia methanol solution was added, and the mixture was heated under reflux for 20.5 hours. Water was added to the reaction solution, and extracted with CHC 1 _3, after brine washing the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by preparative thin layer chromatography _{(CHC l 3 / Me OH 1} 0/1), to give Compound 7 3 free base 40 mg (24).

Process 2

 In accordance with Step 2 of Example 2 1, compound 73 free base 34 mg (0.07 mmo 1) and 4 N hydrogen chloride / AcOEt solution 0.05 ml (0.2 Ommo 1) Thus, 34 mg (93%) of compound 73 was obtained.

 Ή NMR (DMS0-dJ δ; 2.58 (s, 6H), 3.08 (s, 3H), 3.40 (m, 2H), 4.00 (s, 3H), 4.40 (m, 2H), 7.26 (d, 1H, J = 9.1Hz), 7.41 (t, 1H, J = 7.6Hz). 7.68 (t.1H, J = 7.6Hz), 7.76 (d, 1H, 7.6Hz), 7.87 (s, 1H), 7.95 (s, 1H), 8.0 4 (d.1H, J = 9.1Hz), 8.97 (d, 1H, J = 7.6Hz), 9.90 (br, 2H).

FABMS (m / z); 471 [Mil] ⁺ .

 Example 7 1 Compound 74

 Process 1

08 According to Step 1 of Example 70, compound 72 free base 202 mg (0.40 mmo 1) and p-dinitrophenol 95 mg (0.68 mmo 1), iodide 2-chloro-1,1-methylpyri Compound 74 free base 1 from 178 mg (0.68 mmo 1) of dizinium, 0.25 ml (1.79 mmo 1) of triethylamine and 0.16 ml (2.0 Ommo 1) of methylamine 76 mg (92%) were obtained.

Process 2

 Example 2 According to Step 2 of 1, from compound 74 free base 38 mg (0.40 mmo 1) and 4N hydrogen chloride / AcOEt solution 0.06 ml (0.24 mmo 1), Compound 74, 38 mg (93%) was obtained.

'Η NMR (DMS0-d ₆ ) 6; 2.56 (s, 6H), 2.79 (d, 3H, J = 4.7 Hz), 3.07 (s, 3H), 3.26 (m.2H), 4.00 (s, 3H) , 4.37 (m, 2H), 7.26 (d.1H, J = 8.8Hz). 7.40 (t, 1H, J-7.7Hz), 7.67 (t, 1H, J-7.7Hz), 7.76 (d, 1H, J = 7.7Hz), 7.89 (s, 1H), 7.91 (d, 1H, 2.4Hz), 7.99 (dd, 1H, 1-2.4, 8.8Hz). 8.38 (q, 1H, J = 4.7Hz), 8.97 (d, 1H, 1 = 1.7Hz).

EIMS (m / z); 484 [M] ⁺ .

Example 72 Compound 75

Process 1

 According to Step 70 of Example 70, compound 72 free base 202 mg (0.40 mmo 1) and p-ditrophenol 95 mg (0.68 mmo 1), iodide 2-chloro- 1-methylpyridinium! _ 8 Omg (0.68 mmol), triethylamine 0.25 ml (1.79 mmo1) and 50% aqueous dimethylamine solution 0.18 ml (1.92 mmo1), compound 75 free base 1 94 mg (97 %).

Process 2

 According to Step 2 of Example 2 1, Compound 75 was obtained from Compound 75 free base 37 mg (0.07 mmo 1) and 4N hydrogen chloride ZA c OEt solution 0.06 ml (0.24 mmo 1). 37 mg (93%) were obtained.

■ H NMR (DMS0-d ₆ ) <5; 2.56 (s, 6H), 3.02 (s, 6H), 3.07 (s, 310, 3.25 (m, 2H), 3.99 (s, 3H). 4.38 (m, 2H). 7.24 (d, 111, J = 8.4Hz), 7.39 (dt, 1H, J

09 = 1.0, 7.7Hz), 7.45 (d, 1H, J = 2.5Hz), 7.56 (dd, 1H, J -2.5, 8.4Hz), 7.67 (dt, 1H, J = l.0, 7.7Hz), 7.74 (d, 1H, J = 7.7Hz), 7.87 (s, 1H), 8.96 (d, 1H, J = 7.7Hz).

 EIMS (m / z); 498 [M] +.

Example 7 3 Compound 76

Process 1

 According to Step 1 of Example 70, compound 72 free base 1 94 mg (0.38 mmo 1), p-ditrophenol 92 mg (0.66 mmo 1), iodide 2-chloromethyl 1-methylpyridini 173 mg (0.66 mmol) of triethylamine, 0.24 ml of triethylamine (1.72 mmo 1) and 0.17 ml of morpholine (1.92 mmo 1), compound 75 free base 1 85 mg (90 %).

Process 2

 According to Step 2 of Example 2 1, from compound 77 free base 177 mg (0.33 mmo 1) and 4N hydrogen chloride / AcOEt solution 0.09 ml (0.36 mmo 1), Compound 76, 127 mg (67%) was obtained.

Ή NMR (DMS0-d ₆ ) δ; 2.56 (s, 6H), 3.07 (s, 3H), 3.27 (m, 2H), 3.58 (m, 4H), 3.62 (m, 4H), 3.99 (s, 3H ), 4.40 (m, 2H), 7.26 (d, 1H, J = 8.4Hz), 7.39 (t, 1H, J = 7.5Hz), 7.45 (d, 1H, J = 2.0Hz), 7.56 (dd , 1H, J = 2.0, 8.4Hz), 7.66 (t.1H, J = 7.5Hz), 7.74 (d, 1H, J = 7.5Hz), 7.90 (s, 1H), 8.96 (d, 1H, J = 7.5Hz), 10.26 (br s, 1H).

 EIMS (m / z); 540 [M] +.

Example 74 Compound 7 7

Process 1

According to Step 1 of Example 70, compound 72 free base (192 mg, 0.380 mmol), p-ditrophenol 92 mg (0.66 mmo 1), iodide 2-chloro-11 From methylpyridinium 17 Omg (0.64 mmo l), triethylamine 0.24 ml (1.72 mmo 1) and ethanolamine 0.24 ml (3.9 Ommo 1), compound 77 free base 158 mg (81%) were obtained. Process 2 According to Step 2 of Example 2 1, from compound 77 free base 15 2 mg (0.30 mm o 1) and 4 N hydrogen chloride ZAc OEt solution 0.08 ml (0.32 mm o 1) The compound 77, 132 mg (81%) was obtained.

Ή NMR (DMS0-d ₆ ) δ; 2.52 (s, 3H), 2.56 (s, 3H), 3.07 (s, 3H), 3.36 (m, 2H), 3.52 (m, 2H), 4.01 (s, 3H ), 4.38 (m, 2H), 4.71 (m, 2H), 7.25 (d, 1H, J = 8.6Hz), 7.40 (t, 1H.J = 7.7Hz), 7.67 (d, 1H, J = 7.7) Hz), 7.76 (d, 1H, 7.7Hz), 7.89 (s, 1H), 7.94 (d, 1H, J = 2.1Hz), 8.02 (dd, 1H, J = 2.1, 8.6Hz), 8.40 (t , 1H, J = 5.4Hz), 8.97 (d, 1H, J = 7.7Hz), 10.06 (br s, 1H).

 EIMS (m / z); 514 [ΜΓ ·

Example Ί5 Compound 78

 Example 2 According to step 1 of 1, compound 72 free base, 38 mg (0.08 mmol), triethylamine 0.025 ml (0.18 mmol) and thionyl chloride 0.03 ml (0 33 mmo 1) to obtain the acid chloride, which is then reacted with hydroxylamine hydrochloride 77.8 mg (1.09 mmo 1) and triethylamine 0.15 ml (1.08 mmo 1) As a result, 35 mg (95%) of compound 78 was obtained.

Ή NMR (DMS0-d ₆ ) δ; 2.02 (s, 6H), 2.39 (m, 2H), 3.07 (s, 3H), 4.00 (s, 3H), 4.05 (m, 2H), 7.16 (d, 1H , J = 8.4Hz), 7.39 (t, 1H.J = 7.6Hz), 7.65 (d, 1H, J = 7.6Hz), 7.74 (d, 1H, J = 7.6Hz), 7.84 (m, 2H), 7.86 (dd, 1H, J = 2.5, 8.4Hz), 8.94 (br, 2H), 8.96 (d, 1H, J = 7.6Hz), 11.12 (br s, 1H).

 FABMS (m / z); 487 [Mil] +.

Example 76 Compound 7 9

Process 1

 According to Example 25, compound 72 free base 305 ml (0.6 Ommo 1), WSCHC1, 122 mg (0.64 mmo 1), triethylamine 0.18 ml (1.29 mmo Compound 79 free base (104 mg, 31%) was obtained from I) and benzylamine (0.22 ml, 2.01 mmo 1).

Process 2

Example 2 Compound 79 free base l O Omg (0.29 mm Compounds 79 and 82 mg (77%) were obtained from 0.05 ml (0.20 mm o 1) of the o 1) and 4 N hydrogen chloride / A c〇Et solutions.

 Ή NMR (DMSO-dt) δ; 2.54 (s, 6H), 3.07 (s, 3H), 3.26 (m, 210, 4.00 (s, 3H), 4.36 (m.2H), 4.50 (d, 2H, J = 6.0Hz), 7.27 (d, 1H, J = 8.6Hz), 7.31-7.33 On, 5H). 7.40 (t, 1H, J = 7.9Hz), 7.67 (t, 1H, J = 7.9Hz), 7.75 (d, 1H, 7.9Hz), 7.89 (s, 1H), 7.98 (d, 1H, J = 2.1Hz), 8.07 (dd.1H, J = 2.1, 8.6 Hz), 8.97 (d.1H, J- 7.9Hz), 8.99 (t, 1H, J = 6.0Hz), 10.07 (br s, 1H).

 EIMS (m / z); 560 [M] *.

Example Ί7 Compound 80

 According to Step 1 of Example 49, Compound 80, 0.90 was obtained from Compound 69, 1.01 g (2.22 mmo 1) and 2N hydrochloric acid 50.5 m 1 (0.1 Omol). g (quantitative) was obtained.

 Ή NMR (DMSO-dfc) δ; 2.54 (s, 1H), 3.12 (s, 3H), 3.99 (s, 3H), 7.01 (d, 1H, 8.9Hz), 7.38 (t, 1H, J = 7.9Hz 7.65 (t, 1H, J = 7.9Hz), 7.73 (d, 1H, J = 7.9Hz), 7.81 (s, 1H), 7.87-7.89 (m, 2H), 8.96 (d, 1H, J = 7.9Hz).

Example 78 Compound 81

 Compound 81, 5 mg (26) was obtained from compound 80, 2 Omg (0.05 mmol) and borane-methyl sulfide complex 0.03 ml (0.32 mmo1) according to step 1 of Example 15. Obtained.

 Ή NMR (DMSO-dJ δ; 3.07 (s.3H), 3.97 (s, 3H), 4.47 (d, 2H, J = 5.4Hz), 5.02 (t, 1H, J = 5.4Hz), 6.88 (d, 1H, 1 = 7.9Hz), 7.20 (m, 2H), 7.37 (t, 1H, J = 7.4Hz), 7.64 (dt, 1H, J = l.0, 7.4Hz), 7.72 (d, 1H, J -7.4Hz), 7.73 (s, 1H), 8.95 (d, 1H, J = 7.4Hz). 9.28 (s, 1H).

 EIMS (m / z); 386 [M ·

 Example 79 Compound 82

Compound 80, 205 mg (0.51 mmo 1) was dissolved in DMF 5.5 ml, and t-butyldimethylchlorosilane 41 Omg (2.64 mmo 1) and imidazole 356 mg (5.17 mmo 1) were dissolved. 1) was added, and the mixture was stirred at room temperature for 19 hours. Water was added to the reaction solution, extracted with AcOEt, and the organic layer was washed with 1N hydrochloric acid and then brine. After purification, the extract was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (CHC 1 a ZMeOH 25/1) to give compound 82,

1 47 mg (58%) were obtained.

 Ή NMR (DMSO-dfc) δ; 0.04 (s, 6H), 0.90 (s, 9H), 3.11 (s, 3H). 4.03 (s,

3H) .7.05 (d, 1H, J = 9.4Hz), 7.42 (t, 1H, J = 7.7Hz), 7.69 (t, 1H, J = 7.7Hz), 7.76 (d, 1H, J = 7.7Hz) ), 7.85 (s, 1H), 7.90-7.93 (m, 2H), 9.00 (d, 1 H, J = 7.7Hz).

Example 80 Compound 83

 According to Step 1 of Example 15, Compound 82, 81 mg (0.16 mmol) and borane 'methyl sulfide complex 0.05 ml (0.58 mmol) 1 gave Compound 83, 64 mg (0.58 mmol). 80%).

 Ή NMR (CDC) δ; 0.03 (s, 6H), 0.67 (s, 911), 1.74 (t, 1H. J = 5.9Hz), 3.21 (s, 3H), 3.93 (s, 3H), 4.74 (d, 2H, J = 5.9Hz), 6.99 (d, 1H, J-8.4Hz), 7.37 (dd, 111.J = 2.0.8.4Hz), 7.44 (m, 2H), 7.50 (d, 1H, J = 7.9Hz), 7.55 (s, 1H), 7.67 (dt, 1H, J = l. 7.9Hz), 9.15 (d, 1H, J = 7.9Hz).

EIMS (m / z); 500 [M] ⁺ .

Example 8 1 Compound 84

 According to Step 3 of Example 5, Compound 84, 494 mg (86%) was obtained from Compound 83, 58 Omg (1.16 mmol) and manganese dioxide 1.50 g (17.3 mmol 1). Obtained.

 Ή NMR (CDCls) δ; 0.09 (s, 6H), 0.64 (s, 9H), 3.18 (s, 3H), 3.93 (s, 3H), 7.07 (d, 1H, 8.4 Hz), 7.43 (dt, 1H, J = l.3, 7.6Hz), 7.49 (d, 1H, J = 7.6Hz), 7.50 (s, 1H). 7.66 (dt, 1H, J = l.3, 7.6Hz), 7.89 ( dd, 1H, J = 2.3, 8.4Hz), 7.94 (d, 1H, 1-2.3Hz), 9.13 (d, 1H, J = 7.6Hz), 9.96 (s, 1H).

 EIMS (m / z); 498 [M] +.

Example 82 Compound 85

Process 1

According to Example 28, (Methyl) triphenylphosphonium bromide 143 mg (0.40 mmol), 1.68 M n-butyllithium Zn-hexane solution 0. 25ml (0.42mmo1) and 4- [2- (2-dimethylaminoethoxy) -l-formylphenyl] -l, 3-dioxo-2,6-dimethyl-1,2,3,6-tetra 61 mg (68%) of Compound 85 free base was obtained from 90 mg (0.20 mMol) of lahydropyrro [3,4-c] potassium.

Process 2

 According to Step 2 of Example 2 1, 58 mg (0.13 mmo 1) of Compound 85 free base and 0.04 ml (0.16 mmo 1) of 4N hydrogen chloride c〇Et solution gave Compound 8 5, 5 lmg (78%) were obtained.

Ή NMR (DMS0-d ₆ ) δ; 2.54 (s, 6H), 3.07 (s, 3H), 3.19 (tn, 2H), 4.00 (s, 3H), 4.32 (m, 2H), 5.20 (d, 1H , J-ll.2Hz), 5.76 (d, 1H, J = 17.6Hz), 6.7 6 (dd, 1H, J = 11.2, 17.6Hz), 7.16 (d, 1H, J-8.7Hz), 7.39 (t , 1H, J = 7.8Hz), 7.50 (d, 1H.2.3Hz), 7.55 (dd, 1H, J-2.3, 8.7Hz), 7.66 ((, 1H, J = 7.8Hz). 7.74 (d. 1H, J = 7.8Hz), 7.86 (s, 1H), 7.79 (s, 1H), 8.97 (d, 1H. J = 7.8Hz).

 FAB S (m / z); 454 [M + l] +.

Example 83 Compound 86

Process 1

 According to Example 28, (n-propyl) triphenylphosphonium bromide (212 mg, 0.555 mmol), 1.68 M n-butyllithium / n-hexane solution 0 34 ml (0.57 mmo 1) and 4- [2- (2-dimethylaminoethoxy) -1-5-formylphenyl] -1,3-dioxo-2,6-dimethyl-1,2,3,6-tetrahydro Compound 86 free base (E-form) (105 mg, 81%) was obtained from 123 mg (0.27 mmo 1) of pyruvone [3,4-c] phenol. Process 2

 According to Step 2 of Example 2 1 from Compound 86 free base 10 Omg (0.21 mmo 1) and 4N hydrogen chloride / AcOEt solution 0.06 ml (0.24 mmo 1) The compound 86 was obtained in an amount of 88 mg (81%).

Ή NMR (DMS0-d ₆ ) 6; 1.06 (t, 3H, J = 7.4 Hz), 2.21 (m, 2H), 2.54 (s, 6H) .3.07 (s, 3H), 3.22 (m, 2H), 3.99 (s, 3H), 4.30 On, 2H), 6.25 (dt, 1H, J

Four = 6.2, 16.1Hz), 6.41 (d, 1H, J = 16.1Hz), 7.12 (d, 1H, J = 8.9Hz), 7.39 (t, 1H, J = 7.7Hz), 7.41 (m , 2H), 7.45 (dd, 1H, J = 2.0, 8.9Hz), 7.66 (t.1H, J = 7.7Hz), 7.74 (d, 1H, J = 7.7Hz), 7.84 (s, 1H). (d, 1H, J = 7.7Hz), 10.0 5 (br s, 1H).

 FABMS (m / z); 482 [M + l] +.

Example 8 4 Compound 8 7

Process 1

 In accordance with Step 1 of Example 1, 4- [2- (2-dimethylaminoethoxy) -15-formylphenyl] 1-1,3-dioxo-2,6-dimethyl-1,2,3,6-tetrahydropyrole [3, 4-c] Cyruvazole 203 mg (0.45 mm o

1), 60% sodium hydride (24 mg, 0.59 mmo 1) and getylphosphonoacetate ethyl (0.12 ml, 0.61 mmo 1), compound 87 free base

(E-isomer) 238 mg (quantitative) was obtained.

Process 2

 In accordance with Step 2 of Example 2, compound 87 7 free base 73 mg (0.14 mm o 1) and 4N hydrogen chloride c〇Et solution 0.04 ml (0.16 mm o 1 )) To obtain Compounds 87 and 66 mg (85%).

Ή NMR (DMS0-d _t ) δ; 1.26 (t, 3H, J = 7.2 Hz), 2.55 (s, 6H), 3.07 (s, 3H), 3.25 (m, 2H), 4.00 (s, 3H), 4.18 (q, 2H. 1 = 7.2Hz), 4.37 (m. 2H), 6.57 (d, 111 J-16.3Hz), 7.24 (d, 1H, J = 8.4Hz), 7.40 (t, 1H, ] = 7.4Hz), 7.67 (t, 1H, J = 7.4Hz), 7.69 (d, 1H, J = 16.3Hz), 7.75 (d, 1H, J = 7.4Hz), 7.79 (t, 1H, J = 2.0Hz), 7.83 (dd, 1H, J = 2.0, 8.4Hz), 7.89 (s, 1H), 8.97 (d, 1H, J = 7.4Hz).

 FABMS (m / z); 527 [M + l] +.

Example 8 5 Compound 8 8

Process 1

According to Example 30, Compound 87 free base 7 l mg (0.14 mmo 1) and 10% PdZC, 37 mg, Compound 88 free base 62 mg (88%) Was obtained. Process 2

 According to Step 2 of Example 2 1, compound 8 8 free base 62 mg (0.12 mmo 1) and 4N hydrogen chloride / AcOEt solution 0.0 4 ml (0.1 6 mmo 1 )) To give Compound 88, 47 mg (71%).

Ή NMR (DMS0-d _t ) <5; 1.18 (t, 3H, 1 = 7.2 Hz), 2.54 (s, 6H), 2.65 (t, 2H, J = 7.6 Hz), 2.89 (t, 2H, J- 7.6Hz), 3.07 (s, 3H), 3.21 (m, 2H), 3.99 (s, 3H), 4.07 (q, 2H, J = 7.2Hz), 4.27 (m, 2H), 7.09 (d, 1H) , J- -8.4Hz), 7.25 (d, 1H, J-.2Hz), 7.31 (dd, 1H, J = 2.2, 8.4Hz), 7.39 (t, 1H, J = 7.8Hz). 7.66 (dt, 1H, Jl.2, 7.8Hz), 7.74 (d, 1H, J = 7.8Hz), 7.80 (s, 1H), 8.97 (d, 1H, J = 7.8Hz).

FAB S (m / z); 528 [M + l] ⁺ .

Example 8 6 Compound 8 9

 In accordance with the step 1 of Example 49, Compound 89, 4 9 mg (0.1 lmmo 1) and 2N hydrochloric acid 1.5 ml (3.0 mmo 1) 8 mg (81%) were obtained.

 Ή NMR (DMSO-dt) <5; 2.55 (s, 6H), 3.08 (s.3H), 3.27 (m, 2H), 4.00 (s, 3H), 4.38 (m.2H), 6.46 (d, 1H , J = 15.8Hz), 7.24 (d, 1H, J = 8.7Hz), 7.40 (t, 1H. J = 7.7Hz). 7.63 (d, 1H, J = 15.8Hz), 7.66 (t, IH, J = 7.7Hz), 7.74 (d, 1H, J = 2.0Hz), 7.75 (d, 1H, J = 7.7Hz), 7.79 (dd.IH, J = 2.0, 8.7Hz), 7.90 (s, IH ), 8.97 (d, IH, J-7.7Hz), 10.14 (br, IH), 12.20 (br, IH).

 FABMS (m / z); 498 [M + l] +.

Example 8 7 Compound 90

Process 1

 According to Step 6 of Example 3, 1,3-dioxo-4- (2-hydroxy-5-nitrophenyl) -1,2,6-dimethyl-1-1,2,3,6-tetrahydropyro

[3, 4-c] Power rubazole 3.58 g (8.91 mmo 1), 2-dimethylaminoisopropyl hydrochloride 2.15 g (1 3.58 mmo 1) and potassium carbonate 3.75 g (27.20 mmol) of 4- (2- (2-dimethylaminoisopropoxy) -1-5-nitrophenyl) —1,3-dioxo—2,6-dimethyl 1.26 g (29%) of 1,2,3,6-tetrahydropyrro [3,4-c] pyruvazole were obtained.

 Ή NMR (CDCU) (5; 1.27 (d, 3H, J = 5.9Hz), 2.12 (s, 6H), 2.26 (dd, 1H, J = 5.3, 13.0Hz), 2.39 (dd, 1H, 5.9, 13.0 Hz), 3.20 (s.3H), 3.95 (s, 3H), 4.63 On, 1H), 7.13 (d, 1H, J = 9.2Hz), 7.44 (dd, IH, J = 7.2, 7.9Hz), 7.50 (s, 1H), 7.51 (d, 1H.J = 8.2Hz), 7.67 (dd, 1H, 1 = 7.2, 8.2Hz), 8.30 (d, 1H, J = 3.0Hz), 8.36 (dd, 1H, J = 3.0, 9.2Hz), 9.1 (d, 1H, J = 7.9Hz).

FABMS (m / z); 487 [M + l] ⁺ .

Process 2

 According to Example 30, 4- [2- (2-dimethylaminoisopropoxy) -15-nitrophenyl] —1,3-dioxo-2,6-dimethyl-1,2,3,6-tetrahydropyro [ 3, 4-c] force 1.14 g (2.35 mmo 1) 10%? 01. From 0.55 g, 4- [5-amino-2- (2-dimethylaminoisopropoxy) phenyl] — 1,3-dioxo-1,2,6-dimethyl-1,1,2,3,6-tetrahydro 0.96 g (90%) of pyrrole [3,4-i-c] potassazole was obtained.

 Ή NMR (CDC) (5; 1.03 (d, 3H, J = 6.3 Hz), 2.04 (s, 6H), 2.11 (dd, 1H, J = 5.9, 12.5 Hz), 2.28 (dd, 1H, J = 5.9) , 12.5Hz), 3.19 (s, 3H), 3.50 (br, 2H), 3.90 (s, 3H), 4.12 (m, 1H), 6.93 (m, 1H), 6.75 (m, 2H), 7.40 (dd , III J = 7.0, 7.8Hz), 7.46 (d, 1H, J = 8.3Hz), 7.53 (s, 1H), 7.63 (dd, IH, J = 7.0, 8.3Hz), 9.11 (d, IH, J = 7.8Hz).

 FABMS (m / z); 457 [M + l] +.

Process 3

 According to Step 4 of Example 47, 4- [5-amino-2- (2-dimethylaminoisopropoxy) phenyl] -1,3-dioxo-1,2,6-dimethyl-1,2,3,6-tetrahydropyro Mouth [3,4—c] carbazole 0.91 g (2.00 mmo 1) and 145 ml (2.46 mmo 1) of methyl isocyanate gave 0.99 g (86 %).

Process 4 Example 2 According to step 2 of 1, compound 90 free base 0.30 g (0.59 mmo 1) and 4N hydrogen chloride / AcOEt solution 0.2 2mi (0.8 From 8 mmo 1), 90 and 0.30 g (93%) of a compound were obtained.

Ή NMR (DMS0-d _fc ) δ; 1.00 On, 3H), 2.58 (s, 6H), 2.64 (d, 3H. J = 4.6Hz). 3.06 (s, 3H), 3.12 (m, 2H) , 3.98 (s, 3H), 4.74 (m, 1H), 6.07 (d, 1H, J = 4.6Hz), 7.15 (m, 1H), 7.42 (m, 3H), 7.65 (m, 1H), 7.74 (d, 1H, J = 8.3Hz), 7.78 (br s, III), 8.61 (br s, 1H), 8.96 (d, Ul, J = 7.6Hz), 9.85 (br, 1H) .FABMS (m / z); 514 [M + l] ⁺ .

Example 8 8 Compound 9 1

 According to Example 20, from compound 7, 1.42 g (3.19 mmo 1) and DDQ 1-44 g (6.35 mmo 1), compound 91, 1.17 g ( 8 3%).

