WO2002053548A1 - Benzothiazepine derivatives - Google Patents

Abstract

Compounds represented by the general formula [I]: [I] [wherein R?1 and R2¿ are each hydrogen or C¿1-3? alkyl; R?3¿ is hydrogen or C¿1-6? alkyl(except n-butyl); R?4¿ is hydrogen, hydroxyl, or C¿1-3? alkyl; R?5¿ is a cyclic, saturated or unsaturated C¿3-6? aliphatic group, or a linear or branched, saturated or unsaturated C1-9 aliphatic group; Ar is a cyclic, saturated or unsaturated C3-9 aliphatic group, or a linear or branched, saturated or unsaturated C1-9 aliphatic group; and n is an integer of 0 to 2]. The compounds exhibit an activity of bringing about a high blood GLP-1 concentration and are therefore useful as diabetes remedies, preventives for chronic complications of diabetes, antiobestics, and so on.

Description

技 術 分 野

Technical field

 The present invention is clearly useful in the field of medicine. More specifically, since the benzothiazepine derivative of the compound of the present invention has an activity of exhibiting a high blood GLP-1 concentration, it is useful as a therapeutic agent for diabetes, a preventive agent for chronic complications of diabetes or an antiobesity agent. is there. Background technology

 The blood sugar level of a healthy person is constantly controlled by the action of insulin. Diabetes refers to a chronic hyperglycemic state in which this control is ineffective and a disease caused by it.

 The basis of diabetes treatment is to correct hyperglycemia, i.e., to return blood glucose levels to normal levels.In recent years, however, it has been particularly important in recent years to prevent a rapid rise in blood glucose after eating without affecting fasting blood glucose. It has been recognized that it is extremely important in terms of treatment to control the amount of the drug.

 At present, there are three main types of diabetes therapeutic agents used in clinical practice, in addition to various insulin preparations, as follows. The first is a group of drugs called insulin-releasing drugs typified by sulfonylprea drugs, which promote insulin secretion directly from the brain and lower blood sugar levels. The second is a drug that has recently been launched, called an insulin sensitizer, that lowers blood glucose by promoting glucose uptake in peripheral tissues without directly promoting insulin release. is there. The third monoglucosidase inhibitor is a drug that controls the rapid rise in blood glucose by delaying the digestion and absorption of carbohydrates in the gastrointestinal tract and suppressing the temporary rise in blood glucose after meals. is there. .

On the other hand, glucagon-like peptide-1 (hereinafter referred to as GLP-1) It is a hormone secreted by L cells, which are endocrine cells present in the small intestinal intestinal epithelium due to intensification, etc., and acts on β cells present in the islets of Langerhans to promote the secretion of insulin to lower blood sugar. I know (Eur. J. Clin. Invest, Vol. 22, p. 154, 1992). It has been reported that insulin secretion by GLP_1 depends on blood glucose level.Insulin secretion by GLP-1 is not observed in normoglycemia, and it is reported that insulin secretion is enhanced only in hyperglycemia. (Lanc et, Vol. 2, p. 1300, 1987). GLP-1 not only enhances insulin secretion but also enhances insulin biosynthesis (Endocri no lgygy, 130, 159, 1992) and promotes the proliferation of] 3 cells (Diabeto 1 ogia, Vol. 42, p. 856, 1999), which is an essential factor for maintaining 8 cells.

 It has been shown that maintaining GLP-1 in blood at a high level by administering GLP-1 to general type 2 diabetic patients significantly improves hyperglycemic status. (Diabeto 1 ogia, 36, 741, 1994 or 39, 1546, 1996)

 Furthermore, the action point of GLP-1 was not limited to i3 cells, but was also found to enhance sugar utilization in peripheral tissues (Endocrinology, 135, 2070, 1994 or Diabeto 1 ogia, 37, 1163, 1994), and it has been reported that intracerebroventricular administration of GLP-1 exerts an antifeeding effect (Digestion, Vol. 54). , 392, 1993). It has also been reported that GLP-1 administration has a gastrointestinal motility inhibitory effect (Dig. Dis. Sci., 43, 1113, 1998).

The compounds whose structures are most similar to the compounds of the present invention are described in JP-A-7-503724 (hereinafter referred to as Reference A), JP-A-8-506376 (hereinafter referred to as Reference B), and the like. Japanese Patent Publication No. 8-5050749 (hereinafter referred to as Reference C), Japanese Patent Publication No. 10-504035 (hereinafter referred to as Reference D), Japanese Patent Publication No. 10-279568. Publication No. WOO 0 61568 (hereinafter referred to as Reference F.), J. Lipid Res., 36, 1106, 1995 (hereinafter referred to as Reference). G.), J. Lipid Res., 36, p. 1098, 1995 (hereinafter referred to as Reference H;), Dr. Metatab. D is pos., 27, p. 637 , 1999 (hereinafter referred to as Reference I), Curr. Opin. Cardiova sc., Renal Instst Drugs, 1, p. 276, 1999 (hereinafter referred to as Reference J). ), J. Lipid Res., 40, p. 2158, 1999 (hereinafter referred to as Reference K), Anal. Biochem., 282, p. 94, 2000 (hereinafter referred to as Reference L). ), International Publication No. WOO 0Z38725 (hereinafter referred to as Reference M), International Publication No. WO00 / 38726 (hereinafter referred to as Reference N), and International Publication No. WO00 / 38727 (hereinafter referred to as Reference 0). ), International Publication Number WO00 / 3 No. 8728 (hereinafter referred to as Reference P), International Publication No. WO 00/38729 (hereinafter referred to as Reference Q), and International Publication No. WO00 / 55355 (hereinafter referred to as Reference R). ing.

 References A to R describe compounds having a 1,4-benzothiazepine skeleton.

However, in the compound of the present invention, although the 1,4-benzothiazepine 1,1-dioxoside skeleton is common to the compounds of References A to R, the 3-position substituent on the skeleton is a monosubstituted compound. Linear — A compound having a C ₆ , disubstituted alkyl group, specifically a compound having a completely different structure from the compounds of References A to R having disubstitution, for example, an ethyl group or a butyl group.

 The uses of References A to R are hypolipidemic compounds caused by the inhibitory action of bile acid uptake, and have the same industrial application fields as the present invention, but are completely different from the uses of the present invention. This is an unrelated application. Further, it is not disclosed in the patent specification that the compound disclosed in the patent is useful as a therapeutic agent for diabetes or an agent for preventing chronic complications of diabetes.

Further, US Pat. No. 3,362,962 (hereinafter referred to as Reference S) discloses a 1,4-benzothiazepine skeleton and its oxidized and reduced forms, specifically, 1,4-benzen. Scaffolds such as 4,5-dihydro, 4,5-dihydro, N-oxidized, and 4,5-year-old oxaziridine derivatives of the zothiazepine skeleton are described.

 However, although the compounds of the present invention have a 1,4-benzothiazepine skeleton in common with the compound of Reference J, the 4-benzodiazepine skeleton has a 4-dihydro form, a 4-dihydroform, an N-oxidized form, and a 4,5-year-old compound. Oxaziridines are compounds with completely different structures outside the scope of the present invention. The use of Reference S is a compound having a muscle relaxant and anticonvulsant activity and has the same industrial field of application, but is completely unrelated to the use of the present invention. Further, it is not disclosed in the patent specification that the compound disclosed in the patent is useful as a therapeutic agent for diabetes or an agent for preventing chronic complications of diabetes.

 Furthermore, Japanese Patent Application Laid-Open No. 53-65895 (hereinafter referred to as Reference T) discloses a three-ring fused ring containing a 1,4-benzothiazepine skeleton, pyrrole [1,2-d]-. Compounds having a 1,4-benzothiazepine skeleton have been described.

 However, Reference T is a condensed tricyclic ring, and is a compound having a completely different structure outside the scope of the present invention. The use of Reference T is a compound having a locomotor activity-suppressing action, and although it has the same industrial field of application, it has no relation to the use of the present invention. Further, it is not disclosed in the patent specification that the compound disclosed in the patent is useful as a therapeutic agent for diabetes or an agent for preventing chronic complications of diabetes.

 U.S. Pat. No. 5,276,025 (hereinafter referred to as Reference U) discloses a cheno [3,2-f] _1,4,1-benzothiazepine containing a 1,4-benzothiazepine skeleton. Compounds having a skeleton are described.

However, Reference U is a compound in which the substituent at the 5-position on the skeleton has hydrogen, a straight-chain C ₅ alkyl group or a C ₃ -C ₇ cyclic alkyl group, and the compound of the present invention has a substituent. The compound has a completely different structure in that it may have an aromatic ring or a heterocyclic ring. Although it has the same industrial field of application as a drug for suppressing intraocular pressure rise and for treating glaucoma, it is a use that has no relation to the use of the present invention. Further, it is not disclosed in the patent specification that the compound disclosed in the patent is useful as a therapeutic agent for diabetes or an agent for preventing chronic complications of diabetes.

At present, antidiabetic drugs such as sulfonylprea drugs, insulin resistance Drugs such as sex-improving agents and mono-dalcosidase inhibitors are widely used in the clinic, but have the following problems, and they cannot be said to be sufficient drugs. In other words, sulfonylurea agents have a slow onset of action and a long duration of action, making it difficult to develop a synergistic effect during postprandial hyperglycemia, and also lower fasting blood sugar and are often life-threatening Such severe hypoglycemic attacks can be caused. Insulin sensitizers often have side effects on the liver and require careful use under strict control. It may also cause edema and other side effects. In addition, side effects such as bloating and diarrhea have become a problem with Hi-Dalcosidase inhibitors.

 Therefore, with the recent increase in the number of diabetic patients, clinical sites are now demanding the development of more beneficial antidiabetic drugs that have no side effects and can control blood glucose levels in dependence on blood glucose levels. Disclosure of the invention

 An object of the present invention is to provide a therapeutic agent for diabetes, a preventive agent for chronic complications of diabetes, an anti-obesity drug, and the like, since they exhibit an activity of exhibiting a high blood GLP-1 concentration.

 The present inventors have intensively studied for the purpose of creating a therapeutic agent for diabetes, a preventive agent for chronic complications of diabetes, or an anti-obesity agent capable of controlling blood glucose level depending on the blood glucose level. ]

Wherein, ¹ and R ² are the same or different and each represents a hydrogen atom, a C—C ^ alkyl group,

R ³ is a hydrogen atom, a C, —C ₆ alkyl group (excluding an n-butyl group), R ⁴ is a hydrogen atom, a hydroxyl group, a C ₃ alkyl group,

R ⁵ is a hydrogen atom, an azide group, an amino group, a carbamoyl group, a carbamoylamino group, a carbamoyloxy group, a carboxyl group, a cyano group, a sulfamoyl group, a sulfo group, a nitro group, a halogen atom, a hydroxy group, a formyl group Group, formylamino group, cyclic saturated or unsaturated C ₃ -C ₉ aliphatic group, aralkyl group, N-aralkylamino group, N, N-diaralkylamino group, aralkyloxy group, aralkylcarbonyl group, N -Aralkyl groups: rubamoyl group, aryl group, N-arylamino group, N, N-diarylamino group, aryloxy group, arylsulfonyl group, arylsulfonyloxy group, N-aryl Suruhoniruamino group, N- § Li one Le sulfonyl § amino CI- Ce alkylamino group, N- § Li one Rusuruhoniruami Roh one C ₁₀ Al Le force Rubamoiru group, N- § Li one Le sulfonyl § amino C i one C ₆ alkoxy Cal Poni group, § reel sulfamoyl group, § reel sulfamoyl Okishi group, 7 Li one Rusurufamoiru C _x - C 0 alkyl Scarpa moil group, Arylsulfamoyl〇 ₁ _ (: ₆ alkoxycarbonyl group, N-arylcarbamoyl group, aroyl group, alkoxy group, N-aroyl group, N- (N-aroylamino) C! -C ₁₀ alkyl rubamoyl group, N- Aroiruamino C - C ₆ Arukokishikaru Poniru group, C ₂ _C ₆ Arukanoiru group, C ₂ -C ₆ § Luke Noi Ruo alkoxy group, NC ₂ one C ₆ alkanoyloxy Noi Rua amino group, N, N- di - C ₂ _C ₆ alkanoylamino group, N — Ci—C ₆ alkylamino group, N, N—di-C ₆ alkylamino group, NC! -C ₁₀ alkyl rubamoyl group, N, N—Gi Ci-CiQ alkyl Lubamoyl group, NC ₂ _ C ₆ alkenyl carbamoylmethyl group, N, N- di C ₂ - C ₆ alkenyl carbamoyl group, N- Amino ^ - C ^ alkyl force Rubamoiru group, NC _x -C 6 alkoxy C, ~ 0 ₁₀ alkyl force Rubamoyl group, N—CC ₆ alkoxycarbonyl-C ₁₀ alkyl group Rubamoyl group, N—C i _C ₆ alkoxycarbonylamino—C ₁₀ alkyl group Lubamoyl group, N—C “C ₆ alkoxycarbonylamino C — Ce Alkoxycarbonyl group, C — Ce alkylthio group, N— — C ₆ alkylsulfamoyl group, N, N—G C 1 C ₆ alkylsulfamoyl group, C 1 C ₆ alkylsulfinyl group, d—C ₆ alkylsulfonyl Group, c _: -c ₆ alkoxy group, Ci—C ₆ alkoxy carbonyl group, amino di-C _fi alkoxy Carbonyl group, N_C ₃ — < ₆ cycloalkylamino group, N, N-di C ₃ — C ₆ cycloalkylamino group, C ₃ — ₆ cycloalkyloxy group, N—C ₃ — C ₆ cycloalkyl force A group selected from the group consisting of a rubamoyl group, a N, N-di-C ₃ — ( _6- cycloalkyl group and a 5- or 6-membered heterocyclic group, a nitrogen atom, an oxygen atom, and a sulfur atom A mono- to tri-cyclic heteroaromatic group having 1 to 5 heteroatoms per ring system selected from the group consisting of a straight or branched saturated or unsaturated C ! - C ₉ aliphatic groups, C i one C ₆ alkoxy group, one C ₆ alkylthio group, Nyu- - C ₆ alkylamino group, N-CI- C ₆ alkyl force Rubamoiru group, N-Ci-C ₆ alkyl A carbon atom which may have a substituent selected from the group consisting of thiocarbamoyl groups; Kowamoto, 1 to tricyclic C 7-C ₁₅ carbon ring group or a 5- or 6-membered heterocyclic group or a nitrogen atom, a heteroatom 1 ring system selected from the group consisting of SansoHara bar and a sulfur atom 1 to 5 mono- to 3-cyclic heteroaromatic groups (excluding 5- or 6-membered heterocyclic groups),

Ar represents a hydrogen atom, an azide group, an amino group, a rubamoyl group, a rubamoylamino group, a rubamoyloxy group, a lipoxyl group, a cyano group, a sulfamoyl group, a sulfo group, a nitro group, a halogen atom, a hydroxy group, a formyl group, Formylamino group, cyclic saturated or unsaturated C ₃ -C ₉ aliphatic group, aralkyl group, N-aralkylamino group, N, N-diaralkylamino group, aralkyloxy group, aralkylcarbonyl group, N -Aralkyl groups: rubamoyl group, aryl group, N-aryl amino group, N, N-diarylamino group, aryloxy group, arylsulfonyl group, arylsulfonyloxy group, N-arylsulfonylamino group, N - § Li one Le sulfonyl § Mino one C ₆ Arukiruamino group, N- § Li one Rusuruhonirua amino C 〖one C ₁₀ Alkyl force Rubamoiru group, N- § Li one Le sulfonyl § amino C E one C ₆ alkoxy Cal Poni group, § Li one Rusurufamoiru group, § Li one Rusurufamoi Ruokishi group, 7 Li one Rusurufamoiru C _x - C 0 alkyl force Rubamoiru group, Alisulfamoyl. _ C ₆ alkoxycarbonyl group, N-aryl carbamoyl group, aroyl group, alkoxy group, N-aroyl group, N— (N-arylamino) C “C ₁₀ alkyl carbamoyl group, N-aroylamino 1 C ₆ Alkoxy force Luponyl group, C ₂ —C ₆ alkanoyl group, C ₂ —C ₆ alkanoyloxy group, N—C ₂ — C ₆ alkanoylamino group, N, N—di C ₂ — C ₆ alkanoylamino group, N—C ^ —C ₆ alkylamino group, N, N—di-C ₆ alkylamino group, N — Ci—. Alkyl rubamoyl groups, N, N-di-I. Alkyl Scarpa model I le group, N- C ₂ - C ₆ alkenyl carbamoylmethyl group, N, N- di C ₂ -. C ₆ alkenyl carbamoylmethyl group, N- amino (^ primary alkyl force Rubamoiru group, N- one C ₆ Alkoxy G ₁₀ Alkyl Lubamoyl group, NC _x -C ₆ Alkoxy Luponyl C! -1 C. Alkyl Lubamoyl group, N-C "C ₆ Alkoxy Lubamoyl group C ₁₀ Alkyl Lubamoyl group, NC i -Ce alkoxycarbonylamino (^ — Ce alkoxycarbonyl group, 1 C ₆ alkylthio group, NC i 1 C ₆ alkylsulfamoyl group, N, N-di C — C ₆ alkylsulfamoyl group, C! — C ₆ alkylsulfinyl group, C.-Ce alkylsulfonyl group, C ₁ -C ₆ alkoxy group, C ₁ - C ₆ alkoxycarbonyl group, amino one C ₆ alkoxy Kishikaruponiru group, N-C ₃ - C ₆ cycloalkyl § Mino group N, N-di - C ₃ - C ₆ cycloalkylamino group, C ₃ - C ₆ consequent opening Arukiruokishi group, NC ₃ -C ₆ cycloalkyl force Rubamoiru group, N, N-di-C ₃ - ₍₆ cycloalkyl carba A substituent selected from the group consisting of a moly group, a 5- or 6-membered heterocyclic group, and 1 to 5 hetero atoms per ring system selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom A linear or branched saturated or unsaturated C 丄 -C ₉ aliphatic group, which may be substituted with a 1 to 3 cyclic heteroaromatic group or the substituent, a C 1, 1 C ₆ alcohol alkoxy group, CI- Ce alkylthio group, N- one C ₆ alkylamino group, N- E -. C ₆ alkyl force Rubamoiru group has a NC-Ce. alkylthio force Rubamoiru substituents selected from the group ing from the base which may be a carbon aromatic ring group, 1 to 3 rings of the C ₇ - C ₁₅ carbon ring group or 5 young Or a 6-membered heterocyclic group, or a 2- or 3-cyclic fused heteroaromatic group having 1 to 5 heteroatoms per ring system selected from the group consisting of nitrogen, oxygen and sulfur , And 5 or 6 membered heterocyclic groups are excluded.), And n is an integer of 0 to 2.] It has been found that the compound represented by the formula (1) achieves a high blood GLP-1 concentration in vivo. Completed the invention.

The present invention relates to benzothiazepine derivatives and uses thereof, and these inventions are novel ones not described in the literature. Next, various symbols and terms described in this specification will be described.

The C er C ₃ alkyl group such as methyl group, Echiru group, a propyl group can be mentioned, et al are, inter alia methyl, and the like Echiru group.

A C ₆ alkyl group includes, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a neopentyl group, a hexyl group, and an isohexyl group. Among them, isopropyl group, isobutyl group, sec-butyl group, neopentyl group, isohexyl group and the like are preferable.

 Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, among which a fluorine atom, a chlorine atom and an iodine atom are preferred, and a fluorine atom and a chlorine atom are more preferred.

The cyclic saturated or unsaturated C ₃ -C ₉ aliphatic group includes a cyclic alkyl group or alkenyl group having 3 to 9 carbon atoms, among which a cyclic alkyl group having 3 to 6 carbon atoms. Or an alkenyl group, and more preferably a cyclic alkyl group having 3 to 6 carbon atoms.

 Examples of the cyclic alkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and a cyclononyl group. A tyl group and a cyclohexyl group are preferred.

 Examples of the cyclic alkenyl group include a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, a cyclohexenyl group, and a cyclononenyl group. Among them, a cyclopropenyl group, a cyclobutenyl group and the like are exemplified. Group, cyclopentenyl group, cyclohexenyl group and the like.

The aralkyl group means an aralkylyl group having 7 to 15 carbon atoms, specifically, for example, a benzyl group, a monomethylbenzyl group, a phenethyl group, a 3-phenylpropyl group, a 1-naphthylmethyl group. , 2-naphthylmethyl group, α-methyl (1-naphthyl) methyl group, a-methyl (2-naphthyl) methyl group, α-ethyl (1naphthyl) methyl group, Q! -Ethyl (2-naphthyl) ) Methyl group, dibenzylmethyl group, etc., and dinaphthylmethyl group. Among them, benzyl group, 11-naphthylmethyl group Group, 2-naphthylmethyl group, monomethylbenzyl group, phenethyl group, etc.

The N-aralkylamino group means a group in which the above-mentioned aralkyl group is substituted on the amino group, and specifically, for example, N-benzylamino group, N- (1-methylbenzyl) amino group, N-phenethylamino group, N- (3-Phenylpropyl) amino group, N— (1-naphthylmethyl) amino group, N— (2-naphthylmethyl) amino group, N— [Hi-methyl (1-naphthyl) methyl] amino group, N— [1-methyl (2-naphthyl) methyl] amino group, N— [1-ethyl (1-naphthyl) methyl] amino group, N — [— ethyl (2-naphthyl) methyl] amino group, diphenylmethyl amino group, Examples include an N- (dinaphthylmethyl) amino group, and among them, an N-benzylamino group, an N- (α-methylbenzyl) amino group, a Ν-phenethylamino group and the like are preferable.

The Ν, Ν-aralkylamino group means a group obtained by substituting the above aralkyl group for an amino group, and specifically, for example, Ν, Ν-dibenzylamino group, Ν, Ν-di (monomethyl) group. Benzyl) amino group, Ν, Ν-diphenethylamino group, Ν, Ν-di (3-phenylpropyl) amino group, Ν, Ν-di (1-naphthylmethyl) amino group, Ν, Ν-di (2-naphthylmethyl) amino group, Ν, Ν-di [1-methyl (1-naphthyl) methyl] amino group, Ν, ジ -di [monomethyl (2-naphthyl) methyl] amino group, Ν-benzyl- Ν— (α-methylbenzyl) amino group, Ν-benzyl-Ν-phenethylamino group, べ -benzyl-Ν— (3-phenylpropyl) amino group and the like, among which Ν, Ν-dibenzylamino group, Ν,ジ -di (<< _ methylbenzyl) amino group, Ν, Ν-diphen Chiruamino group, and the like are preferable. An aralkyloxy group means a group in which an oxygen atom is substituted by the above aralkyl group. Specifically, for example, a benzyloxy group, an α-methylbenzyloxy group, a phenethyloxy group, a 3-phenylpropoxy group, an Naphthylmethoxy group, 2-naphthylmethoxy group, α-methyl (1-naphthyl) methoxy group, a-methyl (2-naphthyl) methoxy group, α-ethyl (1-naphthyl) methoxy group, α-ethyl (21-naphthyl) methoxy group Naphthyl) methoxy group, diphenylmethoxy group, dinaphthylmethoxy group, etc., among which benzyloxy group, phenylmethylbenzyloxy group, phenethylo group Xyl groups and the like are preferred.

 The aralkylcarbonyl group means a group in which the aralkyl group is substituted on the carbonyl group, specifically, for example, a benzylcarbonyl group, a monomethylbenzylcarbonyl group, a phenethylcarbonyl group, Phenylpropyl carbonyl group, 1-naphthylmethyl carbonyl group, 2-naphthylmethyl carbonyl group, mono-methyl (1-naphthyl) methyl carbonyl group, α-methyl (2-naphthyl) methyl carbonyl group, a-ethyl (1-naphthyl) ) Methylcarbonyl group, methylethyl (2-naphthyl) methylcarbonyl group, diphenylmethylcarbonyl group, dinaphthylmethylcarbonyl group, etc., among which benzylcarbonyl group, 1-methylbenzylcarbonyl group, phenethylcarbonyl group And the like.

 The N-aralkyl molybamoyl group means a group obtained by substituting the above-mentioned aralkyl group with a molybmoyl group, and specifically includes, for example, N-benzylcarbamoyl group, N- (monomethylbenzyl) molybmoyl group, Netyl carbamoyl group, N— (3-phenylphenyl) dirubamoyl group, N— (1-naphthylmethyl) dirubamoyl group, N— (2-naphthylmethyl) dirubamoyl group, N- (α-methyl (1 Naphthyl) methyl) dirubamoyl group, N— (Hi-methyl (2-naphthyl) methyl) dirubamoyl group, N— (1-ethyl (1-naphthyl) methyl) dirubamoyl group, N- (α-ethyl) 2-naphthyl) methyl) rubamoyl group, N- (diphenylmethyl) rubamoyl group, N- (dinaphthylmethyl) rubamoyl group and the like. Yl group, N-(alpha-methylbenzyl) Cal Bamoiru group, Nyu- Hue phenethyl carbamoyl group and the like.

 The aryl group means an aryl group having 6 to 15 carbon atoms, for example, a naphthyl group, a phenyl group and the like, among which a phenyl group and the like are preferable.

 The term "arylamino" means a group obtained by substituting the above-mentioned aryl group with an amino group, specifically, for example, a phenylamino group, a Ν (1-naphthyl) amino group, an Ν— (2— Naphthyl) amino group and the like, among which a Ν-phenylamino group and the like are preferable.

The Ν, Ν-diarylamino group means a group obtained by disubstituting the above aryl group with an amino group. Specifically, for example, 例 え ば, Ν-diphenylamino group, Ν, Ν- Naphthyl) amino group, N, N-di (2-naphthyl) amino group, N-phenyl N- (1-naphthyl) amino group, N-phenyl-N— (2-naphthyl) amino group, N— ( 1-naphthyl) 1 N- (2-naphthyl) amino group, among which N, N-diphenylamino group, N, N-di (1-naphthyl) amino group, N, N-di (2-naphthyl) Amino groups and the like are preferred.

 The aryloxy group means a group in which an oxygen atom is substituted by the above aryl group, and specific examples include a phenoxy group and a naphthyloxy group. Among them, a phenoxy group and the like are preferable.

 The arylsulfonyl group means a group in which the above-mentioned aryl group is substituted on the sulfonyl group, specifically, for example, a phenylsulfonyl group, a naphthylsulfonyl group and the like. Groups and the like are preferred.

 The arylsulfonyloxy group means a group in which a sulfonyloxy group is substituted with the above-mentioned aryl group, and specifically, for example, phenylsulfonyloxy group, naphthylsulfonyloxy group and the like. Among them, a phenylsulfonyloxy group and the like are preferable.

 The N-arylsulfonylamino group means a group in which the above-mentioned arylsulfonyl group is N_substituted for an amino group, specifically, for example, an N-phenylsulfonylamino group, (1_naphthylsulfonyl) amino group, N- (2-naphthylsulfonyl) amino group and the like are preferable, and among them, N-phenylsulfonylamino group and N- (2-naphthylsulfonyl) amino group are preferable.

The N- § Li one Le sulfonyl § amino d-C ₆ alkylamino group, d-C ₆ alkyl groups having on the Symbol of § Li one Le sulfonyl § amino group to Amino group means a N- substituted group Specifically, for example, N-phenylsulfonylaminomethylamino group, N- (1-phenylsulfonylaminoethyl) amino group, N— (2-phenylsulfonylaminoethyl) amino group, N-naphthylsulfonylamino Methylamino group, N- (1-naphthylsulfonylaminoethyl) amino group, N- (2-naphthylsulfonylaminoethyl) amino group and the like, among which N-phenylsulfonylaminomethylamino group, N- (2 —Phenylsulfonylaminoethyl) amino group and the like are preferred. N- § Li one Le sulfonyl § amino d - A C _{1 0} alkyl force Rubamoiru group, C i one C ₆ alkyl group having the above-mentioned § Li one Le sulfonyl § amino group to cull Bamoiru group N- substituted group And specifically, for example, an N-phenylsulfonylaminomethylcarbamoyl group, an N- (1-phenylsulfonylaminoethyl) caproluvyl group, an N- (2-phenylsulfonylaminoethyl) caproluvyl group , N-naphthylsulfonylaminomethylcarbamoyl group, N_ (1-naphthylsulfonylamino) ethyl group, a rubamoyl group, N— (2-naphthylsulfonylaminoethyl) group, and a rubamoyl group Minomethylcarbamoyl group, N- (2-phenylsulfonylaminoethyl) carbamoyl group, N— (2-naphthylsulfonylaminoethyl group Le) force Rubamoiru group are preferable.

The N- § reel sulfonyl § amino d-C ₆ alkoxy Cal Poni Le group, N- § Li one Le sulfonyl § Mino C! - The C ₆ alkoxy Cal Poni group, a group of the above N- § Li one Le sulfonyl § amino group is substituted with one C ₆ alkoxy Cal Poni Le group was meaning taste, specifically, for example N- phenylalanine sulfonylamino methoxy Cal Poni Le Group, N-naphthylsulfonylaminomethoxycarbonyl group, 1- (N-phenylsulfonylamino) ethoxycarbonyl group, 2- (N-phenylsulfonylamino) ethoxycarbonyl group, etc., among which N-phenylsulfonylaminomethoate Xycarbonyl group, N-naphthylsulfonylaminomethoxycarbonyl group and the like are preferable.

 The arylsulfamoyl group means a sulfamoyl group substituted with the above aryl group, and specifically includes, for example, a phenylsulfamoyl group, a naphthylsulfamoyl group and the like, and among them, a phenylsulfamoyl group and the like. preferable.

 The arylsulfamoyloxy group means a sulfamoyloxy group substituted with the above aryl group, specifically, for example, phenylsulfamoyloxy group, naphthylsulfayl group Moyloxy groups and the like can be mentioned, among which phenylsulfamoyloxy groups and the like are preferable.

The arylsulfamoyl C 11 -C] _ 0 alkyl rubamoyl group means a group in which the above arylsulfamoyl is substituted with a d-C ₁₀ alkyl rubamoyl group, and specifically, for example, phenylsulfamoyl Moylmethylcarbamoyl group, naphthyls And a phenylsulfamoylmethylcarbamoyl group.

§ Li one Rusurufamoiru (^ - The C ₆ alkoxy Cal Poni group, means a group above § Li one Rusurufamoiru has been substituted with d-C ₆ alkoxy Cal Poni group, concrete in, for example Hue acylsulfamoyl methoxy Cal Poni Le group And a naphthylsulfamoylmethoxycarbonyl group, among which a phenylsulfamoylmethoxycarbonyl group and the like are preferable.

 The N-arylcarbamoyl group means a group in which the above aryl group is N-substituted with a carbamoyl group, and specifically includes, for example, a phenylcarbamoyl group, a naphthylcarbamoyl group and the like. And the like.

 An aroyl group means a group in which a carbonyl group is substituted with the above-mentioned aryl group, and specific examples thereof include a benzoyl group and a naphthylcarboel group, and among them, a benzoyl group and the like are preferable.

 The alkoxy group means a group in which the above-mentioned aroyl group is substituted by an oxygen atom, and specifically includes, for example, a benzoyloxy group, a naphthylcarponyloxy group and the like, and among them, a benzoyloxy group and the like are preferable.

 The N-aroyl group means a group in which the above-mentioned aroyl group is substituted by a nitrogen atom, and specific examples include a benzoylamino group and a naphthylcarponylamino group, and among them, a benzoylamino group and the like are preferable.

The N— (N-aroylamino) d _C ₁₀ alkyl rubamoyl group means a group obtained by substituting a rubamoyl group with the above-mentioned N-aroylamino C 11 -Ci 0 alkyl group. N- (N-benzoylaminomethyl) rubamoyl group, N- (1- (N-benzoylamino) ethyl) rubamoyl group, N— (2- (N-benzoyl) aminoethyl) rubamoyl group, N— (N-naphthylcarbonylaminomethyl) rubamoyl group, N— (1- (N-naphthylcarbonylamino) ethyl) rubamoyl group, N— (2- (N-naphthylcarbonylamino) ethyl) rubamoyl group Among them, an N- (N-benzoylaminomethyl) carbamoyl group and an N- (2- (N-benzoylamino) ethyl) rubamoyl group are preferable. The N-aroylamino d-Ce alkoxycarbonyl group means a group in which the above-mentioned N-aroylamino d-C ₆ alkyl group is substituted for an oxycarbonyl group, and specifically, for example, an N-benzoylaminomethoxycarbonyl group , 1- (N-benzoylamino) ethoxycarbonyl group, 2_ (N-benzoylamino) ethoxycarbonyl group, N-naphthylcarbonylaminomethoxycarbonyl group, 1- (N-naphthylcarbonylamino) ethoxycarbonyl group, 2- (N-naphthylcarbonylamino) ethoxycarbonyl group and the like, among which an N-benzoylaminomethoxycarbonyl group and a 2_ (N-benzoylamino) ethoxycarbonyl group are preferable.

The C ₂ -C ₆ alkanol group means a carbonyl group substituted with an alkyl group having 1 to 5 carbon atoms, and specifically includes, for example, an acetyl group, a propionyl group, a butyryl group, an isoptyryl group, and a valeryl group. Group, isovaleryl group, pivaloyl group, pentanoyl group and the like. Among them, acetyl group, propionyl group, pivaloyl group and the like are preferable.

The C ₂ —C ₆ alkenyl group refers to a group in which the above-mentioned C ₂ -C ₆ alkynyl group is substituted for a hydroxyl group, specifically, for example, an acetyloxy group, a propionyloxy group, a butyryloxy group, Examples include an isoptyryloxy group, a valeryloxy group, an isovaleryloxy group, a pivaloyloxy group, and a pentanoyloxy group. Of these, an acetyloxy group, a propionyloxy group, and a vivaloyloxy group are preferable.

The N—C ₂ —C ₆ alkanoylamino group refers to a group in which the above C ₂ —C ₆ alkanoyl group is substituted for an amino group, and specifically, for example, an N—acetylamino group, Mouth pionylamino, N-butyrylamino, N-isobutyrylamino, N-valerylamino, N-isovalerylamino, N-bivaloylamino, N-pentanoylamino, etc. Preferred are an acetylamino group, an N-piopenylamino group, an N-pivaloylamino group and the like.

N, N - The C ₆ alkanoyloxy Noi Rua amino group, the Amino group of the C ₂ - - di -C ₂ C ₆ Arukanoiru group means two substituted groups, and specific examples N, N-Jiasechi A lumino group, an N, N-dipropionylamino group, an N, N-dibutyrylamino group, N, N-diisobutyrylamino group, N, N-divalerylamino group, N, N-diisovalerylamino group, N, N-dipiparylylamino group, N, N-dipentanoylamino group, N-acetyl-N- A propionylamino group, an N-acetyl-N-butylylamino group, an N-acetyl-N-piparylylamino group and the like, among which N, N-diacetylamino, N, N-dipropionylamino, N, N-diisopropyl Amino group, N, N-dibutylamino group, N, N-dipivaloylamino group and the like are preferable.

The N-Ci-C ₆ alkylamino group means a group in which an amino group is substituted with an alkyl group having 1 to 6 carbon atoms, specifically, for example, N-methylamino group, N-ethylamino group, N- To propylamino group, N-isopropylamino group, N-butylamino group, N-isobutylamino group, N-sec-butylamino group, N-tert-butylamino group, N-pentylamino group, N-neopentylamino group, N- Xylamino group, N-isohexylamino group and the like. Among them, N-methylamino group, N-ethylamino group, N-propylamino group, N-isopropylamino group, N-butylamino group, N-isobutylamino group, — Tert-butylamino group and the like are preferable.

The N, N-di-d-C ₆ alkylamino group means a diamino-substituted alkyl group having 1 to 6 carbon atoms, specifically, for example, N, N-dimethylamino group, N, N-diethylamino, N, N-dipropylamino, N, N-diisopropylamino, N, N-dibutylamino, N, N-ditert-butylamino, N, N-dipentylamino, N, N-dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N-isopropyl-N-methylamino group, N-tert-butyl-N-methylamino group, N-ethyl N-isopropylamino group and the like, among which N, N-dimethylamino group, N, N-diethylamino group, N, N-diisopropylamino group, N, N-dibutylamino group, N, N-ditert-butylamino group The N_ethyl N-methylamino, N-methyl-N-propylamiso, N-isopropyl N-methylamino, N-ethyl-N-isopropylamino and the like are preferred.

N—Ci—C ₁₀ alkyl rubamoyl group means that the rubamoyl group does not have 1 carbon atom And a group substituted by 10 alkyl groups, specifically, for example, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, Butylcarbamoyl, N-isobutyl carbamoyl, N-sec-butylcarbamoyl, N-tert-butylcarbamoyl, N-pentylcarbamoyl, N-neopentylcarbamoyl, N-hexylcarbamoyl, N-iso A xylcarbamoyl group, an N-octylcarbamoyl group, an N-decylcarbamoyl group, and the like. Among them, an N-methyl rubamoyl group, an N-ethyl carbamoyl group, an N-propyl carbamoyl group, an N-isopropyl carbamoyl group, N-isobutylcarbamoyl group, N-sec-butyl carbamoyl group, N-tert-butyl Rubamoiru group, N- old Kuchiruka Rubamoiru group, N- dodecylcarbamoyl group and the like.

 The N, N-di-C i-C ioalkyl rubamoyl group refers to a group obtained by disubstituting a carbamoyl group with an alkyl group having 1 to 10 carbon atoms. Specifically, for example, N, N —Dimethylcarbamoyl group, N, N-Getylilecarbamoyl group, N, N —Dipropyl rubamoyl group, N, N-Diisopropyl rubamoyl group, N, N-dibutylcarbamoyl group, N, N-ditert-butylcarbamoyl N, N-dipentylcarbamoyl, N, N-dihexylcarbamoyl, N-ethyl N-methylcarbamoyl, N-isopropyl-N-methylcarbamoyl, N-tert-butyl-N-methylcarbamoyl , N-ethyl-N-isopropyl pyrumomoyl group and the like, among which N, N-dimethylcarbamoyl group, N, N-getylcarbamoyl group, N, N-diisopropyl N-N-dibutylcarbamoyl, N, N-ditert-butylcarbamoyl, N-ethyl-N-methylcarbamoyl, N-isopropyl-N-methylcarbamoyl, N-ethyl-N— Isopropyl rubamoyl groups and the like are preferred.

N - C ₂ - A C ₆ alkenyl carbamoylmethyl group, having 2 to carbon Karupamoiru based means a group alkenyl group substituted consisting six, specifically for example, N- vinyl carbamoyl group, N- Ariru force Rubamoyl group, N- (1-probenyl) carbamoyl group, N-isoprobenylcarbamoyl group, N- (2-butenyl) carbamoyl group, N-isobutenylcarbamoyl group, N— (2-pentenyl) Cal Bamoyl group, N- (2-hexenyl) carpamoyl group, N- (2-heptenyl) -powered rubamoyl group, N- (2-octenyl) -powered rubamoyl group, etc., among which N-vinylcarbamoyl group, Preferred are an N-arylcarpamoyl group, an N- (1-proenyl) capilluvyl group and the like.

The N, N-di-C ₂ -C ₆ alkenylcarbamoyl group refers to a disubstituted alkamoyl group having 2 to 6 carbon atoms in a carbamoyl group. Specifically, for example, N, N— Dipinylcarbamoyl group, N, N-diallyl rubamoyl group, N, N-di (1-propenyl) rubamoyl group, N, N-diisopropenyl carbamoyl group, N-aryl-1-N-vinylcarbamoyl group , N-aryl-N-isobutenyl carbamoyl group, N-aryl-N- (2-pentenyl) -powered rubamoyl group, N-aryl-N- (2-hexenyl) -powered rubamoyl group, N-aryl-N- (2 —Heptenyl) carbamoyl group, N-aryl-N— (2-octenyl) carbamoyl group, etc., among which N-aryl-N-vinylcarbamoyl group, N, N—diaryl lvamoyl group, N-aryl — N— (1—Pro Yl) force Rubamoiru group are preferable.

N- The Amino Ci one C _{1 0} alkyl force Rubamoiru group, 1 -C force Rubamoiru based means a group aminoalkyl group consisting of 1 0-substituted, specifically, example if N- amino-methylcarbamoyl N-aminoethylcarbamoyl group, N-aminopropylcarbamoyl group, N-aminomethylethylcarbamoyl group, N-aminobutylcarbamoyl group, N-aminopropylcarbamoyl group, N-aminopropylcarbamoyl group, N-aminopentylcarbamoyl group, N— Examples include an aminohexylcarbamoyl group, and among them, an N-aminomethylcarbamoyl group, an N-aminoethylcarbamoyl group, an N-aminopropylcarbamoyl group, and an N_aminomethylethylcarbamoyl group are preferable.

N—d—C ₆ alkoxy d—C ₁₀ alkyl rubamoyl group refers to a group in which an alkoxy group having 1 to 10 carbon atoms is N-substituted to the above-mentioned C ₁ -C _{1 0} alkyl rubamoyl group. And specifically, for example, N-methoxymethylcarbamoyl, N-methoxyethylcarbamoyl, N-methoxypropylcarbamoyl, N-methoxybutylcarbamoyl, N-ethoxypentylcarbamoyl And N-butoxyhexylcarbamoyl group, among which N-methoxymethylcarbamoyl group, N-methoxyethylcarbamoyl group, N-methoxypropylcarbamoyl group, N-methoxybutylcarbamoyl group and the like are preferable.

N - a Ci o alkyl force Rubamoiru 1 -C based to an alkoxycarbonyl group composed of six N- substituted group - C i - Ce alkoxy Cal The Poni Le Ci _ C _{1 0} alkyl force Rubamoiru group, the above d And specifically, for example, N-methoxycarbonylmethylcarbamoyl group, N-methoxycarbonylethylcarbamoyl group, N-methoxycarbonylpropyl carbamoyl group, N-methoxycarbonylbutylcarbamoyl group, N-ethoxycarbonyl A pentylcarbamoyl group, an N-butoxycarbonylhexylcarbamoyl group, an N-tert-butoxycarbonylethylcarbamoyl group, etc., among which an N-methoxycarbonylmethylcarbamoyl group, an N-methoxycarbonylethylcarbamoyl group, —Methoxycarbonylpropyl group rubamoyl group, N-meth A xycarbonylbutylcarbamoyl group, an N-tert-butoxycarbonylethylcarbamoyl group and the like are preferable.

N—C 1 -C ₆ alkoxycarbonylamino d — C ioalkylcarbamoyl group means a C 1 C] L 0 alkyl group having an alkoxycarbonylamino group having 1 to 6 carbon atoms in addition to an N-alkylcarbamoyl group. Means a substituted group, specifically, for example, N-methoxycarbonylaminomethylcarbamoyl group, N-methoxycarbonylaminoethylcarbamoyl group, N-methoxycarbonylaminopropyl carbamoyl group, N-methoxycarbonylaminobutylcarbamoyl Group, N-ethoxycarbonylaminopentylcarbamoyl group, N-butoxycarbonylaminohexylcarbamoyl group, N-tert-butoxycarbonylaminoethylcarbamoyl group, etc., among which N-methoxycarbonylaminomethylcarbamoyl Group, N-methoxycarbonylaminoethylcal Moil group, N- methoxy Cal Poni Rua amino propyl force Rubamoiru group, N- methoxycarbonylamino butylcarbamoyl group, N- tert-butoxy-carbonitrile El amino Edji carbamoyl group and the like

N - d - Ce alkoxy force Ruponiruamino C i - The C ₆ alkoxy force Ruponiru group, 1 -C on Ci one C ₆ alkoxy Cal Poni Le group consisting of six alkoxy It means a N-substituted cycarponylamino group, specifically, for example, N-methoxycarbonylaminomethoxycarbonyl group, N-methoxycarbonylaminoethoxycarbonyl group, N-methoxycarbonylaminopropoxycarbonyl group N-methoxycarbonylaminobutoxycarbonyl group, N-ethoxycarbonylaminopentyloxycarbonyl group, N-butoxycarbonylaminohexyloxycarbonyl group, N-tert-butoxycarbonylaminoethoxycarbonyl group, etc. N-methoxycarbonylaminomethoxycarbonyl group, N-methoxycarbonylaminoethoxycarbonyl group, N-methoxycarbonylaminopropoxycarbonyl group, N-methoxycarbonylaminobutoxycarbonyl group, N-tert-butoxy Cal Poni Le aminoethoxy Cal Poni Le group and the like.

 The d-Cealkylthio group means a group in which a sulfur atom is substituted with an alkyl group having 1 to 6 carbon atoms, and specifically, for example, a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group Group, isobutylthio group, sec monobutylthio group, tert-butylthio group, pentylthio group, neopentylthio group, hexylthio group, isohexylthio group, etc., among which methylthio group, ethylthio group, propylthio group, isopropylthio group, A butylthio group, a tert-butylthio group and the like are preferred.

 The N-d-Ce alkylsulfamoyl group means a group in which a sulfamoyl group is substituted by an alkyl group having 1 or 6 carbon atoms, specifically, for example, an N-methylsulfamoyl group, an N-ethyls group. Rufamoyl group, N_propylsulfamoyl group, N_isopropylsulfamoyl group, N-butylsulfamoyl group, N-isobutylsulfamoyl group, N-sec monobutylsulfamoyl group, N— tert-butylsulfamoyl group, N-pentylsulfamoyl group, N-neopentylsulfamoyl group, N-hexylsulfamoyl group, N-isohexylsulfamoyl group, and the like. Famoyl, N-ethylsulfamoyl, N-isopropylsulfamoyl, N-tert-butylsulfamoyl and the like are preferred.

N, N-Gee d—C ₆ alkylsulfamoyl group means It means a group in which an alkyl group having 1 to 6 carbon atoms is disubstituted. For example, N, N-dimethylsulfamoyl, N, N-getylsulfamoyl, N, N-dipro Pyrsulfamoyl group, N, N-diisopropylsulfamoyl group, N, N-dibutylsulfamoyl group, N, N-ditert-butylsulfamoyl group, N, N-dimethylsulfamoyl group, N, N-dihexylsulfamoyl, N-ethyl-N-methylsulfamoyl, N-isopropyl-N-methylsulfamoyl, N-tert-butyl-N-methylsulfamoyl, N-ethyl-N- Isopropylsulfamoyl group; among them, N, N-dimethylsulfamoyl group, N, N-diethylsulfamoyl group, N, N-diisopropylsulfamoyl group, N, N-dibutylsulfamoyl group Group, N, N-ditert-butylsulfamoyl group, N-ethyl-N-methylsulfamoyl group, N-isopropyl-N-methylsulfamoyl group, N-ethyl-N- ^ Rufamoyl and the like are preferred.

The Ci one C ₆ alkyl sulfide El group, 1 -C sulfinyl alkyl group composed of six is meant substituted group, specifically, for example Mechirusurufi two group, E chill sulfide El, propyl sulfinyl Group, isopropylsulfinyl group, butylsulfinyl group, isobutylsulfinyl group, sec-butylsulfinyl group, tert-butylsulfinyl group, pentylsulfinyl group, neopentylsulfinyl group, hexylsulfinyl group, isohexylsulfinyl group, etc. Among them, a methylsulfinyl group, an ethylsulfinyl group, a propylsulfinyl group, an isopropylsulfinyl group, a butylsulfinyl group, a tert-butylsulfinyl group and the like are preferable.

d—C ₆ alkylsulfonyl group means a group in which a sulfonyl group is substituted by an alkyl group having 1 to 6 carbon atoms, specifically, for example, methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropyl A sulfonyl group, a butylsulfonyl group, an isobutylsulfonyl group, a sec-butylsulfonyl group, a tert-butylsulfonyl group, a pentylsulfonyl group, a neopentylsulfonyl group, a hexylsulfonyl group, and an isohexylsulfonyl group. Methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl And a tert-butylsulfonyl group and the like.

 The C i -Ce alkoxy group means a group in which an oxygen atom is substituted by an alkyl group having 1 to 6 carbon atoms, and specifically, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group Group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, neopentyloxy group, hexoxy group, isohexyloxy group, etc., among which methoxy group, ethoxy group, propoxy group, isopropoxy group Group, butoxy group, isobutoxy group, tert-butoxy group and the like are preferable.

The d—C ₆ alkoxycarbonyl group means a group in which a carbonyl group is substituted with an alkoxy group having 1 to 5 carbon atoms, specifically, for example, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group. Group, isopropoxyl propyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, neopentyloxycarbonyl group, and the like. Among them, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, a tert-butoxycarbonyl group and the like are preferable. The amino d-C ₆ alkoxycarbonyl group means a group in which a carbonyl group is substituted with an aminoalkoxy group having 1 to 6 carbon atoms, specifically, for example, an aminomethoxycarbonyl group, an aminoethoxycarbonyl group, Aminopropoxy carbonyl, 2-amino-2-methylpropoxy carbonyl, 2-aminomethyl ethoxycarbonyl, aminobutoxy carbonyl, 2-amino propoxy Luponyl, aminopentyloxy carbonyl, amino Xyloxycarbonyl group and the like, among which aminomethoxycarbonyl group, aminoethoxycarbonyl group, aminopropoxycarbonyl group, 2-aminomethylethoxycarbonyl group, 2-amino-2-methylpropoxycarbonyl group, etc. Is preferred.

N—C ₃ — ( _6- cycloalkylamino group refers to a group in which a cyclic alkyl group having 3 to 6 carbon atoms is N-substituted on an amino group, and specifically, for example, an N-cyclopropylpyramino group , N-cyclobutylamino group, N-cyclopentylamino group, N-cyclohexylamino group and the like, among which N-cyclopropylamino group , N- cyclopentyl Rua amino group, N- cycloheteroalkyl Kishiruamino group and the Shi-liked ^ N, N- di C ₃ - and Ji ₆ cycloalkylamino group, an annular in Amino group consisting six number 3 of stone carbon It means a group in which an alkyl group is disubstituted, and specifically, for example, N, N-dicyclopropylamino group, N, N-dicyclobutylamino group, N, N-dicyclopentylamino group, N, N -Dicyclohexylamino group, N-cyclobutyl-N-cyclopropylamino group, N-cyclopentyl-N-cyclopropylamino group, N-cyclohexyl N-cyclopropylamino group and the like. , N-dicyclopropylamino, N, N-dicyclobutylamino, N, N-dicyclopentylamino and the like.

Flip ₃ _ ₍₆ Cycloalkyl O alkoxy group, C 3 -C oxygen atom 6 becomes ring-shaped alkyl group means a group obtained by substituting, for example, N- cyclopropoxy group, N- sheet Kurobutokishi group, Examples thereof include an N-cyclopentyloxy group and an N-cyclohexyloxy group, among which an N-cyclopropoxy group, an N-cyclopentyloxy group, an N-cyclohexyloxy group and the like are preferable.

N - C ₃ - The C ₆ cycloalkyl force Rubamoiru group, 3 -C force Rubamoiru based means 6 comprising a cyclic group in which the alkyl group is substituted, such as N- Shikuropuro pills force Rubamoiru group, N- cyclo Examples include a butylcarbamoyl group, an N-cyclopentylcarbamoyl group, an N-cyclohexylcarbamoyl group, and among them, an N-cyclopropylcarbamoyl group, an N-cyclopentylcarbamoyl group, and an N-cyclohexylcarbamoyl group are preferable.

The N, N-di-C ₃ -C ₆ cycloalkyl forcerubamoyl group means a group in which a forcerubamoyl group is disubstituted with a cyclic alkyl group having 3 to 6 carbon atoms. N-dicyclopropyl rubamoyl group, N, N-dicyclobutyl carbamoyl group, N, N-dicyclopentylcarbamoyl group, N, N-dicyclohexylcarbamoyl group, N-cyclobutyl-N-cyclopropyl rubamoyl group, N-cyclopentyl -N-cyclopropyl rubamoyl group, N-cyclohexyl N-cyclopropyl rubamoyl group, etc., among which N, N-dicyclopropyl rubamoyl group, N, N-dicyclobutylcarbamoyl group, N, N —Dicyclopentylcarbamoyl group and the like are preferable. The 5- or 6-membered heterocyclic group includes, for example, an isoxazolyl group, an isothiazolyl group, an imidazolyl group, an oxazolyl group, an oxaziazolyl group, a thiazolyl group, a thiaziazolyl group, a chenyl group, a triazinyl group, a triazolyl group, a pyridyl group, a pyrazyl group, Pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group, pyrrolyl group, virazyl group, furyl group, furazanyl group, imidazolidinyl group, imidazolinyl group, tetrahydrofuranyl group, pyrazolidinyl group, pyrazolinyl group, piperidinyl group, piperidinyl group Group, pyrrolidinyl group, pyrrolinyl group, morpholino group and the like. Among them, isooxazolyl group, isothiazolyl group, imidazolyl group, oxazolyl group, thiazolyl group, chenyl group, pyridyl group, pyrazyl group Piraji group, pyrimidinyl group, pyridazinyl group, pyrazolyl group, pyrrolyl group, pyranyl group, furyl group, tetrahydrofuranyl group, morpholino group and the like are preferable.

 A mono- to tri-cyclic heteroaromatic group having 1 to 5 heteroatoms per ring system selected from the group consisting of nitrogen, oxygen and sulfur is, for example, an acridinyl group, an isoquinolyl group, an isoindolyl group , Indazolyl group, indolyl group, indolizinyl group, ethylenedioxyphenyl group, carbazolyl group, quinazolinyl group, quinoxalinyl group, quinolizinyl group, quinolyl group, coumalonyl group, chromenyl group, fenanslidinyl group, fenansloryl Nyl group, dibenzofuranyl group, dibenzothiophenyl group, cinnolinyl group, thonaphthenyl group, naphthyridinyl group, phenazinyl group, phenaxazinyl group, phenothiazinyl group, phthalazinyl group, pteridinyl group, purinyl group, benzoimidazolyl group, benzoxazolyl group Le Benzothiazolyl group, benzotriazolyl group, benzofuranyl group, methylenedioxyphenyl group, etc., among which ethylenedioxyphenyl group, dibenzofuranyl group, dibenzothiophenyl group, methylenedioxyphenyl group, etc. Is preferred.

The linear or branched, saturated or unsaturated d-C ₉ aliphatic groups, straight-chain or branched alkyl group 1 -C consisting nine, alkenyl or include alkynyl groups Among them, a linear or branched alkyl group having 1 to 6 carbon atoms, an alkenyl group or an alkynyl group is preferred.

The alkyl group is, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group. Butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, neopentyl group, hexyl group, isohexyl group, heptyl group, octyl group, nonyl group, etc., among which methyl group, ethyl group Group, propyl group, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group and the like. The alkenyl group includes, for example, vinyl group, aryl group, 1-propenyl group, isopropenyl group, 2-butenyl group, isobutenyl group, 2-pentenyl group, 2-hexenyl group, 2-heptenyl group And 2-octenyl group, among which vinyl group, aryl group, 1-propenyl group and the like are preferable.

 The alkynyl group includes, for example, ethynyl group, 1-propenyl group, 1-butenyl group, 11-pentenyl group, 1-hexynyl group, 11-heptynyl group, 1-octynyl group and the like. And a 1-propynyl group.

 The N-Ci-Cjo alkyl rubamoyl group means a carbamoyl group substituted with an alkyl group having 1 to 10 carbon atoms, specifically, for example, an N-methylcarbamoyl group, —Ethylcarbamoyl group, N _propylcarbamoyl group, N-isopropylcalilevamoyl group, N-butylcarbamoyl group, N_isobutylcarbamoyl group, N-sec-butylcarbamoyl group, N-tert-butylcarbamoyl group, N-pentylcarbamoyl group, N-neopentylcarbamoyl group, N-hexylcarbamoyl group, N-isohexylcarbamoyl group, N-butylcarbamoyl group, N-decylcarbamoyl group, etc., among which N-methyl L-bamoyl group, N-ethylcarbamoyl group, N-propyl-lubamoyl group, N-isopropyl l-rubamoyl group, N-iso A butylcarbamoyl group, N-sec-butylcarbamoyl group, N-tert-butylcarbamoyl group, N-octylcarbamoyl group, N-decylcarbamoyl group and the like are preferable.

N—C “CJ 0 alkylthioalkavamoyl group means a group in which a thiocarbamoyl group is N-substituted with an alkyl group having 1 to 10 carbon atoms, and specifically, for example, an N-methylthioalkavamoyl group N-ethylthiolrubamoyl group, N-propylthiolrubamoyl group, N-isopropylthiolrubamoyl group, N-butyltylylrubamoyl group, NTsobutylthiolrubamoyl group, N-sec-butylbutylcarbamoyl group, N-tert —Butylthiocarpamoyl group, N—Pentylchi Carbamoyl group, N-neopentylthiolrubamoyl group, N-hexylthiolrubamoyl group, N-isohexylthiolrubamoyl group, N-octylthiolrubamoyl group, N-decylthiolrubamoyl group, and the like. Among them, N-methylthiol-rubamoyl, N-ethylthiol-rubamoyl, N-propylthio-lumbamoyl, N-isopropylthio-lumbamoyl, N-isobutylthiol-luvamoyl, N-sec-butylthiol-luvamoyl, N-tert -A butylthiocarbamoyl group, an N-octylthiolrubamoyl group, an N-decylthiolrubamoyl group and the like are preferable.

The monocyclic to tricyclic C ₇ -C ₁₅ carbon aromatic ring group excludes the above aryl group, and includes, for example, an acenaphthylenyl group, an adamantyl group, an anthryl group, an indenyl group, a norpolnyl group, a phenanthryl group and the like. Among them, an anthryl group and a phenanthryl group are preferred.

 A mono- to tricyclic fused heteroaromatic group having 1 to 5 heteroatoms per ring system selected from the group consisting of nitrogen, oxygen and sulfur atoms (however, a 5- or 6-membered heterocyclic group ) Means, for example, an acridinyl group, an isoquinolyl group, an isoindolyl group, an indazolyl group, an indolyl group, an indolizinyl group, an ethylenedioxyphenyl group, a carbazolyl group, a quinazolinyl group, a quinoxalinyl group, a quinolyl group, a cumaronyl group, an isochromanyl group; Chromenyl group, phenanthridinyl group, phenanthrolidyl group, dibenzofuranyl group, dibenzothiophenyl group, thionaphthenyl group, naphthyridinyl group, fenadinyl group, phenaxazinyl group, phenothiazinyl group, furazinyl group, pteridinyl group, Purinyl group, benzimi Dazolyl group, benzoxazolyl group, benzothiazolyl group, benzoto, liazolyl group, benzofurayl group, dihydrobenzozofuranyl group, methylenedioxyphenyl group, etc., among which ethylenedioxyphenyl group, dibenzofuranyl Group, dibenzothiophenyl group, methylenedioxyphenyl group and the like.

R ¹ and R ² are the same or different and each represent, for example, a hydrogen atom or a -alkyl group, and among them, a hydrogen atom is preferable.

R ³ represents, for example, a hydrogen atom or a ^-^ alkyl group (excluding n-butyl group), and among them, a C ₂ -C ₆ alkyl group (excluding n-butyl group) is preferable. Particularly, for example, a C ₃ -C ₅ branched alkyl group is suitable.

R ⁴ represents, for example, a hydrogen atom, a hydroxyl group or a 1 C ₃ alkyl group, among which a hydrogen atom and a —C ₃ alkyl group are preferable, and a hydrogen atom is particularly preferable.

R ⁵ is, for example, a hydrogen atom, an azide group, an amino group, a carbamoyl group, a carbamoylamino group, a carbamoyloxy group, a propyloxyl group, a cyano group, a sulfamoyl group, a sulfo group, a nitro group, a halogen atom, a hydroxy group, Formyl group, formylamino group, cyclic saturated or unsaturated C ₃ -C ₉ aliphatic group, aralkyl group, N-aralkylamino group, N, N-diaralkylamino group, aralkyloxy group, aralkyl Kilcarponyl group, N-aralkyl rubamoyl group, aryl group, N-aryl amino group, N, N-diarylamino group, aryloxy group, arylsulfonyl group, arylsulfonyloxy group, N-arylsulfonyl Amino group, N-arylsulfonylamino CC ₆ alkylamino group, N-arylsulfonylamino C _{1 0} alkyl force Rubamoiru group, N- § Li - Le sulfonyl § amino CI- C ₆ alkoxy Cal Poni group, § Li one Rusurufamoiru group, § Li one Rusurufu Amoiruokishi group, § reel sulfamoyl. One. Alkylsulfamoyl group, arylsulfamoyl. i one C ₆ alkoxycarbonyl group, N- Arirukaru Bamoiru group, Aroiru group, Arokishi group, N- Aroiru group, N- (N-Aroirua Mino) C ^ Co alkyl force Rubamoiru group, N- Aroiruamino (:丄one C ₆ Alkoxycarbonyl group, C ₂ —C ₆ alkanoyl group, C ₂ —C ₆ alkanoyloxy group, N—C ₂ _C ₆ alkanoylamino group, N, N—di—C ₂ _C ₆ alkanoylamino group, N—Ci—C ₆ alkylamino group, N, N—diCi—C ₆ alkylamino group, N——C _1Q alkyl rubamoyl group, N, N—di — (^-^^ alkircalcarbamoyl group, N— C ₂ - C ₆ alkenyl carbamoylthiopheno Sole group, N, N-di-C ₂ - C ₆ alkenyl carbamoylmethyl group, N_ Ami one C ₁₀ alkyl force Rubamoiru group, N -, - C ₆ alkoxy C -!. C i alkyl L-bamoyl group, N — ^-C ₆ alkoxycarbonyl C _{1 ()} alkyl rubamoyl group, N—1 C ₆ alkoxy ruponylamino Ci—C i Q alkyl rubamoyl group, N _C i—C ₆ alkoxy rupponylamino d—C ₆ alkoxy carbonyl, Ci— Ce alkylthio group, N eleven C ₆ alkylsulfamoyl group, N, N-di-C - Ce alkylsulfamoyl Moil group, C - C ₆ alkylsulfinyl group, CI- C ₆ alkylsulfonyl group, Ct-C ₆ alkoxy group, an alkoxycarbonyl Cal Poni group, an amino one ₍₆ § Le Koki deer Lupo sulfonyl group, N-C ₃ - C ₆ cycloalkyl amino group, N, N-di--C ₃ _C ₆ cycloalkylamino group, C ₃ -〇 ₆ cycloalkyl O alkoxy group, N-C ₃ one C ₆ cycloalkyl force Rubamoiru group, N, N-di-C ₃ - ( ₆ Cycloalkyl group) A substituent selected from the group consisting of a rubamoyl group, a 5- or 6-membered heterocyclic group, a heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom is contained in one ring system. A linear or branched, saturated or unsaturated C A C ₉ aliphatic group which may be substituted with a mono- to tricyclic heteroaromatic ring group having 5 C ₆ alkoxy group, C—C ₆ alkylthio group, A carbon aromatic ring group which may have a substituent selected from the group consisting of N-Ci-Ce alkylamino group, NC _x -C ₆ alkyl rubamoyl group, and N-Ci-C ₆ alkylthio rubamoyl group , 1 to 3 cyclic C ₇ — C] L ₅ carbon aromatic ring groups or 5 or 6 membered heterocyclic groups or a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur atoms per ring system A 5- to 6-membered heteroaromatic group (excluding a 5- or 6-membered heterocyclic group) having 5 to 5 carbon atoms, and among them, a carbon-aromatic ring group is a phenyl group or a naphthyl group; The substituent of the carbon-aromatic ring group which may be substituted is a hydrogen atom, an azide group, an amino group, a carbamoyl group, a carbamoylamino group, a carbamoyloxy group, a propyloxyl group, a cyano group, a nitro group, Halogen atom, hydroxy group, cyclic saturation Or unsaturated C ₃ -C ₉ aliphatic group, aralkyl group, N-aralkylamino group, aralkyloxy group, aralkylcarbonyl group, N-aralkyl carbamoyl group, aryl group, N-arylalkylamino group, araryloxy group, § reel sulfonyl group, Arirusuru Honiruokishi group, N- § Li one Le sulfonyl § amino C i-C ₆ alkoxy Cal Poni group, § reel sulfamoyl group, § Li one Rusuru sulfamoyl O alkoxy group, Arirusu Rufamoiru C E _ C i. Alkyl carbamoyl group, arylsulfamoyl 〇 ₁ _C ₆ alkoxycarbonyl group, N-arylcarbamoyl group, aroyl group, alkoxy group, N-aroyl group, C ₂ _C ₆ alkanol group, C ₂ — C ₆ alkanoyloxy, N—C ₂ _C ₆ alkanoylamino, N, N—di C ₂ —C ₆ alkanoylamino, N—C ₆ alkylamino, N—C ₁₀ alkyl Moil group, N, N- di - C i- C _{1 0} alkyl force Rubamoiru group, N _ C ₂ - C ₆ Al en-carbamoyl, N, N- di one C ₂ - C ₆ alkenyl carbamoylmethyl group, N- amino C ₁ Alkyl carbamoyl group, N—C—C ₆ alkoxyl C ₁₀ Alkyl rubamoyl group, N—C “C ₆ alkoxycarbonyl C! -C _{1 Q} alkylcarbamoyl group, C ^ —C ₆ alkyl sulfinyl group, Ji E one C ₆ alkoxy group, C ₁ - C ₆ alkoxy Cal Poni group, amino C "C ₆ alkoxy Cal Poni group, N-C ₃ - (- ₆ cycloalkylamino group, (: ₃ -〇 ₆ cycloalkyl Okishi group, N one C ₃ - C ₆ cycloalkyl force Rubamoiru group, imidazolidinyl group, imidazolin group, tetrahydrofuranyl elm group, pyrazolidinyl group, pyrazolinyl group, piperazine group, a piperidinyl group, pyrosulfate Dinyl group, pyrrolinyl group, morpholino group, isooxazolyl group, isothiazolyl group, imidazolyl group, oxazolyl group, oxadiazolyl group, thiazolyl group, thiadiazolyl group, chenyl group, triazolyl group, pyridyl group, pyridinyl group, pyrimidinyl group Pyrazolyl, pyrrolyl, pyranyl, furyl, acridinyl, isoquinolyl, isoindolyl, indazolyl, indolyl, ethylenedioxyphenyl, carbazolyl, quinazolinyl, quinoxalinyl, quinolyl, chromanyl Chromenyl group, phenanthridinyl group, phenanthrolinyl group, dibenzofuranyl group, dibenzothiophenyl group, cinnolinyl group, thonaphthenyl group, naphthyridinyl group, Enazinyl group, phenaxazinyl group, benzimidazolyl group, benzoxazolyl group, benzothiazolyl group, benzotriazolyl group, benzofuranyl group, dihydrobenzozofuranyl group, methylenedioxyphenyl group. The C ₇ -C ₁₅ carbon aromatic ring group is an acenaphthylenyl group, an adamantyl group, an anthryl group, an indenyl group, a phenanthryl group, and the 5- or 6-membered heterocyclic group is an isoxazolyl group, an isothiazolyl group, an imidazolyl group, an oxazozolyl group. Group, thiazolyl group, thiadiazolyl group, chenyl group, triazolyl group, pyridyl group, pyrazinyl group, pyrimigel group, pyridazinyl group, pyrazolyl group, pyrrolyl group, pyranyl group, and furyl group, and nitrogen, oxygen, and sulfur Selected from the group consisting of atoms 1- to 3-cyclic heteroaromatic groups having 1 to 5 heteroatoms per ring system (excluding 5- or 6-membered heterocyclic groups. ) Is an acridinyl group, Noryl group, isoindolyl group, indazolyl group, indolyl group, indolizinyl group, ethylenedioxyphenyl group, carbazolyl group, quinazolinyl group, quinoxalinyl group, quinolyl group, chromanyl group, isochromanyl group, chromenyl group, phenanthridinyl group, phenyl Nanthrolidyl group, dibenzofuranyl group, dibenzothiophenyl group, thonaphthenyl group, naphthidinyl group, phenazinyl group, phenaxazinyl group, phenothiazinyl group, phthalagel group, pteridinyl group, purinyl group, benzimidazolyl group, benzoxazolyl group , A benzothiazolyl group, a benzotriazolyl group, a benzofurayl group, a dihydrobenzofuranyl group or a methylenedioxyphenyl group, and particularly a carbon aromatic ring group is a phenyl group. , A naphthyl group, and a substituent of the optionally substituted carbon aromatic ring group may be a hydrogen atom, an azide group, an amino group, a carbamoyl group, a carboxy group, a cyano group, a nitro group, Rogen atom, hydroxy group, aralkyl group, N-aralkylamino group, aralkyloxy group, aralkylcarponyl group, N-aralkyl rubamoyl group, aryl group, aryloxy group, arylsulfonyl group, arylsulfonyl Okishi group, § reel sulfamoyl group, Aroiru group, Arokishi group, N- Aroiru group, C ₂ one C ₆ Arukanoiru groups, C ₂ - C ₆ alkanoyloxy Noi Ruo alkoxy group, N- C ₂ - C ₆ alkanol Iruamino group An N-Cj-Ce alkylamino group, an N-C ₁₀ alkyl radical, a N-N-di-C ₁ -C ₁ alkyl group. Alkyl carbamoyl group, N—C ₂ —C ₆ alkenylcarbamoyl group, N, N—di C ₂ —C ₆ alkenylcarbamoyl group, N—amino C 1 CJ 0 Alkyl rubamoyl group, N—C — Ce alkoxy ( : C ₁₀ alkyl alkyl group, NC _x -C ₆ alkoxycarbonyl C! -0 ₁₀ alkylcarbamoyl group, C — C ₆ alkylsulfinyl group, C — C ₆ alkoxy group, C ₁ -C ₆ alkoxycarbonyl Group, amino Ci—C ₆ alkoxycarbonyl group, N—C ₃ — ( ₆ cycloalkylamino group, (: ₃ _ ( ₆ cycloalkyloxy group, isoxoazolyl group, isothiazolyl group, oxazolyl group, thiazolyl group, Nyl, pyridyl, pyrazinyl, pyrimigel, pyridazinyl, furyl, tetrahydrofuranyl, morpholino, isoquinolyl, iso Ndoriru group, ethylenedioxy O carboxymethyl-phenylalanine group, quinazolinyl group, quinoxalinyl group, quinolyl group, a dibenzofuranyl El group, dibenzothiophenyl group, benzimidazolyl group, Baie Nzookisazoriru group, benzothiazolyl group, benzofuranyl group, a Mechirenjioki Shifueeru group, 1 to 3 rings of the C ₇ - C _{1 5} carbon aromatic ring group, Asenafuchi Reniru group, indenyl group, a Fuenansuriru group, 5- or 6-membered The heterocyclic group is an isoxazolyl group, an isothiazolyl group, an oxazolyl group, a thiazolyl group, a chenyl group, a pyridyl group, a virazinyl group, a pyrimigel group, a pyridazinyl group, or a furyl group; and the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom A mono- to tricyclic heteroaromatic group having 1 to 5 heteroatoms selected per ring system (excluding a 5- or 6-membered heterocyclic group) is an isoquinolyl group, an isoindolyl group, an ethylenedioxyphenyl group, Quinazolinyl group, quinoxalinyl group, dibenzofuranyl group, Zochiofeniru group, Fuenakisajiniru group, benzimidazolyl group, Benzoo Kisazoriru group, benzothiazolyl group, benzofuranyl group, dihydrobenzofuranyl two Le group or methylenedioxy O carboxymethyl phenylalanine group is more preferable.

Ar is, for example, a hydrogen atom, an azide group, an amino group, a carbamoyl group, a carbamoylamino group, a carbamoyloxy group, a propyloxyl group, a cyano group, a sulfamoyl group, a sulfo group, a nitro group, a halogen atom, a hydroxy group, Formyl group, formylamino group, cyclic saturated or unsaturated C ₃ -C ₉ aliphatic group, aralkyl group, N-aralkylamino group, N, N-diaralkylamino group, aralkyloxy group, aralkyl Kill carbonyl group, N-aralkyl rubamoyl group, aryl group, N-aryl amino group, N, N-diarylamino group, aryloxy group, arylsulfonyl group, arylsulfonyloxy group, N-alpha Li one Le sulfonyl § amino group, N- § Li - Le sulfonyl § amino C "C ₆ Arukiruamino group, N- § Li one Rusuruho Niruamino C" C ₁₀ alkyl alkyl group, N-arylsulfonylamino C! C ₆ alkoxycarbonyl group, arylsulfamoyl group, arylsulfamoyloxy group, arylsulfamoyl C_Ci.alkyl Carpamoyl, arylsulfamoyl C ₆ alkoxycarbonyl, N-arylcarbamoyl, aroyl, alkoxy, N-aroyl, N— (N-aroylamino) C _x -C ₁₀ Alkyl force Rubamoiru group, N- Aroiruamino one C ₆ alkoxy Kishikaruponiru groups, C ₂ - C ₆ Arukanoiru groups, C ₂ - C ₆ alkanoyloxy Noi Ruo alkoxy group, N- C ₂ _ C ₆ alkanoyloxy Noi Rua amino group, N, N- Gee C ₂ — C ₆ alkanoylami Group, N—C ^ —C ₆ alkylamino group, N, N—diCi—Ce alkylamino group, N——. Alkyl Rubamoyl group, N, N—Gee Ci—. Alkyl force Rubamoiru group, N- C ₂ - C ₆ alkenyl carbamoylmethyl group, N, N- di C ₂ - C ₆ alkenyl carbamoylmethyl group, N- amino (^ one C _1Q alkyl force Rubamoiru group, N one CI- C ₆ alkoxy _1. Alkyl carpamoyl group, N—C “C ₆ alkoxycarbyl (31-C ₁₀ alkyl group Lubamoyl group, NC, —C ₆ alkoxy group Luponylamino C—C i. Alkyl group Lbamoyl group, N—C i-C ₆ alkoxyl force L-ponylamino C, _ C ₆ alkoxycarbonyl group, C ₆ alkylthio group, N-C! -C ₆ alkylsulfamoyl group, N, N-G C-C ₆ alkylsulfamoyl group, C ₁ -C ₆ alkylsulfinyl group, C i — C ₆ alkylsulfonyl group,

Cj—c ₆ alkoxy group, c! -C ₆ alkoxycarbonyl group, amino-c ₆ alkoxycarbonyl group, N_C ₃ —〇 ₆ cycloalkylamino group, N, N-di-C ₃ _ C ₆ cycloalkylamino group, C ₃ — C ₆ A cycloalkyloxy group, a substituent selected from the group consisting of NC ₃ _ C ₆ cycloalkyl group rubamoyl group, N, N-di-C ₃ — ( ₆ cycloalkyl group rubamoyl group, 5- or 6-membered heterocyclic ring Group, a nitrogen atom, an oxygen atom, and a sulfur atom, a mono- to tricyclic heteroaromatic group having 1 to 5 heteroatoms per ring system selected from the group consisting of an oxygen atom and a sulfur atom, Linear or branched saturated or unsaturated Ci—Cg aliphatic group, C—C ₆ alkoxy group, C 1 C ₆ alkylthio group, N—C 1 C ₆ alkylamino group, N—C _x -C ₆ alkyl force Rubamoiru group, Ranaru group or NC _x -C ₆ alkylthio force Rubamoiru group Good carbon aromatic ring group optionally having a substituent selected from 1 to 3 rings of the C ₇ - C i ₅ carbon aromatic ring group or a 5- or 6-membered heterocyclic group, or a nitrogen atom, oxygen atom and sulfur A bicyclic to tricyclic fused heteroaromatic ring group having 1 to 5 heteroatoms per ring system selected from the group consisting of atoms (excluding a 5- or 6-membered heterocyclic group); The aromatic ring group is a phenyl group or a naphthyl group, and the optionally substituted carbon aromatic ring group is a hydrogen atom, an azide group, an amino group, a carbamoyl group, a carbamoylamino group, Rubamoyloxy group, hydroxyl group, cyano group, nitro group, halogen atom, hydroxy group, cyclic saturated or unsaturated C ₃ -C ₉ aliphatic group, aralkyl group, N-aralkylamino group, ara Ruxyoxy group, aralkylcarbonyl group, N-aralkylcarbamoyl group, aryl group, N-arylamino group, aryloxy group, arylsulfonyl group, arylsulfonyloxy group, N— Arylsulfonylamino C 1 C ₆ alkoxycarbonyl group, arylsulfamoyl group, arylsulfo 7 moyloxy group, arylsulfamoyl (^ C ₁₀ alkyl alkyl group, arylsulfamoyl group, arylsulfamoyl group) C ₆ alkoxy Cal Poni Le group, N- § Li one carbamoyl group, § b I group, Arokishi group, N- Aroiru group, C ₂ - C ₆ Arukanoiru groups, C ₂ - C ₆ Al Kanoiruokishi group, NC ₂ -C ₆ Al force Noiruamino group, N, N-di-C ₂ - C ₆ alkanoyloxy Noi Rua amino group, N- Ci- C ₆ alkylamino group, N-C ₁ over C ₁₀ Aruki carbamoyl group, N, N-di One C _1Q alkyl force Rubamoiru group, N- C ₂ one C ₆ alkenyl carbamoylmethyl group, N, N- di _ C ₂ - C ₆ alkenyl carbamoylthiopheno Le group, N- Ami one C ₁₀ alkyl force Rubamoiru group, N-Ci - C ₆ alkoxy one G ₁₀ alkyl force Rubamoiru group, N-C i one C ₆ alkoxy force Lupo sulfonyl Ji ₁ one C ₁₀ alkyl force Rubamoiru groups, C丄one C ₆ alkylsulfinyl groups, C "C ₆ alkoxy group , C ₁ - C ₆ alkoxy Cal Poni group, an amino C i _ C ₆ alkoxy force Lupo sulfonyl group, N- C ₃ - _{(3 6} cycloalkylamino group, C ₃ - C ₆ cycloalkyl O key sheet group, N-C ₃ - Ji ₆ cycloalkyl force Rubamoiru group, imidazolidinyl group, imino Dazoriniru group, tetrahydrofuranyl El group, Birazorijiniru group, pyrazolinyl group, a piperazinyl group, a piperidinyl group, pyrrolidinyl group, pyrrolinyl group, Moruhori Group, isoxazolyl group, isothiazolyl group, imidazolyl group, oxazolyl group, oxdiazolyl group, thiazolyl group, thiadiazolyl group, chenyl group, triazolyl group, pyridyl group, virazinyl group, pyrimigel group, pyridazyl group, pirazolyl group Group, furyl group, acridinyl group, isoquinolyl group, isoindolyl group, indazolyl group, indolyl group, ethylenedioxyphenyl group, carbazolyl group, quinazolinyl group, quinoxalinyl group, quinolyl group, chromanyl group, chromenyl group, phenyl Nanthridinyl group, phenanthrolinyl group, dibenzofuranyl group, dibenzothiophenyl group, cinnolinyl group, thonaphthenyl group, naphthyridinyl group, phenazinyl group, phenaxazinyl group, Benzoimidazolyl group, Benzoxazolyl group, Benzothiazolyl group, Benzotriazolyl group, Benzofuranyl group, dihydro base Nzofuraeru group, a methylenedioxy O carboxymethyl-phenylalanine group, 1 to 3 rings of - ₅ carbon aromatic ring group, Asenafuchireniru group, § Da Manchiru group, anthryl group, indenyl group, a Fuenansuriru group , A 5- or 6-membered heterocyclic group is an isooxazolyl group, an isothiazolyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, a thiadiazolyl group, a phenyl group, a pyridyl group, a pyrazinyl group, a pyrazolyl group A pyranyl group or a furyl group, a 1 to 3 ring condensed compound aromatic ring group having 1 to 5 hetero atoms per ring system selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom ( Excluding a 5- or 6-membered heterocyclic group.) Is an acridinyl group, isoquinolyl , Isoindolyl group, indazolyl group, indolyl group, indolizinyl group, ethylenedioxyphenyl group, carbazolyl group, quinazolinyl group, quinoxalinyl group, quinolyl group, chromanyl group, isochromanyl group, chromenyl group, fenansuridinyl group, fenansloryl Zyl group, dibenzofuranyl group, dibenzothiophenyl group, tonaphthenyl group, naphthidinyl group, phenazinyl group, phenaxinyl group, phenothiazinyl group, phthalagel group, pteridinyl group, purinyl group, benzoimidazolyl group, benzothiazolyl group, benzothiazolyl group Group, a benzotriazolyl group, a benzofuranyl group, a dihydrobenzofuranyl group or a methylenedioxyphenyl group. Particularly, the carbon aromatic ring group is preferably a phenyl group or a naphthyl group. A hydrogen atom, an azide group, an amino group, a carbamoyl group, a propyloxyl group, a cyano group, a nitro group, or a nitrogen atom, which may have a substituent. Atom, hydroxy group, aralkyl group, N-aralkylamino group, aralkyloxy group, aralkylcarbonyl group, N-aralkyl rubamoyl group, aryl group, aryloxy group, arylsulfonyl group, arylsulfonyloxy group, aryl group reel sulfamoyl group, Aroiru group, Arokishi group, N- Aroiru group, C ₂ one C ₆ Arukanoiru groups, C ₂ - C ₆ alkanoyloxy Noi Ruo alkoxy group, N- C ₂ - C ₆ alkano Iruamino group, N- one C ₆ alkylamino group, N-C i- C _{1 0} alkyl force Luba moil group, N, N-di - C i - C ^ alkyl force Rubamoiru group, N- C ₂ - C ₆ Al Kenirukarubamo Le group, N, N- di C ₂ - C ₆ alkenyl carbamoylmethyl group, N- amino C i-C _{1 0} alkyl force Rubamoiru group, N- - C ₆ alkoxy d-C _{1 0} Alkyl force Rubamoiru group, N _ C one C ₆ alkoxy Cal Poni Le C i-C. ! Alkylcarbamoyl group, C i one C ₆ alkylsulfinyl group, ₍₁ -0 ₆ Arukokishi groups, C one C ₆ alkoxy Cal Poni group, an amino C i one C ₆ alkoxycarbonyl alkylsulfonyl group, N-C ₃ - C ₆ cycloalkyl Alkylamino group, C ₃ — (: ₆ cycloalkyloxy group, dioxoxazolyl group, isothiazolyl group, oxazolyl group, thiazolyl group, cetyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, furyl group, tetrahydrofura Nyl, morpholino, isoquinolyl, isoindolyl, ethylenedioxyphenyl, quinazolinyl, quinoxalinyl, quinolyl, dibenzofuranyl, dibenzothiophenyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl Group, methylene A dioxy phenyl group, a 1 to 3 cyclic C _{7 to} C ₁₅ carbon aromatic ring group is an acenaphthylenyl group, an indenyl group, or a phenanthryl group; and a 5- or 6-membered heterocyclic group is an isoxazolyl group or an isothiazolyl group. Group, oxazolyl group, thiazolyl group, thienyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, and furyl group, and a heteroatom selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom as one ring 1 to 5 mono- to 3-cyclic heteroaromatic groups (excluding 5- or 6-membered heterocyclic groups) per group include isoquinolyl, isoindolyl, ethylenedioxyphenyl, quinazolinyl, quinoxalinyl, and dibenzofuran. L group, dibenzothiophenyl group, phenaxazinyl group, benzimidazolyl group, ben A zoxazolyl group, a benzothiazolyl group, a benzofuranyl group, a dihydrobenzofuranyl group or a methylenedioxyphenyl group is more preferred.

 n represents an integer of 0 to 2, and 0 or 2 is preferable, and 2 is more preferable.