Ή NMR (DMS0-d ₆ ) δ; 1.91 (s, 3H), 3.07 (s, 3H), 3.98 (s, 3H), 7.41 (dd d, 1H, J = 0.9. 7.0, 7.9 Hz), 7.68 ( 7.76 (m, 2H). 7.86 (d, 1H.J = l.5Hz), 7.95 (dd, 1H, J = l.5, 7.9Hz), 8.96 (dd.1H, J = l .2, 7.9Hz).

 FABMS (m / z); 443 [M + l] +.

Example 8 9 Compound 9 2

 According to Example 25, compound 91, 869 mg (1.96 mmo 1), DMAP 26 mg (0.21 mmo 1), ethanethiol 0.58 ml (7.8 mmo Compounds 92 and 77 Omg (81%) were obtained from 1) and WS C · HC 1> 4.55 mg (2.372 mmo 1).

 Ή NMR (CDC) δ; 1.38 (t, 3H, J = 7.3Hz), 1.92 (s, 3H), 3.13 (q.2H, J = 7.3Hz), 3.20 (s, 3H), 3.91 (s , 3H), 7.43 (dd, 1H. J = 7.0, 7.9Hz), 7.44 (s, 1H), 7.49 (d, 1H, J = 8.2Hz), 7.55 (d, III, J = 7.9Hz), 7.66 (ddd, 1H, J = l.2, 7.0, 8.2Hz), 7.84 (d, 1H, J = l.8Hz), 7.99 (dd, 1H, J = l.8, 7.9Hz), 9.12 (br d , 1H, J = 7.9Hz).

FABMS (m / z); 487 [M + l] ⁺ .

 Example 90 Compound 9 3

According to Example 30, compounds 92, 1.00 g (2.1 Ommo 1) and 1 Compound 47, 878 mg (quantitative) was obtained from 4.47 g of 0% Pd / C. lH NMR (CDC) δ; 1.93 (s, 3H), 3.21 (s, 3H). 3.92 (s, 3H), 7.44 (ddd, 1H. J = 0.9, 7.0, 7.9Hz), 7.45 (s, 1H) , 7.50 (br d, 111, J = 8.2Hz), 7.65 (d, 1H, 7.8Hz), 7.67 (ddd, 1H, J = l.2, 7.0, 8.2Hz), 7.78 (d, 1H, J = l.5Hz), 7.91 (del, 1H, J = 1.5, 7.8Hz), 9.12 (dd, 1H, J = l.2, 7.9Hz), 10.09 (s, 1

H).

FABMS (m / z); 427 [M + l] ⁺ .

Example 9 1 Compound 94

 According to step 6 of Example 37, compound 94, 0.77 g (97%) was obtained from compound 93, 878 mg (2.06 mmol) and potassium carbonate 339 mg (2.45 mmol).

 Ή NMR (DMSO-dt) 6; 3.06 (s, 311), 3.99 (s, 3H), 7.40 (dd, 1H,] = 7.1, 8.1 Hz), 7.42 (d, 1H, J = l.4Hz) , 7.49 (dd, 1H, J = l.4, 7.6Hz), 7.54 (d, 1H, J = 7.6Hz), 7.67 (ddd, 1H, Jl.0, 7.1, 8.3Hz), 7.75 (d, 1H , 8.3Hz), 7.84 (s, 1H), 8.96 (br d, IH, J = 8.1Hz), 10.01 (s, 1H), 10.05 (s, 1H).

 FABMS (m / z); 385 [M + l] +.

Example 92 Compound 95

 According to step 6 of Example 3, compound 94, 17 Omg (0.441 mmo 1), 2-dimethylaminoethyl chloride hydrochloride 96 mg (0.67 mmol) and potassium carbonate 315 mg (2. Compound 28, 256 mg (82%) was obtained from 28 mmo1).

 Ή NMR (CDC) δ; 2.12 (s. 6H), 2.50 (t. 2H, J = 5.8Hz), 3.19 (s, 3H), 3.93 (s, 3H), 4.15 (t, 2H, J = 5.8Hz), 7.42 (ddd, 1H, J = 0.9, 7.3, 7.9Hz), 7.48 (br d, 1H, 8.2 ·), 7.50 (s' 1H), 7.53 (d, IH, J = l .3Hz), 7.55 (d, 1H, 7.5Hz), 7.60 (dd, IH, J = l.3, 7.5Hz), 7.65 (ddd, IH, J = l.2, 7.3, 8.2Hz), 9.12 (dd, IH, J = l.2.7.9Hz), 10.06 (s, IH).

FABMS (mIz); 456 [M + l] ⁺ .

Example 93 Compound 96

Compound 95, 148 mg (0.326 mmo 1) was treated with THF 10 ml and Me OH was dissolved in a mixed solvent of 10 ml, sodium borohydride (17 mg, 0.44 mmol) was added, and the mixture was stirred at 0 for 20 minutes. A small amount of acetone and 3.95N hydrogen chloride ZMeOH solution were added to the reaction solution, the solvent was distilled off, a saturated aqueous solution of sodium hydrogencarbonate was added to the residue, and the mixture was extracted with methylene chloride, dried over anhydrous sodium sulfate, and dried. The solvent was distilled off. The residue was triturated with AcOEt to give compound 96, 124 mg (83%).

 Ή NMR (CDC) δ; 2.12 (s, 6H), 2.47 (t, 2H, J = 5.9Hz), 3.18 (s.3H), 4.08 (t, 2H. 5.9Hz), 4.78 ( s, 2H), 7.06-7.07 (m.2H), 7.35 (d, 1H, J = 8.2Hz), 7.40 (ddd, 1H, J = 0.9, 7.0, 7.9Hz), 7.46 (br d, 1H. J = 8.2Hz), 7.49 (s, 1H), 7.62 (ddd, 1H, J = l.2, 7.0, 8.2Hz), 9.11 (dd, 1H, J = l.2, 7.9Hz).

FABMS (mIz); 458 [M + l] +.

Example 94 Compound 9 7

 Compound 25, 41 mg (0.09 Ommo 1), 50% aqueous dimethylamine solution 0.08 2 ml (0.91 mmo 1) and cyano hydrogen according to Step 2 of Example 27 Compounds 97 and 40 mg (91%) were obtained from 33 mg (0.53 mmol) of sodium borohydride.

 Ή NMR (CDC) (5; 2.11 (s, 6H), 2.32 (s, 6H), 2.47 (t, 2H, J = 5.9 Hz), 3.18 (s, 3H), 3.51 (s, 2H), 3.90 (s, 3H), 4.08 (t, 2H, J = 5.9Hz), 7.01 (dd, 1H, J = l.4, 7.6Hz), 7.03 (br s, 1H), 7.31 (d, 1H, J = 7.6Hz), 7.40 (ddd, 1H, 0.9, 7.3, 7.9Hz), 7.46 (br d, 1H, J = 8.2Hz), 7.51 (s, 1H), 7.62 (ddd, 1H, J = l .2, 7.3, 8.2Hz), 9.11 (dd, 1H, J = l.2, 7.9Hz).

 FABMS (m / z); 485 [Mil] +.

Example 9 5 Compound 98

 According to Step 6 of Example 3, compound 94, 29 mg (0.077 mmo 1), p-toluenesulfonic acid 2-chloroethyl 0.03 3 ml (0.18 mmo 1) And potassium carbonate 49 mg (0.36 mmol), compound 98, 22 mg

(64%).

Ή NMR (DMS0-d ₆ ) δ 3.04 (s, 3H), 3.76 (t, 1H, J = 5.0 Hz), 4.00 (s, 3H), 4.32 (br s, 2H), 7.40 (dd, 1H, J = 7.1, 7.8Hz), 7.62 (s, 1H), 7.65-7.71

20 (m, 311), 7.76 (d, 1H, J = 8.3Hz), 7.89 (s, 111), 8.95 (d, 1H, J = 7.8Hz), 10.09 (s, 1H).

 FABMS (mIz); 447 [M + l] +.

Example 9 6 Compound 9 9

Process 1

 According to Step 6 of Example 3, compounds 91, 382 mg (0.863 mmol), potassium carbonate 22 24 mg (1.62 mmo1) and methyl iodide 0.099 m

From 1 (1.6 mmo 1), there were obtained 364 mg (92%) of the methyl ester. According to Step 6 of Example 37, the methyl ester was converted to 14 lmg (1.0 mmo) of potassium carbonate. The deacetylated product was obtained by reacting with 1) The deacetylated product was then converted to 2-dimethylaminoethyl hydrochloride 17 according to Step 6 of Example 3.

5 mg (1.22 mmo 1) and potassium carbonate 596 mg (4.3 1 mm o

By reacting with 1), 4 9 mg (99%) of compound 99 free base was obtained.

_{Ή NMR (CDC1 3) 6;} 2.13 (. S 6H), 2.50 (t, 2H, J = 5.8Hz), 3. 19 (s, 3H), 3. 92 (s, 3H), 3.96 (s, 3H ), 4.14 (t, 2H, J = 5.8Hz), 7.41 (ddd, 1H, J = 0.8, 7.2, 7.9Hz), 7.43 (d, 1H, J = 7.8Hz), 7.48 (dd. J = 0.8, 8.5Hz), 7.49 (s, 1H), 7.64 (ddd, 1H, J = l.2, 7.2, 8.5Hz), 7.69 (d, 1H, J = l.5Hz), 7.78 (dd,

1H. J = l.5, 7.8Hz). 9.12 (dd, 1H, J = l.2, 7.9Hz).

 FABMS (m I z); 486 [M + l] +.

Process 2

 Example 2 Compound 9 9 Free base 84 mg (0.17 mmo 1) and 0.88 N hydrogen chloride / A c〇Et solution 0.40 ml (0. Compounds 99 and 49 mg (55%) were obtained from 35 mmo 1).

Ή NMR (DMS0-d ₆ ) 6; 2.56 (s, 6H), 3.06 (s, 3H), 3.24-3.30 (m, 2H), 3.94 (s, 3H), 3.99 (s, 3H), 4.41 (br s, 2H), 7.41 (dd, 1H, J = 7.3, 7.8Hz), 7.56 (d, 1H, J = 7.8Hz), 7.66-7.70 (m, 2H), 7.73 (d, 1H, J = l.5Hz), 7.76 (d, 1H, 8.3Hz), 7.90 (s, 1H), 8.96 (d, 1H, J = 7.8Hz), 10.16 (br s. 1H).

FABMS (m I z); 486 [M + l] ⁺ .

Example 9 7 Compound 1 0 0

twenty one According to Step 1 of Example 49, compound 100, 320 mg (75%) was obtained from 407 mg (0.839 mmol) of compound 99 free base and 20 ml of 1N hydrochloric acid.

Ή NMR (DMS0-d ₆ ) δ; 2.52 (s, 6H), 3.06 (s, 3H), 3.27 (br s, 2H). 3.99 (s, 3H), 7.41 (ddd. 1H, J = 0.9, 7.0 , 7.9Hz), 7.52 (d, 1H, J = 7.7Hz). 7.67 (d, 1H, J = l.4Hz), 7.68 (ddd, 1H, J = l.2, 7.0, 8.2Hz), 7.72 ( dd, 1H, J = l.4, 7.7Hz), 7.76 (br d, 1H, J = 8.2Hz), 7.89 (s, 1H), 8.96 (dd, 1H, J = l.2, 7.9Hz) .

 FABMS (m / z); 472 [M + l] +.

Example 98 Compound 101

According to Example 20, compound 101, 68 mg (98%) was obtained from compound 5, 7 Omg (0.1700101) at 30] (3 78 mg (0.34 mmo1). _{NMR (CDC1 3) δ; 1.88} (s, 3H), 2.46 (s, 3H), 3.20 (s, 3H), 3.89 (s, 3 H), 7.06 (d, 1H, J = 0.7Hz), 7.20 ( dd, 1H, J = 0.7, 7.8Hz), 7.35 (d, 1H, J = 7.8Hz), 7.41 (ddd, 1H.J = 0.9, 7.2, 7.9Hz), 7.44 (s, 1H), 7.47 ( br d, 1H, J = 8.3Hz), 7.64 (ddd, 1H. J = l.2, 7.2, 8.3Hz). 9.11 (dd, 1H, 1.2, 7.9Hz).

FABMS (m / z); 413 [M + l] ⁺ .

Example 99 Compound 102

 According to Step 6 of Example 37, 59 mg (quantitative) of Compound 102 was obtained from 65 mg (0.16 mm 01) of Compound 101 and 27 mg (0.2 Ommo 1) of potassium carbonate. .

 'Η NMR (CDC) δ; 2.41 (s, 3H). 3.18 (s, 3H), 3.87 (s, 3H), 5.50 (s, 1H), 6.90-6.92 (m, 2H), 7.21 (d, 1H, J = 8.OHz), 7.37 (ddd, 1H, J-0.9, 7.3, 7.9Hz), 7.40 (br d, 1H, 8.2Hz). 7.49 (s, 1H), 7.61 (ddd, 111) , J = l.2, 7.3, 8.2Hz), 9.00 (br d, 1H, J = 7.9Hz).

 FABMS (m / z); 371 [M + l] +.

 Example 100 Compound 103

According to Step 6 of Example 3, compound 102, 56 mg (0.15 mmol), 2-dimethylaminoethyl hydrochloride 33 mg (0.23 mmol) and carbonic acid From 103 mg (0.746 mmo 1) of potassium, compounds 103 and 63 mg (9

4%).

'Η 瞧 (CDC1 ₃ ) δ; 2.12 (s, 6H), 2.44 (s, 3H), 2.47 (t, 2H. J = 5.9Hz). 3.18 (s, 3H). 3.90 (s, 3H) , 4.06 (t, 2H, J = 5.9Hz), 6.85 (br s, 1H), 6.90 (dd, 1H, J = l.5, 7.6Hz), 7.25 (d, 1H, J = 7.6Hz), 7.39 (ddd, 1H, J-0.9, 7.0, 7.9Hz), 7.45 (br d, 1H, J = 8.2Hz), 7.9 (s, 1H), 7.62 (ddd, 1H, J = l.2, 7 0, 8.2Hz), 9.11 (dd, 1H, J: l.2, 7.9Hz).

 FABMS (m / z); 442 [M + l]

Example 101 Compound 104

 According to Example 20, Compounds 6, 66 2 mg (1.3 Ommo 1) and DDQ 594 mg (2.616 mmo 1) were used to obtain Compounds 104, 62 8 mg (9 6%).

_{Ή NMR (CDC1 3) δ;} 1.89 (s, 3H), 3.21 (s, 3H), 3.90 (s, 3H), 6.90 (d, 1 H, J = 2.4Hz), 7.01 (dd, 1H, J = 2.4, 8.5Hz), 7.34-7.49 (m, 9H), 7.64 (ddd, 1H, J = l.1, 7.3, 8.3Hz), 9.11 (dd, 1H, J = l.1, 8.1h).

 FABMS (m / z); 505 [M + l] +.

Example 10 2 Compound 1 0 5

 According to Step 6 of Example 37, Compounds 104, 393 mg (0.779 mmo 1) and potassium carbonate 127 mg (0.918 mmo 1) were obtained from Compounds 105, 345 mg ( 9 6%).

_{Ή NMR (CDC1 3) δ;} 3.18 (s, 3H), 3.86 (s, 3H), 5. 12 (s, 2H), 5.78 (br s, 1H), 6.72 - 6.74 (m, 2H), 7.23 - 7.49 (m, 8H), 7.48 (s, 1H), 7.60 (ddd, 1H, 1.2, 7.2, 8.2Hz), 8.98 (br d, 1H, 7.9Hz).

 FABMS (m / z); 463 [M + l] +.

Example 10 3 Compound 10 6

 According to Step 6 of Example 3, compound 105, 918 mg (1.99 mm 01), 2-dimethylaminoethyl chloride hydrochloride 4.56 mg (3.17 mmol) and carbonic acid Compounds 106 and 858 mg (81%) were obtained from potassium 1.38 g (10. Ommo 1).

twenty three Ή NMR (CDCI3) δ; 2.12 (s, 6H), 2.48 (t, 211, J = 5.9 Hz). 3.19 (s, 3H), 3.90 (s, 3H). 4.04 (t, 2H, J = 5.9Hz), 5.13 (s, 2H), 6.69-6.71 (m, 2H) .7.28-7.50 (m.8H), 7.49 (s, 1H), 7.61 (ddd.III, J = l.2, 7.0, 8.2Hz), 9.11 (dd, 1H, Jl.2, 7.9Hz).

FABMS (m / z); 534 [M + l] ⁺ .

Example 104 Compound 1 07

According to Example 30, Compound 107, 0.77 g (quantitative) was _obtained from Compound 106, 858 mg (1.61 mmo 1) and 10% Pd / C¾33 1 mg. Obtained.

! H Note (DMS0-d ₆ ) δ; 2.03 (s. 6H), 2.39 (t, 2H, J = 5.7 Hz), 3.06 (s, 3H), 3.93 (t, 2H, J = 5.7 Hz), 3.96 (s, 3H), 6.47 (dd, 1H. 1 = 2.2, 8.1Hz), 6.51 (d, 1H, J = 2.2Hz), 7.18 (d, 1H, J = 8.1Hz), 7.36 (ddd, 111, J = 0.9, 7.0, 7.9H z), 7.63 (ddd, 1H, J = l.2, 7.0, 8.2Hz), 7.71 (br d, 1H, J = 8.2Hz), 7.73 (s, 1H), 8.93 (br d. 1H, J = 7.9Hz), 9.58 (s, 1H).

 FABMS (m / z); 444 [M + l] +.

Example 10 Compound 1 08

Dissolved compound 107, 63 mg (0.14 mmo 1) was dissolved in a mixed solvent of 9 ml of acetonitrile and 1 mL of MeOH 1 Om 1, and 0.1 ml of diisopropylethylamine 0.1 ml (0.643 mmo 1 ) And 2.0 M (trimethylsilyl) diazomethane-hexane solution (0.32 ml, 0.63 ml) were added, and the mixture was stirred at room temperature for 2 days. The solvent was distilled off, water was added to the residue, extracted with methylene chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by preparative thin layer chromatography _{(CHC 1 3 / MeOH 1 0/1} ), to give Compound 1 08, 24 mg of (3-7%).

 Ή NMR (CDCls) δ; 2.13 (s, 6H), 2.48 (t, 2H, J = 6. OHz), 3.19 (s.3H), 3.88 (s, 3H), 3.90 (s, 3H), 4.05 (t, 2H, J = 6.OHz), 6.61 (d, 1H, J = 2.4Hz), 6.63 (dd, 1H, 1 = 2.4, 8.2Hz), 7.29 (d, IH, J = 8.2Hz) , 7.39 (ddd, 1H, J = 0.9, 7.0, 7.9Hz), 7.45 (br d, 1H, J = 8.2Hz), 7.49 (s, 1H), 7.61 (ddd, 1H, J = l. 2, 7.0 , 8.2Hz), 9.11 (dd, 1H. J = l.2, 7.9Hz).

 FABMS (m / z); 458 [M + l] +.

Example 106 Compound 109 Compounds 109 and 25 mg (64) were obtained from Compounds 105 and 49 mg (0.11 mmo 1) and 10% Pd / C, 21 mg according to Example 30. .

 Ή NMR (DMSO-dt) δ; 3.06 (s, 3H), 3.95 (s, 3H), 6.32 (dd, 1H, J = 2.3.8.2 Hz), 6.40 (d, 1H, J = 2.3 Hz), 7.07 (d, 1H, J = 8.2Hz), 7.36 (ddd, 1H, J = 0.9, 7.0, 7.9Hz), 7.63 (ddd.1H, J = l.2, 7.0, 8.2Hz), 7.71 (s, 1H), 7.71 (br d, 1H, J = 8.2Hz). 8.94 (br d, 1H, J = 7.9Hz), 9.25 (s, 1H), 9.34 (s, 1H).

FABMS (m I z); 373 [MH] +.

Example 10 7 Compound 1 10

 According to Step 5 of Example 37, compound 106, 51 mg (0.095 mmo1) and tetra-n-butylammonium tribromide 5 lmg (0.1 mm0 From 1), compound 110 and 49 mg (83%) were obtained.

_{Ή NMR (CDC1 3) δ;} 2.11 (s, 6H), 2.43 (t, 2H, J = 5.9Hz), 3.19 (s, 3H), 3. 91 (s, 3H), 3.99 (t, 2H, J -5.9Hz). 5.24 (s, 2H), 6.68 (s.1H), 7.34 — 7.43 (m, 4H), 7.44 (s, 1H), 7.46 (d, 1H, J = 8.3Hz), 7.53 -7.54 (m, 2H) .7.55 (s, 1H). 7.62 (ddd, 1H, J = l.2, 7.1, 8.3Hz), 9.10 (br d, 1H, J = 7.8Hz).

FABMS (m / z); 612 [M + l] +.

Example 10 08 Compound 1 1 1 and Compound 1 1 2

 According to Step 5 of Example 37, from compound 107, 36 mg (0.082 mmo 1) and tetra n-butylammonium tribromide 4 Omg (0.083 mmo 1), Compound 1 1 1, 39 mg (91%) and Compound 112, 5 mg

(9%).

Compound 1 1 1

 Ή NMR (DMS0-dJ δ; 2.02 (s, 6H). 2.39-2.41 (m, 2H), 3.06 (s, 3H), 3.92 (t, 2H, J-5.7Hz), 3.97 (s, 3H) ), 6.70 (s, 1H), 7.37 (dd, 1H, J = 7.3, 7.9Hz), 7.46 (s, 1H), 7.65 (ddd, 1H, J = l. 1, 7.3, 8.3Hz), 7.73 (d, 1H, J = 8.3Hz), 7.79 (s, 1H), 8.93 (br d, IH.J = 7.9Hz).

 FABMS (m / z); 522 [M + l] +.

Compound 1 1 2

 FABMS (m / z); 602 [M + l]

twenty five Example 10 9 Compound 1 1 3

 According to Step 4 of Example 47, compound 107, 69 mg (0.16 mmo 1), triethylamine 0.40 ml (2.9 mmo 1) and methyl isocyanate 0.020 ml From (0.34 mmo 1), 51 mg (65%) of compound 113 was obtained.

 Ή NMR (CDC) 6; 2.11 (s, 6H), 2.47 (t, 2H, 6.0Hz), 2.94 (d, 3H, J = 4.9Hz), 3.18 (s, 3H), 3.90 (s, 3H) ), 4.04 (t, 2H, J = 6.0Hz), 5.02-5.05 (m, 1H), 6.83 (d, 1H, 2.2Hz), 6.87 (dd, III J-2.2.8.3Hz), 7.34 (d, 7.39 (ddd, 1H, J = l.0, 7, 1, 8.1 Hz), 7.46 (br d, 1H.J = 8.3Hz), 7.49 (s, 1H), 7.62 (ddd, 1H, J = l.2, 7.1, 8.3Hz), 9.11 (dd, 1H, Jl.2, 8.1Hz).

FABMS (m / z); 501 [M + l] ⁺ .

Example 11 Compound 1 1 4

Process 1

 According to Step 2 of Example 3, compound 107, 78 mg (0.18 mmo 1), triethylamine 0.05 3 ml (0.38 mmo 1) and valeryl chloride 0.03 4 ml From (0.29 mmo 1), 82 mg (87) of the compound 114 free base were obtained.

Process 2

 Example 2 Compound 1 14 free base 8.2 mg (0.16 mm 〇 1) and 0.88 normal hydrogen chloride / Ac〇Et solution 1.0 ml (0 From 8.8 mmo 1), 67 mg (76%) of compound 114 were obtained.

Ή NMR (DMS0-d ₆ ) δ; 0.96 (t, 3H, J = 7.4 Hz), 1.40-1.7 (m, 2H), 1.66-1.72 (m, 2H), 2.57 (s, 6H), 2.64 (t, 2H, J-7.4Hz), 3.07 (s, 3H), 3.27 (br s, 2H), 3.99 (s, 3H), 4.30 (br s, 2H), 6.90 (dd, 1H. J = 2 1, 8.2Hz), 7.01 (d, 1H, J = 2.1Hz), 7.40 (ddd, 1H, J = 0.9, 7.0, 7.9Hz), 7.42 (d.1H, I = 8.2Hz), 7.67 (ddd , 111 J = l. 1, 7.0, 8.3Hz), 7.76 (br d, 1H, J = 8.3Hz), 7.88 (s, 1H), 8.96 (dd, 1H, J = l. 1, 7.9Hz ), 9.87 (br s, 1H).

FABMS (m / z); 528 [M + l] ⁺ .

26 Example 1 1 1 Compound 1 1 5

Process 1

 According to Step 2 of Example 3, compound 107, 78 mg (0.18 mmo 1), triethylamine 0.053 ml (0.38 mmo 1) and n-decanoyl chloride 0.059 m l (0.29mmo 1), Compound 1 15 Free base 10 Omg

(93%).

Process 2

 Example 2 Compound 1 15 Free base 10 Omg (0.168 1111110 1) and 0.88 N hydrogen chloride solution AcOEt solution 1.Oml (0 From 88 mmo 1), 82 mg (77%) of compound 115 was obtained.

 Ή NMR (DMSO-dJ (5: 0.88 (t, 3H, J = 7.OHz), 1.28-1.42 (m, 12H), 1.66-1.72 (m, 2H), 2.56 (s, 6H), 2.63 (t , 2H, J = 7.4Hz), 3.07 (s, 3H), 3.26 (br s, 2H), 3.99 (s, 3H), 4.30 (br s, 2H), 6.89 (dd, 1H, J = 2.1, 8.2 Hz), 7.01 (d, 1H, J = 2.1Hz) .7.40 (dd, 1H, J = 7.2, 7.8Hz), 7.42 (d, 1H.J = 8.2Hz), 7.67 (ddd, 1H, J = l.1, 7.2, 8.3Hz), 7.76 (d, 1H, J = 8.3Hz), 7.87 (s, 1H), 8.96 (br d, 1H, J = 7.8Hz). 9.87 (br s, 1H) .

FABMS (m / z); 598 [M + l] ⁺ .

Example 1 1 2 Compound 1 1 6

Process 1

 According to step 2 of Example 3, compound 107, 98 mg (0.22 mmo 1), triethylamine 0.06 1 ml (0.44 mmo 1) and palmitoyl chloride 0.09 1 ml (0.33 mmo From 1), 118 mg (78%) of compound 116 free base was obtained.

Process 2

 Example 2 Compound 1 16 free base 1 18 mg (0.173 mmo 1) and 0.88 N hydrogen chloride / A c〇Et solution 1.Oml (0. From 88 mmo 1), 73 mg (59%) of compound 116 was obtained.

Ή NMR (DMS0-d ₆ ) δ; 0.85 (t, 3H. J = 7.3 Hz), 1.24-1.42 (m. 24H), 1.65-1.73 (m, 2H), 2.57 (s, 6H), 2.63 (t , 2H, J = 7.4Hz), 3.07 (s, 3H), 3.27 (br s, 2H), 3.99 (s, 3H), 4.30 (br s, 211), 6.89 (dd, 1H, 2.0, 8.3Hz), 7.01 (d, 1H, J 2.0Hz), 7.40 (dd, 1H , J = 7.1, 7.8Hz), 7.42 (d, 1H, J = 8.3H z). 7.67 (ddd, 1H, J = l.2, 7.1, 8.3Hz), 7.76 (d, 1H, J = 8.3Hz), 7.87 (s, 1H), 8.96 (br d, 1H, J = 7.8Hz), 9.82 (br s, 1H).

 FABMS (m / z); 681 [M + l] *.

Example 1 1 3 Compound 1 1 7

 In accordance with Example 20, Compound 8, 3.60 g (8.05) 1 1110 1) and 00 Q 3.5 1 g (15.2 mm o 1) showed Compound 11 7, 3.28 g (92%) were obtained.

_{Ή NMR (CDC1 3) δ;} 1.95 (s, 3H), 3.21 (s, 3H), 3.93 (s, 3H), 7.43 (s, 1 H), 7.44 (dt, 1H, J = l.0, 7.9 Hz), 7.50 (d, 1H, J = 7.9Hz), 7.66 (d.1H, J = 8.4Hz), 7.68 (dt, 1H, J = l.0, 7.9Hz), 8.16 (d, 8.26 (dd, 1H, J = 2.0, 8.4Hz), 9.11 (d, 1H, J = 7.9Hz).

 EIMS (m / z); 443 [M] +.

Example 1 1 4 Compound 1 1 8

 According to Step 6 of Example 37, Compound 1 17 was obtained from 1.44 g (3.26 mmo 1) and potassium carbonate 0.55 g (3.98 mmo 1). 1.23 g (95%) were obtained.

Ή NMR (DMS0-d _fc ) δ; 3.06 (s, 3H), 3.98 (s, 3H), 7.39 (dt, 1H, 1 = 1.0, 7.4 Hz), 7.55 (d, 1H, J = 7.4 Hz) , 7.66 (dt, 1H,) = 1.0, 7.4Hz), 7.72-7.79 (m, 3H), 7.85 (s, 1H), 8.95 (d, 1H. J = 7.Hz).

EIMS (m / z): 401 [] ⁺ .

Example 1 1 5 Compound 1 1 9

 According to Step 6 of Example 3, compound 118, 1.16 g (2.90 mmol), potassium carbonate 0.82 g (5.91 mmol) and 2-bromopropionic acid mesylate From 0.5 ml (4.44 mmo 1) of chill, compound 119 and 1.38 g (quantitative) were obtained.

 Ή NMR (CDC) (5; 1.43 (d, 3H, J = 6.9Hz), 3.19 (s, 3H), 3.76 (s, 3H), 3.95 (s, 3H), 4.91 (q, 1H,] = 6.9Hz), 7.42 (dt, 1H, J = l.0, 7.9Hz), 7.49 (d,

28 1H, J = 7.9Hz), 7.58 (d, 111.J-8.4Hz), 7.65 (m, 2H), 7.73 (d.1H, J = l.9H z) .8.01 (dd, 1H, J = 1.9 , 8.4Hz), 9.11 (d, 1H, J = 7.9Hz).

 EIMS (mIz); 487 [M] +.

Example 1 16 Compound 1 2 0

 According to Step 1 of Example 49, Compound 1 19, 1.29 g (2.80 mmo 1), 2N hydrochloric acid 35 mL (70. 1.39 g (quantitative) were obtained.

NMR (DMS0-d ₆ ) δ; 1.35 (d. 3H, J = 6.7 Hz), 3.07 (s. 3H), 3.32 (s, 3H),

3.99 (s, 3H), 5.00 (q, 1H, J-6.7Hz), 7.40 (t, 1H, J = 7.8Hz), 7.67 (t, 1H, J = 7.8Hz), 7.73 (d, 1H, J = 8.4Hz), 7.75 (d, 1H, J = 7.8Hz), 7.77 (d, 1H, J =

2.0Hz), 7.98 (dd, 1H, J = 2.0, 8.4Hz), 8.01 (s. 1H), 8.95 (d. 1H, J = 7.8Hz).

 FABMS (m / z); 474 [Mil] +.

Example 1 1 7 Compound 1 2 1

 According to Step 1 of Example 15, compound 120, 1.31 g (2.92 mmo 1), 1 M borane 'THF complex 4.4 ml (4.40 mmol) 1. 21 and 1.27 g (95%) were obtained.

_{lH NMR (CDC1 3) δ;} 1.18 (d, 3H, J = 6.8Hz), 3.20 (s, 3H), 3.48 (dd, 1H, J = 6.9, 12.4Hz), 3.70 - 3.88 (m, 1H), 3.94 (s, 3H), 4.12 (q, 1H, J = 6.8Hz),

4.77 (m, 1H), 7.43 (t, 1H, J-7.6Hz), 7.49 (d, 1H, J = 8.4Hz), 7.58 (d, 1H, J = 7.6Hz). 7.66 (t, 1H, J = 7.6Hz). 7.94 (s, 1H), 7.97 (d, 1H, J = 2.0Hz),

8.03 (dd, IH, 2.0, 8.4Hz), 9.11 (d, 1H, J = 7.6Hz).

 EIMS (m / z); 459 [M] +.

Example 1 18 Compound 1 2 2 and Compound 1 2 3

Compound 1 2 1, 1.45 g (3.33 mmo 1) was dissolved in 1,2-dichloromethane 34 mL, and pyridine 4.4 mL (54.4 mm 01) and chloride p —Toluenesulfonyl (7.71 g, 40.4 mmo 1) was added, and the mixture was stirred at 60 for 17 hours. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and extracted with CHC 1 _3, the organic layer 2 N hydrochloric acid, followed after brine washed, dried over anhydrous sodium sulfate, solvent

29 The medium was distilled off. The residue papermaking rectification by silica gel column chroma Bok chromatography (CHC 1 _3>, Compound 1 2 2, 0. 6 8 g (3 3%) and Compound 1 2 3, 0. 3 2 g

(20%).

Compound 1 2 2

 'H Marauder (CDC) (5; 1.24 (d, 3H, J-5.7Hz), 2.32 (s, 3H), 3.17 (s, 3H). 3.90-4.00 (m, 2H), 3.96 (s, 3H), 4.64 (q, 1H.J = 5.7Hz), 7.11 (d, 1H, 1 = 8.lHz), 7.44 (t, 1H, J = 7.8Hz), 7.50 (d, 1H, J-7.8Hz) ), 7.52 (d, 2H, J = l.5H z) .7.55 (d, 211, 1 = 1.5Hz), 7.67 (dt, 1H, J = 1.0, 7.8Hz), 7.75 (d, 1H, J = 2.1Hz), 7.97 (dd, 1H, J = 2.1, 8.1Hz), 9.14 (d, 111, J = 7.8Hz).

 EIMS (m / z); 613 [M] +.

Compound 1 2 3

 Ή NMR (DMSO-dJ δ; 1.24 (d, 3H, J = 6.4 Hz), 3.06 (s, 3H), 3.73 (m, 1H), 3.99 (s, 3H), 4.95 (m, 1H), 7.40 ( t, 1H.J = 7.8Hz), 7.67 (t, 1H, J = 7.8Hz), 7.75 (d, 1H.J = 8.4Hz), 7.88 (s, 1H), 7.94-7.99 (m, 2H) , 8.95 (d, 1H, J = 7.8Hz).

 EIMS (m / z); 477 [M] +.

Example 1 1 9 Compound 1 24

Process 1

 According to Example 53, compound 122, 585 mg (0.96 mmo 1) and 50% aqueous dimethylamine solution 8.6 m 1 (95.4 mmo 1) were used to release compound 124. 441 mg (95%) of the base were obtained.

 Process 2

 Example 2 According to step 2 of 1, compound 124 free base 21.4 mg (0.44 mmol) and 4N hydrogen chloride ZAc〇Et solution 0.2 ml (0.80 mm o 1 )) To obtain Compounds 124 and 209 mg (91%).

Ή NMR (DMS0-d ₆ ) δ; 1.17 (d, 3H, J = 2.5 Hz), 2.62 (s, 6H), 3.01-3.18 (m, 2H), 3.07 (s, 3H), 4.00 (s, 3H), 5.20 (m, 1H), 7.41 (t, 1H, J-7.7Hz), 7.68 (I, 1H, J = 7.7Hz), 7.76 (d, 1H, J2 7.7Hz), 7.80 — 8.08 (m, 4H), 8.96 (d, 1H, J = 7.7Hz), 10.05 (br, IH). FABMS (m / z); 487 [+ l] +.

Example 12 0 Compound 1 25 and Compound 1 2 6

Process 1

 Compound 105 was obtained from compound 104, 3.02 g (4. O Ommo 1) and potassium carbonate 70 O mg (5.0 7 mmo 1) according to step 6 of Example 37. Then, according to Step 6 of Example 3, the obtained compound 105 was treated with 2-dimethylaminoisopropyl hydrochloride 1.07 g (6.75 mmo 1) and potassium carbonate 2.8 0 g (20.2 mmo 1) to give 7235 mg (34%) of compound 125 free base and 1.25 g (57%) of compound 125 free base.

Process 2-1

 Example 2 According to Step 2 of 1, Compound 1 25 free base 205 mg (0.373 mmo 1) and 4N hydrogen chloride ZA c OEt solution 0.20 ml (0.8 Omm From o 1), Compounds 125 and 133 mg (63%) were obtained.

Ή NMR (DMS0-d ₆ ) δ; 1.01 (d, 3H, J = 5.9 Hz), 2.53 (br s, 6H), 2.99 (s, 3 H), 3.10 (m.2H), 3.90 (s , 3H), 4.92 (m, 1H), 5.15 (s, 2H), 6.72 (dd, 1H,

J = 2.2, 8.6Hz), 6.89 (br s, 1H), 7.25 (d, 1H, J = 8.6Hz) .7.28-7.72 (m, 9H), 8.88 (d, 1H, J = 7.6Hz). 9.99 (br s, 1H).

Process 2-2

 Example 2 According to Step 2 of 1, Compound 1 26 free base 1 96 mg (0.358 mmo 1) and 4N hydrogen chloride ZA c〇Et solution 0.2 0 ml (0.8 Omm From o 1), 204 mg (98) of compound 122 were obtained.

Ή NMR (DMS0-d _b ) δ; 1.02 (d, 3H, J = 6.9 Hz), 2.39 (br s, 6H), 2.99 (s, 3H), 3.45 (m, 1H), 3.90 (s, 3H ), 4.16 (m, 2H), 5.15 (s, 2H), 6.73 (dd, 1H, J = 2.0, 8.6Hz), 6.82 (d, 1H, 2.0Hz), 7.26 (d, 1H, J = 8.6Hz), 7.29-7.69 (m, 8H), 7.74 (s, 1H), 8.87 (d, 1H, J = 7.6Hz), 10.38 (br s, 1H).

Example 1 2 1 Compound 1 2 7

Process 1

According to Example 30, Compound 1 25 free base 20 Omg (0.366 mmo From 1) and 130 mg of 10% Pd / C, compound 127 free base 13 Omg (78%) was obtained.

Process 2

 Example 2 In accordance with Step 2 of 1, Compound 1 27 free base 157 mg (0.343 mmo 1) and 4N hydrogen chloride / AcOEt solution 0.17 ml (0.68 mmo1), 148 mg (87%) of compound 127 were obtained.

Ή NMR (DMS0-d ₆ ) <5; 1.04 (d, 3H, J = 5.9 Hz), 2.51 (br s. 6H), 2.92-3.13 (m, 2H), 2.99 (s, 3H), 3.90 (s, 3H), 4.78 (m, 111), 6.47 (dd, 1H.J = 2.3, 8.3Hz), 6.58 (br s, 1H), 7.12 (d, 1H, 8.3Hz), 7.31 (dd, 1H, J = 6.9, 7.6Hz), 7.58 (ddd, 1H, J = l.2, 6.9, 8.3Hz), 7.67 (d, 1H, J = 8.3Hz), 7.69 (s, 1H), 8.88 ( br d, 1H, J = 7.6Hz), 9.71 (s, 1H), 9.94 (br s, 1H).

 FABMS (m / z); 458 [M + l] +.

Example 1 2 2 Compound 1 2 8

Process 1

 According to Example 30, Compound 128 free base (0.279 mg o.1) and 10% PdZC, 11 Omg, Compound 122 free base 122 mg ( 7 1%).

Process 2

 Example 2 According to step 2 of 1, compound 1 28 free base 157 mg (0.343 mmo 1) and 4N hydrogen chloride ZA c OEt solution 0.17 ml (0.68 From mmo 1), Compounds 128 and 121 mg (71%) were obtained.

Ή NMR (DMS0-d _t ) δ; 1.02 (d, 3H, J = 6.9 Hz), 2.36 (br s, 6H), 2.95 (m, 1 H), 2.99 (s, 3H), 3.90 (s, 3H ), 4.09 (m, 2H), 6.48 (dd, 1H, J = 2.0, 8.1Hz), 6.52 (d, 1H, 2.0Hz), 7.12 (d, 1H, 8.1Hz), 7.32 (dd , 1H, J = 7.1, 7.9 Hz), 7.58 (dd, 1H, J = 7.1.8.3 Hz), 7.68 (d, 1H, 8.3 Hz), 7.71 (s.1H), 8.87 (d , 1H, 7.9Hz), 9.72 (s, 1H), 10.10 (br s, 1H).

 FABMS (m / z); 458 [M + l] +.

 Example 1 2 3 Compound 1 2 9

 According to Example 25, compound 91, 2 Omg (0.05 mmo 1), WS C-

l 32 HC ll mg (0.06 mmo 1), HOB t 7.5 mg (0.05 mmo 1), dimethylamine hydrochloride 6.7 mg (0.08 mmo 1) and triethylamine 0.02 ml From (0.16 mmo 1), 20 mg (92) of the compound 122 were obtained.

_{• H NMR (CDC1 3) δ} ; 1.90 (s, 3H), 3.14 (s, 3H), 3.20 (s, 3H), 3.90 (s, 3 H), 7.35 (t, 1H, J = l.4Hz) , 7.41 (dt, 1H, J = l.3, 7.7Hz), 7.43 (s, 1H), 7.46 (dd, 1H, J = l.4, 7.8Hz), 7.48 (d, 1H, J = 7.8Hz), 7.53 (d, 1H, J = 7.7Hz), 7.65 (dt, 1H, 1.3, 7.7Hz), 9.10 (d, 1H, J = 7.7Hz).

EIMS (m / z); 469 [M] ⁺ .

Example 1 2 4 Compound 1 3 0

 According to Step 6 of Example 37, Compounds 128, 54 mg (0.12 mmo 1) and potassium carbonate 31 mg (0.22 mmo 1) were used to obtain Compounds 130, 32 mg. (65%).

* H NMR (DMS0-d ₆ ) δ; 3.02 (s, 6H), 3.07 (s, 3H), 3.98 (s, 3H), 6.92 (dd, 1H, J = l.5, 8.4 Hz), 6.93 ( d, 1H, J = l.5Hz), 7.33 (t, 1H, J = 8.4Hz), 7.38 (t, 1H, J = 7.7Hz), 7.65 (d, 1H, J = 7.7Hz), 7.73 (d , 1H, J-7.7Hz), 7.81 (s, 1H), 8.95 (d, 1H, J = 7.7Hz), 9.73 (s, 1H).

 EIMS (m / z); 427 [M] +.

Example 1 2 5 Compound 1 3 1

 According to step 6 of Example 3, compound 130, 1.89 g (4.43 mmo 1), potassium carbonate 1.23 g (8.93 mmo 1) and 2-bromopropionic acid mesylate From 0.75 ml (6.72 mmol) of chill, compound 131, 2.13 g (94%) were obtained.

 Ή NMR (CDC) δ; 1.38 (d, 3H.6.8 Hz), 2.88 (s.3H), 2.95 (s, 3H), 3.19 (s, 3H), 3.69 (s, 3H), 3.91 (s , 3H), 4.79 (q, 1H, J = 6.8Hz), 6.96 (s, 1H), 7.17 (dd, 1H, J = l.5, 7.9Hz), 7.38 (dt, 1H, J = l .3, 7.7Hz), 7.45 (d, 1H, J-7.7Hz), 7.62 (dt, 1H, J = l.3, 7.7Hz), 8.01 On, 2H), 9.08 (d, 1H, J = 7.7) Hz).

EIMS (m / z); 513 [M] +. Example 1 2 6 Compound 1 3 2

 According to Step 1 of Example 49, Compound 131, 2.03 g (2.80 mmo1) and 2N hydrochloric acid 30 ml (60.0 mmo1) were used to obtain Compound 13 2, 1.39 g (71%) were obtained.

 Ή NMR (DMSO- () δ; 1.10 (d, 3H, J = 6.1 Hz), 2.25 (s, 6H), 3.06 (s, 3H), 3.96 (s, 3H), 4.38 (q, 1H , J = 6.1 1Hz), 6.94 (d, 1H, J = 7.7Hz), 7.07 (s, 1H), 7.32 (d, 1H, 7.7Hz), 7.36 (t, 1H, J = 7.5Hz), 7.63 (t, 1H, J = 7.5Hz), 7.71 (d, 1H, J = 7.5Hz), 7.85 (s, 1H), 8.94 (d, 1H, J = 7.5Hz).

FABMS (m / z); [M + l] ⁺ .

Example 1 2 7 Compound 1 3 3

 Example 2 According to Step 1 of 1, the acid chloride was prepared from Compound 1332, 961 mg (1.93 mmo 1) and thionyl chloride 0.45 ml (6.17 mmo 1). Obtained. Then, according to Example 93, the acid chloride was reacted with 126 mg of sodium borohydride (3.33 mmo 1) to give Compounds 13 and 25 58 mg (28%). Obtained.

_{Ή NMR (CDC1 3) δ;} 1. 12 (d, 3H, J = 5.9Hz), 1.89 (br s, 1H), 3.12 (s, 3H),

3.18 (s, 3H), 3.43 (dd, 1H,) = 6.9, 11.9Hz), 3.61-3.78 (m, 1H), 3.87 (s, 3H), 4.62 (m, 1H), 7.10 (dt, 1H, 1 = 1.3, 7.6Hz), 7.13 (s, 1H), 7.13 (d, 1H, J = l.3Hz), 7.37 (d, 1H.J = 7.6Hz), 7.39 (d, 1H, J = 7.6Hz) ), 7.42 (d,

1H, J = 7.6Hz), 7.60 (dt, 1H, J = l.3, 7.6Hz), 9.04 (d, 1H, J = 7.6Hz).

 EIMS (DI / z); 485 [M] +.

Example 1 2 8 Compound 1 3 4

 According to Step 1 of Example 15, compound 132, 84 mg (0.17 mmo 1) and 0.15 ml (1.58 mmo 1) of polan 'methylsulfide complex, compound 134, 36 mg (46%).

_{Ή NMR (CDC1 3) (5} ; 1. 12 (d, 3H, J = 5.9Hz), 1.85 (br, IH), 2, 61 (s, 3H),

3.19 (s. 3H) .3.44 (dd, 1H, J-6.7, 12.2Hz), 3.66-3, 80 (m, IH), 3.91 (s, 3H), 4.04 (d, 2H,] = 1.5 Hz) .4.62 (m, IH), 7.03 (dd, IH, J = l.0, 7.9Hz), 7.06 (d, IH, J-1.0Hz), 7.39 (d, IH.J = 7.9Hz ), 7.43 (t, III, J: 7.7Hz), 7.46 (d. 1H, J = 7.7Hz). 7.63 (dt.111, 1.0, 7.7Hz), 9.08 (d, 1H. J = 7.7Hz).

FABMS (m / z); [M + l] ⁺ .

Example 1 2 9 Compound 1 3 5

 According to Example 118, compound 133, 114 mg (0.23 mmol), methanesulfonyl chloride 0.44 ml (5.69 mmol) and triethylamine 0.46 ml (3. Compounds 35 and 35 mg (27) were obtained from 3 Ommo 1).

 Ή NMR (CDC) δ; 1.23 (d, 3H, J = 5.7Hz), 2.70 (s, 3H), 3.14 (s, 3H), 3.15 (s, 3H), 3.20 (s, 3H) , 3.93 (s, 3H), 4.09 (dd, 1H, J = 5.7, 10.9Hz), 4.15 (dd, 1H, J = 4.0, 10.9), 4.63 (q, 1H, J = 5.7Hz), 7.14 (d, 1H,] = 1.5Hz), 7.16 (dd, 1H, J = l.5, 8.4Hz), 7.40 (d, 1H, J = 8.4Hz), 7.41 (t, 1H, J = 7.6Hz ), 7.47 (s, 1H). 7.48 (d, 1H, J = 7.6Hz), 7.65 (dt, 1H, J = l.5.7.6Hz), 9.12 (d, 1H. J = 7.6Hz) .

 EIMS (m / z); 563 [M] +.

Example 13 Compound 13

Process 1

 According to Example 53, Compounds 135, 185 mg (0.33 mmo 1) and 50% aqueous dimethylamine solution 3.OmI (3 3.3 mmo 1), Compound 13 36 free base 128 mg (76%) were obtained.

Process 2

 Example 2 Compound 1 36 Free base 12 lmg (0.24mmo 1) and 4N hydrogen chloride / AcOEt solution 0.1 ml (0.4 Ommo 1) As a result, Compounds 1336 and 126 mg (98%) were obtained.

Ή NMR (DMS0-d ₆ ) <5; 1.12 (d, 3H, J = 5.9 Hz), 2.58 (s, 3H), 2.59 (s, 3H), 2.96-3.18 (m, 2H), 3.05 ( s, 6H), 3.07 (s, 3H), 3.99 (s.3H), 4.90-5.10 On, 1H), 7.1 (d, 1H, J-7.7Hz), 7.29 (br s, 1H) , 7.39 (dt, 1H,) = 1.0, 8.0Hz), 7.45 (d, 1H, J = 7.7Hz), 7.67 (dl, III, J = l.0, 8.0Hz), 7.74 (d, 1H, J = 8.0Hz), 7.84 (br s, 1H), 8.96 (d, 1H, J = 8.0Hz). 9.88 (br s, 1H).

 FABMS (m / z); 513 [M + l] +.

35 Example 13 1 Compound 1 3 7

 According to Example 118, compound 134, 33 mg (0.07 mmo1), methanesulfonyl chloride 0.06 ml (0.75 mmo1) and triethylamine 0.11 ml (0 From 75 mmo 1), 35 mg (91%) of compound 1337 were obtained.

_{Ή NMR (CDC1 3) δ;} 1.23 (d, 3H, J = 6.4Hz), 1.85 (br s, 1H), 2.63 (s, 6H), 2.70 (s, 3H), 3. 18 (s, 3H) , 3.91 (s, 3H), 4.03 (s.2H), 4.12 (d, ZH, J = 4.5Hz) .4.56-4.64 (m, 1H), 7.08 (dd, 1H, 1.5, 8.4Hz), 7. 10 (d, 1H, J = 1.5Hz), 7.39 (d, 1H, J27.7Hz), 7.42 (d, 1H, J-7.7Hz), 7.46 (d, 1H, J = 8.4Hz), 7.50 (s, 1H), 7.63 (dt.1H, 1.0, 7.7Hz), 9.08 (d, 1H, J = 7.7Hz). Example 1 3 2 Compound 1 3 8

 According to Example 53, Compounds 13 7 and 31 mg (0.06 mmo 1) and 50% aqueous dimethylamine solution 0.1 ml (1.11 mmo 1) gave Compounds 13 8 and 11

2 Omg (72%) was obtained.

 Ή NMR (CDCU) δ; 1.22 (d, 3H, J = 6.6Hz), 2.33 (s.6H), 2.66 (s, 6H), 3.18 (s, 3H), 3.52 (s, 2H), 3.90 (s, 3H), 4.06 ― 4.18 (m, 1H), 7.05 (d, 1H, J = 7.6Hz), 7.08 (s, 1H), 7.33 (d, 1H, J = 7.9Hz), 7.39 ( t, 1H, J = 7.9Hz), 7.46 (d, 1H, J = 7.9Hz). 7.49 (s, 1H), 7.62 (t, 1H, J = 7.6Hz), 9.10 (d, 1H, J = 7.9Hz).

Example 13 Compound 1 3 9

Process 1

 Compound 1 2 4 Free base 203 mg (0.42 mmo 1) was dissolved in a mixed solvent of DMF 5 ml and ethanol 5 ml, and a 35% formalin aqueous solution 5 ml (58.

3 mmo 1) and 147 mg of 10% PdZC were added, and the mixture was stirred under a hydrogen atmosphere at room temperature under normal pressure for 24 hours. After the reaction solution was filtered through celite, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography _{(CHC 1 3 / M e OH} 2 0 1), to give Compound 1 3 9 free base 1 2 2 mg (6 0%).

 Process 2

 Example 2 According to step 2 of 1, compound 13 9 free base 1 18 mg (0.24mmo 1) and 4N hydrogen chloride / AcOEt solution 0.3 ml (1.20 mmo

36 From 1), compound 139 and 128 mg (94%) were obtained.

lH NMR (D S0-d ₆ ) δ; 1.08 (d, 3H, J = 6.4 Hz). 2.63 (s, 3H). 2.65 (s, 3H), 3.01-3.31 (ιη '2H), 3.07 (s, 3H), 3.09 (s, 6H), 3, 97 (s, 3H), 4.98-5.00 (m, 1H), 6.70-6.87 (m, 211), 7.30 (d, 1H, J = 8.4Hz) , 7.37 (t, 1H, J = 7.8 Hz). 7.64 (t, 1H, J = 7.8 Hz), 7.71 (d, 1H, J = 7.8 Hz), 7.75 (s, 1H), 8.96 (d, 1H) , J = 7.8Hz), 10.17 (br, 1H).

FABMS (m / z); 485 [Ml] ⁺ .

Example 1 34 Compound 1 40

 According to Example 20, Compound 10, 8.28 g (18.0 mmo 1) and D DQ 8.17 g (36.0 mmo 1) gave Compound 140, 7.68 g (94%).