General formula [I] of the present invention

[Wherein, RR ² , R ³ , R ⁴ , R ⁵ and Ar have the above-mentioned meanings. ] Are shown in Table 1 and Table 15.

z H Jd-! HH Md 0201- z Md- ⁹ IAI-8 H ^J d-! HH Md 6UU z Md- ⁹ I ^ I-i7 H Jd-! HH Md 8L0L

0 Md "d-! H H Md LlOi z d H "d-! H H Md 9L0L

0 Md H "d-! H H Md 1 1

0 | jnj-2H "d-! H H Md OL

0 | Au9jm-2 H "d-! H H Md

 0 1 8 ρμ 8 d-2 H Jd-! H H Md ZlOl z ιΑρμ 8 d-ε H H H Md not

0 | Eight d-ε H ^J d-! HH Md OiOl

2 | Λρμ8 d-H ^ d-! H H Md 600

0 | Λρμ8 d-H "d-! H H Md 8001 z Md H H H" d-! Hd Loov

0 Md HHH ^J d-! Hd 900 Lu 1 M Jd '' 1 I

 H H H 1 H 1d "

U Md u Π 1 u u u Π Md 1700L

2 Md H ⁹ IAI HH Hd εοοΐ

0 Md H ⁹ ΙΛΙ HH Md 200 L

0 Md H H H H Md 瞧

-u 9id l7d Z m

Z, 9Zll / lOdf / 13d Table 2

 Compound example Ar R1 R2 R3 R4 R5 n =

1021 Ph HH i-Pr H 3-CF ₃ -Ph 2

1022 Ph HH Pr H 4-GF ₃ -Ph 2

1023 Ph H H Pr Pr H 4-Ph-Ph 2

1024 Ph H H i-Pr H 3-Ph-Ph 2

1025 Ph H H i-Pr H 2-Ph-Ph 2

1026 Ph H H i-Pr H 4-Cl-Ph 2

1027 Ph H H b Pr H 3-Cl-Ph 2

1028 Ph H H Pr Pr H 2-G Ph Ph 2

1029 Ph H H Pr Pr H 3-F-Ph 2

1030 Ph H H i-Pr H 4-F-Ph 2

1031 Ph H H i-Pr H 4-OH-Ph 0

1032 Ph H H Pr H 4-OH-Ph 2

1033 Ph H H i-Pr H 3-OH-Ph 2

1034 Ph H Ht Pr H 2-OH-Ph 2

1035 Ph H H Pr Pr H 4-MeO-Ph 2

1036 Ph H H r Pr H 3-MeO-Ph 2

1037 Ph H H r Pr H 2-MeO-Ph 2

1038 Ph H H Pr Pr H 4-PhO-Ph 2

1039 Ph H H i-Pr H 4-PhCOO-Ph 2

1040 Ph HH i-Pr H 4-PhCH O-Ph 0

22 () h HCp o〇H0- σ>

o CO

"D

End

E

Engineering

1

 ■ D

,

E

l \ 3

/ Oyo AV-

CM CM CM CM CM CM CM CM CM CsJ Csl CM M CM CM C CM CM CvJ CM

x:

 Q.

 Q.

 CL I

CL CL

 〇

 Eh eh

 〇 〇 〇

 z

LO dd_] 〇 M '' .l

 Dimensions d δο Dimensions-Dimensions

 01 X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X

CO ο Dimension Md Ηοώ- HG 丄 Dimension d ldOdM ”” -l

 (Nl

 (Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η — — ω Η Η — Η Η Η D)

X: JZ ぷ z

 <CL Q_ Q_ 0- Q_ Q_ CL Q_ HH dimension 4d Q0N, '' '' _ Q_ Q_ CL £ L GL G_ CL CL CL Q. dimension CM CO dimension LO O CO σ> 0 dimension o 4dH ''-CM 00 dimension CO 00 σ> Ο o O CD CD CD CD OOO CO N

 00 00 O O O O o o o o o o o o o o o o o ο ο

 T〇Dimension C MC¾HT '' I

 £ 01 inch d-/ "ω-ιl

 Md23 dll-

Mdo¾H dimension d '' l-I

 ) 〇HN 1ΛsizeΙ £ Ι1

 £ 1

Dry d- Table 5

 Compound example Ar R1 R2 R3 R4 R5 n =

1081 Ph H H Pr Pr H MeCONH-Ph 2

1082 Ph H H i-Pr H PhCONH-Ph 2

1083 Ph H H i-Pr H 2-Me-3-Me-Ph 2

1084 Ph H H i-Pr H 2-Me-4- Me-Ph 2

1085 Ph H H i-Pr H 2-Me-5-Me-Ph 2

1086 Ph H H Pr Pr H 2-Me + Me-Ph 2

1087 Ph H H i-Pr H 3-Me-4-Me-Ph 2

1088 Ph H H Pr H 3-Me-5-Me-Ph 2

1089 Ph H H Pr H 2,4,6-triMe-Ph 2

1090 Ph H H Pr H 3-F-4-Me-Ph 2

1091 Ph H Hi-Pr H 3-CI-4-Me-Ph 2

1092 Ph H H Pr Pr H 3-Me-4-F-Ph 2

1093 Ph H H i-Pr H 3-Me-4-C Ph 2

1094 Ph H H b Pr H 3-F-4-F-Ph 2

1095 Ph H H to Pr H 3-F-4-C to Ph 2

1096 Ph H H H Pr H 3-CI-4-CI-Ph 2

1097 Ph H H Pr H 3-OH-4-Me-Ph 2

1098 Ph HH i-Pr H 3-PhCH ₂ 0-4-Me-Ph 2

1099 Ph H H i-Pr H 3-MeO-4-Me-Ph 2

1 100 Ph HH Pr H 3-Me—4—MeO-Ph 2 Table 6

 Compound example Ar R1 R2 R3 R4 R5 n =

1101 Ph H H Pr Pr H 3-Vinyl-4-MeO-Ph 2

1102 Ph H Ht Pr H 3 + PrO-4 Me-Ph 2

1103 Ph H Ht Pr H 3-MeO-4 1 MeO-Ph 2

1104 Ph H H p Pr H 3,4-Methylendioxy-Ph 2

1 105 Ph H H i-Pr H 3,4-Ethylendioxy-Ph 2

1 106 Ph H H i-Pr H 3-OH-4 MeO-Ph 2

1107 Ph H H i-Pr H 3-to 4 OH-Ph 0

1 108 Ph H H i-Pr H 3-to 4 OH-Ph 2

1109 Ph H H i-Pr H 2-OH-5-G Ph 2

1110 Ph H H i-Pr H 2-1-5-OH-Ph 2

1 1 1 1 Ph Π u u

 Π D u Π ゥ 一 I 1 "T 一一 ■! — Μ Me ΛU— D r Un> ά

1112 Ph H H Pr Pr H 3-C 4- 4-MeO-Ph 2

11 13 Ph H H i-Pr H 3-Br-4-MeO- Ph 2

1114 Ph H H Pr Pr H 3-1-4-MeO-Ph 0

1115 Ph H H i-Pr Me 3 + 4-MeO-Ph 0

11 16 Ph H Ht Pr H 3 + 4-MeO-Ph 2

11 17 Ph H H Pr Pr H 2 + 5-MeO-Ph 2

1118 Ph H H Pr Pr H 2-MeO- 5- 卜 Ph 2

1 119 Ph H H Pr Pr H 3- 卜 4-EtO-Ph 2

1120 Ph HH Pr H 3-1-4-i-PrO-Ph 2 3 丫 lphco 44N〇3-ll CO CO CO CO 3> (hG 4NpO 3 丁 4〇-1-- u "0 ■ ϋ" D

 3) (hco 34Np〇l4lll-- 3 "

1 1 1 1 1

"D" D "D" 0 "D

ID -a

 r r

■ ϋ End

Table 8

合物例 Ar 1 R2 R3 R誦、4 R5 pi二

Compound example Ar 1 R2 R3 R recitation, 4 R5 pi

1141 Ph HH Pr Pr H 4-(4-N ₃ -3- Ph PhCOO) -Ph 2

1142 Ph HH i-Pr H 3 + 4-MeNHCOCH ₂₀ -Ph 2

1143 Ph HH Pr H 3- | -4-EtNHCOCH ₂ 0-Ph 2

1144 Ph HH i-Pr H 3— 4-p _r NHG〇GH ₂ 〇-Ph 2

1145 Ph HH i-Pr H 3 + 4-n-BuNHG〇GH ₂ 0-Ph 2

1146 Ph HH i-Pr H 3 + 4— n— PrNHGOGH ₂₀ -Ph 0

1147 Ph n μ i 1-p “ _r i H o 1 11“ [i> in lily η ^ · li “ιι ί 0.

1148 Ph HH Pr Pr H 2 + 5-n-PrNHCOCH _20- Ph 2

1149 Ph HH i-Pr H 2-n-PrNHGOCH ₂ 0-5 + Ph 2

1150 Ph HH Pr H 3-CH ₂ OH- 4-MeO-Ph 2

1151 Ph HH Pr H 3- (1,2-CH (OH) CH ₂ OH) -4_MeO-Ph 2

1152 Ph HH Pr H 3-MeOCH ₂ -4-MeO-Ph 2

1153 Ph HH i-Pr H 3 - MeS0 2 NCH 2 - 4-MeO-Ph 2

1154 Ph HH Bok _{Pr H 3-MeS0 2 N (} Me) CH 2 - 4- MeO-Ph 2

1155 Ph HH i-Pr H 3-(4- CH ₂ OH) pneny 4-MeO-Ph 2

1156 Ph HH Bok _{Pr H 3-MeS0 2 N (} Me) CH 2 - 4- Me - Ph 2 Ph 9cho H HrP--Ph 9κCT H Hpr 〇--

9PhICT P H〒 HPr force--

-J -J »J

 CD CXJ ~ «J 0> CD

 9PhhCTl He Hpr Mu ---

Co co

3 "3

 3 "

 Ks)>

O CD CO ~~ J

CO O

Meh4pFI-- 1-1

〇 〇

1 4Mph Mee 1Ill3 Completed

1 1 J

C0 C

)>

table 1

 Compound example A r R1 2 3 R 1, 4 ~ r 5 ri

1 199 9- -p μ Π Π i 1-p `` _r 1 μ Γ 1 Ji * τ ΙΥΙσ r 1 1 0.

1200 9- -P “h 1 1 μ Η 1 1 1” I μ π V, t5 * ϊ-£ 0-

1201 9--P μ μ π i_p _r ί U π ο m 0 l hi t π ί.

1202 9- G -P "h [, μπππi 1 P" r 0

 Γ μ l * \ J \ Π

 1203 9- -ci- -Ph Η Η i-Pr Η 3— PhCH 0-1 4 1 Me-1 Ph 2

1204 9- _D rn U π U π 1 Γ u π MeU 4 Me rn ο

1205 9- U U

 "" Then rn π Π 1 1 u π Θ Ulvie rrl

1 206 9- U

 "" Then rn π U

 Π i r u π o Vinyl 4 βυ rn

 1207 9- 1

 -Sh ι--nrn π 1 1

 Π i-Hr 1 π 3-1-PrO-4-Me-Ph 2

1208 9- -ci- -Ph Η Η i-Pr Η 3-F-4 OMe-Ph 2

1209 9- -ci- -Ph Η Η i-Pr Η 3-C 4-OMe-Ph 2

1210 9- -ci- -Ph Η Η i-Pr Η 3 + 4-OMe-Ph 2

121 1 9- -Cl- -Ph Η 卜 Pr Pr 3 + 4-EtO-Ph 2

1212 9- -ci- -Ph Η Η i-Pr Η 3-1-4-i-PrO-Ph 2

1213 9- -ci- -Ph Η Η i-Pr Η 3-Tri 4-n- BuO- Ph 2

1214 9- -Cl- -Ph Η Η i-Pr Η 3-l-4-PhCH ₂ 0-Ph 2

1215 9- -ci- -Ph Η 卜 Pr Pr Η 3-Ph-4-MeO-Ph 2

1216 9- -ci- -Ph Η 卜 Pr Pr Η 3-C0 ₂ Me-4-MeO-Ph 2

1217 9- -ci- -Ph Η Η i-Pr Η 3-CONMe _2-4 -MeO-Ph 2 Table 1 2

Compound example Ar R1 R2 R3 R4 R5 n =

1218 9-CI-Ph HH i-Pr H 3-CONHCH ₂ Ph-4-MeO-Ph 2

1219 9-C Ph HH i-Pr H 3-l-4-n-PrNHCOCH ₂ 0-Ph 2

1220 9-CI-Ph H Hi i-Pr H 3 + 4-MeO-Ph 2

1221 9-CI-Ph H Hi i-Pr H 3-pot 4-PhCOO-Ph 2

1222 9-CI-Ph HH i-Pr H 3-l-4-MeNHCOCH ₂ 0-Ph 2

1223 9-CI-Ph HH Pr H 3-CH ₂ OH-4- MeO-Ph 2

1224 9-CI-Ph HH i-Pr H 3-MeOCH ₂ -4-MeO-Ph 2

1225 9-CI-Ph H Hi i-Pr H 3-C 4-C Ph 2

1226 Q_Q | _p H H i-Pr H 3-F-4-OMe-Ph 2

1227 9-F-Ph H H Pr Pr H Ph 2

1228 9-F-Ph H Hi i-Pr H 4-Me-Ph 2

1229 9-F-Ph H Hi i-Pr H 3-Ph-Ph 2

1230 9-F-Ph H Hi-Pr H 4-C Ph 2

1231 9-F-Ph H Hi i-Pr H 3-F-Ph 2

1232 9-F-Ph H H H Pr H 4-MeO-Ph 2

1233 9-F-Ph HH i-Pr H 4-PhC ₂ H _40- Ph 2

1234 9-F-Ph HH Pr H 4-EtNHCOCH ₂ 0-Ph 2

1235 9-F-Ph HH Pr H 3-n-PrNHCOCH ₂₀ -Ph 2

1236 9-F-Ph HH i-Pr H 4 1 n-PrNHCOCH (Me) 0-Ph 2 Table 13

物例 Ar P?ク ΓνΟ n—

Object example Ar P? ク ΓνΟ n—

 1237 9-F- -Ph H Hi i Pr H 4 * r-M viec? 2NCOCHo 2O ^-^-Ph 2

1238 9-F- -Ph H Hi-Pr H 40 BuO GCH 0--Ph 2

1239 9-F- -Ph H H i-Pr H 3— MeOCH Ph 2

1240 9-F- -Ph H H i-Pr H 4-MeOCH -Ph 2

1241 9-F- -Ph H H i-Pr H 4-i-PrOCH -Ph 2

1242 9-F- -Ph H Hi i-Pr H 4— EtG G— Ph 2

1243 9-F- -Ph H H i-Pr H 4-HoNOC-Ph 2

1244 9-F- -rh Π Π r Π 4 One Me! H Rishi one Hi I

1245 9-F- rn Π u Π 1 rr Π 4 "MenN" rh L

1246 9-F- -Ph HH 1-1 Pr H 4-1 Me ₂ N-Ph 2

1247 9-F- -Ph H H i-Pr H 4-PhCONH-Ph 2

1248 9-F- -Ph H H i-Pr H 3-Me-4-Me-Ph 2

1249 9-F- -Ph H H i-Pr H 3-F-4-Me-Ph 2

1250 9-F--Ph H H Pr Pr H 3-C 4 4-Me-Ph 2

1251 9-F- -Ph H Hi-Pr H 3-Me-4-Ct Ph 2

1252 9-F--Ph H H i-Pr H 3-F-4-C G Ph 2

1253 9-F- -Ph H Hi-Pr H 3-CM-C Ph 2

1254 9-F- Ph HH Pr H 3-PhCH ₂ 0-4-Me- -Ph 2

1255 9-F- ■ Ph HH i-Pr H 3-MeO— 4-Me-Ph 2 table

 Compound example A f D ΓΛ11 Γ * τ 1

1256 9- Γ -p `` U u

 π 1 1 1 I— P ΙΓ r U

 Π IVI6 UIVI6 ΓΠ

 1 2 9- Γ u

 57 1 1 u Π p U

 1 _ Γ ^ Π v inyl ^ ινιβυ rn L

1258 C "u

 9- Γ • D rn Π Π 1 Mr Π 3- PrO-4-Me-Ph L

1259 9- u LI

 1 ^ rn Π U Π 1 T Π 3-F-4-OMe-Ph

1260 9- Γ -P `` hu u

 n 1 1 Π 1 “U

 i 1 1 3-C 4-OMe-Ph L

1261 9---_p u u u

 ir i i Π Π 1 T Π 3-1-4-MeO-Ph Δ

1262 9- 1 ^ n u ■ D

 Π u «

 Π 1 Kr Π 3-1-4-EtO-Ph

 1263 9- 1 ^ n u Π u Π 1 D K ^ r- Π 3- 4- i-PrO-Ph L

1264 9-10 ■ rh H Hi-Pr Π 3-1-4-n-BuO-Ph 2

1265 9- u Π 1 Mr n 3-l-4-PhCH ₂ 0-Ph

 1266 9- -F- -Ph H H i-Pr H 3-Ph—4-MeO-Ph 2

1267 9- -F- -Ph HH i-Pr H 3-C0 ₂ Me-4—MeO-Ph 2

1268 9- -F- -Ph HH i-Pr H 3-CONMe _2-4- MeO-Ph 2

1269 9- -F-Ph HH Pr H 3-CONHCH ₂ Ph-4-MeO -Ph 2

1270 9- -F- -Ph H H i-Pr H 3-1-4-PhCOO-Ph 2

1271 9- ■ F- -Ph HH i-Pr H 3-l-4-MeNHCOCH ₂₀ --Ph 2

1272 9- -Ph HH i-Pr H 3 + 4-n-PrNHCOGH ₂₀ -Ph 2

1273 9- ■ F- -Ph HH Pr H 3-CH ₂ OH-4-MeO-Ph 2

1274 9- ■ Ph HH Pr H 3-MeOCH ₂ -4-MeO- Ph 2 Table 15

Compound example Ar R1 R2 R3 R4 R5 n =

1275 7-l-8-n-PrNHCOCH ₂ 0-Ph HH i-Pr H Ph 2

 1277 6 1 MeO 1 9 Ph H H i-Pr H Ph 2

1278 6-1-9-MeO-Ph H H i-Pr H Ph 2

1279 3 4-Pvridvl- H H Pr Pr H Ph 0

1280 34-Pvridvl- H H i-Pr H Ph 2

1281 3,4-Pyridyl- HH Pr H 4-PhCH ₂ 0- -Ph 0

1282 o, rynoyi U

 Π H i-Pr H 3-F-4-Me.-Ph 2

1283 3,4-Pyridyl- H H pr Pr H 3-CI-4-Me -Ph 2

1284 3,4-Pyridyl- H Hi i-Pr H 3-Me- 4-CI -Ph 2

1285 3,4-Pyridyl- H H Pr H 3-F-4-CI- Ph 2

1286 3,4-Pyridyl- H Hi-Pr H 3-CI-4-CI- -Ph 2

1287 3,4-Pyridyl- HH i-Pr H 4-P CH ₂ 0- -Ph 2

1288 2,3-Pyridyl- H H i-Pr H Ph 0

1289 2,3-Pyridyl- H H pr Pr H Ph 2

1290 2,3-Pyridyl- H Hi i-Pr H 4-CI-Ph 2

1291 45— Pyridyl— H H Pr Pr H Ph 0

1292 45— Pyridyl— H H Pr Pr H Ph 2

1293 4,5-Pyridyl- HH i-Pr H 4-F-Ph 2 Among these compounds, suitable compounds include, for example, 1009, 1011, 1

016, 1018, 1023, 1026, 1027, 1029, 1030, 1032, 1035, 1038, 1040, 1043, 1044, 1046, 1048, 1049, 1051, 1052, 1054, 1056, 1063, 1072, 1073, 1084, 1087, 1090, 1091, 1092, 1093,

1094, 1095, 1096, 1100, 1101, 1104, 1108, 1 111, 1112, 1113, 1116, 1119, 1120, 1121, 11 22, 1124, 1126, 1 127, 1131, 1135, 1 136, 114 2, 1143 , 1147, 1158, 1159, 1162, 1170, 1171, 1173, 1174, 1175, 1178, 1180, 1182, 1184,

1190, 1197, 1199, 1200, 1201, 1202, 1208, 1

210, 1213, 1219, 1220, 1225, 1227, 1230, 1232, 1237, 1241, 1242, 1248, 1251, 1253, 125 9, 1260, 1261, 1266, 1282, 1283, 1286, 1290, 1293, etc. Of which 1011, 1016, 1018, 1023, 1

026, 1027, 1029, 1030, 1032, 1035, 1038, 1040, 1043, 1044, 1046, 1048, 1049, 1051, 105 2, 1054, 1063, 1072, 1073, 1084, 1087, 1090, 1091, 1092, 1093, 1094, 1095, 1096, 1100, 1101, 1104, 1108, 1111, 1112, 11 13, 1116, 1

119, 1 120, 1 121, 1 122, 1124, 1126, 1127, 11 31, 1135, 1136, 1 147, 1158, 1 159, 1 162, 117 5, 1178, 1180, 1 199, 1200, 1201, 1202 , 1208, 1210, 1219, 1220, 1227, 1230, 1232, 1248, 1251, 1253, 1261, 1266, 1282, 1283, 1286, 1

Compounds 290 and 1293 are preferred.

Next, a method for producing the compound represented by the general formula [I] of the present invention will be described. The compound represented by the general formula [I] can be produced by the following production methods AH. Manufacturing method A

 (First step)

General formula [Π]

 [Wherein, Ar has the meaning described above], a compound represented by the general formula [III]

R ⁵ — CN [III]

[Wherein R ⁵ has the meaning described above] to obtain a compound represented by the general formula [IV]

[Wherein, R ⁵ and Ar have the same meanings as described above] can be synthesized.

 The reagent used in the reaction can be appropriately increased or decreased depending on the starting compounds and reaction conditions. Usually, the reaction is carried out by using a base in a dehydrated inert organic solvent in the presence of a suitable additive. The compound represented by the general formula [II] can be obtained by reacting the solvent at a temperature of from 0 ° C to the boiling point of the solvent, preferably from 17 to 30 ° C, for from 0.5 to 96 hours, preferably from 12 to 24 hours. Then, a solution of arylnitrile represented by the general formula [III] in an inert solvent is added dropwise at a temperature of 100 ° C. to the boiling point of the solvent, preferably −78 to 3O: 0.5. The reaction is carried out for up to 96 hours, preferably 12 to 24 hours. The inert organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction. Specific examples thereof include hexane, cyclohexane, pentane, ether, 1,4-dioxane , Tetrahydrofuran, tetrahydropyran and the like. Among them, ether, tetrahydrofuran, cyclohexane and the like are preferable.

Additives used in the reaction include N, N, N ', N' And TMEDA, hexamethylphosphoramine HMPA, lithium chloride and the like. Among them, Ν, Ν, Ν ′, Ν′-tetramethylethylenediamine is preferable.

 Examples of the base used in the reaction include η-butyllithium, sec-butyllithium, t-butyllithium, phenyllithium, methyllithium and the like. Among them, n-butyllithium and sec-butyllithium are preferable. is there.

 The amount of the reagent used in the reaction can be appropriately increased or decreased depending on the raw material compound and the reaction conditions. And 1 to 10 equivalents, preferably 1.5 to 2 equivalents, of arylyl nitrile represented by the above general formula [III] is used.

 (2nd step)

 Next, the general formula [IV]

[Wherein R ⁵ and Ar have the above-mentioned meanings] and a compound represented by the general formula [V]

[Wherein, RR ² is a hydrogen atom or a C ₃ alkyl group, and R ³ is a hydrogen atom or a C 1 C ₆ alkyl group (however, excluding n-butyl group)]. By reacting in an organic solvent such as

[式中、 R R ²、 R ³、 R ⁵及び A rは前記の意味を有する] で表される化合物 を合成できる。

[Wherein, RR ² , R ³ , R ⁵ and Ar have the above-mentioned meanings].

 The reagent used in the reaction can be appropriately increased or decreased depending on the raw material compound and the reaction conditions. Usually, for example, the reaction is carried out in an organic solvent such as lutidine with the compound represented by the above general formula [IV]. The compound represented by the above general formula [V] is reacted at room temperature for 0.5 to 96 hours, preferably 3 to 24 hours.

 The organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction. Specific examples thereof include methylene chloride, chloroform, 1,2-dichloroethane, trichloroethane, and tetrachloroethane. Carbon chloride, N, N-dimethylformamide, ethyl acetate, methyl acetate, acetonitrile, methyl alcohol, ethyl alcohol, benzene, xylene, pyridine, lutidine, toluene, xylene, 1> 4-dioxane, tetrahydrofuran, etc. Among them, methyl alcohol, ethyl alcohol, pyridine, lutidine, N, N-dimethylformamide, toluene, xylene and the like are preferable.

 The reagent used in the reaction can be appropriately increased or decreased depending on the starting compound and the reaction conditions, but is usually 1.2 to 10 equivalents, preferably 1 to 10 with respect to the compound represented by the above general formula [IV]. 1.2—Use 2 equivalents of aziridin represented by the above general formula [V].

 (3rd step)

 Next, the general formula [V I]

[Wherein, R ¹ R ² , R ³ , 1 ^ ⁵ and 8] has the above-mentioned meaning] in a suitable solvent such as 2,6-lutidine. Azeotropic distillation, optionally in the presence of an acid, or heating to reflux in the presence of a desiccant, for example, molecular sieves. The general formula [VII]

[Wherein, R ¹ R ² , R ³ , R ⁵ and Ar have the above-mentioned meanings].

 The reagents used in the reaction can be appropriately increased or decreased depending on the starting compounds and reaction conditions, but usually the reaction is carried out in the presence of a desiccant such as molecular sieves, and in an appropriate solvent such as 2,6-lutidine. The reaction is completed by refluxing for 5 to 96 hours, preferably 12 to 24 hours, in the presence of a suitable acid such as hydrochloric acid.

 The organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction. Specific examples include methylene chloride, chloroform, 1,2-dichloroethane, trichloroethane, and N , N-dimethylformamide, acetic anhydride, ethyl acetate, methyl acetate, acetonitrile, methyl alcohol, ethyl alcohol, n-propanol, benzene, xylene, pyridine, lutidine, toluene, xylene, 1,4-dioxane, tetrahydrofuran, etc. From the viewpoint of securing a suitable reaction temperature, pyridine, lutidine, N, N-dimethylformamide, toluene, xylene and the like are particularly preferable.

Examples of the acid used in the reaction include inorganic acids such as hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, hydrofluoric acid, and perchloric acid; for example, Lewis such as trifluoroboric acid, titanium tetrachloride, and zinc chloride. Acids; for example, sulfonic acids such as P-toluenesulfonic acid, trifluoromethanesulfonic acid, and methanesulfonic acid; and organic acids such as formic acid, trifluoroacetic acid, and acetic acid, and among them, hydrochloric acid, acetic acid, and P-toluenesulfonic acid Preferred examples of the desiccant used in the reaction include molecular sieves, magnesium sulfate, and sodium sulfate. Among them, molecular sieves are preferred. The amount of the reagent used in the reaction can be appropriately increased or decreased depending on the starting compound and the reaction conditions, but usually, 1.2 to 10 equivalents, preferably 1 to 10 equivalents to the compound represented by the above general formula [VI] is used. Use 2 to 2 equivalents of desiccant, 1 to 50 equivalents, preferably 3 to 5 equivalents of acid. The acid and the desiccant may be used alone or in appropriate combination of two or more.

 (4th step)

 Next, the general formula [V I I]

Wherein R ¹ R ² , R ³ , R ⁵ and Ar have the meaning described above, in an appropriate organic solvent with an oxidizing agent to give a compound of the general formula [VIII ]

[Wherein, RR ² , R ³ , R ⁵ and Ar have the above-mentioned meanings].

The reagent used in the reaction can be appropriately increased or decreased depending on the starting compound and the reaction conditions.In general, the reaction is carried out in a suitable organic acid solvent such as trifluoroacetic acid, for example, a suitable oxidizing agent such as hydrogen peroxide. The reaction is completed by stirring for 5 to 96 hours, preferably 12 to 24 hours, in the presence of Alternatively, stirring in a suitable inert organic solvent, such as, for example, methylene chloride, in the presence of a suitable oxidizing agent, such as, for example, methacrylic acid mouth perbenzoic acid, for 5 to 96 hours, preferably 12 to 24 hours. Thus, the reaction is completed. The inert organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction. Specific examples thereof include methylene chloride, methylene chloride, 1,2-dichloroethane, and trichloroethane. Ethane, carbon tetrachloride, ethyl acetate, methyl acetate, acetonitrile, methyl alcohol, ethyl alcohol, benzene, xylene, toluene, xylene, ether, 1,4-dioxane, tetrahydrofuran, tetrahydropyran, etc. Preferred are methylene, chloroform, 1,2-dichloroethane, trichloroethane, toluene, xylene and the like.

 Examples of the acid solvent used in the reaction include organic acids such as formic acid, trifluoroacetic acid and acetic acid, among which trifluoroacetic acid is preferred.

 The oxidizing agent used in the reaction is not particularly limited as long as it does not adversely affect the reaction.Specifically, for example, hydrogen peroxide, peracetic acid, trifluoroperacetic acid, methachloroperbenzoic acid, oxone, Examples thereof include chromic acid and permanganese sun. Among them, hydrogen peroxide, metachloroperbenzoic acid, and the like are preferable.

 The reagent used in the reaction can be appropriately increased or decreased depending on the raw material compound and reaction conditions, but is usually 1.2 to 10 equivalents, preferably 1 to 10 equivalents to the compound represented by the above general formula [VII]. 1.2 Use 2 to 2 equivalents of oxidizing agent.

 (Fifth step)

 Next, the general formula [V I I I]

[Wherein, R ¹ , R ² , R ³ , ⁵ and 8] have the above-mentioned meanings] in a suitable organic solvent such as tetrahydrofuran (THF). Reduction using a reducing agent or catalytic hydrogenation using a catalyst such as 10% palladium on carbon, or reaction with zinc chloride in the presence of an acid catalyst such as hydrochloric acid The general formula [I]

[Wherein, R ¹ , R ² , R ³ , R ⁵ and Ar have the above-mentioned meanings].

 The reagents used in the reaction can be appropriately increased or decreased depending on the starting compounds and reaction conditions. However, the reaction can be carried out in a suitable organic acid solvent such as THF, for example, using a suitable reducing agent such as porane. The reaction is completed by stirring for up to 96 hours, preferably 12 to 24 hours. Alternatively, by stirring in a suitable organic solvent such as methyl alcohol in the presence of a suitable palladium catalyst such as 10% palladium on carbon for 5 to 96 hours, preferably 12 to 24 hours, The reaction is complete. Alternatively, the reaction is completed by appropriately stirring with a metal or a metal salt for 5 to 96 hours, preferably 12 to 24 hours in an acid or alkali solution.

 The organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction. Specific examples thereof include methylene chloride, chloroform, 1,2-dichloroethane, trichloroethane, and tetrachloroethane. Carbon chloride, acetic acid, ethyl acetate, methyl acetate, acetonitrile, methyl alcohol, ethyl alcohol, benzene, xylene, toluene, xylene, ether, 1,4-dioxane, tetrahydrofuran, tetrahydropyran, etc., among which methylene chloride, Preferred are chloroform, 1,2-dichloroethane, trichloroethane, toluene, xylene and the like.

Examples of the reducing agent used in the reaction include lithium borohydride, sodium borohydride, sodium cyanotrihydroborate, porane methyl sulfide complex, porane THF complex, and lithium aluminum hydride. Among them, a porane methylsulfide complex and a porane THF complex are preferable. The amount of the reagent used in the reaction can be appropriately increased or decreased depending on the raw material compound and the reaction conditions, but is usually 1.2 to 10 equivalents, preferably 1 to 10 equivalents to the compound represented by the above general formula [VIII]. Use 2 to 2 equivalents of reducing agent.

 Catalysts used in the catalytic hydrogenation reaction include, for example, palladium activated carbon, Raney nickel, platinum oxide, etc., and among them, 10% palladium activated carbon is preferred.Metal used in the reaction is, for example, zinc, aluminum, iridium. , Chromium, titanium, tin, cerium, iron, copper, vanadium, magnesium, etc., of which zinc and magnesium are preferred.

 It should be noted that even if the order of the production steps of “fourth step” and “fifth step” is reversed, the compound can be similarly converted to the compound represented by the above general formula [I].

 After completion of the reaction, the product represented by the above general formula [I] can be obtained by purifying the product by a conventional method. The compound represented by the general formula [I] or a salt thereof can be isolated and purified from the reaction solution by a known separation means such as solvent extraction, recrystallization, and chromatography. Manufacturing method B

 The compound represented by the general formula [IV] is represented by the general formula [IX]

[Wherein ⁵ and 8 1 "have the meanings described above." For example, the compound represented by the above general formula [IX] and a suitable inert organic solvent may be used. General formula [X

[ X ] ]

[X]

[Wherein, R represents an alkyl group such as a methyl group, and R ⁵ and Ar have the above-mentioned meanings] by heating the compound represented by the formula [XI]

[Wherein, R ⁵ , 1 ″ and the scale have the same meanings as in the above formula).

 The reagent used in the reaction can be appropriately increased or decreased depending on the starting compounds and reaction conditions, but usually the reaction is carried out in a suitable organic acid solvent such as N, N-dimethylformamide, for example, sodium hydride. The reaction is completed by reacting the mixture with a suitable base at 0 ° C. to the boiling point of the solvent, preferably 0 to 150, 0.5 to 96 hours, preferably 12 to 24 hours. Then, for example, in an inert organic solvent or neat, from 0 ° C. to the boiling point of the solvent, preferably 100 to 300 ° C., 0.1 to 96 hours, preferably 0.5 to 2 hours. The reaction is completed by stirring for an hour.

The organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction, but specific examples thereof include, for example, Shiridani methylene, chloroform, 1,2-dichloroethane, trichloroethane, Carbon tetrachloride, N, N-dimethylformamide, acetonitrile, acetone, benzene, toluene, ether, 1,4-dioxane, tetrahydrofuran, tetrahydropyran, etc., among which N, N-dimethylformamide, toluene, xylene, acetone , Ether, tetrahydrofuran and the like are preferred. Examples of the base used in the reaction include trimethylamine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, N-methylpiperidine, N, N-dimethylaniline, Tertiary aliphatics such as 1, 8-diazabicyclo [5.4.0] pendant force _7-en (DBU), 1,5-azabicyclo [4.3.0] nona5 -en (DBN) Amines, for example, alkali metal hydrides such as sodium hydride and potassium hydride, for example, alkali metal alkoxides such as potassium tert-butylate, sodium ethylate, and sodium methylate; for example, potassium hydroxide, sodium hydroxide, and the like Alkali metal hydroxides; for example, alkali metal carbonates such as carbonated lime; and the like, among which triethylamine, N, N-diisopropylethylamine, Sodium hydride, potassium hydride, potassium tert-butylate, sodium ethylate, sodium methylate and potassium carbonate are preferred.

 The reagent used in the reaction can be appropriately increased or decreased depending on the starting compounds and reaction conditions, but is usually 1.2 to 10 equivalents, preferably 1 to 10 relative to the compound represented by the above general formula [IX]. Use 2 to 2 equivalents of base, use 1.2 to 10 equivalents, preferably 1.2 to 2 equivalents of dimethylthiopotassium chloride.

 As the inert solvent used in the rearrangement reaction, for example, toluene, xylene, diphenyl ether, dipara-tolyl ether and the like can be mentioned, and among them, diphenyl ether is preferable.

 The compound represented by the general formula [XI] is hydrolyzed with a base such as sodium hydroxide in a suitable organic solvent, or with a reducing agent such as lithium aluminum hydride in a non-polar solvent such as THF. The compound represented by the above general formula [IV] can be prepared by reduction.

The organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction. Specifically, for example, ethyl acetate, methyl acetate, acetonitrile, methyl alcohol, ethyl alcohol, benzene, benzene Examples thereof include silene, toluene, xylene, ether, 1,4-dioxane, tetrahydrofuran, and tetrahydropyran. Among them, methyl alcohol, ethyl alcohol, ether, 1,4-dioxane, and tetrahydrofuran are preferable. Examples of the base used in the reaction include alkali metal alkoxides such as potassium tert-butylate, sodium ethylate and sodium methylate; for example, alkali metal hydroxides such as lithium hydroxide and sodium hydroxide. For example, alkali metal carbonates such as potassium carbonate and the like, among which potassium tert-butylate, sodium ethylate, sodium methylate, potassium hydroxide and sodium hydroxide are preferred.

 The inert organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction. Specific examples thereof include hexane, cyclohexane, pentane, ether, 1,4-dioxane And tetrahydrofuran, tetrahydropyran and the like, among which ether, tetrahydrofuran, cyclohexane and the like are preferable.

 Lithium aluminum hydride is suitable as the reducing agent used in the reaction. The compound represented by the above general formula [IV] thus obtained is prepared in the same manner as in Step 2-5 of Production Method A. The compound represented by the above general formula [I] can be obtained by reacting

 The compound represented by the above general formula [IX] can be synthesized by a known method. For example, the general formula [X I I]

[Wherein, Ar has the above-mentioned meaning] salicylic acid; an aryl compound represented by R ⁵ —H (where R ⁵ has the above-mentioned meaning); It can be synthesized by a Friedel-Crafts reaction using lumimium.

Or the general formula [XIII]

[Wherein, Ar has the above-mentioned meaning] by converting an aryl halide compound and metallic magnesium into a suitable ether-based dehydrating solvent such as, for example, ethyl ether, tetrahydrofuran, etc., at a low temperature. The Grignard reagent prepared by reacting at the boiling point of the solvent is reacted with the above-mentioned dehydrated inert organic solvent at a low to room temperature in the above-mentioned dehydrated inert organic solvent, and the resulting product is subsequently dissolved in a suitable solvent such as dichloromethane. For example, it can be produced by reacting with an oxidizing agent such as manganese dioxide. Manufacturing method C

 (First step)

General formula [XIV]

 [Wherein, PG represents a carboxyl-protecting group, and Ar has the above-mentioned meaning] The compound represented by the general formula [V]

Wherein, R ² and 1 ³ are as defined above] is reacted with a compound represented by then formula by the resulting amino group apply a protecting group suitable Amino group [XV]

[Wherein, PG ¹ represents a protecting group for an amino group, and R ¹ R ² , R Ar and PG have the above-mentioned meanings].

 The reagent used in the reaction can be appropriately increased or decreased depending on the starting compound and the reaction conditions. Usually, for example, the reaction is carried out in an organic solvent such as lutidine with the compound represented by the above general formula [XIV] and the above general formula The compound [V] is reacted at room temperature for 0.5 to 96 hours, preferably 3 to 24 hours.

 The organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction, and specific examples thereof include methylene chloride, chloroform, 1,2-dichloroethane, trichloroethane, and tetrachloroethane. Carbon chloride, N, N-dimethylformamide, ethyl acetate, methyl acetate, acetonitrile, methyl alcohol, ethyl alcohol, benzene, xylene, pyridine, lutidine, toluene, xylene, 1,4-dioxane, tetrahydrofuran, etc. Among them, methyl alcohol, ethyl alcohol, pyridine, lutidine, N, N-dimethylformamide, toluene, xylene and the like are preferable.

 The amount of the reagent used in the reaction can be appropriately increased or decreased depending on the starting material and the reaction conditions. Usually, 1.2 to 10 equivalents, preferably 1 Use 2 to 2 equivalents of the aziridine represented by the above general formula [V].

 Examples of the protective group for the carbonyl group include lower alkyl groups such as methyl group, ethyl group and tert-butyl group, and aralkyl groups such as benzyl group and p-methoxybenzyl group. , An ethyl group, a tert-butyl group, a benzyl group and the like.

Examples of the protecting group for the amino group include benzyl, p-nitrobenzyl and the like. An aralkyl group; for example, an acyl group such as a formyl group or an acetyl group; a lower alkoxy group such as an ethoxycarbonyl group, an aryloxycarbonyl group, or a tert-butoxycarbonyl group; for example, a benzyloxycarbonyl group, p-nitro Aralkyloxycarbonyl groups such as benzyloxycarbonyl group, triphenylmethyl group, paramethoxyphenyldiphenylmethyl group, diphenylphosphonyl group, and benzenesulfenyl group; among them, aryloxycarbonyl group Tert-butoxycarbonyl, benzyloxycarbonyl, triphenylmethyl and the like are preferred.

 The introduction of the protecting group depends on the type and the stability of the compound, but the method described in the literature [Protective Groups in Organic Synthesis (Protective Groups in Organic Synthesis)] , T. W. Green (Tw Greene, John John & Sons, 1981)] or a method analogous thereto. (2nd step)

General formula [XV]

[Where RR ² , R ³ , Ar,? And 0 ^1, the carboxyl-protecting group is removed in the compound represented by have the meanings mentioned above, then, N, O-Jimechiruhido Rokishiruamin and example Shioi匕in methylene appropriate base, condensation assistant and or condensation Reacting in the presence of an agent to form a general formula [XVI] [XVI]

[Wherein, Me represents a methyl group, and RR ² , R ³ , Ar, and PG ¹ have the above-mentioned meaning].

 The removal of the protecting group of the hydroxyl group depends on the type and stability of the compound, but the method described in the literature [Protective Groups 'In' Organic Synthesis (Organic Synthesis), TW Greene, John John & Sons (1981)] or a method analogous thereto, for example, solvolysis using an acid or base, chemical reduction using a metal hydride complex, or the like. It can be carried out by corrosion reduction using a palladium carbon catalyst, Raney nickel catalyst or the like.

 The reagent used in the reaction can be appropriately increased or decreased depending on the starting compound and the reaction conditions, but usually, the reaction is carried out by reacting the deprotected carboxylic acid with N, 1-dimethylhydroxylamine in a dehydrated inert organic solvent. , In the presence of a base, a condensation aid and Z or a condensing agent as appropriate — from 100 ° C. to the boiling point of the solvent, preferably from 0 to 30 ° C., from 0.5 to 96 hours, preferably from 3 to 24 hours. Let it.

The inert organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction, and specific examples thereof include methylene chloride, chloroform, 1,2-dichloroethane, and trichloroethane. , N, N-dimethylformamide, ethyl acetate, methyl acetate, acetonitrile, acetic anhydride, methyl alcohol, ethyl alcohol, benzene, xylene, water, acetic acid, toluene, 1,4-dioxane, tetrahydrofuran and the like. From the viewpoint of securing a suitable reaction temperature, among them, methylene chloride, chloroform, 1,2-dichloroethane, acetonitrile, N, N-dimethylformamide, 1,4-dioxane, toluene, etc. Is preferred.

 Bases used in the reaction include, for example, trimethylamine, triethyl ^ / ami, N, N-diisopropylethylamine, N-methylmorpholine, N-methylvinyl lysine, N-methylpiperidine, N, N-dimethyl Anilin, 1,8-diazabicyclo [5.4.0] pendant 7-ene (DBU), 1,5-azabicyclo [4.3.0] nona-5-ene (DBN), etc. Tertiary aliphatic amines; for example, aromatic amines such as pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline, and isoquinoline; metal salts such as potassium metal, sodium metal, and lithium metal; Metal hydrides such as sodium hydride and hydrogen hydride; alkyl metal hydrides such as butyl lithium; potassium lithium-tert-butylate, sodium ethylate Alkali metal alkoxides such as sodium methylate and the like; alkali metal hydroxides such as hydroxylated sodium hydroxide and sodium hydroxide; alkali metal alkoxides such as carbonated lithium and the like. Tertiary aliphatic amines and the like are preferred, and in particular, triethylamine, N, N-diisopropylethylamine and the like are more preferred.

 Examples of the condensation auxiliary used in the reaction include N-hydroxybenzotriazole hydrate, N-hydroxysuccinimide, N-hydroxy-15-norpolene-2,3-dicarboximide, and 3-hydroxy-3 , 4-dihydro-4-oxo-1,2,3-benzotriazol and the like. Among them, N-hydroxybenzotriazole and the like are preferable.

Examples of the condensing agent used in the reaction include thionyl chloride, N, N-dicyclohexylcarbodiimide, 1-methyl-2-bromopyridinium iodide, and N, N'-capillonyldiimidazole , Diphenylphosphoryl chloride, diphenylphosphoryl azide, N, N, disuccinimidyl carbone, N, N'-disuccinimidyl oxalate, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide Hydrochloride, ethyl ethyl chloroformate, isoptyl chloroformate, benzotriazo-1-lyloxysheetris (dimethylamino) phosphonium hexafluorophosphate, and the like, among which N, N-dicyclohexylcarposimide, 1-ethyl-3- ( 3-dimethylaminopropyl) carposi Preference is given to imide hydrochloride, ethyl ethyl chloroformate, isobutyl chloroformate and the like. The reagent used in the reaction can be appropriately increased or decreased depending on the starting compounds and reaction conditions, but is usually 1 to 50 equivalents, preferably 1 to 2 equivalents of N, di-dimethylhydroxyl hydroxylase relative to the carboxylic acid. Min, 1 to 50 equivalents, preferably 3 to 5 equivalents of base, 1 to 50 equivalents, preferably 1 to 5 equivalents of condensation aid and / or 1 to 50 equivalents, preferably 1 to 5 equivalents Use an equal amount of condensing agent. The base, the condensation aid, and the condensing agent can be used alone or in appropriate combination of two or more.

 (3rd step)

 General formula [XV I]

[Wherein, RR ² , R ³ , Ar, PG ¹ and Me have the above-mentioned meaning], by converting a halogenated aryl compound and metal magnesium to a suitable ether-based compound such as, for example, methyl ether, tetrahydrofuran, etc. A general formula [XVI I] is obtained by reacting in a dehydrated inert organic solvent at a low temperature to room temperature with a Grignard reagent prepared by reacting at a low temperature to the boiling point of the solvent in a dehydrated solvent.

[Wherein, R ¹ , R ² , R ³ , R ⁵ , Ar and PG ¹ have the above-mentioned meaning]. The reagent used in the reaction can be appropriately increased or decreased depending on the starting compounds and reaction conditions. Usually, the reaction is carried out in an inert organic solvent that has been dehydrated by reacting the compound represented by the above general formula [XVI] with the Grignard reagent. The reaction is carried out at a temperature of 100 to the boiling point of the solvent, preferably -78 to 30 ^, for 0.5 to 96 hours, preferably for 12 to 24 hours. The inert organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction. Specific examples thereof include hexane, cyclohexane, pentane, ether, 1,4-dioxane , Tetrahydrofuran, tetrahydropyran and the like, among which ether, tetrahydrofuran, cyclohexane and the like are preferable.

 The reagent used in the reaction can be appropriately increased or decreased depending on the starting compound and reaction conditions, but is usually 2 to 10 equivalents, preferably 2 to 10 equivalents to the compound represented by the above general formula [XVI]. Use 3 equivalents of Grignard reagent.

 (4th step)

 General formula [XV I I]

[Wherein, R ¹ R ² , R ³ , R ⁵ , Ar and PG ¹ have the above-mentioned meaning] The protecting group for the amino group of the compound represented by the general formula [VI]

[Wherein, R ¹ R ² , R ³ , ¹⁵ and 18 "have the meanings described above] Can be synthesized.

 The removal of the protecting group depends on the type and stability of the compound, but the method described in the literature [Protective Groups in Organic Synthesis, T.W. Green (TW Greene, John Wiley & Sons (1981)) or a method analogous thereto, for example, solvolysis using an acid or a base, chemical reduction using a metal hydride complex, or the like. Alternatively, it can be carried out by catalytic reduction using a palladium carbon catalyst, a Raney nickel catalyst or the like. The compound represented by the above general formula [VI] can be synthesized by subsequently reacting the compound represented by the above general formula [VI] by the method of Step 3-5 of Production method A. . Manufacturing method D

 (First step)

 The general formula [X I X]

[Wherein L ¹ represents a leaving group such as halogen, and R ⁵ and Ar have the above-mentioned meanings] can be synthesized by a known method.

For example, the general formula [XV I I I]

[In the formula, eight! :as well as! ^ Has the meaning R ⁵ — H (where R ⁵ is The compound can be synthesized by reacting with an aryl compound represented by the following formula) by, for example, a Friedel-Crafts reaction using aluminum chloride.

 (2nd step)

 The general formula [X I X] and the general formula [XX]

[Where RR ² , ³ and? 0 ¹ of the general formula in by reaction with a thiol compound represented by have the meanings of the [XV II]

I]

[式中、 R R²、 R³、 R⁵、 八1"及び？ ¹は、 前記の意味を有する]で表され る化合物が合成できる。

[Wherein, RR ² , R ³ , R ⁵ , 8 1 "and? ¹ have the above-mentioned meanings].

 The reagents used in the reaction can be appropriately increased or decreased depending on the starting compounds and reaction conditions. Usually, the reaction is carried out in a suitable organic acid solvent such as N, N-dimethylformamide, for example, potassium carbonate. The reaction is completed by reacting with a suitable base at o: from the boiling point of the solvent, preferably 50 to 120 ° C, for 0.5 to 96 hours, preferably 2 to 12 hours.

 As the organic solvent used in the reaction, any organic solvent that does not adversely affect the reaction can be used.

Although not particularly limited, specifically, for example, salt dimethylene, black form,

2-dichloroethane, trichloroethane, carbon tetrachloride, N, N-dimethylformamide, acetonitrile, acetone, benzene, toluene, ether, 1,4-dioxane, tetrahydrofuran, tetrahydropyran, etc., among which N , N-dimethylformamide, toluene, xylene, acetone, ether, tetrahydrofuran and the like are preferred.

 Examples of the base used in the reaction include trimethylamine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, N-methylpiperidine, N, N-dimethylaniline, Tertiary fats such as 1,8-diazabicyclo [5.4.0] pendant 7-ene (DBU) and 1,5-azabicyclo [4.3.0] noner 5-ene (DBN) Aliphatic amines, for example, alkali metal hydrides such as sodium hydride and potassium hydride, for example, alkali metal alkoxides such as potassium tert-butylate, sodium ethylate, sodium methylate; potassium hydroxide, 7jc oxidation Alkali metal hydroxides such as sodium; for example, alkali metal carbonates such as carbon dioxide, etc., among which triethylamine, N, N-diisopropylethyl Amin, sodium hydride, potassium hydride, potassium one t e r t-Puchirato, sodium E Ji methoxide, sodium methylate, potassium carbonate is preferred.

 The reagent used in the reaction can be appropriately increased or decreased depending on the raw material compounds and reaction conditions, but is usually 1.2 to 20 equivalents, preferably 1 to 20 equivalents to the compound represented by the above general formula [XIX]. 1. Use 2 to 5 equivalents of the compound represented by the general formula [XX].

 The compound represented by the above general formula [XV II] is synthesized into the compound represented by the above general formula [I] by the method of the fourth step of the production method C and the third to fifth steps of the production method A. can do.

 Manufacturing method E

 (First step)

General formula [XX I]

[Wherein L ² represents a leaving group such as halogen, and Ar has the above-mentioned meaning] Compound represented by general formula [V]

[Wherein RR ² and R ³ have the above-mentioned meanings] and a polar solvent such as lutidine to react with a compound represented by the general formula [XXII]

[Wherein, R ¹ , R ² , R ³ , R ⁵ , Ar, and L ² have the above-mentioned meanings].

 The reagent used in the reaction can be appropriately increased or decreased depending on the starting compound and the reaction conditions. Usually, for example, the reaction is carried out in an organic solvent such as lutidine with the compound represented by the above general formula [XXI] and the above general compound. The compound represented by the formula [V] is dissolved at room temperature in 0.

The reaction is performed for 5 to 96 hours, preferably 3 to 24 hours.

 As the organic solvent used in the reaction, any organic solvent that does not adversely affect the reaction can be used.

Although not particularly limited, specifically, for example, methylene chloride, chloroform,

2-dichloroethane, trichloroethane, carbon tetrachloride, N, N-dimethylformamide, ethyl acetate, methyl acetate, acetonitrile, methyl alcohol, ethyl alcohol, benzene, xylene, pyridine, lutidine, toluene, xylene, 1 , 4-dioxane, tetrahydrofuran and the like, among which methyl alcohol, ethyl alcohol, pyridine, lutidine, N, N-dimethylformamide, toluene, xylene and the like are preferable.

 The reagent used in the reaction can be appropriately increased or decreased depending on the raw material compound and the reaction conditions, but usually, the amount of the compound represented by the above general formula [XXI] is 1.

2 to 10 equivalents, preferably 1.2 to 2 equivalents of the aziridyl represented by the above general formula [V] Use gin.

 (2nd step)

 General formula [XXI I]

[Wherein, R ¹ R ² , R ³ , Ar and L ² have the above-mentioned meanings] and a general formula [XIII]

R ⁵ CH0 [XXI 111

Wherein R ⁵ has the meaning described above, and azeotropic distillation in a suitable solvent such as 2,6-lutidine in the presence of an appropriate acid, or for example, By heating to reflux in the presence of a desiccant such as Ura sieves, the general formula [XXIV]

[Wherein, R ¹ R ² , R ³ , R ⁵ , Ar, and L ² have the above-mentioned meanings].

 The reagent used in the reaction can be appropriately increased or decreased depending on the starting compound and the reaction conditions, but usually the reaction is carried out in the presence of a desiccant such as molecular sieves, for example, using a suitable agent such as 2,6-lutidine. The reaction is completed by refluxing in a solvent, for example for 5 to 96 hours, preferably 12 to 24 hours, in the presence of a suitable acid such as hydrochloric acid.

As the organic solvent used in the reaction, any organic solvent that does not adversely affect the reaction can be used. Specific examples include, but are not limited to, methylene chloride, chloroform, 1,2-dichloroethane, trichloroethane, N, N-dimethylformamide, acetic anhydride, ethyl acetate, methyl acetate, acetonitrile, and methyl alcohol. , Ethyl alcohol, n-propanol, benzene, xylene, pyridine, lutidine, toluene, xylene, 1,4-dioxane, tetrahydrofuran, and the like. Among them, pyridine, lutidine, N, N-dimethylformamide, toluene, xylene and the like are preferred.

 Examples of the acid used in the reaction include inorganic acids such as hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, hydrofluoric acid, and perchloric acid; for example, Lewis acids such as trifluoroboric acid, titanium tetrachloride, and zinc chloride; !) Sulfonic acids such as mono-toluenesulfonic acid, trifluoromethanesulfonic acid, and methanesulfonic acid; organic acids such as formic acid, trifluoroacetic acid, and acetic acid; and hydrochloric acid, acetic acid, and p-toluenesulfonic acid are preferable. The desiccant used in the reaction includes, for example, molecular sieves, magnesium sulfate, sodium sulfate, etc. Among them, the molecular sieves are preferable. Although it can be increased or decreased as appropriate, it is usually 1.2 to 10 equivalents to the compound represented by the above general formula [XXII]. Preferably 1.2 to 2 equivalents of the aldehyde represented by the above general formula [XXIII], 1.2 to 10 equivalents, preferably 1.2 to 2 equivalents of the desiccant, 1 to 50 equivalents Preferably, 3 to 5 equivalents of acid are used. The acid and the desiccant may be used alone or in combination of two or more.

 (3rd step)

 General formula [XX I V]

[XXIV]

[式中、 R¹, R²、 R³、 R⁵、 Ar、 L²は、 前記の意味を有する] で表される 化合物を適宜塩基によって、 不活性な有機溶媒中で例えば一 78°Cの様な低温で 処理することにより閉環させ一般式 [XXV]

Wherein R ¹ , R ² , R ³ , R ⁵ , Ar, and L ² have the above-mentioned meanings. The compound represented by the formula: The ring is closed by treating at a low temperature, such as the general formula [XXV]

[式中、 R R R³、 R⁵、 Arは、 前記の意味を有する] で表される化合物 が合成できる。

[Wherein, RRR ³ , R ⁵ , and Ar have the above-mentioned meanings].

 The reagent used in the reaction can be appropriately increased or decreased depending on the starting compound and the reaction conditions.Normally, the reaction is carried out in a dehydrated inert organic solvent using a suitable base in the presence of an appropriate additive at a temperature of 100 ° C. To the boiling point of the solvent, preferably 1 to 78 to 30 ° (: 0.5 to 96 hours, preferably 12 to 24 hours to complete the intramolecular ring closure reaction.

 The inert organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction. Specific examples thereof include hexane, cyclohexane, pentane, ether, and 1,4-dioxane. And tetrahydrofuran, tetrahydropyran and the like, and particularly, for example, ether, tetrahydrofuran, cyclohexane and the like are preferable.

 Examples of the additives used in the reaction include Ν, Ν, Ν ′, Ν′-tetramethylethylenediamine TMEDA, hexamethylphosphoramine HMPA, lithium salt, and the like. ', Ν'-Tetramethylethylenediamine is preferred.

 Examples of the base used in the reaction include η-butyllithium, sec-butyllithium, t-butyllithium, phenyllithium, methyllithium and the like. Among them, n-butyllithium and sec-butyllithium are preferred. is there.

The reagent used in the reaction can be appropriately increased or decreased depending on the raw material compound and the reaction conditions. However, usually, the amount of the reagent represented by the above general formula [XXIV] is 2%. ~ 10 equivalents, preferably 2-3 equivalents of base are used.

 The obtained compound represented by the general formula [XXV] can be synthesized by the method of the fourth step of the production method A to produce the compound represented by the general formula [I]. Manufacturing method F

 (First step)

General formula [XXV I]

 [Wherein, Ar has the meaning described above] and a general formula [V]

Wherein R ¹ R ² and R ³ have the above-mentioned meanings in a polar solvent such as lutidine, and the compound represented by the general formula [XXVI I]

[XXVII]

[Wherein, R ¹ R ² , R ³ , and Ar have the above-mentioned meanings].

 The reagent used in the reaction can be appropriately increased or decreased depending on the starting compounds and reaction conditions. Usually, for example, the reaction is carried out in an organic solvent such as lutidine with the compound represented by the above general formula [XXVI] and the compound represented by the above general formula. The compound represented by [V] is reacted at room temperature for 0.5 to 96 hours, preferably 3 to 24 hours.

As the organic solvent used in the reaction, any organic solvent that does not adversely affect the reaction can be used. Specific examples include, but are not limited to, methylene chloride, chloroform, 1,2-dichloroethane, trichloroethane, carbon tetrachloride, N, N-dimethylformamide, ethyl acetate, methyl acetate, and acetate nitrite. Ryl, methyl alcohol, ethyl alcohol, benzene, xylene, pyridine, lutidine, toluene, xylene, 1,4-dioxane, tetrahydrofuran, etc., among which methyl alcohol, ethyl alcohol, pyridine, lutidine, N, N —Dimethylformamide, toluene, xylene and the like are preferred.

 The reagent used in the reaction can be appropriately increased or decreased depending on the raw material compounds and reaction conditions, but is usually 1.2 to 10 equivalents, preferably 1 to 10 equivalents to the compound represented by the above general formula [XXV II]. 1. Use 2 to 2 equivalents of the aziridine represented by the above general formula [V].

 (2nd step)

General formula [XXV I I]

[XXVII]

[Wherein, RR ² , R ³ and Ar have the above-mentioned meanings] The compound represented by the general formula [XXV III]

[XXVIII]

[Wherein RR ² , R ³ and Ar have the above-mentioned meanings] can be synthesized, and subsequently, in the presence of a desiccant such as molecular sieves, for example, 2,6-lutidine By heating to reflux in a suitable solvent in the presence of a suitable acid such as hydrochloric acid, the compound represented by the general formula [XX IX]

[Wherein, RR ² , shaku ³ and yachi 1 ”have the above-mentioned meanings].

 The reagent used in the oxidation reaction can be appropriately increased or decreased depending on the starting compound and the reaction conditions.In general, the reaction is carried out, for example, in a suitable solvent with a suitable oxidizing agent such as manganese dioxide at room temperature for 5 to 96 hours. The reaction is completed for a period of time, preferably 12 to 24 hours.

 The oxidizing agent used in the reaction is not particularly limited as long as it does not adversely affect the reaction, but specific examples thereof include manganese dioxide, chromic acid, t-butyl chromate, lead tetraacetate, and tetroxide. Ruthenium, selenium dioxide, halogen, oodosil compounds, oxygen, organic peroxides, silver peroxosulfate, nitric oxide, dimethyl sulfoxide, o-chloranil, silver oxide, etc., among which manganese dioxide, chromic acid, selenium dioxide And dimethyl sulfoxide.

 The reagent used in the reaction can be appropriately increased or decreased depending on the starting compound and the reaction conditions, but is usually preferably from 0.22 to 50 equivalents, preferably from the compound represented by the above general formula [VII]. Use 1.2 to 2 equivalents of oxidizing agent.

 The reagent used in the ring closure reaction can be appropriately increased or decreased depending on the starting compound and reaction conditions, but usually the reaction is carried out in the presence of a desiccant such as molecular sieves, for example, 2,6-lutidine. The reaction is completed by refluxing in a suitable solvent, for example in the presence of a suitable acid such as hydrochloric acid for 5 to 96 hours, preferably 12 to 24 hours.

The organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction. Specific examples include methylene chloride, chloroform, 1,2-dichloroethane, trichloroethane, and N , N-dimethylformamide, acetic anhydride, ethyl acetate, methyl acetate, acetonitrile, methyl alcohol, ethyl alcohol, n-propanol, benzene, xylene, pyridine , Lutidine, toluene, xylene, 1,4-dioxane, tetrahydrofuran and the like. Among them, pyridine, lutidine, N, N-dimethylformamide, toluene, xylene and the like are preferable.

 Examples of the acid used in the reaction include inorganic acids such as hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, hydrofluoric acid and perchloric acid; for example, Lewis acids such as trifluoroboric acid, titanium tetrachloride, zinc chloride and the like. Sulfonic acids such as p-toluenesulfonic acid, trifluoromethanesulfonic acid, and methanesulfonic acid; organic acids such as formic acid, trifluoroacetic acid, and acetic acid; and hydrochloric acid, acetic acid, and p-toluenesulfonic acid. Suitable desiccants used in the reaction include, for example, molecular sieves, magnesium sulfate, and sodium sulfate, with molecular sieves being preferred. The amount of the reagent used in the reaction can be appropriately increased or decreased depending on the starting compound and the reaction conditions, but is usually 1.2 to 10 equivalents to the compound represented by the above general formula [XXVIII]. Preferably, 1.2 to 2 equivalents of desiccant, 1 to 50 equivalents, preferably 3 to 5 equivalents of acid are used. The acid and the desiccant may be used alone or in appropriate combination of two or more.

 (3rd step)

General formula [X X I X]

[Wherein, R ¹ R ² , R ³ and Ar have the above-mentioned meanings] and a compound obtained by activating a halogenated aryl compound with a metal such as magnesium, lithium, copper or zinc. Is reacted in a suitable ether-based dehydrating solvent at a low temperature to the boiling point of the solvent to obtain the general formula [XXV]

[Wherein, R ¹ R ² , R ³ , R ⁵ , and Ar have the above-mentioned meanings].

 Using the obtained compound represented by the general formula [XXV], the compound represented by the above general formula [I] can be synthesized by the method of the fourth step of the production method A. Manufacturing method G

This production method is a method for producing a compound represented by the general formula [I] wherein R ⁴ is 1 C ₃ alkyl.

 General formula [V I I]

[Wherein, R ¹ R ² , R ³ , R ⁵ , and Ar have the above-mentioned meanings] and a general formula [XXX]

R ⁴ L ³ [XXX]

[Wherein, R ⁴ represents one C ₃ alkyl and L ³ represents a leaving group such as halogen] by reacting an alkyl octride represented by the general formula [XXX I]

[Wherein, R ¹ R ² , R ³ , R ⁴ , R ⁵ , and Ar have the above-mentioned meanings] A quaternary salt can be synthesized.

 The reagent used in the reaction can be appropriately increased or decreased depending on the starting compounds and reaction conditions. Usually, the reaction is carried out by reacting the compound represented by the above general formula [VII] with the alkyl halide represented by the above general formula [XX]. The reaction is completed by heating to reflux in an inert organic solvent for 5 to 96 hours, preferably 12 to 24 hours.

 The organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction. Specific examples thereof include methylene chloride, chloroform, 1,2-dichloroethane, trichloroethane, and N , N-dimethylformamide, acetic anhydride, ethyl acetate, methyl acetate, acetonitrile, methyl alcohol, ethyl alcohol, n-propanol, benzene, xylene, toluene, xylene, 1,4-dioxane, tetrahydrofuran, and the like. Of these, acetonitrile, toluene, xylene and the like are preferred.

 The reagent used in the reaction can be appropriately increased or decreased depending on the starting compound and reaction conditions, but is usually 1 to 50 equivalents, preferably 10 to 10 equivalents to the compound represented by the above general formula [VII]. Use 50 equivalents of the compound represented by the above general formula [XXX].

 Using the obtained compound represented by the above general formula [XXX], the compound of the above general formula [I] can be synthesized by the method of the fifth step of Production method A. Manufacturing method H

This production method is a method for producing a compound represented by the general formula [I] wherein R ⁴ is a hydroxyl group.

 General formula [XXV]

[Wherein RR ² , R ³ , and R ⁵ Ar have the meaning described above] The compound represented by the above general formula [I] can be synthesized by appropriately reacting with an oxidizing agent.

 The reagents used in the reaction can be appropriately increased or decreased depending on the starting compounds and reaction conditions.Normally, the reaction is carried out in a suitable inert organic solvent such as methylene chloride, for example, The reaction is completed by stirring at room temperature for 5 to 96 hours, preferably 12 to 24 hours, in the presence of a suitable oxidizing agent.

 The inert organic solvent used in the reaction is not particularly limited as long as it does not adversely affect the reaction, and specific examples thereof include methylene chloride, chloroform, 1,2-dichloroethane, and trichloroethane. , Carbon tetrachloride, ethyl acetate, methyl acetate, acetonitrile, methyl alcohol, ethyl alcohol, benzene, xylene, toluene, xylene, ether, 1,4-dioxane, tetrahydrofuran, tetrahydropyran and the like. Preferred are methylene, chloroform, 1,2-dichloroethane, trichloroethane, ethyl acetate and the like.

 The oxidizing agent used in the reaction is not particularly limited as long as it does not adversely affect the reaction.Specifically, for example, hydrogen peroxide, peracetic acid, trifluoroperacetic acid, methachloroperbenzoic acid, oxone, Examples thereof include chromic acid and permanganese sun. Among them, for example, hydrogen peroxide, metachloroperbenzoic acid, and the like are particularly preferable. The reagent used in the reaction can be appropriately increased or decreased depending on the raw material compound and the reaction conditions, but is usually 1.2 to 10 equivalents, preferably 1.2 to 10 equivalents to the compound represented by the above general formula [XXV]. Use 1.2 to 2 equivalents of oxidizing agent.

 Next, in order to specifically demonstrate the usefulness of the present invention, the compound of Compound Example 116 was used as a representative compound, and the effect on GLP-1 concentration in plasma after administration of the compound was examined. .

The test method and results are shown below.

 (Test method)

Male Wistar rats (9-week old, n = 6) bred under free-feeding and water-feeding conditions were fasted the night before the test, and administered with a compound suspended in a 1% carboxymethylcellulose solution. As a control, a 1% carboxymethylcellulose solution was orally administered to rats. Blood was collected 30 minutes after administration of the test drug, and was separated from the obtained blood. Plasma was separated by cardiac separation. GLP-1 concentration in plasma was determined by a radioimmunoassay method using a commercially available anti-GLP-1 antibody (Cosmo Bio Inc.). The obtained values were analyzed using the Student T test, and the statistical significance was calculated. The results are shown in the table below.

 (Test results)

 Table 9

 Control group 111 610 mg / kg group Based on the above results, 30 minutes after administration, plasma GLP_1 was significantly higher in the plasma of the group to which 1 Omg / kg of the compound was administered compared to the control group. Was. From these results, it was shown that the compound of the present invention has an activity capable of exhibiting a high blood GLP-1 concentration in rats.

The compound of the present invention is useful as a therapeutic agent for diabetes mellitus, a preventive for chronic complications of diabetes or an antiobesity drug, since it exhibits an activity of exhibiting a high blood GLP-1 concentration. The compound of the general formula [I] of the present invention can be used as a medicament containing the same as an active ingredient, particularly as an agent for treating diabetes, an agent for preventing chronic complications of diabetes or an antiobesity agent. The compound of the present invention in a therapeutic agent, a preventive agent for chronic complications of diabetes or an anti-obesity agent means a pharmaceutically acceptable conventional one, For example, the general formula [I]

[Wherein, RR ² , R ³ , R ⁴ , R ⁵ , Ar and n have the above-mentioned meanings. Compounds represented by, E ester or a pharmaceutically acceptable salt in the force Rupokishiru group on R ⁵ or A r, salts in hydroxyl groups on R ⁵ or A r, or at the amino group on R ⁵ or A r Salts are included.

 Examples of the salt in the carboxyl group or the hydroxy group include alkali metal salts such as sodium salt and potassium salt; and alkaline earth metal salts such as calcium salt and magnesium salt.

 Examples of the acid addition salt for the amino group include inorganic salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, hydrogencarbonate and perchlorate; for example, acetate, propionate and lactic acid Organic salts such as salt, maleate, fumarate, tartrate, malate, citrate, and ascorbate; for example, methanesulfonate, isethionate, benzenesulfonate, toluenesulfonate, etc. Sulfonic acid salts; for example, acidic amino acid salts such as aspartate and glutamate.

 When the compound of the present invention is used as a therapeutic agent for diabetes, a preventive agent for chronic complications of diabetes, or an antiobesity agent, it can also be used as a pharmaceutically acceptable salt thereof. Typical examples of the pharmaceutically acceptable salts include, for example, salts with alkali metals such as sodium and potassium.

 The method for producing a pharmaceutically acceptable salt of the compound of the present invention can be carried out by appropriately combining methods usually used in the field of synthetic organic chemistry. Specific examples include neutralization titration of a free solution of the compound of the present invention with an alkaline solution.

Compounds of the present invention for treating diabetes, preventing chronic complications of diabetes or treating obesity Various forms can be selected as the dosage form for use as a tablet, for example, oral preparations such as tablets, capsules, powders, granules, and liquid preparations, and sterilized liquid parenteral preparations such as solutions and suspensions. Is mentioned.

 Solid preparations can be produced as they are in the form of tablets, capsules, granules or powders, or they can be produced using appropriate additives. Examples of the additive include sugars such as lactose and glucose; starches such as corn, wheat and rice; fatty acids such as stearic acid; inorganic salts such as sodium metasilicate, magnesium aluminate and anhydrous calcium phosphate; Synthetic polymers such as polyvinylpyrrolidone and polyalkylene glycol; fatty acids such as calcium stearate and magnesium stearate; alcohols such as stearyl alcohol and benzyl alcohol; methyl cellulose, carboxymethyl cellulose, and ethyl cellulose And synthetic cellulose derivatives such as hydroxypropylmethylcellulose, and other commonly used additives, such as water, gelatin, talc, vegetable oil, and gum arabic.

 These tablets, capsules, granules, powders and other solid preparations can generally contain 0.1 to 100% by weight, preferably 5 to 100% by weight, of the active ingredient. For liquid preparations, use appropriate additives normally used in liquid preparations such as water, alcohols or plant-derived oils such as soybean oil, peanut oil, sesame oil, etc. It can be manufactured as a form. Particularly suitable solvents for parenteral administration include, for example, distilled water for injection, aqueous lidocaine hydrochloride (for intramuscular injection), physiological saline, aqueous dextrose, ethanol, and liquid for intravenous injection (for example, quinic acid). , Sodium citrate, etc.), an electrolyte solution (for example, intravenous drip, intravenous injection) and the like, or a mixed solution thereof.

 Liquid preparations such as suspensions or syrups for oral administration may contain 0.5 to 10% by weight of active ingredients.

The practically preferred dosage of the compounds of the present invention may be adjusted as appropriate depending on the type of compound used, the type of composition formulated, the frequency of application and the particular site to be treated and the condition of the patient. . For example, the daily dose per adult per day is 0.1 to 100 mg for oral administration and 100 mg / day for parenteral administration. It is 0.01 to 50 Omg. The frequency of administration varies depending on the administration method and symptoms, but it can be administered once or in 2 to 5 doses. BEST MODE FOR CARRYING OUT THE INVENTION

 The present invention will be described more specifically with reference to examples, but the present invention is not limited thereto.

 The thin-layer chromatograph of the example has a plate of Si 1 i c ag e 160 F

₂₄₅ (Merck) was detected using a UV detector. The silica gel for the column is Wakoge 1 ^™ C-300 (Wako Pure Chemical Industries), and the silica gel for the reversed-phase column is LC-SORB ^™ S PB-ODS (Chemco) or Y

MC-GEL ™ ODS-AQ 120 _ S 50 (Yamamura Chemical Laboratory) was used. i-Bu: isobutyl group

n-Bu: n-butyl group

 t-Bu: t-butyl group

Me: methyl group

 E t: ethyl group

 Ph: phenyl group

 i—Pr: isopropyl group

n—Pr: n—propyl group

CDC 1 _3: heavy black hole Holm

me th ano l— d ₄

DMSO-d _6: deuterated dimethyl sulfoxide Example 1

Preparation of Compound Example 1016 (3 ^^-sopropyl-1-5-phenyl-2,3,4,5-tetrahydro-Iff-1 ¹⁶ , 4-benzothiazepine _1,1dione)

Dichloromethane (300 ml) and 2-amino-3-methyl-1-butanol (50.0 g, 485 mmo 1) are mixed under a nitrogen atmosphere, and sulfonic acid chloride (35.0 ml, 524 mmo 1) is added at 0 ° C. It was dropped. After the addition is complete, mix the mixture at room temperature. Stir for 2 hours. Water (100 ml) and 50% aqueous τΚ sodium oxide solution (10 Og) were added and the mixture was distilled at atmospheric pressure. The organic layer was separated from the distillate and dried over solid potassium hydroxide to give the desired product 2-isopropylaziridine (36.3 g, 426 mmo 1) (88% yield).

_{^ NMR (CDC 1 3):} 0. 97 (3H, d, J = 6. 2Hz), 1. 0

3 (3H, d, J = 5.9Hz), 1.04-1.20 (1H, m), 1.35-1.37 (1H, m), 1.71-1.77 (2H, m)

 Cool a solution of N, N, N,, N, —tetramethylethylenediamine (TMEDA) (63.9 ml, 424 mmo 1) in cyclohexane (300 ml), and cool n-butyllithium to 2.5 M cyclohexane. A solution (170 ml) was added. Thiophanol (23.3 g, 212 mmo 1) was added slowly and the reaction was stirred at room temperature. Addition of benzonitrile (21.8 g, 212 mm 01) gave a slurry which was stirred at room temperature overnight. After adding water (200 ml) and stirring the mixture for 30 minutes, the aqueous layer was separated and treated with solid sodium hydroxide to a pH of 14. The solution was boiled for 90 minutes, cooled to room temperature, and acidified to pH 〜2 with concentrated hydrochloric acid. The acidic solution was extracted with dichloromethane, and the combined extracts were dried and concentrated to give a red oil. This oil was treated with a 1 M aqueous sodium hydroxide solution, extracted with dichloromethane, the water tank was separated, and treated with concentrated hydrochloric acid to obtain an oil. The oil was extracted into dichloromethane, the extracts were combined, dried and concentrated under reduced pressure to give the desired orange-red oily product phenyl (2-sulfanylphenyl) methanone (36.4 g, 17 Ommo). 1) was obtained (80% yield).

_{^ NMR (CDC 1 3) δ} :.. 4. 21 (1 Η, s), 7. 14-7 25 (1 H, m), 7. 31-7 39 (1 H, m), 7. 40 -7.63 (5H, m), 7.75-7.80 (2H, m)

FAB-MS (mZe): 215 [M + H] ⁺

 The compound obtained in Step 1 (0.3 ml) was combined with the product of Step 2 (300 mg, 1.

4 Ommo 1) was added dropwise to a suspension of 2,6-lutidine (3. Oml) at room temperature. After the addition was completed, the mixture was stirred at room temperature for 3 hours, and concentrated hydrochloric acid (1. Oml) was added. After the addition was completed, the mixture was azeotropically distilled for 3 hours and distilled under reduced pressure. The residue was saturated with sodium bicarbonate The reaction solution was collected with an aqueous solution of water, and the solution was extracted twice with ethyl acetate. The combined extracts were washed with saturated brine solution, dried and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel using hexane Z ethyl acetate (90Z10) as an eluent to give a pale yellow oily substance, 3-isopropyl-15-phenyl-1,2,3-dihydro-1,4-benzothiazepine. (266 mg, 0.947 mmo 1) (yield 68%

) o

_{^{: HNMR (CDC 1 3) <}} 5: 0. 95 (3H, d, J = 6. 7Hz), 1. 0 6 (3H, d, J = 6. 7Hz), 1. 94- 2. 1 1 ( 1H, m), 2.96 (1H, ddd, J = 12.3, 6.5, 4.0Hz), 3.27 (1H, dd, J = 12.3, 11.3Hz), 3. 62 (1H, dd, J = 11.3, 4.0Hz), 7.09-7.15 (1H, m), 7.32-7.64 (8H, m) FAB-MS (mZe): 282 [M + H] +

To a solution of the product of step 3 (180 mg, 0.64 Ommo 1) in trifluoroacetic acid (3.0 ml) was added 30% aqueous hydrogen peroxide (1.0 ml) at a temperature of about 0. After the addition was completed, the mixture was stirred at room temperature overnight, treated with a 10% aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution, and extracted twice with ethyl acetate. And concentrated under reduced pressure. The residue and 4-hydrogen chloride 1,4-dioxane solution (3.0 ml) were mixed, and zinc powder (200 mg, 3.06 mmol 1) was gradually added. The mixture was stirred at room temperature, treated with a saturated aqueous solution of sodium bicarbonate, and filtered through celite. The extract was extracted twice with ethyl acetate, and the extracts were collected, washed with a saturated saline solution, dried, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel using hexane Z ethyl acetate (80/20) as eluent to give the desired compound 3-isopropyl-15-phenyl-2,3,4,5-tetrahydro-Iff - 1 lambda ^6, 4 one base Nzochiazepin - 1, -1-di-one Jiasutereoma a (35. 8mg, 0. 114mmo 1 , 18% yield) and b (62. 6mg, 0. 199 mmo 1, yield 31 %) As a pale yellow oily product.

Diastereomer a

_{^ NMR (CDC 1 3) δ} : 0. 98 (3H, d, J = 6. 8Hz), 0. 9 8 (3H, d, J = 6.8Hz), 1.75-1.85 (lH, m), 3.07 (1H, dd, J = 11.4, 14.3Hz), 3.44 (1 H, dd, J = 2.3, 14.3 Hz), 3.49—3.58 (1H, m), 5.99 (1H, s), 6.68—6.71 (lH, m), 7.33—7.43 (7H, m), 8.13—8.18 (lH, m)

 FAB-MS (m / e): 316 [M + H] +

Geostereomer b

_{^ NM (CDC 1 3) (} 5:. 0. 95 (3H, d, J = 6. 8Hz), 1. 0 0 (3H, d, J = 6. 7Hz), 1. 90 -2 05 (1 H, m), 2.94 -3. 02 (1H, m), 3.42-3.50 (2H, m), 5.85 (1H, s), 6.88-6.95 (lH, m), 7.29-7.42 (5H, m), 7.44-7.50 (2H, m), 8.12-8.20 (lH, m)

 FAB-MS (m / e): 316 [M + H] + The physical constants of the compound obtained in the same manner as in Example 1 are shown below.