 Ή NMR (CDC) δ; 1.77 (s.3H), 3.17 (s, 3H), 3.60 (s, 3H), 3.87 (s, 3H), 7.33 (s, 1H), 7.39 (dd, 1H, J = l.2, 8.1Hz), 7.41 (ddd, 1H, J = 0.9, 7.0,

7.9Hz), 7.46 (dd, 1H, J = 0.9, 8.2Hz), 7.58 (t, 1H, J = 8.1Hz), 7.64 (ddd, 1H, J = l.2, 7.0, 8.2Hz), 8.05 ' (dd, 1H, J = l.2, 8.1Hz), 9.10 (dd, 1H, J = l.2,

7.9Hz).

 FABMS (m I z); 457 [Mil] + ·

Example 1 3 5 Compound 14 1

 According to step 6 of Example 37, a deacetyl derivative was obtained from compound 140, 997 mg (2.18 mmo 1) and potassium carbonate 361 mg (2.6 lmmo I). Then, the deacetylated product was reacted with 467 mg (3.24 mmo 1) of 2-dimethylaminoethyl hydrochloride and 1.51 g (1 1.Ommo 1) of potassium carbonate according to Step 6 of Example 3. The compound 141, 8889 mg (84%) was obtained.

^{J H NMR (CDC) δ;} 2.01 (s, 6H), 2.37 (t, 2H, J-5.9Hz), 3.15 (s, 3H), 3. 55 (s, 3H), 3.87 (s, 3H), 3.98 (dt, 1H, J = 5.9, 9.8Hz), 4.03 (dt, 1H, J = 5.9, 9.8Hz), 7.19 (dd, 1H. 1.1, 8.2Hz), 7.35 (s, 1H), 7.39 (ddd.1H, J = 0.9, 7.3, 7.9Hz), 7.45 (br d, 1H, J = 8.3Hz), 7.48 (t.1H, 1 = 8.2Hz), 7.62 (d dd, 1H, J = l.2, 7.3, 8.3Hz), 7.69 (dd, 1H.J) = l.1, 8.2Hz), 9.10 (dd, 1H.J = 1.2, 7.9Hz).

 FABMS (m / z); 486 [M + l] +.

Example 1 3 6 Compound 1 4 2

 According to Step 1 of Example 49, compounds 141, 825 mg (1.7 Ommo 1) and 1N hydrochloric acid 15 m1 were used to obtain compounds 144, 643 mg (74) from 1N hydrochloric acid 15 m1. .

Ή NMR (DMSO-d ₆ ) δ; 2.38 (s, 6H), 3.04 (s, 3H), 3.15-3.22 (m, 2H), 3.95 (s, 3H), 4.25-4.33 (m, 2H) 7.38 ― 7.75 (tn.6H), 7.74 (s, 1H), 8.93 (dd, 1H, 0.9, 7.9Hz).

FABMS (m / z); 472 [Mil] ⁺ .

Example 1 3 7 Compound 1 4 3

 According to Example 25, compound 14 2, 95 mg (0.19 mmo 1), DMAP 12 mg (0.1 Ommo 1), ethanethiol 0.0 3 5 ml (0.4 7 mmo Compounds 144 and 29 mg (30%) were obtained from 1) and WS C · HC 1,4 3 mg (0.23 mmo 1).

_{Ή NMR (CDC1 3) 6;} 1.07 (t, 3H, have 7.4Hz), 2.03 (s, 6H ), 2.39 (t, 2H, J = 5.7Hz), 2.75 (m, 2H), 3. 17 (s , 3H), 3.86 (s, 3H), 3, 98 — 4.07 (m, 2H), 7.15 (dd.1H, J = 2.3, 7.0Hz), 7.36 (s, 1H), 7.39 (ddd, 1H) , J = l.0, 7.1, 7.8H z), 7.44 — 7.52 (m. 3H). 7.62 (ddd, III, J = l.2, 7.1, 8.3Hz) _t 9. 10 (br d, 1H, 7.8Hz).

 FABMS (m / z); 516 [M + l] +.

Example 1 3 8 Compound 1 44

 According to Step 1 of Example 49, Compound 140, 4.10 g (8.97 mmo 1) and 1N hydrochloric acid 2 35m1 were used to obtain Compound 144, 2.02 g (56 %).

Ή NMR (DMSO-dt) <5; 3.08 (s, 3H), 3.94 (s, 3H), 7.14 (dd, 1H, J = l.2, 7.9Hz), 7.35 (t, 1H, J = 7.9Hz), 7.38 (ddd, 1H, J = 0.9, 7.2, 7.9Hz), 7.45 (dd, 1H, J = l.2, 7.9Hz). 7.65 (ddd, 111, Jl.2, 7.2, 8.4) Hz), 7.65 (s, 1H), 7.72 (br d, 1H, J = 8.4Hz), 8.93 (dd, 1H, J = l.2, 7.9Hz), 9.57 (s, 1H). FABMS (m / z); 401 [M + l] +.

Example 1 39 Compound 145

 According to Step 1 of Example 15 from Compound 144, 2.02 g (5.05 mmo 1) and 3.0 ml (32 mmo 1) of borane-dimethylsulfide complex, Compounds 1 45 and 1. 4 1 (73%) was obtained.

Ή NMR (DMS0-d ₆ ) δ; 3.04 (s, 3H), 3.96 (s, 3H), 4.12 (dd, 1H, J = 5.5, 1 4.0 Hz), 4.21 (dd, 1H, J = 5.5, 14.0 Hz), 4.87 (t, 1H, J = 5.5Hz), 6.82 (d, 1H, J = 7.8Hz), 7.06 (d, 1H, J = 7.8Hz), 7.23 (t, III, J-7.8Hz) , 7.39 (t, 1H, J = 7.6Hz), 7.66 (ddd.1H, J = l.0, 7.6, 8.2Hz), 7.70 (s, 1H), 7.73 (d, 1H, J = 8.2Hz), 8.95 (br cl, 1H, J = 7.6Hz). 9.09 (s, 1H).

FABMS (m / z); 386 [M] ⁺ .

Example 1 40 Compound 1 46

 According to Step 3 of Example 5, compound 146, 20 Omg (64%) was obtained from compound 145, 313 mg (0.811 mmo 1) and manganese dioxide 3.14 g. .

'Η supplement (CDCl ₃ + D S0-dt) δ; 3.14 (s, 3H), 3.93 (s, 3H), 7.31 (dd, 1H, J = 1.5, 8.1Hz), 7.39 (ddd, 1H, J = l.0, 7.1, 7.8Hz), 7.43 (1, 1H, J = 8.1Hz), 7.50 — 7.55 (m, 2H), 7.54 (s, 1H), 7.64 (ddd, 1H, J = l. 2, 7.1, 8.3Hz), 9.07 (dd, 1H, J = l.2, 7.8Hz), 9.28 (s, 1H), 9.75 (s, 1H).

 FABMS (DI Iz); 385 [Mil] +.

Example 1 4 1 Compound 147

 According to Step 6 of Example 3, compound 146, 143 mg (0.373 mmo 1), 2-dimethylaminoethyl chloride hydrochloride 79 mg (0.55 mmo 1) and potassium carbonate 256 mg ( The compound 147 (149 mg, 88%) was obtained from 1.85 mmo 1).

_{Ή NMR (CDC1 3) 6;} 2.05 (s, 6H), 2.42 (t, 2H, J = 5.8Hz), 3.17 (s, 3H), 3. 90 (s, 3H), 4.03 (dt, 1H, J = 5.8, 9.8Hz), 4.08 (dt, 1H, J = 5.8, 9.8Hz), 7.26 (dd, 1H, 1.0, 8.2Hz), 7.42 (s, 1H), 7.43 (ddd, 1H, J = 0.9.7.3, 7.9Hz), 7.49 (br d, 1H, J = 8.2Hz), 7.57 (dd, 1H, J = 7.8, 8.2Hz), 7.69 (dd, 1H, Jl.0, 7.8Hz), 9.13 (br d, 111, J = 7.9Hz), 9.80 (s, 1H).

 FABMS (mIz); 456 [M + l] +.

Example 1 4 2 Compound 1 4 8

Compound 144, 109 mg (0.282 mmo 1) was suspended in thionyl chloride 3.Oml (42 mmo 1), and the mixture was stirred at room temperature for 2.5 hours. It was distilled off under reduced pressure chloride Chioniru, after purification of the residue by preparative thin layer chromatography _{(CHC l 3 ZM e OH 3} 0/1), and Torichu Les one Chillon with a mixed solvent of A C_〇_E t and diisopropyl ether Compound 148, 98 mg. (86%) was obtained.

 Ή NMR (CDC) δ; 3.16 (s, 3H), 3.90 (s, 3H). 4.16 (d.1H, J = 10.5Hz), 4.43 (d, 1H, J = 10.5Hz), 5.03 (d , 1H, J = l.0Hz), 7.03 (dd, 1H, J = l.0, 7.9H z), 7.19 (br d, 1H, J = 7.9Hz), 7.39 (t, 1H,] = 7.9Hz), 7.40 (ddd, 1H, J = 0.9, 7.1, 7.8Hz), 7.44 (br d, 1H, J = 8.3Hz), 7.63 (ddd, 1H, J = l.2, 7 1, 8.3 Hz), 7.64 (s.1H), 9.00 (br d, 1H, J = 7.8Hz).

 FABMS (m / z); 405 [M11] +.

Example 1 4 3 Compound 1 49

 According to Example 30, compound 148, 95 mg (0.24 mmo 1), sodium hydrogen carbonate 38 mg (0.46 mmo 1) and 10% Pd / C, 99 mg Thus, Compounds 149 and 87 mg (quantitative) were obtained.

 Ή NMR (CDC) <5; 2.05 (s, 3H), 3.17 (s, 3H), 3.90 (s, 3H), 4.79 (s.1H), 6.88 (dd, 1H, 0.9, 7.9Hz), 6.94 (dd, IH, J = 0.9, 7.9Hz), 7.26 (i, 1H, 7.9Hz), 7.40 (ddd.1H, 1 = 0.9, 7.0, 7.9Hz), 7.44 (br d, 1H, J = 8.2 Hz),

7.46 (s, 1H). 7.63 (ddd, 1H, J = l.2, 7.0, 7.9Hz), 9.04 (dd, 1H, 1.2. 7.9Hz).

FABMS On Iz); 371 [M + l] ⁺ .

Example 1 44 Compound 150

According to Step 6 of Example 3, compound 149, 86 mg (0.23 mmo 1), 2-dimethylaminoethyl hydrochloride 5 Omg (0.34 mmo 1) and potassium carbonate 156 mg From (1.13 mmo 1), 75 mg (73%) of compound 150 were obtained. Ή NMR (CDCI3) 6; 2.03 (s, 6H). 2.08 (s, 311). 2.39 (m, 2H), 3.17 (s, 3H), 3.89 (s, 3H), 3.97 (dt,! H, J = 5.8.9.8Hz), 4.02 (dl, 1H, J = 5.8, 9.8Hz), 6.86 (d.1H, J = 7.9Hz), 6.97 (d, 1H, J = 7.9Hz), 7.31 (t , 1H, J = 7.9Hz), 7.39 (s, 1H). 7.40 (ddd, 1H, J = 0.8, 7.3, 7.9Hz), 7.47 (br d, 1H, J = 8.2Hz), 7.63 (ddd, 1H. J = l.2, 7.3. 8.2Hz), 9.11 (dd, 1H,] = 1.2, 7.9Hz).

 FABMS (m / z); 442 [M + l] +.

Example 1 45 Compound 1 5 1

 According to Example 93, compound 151, 53 mg (99%) was obtained from compound 144, 53 mg (0.12 mmol) and sodium borohydride 7.Omg (0.2 Ommo 1). I got

 Ή NMR (CDC) δ; 2.05 (s, 6H), 2.38 (m, 2H), 3.16 (s.3H), 3.89 (s, 3H), 3.97 (dt, IH, J = 5.8, 9.8Hz), 4.03 (dt.1H.J = 5.8, 9.8Hz), 4.38 (d, 1H, J = 12.2Hz), 4.39 (d, 1H, J = 12.2Hz), 6.98 (dd, 1H, J = 0.7.7.9 Hz), 7.26 (dd, 1H, J = 0.7, 7.9Hz) .7.41 (ddd, 1H, J = 0.9, 7.3, 7.9Hz), 7.44 (s, 1H), 7.45 (t, 1H, J = 7.9Hz) ), 7.47 (br d, 1H, J = 8.2Hz), 7.64 (ddd, HI, J = l.2, 7.3.8.2Hz), 9.11 (dd, IH, J = l.2, 7.9Hz).

 FABMS (m / z); 458 [M + l] +.

Example 1 46 Compound 1 52

 According to Example 20, Compounds 17 and 91 mg (1.98 mmo 1) and D DQ 9 50 mg (3.98 mmo 1) were used to obtain Compounds 152 and 900 mg (quantitative). I got

_{Ή NMR (CDC1 3) 6;} 0.89 (s, 9H), 3.16 (s, 3H), 3.66 (s, 3H), 5.78 (s, 1 H), 6.80 (dd, IH, 1 = 1.0, 8.3Hz) , 7.09 (br, IH), 7.27 (d, IH, 1-7.9Hz), 7.29 (t, IH, 8.3Hz), 7.37 (1, IH, J = 7.9Hz), 7.51 (s, IH) , 7.55 (m, 2H), 7.98 (d, IH. J = 7.9Hz).

FABMS (m / z); 456 [M + l] ⁺ .

Example 1 47 Compound 1 53

Process 1

According to Step 6 of Example 3, compound 152, 83 Omg (1.82 mm01), From 2-95 mg (2.74 mmo 1) of 2-dimethylaminoethyl chloride hydrochloride and 379 mg (2.75 mmo 1) of potassium carbonate, compound 15 3 free base 18 3 mg (1 9 %).

Process 2

 Example 2 Compound 15 3 Free base 8 Omg (0.15 mmo 1) and 4 N hydrogen chloride ZA c OEt solution 0.04 2 ml (0.17 mm From 1), Compounds 15 3 and 8 4 mg (98%)

I got

Ή NMR (DMSO-dt) δ; 0.80 (s, 9H), 2.47 (s, 6H), 3.08 (s, 3H), 3.21 (br, 2H), 3.93 (s, 3H), 4.30 (m, 2H) , 7.05 (d, 1H, J = 7.9Hz) _t 7.24 (d, 1H, 7.9Hz), 7.40 On, 2H), 7.70 (m, 2H), 7.70 (s, 1H). 8.36 (s, 1H), 8.95 (d, 1H, J = 7.9Hz), 10.20 (br, 1H).

FABMS (m / z); 527 [Mil] ⁺ .

Example 1 4 8 Compound 1 5 4

 According to Example 20, Compounds 1, 400 mg (1.03 mmo 1) and D DQ 4488 mg (2.06 mmo 1) gave Compounds 154, 219 mg (5 5%).

Ή NMR (DMS0- d _fc ) δ; 3.04 (s.3H), 3.61 (s, 3H), 3.96 (s, 3H), 6.58 (d, 1H. 1-8.9 Hz), 6.59 (d, 1H, J = 8.9Hz), 7.19 (t.1H, J = 8.2Hz), 7.37 (t, 1H, 7.9Hz), 7.64 (t, 1H, J = 7.9Hz), 7.71 (s, 1H), 7.72 ( d, 1H, J2 8.0Hz), 8.94 (d, 1H, J = 7.9Hz), 9.29 (s, 1H).

FABMS (m / z); 387 [M + l] ⁺ ·

 Example 1 4 9

 Process 1

 According to Step 6 of Example 3, compound 154, 204 mg (0.53 mmol), 2-dimethylaminoethyl chloride hydrochloride 154 mg (1.07 mmol) and potassium carbonate 219 mg From (1.59 mmo 1), 152 mg (63%) of the compound 1555 free base was obtained.

Process 2 Example 2 In accordance with Step 2 of 1, compound 150 5 free base 107 mg (0.23mmo 1) and 4N hydrogen chloride / A c〇Et solution 0.06 2 ml (0.2 Compounds 55.5 and 114 mg (99%) were obtained from 5 mmo1).

Ή NMR (DMS0-d _fc ) δ; 2.44 (s, 6H), 3.03 (s, 3H), 3.20 (m, 2H), 3.63 (s, 3H), 3.95 (s, 3H), 4.30 (m, 2H ), 6.81 (d, 1H, J = 8.3Hz), 6.82 (d, 1H, J- 8.6Hz). 7.37 (t, 1H, J = 8.2Hz), 7.40 (t, 1H, J = 8.4Hz), 7.64 (t, 1H, J = 8.3 Hz), 7.72 (d, 1H, 8.3 Hz), 7.78 (s, 1H), 8.93 (d, 1H, J = 7.9 Hz), 10.30 (br, 1H).

FABMS (m / 2); 458 [M + l] ⁺ .

Example 15 Compound 15

 According to Example 20, Compounds 1 56 and 12.1 were obtained from Compounds 12 and 16.7 g (35.8 mmo 1) and D DQ 16.3 g (7 1.6 mmo 1). (73%).

 Ή NMR (DMSO-dt) δ; 3.01 (s, 3H), 3.95 (s, 3H), 4.91 (d, 111,) = 12.2 Hz), 5.03 (d, 1H, 11.9 Hz), 6.63 (d, 1H , J = 8.3Hz), 6.67 (d, 1H, J = 8.3Hz). 7.00-7.30 (m, 6H), 7.36 (1H, J = 7.9Hz), 7.64 (t, IH, J = 8.3 Hz), 7.72 (d, 1H, J = 8.3Hz), 7.79 (s, 1H), 8.92 (d, 1H, J-7.9Hz), 9.40 (s, 1H).

 FABMS (m / z); 463 [M + l] +.

Example 15 Compound 1 5 7

Process 1

 According to Step 6 of Example 3, Compounds 15 6 and 79 Omg (1.71 mmo 1), 2-dimethylaminoethyl hydrochloride 494 mg (3.43 mmol) and potassium carbonate 70 From 8 mg (5.13 mmo 1), 677.3 mg (74%) of compound 1557 free base was obtained.

Process 2

 Example 2 According to step 2 of 1, compound 1557 free base 8 Omg (0.15 mm o 1) and 4N hydrogen chloride c〇Et solution 0.042 ml (0.17 mm o 1) Compound 1 5 7 and 8 1 mg (95)

I got

43 Ή NMR (DMS0-d ₆ ) δ; 2.51 (s, 6H), 3.03 (s, 3H), 3.25 (m. 211), 3.97 (s, 3H). 4.30 (m, 2H), 4.97 (d. , J = I2.2Hz), 5.09 (d, 1H, J = ll.9Hz), 6.85 (d, 1H, J = 8.6Hz), 6.92 (d, 1H, J = 8.6Hz), 7.10-7.30 (m. 511), 7.37 (t, 1H, J = 7.6Hz), 7.42 (t, 1H, J = 8.6Hz), 7.65 (t, 1H, J = 7.9Hz), 7, 73 (d, 1H.

 (8.3Hz), 7.87 (s, 1H), 8.93 (d, 1H, J = 7.9Hz), 10.20 (s, 1H).

 FABMS (m / z); 534 [M + l] +.

Example 1 5 2 Compound 1 5 8

 According to Example 20, from Compounds 13 and 3 76 mg (0.82 mmo 1) and D DQ 38 3 mg (1.64 mmo 1), Compounds 15 8 and 25 2 mg ( 6 8%).

Ή NMR (CDC1 ₃ ) δ; 0.41 (t, 3H, J = 6.9 Hz), 0.82 (t, 3H, J = 6.9 Hz), 2.50-2.90 (m, 2H), 3.25 (m, 1H), 3.50 ( m, 111), 3.17 (s, 3H), 3.60 (s, 3H), 6.42 (br, 1H), 6.94 (d, 1H, 7.6Hz), 7.10-7.40 On, 3H), 7.52 ( t, 1H, J = 7.3Hz), 7.59 (s, 1H), 8.96 (d, 1H, J = 7.9Hz).

FABMS (m / z); 456 [MH] ⁺ .

Example 15 3 Compound 15 9

Process 1

 According to Step 6 of Example 3, Compounds 158 and 212 mg (0.47 mmo 1), 2-dimethylaminoethyl chloride hydrochloride 134 mg (0.93 mmol) and potassium carbonate 1 From 95 mg (1.41 mmo 1), 104 mg (42%) of compound 159 free base was obtained.

Process 2

 Example 2 Compound 15 9 Free base 9 Omg (0.17 mm o 1) and 4 N hydrogen chloride ZA c OEt solution 0.04 8 ml (0.19 mm o) From 1), compound 15 9 and 78 mg (8 1%)

 I got

Ή NMR (DMS0-dJ δ; 0.28 (br, 3H), 0.80 (br, 3H), 2.60 (m, 2H), 2.47 (s.6H), 3.20 (m, 2H), 3.07 (s, 3H), 3.20 (m, 2H), 3.93 (s, 3H), 4.30 (m, 2H) .7.04 (d, 1H, J = 7.6Hz), 7.21 (d, 1H, J = 7.2Hz), 7.40 (t, 1H , J = 7.6H z), 7.53 (t, 1H, J-7.6Hz), 7.66 (s, 1H), 7.66 (t, 1H, 7.9Hz), 7.76 (d, 1H, J = 8.3Hz), 8.94 (d, 1H, J = 7.6Hz), 10.40 (br, 1H).

FABMS (mIz); 527 [M + l] ⁺ .

Example 1 54 Compound 1 60

Process 1

 Compound 157 free base 37 Omg (78%) was obtained from Compound 157 free base 569 mg (1.07 mmo 1) and 10% PdZC (50 wt%) and 270 mg according to Example 30. Was.

Process 2

 Example 2 Compound 1 60 free base 23 Omg (0.52 mmol) and 4 N hydrogen chloride AcOEt solution 0.143 ml (0.57 mmo 1) ), Compounds 160 and 25 Omg (quantitative) were obtained.

 Ή NMR (DMSO-dfc) δ; 2.47 (s, 6H), 3.06 (s, 3H), 3.20 (br, 2H), 3.97 (s, 3H), 4.25 (m, 2H), 6.62 (d, 1H, J = 8.3Hz), 6.67 (d, 1H, 8.3Hz), 7.22 (d, 1H, J = 8.3Hz), 7.38 (t, 1H.J = 7.9Hz), 7.65 (t, 1H, J = 7.9Hz) ), 7.73 (d, 1H, J = 8.3Hz), 7.79 (s, 1H), 8.95 (d, 1H, J = 7.9Hz), 9.45 (s, 1H), 10.30 (br, 1H).

FABMS (m / z); 444 [+ l] ⁺ .

Example 1 5 5 Compound 16 1

Process 1

 According to Step 2 of Example 3, Compound 1 60 free base 14 lmg (0.29 mmo 1), triethylamine 0.125 ml (0.90 mmo 1), DMAP 5 mg (0.04 mmo 1) ) And 0.055 ml (0.58 mmo 1) of acetic anhydride to give 11 Omg (78%) of compound 161 free base.

Process 2

 Example 2 According to step 2 of 1, compound 16 1 93 mg of free base (0.19 mmo 1) and 4N hydrogen chloride ZA c OEt solution 0.054 ml (0.22 mmo 1) Compound 1 61, 94 mg (94%)

I got _{^{l H NMR (DMSO- d b)}} δ: 1.82 (s, 3H), 2.49 (s, 6H), 3.07 (s, 311), 3.25 (m, 2H), 3.95 (s, 3H), 4.30 (m, 2H), 6.96 (d, 1H, J = 7.9Hz), 7.13 (d, 1H, J = 8.3Hz), 7.41 (t, 111, J = 7.3Hz), 7.51 (t, 1H, J = 8.2Hz) , 7.68 (ddd, 1H, J = l. 0, 7.3, 8.2Hz), 7.72 (s, 1H), 7.76 (d, 1H, J = 8.6Hz), 8.96 (d, 1H, J: 7.9Hz) 10.20 (br, 1H).

 FABMS (m / z); 486 [M + l] *.

Example 1 56 Compound 1 62

 According to Example 20, from Compounds 16 and 8 16 mg (1.96 mmo 1) and D DQ 92 Omg (3.92 mmo 1), Compounds 162 and 42 1 mg (52%) I got

 Ή NMR (CDCla) δ; 0.69 (t, 3H, 7.6Hz), 1.11 (sextet, 2H, J-7.6Hz), I. 39 (quint., 2H, J = 7.6Hz), 2.20 — 2.50 (m, 2H), 3.17 (s, 3H), 3.89 (s, 3H), 4.79 (s, 1H), 6.87 (d, 1H, J = 8.3Hz), 6.97 (d.1H,] = 7.3Hz), 7.30 (t, 1H, J = 8.3Hz), 7.30-7.50 (m.2H), 7.46 (s, 1H), 7.64 (ddd, 1H, J = l.0, 7.3.8.3Hz), 9.04 (d, 1H , J = 7.9Hz).

 FABMS (m / z); 413 [M + l] +.

Example 1 57 Compound 1 63

Process 1

 According to step 6 of Example 3, compound 16 2, 407 mg (0.99 mmo 1), 2-dimethylaminoethyl hydrochloride 21 3 mg (1.48 rnmo 1) and potassium carbonate 34 From 1 mg (2.47 mmo 1), 358 mg (75%) of Compound 163 free base was obtained.

 Process 2

 Example 2 According to step 2 of 1, compound 16 3 free base 33 8 mg (0.70 mmol) and 4N hydrogen chloride / AcOEt solution 0.19 ml (0.76 mmo 1 ) To give Compounds 163 and 363 mg (quantitative).

Ή NMR (DMS0-d _t ) δ; 0.61 (t, 3H, J = 7.3 Hz), 1.06 (sextet, 2H. J = 7.3 Hz), 1.33 (quint., 2H, 1 = 7.3 Hz), 2.20-2.50 (in, 2H), 2.39 (s, 6H), 3.10 n.2H), 3.05 (s, 3H), 3.97 (s, 310, 4.30 (m, 2H), 6.99 (d, 1H, J = 8.3Hz) , 7. 02 (d, III, J = 8.3Hz), 7.40 (m, 1H), 7.38 (t, 1H.J = 8.2Hz), 7.67 (ddd, 1H, J = l.0, 7.3.8.3Hz), 7.75 (d, III, J = 8.6Hz), 7.77 (s, 1H), 8.95 (d, 1H.J -7.6Hz), 10.10 (br, 1H).

FABMS (m / z); 484 [+ l] ⁺ .

Example 1 58 Compound 1 64

 According to Example 20, Compound 14, 1.12 g (2.9961111110 1) and 0 DQ 1.58 g (6.96 mmo 1) gave Compounds 164, 113 mg (10 %).

Ή NMR (DMS0-d ₆ ) δ; 3.06 (s.3H), 3.98 (s, 3H), 6.74 (t, 1H, J = 8.4 Hz), 6.81 (d, 1H, J = 7.9 Hz), 7.28 ( dt, 1H, J = 6.9, 8.4Hz), 7.39 (ddd, 1H, J = l. 0, 6.9, 7.9Hz), 7.66 (ddd, 1H, J = l.5, 6.9, 8.5Hz), 7.75 ( d, III, J = 8.4Hz), 7.85 (s, 1H), 8.95 (d, 1H, J = 7.9Hz), 9.84 (s, 1H).

 FABMS (ni / z); 375 [M + l] *.

Example 1 59 Compound 1 6 5

Process 1

 According to Step 6 of Example 3, compound 164, 98 mg (0.26 mmo 1), 2-dimethylaminoethyl chloride hydrochloride 58 mg (0.40 mmol) and potassium carbonate 9.1 mg (0.66 mmol) From 1), compound 16 5 free base 7 7 mg

(66%).

Process 2

 Example 2 According to step 2 of 1, compound 165 free base 63 mg (0.14 mmo 1) and 4N hydrogen chloride A Ac〇Et solution 0.04 ml (0.16 mmo 1), 66 mg (97%) of compound 165 was obtained.

Ή NMR (DMS0-d _t ) δ; 2.52 (s, 6H) .3.07 (s, 3H), 3.30 (m, 2H), 3.99 (s, 3H), 4.30 Cm, 2H), 7.01 (t, 1H, J = 8.6Hz), 7.07 (d, 1H, J-8.6Hz), 7.1 (ddd, 1H, J = l.0, 6.9, 8.1Hz), 7.52 (dt, 1H, J = 6.9, 8.6Hz ), 7.68 (ddd, 1H, J = l.5, 6.9, 8.1Hz), 7.77 (d, 1H, J = 8.3Hz). 7.98 (s, 1H), 8.96 (d, 1H. J = 7.9Hz) , 10.30 (s, 1H).

FABMS (m / z); 446 [M + l] ⁺ . Example 16 Compound 16

 According to Example 20, Compound 19, 7.22 g (13.72 mmo 1) and DDQ 6.23 g (27.44 mmo 1) gave Compound 1666 ( Diastereomer—ratio 4: 1), 3.64 g (51%) was obtained.

Main stereo stereo:

 Ή NMR (CDC) δ; 1.34 (d, 3H, J = 6.6 Hz), 3.18 (s, 3H), 3.54 (s, 3H), 3.92 (s, 3H), 4.65 (q, 1H, J = 6.6Hz), 6.94 (d, 1H, J = 8.2Hz), 7.26 (t, 1H, J = 8.21k), 7.30-7.50 (m, 2H), 7.43 (s, 1H), 7.47 (d, 1H, 1-8.3Hz), 7.63 (dd, 1H,] = 7.1, 8.3Hz), 9.12 (d, 1H, 1 = 7.9Hz).

 FABMS (m / z); 521 [M + l] +.

Example 16 1 Compound 16 7

 According to step 1 of Example 49, compound 1667 (3.58 g (6.78 mmo 1)) and 2N hydrochloric acid 5 Om 1 were used to obtain compound 1667 (diastereomer ratio of 4: 1). ), 4.09 g (quantitative).

Main stereo stereo:

 Ή NMR (CDC) 6; 1.32 (d, 3H, J = 6.9Hz), 3.19 (s, 3H), 3.89 (s, 3H), 4.74 (q, 1H, J = 6.9Hz), 6.88 (d , 1H.J = 8.6Hz), 7.20-7.50 (m, 4H) .7.53 (s, 1H), 7.63 (t, 1H, J = 8.3Hz), 9.10 (d, 1H, J = 7.9Hz).

 FABMS (m / z): 509 [M + l] +.

Example 16 Compound 2

 According to Step 1 of Example 15, compound 1667, 3.04 g (6.00 mmo 1) and borane-dimethyl sulfide complex 1.75 ml (18.45 mmo 1) Thus, 3.37 g (quantitative) of compound 168 (diastereomer ratio 4: 1) was obtained. Primary diastereomer:

 Ή NMR (CDCU) 6; 1.09 (d, 3H, 5.9 Hz), 3.18 (s, 3H), 3.30-3.60 (m, 2H), 3.92 (s, 3H), 4.40 (m, 1H), 7.06 (d , 1H, J = 7.6Hz), 7.20-7.40 (m, 3H), 7.42 (s, 1H), 7.48 (d, 1H, J = 8.3Hz), 7.65 (m, 1H), 9.11 (d, 111,] = 7.6Hz).

FABMS (m / z); 493 [Mil] Example 16 3 Compound 16 9

 According to Example 118, compound 1668, 1.60 g (3.25 mmο1), methanesulfonyl chloride 0.50 ml (6.46 mmo1) and pyridine 50 ml Thus, 1.39 g (75%) of compound 169 (diastereomer ratio: 4: 1) was obtained.

Primary diastereomer:

 Ή NMR (CDC) δ; 1.14 (d, 3H, J = 6.3 Hz), 2.64 (s, 3H). 3.19 (s, 3H), 3.94 (s, 3H). 4.08 (d, 2H, J = 3.35) .4.55 (m, 1H), 7.03 (d, 1H, J = 8.3Hz), 7.30 (t, 1H, J = 8.3Hz), 7.40 (d, 1H, J = 8.3Hz), 7.41 (m , 1H), 7.45 (s. 1H). 7.49 (d, 1H, J = 8.4Hz), 7.65 (dd, 1H,] = 7.3, 8.4Hz), 9.11 (d, 1H, J = 7.6Hz) ).

 FABMS (m I z); 571 [Mil] +.

Example 1 64 Compound 17 0 and Compound 17 1

Process 1

 According to Example 53, compound 1669, 1.36 g (2.39 mmo 1) and 50% aqueous dimethylamine solution 10.8 ml (1 19.50 mmo 1) 1.16 g (93%) of a mixture of the compound 170 free base and the compound 171 free base was obtained. The mixture was then suspended in AcOEt 17 ml and stirred at room temperature for 1 hour. The resulting precipitate was collected by filtration to obtain 0.65 g (52%) of compound 170 free base (diastereomer ratio 1: 0), and the filtrate was concentrated to give compound 1Ί1 free base (diastereomer). And a monomer ratio of 2: 1), 0.48 g (35%).

Process 2— 1

 Example 2 According to step 2 of 1, compound 17 0 free base 20 Omg (0.39 mmo 1) and 4N hydrogen chloride ZA c〇Et solution 0.15 ml (0.60 mmo From 1), compound 1Ί0 (diastereomer ratio 1: 0) and 217 mg (quantitative) were obtained.

Ή NMR (DMSO-dt) δ; 1.06 (d, 1H, J-5.9Hz). 2.50 (s, 6H), 2.90 On, 1H), 3.15 (m, 1H), 3.06 (s, 3H). 3.98 (s, 3H), 5.00 (m, 1H), 7.20-7.50 (m, 4H), 7.60-7.80 (m, 2H), 7.88 (s, 110, 8.95 (d, 1H, J = 7.6Hz), 10.20 (b r, 1H).

FAB S (m / z); 520 [M + l] ⁺ .

Process 2-2

 According to Step 3 of Example 2-9, compound 17 1 free base 4 75 mg (0.91 mmo 1) and 4N hydrogen chloride ZA c OEt solution 0.3 4 ml (1.36 mmo 1 ), 21 Omg (41%) of the compound 171 (diastereomeric ratio 2: 3) was obtained from the filtrate.

 Ή NMR (DMSO-dfc) 6; 1.14 (d, 3H, J = 6.3Hz), 2.50 (s, 6H), 2.90 (m, 1H), 3.20 On, 1H), 3.05 (s, 3H), 3.99 (s, 3H), 5.00 (m, 1H), 7.22-7.50 (m, 4H), 7.60-7.82 (m, 2H), 7.78 (s, 1H), 8.95 (d, 1H, J = 7.6Hz) , 10.20 (br, 1H).

FABMS (m / z); 520 [M + l] ⁺ .

Example 16 5 Compound 1 Ί 2

 According to step 6 of Example 3, compound 1556, 12.12 g (26.23 mmo 1), methyl 2-bromopropionate 5.90 ml (5.288 mm) o 1) and 5.4.3 g (39.35 mmo 1) of potassium carbonate gave compound 172 (diastereomer ratio 5: 2), 13.1 g (91%). Was.

Main stereo stereo:

 Ή NMR (CDC) δ 1.29 (d, 3H, J-6.9Hz), 3.10 (s, 3H), 3.74 (s.3H). 3.89 (s, 3H). 4.75 (q, 1H, J = 6.9Hz), 4.99 (d, 1H, J = ll.9Hz), 5.06 (d, 1H, J = ll.9Hz), 6.56 (d.1H, J = 8.3Hz), 6.81 (d.1H, J = 7.9Hz), 7.00 — 7.50 (m, 8H), 7.61 (dd, 1H. J-7.3, 8.6Hz), 7.75 (s, 1H), 9.09 (d, 1H, J = 7.6Hz).

FABMS (m / z); 549 [MH] ⁺ .

Example 1 6 6 Compound 1 7 3

 According to Step 1 of Example 49, compound 17 2, 4.00 g (7.30 mm o

From 1) and 2N hydrochloric acid 5 Om 1, compound 17 3 (diastereomer ratio 3:

2) and 3.92 g (quantitative) were obtained.

 The main stereo stereo:

* H NMR (CDCh) δ; 1.37 (d, 3H, J-6.9Hz), 3.11 (s, 3H), 3.82 (s, 3H), 4. 79 (q, 1H, J = 6.9Hz), 5.05 (m, 2H), 6.62 (d, 1H, J = 8.2Hz), 6.82 (d.1H, J = 8.3Hz), 7.00-7.70 (m, 9H ), 7.65 (s, 1H), 9.09 (d, 1H.J-7.9Hz).

 FABMS (m / z); 535 [M + l] +,

Example 1 6 7 Compound 1 7 4

 According to Step 1 of Example 15, compound 173, 3.82 g (7.15 mmo1) and polan'dimethylsulfide complex 2.10 ml (22.1 mmo1) As a result, 3.31 g (89%) of compound 174 (diastereomer ratio 3: 2) was obtained. Main stereo stereo:

^J H NMR (CDCi ₃ ) δ; 1.07 (d, 3H, J = 5.9 Hz), 3.11 (s, 3H), 3.30 — 3.70 (m, 2H), 3.86 (s, 3H). 4.40 (m, 1H), 5.00 (m, 2H), 6.75 (m, 2H), 7.00 ― 7.68 (m, 10H), 9.10 (d, III, J = 7.9Hz).

FABMS (m I z); 521 [M + l] ⁺ .

Example 1 6 8 Compound 1 Ί 5

 According to Example 118, compound 174, 3.26 g (6.27 mmo1), methanesulfonyl chloride 0.97 ml (12.54 mmo1) and pyridine From 60 ml, compound 175 (diastereomer ratio 3: 2), 2.87 g (77%), was obtained.

Primary diastereomer:

Ή NMR (CDC1 ₃ ) δ; 1.12 (d, 3H, J = 6.3 Hz), 2.65 (s, 3H), 3.11 (s, 3H), 3.89 (s, 3H), 4.00-4.20 (m, 2H), 4.60 (m, 1H), 6.80 (m, 2H), 7.00-7.68 (m, 10H), 9.10 (d, 1H, J = 7.9Hz).

 FABMS (m / z); 599 [M + l] +.

Example 16 9 Compound 17 6 and Compound 17 7

Process 1

 According to Example 53, Compound 1 75, 2.81 g (4.70 mmo 1), 50% aqueous dimethylamine solution 2 2 m 1 (24.4 mmo 1), Compound 1 7 6 Free base (diastereomer ratio 1: 0) 0.30 g (12%) and mixture of compound 176 free base and compound 177 free base (diastereomer ratio 3: 2) 1.71 g (67%).

1 5 Process 2-1

 Example 2 Compound 1776 Free base 20 Omg (0.37 mmol) and 4N hydrogen chloride ZAcOEt solution 0.14 ml (0.56 mmo) From 1), 202 mg (quantitative) of compound 176 (diastereomeric ratio 1: 0) was obtained.

 Ή NMR (DMS0-dJ δ; 1.03 (d.3H, J = 5.9 Hz), 2.56 (s, 3H), 2.63 (s, 3H) .3.00 (m, 1H), 3.02 (s, 3H), 3.20 ( m.1H), 4.96 (d, III, J-12.3Hz) .5.00 (m, 1H), 5.08 (d, 1H, J-12.3Hz), 6.91 (d, 1H, J-8.4Hz), 6.93 ( d, 1H, J = 8.4Hz), 7.19 (m, 5H), 7.37 (t, 1H, J = 7.4Hz), 7.42 (t, 1H, J = 8.4Hz), 7.65 (t, 1H, J = 7.6Hz), 7.74 (d.1H, 1 = 7.9Hz), 7.89 (s, 1H), 8.93 (d, 1H,] = 7.6Hz) .10.00 (br s, 1H).

 FABMS (m / z); 548 [M + l] +.

Process 2-2

 According to Step 3 of Example 29, a mixture of compound 176 free base and compound 177 free base (diastereomeric ratio 3: 2) 1.40 g (2.56 mmo 1) and 4N chloride From the filtrate obtained from 1.0 ml (4.0 mmo 1) of hydrogen ZAc OEt solution, 0.476 g (34%) of compound 177 (diastereomer ratio 0: 1) was obtained. .

 Ή NMR (DMS0-db) δ; 1.16 (d, 3H, J = 6.3 Hz), 2.51 (s, 6H), 3.00 (m, 1H), 3.01 (s, 3H), 3.20 (m, 1H) , 3.97 (s, 3H), 4.90 (m, 1H), 4.96 (d, 111, J = 2.2Hz), 5.07 (d, 1H, J = 2.2Hz), 6.92 (d, 1H, J = 8.9Hz) , 6.96 (d.IH, J = 8.9 Hz), 7.17 Cm, 5H), 7.37 (m, 1H), 7.42 (t, 1H, J = 8.9 Hz), 7.65 (t, 1H, J = 7. 6Hz), 7.74 (m, 1H). 7.76 (s, 1H), 8.92 (d, 1H, J = 8.2Hz), 10.00 (br s, 1H).

 FABMS (m / z); 548 [M + l] +.

 Example 17 Compound 17

 According to Example 30, Compound 17 2, 4.00 g (7.30 mmo 1) and 10% Pd / C (50 wt%), 1.50 g 178 (diastereomer ratio 3: 2) and 3.33 g (quantitative) were obtained.

52 Primary diastereomer:

Ή NMR (CDC1 ₃ ) 6; 1.25 (d, 3H, J = 6.6 Hz), 3.14 (s.3H), 3.54 (s, 3H), 3.87 (s.3H), 4.70 (m, 1H), 5.55 (s, 1H), 6.57 (d, 1H.8.3Hz), 6.77 (d, 1H, J-8.3Hz), 7.20 ― 7.41 (m, 3H), 7.54 (s, 1H), 7.55 (m, 1H ), 8.97 (d, 1H, J = 7.9Hz).

 FABMS (m / z); 459 [M + l] +.

Example 17 1 Compound 1 79

 According to Example 20, Compound 18 (3.06 g (6.59 mmol)) and D DQ 3.06 g (13.2 mmol) were used to obtain Compound 179 (diastereomer ratio).

2: 1), 2.79 g (92%) were obtained.

Main stereo stereo:

 Ή NMR (CDC) δ; 1.33 (d, 3H, J = 6.9Hz), 3.20 (s.3H), 3.75 (s, 3H). 3.94 (s, 3H), 4.78 (q, 1H, J = 6.9Hz), 6.67 (d, 1H, J = 8.3Hz), 6.89 (t, 1H, J = 8.3Hz), 7.34 (dt, 1H,] = 6.4, 8.3Hz), 7.40 (1, 1H, J = 8.1Hz), 7.47 (d.1H, J = 8.1Hz), 7.76 (s, 1H), 7.63 (t, 1H, 8.1Hz), 9.11 (d, 1H, J = 8.1Hz).

EIMS (m I z); 460 [M] ⁺ .

Example 1 72 Compound 180

 According to Step 1 of Example 49, Compound 1 79, 2.69 g (5.84 mmo 1) and 2N hydrochloric acid 45 m 1 (90.Ommo 1) were used to obtain Compound 1 80 (diastereomer ratio 3: 2). ), 2.85 g (quantitative).

Main stereo stereo:

Ή NMR (DMS0-d ₆ ) δ; 1.27 (d, 3H, J = 6.6 Hz), 3.08 (s.3H), 3.97 (s.3H), 4.86 (q, 1H, J = 6.6 Hz), 6.89 ( dd, 1H, J = 8.7, 15.6Hz), 6.95 (d, 1H, J = 8.7 Hz), 7.39 (t, 1H.7.5Hz), 7.46 (dt, 1H, J = 2.3, 8.7Hz), 7.66 ( dt, 1H, J = 1.0, 7.5Hz), 7.74 (d, 1H, J = 7.5Hz), 8.05 (s, 1H). 8.96 (d, 1H, J = 7.5Hz).

 FABMS (m / z); 447 [M + l] +.

Example 1 7 3 Compound 181

Compound 180, 2.64 g (5.91 mmo 1), 1.71 ml (1.79 mmo 1) of borane 'methyl sulfide complex gave 2.18 g (83%) of compound 181 (diastereomeric ratio 3: 2).

Primary diastereomer:

 Ή NMR (CDC) δ; 1.12 (d, 3H, J = 5.4Hz), 2.46 (br s, 1H), 3.19 (s, 3H), 3.42 (m, 1H), 3.63 (m, 1H), 3.91 (s, 1H), 4.43 ― 4.49 (m, 1H). 6.86 (dd, 1H, J = 8.4, 17.3Hz), 6.90 (d, 1H, J = 8.4Hz), 7.37 (m, 1H), 7.41 (t, 1H, J = 7.8Hz), 7.47 (d, 1H, J = 7.8Hz), 7.55 (s, 1H), 7.64 (dt, 1H, J = l.0, 7.8Hz), 9.11 (d , 1H, J = 7.8Hz).

 EIMS (m / z); 432 [M] +.

Example 1 7 4 Compound 1 8 2

 According to Example 118, compound 181, 2.04 g (4.73 mmo1), pyridine 3.1 ml (38. 3 mmo1) and p-toluenesulfonyl chloride 5. From 18 g (27.2 mmo 1), compound 18 2 (diastereomer ratio 3:

2), 2.52 g (91%) were obtained.

Main stereo stereo:

 Ή NMR (CDC) δ; 1.11 (d. 3H, J = 6.4Hz), 2.31 (s, 3H), 3.17 (s, 3H), 3.85 (dd, 1H, J = 6.4, 10.9Hz), 3.97 (m, 1H), 3.94 (s, 3H), 4.56 (m, 1H), 6.76 (dd, 1H, J = 8.2, 11.8Hz), 7.08 (d, 1H.J = 8.2Hz), 7.42 ( m.1H), 7.50 (t, 1H, 7.9Hz), 7.53 (d, 1H, J = 7.9Hz), 7.60 (s, 111), 7.65 (dt, 1H,) = 1.0, 7.9Hz), 9. 12 (d, 1H, J = 7.9Hz).

EIMS (m / z); 586 [M] ⁺ .

Example 17 5 Compound 18 3 and Compound 18 4

 Process 1

 According to Example 53, Compound 183, free base of Compound 183 from 65,5 mg (1.12 mmo 1) and 50% aqueous dimethylamine solution 10.Om 〖(0.1 Lmol) And 38 lmg (74%) of a mixture of compound 184 free base were obtained. Process 2

 According to Step 3 of Example 2-9, a mixture of compound 1883 free base and compound 184 free base 20.7 mg (0.45 mmo 1) and 4N hydrogen chloride ZA c〇E

54 t Hydrochloride from 0.24 ml (0.96 mmo 1) of the solution and obtain 102 mg (46%) of compound 183 (diastereomer ratio 1: 0) from the precipitate, and compound 1 from the filtrate 84 mg (0: 1 ratio of diastereomer) and 108 mg (49%) were obtained.

Compound 1 8 3

'Η thigh (DMS0-d ₆ ) 6; 1.08 (d, 3H.J = 5.9Hz), 2.52 (s, 3H), 2.57 (s, 3H), 3.01 ― 3.14 (m.2H), 3.07 ( s, 3H), 3.99 (s, 3H), 5.02 (m, 1H), 6.98 (t, 1H, J = 8.5Hz), 7.14 (d, 1H, J = 8.5Hz), 7.40 (dt, 1H , J = l.3, 7.4Hz), 7.50 (dd, 1H, J = 8.0, 15.3Hz), 7.68 (dt, 1H, J = l.3, 7.4Hz), 7.75 (d, 1H, J-7.4 Hz), 8.00 (s, 1H), 8.96 (d, 1H, J-7.4Hz), 10.10 (br, 1H).

FABMS (m / z); 460 [M + l] ⁺ .

Compound 1 8 4

Ή NMR (DMS0-d _fc ) δ; 1.20 (d, 3H, J = 6.4 Hz), 2.52 (s, 6H), 3.01-3.15 (m, 2H), 3.06 (s, 3H), 4.00 (s , 311) .4, 97 (m, 1H), 6.99 (1, 1H.J = 8.5Hz), 7.17 (d, 1H.J = 8.5Hz), 7.40 (t, 1H, J = 7.8Hz) , 7.51 (dd, 1H.J = 8.5, 15.3 Hz), 7.68 (t, 1H, 7.8Hz), 7.76 (d, 1H, J-7.8Hz), 7.83 (s, 1H), 8.96 (d, 1H, J-7.8Hz), 10.02 (br, 1H).

FABMS (m / z); 460 [+ l] ⁺ .

Example 17 Compound 6

Process 1

 Example 5 According to step 3 of 1, 4- (2-acetoxoxyphenyl) —1,3-dioxo-1,2,6-dimethyl-1,2,3,6-tetrahydropyrro [3,4-c ] 3.0 g (7.5 1 mmo 1), titanium tetrachloride 4.30 ml

(39.22 mmo 1) and 1.78 ml (1.968 mmo 1) of dichloromethyl methyl ether give 4- (1-acetoxyphenyl) 1-1,3-dioxo 9-formyl There were obtained 2.45 g (76%) of 1,2,6-dimethyl-1,2'3,6-tetrahydropyro [3,4-c] potassium.

 FABMS (m / z); 427 [M + l] +.

Process 2

According to Step 6 of Example 37, 4- (2-acetoxyphenyl) -1,3-diene Oxo-9-1-formyl-2,6-dimethyl-1,2,3,6-tetratetrahydropyro [3,4-c] potassium rivazol 2.45 g (5.75 mm o 1) and carbonic acid From 0.95 g (6.87 mmo 1) of potassium, 1,3-dioxo-9-formyl-4-1 (2-hydroxyphenyl) -1,2,6-dimethyl-1,2,3,6 —Tetra hydropyro [3,4—c] -caproluvazole 2.0 g (91%) was obtained.

 Ή NMR (DMSO-dfc) δ; 3.08 (s, 3H), 4.03 (s, 3H), 6.91 (dt, 1H. J = l.0, 7.5Hz), 6.95 (dd, 1H, J = l. 7.27 (ddd, 1H, Jl. 7, 7.5, 8.1 Hz), 7.29 (dt, 1H.Jl. 7.7.5Hz), 7.88 (s, 1H), 7.90 (d , 1H, J = 8.6Hz), 8.16 (dd, 1H, J = l.6, 8.6Hz), 9.45 (d, 1H, J = l.6Hz), 10.14 (s, 1H).

 FAB S (m / z); 385 [M + l] +.

Process 3

 According to Step 6 of Example 3, 1,3-dioxo 9 _formyl-14- (2-hydroxyphenyl) -12,6-dimethyl-1,2,3,6-tetrahydropyrro [3,4- c] 1.67 g (4.33 mmo 1) of sorbazole, 1.25 g (8.68 mmo 1) of 2-dimethylaminoethyl chloride hydrochloride and 2.42 g (17. From 4 8 mmo 1), 4- [2- (2-dimethylaminoethoxy) phenyl] — 1,3-dioxo—9-formyl-1,2,6-dimethyl—1,2,3,6-tetrahydropyrole [3,4-c] 0.55 g (25%) of rubazole was obtained.

 Ή NMR (CDC) δ; 2.13 (s. 6H), 2.48 (t, 2H, J-6. OHz), 3.21 (s, 3H), 3.97 (s, 3H), 4.08 (t, 2H) ,] = 6.OHz), 7.04 (dd, 1H, J = 0.9, 8.3Hz), 7.10 (dt, 1H, J = 0.9, 7.6Hz), 7.37 (dd, 1H, J = l.7, 7.6Hz ), 7.45 (ddd.III.J = l.7, 7.6, 8.3Hz), 7.56 (d, 1H, J = 8.7Hz), 7.59 (s, 1H), 8.23 (dd, 1H, 1.5, 8.7) Hz), 9.58 (d, 1H, J = l.5Hz), 10.22 (s.1H).

FABMS (m / z); 456 [M + l] ⁺ .

Process 4

Example 61 According to 1, 4- [2- (2-dimethylaminoethoxy) phenyl] 1-1,3-dioxo-9-formyl-12,6-dimethyl_1,2,3,6-tetrahydropyro Mouth [3,4-c] sorbazole 6 Omg (0.3 mmo 1), g From 0.013 ml (0.33 mmo 1) of triethylsilane and 0.5 ml of trifluoroacetic acid, 35 mg (60%) of a compound 185 free base were obtained.

Process 5

 Example 2 In accordance with Step 2 of 1, compound 18 5 free base 33 mg (0.07 mmo 1) and 4N hydrogen chloride ZA c OEt solution 0.05 ml (0.2 Ommo 1 )) To obtain Compounds 1885 and 32 mg (89%).

Ή NMR (DMS0-d ₆ ) δ; 2.25 (s, 6H) .3.06 (s, 3H), 3.25 (m, 2H), 3.95 (s.3H), 4.31 (m, 2H), 7.12 (t, 1H , J = 7.3Hz), 7.19 (d, 1H, J: 8.3Hz), 7.39 (dd, 1H,] = 1.7, 7.3Hz), 7.48 (m, 2H), 7.65 (d, 1H, J = 8.6Hz) ), 7.80 (s, 1H), 8.77 (s, 1H), 9.93 (s.1H).