Example 2

Preparation of compound examples ^{1001 (Ar: Ph; R x} : H; R 2: H; R 3: H; R 4: H; R 5: Ph; n = 0)

_{iHNMR (CDC 1 3) δ:} 2. 77 (1H, ddd, J = 3. 0, 10. 4, 14. 1Hz), 2. 86 (1 H, ddd, J = 2. 9, 4. 0, 14.1 Hz), 3.39 (1H, J = ddd, 2.9, 10.4, 14.1 Hz), 3.58 (1H, ddd, J = 3.0, 4.0, 14. 1Hz), 5.71 (1H, s), 6.62-6.65 (1H, m), 7.03-7.14 (2H, m), 7.24-7.40 (5H, m) , 7.60-7.64 (lH, m)

 FAB-MS (m / e): 242 [M + H] + Example 3

Preparation of Compound Example 1002 (Ar r Ph R ^ H j R ^ H ^^-Me; R ⁴ : H; R ⁵ : Ph; n = 0) _{^ NMR (CDC 1 3) 6} : 1. 22 (3H, d, J = 6. 5Hz), 2. 4 6 (1H, dd, J = 10. 4, 14. 1Hz), 2. 87 (1H, dd, J = 2.3, 14.1 Hz), 3.48 (1 H, J = d Q d, 2.3, 6.5, 10.4 Hz), 5.67 (IH, s), 6. 59-6.63 (1H, m), 7.00-7.16 (2H, m), 7.26-7.39 (lH, m), 7.40-7.44 (4H, m) , 7.61-7.66 (IH, m)

 FAB-MS (m / e): 256 [M + H] + Example 4

Preparation of compound examples ^{1006 (Ar: Ph; R 1} : i- P r; R 2: H; R 3: H; R 4: H; R 5: Ph; n = 0)

_{iHNMR (CDC 1 3) (5} : 1. 04 (3H, d, J = 6. 8Hz), 1. 0 7 (3H, d, J = 6. 8Hz), 1. 90 - 2. 02 (lH, m), 2.60-2.68 (IH, m), 3.26 (1H, dd, J = 9.9, 14.1 Hz), 3.44 (IH, dd, J = 2.7) , 14.1 Hz), 5.66 (1H, s), 6.59-6.65 (lH, m), 7.00-7.40 (7H, m), 7.60-7.63 ( IH, m)

 FAB-MS (m / e): 283 [M + H] + Example 5

Preparation of compound examples ^{1007 (Ar: Ph; R 1} : i- P r; R 2: H; R 3: H; R ': H; R 5: P h; n = 2)

_{^ NMR (CDC 1 3) 6} : 1. 09 (3H, d, J = 6. 9Hz), 1. 1 6 (3H, d, J = 6. 9Hz) 2. 85- 2. 95 (IH, m ), 2.96-3.03 (1H, m), 3.50 (IH, dd, J = 2.9, 14.8Hz), 3.74 (IH, dd, J = l 1.1, 14 8Hz), 5.92 (IH, s), 6.68 (1H, d, J = 8.9Hz), 7.30—7.45 (7H, m), 8.13-8.16 (IH , m)

FAB-MS (m / e): 316 [M + H] + Example 6

Preparation of compound examples ^{1015 (Ar: Ph; R 1} : H; R 2: H; R 3: i- P r; R 4: H; R 5: Ph; n = 0)

_{NMR (CDC 1 3) δ:} 0. 95 (3Η, d, J = 6. 8Hz), 0. 9 5 (. 3H, d, J = 6 7Hz), 1. 90- 2. 05 (lH, m ), 2.75-2.85 (1H, m), 2.85-2.94 (2H, m), 5.72 (1H, s), 6.72-6.79 (1H, m), 7.05-7.16 (2H, m), 7.24-7.38 (5H, m), 7.48-7.51 (lH, m)

 FAB-MS (m / e): 284 [M + H] + Example 7

Preparation of Compound Example 1017

Jiasutereoma ^{a (Ar: Ph R 1:} H; R 2: H; R: -P r; R 4: M e; R 5: P h; n = 0)

_{^{X HNMR (CDC 1 3) δ}} : 0 91 (3H, d, J = 6. 9Hz), 1. 0 2 (3H, d, J = 6. 9Hz), 1. 58- 1. 71 (1H, m ), 2.19 (3H, s), 2.47-2.54 (1H, m), 2.70—3.00 (2H, m), 5.97 (1H, s), 6.76 -6.72 (1H, m), 7.22-7.41 (5H, m), 7.60-7.65 (3H, m)

 FAB-MS (m / e): 298 [M + H] +

Diastereomer b (Ar i P j R ^ H j R ^ H j R ³ : i-1 Pr; R ⁴ : Me; R ⁵ : Ph; n = 0)

_{^{X HNMR (CDC 1 3) δ}} : 0. 98 (3H, d, J = 6. 9Hz), 1. 1 7 (3H, d, J = 6. 9Hz), 1. 58- 1. 71 (1 H , m), 1.78 (3H, s), 2.63—3.00 (3H, m), 6.03 (1 H, s), 6.76-6.72 (1H, m), 7.22-7.41 (5H, m), 7.65-7.69 (3H, m)

FAB-MS (m / e): 298 [M + H] + Example 8

Preparation of Compound Example 1031

Jiasutereoma ^{a (Ar: Ph; R 1} : H; R 2: H; R 3 i -P r; R 4: H; R 5: 4-OH-Ph; n = 0)

_{^{X HNMR (CDC 1 3) δ}} : 0. 93 (3Η, d, J = 6. 9Hz), 0. 9 5 (3H, d, J = 6. 8Hz), 1. 65- 1. 75 (lH, m), 2.44 (1H, dd, J = 10.8, 13.9Hz), 2.89 (1H, dd, J = 2.2, 13.9Hz), 3.04 (1H, ddd, J = 2.2, 5.2, 10.8 Hz), 5.07 (1H, s), 6.60-6.64 (1H, m), 6.83 (2H, d, J = 8. 6Hz), 7.02-7.13 (2H, m), 7.27 (2H, d, J = 8.6Hz), 7.60—7.64 (1H, m)

 FAB-MS (m / e): 300 [M + H] +

Diastereomer b (Ar i Ph ^^ H j R ^ H j ³ : i -P r; R ⁴ : H; R ⁶ : 4-OH-Ph; n = 0)

_{^{X HNMR (CDC 1 3) δ}} : 0. 94 (3H, d, J = 6. 8Hz), 0. 9 4 (3H, d, J = 6. 8Hz), 1. 95- 2. 05 (1H, m), 2.76-2.83 (lH, m), 2.87-2.94 (2H, m), 5.65 (1H, s), 6.78-6.82 (lH, m) , 6.80 (2H, d, J = 8.6 Hz), 7.10-7.14 (2H, m), 7.20 (2H, d, J = 8.6 Hz), 7.49-7. 52 (1H, m)

 FAB-MS (m / e): 300 [M + H] + Example 9

Preparation of compound examples 1032 (A r: P h; R 1: H; R 2: H; R 3: i- P r; R 4: H; R 5: 4-OH-Ph; n = 2)

_{^{X HNMR (CDC 1 3) δ}} :. 0. 94 (3H, d, J = 6. 4Hz), 0. 9 8 (3H, d, J = 6. 4Hz), 1. 88 -2 00 (1 H , M), 2.92 -3.00 (lH, m), 3.35-3.52 (2H, m), 5.77 (1H, s), 6.83 (2H, d, J = 8.5Hz), 6.92-6.97 (1H, m), 7.18 (2H, d, J = 8.5Hz), 7.45- 7.48 (2H, m), 8.12-8.16 (1H, m)

 FAB-MS (m / e): 332 [M + H] + Example 10

Preparation of compound examples ^{1033 (Ar: P; R 1} : H; R 2: H; R 3: i one ^{P r; R 4: H;} R 5: 3 -OH-P h; n = 2)

_{^ NMR (CDC 1 3) δ} :. 0. 95 (3H, d, J = 7. 0Hz), 1. 0 0 (3H, d, J = 6. 8Hz), 1. 95-2 10 (1 H , M), 2.98 — 3.04 (lH, m), 3.40-3.55 (2H, m), 5.82 (1H, s), 6.80 (IH, dd, J = 2 9, 7.8 Hz), 6.83 (1H, d, J = 2.9 Hz), 6.90 (IH, d, J = 7.6 Hz), 6.95—6.98 (IH, m) , 7.25 (1H, dd, J = 7.6, 7.8Hz), 7.4.7-7.50 (2H, m), 8.13—8.16 (1H, m)

 FAB-MS (m / e): 346 [M + H] + Example 11

Preparation of Compound Example 1034

Jiasutereoma one a (A r: P h; R 1: H; R 2: H; R 3: i one P r; R ^4: H

R ⁵ : 2-OH-Ph; n = 2)

_{^{X HNMR (CDC 1 3) (}} 5: 1. 00 (3H, d, J = 7. 5Hz), 1. 0 0 (3H, d, J = 7. 5Hz), 1. 82- 1. 94 (1 H, m), 3.17

(IH, dd, J = 11.3, 14, 5Hz), 3.47 (1H, dd, J = 2.8, 14.5Hz), 3.48-3.58 (lH, m), 6 07 (IH, s), 6.80-6.85 (2H, m), 6.94-6.97 (1H, m), 7.06-7.10 (IH, m), 7. 21-7.28 (lH, m), 7.49-7.53 (2H, m), 8.16-8.20 (1H, m)

FAB-MS (m / e): 332 [M + H] + Jiasutereoma one ^{b (Ar: Ph; R 1} : H; R 2: H; R 3: i -P r; R 4: H; R 5: 2-OH-Ph; n = 2)

_{NMR (CDC 1 3) δ:} 0. 98 (3H, d, J = 6. 8Hz), 0. 9 9 (3H, d, J = 6. 9Hz), 1. 92 - 2. 05 (1H, m ), 2.92 -3. 02 (1H, m), 3.46 (1H, dd, J = 9.6, 14.3Hz), 3.57 (1H, dd, J = 1.9, 14) 3Hz), 6.13 (1H, s), 6.80-6.86 (2H, m), 6.96-7.00 (2H, m), 7.1 2-7.17 (1H , m), 7.25-7.32 (1H, m), 7.53-7.61 (2H, m), 8.13-8.17 (lH, m)

 FAB-MS (m / e): 332 [M + H] + Example 12

Preparation of Compound Example 1035

Jiasutereoma a (Ar: P h; R 1: H; R 2: H; R 3 -P r: R 4: H; R 5: 4-MeO-P; n = 0)

_{^ NMR (CDC 1 3) δ} 0. 97 (3H, d, J = 6. 7Hz), 0. 9

7 (3H, d, J = 6.7 Hz), 1.75-1.85 (1H, m), 3.07 (1H, dd, J = l 1.4, 14.3 Hz), 3.43 ( 1 H, dd, J = 2

2, 14.3Hz), 3.51 (1H, ddd, J = 2.2, 4.9, 11.4Hz), 3.85 (3H, s), 5.81 (1H, s) , 6.72-6.76 (lH, m), 6.95 (2H, d, J = 8.8Hz), 7.32 (2H, d, J = 8.8Hz), 7.34-7. 41 (2H, m), 8.12-8.16 (1 H, m)

 FAB-MS (m / e): 346 [M + H] +

Diastereomer b (Ar i Ph j R ^ H j R 'i H j R ³ : i—P r; R ⁴ : H; R ⁵ : 4-MeO-Ph; n = 0)

_{iHNMR (CDC 1 3) d:} 0. 95 (3H, d, J = 6. 7Hz), 0. 9

8 (3H, d, J = 6.7 Hz), 1.90— 2.03 (1H, m), 2.98 (1 H, ddd, J = 3. 7, 5.6, 9.1 Hz) , 3.43 (1H, dd, J = 9.1, 14.6Hz), 3.50 (1H, dd, J = 3.7, 14.6Hz), 3.82 (3H, s), 5.79 (IH, s), 6.88-6.96 (1H, m), 6.91 (2H, d, J = 8.8Hz), 7.24 (2H, d, J = 8.8Hz), 7.43-7. 50 (2H, m), 8.13-8.17 (IH, m)

 FAB-MS (m / e): 346 [M + H] + Example 13

Preparation of compound examples ^{1036 (Ar: Ph; R 1} : H; R 2: H; R 3: i one ^{P r; R 4: H;} R 5: 3-MeO-Ph; n = 2)

_{^{X HNMR (CDC 1 3) δ}} : 0. 95 (3H, d, J = 7. 0Hz), 0. 9 9 (3H, d, J = 7. 0Hz), 1. 92- 2. 05 (1 H , m), 2.95-3.00 (lH, m), 3.40-3.05 (2H, m), 3.79 (3H, s), 5.82 (1H, s), 6. 82-6. 98 (4H, m), 7.29 (1H, dd, J = 7.4, 8.3Hz), 7.43-7.47 (2H, m), 8.12-8. 15 (1H, m)

 FAB-MS (m / e): 346 [M + H] + Example 14

Preparation of Compound Example 1037

Jiasutereoma ^{a (Ar: Ph; R 1} : H; R 2: H; R 3: i-P r; R 4: H

R ⁵ : 2-MeO-Ph; n = 2)

_{XHNMR (CDC 1 3) δ:} 0. 96 (3Η, d, J = 6. 7Hz), 0. 9

6 (3H, d, J = 6.7Hz), 1.76-1.85 (lH, m), 3.06 (IH, dd, J = l 1.5, 14.3Hz), 3.45 ( IH, dd, J = 2

2, 14.3 Hz), 3.54 (IH, ddd, J = 2.2, 4.9, 11.

5 Hz), 3.70 (3H, s), 6.12 (1H, s), 6.67—6.70 (1H, m), 6.92 (1H, d, J = 8.2Hz), 7.06 (IH, t,

J = 7.5Hz), 7.30-7.40 (3H, m), 7.50 (1H, dd, J = 1.5, 7.5 Hz), 8.12-8.16 (IH, m)

 FAB-MS (m / e): 346 [M + H] +

Jiasutereoma ^{b (Ar: Ph; R 1} : H; R 2: H; R 3: i - P r; R 4: H; R 5: 2-MeO-Ph; n = 2)

_{XHNMR (CDC 1 3) δ:} 0. 92 (3H, d, J = 6. 8 Hz), 0. 9 4 (3H, d, J = 6. 8Hz), 1. 90- 2. 01 (IH, m), 2,83-1 2.93 (1H, m), 3.55 (2H, d, J = 6.0 Hz), 3.78 (3H, s), 5.92 (1H, s), 6 86-6. 90 (lH, m), 6.9

4 (IH, d, J = 8.2Hz), 6.99 (1H, t, J = 7.5Hz), 7.26-7.45 (H, m), 8.14-8.18 ( 1 H, m)

 FAB-MS (m / e): 346 [M + H] + Example 15

Preparation of Compound Example 1040

Jiasutereoma a (A r: P h; R 1: H; R 2: H; R 3: i one ^{P r; R 4: H;} R 5: 4-BnO-Ph; n = 0)

_{XHNMR (CDC 1 3) δ:} 0. 94 (3Η, d, J = 6. 8Hz), 0. 9

5 (3H, d, J = 6.8 Hz), 1.65—1.74 (lH, m), 2.43 (IH, dd, J = 10.8, 13.9 Hz), 2.89 (1H , Dd, J = 2.2, 13.9 Hz), 3.04 (IH, ddd, J = 2.2, 5.2, 10.

8Hz), 5.10 (2H, s), 5.59 (1H, s), 6.60-6.64 (1H, m), 7.01 (2H, d, J = 8.8Hz), 7. 02-7. 12 (

2H, m), 7.35 (2H, d, J = 8.8 Hz), 7.33-7.49 (5

H, m), 7.60-7. 64 (IH, m)

 FAB—MS (m / e): 390 [M + H] +

R stereo: b (Ar i Ph! R ^ H j R ^ H j R ³ : i-i Pr; R ⁴ : H

R ⁵ : 4— BnO— Ph; n = 0)

_{iHNMR (CDC 1 3) δ:} 0. 94 (3 H, d, J = 6. 8Hz), 0. 9

4 (3H, d, J = 6.8 Hz), 1.95— 2.09 (1H, m), 2.83 -2.91 (3H, m), 5.07 (2H, s), 5.69 (IH, s), 6.79-6.82 (1H, m), 6.97 (2H, d, J = 8.8 Hz), 7.0 9-7.17 (2H, m), 7.26 (2H, d, J = 8.8 Hz), 7.30-7.49 (5H, m), 7. 50-7.52 (lH, m)

 FAB-MS (m / e): 390 [M + H] + Example 16

Preparation of compound examples ^{1041 (Ar: Ph; R 1} : H; R 2: H; R 3: i -P r; R 4: H; R 5: 4-BnO-Ph; n = 1)

_{XHNMR (CDC 1 3) δ:} 0. 90 (3Η, d, J = 6. 8Hz), 0. 9 4 (3H, d, J = 6. 8Hz), 1. 75 - 1. 90 (IH, m ), 2.58 -2.62 (IH, m), 3.04 (1H, dd, J = 4.8, 13. OHz), 3.50 (IH, dd, 1 = 7.4, 13) OHz), 5.09 (2H, s), 5.28 (IH, s), 6.84 (1H, d, J = 7.9Hz), 6.99 (2H, dd, J = 2. 0, 6.7Hz), 7.25 (2H, dd, J = 2.0, 6.7Hz), 7.30-7.54 (7H, m), 7.95 (1H, dd, J = (1.2, 7.9 Hz)

 FAB-MS (m / e): 406 [M + H] + Example 17

Preparation of compound examples ^{1042 (Ar: Ph; R 1} : H; R 2: H; R 3: i -P r; R 4: OH; R 5: 4-BnO-P h; n = 1)

_{^{X HNM (CDC 1 3) δ}} : 1. 03 (3H, d, J = 6. 8Hz), 1. 1 4 (3H, d, J = 6. 8Hz), 1. 82 - 1. 96 (1H, m), 3.08-3.26 (2H, m), 3.44-3.57 (IH, m), 4.21 (IH, s), 5.10 (2H, s), 5.19 (1H, s), 6.84 (1H, d, J = 7.7Hz), 7.00 (2H, d, J = 8.9Hz), 7.31 (2H, d, J = 8. 9Hz), 7.26-7.56 (7H, m), 7.84-7.94 (IH, m) FAB-MS (m / e): 422 [M + H] Example 18

Preparation of Compound Example 1043 (Al ^ Ph R ^ HR ^ HR ³ Pr; R: H; R ⁵ : 4-BnO-Ph; n = 2)

_{^{X HNMR (CDC 1 3) 5}} : 0. 95 (3H, d, J = 6. 9Hz), 0. 9 8 (3H, d, J = 6. 9Hz), 1. 89- 2. 00 (lH, m), 2.94 — 3.01 (1H, m), 3.41 (1H, dd, J = 9.1, 14.3 Hz), 3.49 (1H, dd, J = 3.4, 14 3 Hz), 5.08 (2H, s), 5.79 (1H, s), 6.93—7.00 (1H, m), 6.99 (1H, d, J = 9.0Hz), 7.25 (2H, d, J = 9.0Hz), 7.32—7.50 (7H, m), 8.13-8.17 (lH, m)

 FAB-MS (m / e): 422 [M + H] + Example 19

Preparation of Compound Example 1044

Jiasutereoma one a (A r: P h R 1: H; R 2: H; R -P r; R 4: H; R 5: 3 - Bn - Ph; n = 2)

_{iHNMR (CDC 1 3) (5} :. 0 97 (3H, d, J = 6. 9Hz), 0. 9 7 (3H, d, J = 6. 9Hz):, 1. 74- 1. 86 (1 H, m), 3.06 (1H, dd, J = l 1.5, 14.3 Hz), 3.43 (1H, dd, J = 2

2, 14.3Hz), 3.52 (1H, ddd, 1 = 2.2, 4.8

 5Hz), 5.08 (2H, s), 5.86 (1H, s), 6.95-7.00 (2H, m), 7.05 (1H, d, J = 1.7Hz), 7.26-7 46 (8H, m), 8.12-8.16 (1H, m)

 FAB-MS (m / e): 422 [M + H] +

Jiasutereoma ^{b (Ar: Ph; R 1} : H; R 2: H; R 3 -P r; R 4: H; R 5: 3-Bn-Ph; n = 2)

_{! HNMR (CDC 1 3) (} 5: 0. 94 (3H, d, J = 6. 7Hz), 0. 9 8 (3H, d, J = 6.8 Hz) 1.90-2.04 (1 H, m), 2.96 (IH, ddd, J = 3. 8, 5 8, 8.7 Hz), 3. 43 (IH, dd, J = 8.7, 14.2Hz), 350 (1H, dd, J = 3.8, 14.2Hz), 5.05 (2H, s), 582 (1H, s), 6.89-6.99 (4 H, m), 7.25-7.50 (8H, m), 8.12-8.16 (1 H, m) FAB-MS (mZe): 422 [M + H] + Example 20

Preparation of Compound Example 1045

Jiasutereoma one a (A r: P h; R 1: H; R 2: H; R 3: i one ^{P r; R 4: H;} R 5: 2 -BnO-Ph; n = 2)

^X HNMR (CDC ") 5: 0.95 (3H, d, J = 7.OHz), 0.95 (3H, d, J = 7.OHz), 1.75-1.86 (1H, m), 3.04 (1H, dd, J = 11.5, 14.3Hz), 3.45 (1H, dd, J = 2.2, 14.3Hz), 3.55 (1H, ddd, J = 2.2, 4. 9, 11.5Hz), 4.95 (1H, d, J = 12.3Hz), 5.03 (1H, d, J = 12.3Hz), 6.25 ( 1H, s), 6.72-6.76 (IH, m), 6.96 (1H, dd, J = l. 0, 8.2Hz), 7.05-7.13 (3H, m ), 7.18-7.29 (3H, m), 7.29-7.39 (3H, m), 7.57 (1H, dd, J = 1.3, 7.5Hz), 8. 12—8.15 (1 H, m)

 FAB-MS (mZe): 422 [M + H] +

Jiasutereoma ^{b (Ar: Ph; R 1} : H; R 2: H; R 3: i- P r; R 4: H; R 5: 2-BnO-Ph; n = 2)

_{'HNMR (CDC 1 3) δ} : 0. 85 (3H, d, J = 6. 8Hz), 0. 8 8 (3H, d, J = 6. 8Hz), 1. 84- 2. 00 (lH, m), 2.85 (IH, dd, J = 6.4, 12.8 Hz), 3.52 (2H, d, J = 6.4 Hz), 5.01 (IH, d, J = 12. OHz), 5.06 (IH, d, J = 12.0 Hz), 5.98 (IH, s), 6.87-6.91 (1H, m), 6 99 -7. 04 (2H, m), 7.13-7. 17 (2H, m), 7.23—7.32 (3H, m), 7.32-7.37 (2H, m) , 7.38—7.46 (2H, m), 8.13-8.17 (IH, m)

 FAB-MS im / e): 422 [M + H] + Example 21

Production of Compound Example 1046 (Ar Ph;! ^ ¹ :! ^;! ^ ² : !!;! ^ ³ : i -P r; R ⁴

_{^ NMR (CDC 1 3) 6} : 0. 97 (3H, d, J = 6. 9Hz), 0. 9 7 (3H, d, J = 6. 8Hz), 1. 70- 1. 88 (IH, m), 3.06 (1H, dd, J = l l. 3, 14.1Hz), 3.13 (2H, t, J = 7.0Hz), 3.42 (1H, dd, J = 2. 2, 14.1 Hz), 3.50 (1 H, ddd, J = 2, 2, 4.9, 11.3 Hz), 4.22 (2H, t, J = 7.0 Hz), 5.79 ( 1H, s), 6.71-6.75 (lH, m), 6.94 (1H, d, J = 8.7Hz), 7.20-7.40 (9H, m), 8.1 0-8. 15 (1H, m)

 FAB-MS (mZe): 436 [M + H] + Example 22

Preparation of compound examples 1047 (A r: P h; R 1: H; R 2: H; R 3: i- P r; R 4: H; R 5: 3-OH-3-Me-Bu; n = 0)

_{iHNMR (CDC 1 3) δ:} 0. 94 (3H, d, J = 6. 8Hz), 0. 9

5 (3H, d, J = 6.8Hz), 1.33 (6H, s), 1.64-1.75 (lH, m), 2.02 (1H, t, J = 6.2Hz), 2.43 (1H, dd, J = 10.7, 13.9Hz), 2.89 (1H, dd, J = 2.2, 13.9Hz), 3.04 (IH, ddd, J = 2 .2, 5.2, 10.7Hz), 4.22 (1H, t, J = 6.2Hz), 5.59 (1H, s), 6.59-6.

63 (IH, m), 6.94 (2H, d, J = 8.5Hz), 7.03-7.12 (2H, m), 7.35 (2H, d, J = 8.5Hz) , 7.61-7.64 (1H, m)

 FAB-MS (m / e): 386 [M + H] + Example 23

Preparation of Compound Example 1050

Diastereomer a (A r: Ph; R ¹ : H; R ² : H; ³ : i-Pr; R ⁴ : H

R ⁵ : 4-nP rNHCOCH20-Ph; n = 0)

_{^ NMR (CDC 1 3) δ} :. 0. 91- 0. 97 (9H, m), 1. 50- 1 65 (3H, m), 2. 42 (1H, dd, J = 10. 8, 13 9Hz), 2.89 (1H, dd, J = 2.2, 13.9Hz), 3.22-3.36 (1H, m), 3.28-3.38 (2H, m), 4.52 (2H, s), 5.62

(1H, s), 6.52-6.57 (1H, m), 6.94 (2H, d, J = 8.8Hz), 7.00-7.12 (2H, m), 7. 38 (2H, d, J = 8.8Hz), 7.62-7.65 (1H, m)

 FAB-MS (m e): 399 [M + H] +

Diastereomer b (Ar: Ph j R ^ H .- R 'r H j R ³ : i -P r; R ⁴ : H

R ⁵ : 4-nP rNHCOCH20-Ph; n = 0)

_{^ NMR (CDC 1 3) δ} :. 0. 85- 1. 00 (9H, m), 1. 50- 1 65 (2H, m), 1. 90 - 2. 00 (lH, m), 2. 73-2.89 (3H, m), 4.50 (2H, s), 5.67 (1H, s), 6.72—6.73 (lH, m), 6.90 (2H, m) d, J = 8.7 Hz), 7.10—7.15

(2H, m), 7.28 (2H, d, J = 8.7 Hz), 7.50-7.53 (1H, m)

 FAB-MS (mZe): 399 [M + H] + Example 24

Preparation of Compound Example 1051

Jiasutereoma ^{a (Ar: Ph; R 1} : H; R 2: H; R 3 i -P r; R 4: H; R 5: 4-nP rNHCOCH 2 0-Ph; n = 2) _{iHNMR (CDC 1 3) δ:} 0. 94 (3H, t, J = 7. 5Hz), 0. 9 8 (3H, d, J = 6. 7Hz), 0. 98 (3H, d, J = 6 .7-Hz), 1.53-1.65 (2H, m), 1.74-1.89 (IH, m), 3.07 (1H, dd, J = 1 1.3, 14. lHz), 3.33 (1 H, t, J = 6.8 Hz), 3.35 (1 H, t, J = 6.8 Hz), 3.44 (IH, dd, J =

2.3, 14.1 Hz), 3.50 (IH, ddd, J-2.3, 5.5.4, 11.3 Hz), 4.53 (2H, s), 5.85 (1H, s) ), 6.59 (1H, brs), 6.69-6.72 (1H, m), 6.97 (1H, d, J = 8.6 Hz), 7.35 (1H, d, J = 8.6Hz), 7.35-7.41 (2H, m), 8.13-8.16 (1H, m)

 FAB-MS (m / e): 431 [M + H] +

Jiasutereoma b (Ar: P h; R 1: H; R 2: H; R 3: one ^{P r; R 4: H;} R 5: 4-nP rNH CO CH 2 0-Ph; n = 2)

_{^ NMR (CDC 1 3) δ} : 0. 94 (3H, t, J = 7 6Hz), 0 9 5 (3H, d, J = 6. 7Hz), 0. 99 (3H, d, J 6. 7Hz ),

51- 1.71 (2H, m), 1.89—2.00 (1H, m), 2.97-

3.04 (IH, m), 3.31 (1H, t, J = 6.9Hz), 3.33 (1H, t, J = 6.9Hz), 3.40-3.50 (2H , M), 4.51 (2H, s), 5.81 (1H, s), 6.60 (1H, brs), 6.91-6.96 (IH, m), 6.93 ( 1 H, d, J = 8.7 Hz), 7.27 (1 H, d, J = 8.7 Hz), 7.45 -7.52 (2H, m), 8.14—8.19 (IH , m)

 FAB-MS (m / e): 431 [M + H] + Example 25

Preparation of Compound Example 1052

Jiasutereoma one ^{a (Ar: Ph; 1:} H; R 2: H; R 3: i one ^{P r; R 4: H;} R 5: 3 - n- P rNHCOCH 2 〇- Ph; n = 2)

_{^ NMR (CDC 1 3) <} 5: 0. 93 (3 H, t, J = 7. 4Hz), 0. 9 9 (3H, d, J = 6.8 Hz), 0.99 (3H, d, J = 6.8 Hz), 1.52-1.65 (2H, m), 1.75-1.89 (lH , M), 3.07 (IH, dd, J = 11.5, 14.4Hz), 3.31 (IH, t, J = 6.6Hz), 3.33 (1H, t, J = 6.6Hz), 3.46 (1H, dd, J = 2.2, 14.4Hz), 3.50 (1H, ddd, J = 2.2, 5.0, 11.5Hz), 4 51 (3H, s), 5.91 (1H, s), 6.61 (1H, brs), 6.69-6.73 (lH, m), 6.87-6.92 (1H , m), 7.04 (1H, d, J = 7.9 Hz), 7.33 -7.43 (3H, m), 8.13-8.17 (IH, m)

 FAB-MS (m / e): 431 [M + H] +

Diastereomer b (Ar i Ph j R ^ H i R ^ H j R ³ : i- 1 Pr; R ⁴ : H; R ⁵ : 3-nP rNHCOCH ₂₀ 0-Ph; n = 2)

_{^{X HNMR (CDC 1 3) δ}} : 0. 92 (3H, t, J = 7. 4Hz), 0. 9 7 (3H, d, J = 6. 9Hz), 1. 01 (3H, d, J = 6.7 Hz), 1.50-1.65 (2H, m), 1.91-2.03 (lH, m), 3.01 (1H, ddd, J = 3.6, 5.5, 8) 9Hz), 3.29 (1H, t, J = 6.4Hz), 3.32 (1H, t, J = 6.4Hz), 3.42 (1H, dd, J = 8.8, 14.3 Hz), 3.46 (1H, dd, J = 3.6, 14.3 Hz), 4.48 (3H, s), 5.84 (1H, s), 6.59 (IH , brs), 6.85-6.89 (lH, m), 6.93 (1H, s), 6.94 (1H, d, J = 7.8Hz), 7.00 (1H, d, J = 7.8Hz), 7.32 (1H, t, J = 7.8Hz), 7.46-7.53 (2H, m), 8.15-8.19 (IH, m)

 FAB-MS (m / e): 431 [M + H] + Example 26

Preparation of Compound Example 1053

Jiasutereoma ^{a (Ar: Ph; R 1} : H; R 2: H; R 3: i - P r; R 4: H; R 5: 2_n- P rNHCOCH 2 〇- Ph; n = 2) _{^{X HNMR (CDC 1 3) (}} 5: 0. 75 (3H, t, J = 7. 4Hz), 1. 0 0 (3H, d, J = 6. 8Hz), 1. 00 (3H, d, J = 6.7 Hz), 1.37-1.52 (2H, m), 1.77—1.85 (IH, m), 3.02—3.22 (2H, m), 3.49 (1H , Dd, J = 2.2, 7.2 Hz), 3.56 (lH, m), 4.21 (1H, d, J = 14.1 Hz), 4.40 (1H, d, J = 14) 1Hz), 6.38 (1 H, s), 6.65— 6.69 (1 H, m), 6.69 (IH, brs), 6.83 (1H, d, J = 7.6 Hz ), 7.17 (IH, t, J = 7.6 Hz), 7.34—7.44 (3H, m), 7.64 (1 H, d, J = 7.6 Hz), 8.10- 8.14 (lH, m) FAB-MS (m / e): 431 [M + H] +

Jiasutereoma one b (Ar: Ph j R ^ H j R 'i H i R 3: i - P r; R 4: H; R 5: 2-nP rNHCOCH 2 0-Ph; n = 2)

_{^{X HNMR (CDC 1 3) δ}} : 0. 77 (3H, t, J = 7. 4Hz), 0. 9 7 (3H, d, J = 6. 9Hz), 1. 00 (3H, d, J = 6.8 Hz), 1.30—1.51 (2H, m), 2.03—2.13 (IH, m), 2.75-2.85 (lH, m), 3.08—3. 23 (2H, m), 3.59-3.62 (2H, m), 4.21 (1H, d, J = 14.2Hz), 4.40 (1H, d, J = 14.2Hz), 6.27 (1H, s), 6.73—6.76 (1H, m), 6.88 (IH, d, J = 7.8Hz), 6.90 (1H, brs), 7 .17 (1H, t, J = 7.8Hz), 7.40 (1H, t, J = 7.8Hz), 7.42-7.49 (2H, m), 7.67 (IH, d , J = 7.8 Hz), 8.05 -8.09 (IH, m)

 FAB-MS (m / e): 431 [M + H] + Example 27

Preparation of Compound Example 1091

Diastereomer a (Ar r Ph j R ^ H j R ^ H j R ³ -P r; R ⁴ : H; R ⁵ : 3—Cl, 4-Me-Ph; n = 2)

^X HNMR (CDC 1 J (5: 0.98 (3H, d, J = 6.8 Hz)), 0.9 8 (3H, d, J = 6.8 Hz), 1.72-1.88 (1H, m), 2.41 (3H, s), 3.04 (1H, dd, J = 1 1.3, 14.2Hz), 3.4

4 (IH, dd, J = 2.3, 14.2 Hz), 3.45—3.55 (1H, m), 5.87 (1H, s), 6.7 1 -6.74 (1H , m), 7.15 (IH, dd, J = 1.6, 7.8 Hz), 7.26 (1H, d, J = 7.8 Hz), 7.35—7.45 (3H, m), 8.12-8.15 (IH, m)

 FAB-MS (m / e): 364/366 [M + H] +

Diastereomer b (Ar i Ph j R ^ H i R ^ H j R ³ : i—P r; R ⁴ : H; R ⁵ : 3-Cl, 4-Me-Ph; n = 2)

_{XHNMR (CDC 1 3) (5} : 0. 95 (3H, d, J = 6. 4Hz), 0. 9

9 (3H, d, J = 6.8 Hz), 1.90-2.01 (IH, m), 2.38 (3H, s), 2.95—3.05 (IH, m), 3. 40- 3.50 (2H, m), 5.99 (1H, s), 6.94 (1H, m), 7.03 (1H, dd, J = 1.6, 7. 8Hz), 7 20 (1H, d, J = 7.8Hz), 7.36 (IH, d, J = 1.6Hz), 7.47-7.50 (2H, m), 8.13—8.16 (IH, m)

 FAB-MS (m / e): 364/366 [M + H] + Example 28

Preparation of Compound Example 1097

Jiasutereoma one ^{a (Ar: Ph; R 1} : H; R 2: H; R 3: i - P r; R 4: H

; R ^5: 3- HO- 4 one Me- Ph; n = 2)

_{NMR (CDC 1 3) (3} : 0. 97 (3H, d, J = 6. 9Hz), 0. 9

7 (3H, d, J = 6.9 Hz), 1.70—1.85 (1H, m), 2.28 (3H, s), 3.07 (1H, dd, J = l 1.3 , 14.3Hz), 3.4

2 (1 H, dd, J = 2.2, 14.3 Hz), 3.46-3.52 (1 H, m

), 5.77 (1H, s), 6.67-6.87 (3H, m), 7.16 (1H, s)

, D, J = 7.6 Hz), 7.36-7.39 (2H, m), 8.1 1—8.1

4 (IH, m) FAB-MS (m / e): 346 [M + H] +

Jiasutereoma ^{b (Ar: Ph; R 1} : H; R 2: H; R 3: i - P r; R 4: H; R 5: 3-HO-4-Me-Ph; n = 2)

_{NMR (CDC 1 3) δ:} 0. 94 (3H, d, J = 6. 8Hz), 0. 9 8 (3H, d, J = 6. 7Hz), 1. 92- 2. 03 (1 H, m), 2.25 (3H, s), 2.94-3.02 (1H, m), 3.48-3.52 (2H, m), 5.75 (1H, s), 6.74 (1H, d, J = 1.5Hz), 6.80 (1H, dd, J = l, 5, 7.6Hz), 6.95-6.98 (lH, m), 7.12 (1H, d, J = 7.6Hz), 7.45—7.48 (2H, m), 8.12-8.15 (1H, m)

 FAB-MS (m / e): 346 [M + H] + Example 29

Preparation of Compound Example 1098

Diastereomer a (Ar i P j R ^ H j R ^ H j R ³ : i—P r; R ⁴ : H; R ⁵ : 3-PhCH20-4-Me-Ph; n = 2)

_{^ NMR (CDC 1 3) δ} : 0. 96 (3H, d, J = 6. 7Hz), 0. 9

6 (3H, d, J = 6.7 Hz), 1.72-1.85 (lH, m), 2.32 (3H, s), 3.07 (1H, dd, J = l 1.6, 14.2Hz), 3.4.2 (1H, dd, J = 2.2, 14.2Hz), 3.47-3.54 (1H, m), 5.06 (1H.d, J = 2. 8Hz), 5.06 (1H, d, J = 2.8Hz), 5.79 (1H, s), 6.74 (1H, dd, J = l. 9, 6.9Hz), 6.91 -6.94 (2H, m), 7.21 (1H, d, J = 7.6Hz), 7.30-7.43 (7H, m), 8.12—8.15 (1H , m)

FAB-MS (m / e): 436 [M + H] ⁺

Jiasutereoma ^{b (Ar: Ph; R 1} : H; R 2: H; R 3: i one ^{P r; R 4 ·· H;} R 5: 3-PhCH20-4-Me-Ph; n = 2)

_{XHNMR (CDC 1 3) d:} 0. 93 (3 H, d, J = 6. 9Hz), 0. 9

7 (3H, d, J = 6.7Hz), 1.92-2.01 (lH, m), 2.30 (3H, s), 2.92-2.98 (lH, m), 3.39—3.53 (2H, m), 5.03 (2H, s), 5.78 (IH, s), 6.82-6.90 (3 H, m), 7.16 (IH, d, J = 7.6 Hz), 7.29-7.49 (7H, m), 8.12-8.15 ( 1H, m)

FAB-MS (m / e): 436 [M + H] ⁺ Example 30

Preparation of compound examples 1099 (A r: Ph; R 1: H; R 2: H; R 3: i- P r; R 4: H; R 5: 3 - MeO- 4 one Me- Ph; n = 2 )

_{^ NMR (CDC 1 3) 6} :. 0. 96 (3H, d, J = 6. 7Hz), 0. 9 9 (3H, d, J = 6. 7Hz), 1. 94-2 07 (lH, m), 2.03 (3H, s), 2.95-3.02 (1H, m), 3.41—3.56 (2H, m), 3.77 (3H, s), 5. 81 (IH, s), 6.79—6.82 (2H, m), 6.92-6.95 (IH, m), 7.13 (IH, d, J = 7.3 Hz), 7.45- 7.48 (2H, m), 8.13—8.16 (1H, m) FAB-MS (m / e): 360 [M + H] ⁺ Example 31

Preparation of Compound Example 1101 (Ar Pt ^ RHR ^ HR ³ : i-P r; R ⁴ : H; R ⁵ : 3-viny 1-4-Me-Ph; n = 2)

_{^{X HNMR (CDC 1 3) δ}} : 0. 95 (3H, d, J = 6. 7Hz), 0. 9

9 (3H, d, J = 6.7 Hz), 1.90—2.02 (IH, m), 2.36 (3H, s), 2.95-3.05 (lH, m), 3. 40- 3.55 (2H, m), 5.28 (IH, dd, J = l. 3, 10.9Hz), 5.59 (1H, d d. J = l. 3, 17.4Hz), 5.81 (1H, s), 6.94 (1H, dd, J = 10.9, 17.4Hz), 6.90- 7.00 (lH, m), 7.

09 (1H, d d, J = l. 9, 7.8Hz), 7.13 (1H, d, J = 7.

8Hz), 7.45-7.50 (2H, m), 7.65-7.75 (lH, m)

, 8. 14-8. 17 (IH, m) FAB-MS (m / e): 356 [M + H] + Example 32

Preparation of compound examples 1 102 (Ar Ph s R ^ HR ^ HR 3: i -P r; _R ^: H; 5: 3- i P rO-4-Me-Ph; n = 2)

_{iHNMR (CDC 1 3) δ:} 0. 95 (3H, d, J = 6. 8Hz), 0. 9 8 (3H, d, J = 6. 8Hz), 1. 29 (3H, d, J = 6 0 Hz), 1.29 (3H, d, J = 6.0Hz), 1.95—2.08 (1H, m), 2.21 (3H, s), 2.93-3.02 ( 1H, m), 3.41-3.54 (2H, m), 4.40-4.50 (lH, m), 5.75 (1H, s), 6.78-6.81 (2H , M), 6.92-6.94 (1H, m), 7.1 (1H, d, J = 7.9Hz), 7.44-7.47 (2H, m), 8.12- 8.15 (1H, m)

 FAB-MS (m / e): 388 [M + H] + Example 33

Preparation of Compound Example 1106

Diastereomer a (Ar i Ph j R ^ H j R ^ H i R ³ : i- 1 Pr; R ⁴ : H

R ⁵ : 3-OH-4 -Me OP h; n = 2)

_{iHNMR (CDC 1 3) δ:} 0. 97 (3H, d, J = 6. 9Hz), 0. 9

7 (3H, d, J = 6.9 Hz), 1.71-1.82 (lH, m), 3.06 (1H, dd, J = 11.5, 14.3 Hz), 3.41 (1 H, dd, J = 2

2, 14.3Hz), 3.50 (1 H, d d d, J = 2. 2, 4. 8, 11.