 FABMS (m / z); 442 [M + l] +.

Example 17 Compound 7

 According to Example 93, 4- [2- (2-dimethylaminoethoxy) phenyl] 1-1,3-dioxo-91-formyl-1,2,6-dimethyl-1,2,3,6-tetrahydropyro [ 3, 4-c] Compound 1 86, 32 mg (62%) from 51 mg (0.11 mm o 〖) of phorbazole and 4 mg (0.1 l mmo 1) of sodium borohydride I got

 Ή NMR (CDC) δ; 2.12 (s, 6H), 2.48 (t, 2H. J = 6. OHz). 3.18 (s, 3H), 3.91 (s, 3H), 4.08 (t, 2H) , J = 6.OHz), 4.93 (s, 2H), 7.02 (d, 1H, 1 = 8.5Hz), 7.10 (t, 1H, J = 7.5Hz), 7.37 (dd, 1H, J = l .7, 7.5Hz), 7.43 (ddd, 1H, J = l.7, 7.5, 8.5Hz), 7.46 (d, 1H, J = 8.4Hz), 7.50 (s, 1H), 7.69 (dd, 1H, J = l.5.8.4Hz), 9.07 (s, 1H).

FABMS (m / z); 458 [M + l] ⁺ .

Example 1 7 8 Compound 1 8 7

Process 1

 According to Step 2 of Example 27, 4- [2- (2-dimethylaminoethoxy) phenyl] 1-1,3-dioxo-9-formyl-1,2,6-dimethyl-1,2,3,6 —Tetrahydropyro mouth [3,4-c] 90 mg (0.23 mmo 1) of potassium hydroxide, 50% aqueous dimethylamine solution 0.8 ml (8.88 mmol) and shear

57 From 0.28 g (4.42 mmo 1) of sodium borohydride, 39 mg (37%) of a compound 1887 free base was obtained.

Process 2

 Example 2 In accordance with Step 2 of 1, Compound 18 87 free base 37 mg (0.08 mmo 1) and 4N hydrogen chloride / AcOEt solution 0.08 ml (0.3 2 mmo 1 ), The compound 187, 4 Omg (94%) was obtained.

Ή NMR (DMS0-d ₆ ) δ; 2.56 (s, 6H), 2.78 (s, 6H), 3.07 (s, 3H). 3.27 (m, 2H), 4.02 (s, 3H), 4.34 (m, 2H ), 4.52 (d, 2H, J = 4.0Hz), 7.14 (t, 1H, J = 7.6Hz), 7.20 (d, 1H, 8.2Hz), 7.39 (dd, 1H.J = l.3, 7.6Hz), 7.49 (m, 1H), 7.88 (m, 2H), 7.91 (s, 1H), 9.04 (s, 1H), 10.31 (br s, 1H).

 FAB S (m / z); 485 [M + l] +.

Example 1-9 Compound 1 8 8

 According to Step 1 of Example 1, 4- [2- (2-dimethylaminoethoxy) phenyl] —1,3-dioxo-9-formyl-1,2,6-dimethyl-1,2,3,6 -Tetrahydropyro mouth [3, 4-c] Rivazole 2 Omg (0.04 mmo 1), potassium carbonate 9 mg (0.1 Ommo 1), tribenzylphosphonium chloride (benzyl) 17 mg (0. 0 6mmo 1) and 18-crown-6, 2 mg (0.01 mmo 1), compound 18 8 (E: Z = 1.4: 1), 19 mg

(82%).

 E body:

 * H NMR (CDCh) δ; 2.12 (s, 6H), 2.47 (t, 2H. J = 5.9 Hz), 3.16 (s, 3H), 3.83 (s, 3H), 4.07 (t, 2H, J -5.9Hz), 6.64 (d, 1H, J = 12.1Hz), 6.88 (d, 1H, J = 12.1Hz), 7.00-7.62 (m, 12H), 9.00 (d, 1H, J = 0.7Hz).

 FABMS (m / z); 530 [M + l] +.

 Example 18 0 Compound 18 9

According to Example 28, 4- [2- (2-dimethylaminoethoxy) phenyl] -1, 3-dioxo-9-formyl-12,6-dimethyl-1,2,3,6-tetrahydropyro [ 3, 4-c] potassium hydroxide 7 Omg (0.15 mmo 1), 1.64 M n-butyllithium / n-hexane solution 0.1 ml (0.16 mmo 1) and (n-butyl) triphenylphosphonium bromide (62 mg, 0.16mmo1), compound 1889 (E: Z = 1.6: 1), 31 mg (42 ) Was obtained.

 FABMS (m / z); 496 [M + 1] +.

Example 18 1 Compound 19

Process 1

 According to Step 2 of Example 59, 4- (2-acetoxyphenyl) —1,3-dioxo-1,2,6-dimethyl-1,2,3,6-tetrahydropyrro [3,4-c ] From 50 Omg (1.26 mmo 1) of olevazole, 836 mg (6.27 mmo I) of aluminum chloride and 0.45 m 〖(6.27 mmo 1) of acetyl chloride, 4 (2 —Acetoxyphenyl) 1 9-Acetyl-1,3-dioxo-2,6-dimethyl-1,2,3,6-tetrahydropyro [3,4-c] carbazol 37 2 mg (67%) was obtained. .

 ^ NMR (CDC) δ; 1.91 (s, 3H), 2.84 (s, 3H), 3.23 (s, 3H), 3.95 (s, 3H), 7.26 (dd, 1H, 1 = 1.2, 8.1Hz) ' 7.40 (dt, 1H,] = 1.2, 7.6Hz), 7.46 (dd, 1H, 1.7, 7.6Hz) .7.52, (s, 1H), 7.53 (m, 2H), 8.35 (dd, 1H, J = l .5, 8.7 Hz), 9.77 (d, 1H, 1.5Hz).

 FABMS (m / z); 441 [M + l] * ·

Process 2

 According to Step 6 of Example 37, 4- (2-acetoxyphenyl) -19-acetyl-1,3-dioxo-2,6-dimethyl-1,2,3,6-tetrahydropyro mouth [3, 4-c] 9-Acetyl-1,3, -dioxo 4-(2—) from 37.2 mg (0.84 mmo 1) of potassium rubazole and 140 mg (1.01 mmo 1) of carbonated lime. Hydroxyphenyl) 1,2,6-dimethyl-1,2,3,6-tetrahydropyrro [3,4-c] potassium rubazole was obtained in an amount of 337 mg (100%).

 , H NMR (DMSO-di) δ; 2.72 (s, 3H), 3.08 (s, 3H), 4.01 (s, 3H). 6.91 (t,

1H, J = 7.3Hz), 6.94 (d, 1H, J = 8.3Hz), 7.28 (m, 2H), 7.81 (d, 1H, J = 8.8Hz), 7.85 (s, 1H) .8.24 (dd , 1H, J = l.7, 8.8Hz), 9.44 (s, 1H), 9.60 (d, 1H,

J = l.7Hz). FABMS (m / z); 399 [M + l] +.

Process 3

 According to step 6 of Example 3, 9-acetyl-1,3-dioxo-41- (2-hydroxyphenyl) -1,2,6-dimethyl-1,2,3,6-tetratetrahydropyro [3,4- c] 16 L Omgolazole (0.40 mmo 1), 2-dimethylaminoethyl hydrochloride 1 I 6 mg (0.81 mmo 1) and potassium carbonate 2.22 mg (1.61 mmo 1) ), 9-acetyl-4- [2- (2-dimethylaminoethoxy) phenyl] -1,1,3-dioxo-1,6-dimethyl-1,2,3,6-tetrahydropyro [3,41-c] force 98 mg (52%) of lubazol were obtained.

'Η NMR (CDC) δ; 2.12 (s, 6H), 2.48 (t, 2H, J = 5.9Hz) _? 2.84 (s, 3H), 3.21 (s, 3H). 3.95 (s, 3H) ), 4.08 (t, 2H, J = 5.9Hz), 7.03 (d, 1H, J = 8.2Hz), 7.01 (dt, 1H, J = l.0, 7.5Hz), 7.37 (dd, 1H, J = l.7, 7.6Hz), 7.44 (ddd, 1H.J = 1.7, 7.3, 8.2Hz), 7.50 (d, 1H, J = 8.6Hz), 7.57 (s, 1H), 8.34 (dd, 1H, 1 = 1.5, 8.6Hz), 9.77 (d.1H, J = l.5Hz).

 FABMS (m / z); 470 [M + l] +.

Process 4

 Example 61 According to 1, 9-acetyl-41- [2- (2-dimethylaminoethoxy) phenyl] —1,3-dioxo-2,6-dimethyl-1,1,2,3,6-tetrahydropyro [ 3, 4-c] Potassium 6 Omg (0.13 mmo 1), triethylsilane 0.05 ml (0.32 mmo 1) and trifluoroacetic acid 0.5 ml, compound 190, 52 mg ( 89%).

 Ή NMR (CDC) (5; 1.39 (t, 3H, J = 7.8Hz), 2.11 (s, 6H), 2.47 (t, 2H, J = 6.0Hz), 2.91 (q, 2H, J = 7.8) Hz), 3.19 (s, 3H), 3.88 (s, 3H), 4.07 (t, 2H, J = 6.0Hz), 7.02 (d, 1H, J = 8.3Hz), 7.08 (t, 1H, 7.6 Hz), 7.37 (dd, 1H, J = 1.6, 7.6Hz), 7.38 (d, 1H, J = 8.5Hz), 7.42 (ddd, 1H, J = l.6, 7.6, 8.3Hz), 7.47 (s, 1H), 7.48 (dd, 1H, J = l.3, 8.5Hz), 8.95 (d, 1H, Jl.3Hz).

 FABMS (m / z); 456 [M + l] +.

 Example 18 Compound 2 9 1

4- (2-acetoxyphenyl) 1-1,3-dioxo 9-formyl 1-2,6 One dimethyl 1, 2, 3, 6-tetrahydrophthalic pyromellitic port [3, 4 - c] force Rubazo Ichiru 5. 9 5 g (1 3. 9 5mmo 1) the DMS_〇, 6 0 0 m 1 and CHC 1 ₃ Dissolved in 300 ml of the mixed solvent and dissolved in 2.14 g (13.72 mmo 1) of sodium dihydrogen phosphate dihydrate dissolved in 20 Om 1 of water and 15 Om 1 of water 5.04 g (55.73 mmo 1) of the dissolved sodium chlorite was added, and the mixture was stirred at room temperature for 1 hour. DMS O, 3 0 Om 1 and CHC 1 ₃ 1 5 0 m l and the mixture was stirred for 1 0 hours at the same temperature, water was added to the reaction solution, and extracted with CHC 1 _3, 1 0% hydrate port Sarufuai preparative sodium After washing with an aqueous solution and then brine, the extract was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was triturated with a mixed solvent of CHC 13 and MeOH to obtain Compound 191, 2.0 g (32).

 Ή NMR (CDCla) <5; 1.89 (s, 3H), 3.08 (s, 3H), 4.01 (s, 3H), 7.31 (d, 1 H, J = 8.1 Hz), 7.40 (d, 1H, 7.6 Hz), 7.54 (m, 211), 7.79 (s, 1H), 7.82 (d,

1H, J = 8.8Hz), 8.24 (dd, 1H,] = 1.7, 8.8Hz), 9.63 (d, 1H, J = l.7Hz), 12.79

(br, 1H).

 FABMS (m / z); 443 [M + l] +.

Example 18 3 Compound 19 2

 According to Example 105, compounds 191, 20 Omg (0.45 mmo 1) and 2. OM (trimethylsilyl) diazomethane-hexane solution 0.3 ml (0.6 Ommo 1) Thus, Compounds 192 and 182 mg (88%) were obtained.

 Ή NMR (CDC) δ; 1.91 (s, 3H), 3.22 (s, 3H), 3.93 (s, 3H), 4.03 (s, 3H), 7.26 (dd, 1H, J = l.0, 8. 1Hz), 7.39 (dt, 1H, J = l.0, 7.5Hz), 7.46 (dd, 1H, Jl.3, 7.5Hz), 7.50 (s.1H), 7.50 (d, 1H, J-8.5Hz) ), 7.52 (ddd, 1H, I = 1.3, 7.5, 8.1 Hz), 8.36 (dd, 1H, J = l.7, 8.5Hz), 9.78 (dd, 1H, J = l.7Hz).

FABMS (m / z); 457 [M + l] ⁺ .

Example 1 84 Compound 1 9 3

 According to Step 6 of Example 37, Compounds 19, 18 1 mg (0.40 mmo 1) and 66 mg of potassium carbonate (0.49 mmo 1) were used to obtain Compounds 193, 1 7 Omg (quantitative) was obtained.

_{Ή NMR (CDC1 3) 6;} . 3.07 (. S 3H), 3.94 (s, 3H), 4.01 (s, 3H) 6.91 (dt, 1H, J = l.2, 7.5Hz), 6.94 (d, III, J = 8.6Hz), 7.27 (m, 1H), 7.83 (d, 1H, J = 8.6Hz). 7.86 (s, 1H) , 8.23 (dd, 1H, J = l.6.8.6Hz), 9.43 (s, 1H), 9.63 (d, 1H, 1.6Hz).

FAB S (m / z); 415 [M + l] ⁺ .

Example 18 5 Compound 1 94

 According to Step 6 of Example 3, compound 93, 10 Omg (0.24 mmo 1) .2-dimethylaminoethyl chloride hydrochloride 7 Omg (0.49 mmo 1) and potassium carbonate 133 mg From 0.96 mmo 1, 73 mg (63%) of compound 194 was obtained.

 Ή NMR (CDC) δ; 2.12 (s, 6H), 2.48 (t, 2H, J = 6. OHz), 3.21 (s, 3H), 3.94 (s, 3H), 4.02 (s, 3H), 4.08 (t, 2H, J = 6.0Hz), 7.03 (d, 111, J = 8.1Hz),

7.09 (d, 1H, 7.6Hz). 7.36 (dd, 1H,] = 1.7, 7.6Hz), 7.44 (ddd, 1H, J = l. 7.7.6, 8.1Hz), 7.49 (d, 1H, J) = 8.8Hz), 7.55 (s, 1H), 8.35 (dd, 1H, J = l.7,

8.8Hz), 9.79 (d, 1H, 1.7Hz).

 FABMS (m / z); 486 [M + l] +.

Example 18 6 Compound 19 5

 Example 61 According to 1, 4- (2-acetoxyphenyl) —1,3-dioxo 9-formyl-1,2,6-dimethyl-1,2,3,6-tetrahydropyro [3,

4-1 c] Compound 1 95, 1 from potassium hydroxide 2 Omg (0.05 mmol), triethylsilane 0.02 m1 (0.12 mmo1) and trifluoroacetic acid 0.3 rn1 6 mg (83%) were obtained.

 Ή NMR (CDC) δ; 1.89 (s, 3H), 2.61 (s, 3H), 3.20 (s, 3H), 3.89 (s.3H), 7.20-7.58 (m, 7H), 8.90 (s, 1H ).

 FABMS (m / z); 413 [M + l].

 Example 18 7 Compound 19 6

 According to Step 6 of Example 37, from compound 1995, 8.53 g (20.70 mmo 1) and 2.59 g (18.77 mmol) of potassium carbonate , Compound 1 96,

5.88 g (77) were obtained.

 Ή NMR (CDC) δ; 2.60 (s, 3H), 3.19 (s, 3H), 3.87 (s, 3H), 5.49 (s, 1

62 H), 7.08 (d, 1H, J = 7.6Hz) _t 7.11 (m, 1H), 7.22-7.50 (m.4H), 7.48 (s, 1H), 8.85 (s, 1H).

 FABMS (m / z); 371 [M + l] +.

Example 18 8 Compound 19 7 and Compound 19 8

Process 1

 According to step 6 of Example 3, compound 196, 2.0 g (5.41 mmol), 2-dimethylaminoisopropyl hydrochloride 2.56 g (1.24 mmo1) And 3.73 g (27.3 mmo 1) of potassium carbonate gave 45 g (18) of compound 197 free base and 0.97 g (39%) of compound 198 free base Was.

Process 2-1

 Example 2 According to step 2 of 1, compound 1997 free base 0.30 g (0.66 mmoI) and 4N hydrogen chloride ZA c OEt solution 0.25 ml (1.0 Ommo 1), Compound 1997, 0.32 g (quantitative) was obtained.

 * H NMR (D SO-dk) <5; 1.10 (d, 3H, J = 5.6 Hz) .2.54 (s, 3H), 2.57 (s, 6H), 3.05 (s.3H), 3.05 (m, 1H ), 3.10 (m, 1H), 3, 94 (s, 3H), 5.00 (m, 1H). 7.11 (t, 1H, J = 7.6Hz). 7.27 (d, 1H, J = 7.6) Hz), 7.39 (d, 1H, J = 7.6Hz), 7.47 (m, 1H), 7.48 (d, 1H, J = 8.6Hz), 7.64 (d, 1H, J = 8.6Hz), 7.77 (s, 1H), 8.7 6 (s, 1H), 10.15 (br s.1H).

 FABMS (m / z); 456 [M + l] +.

Process 2-2

 Example 2 According to Step 2 of 1, compound 1 98 free base 0.30 g (0.66 mmol) and 4N hydrogen chloride solution AcOEt solution 0.25 ml (1.0 From Ommo 1), compound 198 and 0.31 (quantitative) were obtained.

 Ή NMR (DMSO-dJ δ; 1.09 (d, 3H, 1 = 6.9Hz), 2.41 (s, 6H), 2.54 (s.3H), 3.05 (s.3H), 3.50 (m, 1H), 3.95 ( s, 3H), 4.20 (m, 2H), 7.13 (t, 1H, J = 7.6Hz), 7.19 (d, 1H,] = 8.3Hz), 7.41 (m, 1H), 7.43 (d, 1H , J-7.6Hz), 7.49 (d, 1H, J = 8.6Hz), 7.64 (d, 1H, J = 8.6Hz), 7.80 (s, 1H), 8.76 (s, 1H), 10.20 (br s, 1H).

63 FABMS (mIz); 456 [M + l] +.

Example 1 89 Compound 1 99

Process 1

 Dissolve 5.54 g (20.1 mmo 1) of 7-dibutoxymethylindole in 100 ml of THF, and add 13.6 ml of 1-6.3 M n-butyllithium Zn-hexane solution 22.2 mm0 1) was added, and the mixture was stirred at the same temperature for 20 minutes. Carbon dioxide gas was blown into the reaction solution for 50 minutes, and the solvent was distilled off under ice cooling. The residue was dissolved in 100 ml of THF, and 8.13 ml (22 mmo 1) of 2.13 M t-butyllithium non-pentane solution was added at 78X: and the mixture was stirred at the same temperature for 20 minutes. Thereafter, 8.10 l of DMF (lOOmmol) was added, and the mixture was stirred at room temperature for 15 minutes. Water was added to the reaction solution, and the mixture was extracted with ether. The organic layer was washed with water and then with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane / ^ AcOEt 15/1) to obtain 7-dibutoxymethyl-2-formylindole (2.11 g, 35%).

_{Ή NMR (CDC1 3) δ;} 0.92 (t, 6H, J = 7.3Hz), 1.37 - 1.46 (m, 4H), 1.59 - 1. 66 (m, 4H), 3.50 - 3.62 (m, 4H), 5.80 (s, 1H), 7.15 (dd, 1H, J = 7.3, 8.1H z), 7.24 (d, 1H, J = 2.2Hz), 7.38 (d, 1H, J = 7.3Hz). 7.70 (d, 1H) , J = 8.1Hz), 9.72 (br s, 1H), 9.85 (s, 1H).

 FABMS (m / z); 230 [M-73] +.

Process 2

 According to step 6 of Example 3, 7-dibutoxymethyl-2-formylindole 2.1 g (6.95 mmo 1), potassium t-butoxide 1.Olg (8.97 mmo 1 )) And 0.56 ml (9. Ommol) of methyl iodide, 1.48 g (67%) of 7-dibutoxymethyl_2-formyl-1-methylindole was obtained.

Ή NMR (CDC) 6; 0.88 (t, 6H, J-7.3Hz), 1.33 — 1.42 (m, 4H), 1.54-1.62 (m, 4H), 3.45-3.63 (m, 4H), 4.42 ( s, 3H), 5.88 (s, 1H), 7.12 (dd, 1 H, J = 7.2, 7.9Hz), 7.26 (s, 1H), 7.58 (br d, 1H, J = 7.2Hz), 7.69 (dd , 1H, J = l.2, 7.9Hz), 9.87 (s, 1H). FABMS (m / z); 318 [M + l] +.

Process 3

 According to Example 28, 1.48 g (4.66 mmol) of dibutoxymethyl-2-formyl-1-methylindole, (2-hydroxybenzyl) triphenylphosphonium bromide 2. From 64 g (5.87 mmo 1) and 1.63 ^ of 11-butyllithium-hexane solution 8.0 ml (13 mmol), 7-dibutoxymethyl-2- [2- [2-hydroxyphenyl Enyl) vinyl] —1-methylindole 2.10 g (quantitative) was obtained.

'Η thigh (D S0-d _t ) δ; 0.85 (t, 6H, 7.3Hz), 1.29-1.57 (m, 8H), 3.44-3.64 (m, 4H), 4.06 (s, 3H), 5.88 (s , 1H), 6.81-7.67 (m, 10H), 9.77 (s.1H).

FABMS (m / z); 407 [M] ⁺ .

Process 4

 According to Step 2 of Example 3, 7-dibutoxymethyl-2- [2- (2-hydroxyphenyl) vinyl] —1-methylindole, 2.08 g (4.66 mmo 1) 0.5-ml (5.6 mmo 1) of acetic anhydride, 9 mg (0.24 mmo 1) of DMAP 2 and pyridine to give 2- [2- (2-acetoxoxyphenyl) vinyl] 17-diene 2.20 g (quantitative) of butoxymethyl-1 monomethylindole was obtained.

NR NR (DMS0-d _t ) δ; 0.85 (t, 6H, J = 7.3 Hz), 1.29-1.57 (m, 8H), 2.39 (s, 3H), 3.34-3.64 (m, 4H), 4.08 (s , 3H), 5.89 (s, 1H), 6.95 (s, 1H), 6.97-7.53 (m.8H), 7.98 (dd, 1H, J = 2.1, 7.4Hz).

 FABMS (m / z); 449 [M] +.

Process 5

According to Step 2 of Example 1, 2- [2- (2-acetoxyphenyl) bier] -17-dibutoxymethyl-1-methylindole 2.07 g (4.66 mmo 1) and N —Methylmaleimide 2. From 16 g (19.4 mmo 1), 4-1- (2-acetoxyphenyl) -1 7-dibutoxymethyl—1,3, -dioxo-2,6-dimethyl-1-1,2,3 , 3a, 4,5,6,10c -Okuyu hydropyro mouth [3, 4-c] 1.10 g (42%) of carbazole was obtained.

FABMS (m I z); 560 [M] ⁺ .

Process 6

 4-1- (2-acetoxyphenyl) -17-dibutoxymethyl-1,3-dioxo-1,2,6-dimethyl-1,2,3,3a, 4,5,6,10c Hydropyrrolo [3,4-c] sorbazole 2 16 mg (0.385 mmo 1) was dissolved in 10 ml of methylene chloride, and 90 mg (0.836 mmo 1) of DDQ was added. Stirred for hours. The resulting precipitate was filtered, and the filtrate was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was dissolved in 10 ml of THF, 2 ml of 1N hydrochloric acid was added, and the mixture was stirred at room temperature for 20 minutes. Water was added to the reaction solution, extracted with methylene chloride, dried over anhydrous magnesium sulfate, the solvent was distilled off, and 4- (2-acetoxyphenyl) -1,1,3-dioxo-7-formyl-1,2,6-dimethyl- 1,66 mg (quantitative) of 1,2,3,6-tetrahydropyrro [3,4-c] carbazole was obtained.

 Ή NMR (CDC) δ; 1.91 (s, 3H), 3.21 (s, 3H), 4.22 (s, 3H), 7.26 (dd, 1H. J = l.2, 8.1Hz), 7.40 (dt, 1H, J = l.2, 7.6Hz), 7.46 (dd, 1H, J = l.8, 7.6Hz), 7.53 (ddd, 1H, J = l.8, 7.6, 8.1Hz), 7.54 (t, 1H, J = 7.7Hz) .7.58 (s, 1H), 8.08 (dd, 1H, J = l.2, 7.7Hz), 9.51 (dd, 1H, 1 = 1.2, 7.7Hz), 10.36 (s, 1H).

 FABMS (m / z); 427 [MH] +.

Process 7

According to Step 6 of Example 37, 4- (2-acetoxyphenyl) —1,3-dioxo_7-formyl-1,2,6-dimethyl-1,2,3,6-tetrahydropyrrolate [ [3, 4—c] De-acetyl derivative was obtained from lovazole 15 1 mg (0.354 mmo 1) and potassium carbonate 44 mg (0.32 mmo 1). Then, according to Step 6 of Example 3, the deacetylated product was reacted with 66 mg (0.46 mmo I) of 2-dimethylaminoethyl chloride hydrochloride and 185 mg (1.34 mmo 1) of potassium carbonate, to obtain 4- [2- (2-Dimethylaminoethoxy) phenyl] 1,1,3-dioxo 7-formyl-2,6-dimethyl-1,2,3,6 15.6 mg (96%) of 1-tetrahydropyrro [3,4-c] potassazole was obtained.

Ή NMR (CDC) δ; 2.13 (s, 6H), 2.49 (t, 2H, J = 5.9Hz), 3.19 (s.3H), 4.08 (t, 2H, 5.9Hz), 4.23 (s , 3H) .7.04 (br d, III, J = 8.3Hz), 7.10 (dt, 1H, J = l.0, 7.5Hz), 7.37 (dd, 1H, J = l.7.7.5Hz ), 7.44 (ddd, 1H. J = l.7 ₍ 7.5, 8.3Hz), 7.52 (t, 1H, J = 7.7Hz), 7.63 (s, 1H), 8.06 (dd, 1H, J = l.2) , 7.7H z), 9.51 (dd, 1H, J = l.2, 7.7Hz), 10.36 (s, 1H).

 FABMS (m / z); 456 [M + l] +.