5Hz), 3.93 (3H, s), 5.76 (1H, s), 6.77 (1H, m), 6.85—6.90 (2H, m), 7.01 (1H , d, J = l. 9Hz)

, 7.35-7.38 (2H, m), 8.11—8.14 (1H, m)

 FAB-MS (m / e): 362 [M + H] +

Jiasutereoma ^{b (Ar: Ph; R 1} : H; R 2: H; R 3: i - P r; R 4: H

R ⁵ : 3-OH-4-MeO-P; n = 2) _{iHNMR (CDC 1 3) (5} :. 0. 95 (3H, d, J = 6. 7Hz), 0. 9 8 (3H, d, J = 6. 7Hz), 1. 90-2 04 (1H, m), 2.93-3.01 (1H, m), 3.38-3.52 (2H, m), 3.90 (3H, s), 5.74 (1H, s), 6.73 (1H, dd, J = 2.6, 8.2Hz), 6.83 (IH, d, J = 8.2Hz), 6.94-6.99 (2H, m), 7.44- 7. 47 (2H, m), 8.11-8.14 (1H, m)

 FAB-MS (m / e): 362 [M + H] + Example 34

Preparation of Compound Example 1107

Jiasutereoma one ^{a (Ar: Ph; R 1} : H; R 2: H; R 3 -P r; R 4: H

R ⁵ : 4-OH-3-I-Ph; n = 0)

_{^{X HNMR (CDC 1 3) δ}} : 0. 93 (3Η, d, J = 6. 8Hz), 0. 9 5 (3H, d, J = 6. 8Hz), 1. 53- 1. 82 (IH, m), 2.40

(1H, dd, J = 10.8, 13.9Hz), 2.89 (1H, dd, J = 2.2, 13.9Hz), 3.00 (IH, ddd, J = 2.2, 5.0, 10.8 Hz), 5.60 (1H, s), 6.58—6.65 (IH, m), 6.99

(1H, d, J = 8.2Hz), 7.03-7.16 (2H, m), 7.28 (1H, dd, J = l. 7, 8.2Hz), 7.61-7 . 67 (IH, m), 7.77 (1H, d, J = 1.7 Hz)

 FAB-MS (m / e): 426 [M + H] +

Diastereomer b (Ar i P j R ^ H j R ^ H i R ³ : i-P r; ⁴ : H

R ⁵ : 4-OH-3- I -Ph; n = 0)

_{^ NMR (CDC 1 3) δ} : 0. 94 (3H, d, J = 6. 7Hz), 0. 9 5 (3H, d, J = 6. 7Hz), 1. 93- 2. 04 (1 H , m), 2.76 — 2.88 (3H, m), 5.65 (1H, s), 6.76 — 6.80 (1H, m), 6.94 (1H, d, J = 8.4Hz), 7.12-7.20 (2H, m), 7.17 (IH, dd, J = 2.0, 8.4Hz), 7.50-7.54 (IH, m) , 7.68 (1 H, d, J = 2.0 Hz) FAB-MS (m / e): 426 [M + H] + Example 35

Preparation of compound examples 1 108 (A r: Ph; R 1: H; R 2: H; R 3: i- P r; R 4: H; R 5: 3- 1 -4- OH-P; n = 2)

_{NMR (CDC 1 3) δ:} 0. 97 (3Η, d, J = 6. 8Hz), 1. 0 1 (3H, d, J = 6. 8Hz), 1. 88- 2. 00 (1H, m ), 2.92-3.04 (IH, m), 3.36-3.50 (2H, m), 5.79 (IH, s), 6.90-7.00 (lH, m), 6.95 (IH, d, J = 8.3 Hz), 7.13 (IH, dd, J = l, 8, 8.3 Hz), 7.45-7.52 (2H, m), 7.67 (IH, d, J = l. 8Hz), 8.12-8.18 (1 H, m)

 FAB-MS (m / e): 458 [M + H] + Example 36

Preparation of compound examples 1 109 (Ar: P h; R 1: H; R 2: H; R 3: i one ^{P r; R 4: H;} R 5: 5- 1 -2 -OH-Ph; n = 2)

_{^{X HNMR (CDC 1 3) δ}} : 0. 99 (. 3H, d, J = 6 9Hz), 1. 0 0 (3H, d, J = 6. 8Hz), 1. 82- 1. 94 (IH, m), 3.13 (IH, dd, J = 1.6, 14.8 Hz), 3.46 (1H, dd, J = 2.0, 14.8 Hz), 3.47-3. 58 (IH, m), 6.08 (1H, s), 6.71 (IH, d, J = 8.6 Hz), 7.07—7.13 (2H, m), 7.48-7 . 59 (3H, m), 8.16-8.20 (1 H, m)

 FAB-MS (m / e): 457 [M + H] + Example 37

Preparation of compound examples 1 1 10 (Ar: Ph; R 1: H; R 2: H; R 3: i- P r: R 4: H; R 5: 2- 1 -5- OH-Ph; n = 2)

XHNMR (CDC) δ: 0.95 (3H, d, J = 6.8 Hz), 0.9 9 (3H, d, J = 6.9 Hz), 1.90—2.00 (IH, m), 2.95—3.04 (1H, m), 3.35-3.50 (2H, m ), 4.75 (1H, bs), 5.77 (IH, s), 6.60-6.65 (IH, m), 6.85—7.00 (2H, m), 7.32 ( IH, d, J = 8.6 Hz), 7.45-7.52 (lH, m), 7.81 (1H, d, J = 8.6 Hz), 8.13—8.16 (1H, m)

 FAB-MS (mZe): 458 [M + H] + Example 38

Preparation of Compound Example 1 1 12

Jiasutereoma one ^{a (Ar: Ph; R 1} : H; R 2: H; R 3: i one ^{P r; R 4: H;} R 5: 3- B r- 4 one OMe - Ph; n = 2)

_{^ NMR (CDC 1 3) <} 5: 0. 98 (3H, d, J = 6. 9Hz), 0. 9 8 (3H, d, J = 6. 9Hz), 1. 75 - 1. 85 (IH , m), 3.05 (IH, dd, J = l 1.3, 14.1 Hz), 3.44 (1H, dd, 1 = 2.3, 14.1 Hz), 3.46-3.53 (1H, m), 3.94 (3H, s), 5.85 (IH, s), 6.72-6.76 (lH, m), 6.96 (1H, d, J = 8 .5Hz), 7.23 (1H, dd, J = 2.1, 8.5Hz), 7.38-7.42 (2H, m), 7.45 (1H, d, J = 2.1Hz) ), 8.12-8.16 (IH, m)

 FAB-MS (m / e): 380, 382 [M + H] +

Jiasutereoma one ^{b (Ar: Ph; R 1} : H; R 2: H; R 3: i -P r; R 4: H; R 5: 3 - C 1, 4-MeO-Ph; n = 2)

_{XHNMR (CDC 1 3) d:} . 0. 96 (3 H, d, J = 6. 8Hz), 1. 0 0 (3H, d, J = 6. 8Hz), 1. 90-2 10 (1 H , m), 3.00

(IH, ddd, J = 3.4, 56, 9. '0 Hz), 3.41 (IH, dd, J = 9.0, 14.3 Hz), 347 (1H, dd, J-3. 4, 14.3Hz), 3.91 (3H, s), 579 (1H, s), 6.90 (IH, d, J

= 8.7 Hz), 6.93-6.97 (IH, m), 7.08 (1H, dd, J = 1. 6, 8.7 Hz), 7.43 (1H, d, J = l. 6Hz), 7.48-7.51 (2H, m), 8.14—8.18 (IH, m )

 FAB-MS (mZe): 380/382 [M + H] + Example 39

Preparation of Compound Example 1113

Jiasutereoma one ^{a (Ar: Ph; R x} : H; R 2: H; R 3:: P r; R 4: H; R 5: 3-B r-4-OMe-Ph; n = 2)

_{iHNMR (CDC 1 3) δ:} 0. 98 (3Η, d, J = 6. 8Hz), 0. 9 8 (3H, d, J = 6. 8Hz), 1. 73- 1. 88 (IH, m ), 3.05 (IH, dd, J = l 1.4, 14.3Hz), 3.44 (1H, dd, J = 2.3, 14.3Hz), 3.49 (1H, ddd, J = 2.3, 4.9, 11.4 Hz), 3.94 (3H, s), 5.85 (1H, s), 6.73-6.77 (IH, m), 6.94 ( IH, d, J = 8.5 Hz), 7.28 (1H, dd, J = 2.1, 8.5 Hz), 7.38—7.42 (2H, m), 7.63 (1H , D, J = 2.1 Hz), 8.12-8.16 (IH, m)

FAB-MS (m / e): 424/426 [M + H] ⁺

Jiasutereoma ^{b (Ar: Ph; R 1} : H; R 2: H; R 3: i -P r; R 4: H; R 5: 3- B r, 4-MeO-Ph; n = 2)

_{XHNMR (CDC 1 3) δ:} 0. 96 (3H, d, J = 6. 8Hz), 1. 0 0 (3H, d, J = 6. 8Hz), 1. 89- 2. 01 (lH, m ), 3.00 (1H, ddd, J = 3.5, 5. 7, 9.0 Hz), 3.40 (IH, dd, J = 9.0, 14.3Hz), 3.47 (1H , dd, 1 = 3.5, 14.3Hz), 3.91 (3H, s), 5.79 (1H, s), 6.87 (1H, d, J = 8.6Hz), 6.94- 6.98 (IH, m), 7.12 (1H, dd, J = 2.0, 8.6 Hz), 7.46-7.54 (2H, m), 7.62 (IH , d, J = 2.0 Hz), 8.14-8.18 (IH, m)

FAB-MS (m / e): 424/426 [M + H] ⁺ Example 40

Preparation of Compound Example 1 1 4

Jiasutereoma a (Ar Ph R ^ H j R ^ H i R 3 i -P r: R 4:! H; R 5: 4-OMe-3- I -Ph; n = 0)

_{XHNMR (CDC 1 3) δ:} 0. 94 (3Η, d, J = 6. 8Hz), 0. 9 5 (3H, d, J = 6. 8Hz), 1. 65- 1. 78 (1H, m ), 2.40 (1H, dd, J = 10.8, 13.9Hz), 2.89 (1H, dd, J = 2.2, 13.9Hz), 3.01 (1H, ddd, J = 2.2, 5.3, 10.8 Hz), 3.91 (3H, s), 5.60 (1H, s), 6.59-6.63 (1H, m), 6.84 (1H, d, J = 8.5 Hz), 7.06-7.14 (2H, m), 7.36 (1H, dd, J = 2.0, 8.5 Hz), 7.62-7.66 (lH , M), 7.87 (1H, d, J = 2.0Hz)

 FAB-MS (m / e): 440 [M + H] +

Jiasutereoma one ^{b (Ar: Ph; R 1} : H; R 2: H; R 3: i P r: R 4: H; R 5: 4-OMe-3- I -Ph; n = 0)

_{^ NMR (CDC 1 3) δ} : 0. 94 (3H, d, J = 6. 7Hz), 0. 9 5 (3H, d, J = 6. 7Hz), 1. 92- 2. 04 (1H, m), 2.75 — 2.84 (lH, m), 2.85—2.92 (2H, m), 3.89 (3H, s), 5.65 (1H, s), 6.77 -6.80 (lH, m), 6.79 (1 H, d, J = 8.5 Hz), 7.10-7.18 (2H, m), 7.22 (1 H, dd, J = 2. 3, 8.5 Hz), 7.50—7.54 (1H, m), 7.82 (1H, d, J = 2.3 Hz)

 FAB-MS (m / e): 440 [M + H] + Example 41

Preparation of Compound Example 1116

Diastereomer a (Ar i P i R ^ H j R ^ H i R ³ -1 Pr; R ⁴ : H; R ⁵ : 4-OMe-3-I-Ph; n = 2)

_{iHNMR (CDC 1 3) 6:} 0. 98 (3H, d, J = 6. 6Hz), 0. 9 8 (3H, d, J = 6.6Hz), 1.65-1.87 (lH, m), 3.05 (IH, dd, J = 11., 14.5Hz), 3.44 (1H , dd, J = 2.3, 14.5 Hz), 3.44-3.52 (IH, m), 3.92 (3H, s), 5.83 (IH, s), 6.73- 6.77 (lH, m), 6.86 (1H, d, J = 8.5Hz), 7.32 (1H, dd, 1 = 2.0, 8.5Hz), 7.38- 7. 42 (2H, m), 7.84 (1H, d, J = 2. OHz), 8.12-8.16 (IH, m)

 FAB-MS (m / e): 472 [M + H] +

Diastereomer b (Ar i Ph j R ^ H j R ′ i H i R ³ : i-P r; R ⁴ : H; R ⁵ : 3—I, 4-MeO-Ph; n = 2)

_{^ NMR (CDC 1 3) δ} : 0. 96 (3H, d, J = 6. 8Hz), 0. 9 8 (3H, d, J = 6. 8Hz), 1. 88 - 2. 00 (lH, m), 2.99 (IH, ddd, J = 3.4, 5. 7, 9.1 Hz), 3.40 (1H, dd, J = 9.1, 14.4 Hz), 3.47 (1 H, dd, J = 3.4, 14.4Hz), 3.89 (IH, s), 5.77 (1H, s), 6.79 (1H, d, J = 8.5Hz) , 6.94-6.97 (1H, m), 7.14 (IH, dd, J = 2.1, 8.5Hz), 7.48-7.52 (2H, m), 7.85 (1 H, d, J = 2.1 Hz), 8.14-8.18 (1 H, m)

 FAB-MS (m / e): 472 [M + H] + Example 42

Preparation of Compound Example 1117

Jiasutereoma a (Ar r P j R ' i H j R ^ H j 3 P r; R 4: H; R 5: 2- I, 5-MeO-Ph; n = 2)

_{^ NMR (CDC 1 3) (} 5: 0. 98 (3H, d, J = 6. 8Hz), 0. 9 9 (3H, d, J = 6. 8Hz), 1. 72 - 1. 85 (IH , m), 3.06 (IH, dd, J = 11.4, 14.4Hz), 3.46 (1H, dd, J = 1.7, 14.4Hz), 3.48-3.54 (lH, m), 3.86 (3H, s), 5.88 (IH, s), 6.73-6.76 (1H, m), 6.82 (IH, m) , Dd, J = 1.7, 7.9 Hz), 6.87 (1H, d, J = 1.7Hz), 7.37- 7.42 (2H, m), 7.81 (IH, d, 1 = 7.9Hz), 8.1 3-8.17 (IH, m)

 FAB-MS (m / e): 472 [M + H] +

Jiasutereoma b (A r: Ph; R 1: H; 2: H; R 3: i -P r; R 4: H; R 5: 2 - 1, 5-MeO-P; n = 2)

_{^{X HNMR (CDC 1 3) δ}} : 0. 96 (3H, d, J = 6. 9Hz), 1. 0 0 (3H, d, J = 6. 8Hz), 1. 90- 2. 05 (1 H , m), 2.95 — 3.02 (IH, m), 3.38-3.51 (2H, m), 3.83 (3H, s), 5.84 (1H, s), 6. 69 (1H, dd, J = l. 9, 8.2Hz), 6.84 (IH, d, J = 1.9Hz), 6.91—6.95 (1H, m), 7.46- 7.53 (2H, m), 7.75 (1H, d, J = 8.2Hz), 8.14-8.18 (IH, m)

 FAB-MS (m / e): 472 [M + H] + Example 43

Preparation of Compound Example 1 1 18

Jiasutereoma a (A r: P h; R 1: H; R 2 H; R 3: i -P r; RH

R ⁵ : 5-1-2-MeO-Ph; n = 2)

_{^{X HNMR (CDC 1 3) (}} 5: 0. 97 (3H, d, J = 6. 7Hz), 0. 9 7 (3H, d, J = 6. 7Hz), 1. 75 - 1. 89 (1 H, m), 3.02

(1H, dd, J = 1.1.4, 14.3Hz), 3.46 (IH, dd, J = 2.3, 14.3Hz), 3.48-3.54 (1H, m), 3.65 (3H, s), 6.08 (IH, s), 6.65-6.69 (IH, m), 6.67 (1H, d, J = 8.6 Hz), 7.33 — 7.42 (2H, m), 7.63 (1 H, dd, J = 2.3, 8.6 Hz), 7.82 (IH, d, J = 2.3 Hz), 8.1 1- 8.16 (IH, m)

 FAB-MS (m / e): 472 [M + H] +

Diastereomer b (Ar ^ j R ^ H .- R ^ H j R ³ : i -P r; R ⁴ : H R ⁵ : 5-1-2-MeO-Ph; n = 2)

_{iHNMR (CDC 1 3) δ:} 0. 93 (3H, d, J = 6. 8Hz), 0. 9 6 (3H, d, J = 6. 8Hz), 1. 88- 2. 02 (IH, m ), 2.80-2.90 (1H, m), 3.52 (2H, d, J = 6.4Hz), 3.72 (3H, s), 5.92 (1H, s), 6. 70 (1H, d, J = 8.5Hz), 6.79-6.84 (IH, m), 7.39—7.50 (2H, m), 7.56-7.66 (2H, m), 8. 12-8. 16 (lH, m)

 FAB-MS (mZe): 471 [M + H] + Example 44

Preparation of compound examples 1 1 19 (Ai ^ Pl ^ R ^ HR 2:! !!; ^ 3: i - P r; R 4: H; 5: 3- I -4-E t O-Ph; n = 2)

_{^ NMR (CDC 1 3) d} : 0. 96 (3H, d, J = 6. 5Hz), 1. 0 2 (3H, d, J = 6. 5Hz), 1. 48 (3H, t, J = 6.9Hz), 1.90-2.05 (lH, m), 2.92—3.08 (1H, m), 3.35—3.50 (2H, m), 4.09 (2H , q, J = 6.9 Hz), 5.79 (1 H, s), 6.76 (IH, d, J = 8.1 Hz), 6.94—6.97 (IH, m), 7. 13 (1H, dd, J = 4.9, 8. lHz), 7.45-7.5.5 (2H, m), 7.84 (IH, d, J = 4.9Hz), 8.13 8. 1 8 (1 H, m)

 FAB-MS (m / e): 486 [M + H] + Example 45

Preparation of compound examples 1 120 (A r: P h ; R 1: H; R 2 H: R i -P r: R: H; R 5: 3- I -4- i P rO-P; n = 2 )

_{^{X HNMR (CDC 1 3) δ}} : 0. 96 (3H, d, J = 7. 0Hz), 1. 0 0 (3H, d, J = 6. 5Hz), 1. 40 (3H, d, J = (5.8 Hz), 1.40 (3H, d, J = 5.8 Hz), 1.85 -2.00 (1 H, m), 2.90-3.05 (IH, m), 3.35 -3.51 (2H, m), 4.50-4 62 (lH, m), 5.76 (1H, s), 6.78 (1H, d, J = 7.9 Hz), 6.93 -6. 96 (IH, m), 7.11 (1H, dd, J = 1.9, 7.9Hz), 7.45-7.52 (2H, m), 7.84 (IH, d, J = 1.9Hz), 8.13-8. 16 (IH, m)

FAB-MS (m / e): 500 [M + H] ⁺ Example 46

Preparation of compound examples ^{1121 (Ar: Ph; R 1} : H; R 2: H; R 3: i- P r; R 4: H;: 3- I -4-nP r O-Ph; n = 2)

_{XHNMR (CDC 1 3) δ:} 0. 95 (3H, d, J = 6. 8Hz), 1. 0 0 (3H, d, J = 6. 6Hz), 1. 10 (3H, t, J = 7 4 Hz), 1.80-2.00 (3H, m), 2.95-3.04 (IH, m), 3.35-3.50 (2H, m), 3.98 (2H, t , J = 6.3Hz), 5.76 (1H, s), 6.75 (1H, d, J = 8.5Hz), 6.93-6.96 (IH, m), 7.11 ( IH, dd, J = 2.0, 8.5Hz), 7.47-7.50 (2H, m), 7.83 (1H, d, J = 2.2Hz), 8.13-8 . 16 (IH, m)

 FAB-MS (m / e): 500 [M + H] + Example 47

Preparation of Compound Example 1122 (Ai ^ Ph;! ^ ¹ : !!;! ^ ² :! ^;! ^ ³ : i -P r; R ⁴ : H; R ⁵ : 3— I— 4— nBuO— Ph ; n = 2)

_{^{X HNMR (CDC 1 3) δ}} :. 0. 95- 1. 02 (9H, m), 1. 50-1 70 (2H, m), 1. 90 - 2. 00 (IH, m), 2. 95—3.05 (IH, m), 3.40—3.50 (2H, m), 4.02 (2H, t, J = 6.3Hz), 5.78 (1H, s), 6. 73 (1H, d, J = 8.4Hz), 6.92-6.99 (IH, m), 7.12 (1H, dd, J = 2.0, 8.4Hz), 7. 45-7. 52 (2H, m), 7.83 (1H, d, J = 2. OHz), 8.14-8.17 (IH, m) FAB-MS (m / e): 514 [M + H] + Example 48

Preparation of Compound Example 1 123 (Ar z Pi ^ RHRHR ³ : i—P r; R ⁴ : H; R ⁵ : 3-1-4- (2-Me) PrQ-Ph; n = 2)

_{^{X HNMR (CDC 1 3) d}} :. 0. 95- 1. 02 (9H, m), 1. 30- 1 36 (3H, m), 1. 75- 1. 85 (2H, m), 1. 90-2.05 (lH, m), 2.95-3.05 (IH, m), 3.38-3.50 (2H, m), 4.30-4.40 (IH, m), 5.78 (1H, s), 6.75 (1H, d, J = 8.3 Hz), 6.97-6.99 (IH, m), 7.12 (IH, dd, J = 2. 0, 8.3Hz), 7.48-7.53 (2H, m), 7.83 (1H, d, J = 2.0Hz), 8.14-8.17 (1H, m)

 FAB-MS (m / e): 514 [M + H] + Example 49

Preparation of compound examples 1 1 24 (Ar: Ph; R 1: H; R 2: H; R 3: i one ^{P r; R 4: H;} R 5: 3 - 1, 4-PhCH ¾ Q-Ph; n = 2)

_{^ NMR (CDC 1 3) δ} :. 0. 96 (3Η, d, J = 6. 9Hz), 1. 0 0 (3H, d, J = 6. 7Hz), 1. 86-2 00 (1 H , m), 2.99 (IH, ddd, J = 3.4, 5.7, 9.4 Hz), 3.39 (1 H, dd, J = 9.4, 14.3 Hz), 3. 47 (1H, dd, J = 3.4, 14.3Hz), 5.16 (2H, s), 5.77 (1H, s), 6.82 (1H, d, J = 8. 7Hz), 6.93 -6.97 (lH, m), 7.12 (1H, dd, J = 2.0, 8.7Hz), 7.30-7.44 (3H, m), 7 46-7. 5 2 (4H, m), 7.87 (1H, d, J = 2.0Hz), 8.13-8. 17 (IH, m)

FAB-MS (m / e): 548 [M + H] + Example 50 Preparation of compound examples 1 125 (Ar: Ph; R 1: H; R 2: H; R 3: i -P r; R 4: H; R 5: 3 - B r, 4-P CH ^ CH ^ O -Ph; n = 2)

_{^{X HNMR (CDC 1 3) δ}} : 0. 97 (3H, d, J = 6. 8Hz), 0. 9 7 (3H, d, J = 6. 8Hz), 1. 72 - 1. 87 (1 H , m), 3.04 (1H, dd, J = 11.4, 14.5Hz), 3.41 (2H, t, J = 6.8Hz), 3.43 (1H, dd, J = 2.3, 14.5 Hz), 3.48 (1 H, ddd, J = 2, 3, 5.0, 11.4 Hz), 4.25 (2H, t, J = 6.8 Hz), 5 83 (1H, s), 6.70 -6.74 (lH, m), 6.88 (1H, d, J = 8.5 Hz), 7.20—7.43 (8H, m), 7 . 6 1 (IH, d, J = 2.1 Hz), 8.11-8. 1 5 (1 H, m)

FAB-MS (mZe): 514, 516 [M + H] ⁺ Example 51

Preparation of Compound Example 1126 (Ai ^ Phs RHR ^ HR ³ : i-P r; R ⁴ : H; R ⁵ : 3-C 1, 4-P CH ^ CH ^ O-Ph; n = 2)

_{NMR (CDC 1 3) δ:} 0. 97 (3H, d, J = 6. 8Hz), 0. 9

7 (3H, d, J = 6.8 Hz), 1.72-1.84 (lH, m), 3.04 (1H, dd, J = 1 1.4, 14. lHz), 3.18 ( 2H, t, J = 6.

9 Hz), 3.43 (1 H, dd, J = 2.3, 14.1 Hz), 3.48 (1 H, ddd, J = 2, 3, 5.0, 11.4 Hz), 4. 26 (2H, t, J =

6.9 Hz), 5.83 (1H, s), 6.70—6.74 (lH, m), 6.

92 (1H, d, J = 8.5Hz), 7.17 (1H, dd, J = 2.1, 8.

5Hz), 7.23-7.43 (7H, m), 7.44 (1H, d, J = 2.1

Hz), 8.12-8. 1 5 (1 H, m)

 FAB-MS im / e): 470/472 [M + H] + Example 52

Preparation of Compound Example 1127 (Ai ^ Ph R ^ HRHR ³ : i -P r; R ⁴ : H; R ⁵ : 4-OMe— 3— Ph— Ph; n = 2) _{iHNMR (CDC 1 3) d:} 0 96 (3H, d, J = 6. 9Hz), 0. 9 9 (3H, d, J = 6. 9Hz), 1. 90 - 2. 03 (IH, m) , 3.02 (IH, ddd, J = 3.3, 5.7.2.2 Hz), 3.44 (1 H, dd, J = 9.2, 14.3 Hz), 3.49 (1 H , dd, J = 3.3, 14.3Hzz)), 33 .. 8833 ((33HH ,, ss)), 55..84 (1H, s), 7.22-7.26 ( 1H, m), 7.28-7.34 (2H, m), 7.36-7.42 (2H, m), 7.46-7.54 (4H, m), 8.14—8 . 18 (IH, m)

 FAB-MS (m / e): 422 [M + H] + Example 53

Preparation of compound examples 1 128 (Ar: Ph; R 1: H; R 2: H; R 3: i- P r; R 4 H; R 5: 4-OMe - 3 (2-- py ri dy l) --Ph; n = 2)

_{^ NMR (CDC 1 3) δ} :. 0. 94 (3H, d, J = 6. 9Hz), 0. 9 7 (3H, d, J = 7. 5Hz), 1. 90-2 03 (1 H , m), 2.99 (1H, ddd, J = 3.6, 5.6, 8.7Hz), 3.45 (1H, dd, J = 8.7, 14.2Hz), 3.50 (1H, dd, J = 3.6, 14.2Hz), 3.88 (3H, s), 5.87 (1H, s), 6.99-7.04 (1H, m), 7 01 (IH, d, J = 8.5 Hz), 7.18-7.23 (1 H

, m), 7.24-7.29 (IH, m), 7.44-7.49 (2H, m), 7.67 -7. 74 (1H, m), 7.81 (IH, d , J = 1.8 Hz), 7.83 (IH, dd, J = l, 8, 8.5 Hz), 8.12-8.16 (IH, m), 8.66-8.69 (IH, m)

 FAB-MS (m / e): 423 [M + H] + Example 54

Preparation of Compound Example 1129 (Ar r Ph R ^ HRHR i-P r; R: H; R ⁵ : 4-OMe-3 (3-pyri dyl) -Ph; n = 2)

_{'HNMR (CDC 1 3) δ} : 0. 96 (3H, d, J = 6. 8Hz), 0. 9 9 (3H, d, J = 6. 8Hz), 1. 88- 2. 02 (lH, m), 3.05 (1H, ddd, J = 3.3, 5.7, 9.1Hz), 3.45 (IH, dd, J = 9.1, 14.3Hz), 3.48 (IH, dd, J = 3 3, 14.3Hz), 3.84 (3H, s), 5.85 (IH, s), 7.00 (IH, dd, J = l. 9, 7.3Hz), 7.01- 7.07 (1H, m), 7.25-7.34 (3H, m), 7.46-7.52 (2H, m), 7.82—7.87 (1H, m), 8.16-8.20 (IH, m), 8.53 (1H, d, J = 4.8 Hz), 8.76 (1H, s)

 FAB-MS (m / e): 423 [M + H] + Example 55

Preparation of compound examples 1130 (Ai ^ Ph RH '- R ^ R 3: i- P r; R 4: H; R 5: 4-OMe - 3 (4 one py ri dy l) -Ph; n = 2)

_{^{X HNMR (CDC 1 3) δ}} :. 0. 97 (3H, d, J = 6. 8Hz), 1. 0 0 (3H, d, J = 6. 4Hz), 1. 87 -2 00 (1 H , m), 3.06 (IH, ddd, J = 3.4, 5.7, 9.2 Hz), 3.40 (IH, dd, J = 9.2, 14.3 Hz), 3.47 ( 1H, dd, J = 3.4, 14.3Hz), 3.85 (3H, s), 5.85 (1H, s), 6.98—7.06 (2H, m), 7.28-7.33 (2H, m), 7.46 (2H, dd, J = 1.7, 4.5 Hz), 7.49-7.52 (2H, m), 8.16-8 . 21 (1 H, m), 8.60 (2H, dd, J = l. 7, 4.5 Hz)

 FAB-MS (m / e): 423 [M + H] + Example 56

Preparation of compound examples ^{1131 (Ar: Ph; R 1} : H; R 2: H; R 3: i -P r; R 4: H; R 5: 3- COOMe- 4- Me O- P h; n = 2)

_{^{X HNMR (CDC 1 3) δ}} : 0. 95 (3Η, d, J = 6. 7Hz), 1. 0 0 (3H, d, J = 6. 8Hz), 1. 90- 2. 01 (IH, m), 2.94 -3.04 (lH, m), 3.40—3.50 (2H, m), 3.87 (3H, s), 3.92 (3H, s), 5.82 (1 H, s), 6.90-7.00 (2 H, m), 7.45-7.52 (2H, m), 7.65—7.80 (2H, m), 8.12—8.20 (1H, m)

FAB-MS (mZe): 404 [M + H] ⁺ Example 57

Preparation of Compound Example 1 136 (Ai ^ Ph;! ^ ¹ : !!;! ^ ² : !!;! ^ ³ : i—P r; R ⁴ : H; R ⁵ : 3-COhyd roxy ind oly 1 -4-MeO-Ph; n = 2)

_{^{X HNMR (CDC 1 3) (}} 5: 0. 95 (3H, d, J = 7. 0Hz), 1. 0 0 (3H, d, J = 6. 6Hz), 1. 85- 2. 00 (1 H, m), 3.05-3.25 (3H, m), 3.35-3.50 (4H, m), 3.85 (3H, s), 5.79 (1H, s), 6 90-7.25 (7H, m), 7.40—7.55 (2H, m), 8.10—8.20 (lH, m), 8.25 -8.35 (1H, m )

 FAB-MS (m / e): 491 [M + H] + Example 58

Preparation of compound examples 1 137 (Ar: Ph; R 1: H; R 2: H; R 3: i- P r; R 4: H; R 5: 4-PhCOO-Ph; n = 2)

_{iHNMR (CDC 1 3) δ:} 0. 97 (3H, d, J = 6. 5Hz), 1. 0 1 (3H, d, J = 6. 9Hz), 1. 90- 2. 05 (1 H, m), 2.95 — 3.05 (IH, m), 3.35 — 3.50 (2H, m), 5.88 (IH, s), 6.96-7.00 (lH, m) , 7.20-7.32 (2H, m), 7.45-7.56 (4H, m), 7.62-7.70 (lH, m), 7.92 (IH, s), 8 . 15-8.18 (1H, m), 8.27 (2H, d. J = 8.6Hz)

FAB-MS (m / e): 562 [M + H] + Example 59 Preparation of compound examples 1 139 (Ar: Ph; R 1: H; R 2: H; R 3: i- P r; R 4: H; R 5: 4- (4- N3) - PhCOO- Ph; n = 2)

 HNMR (CDC 1 Jδ: 0.97 (3Η, d, J = 6.8 Hz) 0

1 (3H, d, J = 6.6 Hz), 1.85—2.00 (1H, m), 2.98-1.05 (IH, m), 3.35—3.50 (2H, m), 5.88 (1H, s), 6.97-7.00 (1H, m), 7.17 (2H, d, J = 8.3Hz), 7.23 (1H, d, J = 8.3Hz), 7.31 (1H, dd, J = 1.9, 8.3Hz), 7.48-7.55 (2H, m), 7.92 (1H, d, J = 1) 9 Hz), 8.15-8. 18 (1H, m), 8.26 (2H, d. J = 8.3Hz)

 FAB-MS (m / e): 603 [M + H] + Example 60

Preparation of Compound Example 1 146

Jiasutereoma ^{a (Ar: Ph; R x} : H; R 2: H; R 3: i one ^{P r; R 4: H;} R 5: 3-1, 4-nP rNHCOCH20-Ph; n = 0)

_{^{X HNMR (CDC 1 3) d}} : 0. 94 (3H, d, J = 6. 6Hz), 0. 9 5 (3H, d, J = 6. 7Hz), 1. 00 (3H, t, J = 7.4 Hz), 1.55-1.74 (3H, m), 2.49 (1H, dd, J = 10.8, 13.9Hz), 2.89 (IH, dd, J = 2. 2, 13.9 Hz), 3.01 (1 H, ddd. J = 2.2, 5.1, 10.8 Hz), 3.35—3.42 (2H, m), 4.54 (2H, s), 5.64 (1H, s), 6.54-6.58 (lH, m), 6.80 (1H, d, J = 8.4Hz), 7.00-7.15 (2 H, m), 7.40 (IH, dd, J = 2.0, 8.5Hz), 7.63-7.66 (1H, m), 7.88 (IH, d, J = 2.0Hz) )

 FAB-MS (/ e): 525 [M + H] +

Jiasutereoma ^{b (Ar: Ph; R 1} : H; R 2: H; R 3: i- P r; R 4: H; R 5: 3-1, 4-nP rNHCOCH20-Ph; n = 0)

_{iHNMR (CDC 1 3) δ:} 0. 90- 1. 05 (9H, m), 1. 55- 1 70 (2H, m), 1.72-1.85 (3H, m), 1.90-2.00 (1H, m), 3.35-3.40 (2H, m), 4.52 (2H, s), 5.66 (1H, s), 6.70-6.80 (2H, m), 6.95—7.05 (IH, m), 7.06-7.15 ( 2H, m), 7.48-7.52 (IH, m), 7.83 (IH, d, J = 2.2 Hz)

 FAB-MS (m / e): 525 [M + H] + Example 61

Preparation of Compound Example 1147

Diastereomer a (Ar i P i R ^ H j R ^-H j R ³ : i— P r; R ⁴ : H; R ⁵ : 3-I, 4-nP rNHCOCH ₂₀ -Ph; n = 2)

_{NMR (CDC 1 3) δ:} 0. 98 (3H, d, J = 6. 8Hz), 0. 9 8 (3H, d, J = 6. 8Hz), 1. 01 (3H, t, J = 7 .4Hz), 1.50-1.70 (2H, m), 1.70-1.85 (IH, m), 3.05 (IH, dd, J = l1.8,14.7Hz), 3.38 (IH, t, J = 6.5 Hz), 3.40 (1H, t, J = 6.5 Hz), 3.42-3.52 (2H, m), 4.56 (2H, s), 5.88 (1H, s), 6.70—6.73 (1H, m), 6.82 (IH, d, J = 8.5Hz), 7.02 (IH, brs), 7.37 (1 H, dd, J = 2.1, 8.5 Hz), 7.37-7.43 (2 H, m), 7.85 (1H, d, J = 2.1 Hz), 8 . 13-8. 17 (1 H, m)

 FAB-MS (m / e): 557 [M + H] +

Jiasutereoma b (Ar ^ hj R 'i H j R ^ H i R 3: i -P r; R 4: H; R 5: 3- I, 4-nP rNHCOCH 2 0-P; n = 2)

_{^ NMR (CDC 1 3) δ} : 0. 96 (3 H, d, J = 6. 8Hz), 1. 0 0 (3H, t, J = 7. 4Hz), 1. 01 (3H, d, J = 6.7 Hz), 1.53-1.70 (2H, m), 1.90-1.94 (IH, m), 2.98-3.05 (IH, m), 3.30-3 49 (4H, m), 4.52 (1H, s), 5.79 (2H, s), 6.75 (1H, d, J = 8.3 Hz), 6.93 -7.00 (IH, m), 7.01 (IH, brs), 7.18 (1H, dd, J = 1.9, 8.3 Hz), 7.48-7.55 (2H, m) , 7.83 (1 H, d, J = l. 9Hz), 8.15-8.19 (IH, m)

 FAB-MS (m / e): 557 [M + H] + Example 62

Preparation of Compound Example 1 148

Jiasutereoma ^{a (Ar: Ph; R 1} : H; R 2: H; R 3: i P r; R 4: H; R 5: 2 - 1, 5-nP r HCOCH 2 0-Ph; n = 2)

_{^ NMR (CDC 1 3) δ} : 0. 98 (3H, d, J = 6. 8Hz), 0. 9 9 (3H, d, J = 6. 8Hz), 1. 01 (3H, t, J = (7.4Hz), 1.55-1.69 (2H, m), 1.71-1.86 (IH, m), 3.04 (IH, dd, J = l 1.8, 14.7Hz) , 3.36 (1H, t, J = 6.9Hz), 3.38 (1H, t, J = 6.9Hz), 3.45-3.50 (1H, m), 3.47 (IH, dd, J = 2.4, 14.7 Hz), 4.51 (2H, s), 5.94 (IH, s), 6.68-6.72 (1H, m), 6. 82 (1 H, dd, J = 1.8, 8.0 Hz), 6.95 (1 H, d, J = 1.8 Hz), 7.04 (IH, brs), 7.36-7.46 (2H, m), 7.79 (1 H, d, J = 8.0 Hz), 8.1 -8.18 (IH, m)

 FAB-MS (m / e): 557 [M + H] +

Jiasutereoma ^{b (Ar: Ph; R 1} : H; R 2: H; R 3: i one ^{P r; R 4: H;} 5: 2- 1, 5-nP rNHCOCH 2 0-Ph; n = 2)

_{^ NMR (CDC 1 3) (} 5: 0. 96 (3H, d, J = 6. 9Hz), 1. 0 0 (3H, t, J = 7. 4Hz), 1. 01 (3H, d, J = 6.8Hz), 1.55-1.65 (2H, m), 1.87-2.00 (1H, m), 3.31-3.45 (3H, m), 4.43 ( 1H, d, J = l 3.9Hz), 4.46 (1H, d, J = l 3.9Hz), 5.82 (1H, s), 6.70 (1H, dd, J = 1. 3, 8.2 Hz), 6.82 (1 H, d, J = 1.3 Hz), 6.95-7.02 (1H, m), 7.03 (IH, brs), 7. 49-7. 54 ( 2H, m), 7.73 (IH, d, J = 8.2 Hz), 8.16-8.20 (1 H, m)

 FAB-MS (m / e): 557 [M + H] + Example 63

Preparation of compound examples ^{1149 (Ar: Ph; R 1} : H; R 2: H; R 3: i one ^{P r; R 4: H;} R 5: 5- 1 -2 -nP r NHCOCH ^ O-Ph; n = 2)

_{iHNMR (CDC 1 3) d:} 0. 75 (3H, t, J = 7. 4Hz), 1. 0 0 (3H, d, J = 6. 7Hz), 1. 00 (3H, d, J = 6 7 Hz), 1.32-1.47 (2H, m), 1.77-1.89 (IH, m), 3.04 (1H, dd, J = 11.8, 14.8 Hz), 3 .05-3.20 (2H, m), 3.51 (IH, dd, J = 2.2, 14.8 Hz), 3.48-3.58 (IH, m), 4.16 (1H, m d, J = 14.0 Hz), 4.34 (IH, d, J = 14.0 Hz), 6.35 (1H, s), 6.56-6.64 (1H, m), 6.60 (IH, d, J = 8.5 Hz), 6.66-6.69 (1H, m), 7.37 -7. 46 (2H, m), 7.66 (IH, dd, J = 1 9, 8.5 Hz), 7.93 (IH, d, J = 1.9 Hz), 8.10-8.14 (1 H, m)

 FAB-MS (m / e): 557 [M + H] + Example 64

Preparation of Compound Example 1150

Jiasutereoma one a (A r: Ph; R 1: H; R 2: H; R 3: i one ^{P r; R 4: H;} R 5: 3-CH20H-4-OMe-Ph; n = 2)

_{XHNMR (CDC 1 3) δ:} 0. 97 (3 H, d, J = 6. 7Hz), 0. 9 8 (3H, d, J = 6. 7Hz), 1. 70- 1. 85 (1H, m), 3.07 (IH, dd, J = 11.4, 14.4 Hz), 3.43 (IH, dd, J = 2.2, 14.4 Hz), 3.45-3.49 (lH , M), 3.91 (3H, s), 4.71 (2H, s), 5.81 (1H, s), 6.73—6.76 (IH , m), 6.93 (IH, d, J = 8.3 Hz), 7.27-7.39 (4H, m), 8.12-8.15 (1 H, m)

 FAB-MS (m / e): 376 [M + H] +

Diastereomer b (A r: P h; R ¹ : H; R ² H; R i -P r; R ⁴ : H

R ⁵ : 3-CH20H-4-MeO-Ph; n = 2)

_{^ NMR (CDC 1 3) (} 5: 0. 94 (3H, d, J = 6. 7Hz), 0. 9 8 (3H, d, J = 6. 7Hz), 1. 90- 2. 00 (IH , m), 2.95 — 3.02 (lH, m), 3.38-3.52 (2H, m), 3.88 (3H, s), 4.68 (2H, s), 5. 79 (1H, s), 6.88 (1H, d, J = 8.3Hz), 6.93-6.96 (1H, m), 7.18 (1H, dd, J = 2 0, 8.3Hz), 7.29 (1H, d, J = 2.0Hz), 7.45—7.48 (2H, m), 8.13—8.16 (1H, m)

 FAB-MS (m / e): 376 [M + H] + Example 65

Preparation of compound examples ^{1151 (Ar: Ph; R 1} : H; R 2: H; R 3: i - P r; R 4: H; R 5: 3 - (1, 2-di hyd r oxye t hy l ) -4-Me-Ph; n = 2)

_{^{X HNMR (CDC 1 3) (}} 5:. 0. 92- 0. 98 (6H, m), 1. 85- 1 95 (IH, m), 3. 00- 3. 10 (1 H, m), 3.35-3.50 (2H, m), 3.60—3.70 (IH, m), 3.75-3.85 (1H, m), 3.85 (3H, s), 5 00-5.08 (lH, m), 5.78 (1 H, s), 6.86 (1H, dd, J = l. 5, 9.1), 6.95—7.02 (IH , m), 7.12-7.23 (IH, m), 7.45-7.55 (3H, m), 8.15-8.18 (1 H, m)

FAB-MS (m / e): 406 [M + H] ⁺ Example 66

Made in Compound Example 1152 (A r-: Ph; R 1: H; R 2: H; R 3: i -P r; R 4 : H; R ⁵ : 3-CH2QMe-4-MeO-Ph; n = 2)

_{^{X HNMR (CDC 1 3) δ}} : 0. 95 (3H, d, J = 6. 8Hz), 0. 9 8 (3H, d, J = 6. 6Hz), 1. 90 - 2. 05 (IH, m), 2.95-3.04 (lH, m), 3.41 (3H, s), 3.45-3.52 (2H, m), 3.85 (3H, s), 4.49 (2H, s), 5.79 (1H, s), 6.86 (1H, d, J = 8.5 Hz), 6.90-6.95 (IH, m), 7.17 (1H, dd , J = 2.0, 8.5Hz), 7.37 (1H, d, J = 2 • 0Hz), 7.44-7.47 (2H, m), 8.12-8.15 (lH, m)

 FAB-MS (mZe): 390 [M + H] + Example 67

Preparation of Compound Example 1153 (Ar Pt ^ R ^ HRH;! ^ ³ : i -P r; R ⁴

: H; R ⁵ : 3-CH2NHSQ2Me-4-MeO-Ph; n = 2)

_{XHNMR (CDC 1 3) (5} : 0. 95 (3 H, d, J = 6. 9Hz), 1. 0

0 (3H, d, J = 6.7Hz), 1.90—2.44 (1H, m), 2.79 (3H, s), 3.02-3.12 (1H, m), 3.35-3.50 (2H, m), 3.88 (3H, s), 4.27—4.30 (2H, m), 4.91-1 4

92 (IH, m), 5.77 (IH, s), 6.88 (1H, d, J = 8.5 Hz), 6.97-7.00 (IH, m), 7.16 ( 1H, dd, J = 2.0

, 8.5 Hz), 7.21-7.26 (lH, m), 7.48-7.51 (2H

, M), 8.16-8.19 (1 H, m)

 FAB-MS (m / e): 453 [M + H] + Example 68

Preparation of compound examples ^{1154 (Ar: Ph; R 1} : H; R 2: H; R 3: i one ^{P r; R 4: H;} R 5: 3-CH2NMe S_rei_2Me- 4-MeO- Ph; n = 2)

_{NMR (CDC 1 3) 5:} . 0. 95 (3H, d, J = 6. 8Hz), 1. 0 0 (3H, d, J = 6. 8Hz), 1. 90-2 01 (1 H, m), 2.79 (3H, s), 2.81 (3H, s), 3.02-3 10 (IH, m), 3.32-3.49 (2H, m), 3.84 (3H, s) 4. 36 (2H, s), 5.76 (IH, s), 6.86 (IH, d, J = 85 Hz), 6.98-7.04 (1H, m), 7.12 (IH, dd) , J = 23, 8.5Hz), 7.35 (IH, d, J = 2.3Hz), 7.47-7.52 (2H, m), 85-8.19 (1H, m )

 FAB-MS (m / e): 467 [M + H] + Example 69

Preparation of compound examples 1 1 55 (Ar ^ h ^^ - H i R 'i H ^ 3: i -P r; R 4: H; R 5: 3 - (4-CH2QH) Ph-4-MeQ-Ph ; n = 2) iHNMR (CDC 1 3) δ: 0. 96 (3H, d, J = 6. 8Hz), 0. 9 8 (3H, d, J = 6. 8Hz), 1. 90-2. 00 (IH, m), 3.00-3.08 (lH, m), 3.40-3.55 (2H, m), 3.83 (3H, s), 4.72 (2H, s) , 5.83 (1 H, s), 6.95-7.05 (2 H, m), 7.22-7.30 (2H, m), 7.36-7.60 (6H, m) , 8. 14-8. 17 (1H, m)

 FAB-MS (m / e): 452 [M + H] + Example Ί 0

R ¹ : H; R ² : H; R ³ : i—Pr; R ⁴ : H; R ⁵ : 3-Me SQ2N (Me) CH2-4 Me-Ph; n = 2)

_{iHNMR (CDC 1 3) (5} : 0. 95 (3H, d, J = 6. 7Hz), 0. 9 9 (3H, d, J = 6. 7Hz), 1. 90- 2. 01 (lH, m), 2.39 (3H, s), 2.66 (3H, s), 2.81 (H, S), 3.05 (1H, m), 3.40 -3.55 (2H, m ), 4.21 (IH, d, J = 14.OHz), 4.31 (1H, d, J = 14.0 Hz), 5.79 (1H, s), 6.95-6.98 (lH, m), 7.10 (1H, s), 7.19—7.20 (2H, m), 7.48—7.51 (2H, m), 8.16-8.19 (lH, m) FAB-MS (mZe): 451 [M + H] + Example 71

Preparation of compound examples 1161 (Ai ^ y-HO- Ph - ^ R ^ HR 2:! !!; ^ 3: i -P r; R 4: H; R 5: P h; n = 0)

_{^ NMR (CDC 1 3) ά} : 0. 94 (3H, d, J = 6. 8Hz), 0. 9 5 (3H, d, J = 6. 8Hz), 1. 55- 1. 75 (1 H , m), 2.48 (1H, dd, J = 10.8, 13.9Hz), 2.83 (1H, dd, J = 2.2, 13.9Hz), 3.00-3.08 ( 1H, m), 5.64 (1H, s), 6.03 (1H, d, J = 2.6Hz), 6.56 (1H, dd, J = 2.6, 8.3Hz), 7.24-7.48 (5H, m), 7.50 (1H, d, J = 8.3Hz)

FAB-MS (m / e): 300 [M + H] ⁺ Example 72

Preparation of compound examples 1162 (3-isopropyl - 7-methoxy-5-phenylene Lou 2, 3, 4, 5-tetrahydro one Iff- 1 λ ^6, 4 one base Nzochiazepin one 1, 1-dione)

 Sodium hydride (1.75 g, 43.9 mmol 1) was added to a solution of 2-hydroxy-4-methoxybenzophenone (5.00 g, 21.9 mmol 1) in dimethylformamide (20.0 ml). It was added slowly and stirred at room temperature for 30 minutes. Dimethylthiol Rubamoiruku Mouth Ride (3.13 g, 25.2 mmo 1) was added, and the mixture was stirred at 60 overnight. The reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layer was washed with a 2N aqueous solution of sodium hydroxide and saturated saline, dried, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel, using hexane Z ethyl acetate (80Z20) as the eluent, to give the desired pale yellow solid 0— (2-benzoyl 4-methoxyphenyl) N, N— Dimethylcarbamothioate (2.81 g, 8.90 mmo 1) was obtained (yield 41%).

_{^ NMR (CDC 1 3) δ} : 3. 09 (3Η, s), 3. 28 (3H, s), 3.87 (3H, s), 6.73 (1H, d, J = 2.4 Hz), 6.82 (1

H, d d, J = 8.6, 2.4 Hz), 7.38-7.56 (4H, m), 7.74-7.78 (2H, m)

FAB-MS (m / e): 316 [M + H] ⁺

 The product of Step 1 (2.73 g, 8.66 mmol) was suspended in phenyl ether (4.0 g) and heated at 260 ° C. for 30 minutes. After cooling to room temperature, the reaction mixture was subjected to column chromatography on silica gel using hexane and then hexane / ethyl acetate (80/20) as a dissolving agent to give a light yellow solid, S- (2-benzoic). L-4-methoxyphenyl) N, N-dimethylcarbamothioate (2.11 g, 5.96 mmol 1) was obtained (yield 77%).

_{^ NMR (CDC 1 3) <} 5: 2. 89 (6H, s), 3. 88 (3H, s), 6. 96 (1Η, dd, J = 8. 5, 2. 5Hz), 7. 20 (1H, d, J = 2.5Hz), 7.38-7.45 (3H, m), 7.51-7.57 (1H, m), 7.76-7.80 (2H, m )

 FAB-MS (m / e): 316 [M + H] +

 The product of Step 2 (3.14 g, 9.96 mmol) was dissolved in methanol (40.0 ml), a 10% aqueous sodium oxide solution (10. Oml) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was treated with 2N hydrochloric acid and extracted twice with ethyl acetate. The organic layer was washed with saturated saline, dried, and concentrated under reduced pressure. The residue was dissolved in 2,6-lutidine (6. Oml), and 2_isopropylaziridine (1.5 ml) obtained in step 1 of Example 1 was added dropwise at room temperature. After the addition was completed, the mixture was stirred at room temperature for 3 hours, and concentrated hydrochloric acid (2. Oml) was added. After the addition was completed, the mixture was azeotroped for 3 hours and distilled under reduced pressure. The residue was collected with a saturated aqueous solution of sodium hydrogen carbonate, and the solution was extracted twice with ethyl acetate. The collected extracts were washed with a saturated saline solution, dried, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel using hexane / ethyl acetate (90-10) as an eluent to give a light yellow oily substance, 3-isopropyl-17-methoxy-5-phenyl-1,2,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,3-dihydro-1,4-dihydro-1,3-dihydro-1,4-dihydro-1,3-dihydro-1,2-dihydro-1,4-dihydro-1,2-dihydro-1,3-dihydro-1,2-dihydro-1,3-dihydro-1,2-dihydro-1,2-dihydro-1,3-dihydro-1,3-dihydro-1,5-diethyl. 4 Benzothiazepine (

I. 42 g, 4.57 mmo 1) was obtained (46% yield). iHNMR was consistent with the proposed structure. _{^{X HNMR (CDC 1 3) (}} 5: 0. 95 (3H, d, J = 6. 8Hz), 1. 0 6 (3H, d, J = 6. 7Hz), 2. 00- 2. 13 (lH , M), 3.01 (1H, ddd, J = 12.2, 6.5, 3.9 Hz), 3.29 (1H, dd, J = 12.2, 11.1 Hz), 3.64 (1H, dd, J = 11.1, 3.9Hz), 3.86 (3H, s), 6.87 (1H, dd, J = 8.5, 2.6Hz), 7.04 (1H, d, J = 8.5Hz), 7.17 (1H, d, J = 2.6Hz), 7.31-7.43 (3H, m), 7.58- 7.64 (2H , m)

 FAB-MS (m / e): 312 [M + H] +

To a solution of the product of Step 3 (1.42 g, 4.57 mmol) in trifluoroacetic acid (15.0 Oml) was added 30% aqueous hydrogen peroxide (2.5 ml) at a temperature of about 0 ° C. After the addition was completed, the mixture was stirred at room temperature overnight, treated with a 10% aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution, and extracted twice with ethyl acetate. And concentrated under reduced pressure. The residue (502 mg of 1.63 g) and 4N hydrogen chloride 1,4-dioxane solution (14.0 ml) were mixed, and zinc powder (0.81 mg, 12.4 mmo 1) was gradually added. The mixture was stirred overnight at room temperature, treated with saturated aqueous sodium bicarbonate and filtered through celite. The mixture was extracted twice with ethyl acetate, and the extracts were collected, washed with a saturated saline solution, dried, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel using hexane / ethyl acetate (80/20) as an eluent to give 3-isopropyl-7-methoxy-1-5-phenyl 2,3,4,5-tetrahydro- 1 λ ⁶ , 4-Benzothiazepine—a diastereomer of 1,1-dione a (82.0 mg, 0.237 mmo 1, 17% yield) and b (141.9 mg, 0.411 mmo 1, yield 29) %) As a pale yellow oily product.

Diastereomer a

_{^ NMR (CDC 1 3) δ} : 0. 98 (3H, d, J = 6. 9Hz), 0. 9 8 (3H, d, J = 6. 9Hz), 1. 73- 1. 88 (1 H , m), 3.08 (1H, dd, J = 11.4, 14.3Hz), 3.43 (1H, dd, J = 2.2, 14.3Hz), 3.51 (1H, ddd, J = 2.2, 4.8, 11. 4Hz), 3.83 (3H, s), 5.80 (1H, s), 6.59 (1H, d, J = 8.6Hz), 6.85 (1H, dd, J = 2.9) , 8.6Hz), 7.33-7.45 (5H, m), 7.68 (1H, d, J = 2.9Hz)

FAB-MS (m / e): 346 [M + H] ⁺

Geostereomer b

_{^{X HNMR (CDC 1 3) 6}} :. 0 95 (3H, d, J = 6. 8Hz), 0. 9 8 (3H, d, J = 6. 7Hz), 1. 88-2 02 (1H, m ), 2.97 (1H, ddd, J = 3.5, 5.5, 9.1 Hz), 3.43 (1H, dd, J = 9.1, 14.5 Hz), 3.49 (1H , Dd, J = 3.5, 14.5Hzz)), 33 .. 8866 ((33HH ,, ss)), 55..78 (1H, s), 6.80 (1H, d , J = 8.6 Hz), 6.96 (1 H, dd, J = 2.8, 8.6 Hz), 7.26 -7. 42 (5H, m), 7.66 (1 H, d, J = 2.8Hz)

 FAB-MS (m / e): 346 [M + H] + The physical constants of the compound obtained in the same manner as in Example 72 are shown below.

Example 73

Preparation of compound examples 1160 (Ar: e-MeO- Ph j R ^ H ^^ H ^ 3: i - P r; R 4: H; R 5: Ph; n = 2)

_{^ NMR (CDC 1 3) δ} : 0. 99 (3H, d, J = 6. 9Hz), 0. 9 9 (3H, d, J = 6. 9Hz), 1. 80- 1. 98 (1 H , m), 3.10 — 3.20 (1 H, m), 3.20-3.38 (2H, m), 3.74 (3H, s), 6.35 (1H, s), 7 11-7. 16 (2H, m), 7.20-7. 32 (4H, m), 7.49 (1H, t, J = 8.0Hz), 7.88 (1H, dd, J = 1.1, 8.0Hz)

 FAB-MS (m / e): 346 [M + H] + Example 74

Preparation of Compound Example 1163

Diastereomer a (Ar: 9 OMe—Ph; R ¹ : H; R ² : H; R ³ P r; R ⁴ : H; R ⁵ : Ph; n = 2)

_{^{X HNMR (CDC 1 3) δ}} : 0. 97 (3H, d, J = 7. 0Hz), 0. 9 7 (3H, d, J = 7. 0Hz), 1. 70- 1. 85 (IH, m), 3.25-3.50 (3H, m), 3.93 (3H, s), 6.01 (1H, s), 6.32 (IH, d, J = 7.9 Hz), 6 . 92 (1H, d, J = 8.1Hz), 7.22-7.40 (6H, m)

 FAB-MS (m / e): 346 [M + H] +

Diastereomer b (Ar: e-OMe-Ph j R ^ H j R ^ H j R ³ : i-Pr; R ⁴ : H; R ⁵ : Ph; n = 2)

_{^ NMR (CDC 1 3) (} 5: 0. 91 (3H, d, J = 6. 5Hz), 0. 9 6 (3H, d, J = 6. 5Hz), 1. 85- 1. 98 (1 H, m), 3.08-3.15 (IH, m), 3.60 (1H, dd, J = 3.7, 14.8 Hz), 3.74 (IH, dd, J = 10 1, 14.8 Hz), 3.99 (3H, s), 5.41 (1H, s), 6.27 (1H, d, J = 7.9 Hz), 6.96 (1H, d, J = 8.2 Hz), 7.18-7.48 (6H, m)

 FAB-MS (m / e): 346 [M + H] + Example Ί 5

Preparation of Compound Example 1 165

Jiasutereoma a (Ar: 8-OH- Ph; R X: H; R 2: H; R 3: i _P r; R 4: H; R 5: Ph; n = 2)

_{^ NMR (CDC 1 3) δ} : 0. 98 (3 H, d, J = 6. 9Hz), 0. 9 8 (3H, d, J = 6. 9Hz), 1. 73 - 1. 88 (lH , M), 3.11 (IH, dd, J = 1.3, 14.3 Hz), 3.43 (1H, dd, J = 2.2, 14.3 Hz), 3.5.51 ( 1 H, ddd, 1 = 2.2, 4. 7, 1 1.3 Hz), 5.77 (1H, s), 6.55 (1 H, d, J = 8.4 Hz), 6.81 ( IH, dd, J = 2.7, 8.4Hz), 7.30-7.45 (5H, m), 7.66 (IH, d, J = 2.7Hz)

FAB-MS (m / e): 332 [M + H] + Jiasutereoma b (A r: 8- OH- Ph ; R 1: H; R 2: H; R 3 one ^{P r; R 4: H;} R 5: Ph; n = 2)

_{NMR (CDC 1 3) δ:} . 0 95 (3H, d, J = 6. 8Hz), 0. 9 9 (3H, d, J = 6. 7Hz), 1. 88-2 03 (1H, m) , 3.00 (1H, ddd, J = 3.6, 5.7, 9.0Hz), 3.45 (1H, dd, J = 9.0, 14.3Hz), 3.52 (1H, dd , J = 3.6, 14.3Hz), 5.75 (1H, s), 6.77 (1H, d, J = 8.4Hz), 6.92 (1H, dd, J = 2. 7, 8.4 Hz), 7.28-7.40 (5H, m), 7.66 (1H, d, J = 2.7Hz)

 FAB-MS (m / e): 332 [M + H] + Example 76

Preparation of Compound Example 1166

Jiasutereoma a (Ar: g-OH- P j R ^ H j R ^ H j R 3: i one ^{P r; R 4: H;} R 5: Ph; n = 2)

_{iHNMR (CDC 1 3) δ:} 0. 98 (3H, d, J = 6. 6Hz), 0. 9 8 (3H, d, J = 6. 6Hz), 1. 75 - 1. 85 (1H, m ), 3.32 (1H, dd, J = 11.5, 14.1Hz), 4.45 (1H, dd, J = 2.1, 14.1Hz) 3.45—3.55 (1H, m), 5.89 (1H, s), 6.14 (1H, d, J = 7.6Hz), 6.86 (1H, d, J = 8.6Hz), 7.18 (1H, dd, 1 = 7.6, 8.6Hz), 7.30-7.41 (5H, m), 10.36 (1H, s)

 FAB-MS (m / e): 332 [M + H] +

Jiasutereoma b (Ar: 9 -OH-P ; R 1: H; R 2: H; R 3: i- P r; R 4: H; R 5: Ph; n = 2)

_{iHNMR (CDC 1 3) δ:} 0. 98 (3H, d, J = 6. 9Hz), 1. 0 0 (3H, d, J = 6. 9Hz), 1. 95- 2. 05 (1 H, m), 2.95-3.05 (lH, m), 3.49-3.65 (2H, m), 5.90 (1H, s), 6.31 (1H, d, J = 7. 9 Hz), 6.94 (1H, d, J = 8. 4Hz), 7.25-7.45 (6H, m), 10.0 (1H, s)

 FAB-MS (m / e): 332 [M + H] + Example 77

Preparation of Compound Example 1167

Jiasutereoma a (A r: 8- n- P RNHC_〇_CH ₂ 〇 one ^{Ph; R 1: H; R} 2: H; R 3: i -P r; R 4: H; R 5: Ph; n = 2 )

_{^ NMR (CDC 1 3) δ} : 0. 94 (3 H, t, J = 7. 6Hz) 0. 98 (3H, d, J = 7. 2Hz), 0. 98 (3H, d, J = 7 2 Hz), 1.52-1.65 (2H, m), 1.75-1.85 (lH, m), 3.08 (1 H, dd, J = l 1.4, 14.3 Hz) , 3.29 (1H, t, J = 6.3Hz), 3.38 (1H, t, J = 6.3Hz), 3.44 (1H, dd, J = 2.1, 14. 3Hz), 3.52 (1H, ddd, J = 2.1, 4.8.11.4), 4.48 (2H, s), 5.79 (1H, s), 6.52 ( 1H, brs), 6.64 (1H, d, J = 8.6Hz), 6.85 (1H, dd, J = 2.8, 8.6Hz), 7.32-7.45 (5H, m ), 7.76 (1H, d, J = 2.8Hz)

FAB-MS (m / e): 31 [M + H] ⁺

Jiasutereoma b (A r: 8-nP rNHCOCH 2 0-Ph; R 1: H; R 2: H; R 3: i -P r; R 4: H; R 5: Ph; n = 2)

_{^{X HNMR (CDC 1 3) δ}} : 0. 94 (. 3H, t, 1 = 7 4Hz), 0. 9 5 (3H, d, J = 6. 7Hz), 0. 99 (3H, d, J = 6.7 Hz), 1.53-1.68 (2H, m), 1.92-2.02 (lH, m), 2.97 (1H, ddd, J = 3.5, 5. 8, 12 1Hz), 3.31 (1H, t, J = 6.8Hz), 3.34 (1H, t, J = 6.8Hz), 3.45 (1H, dd, J = 12.1) , 14.4Hz), 3.50 (1H, dd, J = 3.5, 14.4Hz), 4.52 (2H, s), 5.78 (1H, s), 6.54 (1 H, brs), 6.85 (1H, d, J = 8.6Hz), 6.97 (1H, dd, J = 2.8, 8.6Hz), 7.29-7.42 (5H , M), 7.74 (1H, d, J = 2.8Hz)

 FAB-MS (m / e): 43 [M + H] + Example 78

Preparation of Compound Example 1 168

Diastereomer a (A r: 9-Me-Ph; R ^-HJR ^ HIR ³ i-Pr; R ⁴ : H; R ⁵ : Ph; n = 2)

_{^{X HNM (CDC 1 3) δ}} : 0. 98 (3H, d, J = 6. 6Hz), 0. 9 8 (3H, d, J = 6. 6Hz), 1. 72- 1. 85 (1 H , M), 2.79 (3H, s), 3.20 (1H, dd, J = 11.3, 14.5Hz), 3.38 (1H, dd, J = 2.1, 14.5Hz) ) 3.47—3.52 (1H, m), 6.13 (1H, s), 6.60 (1H, d, J = 7.2Hz), 7.11-7.20 (2H, m), 7.25-7.45 (5H, m)

FAB-MS (m / e): 330 [M + H] ⁺

Jiasutereoma b (Ar: 9-Me- Ph; R 1: H; R 2: H; R 3: i one ^{P r; R 4: H;} R 5: Ph; n = 2)

_{^{X HNMR (CDC 1 3) 6}} : 0. 94 (3H, d, J = 6. 7Hz), 0. 9 7 (3H, d, J = 6. 8Hz), 1. 87 - 1. 99 (1 H , m), 2.79 (3H, s), 2.95-3.04 (lH, m), 3.60—3.68 (2H, m), 5.64 (1H, s), 6 . 56-6.62 (1H, m), 7.16—7.22 (2H, m), 7.32—7.41 (5H, m)

 FAB-MS (m / e): 330 [M + H] + Example 79

Preparation of Compound Example 1169

Jiasutereoma a (Ar: TC l-Ph j R ^ H j R ^ H j R 3: i-P r; R 4: H; R 5: Ph; n = 2)

_{^ NMR (CDC 1 3) δ} : 0. 99 (3H, d, J = 6. 9Hz), 0. 9 9 (3H, d, J = 6. 9 Hz), 1. 73 - 1. 89 (1 H, m), 3.06 (1H, dd, J = l 1.4, 14.3Hz), 3.44 (1H, dd, J = 2.2, 14.3Hz), 3.47-3.55 (1H, m) , 5.85 (IH, s), 6.67 (IH, d, J = 2.1 Hz), 7.38 (1H, dd, J = 2.1, 8.4 Hz), 7.35-7 . 50 (5H, m), 8.09 (IH, d, J = 8.4 Hz)

 FAB-MS (m / e): 350/352 [M + H] +

Jiasutereoma b (Ar: TC l -Ph j R ^ H j ^ H j R 3: i one ^{P r; R 4: H;} R 5: Ph; n = 2)

_{^{X HNMR (CDC 1 3) δ}} : 0. 95 (3H, d, J = 6. 8Hz), 0. 9 9 (3H, d, J = 6. 8Hz), 1. 90 - 2. 03 (1 H , m), 2.97

(1H, ddd, J = 3.7, 5.7, 8.9Hz), 3.45 (1H, dd, J = 8.9, 14.4Hz), 3.49 (1H, dd, J = 3 7, 14.4 Hz), 5.81 (IH, s), 6.88 (1 H, d, J = 2.0 Hz), 7.30—7.43 (5H, m), 7.45 (1H, dd, J = 2.0, 8.4Hz), 8.09 (1H, d, J = 8.4Hz)

 FAB-MS (m / e): 350/352 [M + H] + Example 80

Preparation of Compound Example 1 172

Diastereomer a (Ar: 8-C 1 Ph RHR ^ HR ³ : i-P r; R ⁴ : H; R ⁵ : Ph; n = 2)

_{^ NMR (CDC 1 3) δ} : 0. 98 (3H, d, J = 6. 7Hz), 0. 9 8 (3H, d, J = 6. 7Hz), 1. 77- 1. 89 (IH, m), 3.08 (IH, dd, J = 1 1.4, 14.4 Hz), 3.44 (1H, dd, J = 2.2, 14.4 Hz), 3.51 (1H, ddd , J = 2.2, 4. 8, 11.4 Hz), 5.82 (IH, s), 6.63 (1H, d, J = 8.3 Hz), 7.31 (IH, dd, J = 2.3, 8.3 Hz), 7.32-7.46 (5H, m), 8.13 (IH, d, J = 2.3 Hz)

FAB-MS (/ e): 350/352 [M + H] + Diastereomer b (Ar: SC l -Ph j R ^ H j R ^ H j R ³ : i- 1 Pr; R ⁴ : H; R ⁵ : Ph; n = 2)

_{^{X HNMR (CDC 1 3) (}} 5: 0. 95 (3H, d, J = 6. 8Hz), 0. 9 9 (3H, d, J = 6. 8Hz), 1. 92- 2. 03 (1H , m), 2.96 (1H, ddd, J = 3.5, 5.9, 8.9Hz), 3.46 (1H, dd, J = 8.9, 14.4Hz), 3.51 (1H, dd, J = 3.5, 14.4Hz), 5.79 (1H, s), 6.84 (1H, d, J = 8.3Hz), 7.30-7.42 (5H, m), 7.42 (1H, dd, 1 = 2.2, 8.3Hz), 8.13 (1H, d, J = 2.2Hz)

 FAB-MS (m / e): 350/352 [M + H] + Example 81

Preparation of Compound Example 1 175

Jiasutereoma a (Ar: 9-C 1 -Ph; R 1: H; R 2: H; R 3: i one ^{P r; R 4: H;} R 5: Ph; n = 2)

_{^{X HNMR (CDC 1 3) δ}} : 0. 99 (3H, d, J = 6. 9Hz), 0. 9 9 (3H, d, J = 6. 9Hz), 1. 75- 1. 89 (1 H , m), 3.29 (1H, dd, J = l 1.2, 14.6Hz), 3.45 (1H, dd, J = 2.3, 14.6Hz), 3.50 (1H , Ddd, J = 2.3, 4.9, 11.2Hz), 6.11 (1H, s), 6.69 (1H, dd, J = l.2, 7.9Hz), 7.20 (1H, t, J = 7.9Hz), 7.31—7.45 (6H, m)

 FAB-MS (m / e): 350/352 [M + H] +

Jiasutereoma b (Ar: 9 -C 1 -Ph ; 1: H; R 2: H; R 3: i one ^{P r; R 4: H;} 5: P h; n = 2)

_{'HNMR (CDC 1 3) δ} : 0. 93 (3H, d, J = 6. 7Hz), 0. 9 8 (3H, d, J = 6. 8Hz), 1. 88- 2. 02 (1 H , m), 3.07 (1H, ddd, J = 4.5, 7.1, 9.5 Hz), 3.67-3.80 (2 H, m), 5.49 (1H, s), 6.65 (1 H, dd, J = 0.7, 7. 9 Hz), 7.19 (1H, t, J = 7.9 Hz), 7.26-7.45 (6H, m)

 FAB-MS (m / e): 350Z352 [M + H] + Example 82

Preparation of Compound Example 1178

Jiasutereoma a (Ar: 9- C 1 one ^{Ph; R 1: H; R} 2: H; R 3 i one ^{P r; R 4: H;} R 5: 4-C l -Ph; n = 2)

_{NMR (CDC 1 3) (5} : 0. 98 (3H, d, J = 6. 8Hz), 0. 9 8 (3H, d, J = 6. 8Hz), 1. 71- 1. 82 (1 H , m), 3.26 (1H, dd, J = 11.5, 14.8Hz), 3.40-3.50 (2H, m), 6.13 (1H, s), 6.66 (1H , d, J = 7.9 Hz), 7.19 -7. 40 (6H, m)

 FAB-MS (m / e): 384X386 [M + H] +

Jiasutereoma b (Ar: 9- CI- Ph ' - RHR 2:! !!; ^: i- P r; R 4: H; R 5: 4-C 1 -Ph; n = 2)

_{^{X HNMR (CDC 1 3) (}} 5: 0. 92 (3H, d, J = 6. 6Hz), 0. 9 7 (3H, d, J = 6. 8Hz), 1. 80- 1. 95 (1 H, m), 2.95-3.10 (1H, m), 3.60-3.80 (2H, m), 5.50 (1 H, s), 6.62 (1H, d, J = 7.9Hz), 7.15-7.45 (6H, m)

 FAB-MS (m / e): 384/386 [M + H] + Example 83

Preparation of Compound Example 1180

Jiasutereoma a (Ar: TC l -Ph i R ^ H j R ^ H j R 3: i one ^{P r; R 4: H;} R 5: 4-MeO-Ph; n = 2)

_{^{X HNM (CDC 1 3) δ}} : 0. 98 (3H, d, J = 6. 9Hz), 0. 9 8 (3H, d, J = 6. 9Hz), 1. 74- 1. 88 (1H, m), 3.29 (IH, dd, J = 1.2, 14.8 Hz), 3.44 (IH, dd, J = 2.4, 14.8 Hz), 3.49 (1 H, ddd, J = 2.4 , 5.2, 11.2Hz), 3.84 (3H, s), 6.01 (IH, s), 6.73 (1H, dd, J = l. 3, 7.9Hz), 6 .94 (2H, d, J = 8. OHz), 7.20 (1H, t, J = 7.9 Hz), 7.27 (IH, d, J = 8. OHz), 7.37 (IH, (dd, J = l. 3, 7.9 Hz)

 FAB-MS (m / e): 380/382 [M + H] +

Jiasutereoma b (A r: 9 - C 1 - P h; R 1: H; R 2: H; R 3: i- P r; R 4: H; R 5: 4-MeO-Ph; n = 2)

_{iHNMR (CDC 1 3) (5} :. 0. 93 (3H, d, J = 6. 7Hz), 0. 9 7 (3H, d, J = 6. 8Hz), 1. 88-2 01 (IH, m), 3.07

(IH, ddd, J = 4.6, 7.0, 9.1 Hz), 3.65-3.84 (2 H, m), 3.84 (3H, s), 5.45 (IH, s ), 6.69 (1H, d, 1 = 7.9 Hz), 6.93 (2H, d, J = 8.8 Hz), 7.19 (IH, t, J = 7.9 Hz), 7.22 (2H, d, J = 8.8Hz), 7.41 (IH, d, J = 7.9Hz)

 FAB-MS (m / e): 380/382 [M + H] + Example 84

Preparation of compound examples 1 181 (A r: 9 - C 1 - P h; R 1: H; R 2: H; R 3: i -P r; R 4: H; R 5: 4-OH-Ph; n = 2)

_{^{X HNMR (CDC 1 3) δ}} : 0. 92 (3H, d, J = 6. 7Hz), 0. 9 7 (3H, d, J = 6. 7Hz), 1. 87- 1. 99 (1H, m), 3.00-3.10 (IH, m), 3.64-3.77 (2H, m), 5.43 (1H, s), 6.67-6.70 (IH, m) , 6.84-6.89 (2H, m), 7.14-7.23 (3H, m), 7.38-7.43 (IH, m)

FAB-MS (m / e): 366/368 [M + H] ⁺ Example 85 Preparation of Compound Example 1199

Jiasutereoma a (A r: 9 -C 1 -P h; R 1: H; R 2: H; R 3: i-P r; R 4: H; R 5: 3-C l -4-Me-Ph ; n = 2)

_{HNMR (CDC 1 3) δ:} 0. 98 (3H, d, 6. 8Hz), 0. 9 8 (3H, d, J = 6. 8Hz), 1. 74- 1. 85 (1 H, m) , 2.39 (3H, s), 3.40-3.50 (2H, m), 6.09 (1 H, s), 6.70 (1H, d, J = 7.7 Hz), 7 . 10 (1 H, d, J = 7.9 Hz), 7.20-7.27 (2H, m), 7.36-7. 41 (2H, m)

FAB-MS (m / e): 398/400 [M + H] ⁺

Diastereomer b (A r: gC l -Ph j R ^ H i R ^ H j R ³ : i—P r; R ⁴ : H; ⁽ R ⁵ : 3 -C 1—4— Me-Ph; n = 2 )

_{^ NMR (CDC 1 3) (} 5: 0. 93 (3H, d, J = 6. 8Hz), 0. 9 7 (3H, d, J = 6. 6Hz), 1. 81- 1. 98 (1 H, m), 2.40 (3H, s), 3.00-3.10 (lH, m), 3.67-3.75 (2H, m), 5.46 (1H, s), 6 66 (1H, d, J = 7.9Hz), 7.07 (1H, dd, J = 1.7, 7.9Hz), 7.21 (1H, dd, J = 6.9, 7. 9Hz), 7.25 (1H, d, J = 7.9Hz), 7.34 (1H, d, J = l.7Hz), 7.42 (1H, d, J = 6.9Hz)

FAB-MS (m / e): 398/400 [M + H] ⁺ Example 86

Preparation of Compound Example 1201

Jiasutereoma a (A r: 9-C 1 -Ph; R 1: Η; R 2: Η; R 3: i-P r; R 4: H; R 5: 3- F- 4 - F - Ph; n = 2)

_{'HNMR (CDC 1 3) d} 0. 98 (3H, d, J = 6. 8Hz), 0. 9 9 (3H, d, J = 6. 7Hz), 1. 72- 1. 84 (1 H, m), 3.25 (1H, dd, J = 11.6, 14.9Hz), 3.40—3.50 (2H, m), 6.17 (1H, s), 6.66 (1H, d, J = 7.5 Hz), 7.00 -7.10 (1H, m), 7.12-7.30 (3H, m), 7.42 (1H, d, J = 8.1 Hz)

 FAB-MS (m / e): 386/388 [M + H] +

Jiasutereoma b (A r: 9 - C 1 - P h; R 1: H; R 2: H; R 3: i- P r; R 4: H; R 5: 3 -F-4-FP h; n = 2)

_{iHNMR (CDC 1 3) <5} : 0. 94 (3H, d, J = 6. 7Hz), 0. 9 8 (3H, d, J = 6. 7Hz), 1. 82- 1. 95 (lH, m), 2.95-3.10 (1H, m), 3.60-3.78 (2H, m), 5.53 (1H, s), 6.63 (1H, d, J = 7 9Hz), 7.00—7.9 (1H, m), 7.13-7.30 (3H, m), 7.45 (1H, d, J = 7.9Hz) FAB-MS (m / e): 386/388 [M + H] + Example 87

Preparation of Compound Example 1208

Jiasutereoma one a (Ar: gC l -Ph j R 'i H j R ^ H j R 3: i-P r; R 4: H; R 5: 3- F- 4- OMe- Ph; n = 2)

_{NMR (CDC 1 3) δ:} 0. 98 (3H, d, J = 6. 8Hz), 0. 9

8 (3H, d, J = 6.8 Hz), 1.72—1.84 (1H, m), 3.26 (1H, dd, J = 11.4, 14.8 Hz), 3.35—3 . 52 (2H, m

), 3.91 (3H, s), 6.07 (1H, s), 6.72 (1H, d, J = 7.5Hz), 6.92-7.05 (2H, m), 7.12-7.27 (2H, m

), 7. 12-7.27 (2H, m), 7.39 (1H, d, J = 8.0Hz) FAB-MS (m / e): 398/400 [M + H] ⁺

Jiasutereoma b (Ar: gC l -Ph j R ^ H j R ^ H j R 3: i-P r; R 4: H; R 5: 3 - F- 4 - OMe- Ph; n = 2)

_{NMR (CDC 1 3) <5} : 0. 93 (3H, d, J = 6. 7Hz), 0. 9

7 (3H, d, J = 6.7Hz), 1.85-1.98 (1H, m), 3.00-3.10 (lH, m), 3.65-3.75 (2H, m ), 3.92 (3H, s), 5.46 (1H, s), 6.68 (1H, d, J = 7.2Hz), 6.9

5-7. 12 (2H, m), 7.22 (1H, t, J = 7.9Hz) FAB-MS (m / e): 398/400 [M + H] + Example 88

Preparation of compound examples 1219 (Ar: 9- CI- Ph RHRHR 3: i -P r; R 4: H; R 5: 3 - 1, 4-nP r NHCOCH £ QP; n = 2

L

_{^ NMR (CDC 1 3) δ} : 0. 94 (3H, d, J = 6. 7Hz), 0. 9 8 (3H, d, J = 6. 7Hz), 1. 01 (3H, t, J = 7.4 Hz), 1.55-1.70 (2H, m), 1.84-1.98 (IH, m), 3.02-3.09 (IH, m), 3.37 (IH, m) t, J = 6.9 Hz), 3.39 (1 H, t, J = 6.9 Hz), 3.65-3.78 (2H, m), 4.55 (2H, s), 5. 48 (1H, s), 6.64 (1H, dd, J = l. 2, 7.9Hz), 6.81 (1H, d, J = 8.4Hz), 7.21 (1H, brs ), 7.22-7.27 (IH, m), 7.30 (1H, dd, J = 2.2, 8.4Hz), 7.45 (IH, dd, J = l.2, 7.9 Hz), 7.77 (1 H, d, J = 2.2 Hz)

FAB-MS (m / e): 591/593 [M + H] ⁺ Example 89

Preparation of compound examples 1220 (Ar: 9_C l- Ph R ^ HR 2:;?!! ^ 3: i -P r; R 4: H; R 5: 3- 1 -4 -MeO-Ph; H; n = 2)

_{^ NMR (CDC 1 3) 6} :. 0. 94 (3H, d, J = 6. 7Hz), 0. 9 8 (3H, d, J = 6. 9Hz), 1. 85-2 00 (1 H , m), 3.02-3.12 (lH, m), 3.68-3.72 (2H, m), 3.91 (3H, s), 5.44 (1H, s), 6. 65-6.69 (1H, m), 6.84 (1H, d, J = 8.5Hz), 7.20-7.27 (2H, m), 7.44 (1H, dd, J = 1.3, 8.1 Hz), 7.76 (IH, d, J = 2.1 Hz) FAB-MS (m / e): 506/508 [M + H] + Example 90

Preparation of Compound Example 1227

Jiasutereoma a (Ar: gF-Ph j R ^ H j R ^ H i R 3: i one ^{P r; R 4: H;} R 5: Ph; n = 2)

_{XHNMR (CDC 1 3) <5} : 0. 98 (3H, d, J = 6. 9Hz), 0. 9 8 (3H, d, J = 6. 9Hz), 1. 70- 1. 85 (1 H , M), 3.00 (1H, dd, J = l 1.1, 14.5Hz), 3.42 (1H, dd, J = 2.3, 14.5Hz), 3.50 (1H , Ddd, 1 = 2.3, 4. 8, 11.1Hz), 5.99 (1H, s), 6.50 (1H, d, J = 7.9Hz), 7.05 (1H, dd) , J = 7.9, 11.0Hz), 7.28-7.45 (6H, m)

FAB-MS (m / e): 334 [M + H] ⁺

Jiasutereoma b (Ar: 9 -F-Ph ; R 1: H; R 2: H; R 3: i-P r; R 4: H; R 5: P h; n = 2)

_{XHNMR (CDC 1 3) δ 0.} 92 (3H, d, J = 6. 7Hz), 0. 9 7 (3H, d, J = 6. 7Hz), 1. 88- 2. 02 (1H, m) , 3.00 — 3.10 (1H, m), 3.60 — 3.75 (2H, m), 5.53 (1H, s), 6.53 (1H, d, J = 7.9 Hz) , 7.11 (1 H, dd, J = 7.9, 10.7 Hz), 7.25-7.45 (6H, m)

 FAB-MS (m / e): 334 [M + H] + Example 91

Preparation of compound examples 1232 (Ar: 9-F- Ph; R 1: H; R 2: H; R 3: i - P r; R 4: H; R 5: 4-MeO-Ph; n = 2)

_{XHNMR (CDC 1 3) d:} 0. 93 (3H, d, J = 6. 7Hz), 0. 9 7 (3H, d, J = 6. 8Hz), 1. 85- 2. 00 (1 H, m), 2.98-3.11 (lH, m), 3.65-3.71 (2H, m), 3.84 (3H, s), 5.48 (1H, s), 6. 56 (1H, d, J = 7.3Hz), 6.93 (2H, d, J = 8.5Hz), 7.05—7.15 (1H, m), 7.24 (2H, d, J = 8.5 Hz), 7.25—7.36 (1H, m) FAB-MS (mZe): 364 [M + H] + Example 92

Preparation of compound examples 1261 (A r: 9 - F - P h; R 1: H; R 2: H; R 3: i one ^{P r; R 4: H;} R 5: 3- 1 -4 -MeO- P; n = 2)

_{^{X HNMR (CDC 1 3) d}} : 0. 94 (3H, d, J = 6. 7Hz), 0. 9

7 (3H, d, J = 6.6 Hz), 1.85-1.98 (lH, m), 3.00-3.10 (lH, m), 3.63-3.70 (2H, m ), 3.91 (3H, s), 5.49 (1H, s), 6.56 (1H, d, J = 7.9Hz), 6.5

8 (1H, d, J = 8.3Hz) 7.10-7.17 (1H, dd, J = 7.9, 8.5Hz), 7.20-7.40 (2H, m), 7 . 78 (1 H, d, J = 2.2 Hz)

 FAB-MS (m / e): 490 [M + H] + Example 93

Preparation of Compound Example 1275

Jiasutereoma a (A r: 7- I one 8- n- P rNHCOCH ₂ 〇 one ^{Ph ^ R 1: H; R} 2: H; R 3: i -P r; R 4: H; R 5: P; n = 2)

_{XHNMR (CDC 1 3) (5} : 0. 95 (3H, t, J = 7. 4Hz), 0. 9 7 (3H, d, J = 7. 5Hz), 0. 97 (3H, d, J = 7.5 Hz), 1.50- 1.68 (2H, m), 1.73-1.88 (1H, m), 3.07 (1H, dd, J = 11.0, 14.1Hz), 3.34 (1H, t, J = 6.7 Hz), 3.36 (1 H, t, J = 6.7 Hz), 3.43 (1 H, dd, J = 2.0, 14.1 Hz ), 3.45-3.52 (1H, m), 4.59 (2H, s), 5.75 (1H, s), 6.86 (1H, brs), 7.10 (1H , s), 7.35-7.48 (5H, m), 7.54 (1H, s)

 FAB-MS (m / e): 557 [M + H] +

Diastereomer b (Ar: 7—I-1 8—n—P rNHC〇CH ₂ PhPh R ^{1 : H; R 2: H;} R 3: i -P r; R 4: H; R 5: P; n = 2) NMR (CDC 1 3) (5: 0. 95 (3H, d, J = 6 8Hz), 0.98 (3H, d, J = 6.8Hz), 1.00 (3H, t, J = 7.3Hz), 1.55-1.70 (2H, m), 1. 90—2.11 (lH, m), 2.95-3.01 (lH, m), 3.36 (1H, t, J = 6.7Hz), 3.38 (1H, t, J = 6.7Hz), 3.42 (1H, dd, J = 9.3, 14.5Hz), 3.49 (IH, dd, J = 3.0, 14.5Hz), 4.61 (2H, s), 5.73 (IH, s), 6.88 (1H, brs), 7.26-7.44 (7H, m), 7.52 (IH, s)

 FAB-MS (m / e): 557 [M + H] + Example 94

Preparation of Compound Example 1276

Jiasutereoma a (Ar: 7- 1 -8 -MeO -Ph j R ^ H j R ^ H j R 3: i -P r; R 4: H; R 5: Ph; n = 2)

_{^{X HNMR (CDC 1 3) (}} 5: 0. 97 (3H, d, J = 6. 9Hz), 0. 9

7 (3H, d, J = 6.9 Hz), 1.75-1.85 (lH, m), 3.08 (IH, dd, J = l 1.2, 14.2 Hz), 3.43 ( IH, dd, J = 2

3, 14.2Hz), 3.48 (1H, ddd, J = 2.3, 5.0, 11.2Hz), 3.95 (3H, s), 5.75 (1H, s) , 7. 08 (1 H, s

), 7.31-7.47 (5H, m), 7.55 (IH, s)

 FAB-MS (mZe): 472 [M + H] +

Diastereomer b (Ar: 7-1 -8 -MeO-Ph j R ^ H j R ^ H j R

³ : i -P r; R ⁴ : H; R ⁵ : Ph; n = 2)

_{NMR (CDC 1 3) δ:} 0. 95 (3H, d, J = 6. 9Hz), 0. 9

8 (3H, d, J = 6.7Hz), 1.88-1.99 (1H, m), 2.98 (1H, ddd, J = 3.0, 5.8, 9.4Hz), 3.41 (IH, dd,

J = 9.4, 14.3 Hz), 3.49 (1H, dd, J = 3.0, 14.3Hz), 3.98 (3H, s), 5.71 (1H, s) , 7.26-7.41 (5 H, m), 7.33 (1H, s), 7.54 (1H, s)

 FAB-MS (m / e): 472 [M + H] + Example 95

Preparation of compound examples 1277 (Ar: Q- Ie-MeQ -Ph i R 1: H; R 2: H; R 3: i -P r; R 4: H; R 5: Ph; n = 2)

_{^{X HNMR (CDC 1 3) δ}} : 0. 96 (. 3H, d, J = 6 9Hz), 0. 9 9 (3H, d, J = 6. 9Hz), 1. 72- 1. 89 (lH, m), 3.10 -3. 33 (3H, m), 3.51 (3H, s), 6.38 (1H, s), 7.18-7.26 (2H, m), 7 26-7.33 (3H, m), 7.79 (1H, d, J = 8.4Hz), 7.99 (1H, d, J = 8.4Hz)

 FAB-MS (m / e): 472 [M + H] + Example 96

Preparation of compound examples 1278 (Ar: 6- I -9- QH-P; R 1: H; R 2: H; R 3: Bok ^{P r; R 4: H;} R 5: Ph; n = 2)

_{^{X HNMR (CDC 1 3) δ}} : 0. 90 (3H, d, J = 6. 6Hz), 0. 9 6 (3H, d, J = 6. 7Hz), 1. 85- 1. 95 (1H, m), 3.00 — 3.10 (lH, m), 3.64 3.71 (2H, m), 4.07 (3H, s), 5.41 (1H, s), 6. 21 (1H, d, J = 8.5Hz), 7.25-7. 45 (5H, m), 7.71 (1H, d, J = 8.5Hz)

 FAB-MS (m / e): 472 [M + H] + Example 97

Preparation of compound examples 1093 (5- (4 one black port - 3-methylphenyl) Single 3-isopropyl one 2, 3, 4, 5 over tetrahydropyran over - 1 ^6, 4 base Nzochiazepi Hmm 1, 1-dione)

2-isopropylaziridine obtained in Step 1 of Example 1 was added to 20 ml of a methanol solution containing 10.0 g (59.5 mmol) of thiosalicylic acid methyl ester. 10 ml was added dropwise over 10 minutes with Ot. After the reaction solution was returned to room temperature and stirred, the reaction solution was concentrated under reduced pressure. To the residue was added 100 ml of a tetrahydrofuran solution, followed by 16.6 ml (119 mmo 1) of triethylamine and 14.2 g (65.4 mmo 1) of t-butyl dicarbonate, followed by stirring for 2 hours. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with a 10% potassium hydrogen sulfate solution and a saturated saline solution, dried over magnesium sulfate, concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. (Hexane: ethyl acetate = 4: 1) to give methyl 2-(-2-{(t-butoxycarbonyl) amino} -1-methylbutyl) sulfanyl) benzoate 12.4 g (yield: 59%) Was obtained as a pale yellow oil.