Process 8

 Example 27 According to step 2 of 7, 4- [2- (2-dimethylaminoethoxy) phenyl] -1,3-dioxo-7-formyl-1,2,6-dimethyl-1,2,3,6-tetrahydro Pyro Mouth [3,4-c] Potassium 47 mg (0.1 l Ommo 1), 50% aqueous dimethylamine solution 0.15 ml (1.7 mmol) and sodium cyanoborohydride 35 mg ( From 0.55 mmo 1), 27 mg (54%) of compound 199 free base was obtained.

Process 9

 Example 2 According to Step 2 of 1, compound 19 9 free base 25 mg (0.05 2m 1110 1) and 0.88 N hydrogen chloride / AcOEt solution 0.2 4 ml ( From 0.21 mmo 1), 31 mg (quantitative) of compound 199 were obtained.

Ή NMR (DMS0-d ₆ ) δ; 2.56 (s, 6H), 2.85 (br s, 6H), 3.07 (s, 3H), 3.32 (br s, 2H), 4.29 (s, 3H). 4.35 (br s, 2H), 4.94 (m, 2H), 7.13 (dt, 1H, J = 0.8, 7.4Hz). 7.20 (br d, 1H, J = 8.1 Hz), 7.39 (dd, 1H, J = l.7, 7.4Hz). 7.4 5 — 7.50 (in, 2H), 7.79 (d, 1H, J = 7.4Hz), 7.99 (s, 1H), 9.22 (d, 1H, J = 7.7Hz), 10.37 (br s, 1H), 10.69 (br s, 1H).

 FABMS (m / z); 485 [M + l] +.

Example 19 Compound 90

Process 1

According to Example 93, 4- [2- (2-dimethylaminoethoxy) phenyl] -1,3-dioxo-7-formyl-1,2,6-dimethyl-1,2,3,6-tetrat From 77 mg (0.17 mmo 1) of lahydropyrro [3,4 -c] olevazole and 12 mg (0.19 mmo 1) of sodium borohydride, compound 200 free base 67 mg ( 8 8%).

Process 2

 Example 2 Compound 200 free base 34 mg (0.075 m 1110 1) and 0.88 N hydrogen chloride ZA c OEt solution 0.17 ml (0. Compounds (200, 31 mg, 82%) were obtained from 15 mmo 1).

 Ή NMR (DMSO-dft) δ; 2.55 (br s, 6H), 3.06 (s, 3H), 3.26 (br s, 2H), 4.28 (s, 3H), 4.32 (br s, 2H), 5.01 (d, 2H, J = 5.1Hz), 5.55 (t, 1H, J = 5.1Hz), 7.13 (dt, 1H, J = 0.6, 7.4Hz), 7.19 (br d, 1H, 8.2Hz) , 7.32 (t, 1H, J = 7.6Hz), 7.39 (dd, 1H, J = l.7, 7.4Hz), 7.47 (m, 1H), 7.56 (dd, 1H, J = l. 1, 7.6Hz ), 7.84 (s, 1H), 9.03 (dd, 1H, J = l. 1, 7.6Hz) .10.05 (br s, 1H).

Process 1

 According to Example 61 1, the compound 200 free base 47 mg (0.1 Ommo 1), triethylsilane 0.05 0 ml (0.3 1 mmo 1) and trifluoroacetic acid 1.Om l (13 mmo 1), 24 mg (53%) of the compound 201 free base was obtained.

Process 2

 Example 2 According to step 2 of 1, compound 201 free base 23 mg (0.05 1m 1110 1) and 0.88 normal hydrogen chloride / AcOEt solution 0.1 2 ml ( Compounds 21 and 21 mg (86%) were obtained from 0.11 mmo 1).

■ H NMR (DMS0-d _t ) δ; 2.56 (s, 6H), 2.90 (s, 3H), 3.05 (s, 3H), 3.30 (br s, 2H). 4.23 (s, 3H), 4.31 (br s, 2H), 7.13 (dt, 1H, J = 0.8, 7.5Hz), 7.19 (br d, 1H, J = 8.2Hz), 7.25 (t, 1H, J-7.6Hz), 7.38 (m , 2H), 7.47 (ddd, 1 H, J = l.7, 7.5, 8.2Hz), 7.82 (s, 1H), 8.92 (d, 1H, J-7.6Hz), 9.87 (br s, 1H).

 Example 19 Compound 2 02

Process 1 According to Step 2 of Example 27, 5.6 ml (57 mmo1) of benzaldehyde, 963 mg (11.1 mmo1) of 3-hydroxypyrrolidine and 3.50 g of sodium cyanoborohydride (55. 7 mmo 1) to obtain 1 -hydroxypyrrolidine, which is then treated with 4 N hydrogen chloride ZAcOEt solution 6.0 ml (24 mmo 1) to obtain 1 -benzyloxy 3- 1.59 g (67%) of hydroxypyrrolidine hydrochloride were obtained.

Ή NMR (DMS0-d ₆ ) δ; 1.87-2.27 (m, 2H), 2.93-3.47 (m, 3H), 4.38 (m, 3H), 5.50 On, 1H>, 7.43-7.61 (m, 5H), 11.00 (br, 1H).

FABMS (m / z); 178 [Mil] ⁺ .

Process 2

 According to Example 118, 1-benzyl-3-hydroxypyrrolidine hydrochloride 1.33 g (6.22 mmo 1), triethylamine 1.74 ml (12.5 mmo 1) and methanesulfonyl chloride 0.58 m From the l (7.5 mm o 1), methane sulfonate was obtained. Then, according to Step 6 of Example 3, the methanesulfonate was converted to 1,3-dioxo-4- (2-hydroxyphenyl) -1,2,6-dimethyl-1,2,3,6-tetrahydropyrrolate [3 , 4-c] by reacting 1.57 g (4.41 mmo 1) of potassium hydroxide and 3.00 g (21.7 mmo 1) of potassium carbonate with the compound 202, 935 mg (4 1%).

 Ή NMR (CDC) δ; 1.86 (m, 1H), 2.19 (m, 1H), 2.43-2.56 (m, 3H), 2.90 (dd, 1H, J = 6.3, 10.2Hz), 3.14 (s, 3H ), 3.25 (d, 1H, J = 12.9Hz), 3.57 (d,

1H, J = 12.9Hz), 3.89 (s, 3H), 4.80 (m, 1H), 6.88 (d, 1H, J = 8.6Hz), 7.05 — 7.45 On, 10H), 7.48 (s, 1H), 7.63 (ddd, 111, J = l.0, 7.3, 8.3Hz), 9.14 (br d, 1H. J = 7.9Hz),

FABMS (m / z); 516 [Mil] ⁺ .

Example 1 93 Compound 203

Process 1

According to Example 30, Compound 98 free base 398 mg (86) was obtained from Compound 202, 56 Omg (0.379 mmol) and 10% PdZC, 565 mg. Process 2

 Example 2 According to Step 2 of 1, from Compound 203 free base 140 mg (0.330 mmo 1) and 4 N hydrogen chloride / AcOEt solution 0.20 ml (0.80 mmo 1) Compound 203 was obtained in an amount of 125 mg (82%).

 Ή NMR (DMSO-dfc) 6; 2.05 (m, 2H), 2.88-3.46 (m, 4H) .3.08 (s, 3H), 4.00 (s, 3H), 5.07 (br s, 1H), 7.14 (m, 2H). 7.38-7.50 (m, 3H), 7.67 (dd, 1H, J = 7.3, 8.3Hz), 7.77 (d.1H, J = 8.3Hz), 7.82 (s, 1H) .8.88 ( br s, 2H), 8.97 (d, 1H, J-7.9Hz).

Example 1 94 Compound 204

Process 1

 According to Step 2 of Example 27, compound 203 free base 221 mg (0.519 mmol), a 37% aqueous formaldehyde solution 0.42 ml, and sodium cyanoborohydride 170 mg (2.71 mmol) gave Compound 204 free base (98 mg, 43%).

Process 2

 According to Step 2 of Example 2 1, from Compound 204 free base 97 mg (0.33 mmo 1) and 4N hydrogen chloride AcOEt solution 0.20 ml (0.80 mmo 1), 73 mg (69%) of compound 204 were obtained.

'Η NMR (DMS0-d ₆ ) δ; 2.00 (m, 2H), 2.56-3.56 (m, 4H), 2.71 (br s, 3H), 3.07 (s, 3H), 4.00 (s, 3H), 5.05 (br s, 1H), 7.09-7.17 (m, 2H), 7.38-7.49 (m, 3H), 7.67 (ddd.1H, J = l.1, 7.3, 8.3 Hz), 7.76 (d.1H, J = 8.3Hz), 7.83 (s, 1H), 8.96 (br d, 1H, 7.6Hz), 10.05 (br, 1H).

FABMS (m / z); 440 [M + l] ⁺ .

 Example 1 95 Compound 205 and Compound 208

 Process 1

 According to Step 2 of Example 27 7, benzaldehyde 4.4 m 1 (43 mmo 1) .prolinol 885 5 mg (8.75 mmo 1) and sodium cyanoborohydride 2.70 g (43.Ommo 1) As a result, 1.46 g (87%) of N-benzylprolinol was obtained.

70 _{Ή NMR (CDC1 3) δ;} 1.65 - 1.92 (rn, 4H), 2.28 (m, 1H), 2.80 (br s, 1H), 2.96 (m, 1H), 3.35 (d, 1H, J = 13. OHz ), 3.42 (dd, 1H, J = 2.1, 10.7Hz), 3.64 (dd, 1H, 3, 5, 10.7Hz), 3.96 (d, 1H, J = 13.OHz), 7.24-7.34 (m. 5H ). FABMS (m / z); 192 [M1 1] +.

Process 2

 According to Example 118, methanesulfonate was obtained from 1.18 g (5.10 mmo 1) of N-benzylprolinol and 0.48 ml of methanesulfonyl chloride (6.2 mmo 1). I got Then, according to Step 6 of Example 3, the methanesulfonate was converted to 1,3-dioxo-14- (2-hydroxyphenyl) -1,2,6-dimethyl-11,2,3,6-tetrahydropyrro Mouth [3,4-c] carbazol, 1.35 g (3.80 mmo 1) and potassium carbonate 2.65 g (1.2 mmo 1) react with compounds 205, 1. 01 g (50%) and compound 208, 58 Omg (29%) were obtained.

Compound 205

_{Ή NMR (CDC1 3) δ;} 1. 4 - 1.70 (m, 2H), 1.76 (m, 1H), 2.02 (m, 1H), 2.7 1 (m, 2H), 3.02 (m, 1H), 3.11 ( br s, 3H), 3.73 (br s, 5H), 3.93 (m, 2H), 6.96-7.19 (m, 7H), 7.28-7.47 (m, 5H), 7.62 (ddd, 1H, J = l.2 , 7.3, 8.3Hz), 9.09 (dd, 1H, J = l.2, 7.3Hz).

 FABMS (m / z); 530 [M † l] *.

Compound 208

_{Ή NMR (CDC1 3) δ:} 1.24 (m, 1H), 1.48 - 1.62 On, 2H), 1.91 - 2.00 (m, 3 H), 2.58 (m, 1H), 2.88 (m, 1H), 3.14 (s , 3H), 3.43 (s, 2H), 3.85 (s, 3H), 4.32 (m.1H), 7.02-7.09 (m, 2H), 7.16-7.47 (m, 9H), 7.55 (s, 1H), 7.63 (ddd, 1H, J = l.0, 7.3, 8.3Hz), 9.12 (dd, 1H, Jl.0, 7.9Hz).

 FABMS (m / z); 530 [MH] +.

Example 1 96 Compound 206

Process 1

 According to Example 30, Compound 205, 985 mg (1.86 mm 01) and 10% Pd / C, 972 mg, Compound 206 free base 608 mg (74%)

71 I got

Process 2

 Example 2 According to Step 2 of 1, from Compound 206 free base 1 76 mg (0.400 mmo I) and 4 N hydrogen chloride ZAc OEt solution 0.20 m 1 (0.80 mmo 1) 174 mg (91%) of compound 206 were obtained.

 Ή NMR (DMS0-d) δ; 1.9-1.95 (m, 4H), 2.89 (m, 2H), 3.00 (s, 3H), 3.63 (m, 1H), 3.93 (s, 3H), 4.11 On, 2H), 7.02 1 7.11 (m, 2H), 7.29 ― 7.43

(m, 3H), 7.59 (ddd, 1H, J = l.2, 6.9, 8.3Hz), 7.69 (d, 1H, J = 8.3Hz), 7.85

(s. 1H). 8.89 (br d, 1H, J-7.6Hz), 9.00 (br, 2H).

Example 1 97 Compound 20 7

Process 1

 According to Step 2 of Example 27, compound 204 free base 204 mg (0.464 mmol), a 37% aqueous formaldehyde solution 0.38 m1 and sodium cyanoborohydride 15 Omg (2.39 From mmo 1), 24 lmg (quantitative) of the compound 207 free base was obtained.

Process 2

 Example 2 According to Step 2 of 1, from Compound 207 free base 236 mg (0.464 mmo 1) and 4N hydrogen chloride ZA c OEt solution 0.25 ml (1.0 mmo 1), Compound 207 and 197 mg (87%) were obtained.

 Ή NMR (DMSO-dfc) δ; 1.53-2.42 (m, 711), 2.87 On, 1H), 3.07 (s, 3H), 3.29 (m, 1H), 3.52 (m.1H), 4.01 (s , 3H), 4.27 (m, 2H), 7.10-7.21 (m, 2H) .7.37 ― 7.51 (m, 3H), 7.66 (m, 1H), 7.75 (d, 1H.J = 8.3Hz), 7.94 (br s,

1H), 8.95 (d, 1H. J = 7.9Hz), 10.59 (br, 1H).

 Example 1 98 Compound 20 9

 Process 1

 According to Example 30, 398 mg (86%) of compound 209 free base was obtained from compound 208, 56 Omg (1.06 mmol) and 10% Pd / C, 565 mg.

Process 2 Example 2 According to Step 2 of 1, from Compound 209 free base 1 49 mg (0.340 mmo 1) and 4N hydrogen chloride ZAc OEt solution 0.17 ml (0.68 mmo 1), Compound 209, 141 mg (87%) was obtained.

 Ή NMR (DMSO-dJ δ; 1.39-1.92 (m, 4H), 2.74 (m, 2H), 2.93 (m, 1H), 3.00 (s.3H), 3.19 (m.1H), 3.92 (s , 3H), 4.50 (i, 1H), 7.06 (t, 1H, J = 7.3 Hz), 7.16 (d, 1H, J = 8.3 Hz), 7.29-7.42 (m.3H), 7.59 (ddd, 1H, J = l.1.7.3, 8.3Hz), 7.68 (d, 1H, J = 8.3Hz), 7.78 (s, 1H), 8.53 (br s, 1H), 8.88 (brd, 1H, 7.9Hz) , 8.98 (br s, 1H).

Example 1 99 Compound 2 10

Process 1

 According to Step 2 of Example 27, compound 209 free base 1 93 mg (0.439 mmo 1), 37% formaldehyde aqueous solution 0.36 m1 and sodium cyanoborohydride 274 mg (4.37 From mmo 1), 2210 mg (quantitative) of the compound 210 free base was obtained.

Process 2

 Example 2 According to step 2 of 1, compound 210 free base 222 mg (0.439 mmo 1) and 4N hydrogen chloride / AcOEt solution 0.22 ml (0.88 mmo 1) As a result, compounds 210 and 182 mg (84%) were obtained.

 Ή NMR (DMS0-de) δ; 1.20-2.04 (m, 4H), 2.61-2.77 (m, 2H), 2.67 (br s, 3H), 3.07 (s, 3H), 3.21 (m, 1H), 3.48 (m, 1H), 3.99 (s, 3H), 4.65 On, 1H), 7.12 (t, 1H, 7.3Hz), 7.25 (d, 1H, J = 8.6Hz), 7.37 — 7.49 (m, 3H),

7.66 (ddd.1H, J = l.0, 7.3, 8.3Hz), 7.76 (d, 1H, J = 8.3Hz), 7.81 (s.1H),

8.95 (br d, 1H, J = 8.3Hz), 10.56 (br s, 1H).

Example 200 00 Compound 211, Compound 212 and Compound 211

Process 1

According to Step 6 of Example 3, 1,3-dioxo-4- (2-hydroxyphenyl) -1,2,6-dimethyl-1,2,3,6-tetrahydropyrro [3,4-c] 36 mg (0.1 mmol), 2-dimethylaminopropyl propyl hydrochloride 38 mg (0.24 mmo 1) and potassium carbonate 72 mg (0.5 mm) From 2 mmo 1), 4- [2- (2-dimethylaminoisopropoxy) phenyl] 1-1,3-dioxo-2,6-dimethyl-1,2,3,6-tetrahydropyrrolo [3, [4-c] Capylazole 12 mg (26%) was obtained.

 NR NR (CDCU) δ; 1.17 (d, 3H. J = 6.1Hz), 2.11 (s, 6H), 2.22 (m, 1H), 2.36 (dd, 1H, J = 5.6, 12.6Hz), 3.18 (s.3H), 3.90 (s, 3H), 4.44 (m, 1H), 7.07 (dd, 1H, J = 0.8, 8.2Hz), 7.07 (dt, 1H, J = 0.8, 7.6Hz). 7.36 (dd, 1H, J = 1.8, 7.6 Hz), 7.40 (dd, 1H,] = 7.2, 8.0 Hz), 7.41 (ddd, 1H. 1.8, 7.6, 8.2 Hz), 7.46 (d, 1H, J = 8.4Hz), 7.52 (s, 1H), 7.62 (ddd, 1H, J = l.0.7.2, 8.4 Hz), 9.12 (dd, 1H, J = l.0, 8.0Hz).

 FABMS (m / z); 442 [M + l] +.

Process 2

4- [2- (2-Dimethylaminoisopropoxy) phenyl] — 1,3-dioxo-1,2,6-dimethyl-1,2,3,6-tetrahydropyro [3,4-1c] Dissolve 800 mg (1.81 mmo 1) of potassium hydroxide in 20 ml of THF, add 72 ml of 1 M polan-THF complex ZTHF solution (72.00 mmo 1) in two portions, and add 60 ml. Stirred for 6 hours. Ice water and 2N hydrochloric acid was added to the reaction solution, and extracted with CH C 1 _3, after brine washed, dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was dissolved in dioxane 2 Om 1, 20 ml of 2 N hydrochloric acid (0.04 mmol) was added, and the mixture was stirred at 100 for 3 hours. Saturated sodium hydrogencarbonate aqueous solution was added to the reaction solution, and extracted with CHC 1 _3, after brine washed, dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography (CHC 13 / MeOH 50/1) to give compound 211 free base 1 39 mg (18%), compound 211 free base 176 mg (23%) and compound 21 3 302 mg (40%) of the free base were obtained.

 Process 3-1

 Example 2 Compound 2 11 1 39 mg (0.33mmo 1) and 4N hydrogen chloride ZA c〇Et solution 0.15 ml (0.60 mmo 1) )) To obtain compound 211 and 122 mg (81%).

MI NMR (DMS0-d ₆ ) δ; 1.11 (d. 3H, J-5.5 Hz). 2.68 (s, 6H), 3.13 (s, 3H), 3.19 (m, 2H), 3.96 (s, 3H), 4.97 (m, III), 4.97 (s, 2H), 7.06 (t.1H, J = 7.4Hz), 7.18-7.47 (m, 4H), 7.49 (s, 1H), 7.58 (t, 1H, J = 7.7Hz), 7.73 (d, 111, J = 8.6Hz), 8.07 (d, 1H, J = 7.9Hz) .9.33 (br, 1H).

FABMS (m / z); 428 [M + l] ⁺ .

Process 3-2

 Example 2 Compound 2 12 Free base 1 76 mg (0.41 mMol) and 4N hydrogen chloride / Ac〇Et solution 0.15 ml (0.6 From Ommo 1), compounds 2 12 and 15 2 mg (77%) were obtained.

_{* HNR (DMS0-d b)} δ; 1. 14 (d, 3H, J = 6.3Hz), 2.52 (s, 6H), 3.15 (s, 3H), 3. 15 (m, 2H), 3.96 (s , 3H), 4.36 (d, 1H, J = 17.3Hz), 4.46 (d, 1H, J = 17.3Hz), 4.92 (m.1H), 7.17 (t, 1H, J = 7.3Hz), 7.25 (dt, 1H, J = l.0, 7.4Hz), 7.35 (d, 1H, J = 7.9Hz), 7.48 On, 2H), 7.53 (dd, 1H, J-7.4, 8.0Hz), 7.66 (d, 1H, J = 8.0Hz), 7.78 (s, 1H), 9.16 (d, 1H, J = 7.4Hz), 9.92 (br, 1H).

FABMS (m / z); 428 [M + l] ⁺ .

Process 3-3

 Example 2 According to Step 2 of 1, Compound 2 13 Free base 30 Omg (0.73 mmo 1) and 4 N hydrogen chloride ZA c OEt solution 0.60 ml (2.4 Ommo 1) As a result, Compounds 2 13 and 25 7 mg (73%) were obtained.

Ή NMR (DMS0-d ₆ ) δ; 1.08 (m, 3H), 2.60 (m, 6H), 3.10 (m, 3H), 3.50 On, 1H), 3.93 (s, 1H), 4.42 (m, 1H), 4.76 (m, 1H), 4.97 (m, 2H), 5.42 On, 1 H), 7.19 (m, 1H), 7.24 — 7.61 (m, 5H), 7.56 (s, 1H), 7.69 (d , 1H, J = 8.5H z), 8.05 (d, 1H, J = 7.9Hz), 10.00 (br s, 1H), 12.01 (br, 1H).

FABMS (m / z); 414 [M + l] ⁺ .

Example 2 O 1 Compound 2 14 and Compound 2 15

Compound 1 6 6 (Jiasutereoma ratio 4: 1) than re silica gel column chromatography _{(CHC l 3 ZA c OE t} 8 0/1) minor di § stereo Ma one compound 1 6 6 obtained by purification in Example 1 61, Compound 1669 (diastereomer ratio 0: 1) was obtained according to Example 162 and Example 163, and then Step 1 of Example 13 and Example 20 According to Step 2 to Step 3-2, Compound 214 and compound 215 were obtained.

Compound 2 1 4

Ή NMR (DMS0-d ₆ ) δ; 1.15 (d, 3H, 1 = 5.9 Hz), 2.44 (m, 3H), 2.50 (m, 3H),

2.94 (m, 1H), 3.12 On, 1H), 3.09 (s, 3H), 3.96 (s, 3H), 4.94 (m, 1H), 4.94 (m, 2H), 7.05-7.40 (m , 4H), 7.42 (s, 1H), 7.58 (m, 1H), 7.72 (d, 1H, 8.3Hz), 8.06 (d, 1H. J = 7.9Hz), 9.95 (m, 1H).

 FABMS (m / z); 506 [Mil] +.

Compound 2 1 5

 Ή NMR (DMSO-dt) (5; 1.24 (d, 3H, J = 6.3Hz), 2.46 (m, 3H), 2.55 (m, 3H),

3.04 (m, 1H), 3.37 (m, 1H), 3.23 (s, 3H), 4.05 (s, 3H), 4.38 (d, 1H, J = 17.6Hz), 4.45 (d, 1H.J = 17.6Hz ), 5.06 (m.1H), 7.36 (t, 1H, J = 7.4Hz), 7.40-7.80 (m, 4H), 7.64 (t, 1H, J = 7.8Hz), 7.77 (s, 1H) , 9.23 (d, 1H, J = 7.9Hz), 10.20 (m, 1H).

 FABMS (m / z); 506 [M + l] +.

Example 20 Compound 2 16

Process 1

 According to Step 6 of Example 3, 44.3 g (19.1 mmo 1) of 2-bromo-6-methoxybenzoic acid, 14.5 ml (229 mmo 1) of methyl iodide and potassium carbonate From 39.7 g (288 mmo 1), 41.9 g (89%) of 2-bromomethyl 6-methoxybenzoate was obtained.

Process 2

 According to Example 11, 20.1 g (81.8 mmo 1) of methyl 2-bromo-6-methoxybenzoate and 1 M boron tribromide / methylene chloride solution 98.Oml (98.8) Ommol), 11.6 g (61%) of methyl 2-bromo-6-hydroxybenzoate was obtained.

 Ή NMR (CDC) δ; 4.00 (s, 3H), 6.99 (m, 1H), 7.25 (m, 2H), 10.95 (s, 1H).

 Process 3

2-Promote methyl 6-hydroxybenzoate5.82 g (25.2 mm o 1) Was dissolved in 50 ml of THF, and under ice-cooling, 7.27 g (27.7 mmo 1) of triphenylphenylphosphine, R- (10) methyl monolactate 2.65 ml (27.7 mmo i) and 4.40 ml (27.9 mmo 1) of getylazodicarboxylate was added, and the mixture was stirred at room temperature for 50 minutes. Water was added to the reaction solution, and extracted with CHC 1 _3, after brine washed, dried over anhydrous magnesium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane ZAc〇Et 4/1), and (S) —2-bromo-6- (1-methoxycarbonylethoxy) methyl benzoate 6.67 g (84%).

_{Ή NMR (CDC1 3) <5} ; 1.59 (d, 3H, J = 6.9Hz), 3.75 (s, 310, 3.95 (s, 3H), 4. 74 (q, 1H, J = 6.9Hz), 6.76 ( m, 1H), 7.13 — 7.21 (m, 2H).

 FABMS (m / z); 317 [M + l] +.

Process 4

 (S) Dissolve 6.61 g (0.9 mmo 1) of 12-bromo-6- (1-methoxycarbonylcarbonylethoxy) methyl benzoate in 100 ml of getyl ether. A solution of 0.98 M diisobutylaluminum hydride in n-hexane (110 ml, 108 mmol) was added, and the mixture was stirred at -20 for 1.3 hours and then at 0 for 1 hour. Ice water and then 1N hydrochloric acid were added to the reaction solution, extracted with AcOEt, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 5.88 g (quantitative) of (S) —2-butanol 6- (2-hydroxyisopropoxy) benzyl alcohol.

 Ή NMR (CDC) δ; 1.37 (d, 3H, J = 6.3Hz), 3.72 (m, 211), 4.46 (m, 1H), 4.84 (d, 1H, 11.9Hz), 4.98 (d, 1H) , J = ll.9Hz), 6.91 (dd.1H, J = l.2, 7.9Hz), 7.11 (t, 1H, J = 7.9Hz), 7.19 (dd, 1H, J = l.3, 7.9 Hz).

 FABMS (m / z); 260 [M] +.

Process 5

 According to Step 3 of Example 5, (S) —2-bromo-6- (2-hydroxyisopropoxy) benzyl alcohol 5.78 g (20.9 mmo 1) and manganese dioxide 18.8 lg, S) — 2-Promo 6- (2-Hydroxyisopropoxy) benzaldehyde 2.36 g (44%) was obtained.

77 Ή NMR (CDC) 6; 1.37 (d, 3H, J-6.3Hz). 3.73 (m, 2 ID, 4.52 (m, 1H), 7.01 (m, 1H), 7.18-7.36 (m, 210, 10.36 (s, 1H).

Process 6

 According to Steps 1 to 2 of Example 1 and Example 20, the compound 2 16 (diastereomer ratio of 3: 7) was obtained from (S) -2-bromo-6- (2-hydroxyisopropoxy) benzaldehyde. ).

FABMS (m / z); 493 [M + 1] ⁺ .

Example 20 3 Compound 2 17 and Compound 2 18

Compound 2 16 (diastereomer ratio 3: 7), 1.53 g (3.10 mm 01) was dissolved in 1,2-dichlorobenzene 2 Om 1 and heated under reflux for 26 hours. Was evaporated Solvent, the residue was purified by silica gel column chromatography _{(CHC 1 3 / Me OH 2} 0/1), Compound 2 1 6 (Jiasutereoma one ratio 4: 5) 1. 3 9 g (2. 8 2mmo 1), and then reacted with 0.79 ml of triethylamine (5.64mmo 1) and 0.49ml of benzoyl chloride (4.23mmo 1) according to Step 2 of Example 3. The compound 217, 0.49 g (29%) and the compound 218, 0.80 g (47%) were obtained.

Compound 2 1 7

 Ή NMR (CDC) δ; 1.22 (d, 3H, J = 6.3Hz), 3.17 (s, 3H), 3.72 (s, 3H), 4.

12 (dd, 1H, J-5.3. 11.8Hz), 4.33 (d, 1H, 1-3.6, 11.8Hz) .4.71 (m, 1H), 7.30 (s, 1H), 7.08 ― 7.20 (m, 3H), 7.31 (d, 1H, J-8.3Hz) .7.34 ― 7.42 (m.4H), 7.57-7.65 (m, 3H), 9.05 (d, 1H, J = 8.6Hz).

FABMS (m / z); 597 [M + 1] ⁺ .

Compound 2 1 8

 Ή NMR (CDCU) δ; 1.29 (d, 3H, J = 6.3Hz), 3.02 (s, 3H), 3.84 (s, 3H), 4.

13 (dd, 111, J = 4.3, 11.6Hz), 4.33 (dd, 1H, J = 3.8, 11.6Hz), 4.66 (m, 1H), 7.30 (s, 1H), 7.04 — 7.12 (m, 3H) , 7.29 (m, 1H), 7.34-7.45 (m, 4H), 7.58-7.67 (m, 3H), 9.03 (d, 111, J = 7.9Hz).

 FABMS (m / z); 597 [M + 1] +.

 Example 20 Compound 2 19

78 Compound 217 (494 mg (0.83 mmo 1)) was reacted with potassium carbonate (14.0 mg, 1.O lmmol) according to step 6 of Example 3-7 to give compound 216 (diastereomer ratio 1). : 0), 419 mg (quantitative). Then, according to Steps 1 and 2 of Example 129 and Example 130, compound 219 was obtained.

 Ή NMR (DMSO-dJ δ; 1.06 (d, 3H, J = 5.9Hz), 2.50 (s, 6H), 2.95 On, 1H), 3.16 (m, 1H), 3.06 (s, 3H), 3.98 (s , 3H), 4.98 On, 1H) .7.20-7.45 (m, 4H), 7.68 (t, 1H.J = 7.9Hz), 7.76 (d, 1H, J = 7.9Hz), 7.86 (s, 1H), 8.95 (d, 1H, 8.3Hz), 10.02 (br, 1H).

 FABMS (m / z); 520 [M + l] +.

Example 20 5 Compound 220

 Compound 220 was obtained from compound 218 according to Example 204.

 'Η NMR (DMSO-dfc) 6; 1.15 (d, 3H, J = 5.9Hz), 2.51 (s, 6H), 2.96 (m, 1H),

3.16 (m, 1H), 3.06 (s, 3H), 3.99 (s, 3H), 4.98 (m, 1H), 7.20-7.50 (m, 4H), 7.68 (m, 1H), 7.75 (d, 1H, J = 6.3Hz), 7.76 (s, 1H), 8.96 (d, 1H,

J = 7.9Hz), 10.23 (br, 1H).

 FABMS (m / z); 520 [M + l] +.

Example 206 Compound 221 and Compound 222

 According to the steps 3 to 6 of Example 202, Example 203, Example 204 and Example 205, Compound 221 and Compound 222 were obtained from S- (1-)-methyl lactate.

Compound 22 1

 Ή NMR (DMS0-dJ δ; 1.06 (d, 3H, J = 5.9Hz), 2.50 (s, 6H), 2.96 (m, 1H),

3.17 (m, 1H), 3.06 (s, 3H), 3.98 (s, 3H), 5.00 (m, 1H), 7.30-7.50 (m, 4H), 7.68 (m, 1H), 7.76 (d, 1H, J = 8.6Hz), 7.87 (s, 1H), 8.95 (d, 1H,

J = 7.9Hz), 10.16 (br, 1H).

FABMS (m / z); 520 [M + l] ⁺ .

Compound 222

Ή NMR (DMSO-dJ δ; 1.14 (d, 3H, J = 5.9Hz), 2.50 (s, 6H), 2.94 (m, 1H), 3.20 (m, 1H), 3.05 (s, 3H), 3.99 (s, 3H), 4.97 (m, 1H) .7.20-7.45 (m.4H). 7.60-7.80 (m, 3H), 8.95 (d, 1H, J = 7.6Hz), 10.15 (m, 1H).

FABMS (m / z); 520 [M + l] ⁺ .

Example 2 07 Compound 2 2 3

 According to Example 53, compound 1669 (diastereomeric ratio 0: 1), compound 89 mg (0.33 Ommo 1) and pyrrolidine 0.275 ml (3.29 mmo 1) There were obtained 172 mg (96%) of the free base of 223, and the compound 223 was obtained according to Step 2 of Example 21.

 Ή NMR (DMSO-d δ; 1.14 (d, 3H, 6.3Hz), 1.55-1.69 (m, 4H), 2.52-3.31 (m, 6H), 3.05 (s, 3H), 3.99 (s, 3H), 4.92 On, 1H), 7.30 ― 7.45 (m, 4H), 7.69 (dd, 1H, J = 7.1, 8.3Hz), 7.77 (d, 1H, J = 8.3Hz), 7.80 (s, 1H), 8.95 (d, 1H, J = 7.9Hz), 10.20 (br s, 1H).

 FABMS (m / z); 546 [MH] +.

Example 2 08 Compound 2 2 4

Process 1

 According to Step 1 of Example 18 and Step 1 of Example 1, 2- {2- [6-bromo-3-methoxy) was prepared from 6-bromo-2-hydroxy-3-methoxybenzaldehyde. 1 2— (1-Methoxycarbonylethoxy) phenyl] vinyl} —1—methylindole was obtained, and then, according to step 4 of Example 202, 2— [2— {6-—butamate 2— (2 —Hydroxyisopropoxy) —3-methoxyphenyl} vinyl-111-methylindole was obtained.

 Ή NMR (CDC) δ; 1.28 (d, 3H, J = 6.4Hz), 3.48 (m, 1H), 3.65 On, 1H), 3.79 (s, 3H), 3.87 (s, 3H), 4.29 ( m, 1H), 6.71 (d, 1H, 8.9Hz), 6.88 (s, 1H), 7.09 (t, 1H, J = 7.6Hz), 7.20 (t, 1H, J = 7.6Hz), 7.23 (d, 1H, J = 16.3H z), 7.29 (d, 1H, J = 7.6Hz), 7.34 (d, 1H, J = 8.9Hz), 7.51 (d, 1H, J = 16.3Hz), 7.60 (d, 1H, J = 7.6Hz).

 EIMS (m / z); 415 [M] +.

 Process 2

 Step 2 of Example 1, Step 20 of Example 20, Steps 1 to 29 of Example 1 and Steps 1 to 30 of Example 130

80 Compound 224 was obtained from 2- {2- [6-promo 2- (2-hydroxyisopropoxy) -13-methoxyphenyl] vinyl} -11-methylindole according to Step 2.

Primary diastereomer:

Ή NMR (DMS0-d ₆ ) δ; 0.86 (d, 3H, 6.3Ηζ), 2.45 (s, 3H), 2.63 (s, 3H),

2.72 (d.2H.4.6Hz), 3.09 (s, 3H), 3.95 (s, 3H), 4.00 (s, 3H), 3.91 (s, 3H), 4.76 (m, 1H), 7.19 (d, 1H , J = 9.1Hz), 7.41 (t, 1H, J = 7.8Hz), 7.5 1 (d, 1H, J = 9.1Hz), 7.68 (t, 1H, J = 7.8Hz), 7.76 (d, 1H, J-7.8Hz), 7.81 (s, 1H), 8.96 (d, 1H, J = 7.8Hz), 9.78 (br, 1H).

 FABMS (m / z); 549 [M] +.

Example 2 0 9 Compound 2 25

 Step 1 to Step 3 of Example 15; Step 1 to Step 2 of Example 18; Step 4 of Example 202; Step 2 of Example 1; Example 20; Example 1 29 and Example 1 30 Compound 225 was obtained from 2-odo-6-methoxybenzoic acid according to Step 1 to Step 2.

Main stereo stereo:

Ή NMR (DMS0-d ₆ ) δ; 1.13 (d, 3H, J = 6.3 Hz), 2.46 (s, 6H), 2.96 (m, 1H),

3.07 (s, 3H), 3.15 (m.1H), 3.99 (s, 3H), 4.89 (m, IH), 7.24 (t, 1H, 7.7Hz), 7.33 (d, 1H, J = 7.7Hz), 7.42 (d, 1H, J = 7.7 Hz). 7.65 (t, 1H, J = 8.0 Hz). 7.71 (s, IH), 7.72 (d, 1H, J = 8.0 Hz), 7.74 (t, III, J = 8.0Hz). 8.96 (d,

1H, J = 8.0Hz), 9.96 (br, IH).

Example 2 Compound 226

Process 1

According to Step 1 of Example 1 and Step 1 of Example 18, 2- {2-} 2-methoxycarbonyl-6_ (1-meth) was obtained from methyl 2-formyl-13-hydroxybenzoate. Toxicarbonylphenyl) vinyl} —1-methylindole was obtained and then reacted with lithium aluminum hydride according to Step 7 of Example 3 to give 2- {2- [2-hydroxymethyl 6- (2-Hydroxyisopropoxy) phenyl] vinyl} 11-methylindole was obtained. By reacting with manganese dioxide according to Step 3, 2- (2- [2-formyl-1-6- (2-hydroxyisopropoxy) phenyl] vinyl} —1-methylindole was obtained.

 Ή NMR (CDCls) (5; 1.35 (d, 3H, J = 6.4Hz), 1.95 (br s, 1H), 3.78 (s, 3H), 3.81-3.89 (m, 2H), 3.57 (dd, 1H, J = 3.0, 11.9Hz), 4.60 (m, 1H), 6.87 (d, 1H, J = 16.1Hz), 6.91 (s, 1H), 7.11 (t, 1H, J = 7.9Hz), 7.22 (d, 1H, J = 7.9Hz), 7.23 (t, 1H, J = 7.9Hz), 7.31 (d, 1H, J = 7.9Hz), 7.38 (t, 1H, J = 7.9Hz), 7.57 (d, 1H, 7.9Hz), 7.62 (d, 1H, J = 7.9Hz), 7.64 (d, 1H.J-16.1Hz), 10.25 (s, 1H).

 EIMS (m / z); 335 [M] + ·

Process 2

 According to Step 2 of Example 3, Step 2 of Example 1, Example 20, Step 6 of Example 37, Step 1 to Step 2 of Example 1 29 and Example 1 30, 2- {2- [2-Formyl-1-6- (2-hydroxyisopropoxy) phenyl] vinyl} —Compound 226 was obtained from 1-methylindole.

Primary diastereomer:

lH NMR (DMS0-d _fc ) δ; 1.07 (d, 3H, J-5.9 Hz), 2.40-2.62 (m, 2H), 2.52 (s, 6H), 3.05 (s, 3H), 3.97 (s, 3H ), 5.03 (m, 1H), 7.43 (d, IH, J = 8.1Hz). 7.60 (t, IH, J-8.1Hz), 7.62-7.68 (m, 2H), 7.74 (t.1H, J = 8.1Hz), 7.76 (d, IH.8.1Hz), 7.95 (s, IH), 8.97 (d, IH, J = 8.1Hz), 9.70 (s, IH), 10.15 (br s, IH).

 FABMS (m / z); 470 [Mil] +.

 Example 2 1 1 Compound 227

 Compound 227 free base, 337 mg (72%) was obtained from compound 226 free base, 300 mg (0.639 mmo 1) and sodium borohydride 28 mg (0.743 mmo 1) according to Example 93. Compound 21 was treated with 4N hydrochloric acid according to the procedure 2 of Example 21 to give 179 mg (89%) of compound 227.

 Primary diastereomer:

82 NR NR (D SO-de) δ; 1.08 (d, 3H, J = 5.9Hz), 2.45 (s, 6H), 2.90 (m, 1H), 3.03 (s, 3H), 3.15 (m, IH ), 3.97 (s, 3H), 4.11-.24 (m, 2H), 4.90 (br, 1H) .5.03 (in, 1H), 7.16 (d, IH, J = 7.9Hz), 7.30 (d , 1H,} = 1.9Hz), 7.40 (t, IH, J = 7.9Hz), 7.46 (t, IH, J = 7.9Hz), 7.67 (t, IH, J = 7.9Hz), 7.70 (s, IH ), 7.74 (d, IH, J = 7.9 Hz). 8.96 (d, IH, J = 7.9 Hz), 10.06 (br s, IH). FABMS (mIz); 472 [M + l] +.

Example 2 1 2 Compound 2 2 8

 Compound 228 was obtained from compound 227 free base according to Step 2 of Example 144, Example 144 and Example 21.

Primary diastereomer:

lH NMR (DMS0-d _fc ) δ; 1.10 (d, 3H,] = 5.9 Hz), 1.99 (s, 3H), 2.48 (s, 6H), 2.89 (m, IH), 3.04 (s, 3H), 3.09 (m, IH), 3.98 (s, 3H). 4.85 On, IH), 7.01 (d, IH, J = 7.8Hz), 7.09 (d, IH.J-7.8Hz), 7.35 (t, 7.40 (t, IH, J = 7.8Hz), 7.67 (t, IH, J = 7.8Hz), 7.69 (s, IH), 7.74 (d, IH, J = 7.8Hz) ). 8.96 (d.IH, J = 7.8 Hz), 9.94 (br s, IH).

Example 2 1 3 Compound 2 2 9

 According to Step 2, Step 20 of Example 1, Example 20 and Example 12 and Step 1 to Step 2 of Example 130, 2- {2- [2-hydroxymethyl-6- (2-hydroxy Compound 2229 was obtained from isopropoxy) phenyl] vinyl} -1-methylindole.

Main stereo stereo:

Ή NMR (DMS0-d _fc ) δ; 1.06 (d, 3H, J = 6.4 Hz), 2.51 (s, 6H), 2.52 (s, 6H), 2.85-2.98 (m, 2H), 3.04 (s, 3H ), 3.90 ― 4.24 (m, 2H), 3.99 (s, 3H), 5.01 (m, IH), 7.38 (d, IH, J = 7.2Hz), 7.42 (t, IH, J = 7.2Hz) , 7.59 (t, IH, J = 7.2Hz), 7.60 (d, IH.J = 7.2Hz), 7.69 (t, IH, 7.2Hz), 7.75 (s, IH), 7.76 (d, IH, J = 7.2Hz), 8.98 (d, IH, J = 7.2Hz), 10.24 (br, IH), 10.36 (br.1H).

EIMS (m / z); 498 [M] ⁺ ·

Example 2 1 4 Compound 2 3 0

83 According to Step 1 of Example 18, Step 4 to Step 5 of Example 202, Step 1 to Step 2 of Example 1, Step 1 of Example 12 and Step 1 of Example 13 —Benzoxy salicylaldehyde afforded compound 230 (1: 1 diastereomer).

 FABMS (m / z); 552 [+1] +.

Example 2 15 Compound 2 3 1

 Compound 231 (diastereomer ratio 1: 1) was obtained from compound 230 according to Step 30 of Example 30 and Example 21.

 FABMS (m / z); 462 [M + 1] +.

Example 2 16 Compound 2 3 2

 According to Example 214, compound 232 was obtained from 5-benzyloxysalicylaldehyde.

 Ή NMR (CDCls) δ; 1.35 (d, 3H, J = 5.9 Hz), 2.25 (s, 6H), 2.43 (dd, 1H, J = 5.1, 12.8 Hz), 2.56 (dd, 1H, J = 5.9, 12.8Hz), 2.79 (s, 3H), 2.93 (dd, 1H, J = 4.3, 15.5Hz), 3.15 (m, 1H), 3.65 (s, 3H) .3.72 (dt, 1H, J = 3.7 , 12.8Hz), 3.92 (dd, 1H, J = 3.7, 7.3Hz), 4.47 (d, 1H, J = 7.3Hz), 5.08 (s, 2H), 6.87 (m, 2H), 7.16- 7.50 (m, 9H), 8.01 (m, 1H).

 FABMS (m / z); 552 [M + 1] +.

Example 2 17 Compound 2 3 3

 Compound 233 was obtained from compound 232 according to Example 215.

 Ή NMR (DMSO-dt) (5; 1.24 (d, 3H, J = 5.9Hz), 2.64 (s, 3H), 2.76 (s, 6H), 2.95 (m, 1H), 3.06 (m, 1H), 3.33-3.65 (m, 3H), 3.68 (s, 3H), 3.94 (dd, 1H, J = 3.6.7.6Hz), 4.51 (d, 1H, J = 7.6Hz), 4.94 (m, 1H), 6.66 (dd, 1H, J = 2.8.8.7Hz), 6.92 (d, 1H, J = 8.7Hz). 6.97 (d, 1H, J = 2.8Hz), 7.03 — 7.16 (m, 2H), 7.41 ( d, 1H,] = 7.9Hz), 7.80 (d, 1H, 1 = 7.6Hz), 8.99 (s, 1H), 9.50 (br s, 1H).

 FABMS (m / z); 462 [M + 1] +.

 Example 2 18 Compound 2 3 4

 According to Example 214, compound 234 was obtained from 5-methylsalicylaldehyde.

84 Ή NMR (DMSO-dt) <5; 1.8 (d.3H, J = 5.9Hz), 2.33 (s, 3H), 2.64 (s, 3H), 2.76 (s, 6H), 3.00 (m, 1H), 3.17 (m, 1H), 3.33-3.63 On, 3H), 3.68 (s, 3H), 3.97 (dd.1H, J = 3.5, 7.3Hz), 4.52 (d, 1H, J = 7.3Hz) , 5.06 (m, 1H), 6.98 — 7.16 (m, 4H), 7.34 (s, 1H), 7.40 (d, 1H. J = 7.9Hz), 7.81 (d, 1H, J = 7.3Hz), 9.75 (br s, 1H).

FABMS (m / z); 460 [M + l] +.

Example 2 19 Compound 235

 According to Example 214, compound 235 (diastereomer ratio: 5: 2) was obtained from 5-bromosalicylaldehyde.

Ή NMR (DMS0-d _t ) <5; 1.11 and 1.28 (2d, total 3H, J = 5.8Hz), 2.64 and 2.66 (2s, total 3H), 2.75 and 2.86 (2br s, total 6H), 3.00 -3.58 (m, 5H), 3.676 and 3.683 (2s, total 3H), 3.94-4.09 (m, 1H) .4.52 (d, 1H, J = 7.6 Hz), 5.10 (m, 1H), 7.03-7.23 ( m, 3H), 7.40 ― 7.51 (m, 2H), 7.63-7.8 1 (m, 2H). 9.78 (br s, 1H).

FABMS On / z); 524 [M + l] ⁺ .

Example 220 Compound 236

 According to Step 4 of Example 202, 2- {2- [6-promo-2- (1-methoxycarbonylethoxy) phenyl] vinyl} is obtained from 2-methyl-2-indole 2- {2- [6-bromo-2- (2-Hydroxyisopropoxy) phenyl] vinyl} 1-1methylindole was obtained, and then compound 236 was prepared according to Step 1, Step 129 of Example 1 and Step 1 to Step 2 of Example 130. I got

 Ή NMR (DMSO-dt) δ; 1.32 (d, 3H, J = 5.9Hz), 2.91 (s, 3H), 2.84 (m, 6H), 3.02 (m, 1H), 3.20-3.95 (m, 5H) , 3.66 (s, 3H), 4.44 (d, 1H, J = 8.3Hz), 5.28 (m, 1H), 7.03-7.43 (m, 6H), 7.78 (d, 1H, J = 7.3Hz), 9.61 ( br s, 1 H).

 FABMS (m / z); 524 [M + l] +.

Example 22 1 Compound 237

According to Example 214, compound 237 (diastereomer ratio 3: 1) was obtained from salicylaldehyde. Ή NR (DMS0-d ₆ ) δ; 1.23 and 1.29 (2d, total 3H, J 6.1Hz), 2.80 (s, 3

H), 2.85 (br s, 6H), 2.89-3.05 (m, 2H), 3.46 (m, 2H), 3.59 and 3.64 (2 s, total 3H), 3.74 (m, 1H), 4.19 (m, 1H ), 4.30 and 4.35 (2d, total 1H, J

= 7.8Hz), 5.13 On, 1H), 6.76-6.85 (m, 2H), 7.01-7.23 (m, 4H), 7.38 and 7.40 (2d, total 1H, J = 7.9Hz), 7.78 and 7.79 (2d , 1H.J = 7.1Hz), 10.28 (br s, 1H).

 FABMS (m / z); 456 [M + l] +.

Industrial applicability

 The present invention provides a novel pyrrolocarbazole derivative or a pharmaceutically acceptable salt thereof, which is useful for treating thrombocytopenia.

86

Claims

 1. General formula (I)

 Come p

 (

 of

Wherein C is a benzene or cyclohexene ring, X and Y are the same or different and are carbonyl or methylene, and R ¹ is lower alkyl or aryl.

R ² is hydrogen, substituted or unsubstituted lower alkyl, lower alkenyl or substituted or unsubstituted aralkyl, R ³ , R ⁴ , R ⁵ , R ^fc , R ⁷ , R ⁸ , R ⁹ , R ^IQ and R ¹ ′ are the same or different, and each represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, halogen, nitro, substituted or unsubstituted lower alkanol, NR ¹² R ¹³ , R ^'2 and R ¹³ are the same or different, excluding hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower Arukanoiru, Aroiru, lower alkoxycarbonyl, hydroxyl carboxylic acids Ararukiru O alkoxycarbonyl or amino acid Residue (the amino group of the amino acid may be protected by a protecting group)}, OR "(where R ¹⁴ is hydrogen, substituted or Is unsubstituted lower alkyl, substituted or unsubstituted alkanoyl, arylo, substituted or unsubstituted aralkyl, substituted or unsubstituted heteromal, CONHR ' ⁵ (wherein R ¹⁵ is hydrogen, lower alkyl or aryl. ) Or tri-lower alkylsilyl), NHCONHR ¹⁶ (where R ¹⁶ is hydrogen, lower alkyl or aryl), or COR ¹⁷ (where R ' ⁷ is hydroxy, lower alkoxy, NR ^IB R' ⁹ (Wherein, R ¹⁸ and R ' ⁹ are the same or different and are hydrogen, hydroxy, aralkyl, substituted or unsubstituted lower alkyl, or Is to a heterocyclic group formed across the N) or SR ^ze (wherein the, R ² ° is a lower alkyl, a Ariru or a heterocyclic group)}.

However, (1) when X and Y are carbonyl at the same time, ring C is a benzene ring, and R ^s , R ⁷ , R ⁸ and R ^IQ are simultaneously hydrogen, then R ³ , R ⁴ , R ⁶ , At least one of R ⁹ and R ′ ¹ is OR ²¹ (wherein R ² ′ is a higher alkanol, a substituted or unsubstituted heterocyclic group, a lower alkyl substituted with a substituted or unsubstituted heterocyclic group, CONHR ' ⁵ (wherein R' ⁵ is as defined above) or tri-loweralkylsilyl}, NHCONHR ¹⁶ (where R ' ^fc is as defined above), substituted or unsubstituted lower alkyl A substituted or unsubstituted lower alkenyl or COR ¹⁷ wherein R ′ ⁷ is as defined above, (2) X and Y are carbonyl, R ^{1 is} benzyl, ² is hydrogen and R ³ and R ⁵ are simultaneously black ^{opening, R 4, R fc, R} 7, R 8, R 9, R '° Contact Fine R ¹ 'are not hydrogen at the same time, (3) X is Karuponiru, Y is methylene, R' if and R ² is ^{methyl, R 3, R 4, R} 5, R fc , R ⁷ , R ⁸ , R 9, R ¹⁰ and R ¹¹ are not simultaneously hydrogen.] Or a pharmaceutically acceptable salt thereof.

 2. The compound according to claim 1, wherein R 'is lower alkyl.

 3. The compound according to claim 2, wherein R ′ is methyl.

4. The compound according to claim 1, wherein R ² is lower alkyl.

5. The compound according to claim 4, wherein R ² is methyl.

6. R ³ is OR ¹⁴ (wherein, R ¹⁴ is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted alkanol, aroyl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclic group, The compound of claim 1 wherein the compound is CONHR ¹⁵ (wherein R ¹⁵ is hydrogen, lower alkyl or aryl) or tri-lower alkylsilyl.

7. The compound according to claim 6, wherein R ¹ and R ² are lower alkyl.

8. The compound according to claim 7, wherein R ³ is a substituted or unsubstituted lower alkoxy.

9. From at least one of the compounds according to claim 1 and a pharmacologically acceptable carrier. A pharmaceutical composition comprising:

 10. A therapeutic agent for thrombocytopenia, comprising at least one of the compounds according to claim 1.

 8 9