_{^ NMR (CDC 1 3) δ} : 0. 93 (3H, d, J = 6. 7Hz), 0. 9 7 (3H, d, J = 6. 7Hz), 1. 42 (9H, s), 2 00—2.10 (lH, m), 3.01—3.15 (2H, m), 3.70—3.82 (1H, m), 3.91 (3H, s), 4.71 (1H, bs), 7.12-7.20 (1H, m), 7.39-7.46 (2H, m), 7.92 (1H, d, J = 6.9Hz)

FAB-MS (m / e): 354 [M + H] ⁺

To a methanol solution (100 ml) of methyl 2-((2-((t-butoxycarbonyl) amino) -3-methylbutyl) sulfanyl) benzoate obtained in Step 1 was added ice-cold solution to 100 ml of methanol. Under cooling, 35 ml of a 2 N aqueous sodium hydroxide solution (70. Ommo 1) was added, and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, a 1N aqueous hydrochloric acid solution (40 ml) was added to the obtained residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. . 50 ml of methylene chloride solution was added to the residue, followed by 1-hydroxybenzotriazole 10.0 g (119 mmo 1), 1- (3-dimethylaminopropyl) -13-ethylcarbodiimide hydrochloride 10. 0 g and 8.79 g of N, O-dimethylhydroxylamine hydrochloride were added, and the mixture was stirred for 4 hours. A saturated aqueous solution of ammonium chloride was added to the organic reaction solution, extracted with ethyl acetate, and the organic layer was washed with a 10% potassium hydrogen sulfate solution and a saturated saline solution. Dried under reduced pressure and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give t-butyl N- (1-{({2-({methoxy (methyl) amino} carbonyl) carbonyl) phenyl. 8.15 g (yield: 60%) of the compound {l-sulfanyl) methyl} -1-methylpropyl) caprate were obtained as a pale yellow oil.

_{^{X HNMR (CDC 1 3) 8}} : 0. 89 (3H, d, J = 6. 6Hz), 0. 9 0 (3H, d, J = 6. 8Hz), 1. 36 (9H, s), 1 82-2. 00 (1H, m), 3.01-3. 20 (3H, m), 3.32 (3H, bs), 3.53 (3H, bs), 5.08 (1H, bs) ), 7.21-7.27 (2H, m), 7.27-7.38 (1H, m), 7.54 (1H, d, J = 7.5Hz)

 FAB-MS (mZe): 383 [M + H] +

 T-Butyl N- (1 — {({2-({methoxy (methyl) amino} carbonyl) phenyl) sulfanyl) methyl} -12-methylpropyl) -capillate obtained in step 2 150 mg (0.39 mm 01) in a tetrahydrofuran solution (2 ml) and magnesium solution 117 mg (4.2 mmo 1) and 2-bromo-1-5-805-bromotoluene 805 mg (3.9 mmo 1) in a tetrahydrofuran solution (5 ml) ) Was added dropwise at −78 ° C. over 10 minutes under a nitrogen atmosphere. After stirring the reaction solution at -70 ° C for 2.5 hours, a saturated aqueous solution of ammonium chloride was added to the reaction solution. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with a saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1), and t-butyl N— (1 — {({2 -— (4-chloro-1,3-methylbenzoyl) phenyl) {Sulfanyl) methyl} -1-methylpropyl) lubamate 107 mg (yield: 61%) was obtained as a pale yellow oil.

_{^{X HNMR (CDC 1 3) δ}} : 0. 84 (3Η, d, J = 6. 8Hz), 0. 8

4 (3H, d, J = 6.8 Hz), 1.37 (9H, s), 1.75—1.85 (lH, m), 2.29 (3H, s), 2.95-3. 05 (2H, m), 3.

50-3.60 (1H, m), 4.75 (1H, bs), 7.26-7.31 ( 2H, m), 7.39 -7.59 (4H, m), 7.68 (1H, d, J = 1.9Hz)

 FAB-MS (m / e): 449 [M + H] +

T-butyl N- (111-(({2- (4-chloro-3-methylpentenezyl) phenyl} sulfanyl) methyl} —2-methylpropyl) obtained in step 3 Carbamate 68 mg (0.15 mm To 1) was added a 4N hydrogen chloride 1,4-dioxane solution (3.0 ml), the mixture was stirred at room temperature overnight, and the reaction solution was concentrated under reduced pressure. 2,6-Lutidine (3.0 ml) was added to the residue, and concentrated hydrochloric acid (1.0 ml) was added. After the addition was completed, the mixture was azeotropically distilled for 3 hours and distilled under reduced pressure. The residue was collected with a saturated aqueous solution of sodium hydrogen carbonate, and the solution was extracted twice with ethyl acetate. The combined extracts were washed with saturated brine solution, dried and concentrated under reduced pressure. To the residue was added a solution of trifluoroacetic acid (3.0 ml), and 30% aqueous hydrogen peroxide (1.0 ml) was added at a temperature of about 0 ° C. After the addition was completed, the mixture was stirred at room temperature overnight, treated with a 10% aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution, extracted twice with ethyl acetate, and the combined extracts were washed with a saturated saline solution. Dry and concentrate under reduced pressure. To the residue was added a 4 N salt / hydrogen 1,4-dioxane solution (3.0 ml), and zinc powder (200 mg) was gradually added. The mixture was stirred overnight at room temperature, treated with saturated aqueous sodium bicarbonate and filtered through celite. The mixture was extracted twice with ethyl acetate, and the combined extracts were washed with a saturated aqueous solution of sodium chloride, dried and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel using hexane / ethyl acetate (4: 1) as an eluent to give 5- (4-chloro-3-methylphenyl) -13-isopropyl-1,2,3,4, 5 one-tetrahydro - Iff- 1 λ ^6, was obtained as a 4 _ benzothiazepine one 1, 1-dione of Jiasu Tereoma a (12. 8 mg) and b (22. 3 mg) as a pale yellow oily product.

Diastereomer a

_{^{X HNMR (CDC 1 3) δ}} : 0. 98 (3Η, d, J = 6. 9Hz), 0. 9 8 (3H, d, J = 6. 9Hz), 1. 75 - 1. 89 (1 H , m), 2.40 (3H, s), 3.05 (1H, dd, J = 11.3, 14.2 Hz), 3.44 (1H, dd, J = 2.3, 14.2 Hz ), 3.50 (1 H, ddd, J = 2.3, 4.8, 11.3Hz), 5.85 (1H, s), 7.18 (1H, dd, J = 2.2, 8.2Hz), 7.26 (1H , d, J = 2.2 Hz), 7.36-7.43 (3H, m), 8.13-8.17 (lH, m)

 FAB-MS (m / e): 364 [M + H] +

Geostereomer b

_{^ NMR (CDC 1 3) d} : 0. 95 (3H, d, J = 6. 8Hz), 0. 9 9 (3H, d, J = 6. 8Hz), 1. 90- 2. 05 (1H, m), 2.37 (3H, s), 2.98 (1 H, ddd, J = 3.5, 5.9, 8.9 Hz),

3.43 (1H, dd, J = 8.9, 14.3Hz), 3.49 (1H, dd, J = 3.5, 14.3Hz), 5.80 (1H, s), 6. 89— 6. 94 (1

H, m), 7.09 (1H, dd, J = 2.1, 8.3Hz), 7.19 (1H, d, J = 2.1Hz), 7.33 (1H, d, J = 8 3 Hz), 7.45-7.52 (2H, m), 8.13—8.18 (1H, m)

 FAB-MS (m / e): 364 [M + H] + The physical constants of the compound obtained in the same manner as in Example 97 are shown below.

Example 98

Production of Compound Example 1008 (Ar:? !!;! ^ ¹ : !!;! ^ ² :! ^;! ^ ³ : i—P r; R ⁴ : H; R ⁵ : 4-Pyri dy 1; n = 0)

_{'HNMR (CDC 1 3) δ} : 0. 95. (3H, d, J = 6. 7Hz), 0. 9 8 (3H, d, 1 = 6. 6Hz), 1. 63- 1. 80 (lH , M), 2.41 (1H, dd, J = 10.9, 14.0 Hz), 2.91 (1H, dd, J = 2.2, 14.0 Hz), 2.96-3.04 (1H, m), 5.75 (1H, s), 6.5 1—6.54 (1H, m), 7.15-7.19 (2H, m), 7.41 (2H, d , J = 6.1 Hz), 7.67-7.71 (1H, m), 8.61 (2H, d, J = 6.1Hz)

FAB-MS (m / e): 285 [M + H] ⁺ Example 99 Preparation of Compound Example 1018

Diastereomer a (Ar i Ph i R ^ H ^^ H, ^ ³ -P r: R ⁴ : H; R ⁵ : 4-Me -Ph; n = 2)

_{^ NMR (CDC 1 3) (} 5: 0. 97 (3H, d, J = 6. 8Hz), 0. 9 7 (3H, d, J = 6. 8Hz), 1. 70 - 1. 87 (lH , M), 2.40 (3H, s), 3.07 (1H, dd, J = 11.4, 14.3 Hz), 3.42 (1H, dd, J = 2.3, 14.3 Hz ), 3.52 (1H, ddd, J =

2, 3, 4.9, 11.4 Hz), 5.82 (1H, s), 6.71-6.75 (1H, m), 7.21-7.30 (4H, m), 7 32-7. 41 (2H, m), 8.12-8. 16 (1H, m)

 FAB-MS (m / e): 330 [M + H] +

Jiasutereoma ^{b (Ar: Ph; R 1} : H; R 2: H; R 3: i- P r; R 4: H; R 5: 4- Me - Ph; n = 2)

_{XHNMR (CDC 1 3) δ:} 0. 96 (3H, d, J = 6. 9Hz), 0. 9 9 (3H, d, J = 6. 7Hz), 1. 93 - 2. 00 (1 H, m), 2.37 (3H, s), 2.96 (1H, ddd, J = 3.6, 5.7, 8.9 Hz),

3.44 (1H, dd, J = 8.9, 14.3Hz), 3.47 (1H, dd, J = 3.6, 14.3Hz), 5.80 (1H, s), 6 91-6. 95 (1 H, m), 7.16-7.23 (4H, m), 7.43-7.49 (2H, m), 8.13-8.17 (1H, m) )

 FAB-MS (m / e): 330 [M + H] + Example 100

Preparation of Compound Example 1019

Diastereomer a (A r: Ph RH; ² : H: R ³ : i -P r; R ⁴ : H; R ⁵ : 3 -Me -Ph; n = 2)

_{XHNMR (CDC 1 3) (5} : 0 97 (3H, d, J = 6. 8Hz), 0. 9 8 (3H, d, J = 6. 9Hz), 1. 73 - 1. 88 (1H, m ), 2.38

(3H, s), 3.07 (1H, dd, J = l 1.4, 14.3 Hz), 3.4 2 (1H, dd, J = 2.2, 14.3Hz), 3.52 (1H, ddd, J =

2, 2, 4. 9, 1 1.4 Hz), 5.83 (1 H, s), 6.70-6.74 (lH, m), 7.12-7.22 (3H, m), 7.27-7. 41 (3H, m), 8.12-8.16 (1H, m)

 FAB-MS (m / e): 330 [M + H] +

Jiasutereoma b (A r: P h; R 1: H; R 2: H; R 3: i one ^{P r; R 4: H;} R 5: 3 - Me- Ph; n = 2)

_{^ NMR (CDC 1 3) 6} : 0. 95 (3H, d, J = 6. 9Hz), 0. 9 9 (3H, d, J = 6. 7Hz), 1. 92- 2. 04 (1 H , M), 2.36 (3H, s), 2.96 (1H, ddd, J = 3. 7, 5. 9, 8.9 Hz),

3.46 (1H, dd, J = 8.9, 14.3Hz), 3.50 (1H, dd, J = 3.7, 14.3Hz), 5.80 (1H, s), 6 88-6. 92 (1 H, m), 7.11-7. 17 (3H, m), 7.25—7.31 (lH, m)

, 7.43-7.50 (2H, m), 8.12-8.16 (lH, m)

 FAB-MS (m / e): 330 [M + H] + Example 101

Preparation of Compound Example 1024

Jiasutereoma ^{a (Ar: Ph; R 1} : H; R 2: H; R 3: i -P r; R 4: H; R 5: 3-Ph-Ph; n = 2)

_{^{X HNMR (CDC 1 3) δ}} : 0. 99 (3Η, d, J = 6. 6Hz), 0. 9 9 (3H, d, J = 6. 6Hz), 1. 75- 1. 85 (1 H , m), 3.10 (1H, dd, J = 1.17, 14.1 Hz), 3.45 (1H, dd, J = 2.1, 14.1 Hz), 3.51-3. 58 (1H, m), 5.97 (1H, s), 6.78 (1H, dd, J = 2.1, 6.3Hz), 7.30—7.70 (11H, m), 8. 10-8. 20 (1 H, m)

 FAB-MS (m / e): 392 [M + H] +

Jiasutereoma ^{b (Ar: Ph; R 1} : H; R 2: H; R 3: ί -P r; R 4: H; R 5: 3-Ph-Ph; n = 2) _{^{X HNMR (CDC 1 3) δ}} : 0. 97 (3H, d, J = 6. 9Hz), 1. 0 1 (3H, d, J = 6. 5Hz), 1. 95- 2. 03 (1 H , M), 2.98-3.18 (IH, m), 3.45-3.56 (2H, m), 5.92 (IH, s), 6.96-6.99 (IH, dd , J = 3.6, 5.5 Hz), 7.28-7.60 (11 H, m), 8.16 (1H, dd, J = 3.5, 5.5 Hz)

FAB-MS (m / e): 392 [M + H] + Example 102

Preparation of Compound Example 1026

Jiasutereoma a (Ar r Ph j R ^ H j R ^ H j R 3 one ^{P r; R 4: H;} R 5: 4-C l -Ph; n = 2)

_{iHNMR (CDC 1 3) d:} 0. 98 (3H, d, J = 6. 9Hz), 0. 9 8 (3H, d, J = 6. 9Hz), 1. 73- 1. 88 (1 H, m), 3.05 (IH, dd, J = l 1.6, 14.5Hz), 3.45 (1H, dd, J = 2.3, 14.5Hz), 3.49 (1H, ddd, J = 2, 3, 4.9, 11.6 Hz), 5.91 (1H, s), 6.60-6.70 (1H, m), 7.31-7.42 (6H, m), 8.12—8.17 (lH, m)

 FAB-MS (m / e): 350/352 [M + H] +

Ge stereomer b

(Ar: Ph; R ^x : H; R ² H; R ³ : i -P r; R ⁴ : H; R ⁵ : 4-C 1-Ph; n = 2)

_{iHNMR (CDC 1 3) δ:} . 0 95 (3H, d, J = 6. 9Hz), 0. 9 9 (3H, d, J = 6. 8Hz), 1. 88 -2 00 (IH, m) , 3.00 (IH, ddd, J = 3.5, 5.6, 8.9 Hz), 3.41 (1H, dd, JJ == 88..99 ,, 1144 .. 33HHzz)), 33..44 (1H, dd, J = 3.5, 14.3Hz), 5.83 (1H, s), 6.90-6.94 (IH, m), 7.26 (2H , d, J = 8.6 Hz), 7.34 (2H, d, J = 8.6 Hz), 7.46 -7.53 (2H, m), 8.14-8.18 (lH, m)

FAB-MS (m / e): 350/352 [M + H] + Example 103

Preparation of Compound Example 1083

Jiasutereoma a (Ar: P h; R 1: H; R 2 H; R: i -P r; R 4: H; R 5: 3-Me-4-Me-Ph; n = 2)

_{^{X HNMR (CDC 1 3) d}} : 0. 98 (3H, d, J = 6. 9Hz), 0. 9 8 (3H, d, J = 6. 9Hz), 1. 72 - 1. 90 (1H, m), 1.95 (3H, s), 2.30 (3H, s), 3.06 (1H, dd, J = l1.4, 14.3Hz), 3.44 (1H, dd, J = 2.2, 14.3 Hz), 3.53 (1 H, dd d, J = 2, 2, 4. 9, 11.1 Hz), 6.09 (1 H, s), 6. 60- 6.64 (1H, m), 7.16—7.26 (2H, m), 7.31 -7.42 (2H, m), 7.46 (1H, d, J = 7.7Hz ), 8. 1 2-8. 16 (1H, m)

 FAB-MS (m / e): 344 [M + H] +

Diastereomer b (Ar Ph j R ^ H j R ^ H j R ³ : i-Pr; R ⁴ : H; R ⁵ : 3-Me-4-Me-Ph; n = 2)

_{HNMR (CDC 1 3) δ:} 0. 95 (3H, d 6. 8Hz), 0. 9

8 (3H, d, J = 6.8 Hz), 1.96 (3H, s), 1.96-2.1 1 (1 H, m), 2.29 (3H, s), 2.77- 2.90 (1H, m), 3.56—3.68 (2H, m), 6.04 (1H, s), 6.69-6.73 (1H, m), 7.19- 7.26 (3H, m), 7.38—7.51 (2H, m), 8.08-8.12 (1H, m)

 FAB-MS (m / e): 344 [M + H] + Example 104

Preparation of Compound Example 1084

Jiasutereoma a (Ar ^ hj R ^ H i R 'r H j R 3 i -P r; R 4: H; R 5: 2- Me- 4- Me- Ph; n = 2)

_{NMR (CDC 1 3) δ:} 0. 98 (3H, d, J = 6. 8Hz), 0. 9 8 (3H, d, J = 6.8 Hz), 1.76-1.83 (lH, m), 2.03 (3H, s), 2.37 (3H, s), 3.05 (1H , Dd, J = l 1.5, 14.3Hz), 3.45 (1H, dd, J = 2.1, 14.3Hz), 3.52 (IH, ddd, J = 2, 1, 4.5, 11.5Hz), 5.99 (1H, s), 6.63-6.66 (lH, m), 7.02 (1H, s) 7.14 (IH, d, J = 8.0Hz), 7.31-7.42 (2H, m) 745 (IH, d, J = 8.0Hz), 8.12-8.15 (lH, m)

 FAB-MS (mZe): 344 [M + H] +

Jiasutereoma ^{b (Ar: Ph; R 1} : H; R 2: H; R 3: i- P r; R 4: H; R 5: 2 -Me -4 -Me -Ph; n = 2)

_{^ NMR (CDC 1 3) δ} :. 0. 94 (3H, d, J = 6. 8Hz), 0. 9 7 (3H, d, J = 6. 8Hz), 1. 98-2 10 (lH, m), 2.205 (3H, s), 2.36 (3H, s), 2.76-2.83 (1H, m), 3.55-3.59 (2H, m), 5 95 (IH, s), 6.71-6.75 (1H, m), 7.03 (IH, s), 7.12 (1H, d, J = 8.2Hz), 7.38- 7.47 (2H, m), 7.44 (1H, d, J = 8.2Hz), 8.08—8.12 (IH, m)

FAB-MS (m / e): 344 [M + H] ⁺ Example 105

Preparation of Compound Example 1085

Jiasutereoma ^{a (Ar: Ph; R 1} : H; R 2: H; R 3: i one ^{P r; R 4: H;} R 5: 2- e-5-Me-Ph; n = 2)

_{XHNMR (CDC 1 3) δ:} 0. 99 (3H, d, J = 6. 8Hz), 1. 0 0 (3H, d, J = 6. 9Hz), 1. 77 - 1. 90 (lH, m ), 2.02 (3H, s), 2.40 (3H, s), 3.05 (1H, dd, J = l 1.5,14.4Hz), 3.47 (1H, dd, J = 2.2, 14.4Hz), 3.53 (IH, ddd, J = 2, 2, 4. 9, 11.5Hz), 6.00 (1H, s), 6.61-6 . 65 (IH, m), 7.07 (1H, d, J = 1.1 Hz) , 7.07 (1H, d, J = 1. lHz), 7.32-7.42 (2H, m), 7.37 (1H, d, J = 1.1 Hz), 8.12-8 . 16 (1H, m)

FAB-MS (m / e): 344 [M + H] +

Diastereomer b (Ar i Ph j R ^ H j R ^ H i R ³ : i- 1 Pr; R ⁴ : H; R ⁵ : 2-Me-5-Me-Ph; n = 2)

_{^ NMR (CDC 1 3) δ} ·· 0. 96 (3H, d, J = 6. 9Hz), 0. 9 9 (3H, d, J = 6. 8Hz), 2. 00- 2. 12 (1 H, m), 2.03 (3H, s), 2.39 (3H, s), 2.81 (1H, ddd, J = 3.8, 6.0, 8.4 Hz), 3.56 (1H, dd, J = 8.4, 14.1Hz), 3.59 (1H, dd, J = 3.8, 14.1Hz), 5.95 (1H, s), 6.70- 6.74 (1H, m), 7.08 (2H, s), 7.36 (1H, s), 7.38-7.48 (2H, m), 8.08-8.12 (1 H, m)

 FAB-MS (m / e): 344 [M + H] + Example 106

Preparation of Compound Example 1087

Jiasutereoma a (Ar: P h; R 1: H; R 2: H; R 3: i- P r; R 4: H; R 5: 3-Me-4-Me-Ph; n = 2)

_{^ NMR (CDC 1 3) (} 5: 0. 97 (3H, d, J = 6. 9Hz), 0. 9 7 (3H, d, J = 6. 9Hz), 1. 75 - 1. 89 (1H , m), 2.29 (3H, s), 2.30 (3H, s), 3.07 (1 H, dd, J = l 1.4, 14.3 Hz), 3.42 (1 H, s) dd, J = 2.2, 14.3 Hz), 3.51 (1H, ddd, J = 2, 2, 4.9, 11.4 Hz), 5.78 (1H, s), 6.73- 6.77 (1H, m), 7.11-7.21 (3H, m), 7.33-7.40 (2H, m), 8.11-8.15 (1H, m)

 FAB-MS (m / e): 344 [M + H] +

Jiasutereoma one ^{b (Ar: P; R 1} : H; R 2: H; R 3: i - P r; 4: H; R 5: 3- Me - 4 one Me- Ph; n = 2)

_{^ NMR (CDC 1 3) δ} : 0. 95 (3H, d, J = 6. 8Hz), 0. 9 8 (3H, d, J = 6.8 Hz), 1.93-2.06 (lH, m), 2.26 (3H, s), 2.28 (3H, s), 2.96 (1H , Ddd, J = 3.6,

5.8, 9.0Hz), 3.45 (1H, dd, J = 9.0, 14.5Hz), 3.51 (IH, dd, J = 3.6, 14.5Hz), 5. 76 (1H, s),

6.91-6.94 (1H, m), 7.04 (1H, dd, J1.6, 7.8 Hz), 7.10 (1H, s), 7.14 (1H, d, J = 7.8Hz), 7.42-7.49 (2H, m), 8.12—8.16 (1H, m)

 FAB-MS (mZe): 344 [M + H] + Example 107

Preparation of Compound Example 1090

Diastereomer a (Ar i Ph j R ^ H j R 'i H j R ³ : i-P r; R ⁴ : H; R ⁵ : 3 -F, 4-Me-Ph; n = 2)

_{XHNMR (CDC 1 3) δ:} 0. 97 (3H, d, J = 6. 8Hz), 0. 9 8 (3H, d, J = 6. 7Hz), 1. 70- 1. 90 (lH, m ), 2.31 (3H, s), 3.05 (IH, dd, J = l 1.4, 14.4Hz), 3.43 (1H, dd, J = 2.3, 14.4Hz) , 3.47-3.55 (1H, m), 5.88 (1H, s), 6.71-6.74 (1H, m), 7.03 (1H, dd, J = 1 5, 7.7 Hz), 7.11 (1H, dd, J = l. 5, 10.6Hz), 7.20 (IH, dd, J = 7.7, 10.6Hz), 7.37 — 7.41 (2H, m), 8.12-8. 16 (lH, m)

 FAB-MS (m / e): 348 [M + H] +

Diastereomer b (Ar r Ph j R ^ H j R ^ H i R ³ : i-Pr; R ⁴ : H; R ⁵ : 3-F, 4-Me-Ph; n = 2)

_{XHNMR (CDC 1 3) δ:} 0. 95 (3H, d, J = 6. 7Hz), 0. 9 9 (3H, d, J = 6. 7Hz), 1. 90- 2. 11 (1 H, m), 2.28 (3H, s), 2.97-3.05 (1H, m), 3.35—3.50 (2H, m), 5.81 (IH, s), 6. 92-7.00 (2H, m), 7.03 (1H, d, J = 10.8 Hz), 7.16 (1H, dd, J = 7.7, 10.8H z), 7.49-7.51 (2H, m), 8.14-8.17 (1H, m) FAB-MS (mZe): 348 [M + H] + Example 108

Preparation of Compound Example 1092

Jiasutereoma one ^{a (Ar: Ph; R 1} : H; R 2: H; R 3: i - P r; R 4: H; R 5: 4-F-3-Me-Ph; n = 2)

_{^{X HNMR (CDC 1 3) δ}} : 0. 97 (3H, d, J = 6. 9Hz), 0. 9 7 (3H, d, J = 6. 9Hz), 1. 75- 1. 85 (1 H , m), 2.30 (3H, d, J _f _H = 1-9 Hz), 3.06 (1 H, dd, J = 11.3, 14.2 Hz), 3.44 (1H, dd, J = 2.3, 14.2 Hz), 3.49 (1H, ddd, J = 2, 3, 4. 9, 11.3 Hz), 5.83 (1H, s), 6.69 -6.74 (1H, m), 7.01-7.08 (lH, m), 7.15-7.22 (2H, m), 7.36-7.43 (2H, m), 8.12— 8.16 (1 H, m)

 FAB-MS (m / e): 348 [M + H] +

Jiasutereoma one b (Ar: P j R ^ H i R 'H j R 3: i- P r; R 4: H; R 5: 4-F-3-Me-Ph; n = 2)

_{^ NMR (CDC 1 3) (} 5:. 0. 95 (3H, d, J = 6. 8Hz), 0. 9 9 (3H, d, J = 6. 7Hz), 1. 88-2 03 (1 H, m), 2.27 (3H, d, J p_H = 1.9 Hz), 2.97 (1 H, ddd, J = 3.5, 5.7, 9.0 Hz), 3.43 (1 H, dd, J = 9.0, 14.3 Hz), 3.47 (1 H, dd, J = 3.5, 14.3 Hz), 5.79 (1 H, s), 6.89-6 .91 (lH, m), 6.91-7.03 (lH, m), 7.07-7.17 (2H, m), 7.45-7.51 (2H, m), 8.13 — 8. 17 (1H, m)

FAB-MS (mZe): 348 [M + H] ⁺ Example 109 " Preparation of Compound Example 1094

Jiasutereoma a (Ar: Ph i R ^ H j R ^ H j R 3: i -P r; R 4: H; R 5: 3 -F, 4-F-Ph; n = 2)

_{^{X HNMR (CDC 1 3) δ}} : 0. 98 (3H, d, J = 6. 4Hz), 0. 9 9 (3H, d, J = 6. 4Hz), 1. 75 - 1. 85 (lH, m), 3.04 (1H, dd, J = l 1.9, 14.2Hz), 3.46 (1H, dd, J = 2.2, 14.2Hz), 3.45-3.54 ( 1 H, m), 5.93 (1H, s), 6.65-6.90 (2H, m), 7.05-7.20 (2H, m), 7.39-7.48 (2H , M), 8.13-8.20 (1 H, m)

 FAB-MS (m / e): 352 [M + H] +

Diastereomer b (Ar Ph j R ^ H j R 'r H j R ³ : i -P r; R ⁴ : H; R ⁵ : 3 -F, 4-F-Ph; n = 2)

 HNMR (CDC 1 J 6: 0.96 (3H, d, J = 6.9 Hz) 0

1 (3H, d, J = 6.4Hz), 1.88—1.99 (1H, m), 2.97 1 3.05 (1H, m), 3.35—3.42 (2H, m ), 5.83 (1H, s), 6.95-7.01 (2H, m), 7.05-7.25 (2H, m), 7.50-7.55 (2H, m), 8. 15-8. 20 (1 H, m)

 FAB-MS (m / e): 352 [M + H] + Example 110

Preparation of Compound Example 1095

Diastereomer a (Ar i Ph j R ^ H ^ 'r H ^ ³ : i -P r; R ⁴ : H; R ⁵ : 3 -F, 4-C 1 -Ph; n = 2)

_{XHNMR (CDC 1 3) δ:} 0. 99 (3H, d, J = 7. 0Hz), 1. 0 0 (3H, d, J = 7. 0Hz), 1. 75 - 1. 90 (1H, m ), 3.05 (1H, dd, J = l 1.4, 14.8 Hz), 3.46 (1H, dd, 1 = 2.3, 14.8 Hz), 3.45-3.52 (lH , M), 5.96 (1H, s), 6.70-6.77 (1H, m), 7.11 (1H, d, J = 8.3Hz), 7.30 (1H, dd, J = l. 7, 8.3 Hz), 7.39-7.47 (3 H, m), 8.14-8.17 (1H, m)

 FAB-MS (mZe): 368/370 [M + H] +

Diastereomer b (Ar i Ph j R ^ H j R ^ H j R ³ i -P r; R ⁴ : H

R ⁵ : 3 -F, 4-C 1 -Ph; n = 2)

'HNMR (CDC 1 ₃ ) (5: 0.96 (3H, d, J = 7.0 Hz), 0 1 (3H, d, J = 7.0 Hz), 1.90-2.00 (1 H, m), 2.98 -3.07 (lH, m), 3.35—3.42 (2H, m), 5.80 (1H, s), 6.92-6.97 (1H, m ), 6.99 (1H, d, J = 8.2Hz), 7.18 (1H, d, J = 10.2Hz), 7.36 (1H, dd, J = 8.2, 10. 2Hz), 7.48-7.55 (2H, m), 8.12-8.20

(1H, m)

 FAB-MS (mZe): 368/370 [M + H] + Example 1 1 1

Preparation of Compound Example 1096

Jiasutereoma a (Ar: P j R ^ H j R 'i H j R 3: i- P r; R 4: H

R ⁵ : 3-Cl-4-Cl-Ph; n = 2)

_{iHNMR (CDC 1 3) δ:} 0. 98 (3H, d, J = 6. 9Hz), 0. 9

9 (3H, d, J = 6.6 Hz), 1.77—1.84 (1H, m), 3.04 (1H, dd, J = 1 1.8, 14.6 Hz), 3.46 ( 1 H, dd, J = 2

3, 14.6 Hz), 3.45-3.52 (lH, m), 5.94 (1H, s

), 6.69-6.73 (1H, m), 7.22 (1H, dd, J = l. 9, 8

3 Hz), 7.39-7.44 (2H, m), 7.48 (1H, d, J = 8.

3Hz), 7.56 (1H, d, J = l. 9Hz), 8.14-8.18 (1H, m)

FAB-MS (m / e): 384/386 [M + H] ⁺

Jiasutereoma ^{b (Ar: P; R x} : H; R 2: H; R 3: i -P r; R 4: H; R 5: 3-C 1 -4-C 1 -Ph; n = 2)

_{NMR (CDC 1 3) δ:} 0. 96 (3H, d, J = 6. 9Hz), 1. 0 1 (3H, d, J = 6.8 Hz) 1.87- 1.98 (1 H, m), 3.02 (IH, d dd, J = 3.6, 5, 5, 8.9 Hz), 3 38 (1H, dd, J = 8.9, 14.4Hz), 343 (IH, dd, J = 3.6, 14.4Hz), 5.83 (IH, s), 693- 6.97 (1H, m), 7.08 (1H, dd, J = 1.9, 8.3Hz), 7.42 (1H, d, J = 8.3Hz), 7.48 (IH , d, J = l. 9Hz), 7.50-7.56 (2H, m), 8.15-5.19 (IH, m)

FAB-MS (m / e): 384/386 [M + H] ⁺ Example 112

Preparation of Compound Example 1 100

Jiasutereoma a (Ar: P h; R 1: H; R 2: H; R 3 i -P r; R 4: H; R 5: 3 -Me, 4-Me OP h; n = 2)

_{NMR (CDC 1 3) (5} : 0. 97 (3H, d, J = 6. 7Hz), 0. 9 8 (3H, d, 1 = 6. 8Hz), 1. 75 - 1. 85 (1 H , m), 2.24 (3H, s), 3.07 (1H, dd, J = 1 1., 14.3 Hz), 3.42 (IH, dd, J = 2.2, 14.3 Hz), 3.50 (1H, ddd, 2.2, 4.8, 11.4Hz), 3.86 (3H, s), 5.75 (1H, s), 6.75-6 78 (1H, m), 6.86 (IH, d, J = 8.4 Hz), 7.14 (1H, d, J = 2.0 Hz), 7.19 (1H, dd, J = 2 0, 8 • 4Hz), 7.35-7.38 (2H, m), 8.11-8.14 (1H, m)

 FAB-MS (m / e) 360 [M + H] +

Jiasutereoma ^{b (A r P; R 1} : H; R 2: H; R 3: i -P r; R 4: H; R 5: 3- Me, 4-MeO-Ph; n = 2)

_{^{X HNMR (CDC 1 3) 6}} : 0. 95 (3H, d, J = 6. 7Hz), 0. 9 8 (3H, d, J = 6. 8Hz), 1. 95 - 2. 05 (lH, m), 2.21 (3H, s), 2.92-3. 01 (lH, m), 3.40—3.55 (2H, m), 3.84 (3H, s), 5. 76 (IH, s), 6.82 (1 H, d, J = 8.3 Hz), 6.92-6.96 (1 H, m), 7.08 (IH, dd, J = 2.3, 8.3 Hz), 7.12 (1H, d, J = 2 3 Hz), 7.44-1 7.47 (2H, m), 8.12—8.15 (lH, m)

 FAB-MS (m / e): 360 [M + H] + Example 113

Preparation of Compound Example 1 103

Jiasutereoma a (Ar i Ph i R ^ H j R ^ H i R 3 i -P r; R 'H; R 5: 3-MeO-4-MeO-Ph; n = 2)

_{^ NMR (CDC 1 3) (} 5: 0. 99 (3H, d, J = 6. 8Hz), 0. 9 9 (3H, d, J = 6. 8Hz), 1. 72 - 1. 87 (lH , M), 3.08 (1H, dd, J = 11.4, 14.3Hz), 3.44 (IH, dd, J = 2.0, 14.3Hz), 3.52 (1H, ddd , J = 2, 0, 5.0, 11.4 Hz), 3.86 (3H, s), 3.93 (3H, s), 5.80 (1H, s), 6.75-6.80 (1H, m), 6.89 (1H, d, J = 1.7Hz), 6.93 (IH, d, J = 8.3Hz), 7.00 (1H, dd, J = 1.7) , 8.3 Hz), 7.38-7.43 (2H, m), 8.13—8.16 (1H, m)

FAB-MS (m / e): 376 [M + H] ⁺

Diastereomer b (Ar i Ph i RH j R ^ H j R ³ : i -P r; R ⁴ : H; R ⁵ : 3-MeO-4-MeO-Ph; n = 2)

_{^ NMR (CDC 1 3) δ} : 0. 96 (3H, d, J = 6. 8Hz), 1. 0 0 (3H, d, J = 6. 8Hz), 1. 92- 2. 07 (1 H , m), 2.98

(1H, ddd, J = 3.5, 5, 7, 9.2Hz), 3.45 (1H, dd, J = 9.2, 14.4.4Hz), 351 (IH, dd, J = 3. 5, 14.4Hz), 3.84 (3H, s), 390 (3H, s), 5.80 (IH, s), 6.83 (1H, dd, J = l. 7, 8. 4Hz), 6.87 (1H, d, J = 8.4Hz), 6.92 (1H, d, J = 1.7Hz), 6.93-6.97 (IH, m), 7.44- 7.51 (2H, m), 8.13-8.17 (1H, m FAB-MS (m / e): 376 [M + H] + Example 114

Preparation of Compound Example 1 104

R ¹ : H; R ² : H; ³ : i-Pr; R ⁴ : H; R ⁵ : 3, 4-Methylene dioxy 1 -Ph; n = 2)

_{^ NMR (CDC 1 3) (} 5: 0. 97 (3H, d, J = 6. 8Hz), 0. 9 7 (3H, d, J = 6. 8Hz), 1. 73- 1. 88 (1 H, m), 3.05 (1H, dd, J = 11.4, 14.3Hz), 3.43 (1H, dd, J = 2.2, 14.3Hz), 3.46-3. 53 (lH, m), 5.79 (1H, s), 6.00 (2H, s), 6.78-6.83 (lH, m), 6.84—6.90 (3H, m ), 7.37—7.41 (2H, m), 8.11—8.15 (1H, m)

 FAB-MS (m / e): 360 [M + H] +

Jiasutereoma ^{b (Ar: Ph; R 1} : H; R 2: H; R 3: i one ^{P r; R 4: H;} R 5: 3, 4-Me t hy 1 enedi oxy 1 - Ph; n = 2 )

_{^{X HNMR (CDC 1 3) 6}} : 0. 96 (3H, d, J = 6. 8Hz), 0. 9 9 (3H, d, J = 6. 8Hz), 1. 90- 2. 04 (lH, m), 2.98 (1H, ddd, J = 3.5, 5. 7, 9.1Hz), 3.43 (1H, dd, J = 9.1, 14.1Hz), 3.48. (1H, dd, J = 3.5, 14.1 Hz), 5.77 (1H, s), 5.99 (2H, s), 6.75 (1H, dd, J = 1.5 , 8.0Hz), 6.80 (1H, d, J = 8.0Hz), 6.87 (1H, d, J = l. 5Hz), 6.95-6.99 (lH, m), 7.46-7.51 (2H, m), 8.12-8.16 (1H, m)

 FAB-MS (m / e): 360 [M + H] + Example 115

Preparation of Compound Example 1105 Jiasutereoma one a (Ar: Ph j R ^ H i R 'i H j R 3: i one ^{P r; R 4: H;} R 5: 3, 4-E t hy l en edi oxy l -Ph; n = 2)

_{XHNMR (CDC 1 3) δ 0.} 97 (3H, d, J = 6. 9Hz), 0. 9

7 (3H, d, J = 6.9 Hz), 1.70—1.85 (1 H, m), 3.05 (1H, dd, J = 1 1.5, 14.3 Hz), 3.41 (IH, dd, J = 2

.2, 14.3Hz), 3.50 (1H, ddd, J = 2, 2, 4.8, 11.5Hz), 4.30 (4H, s), 5.76 (1H, s) ), 6.78-6.83 (lH, m), 6.83 (IH, dd, J = l. 9, 8.3Hz), 7.35—7.42 (2H, m), 8.1 1—8.15 (1H, m)

 FAB-MS i / e): 374 [M + H] +

Jiasutereoma one ^{b (Ar: Ph; R 1} : H; R 2: H; R 3: i- P r; R 4: H; R 5: 3, 4-E t hy l en edi oxy l -P; n = 2)

_{XHNMR (CDC 1 3) 5:} 0. 95 (3H, d, J = 6. 8Hz), 0. 9

8 (3H, d, J = 6.8 Hz), 1.90-2.03 (lH, m), 2.97 (IH, dd d, J = 3.5, 5. 7, 9. OHz), 3.42 (IH, dd,

J = 9.0, 14.3Hz), 3.48 (1H, dd, J = 3.5, 14.3Hz), 4.27 (4H, s), 5.73 (1H, s) , 6.77 (1H, dd, J = 1.9, 8.6Hz), 6.85 (1H, d, J = 8.6Hz), 6.87 (IH, d, J = 1.9Hz) ), 7.42-7.51 (2H, m), 8.11 1 8.15 (1H, m)

 FAB-MS (mZe): 374 [M + H] + Example 1 16

Preparation of compound examples 1 1 1 1 (Ai ^ Pt ^ R ^ HRHR 3: i- P r; R 4: H; R 5: 3- F, 4 one Me_〇- P h; n = 2)

_{^{X HNMR (CDC 1 3) (}} 3: 0. 96 (3H, d, J = 6. 8Hz), 0. 9 9 (3H, d, J = 6. 7Hz), 1. 90- 2. 00 (IH , m), 2.98-3.04 (IH, m), 3.35-3.50 (2H, m), 3.90 (3H, s), 5.79 (IH, s), 6. 92-6.97 (2H, m), 7.15 (1 H, dd, J = l. 3, 11.6 Hz), 7.48-7.51 (2H, m), 8.14-8.17 (1H, m)

FAB-MS (m / e): 364 [M + H] ⁺ Example 117

Preparation of compound examples 1 1 58 (3-isopropyl one 7-nitro-one 5-phenyl 2, 3, 4, 5, Tetorahidoro - 1 one 1 lambda ^6, 4 one base Nzochiazepin - 1, -1-di-one)

 2-Promo 5-2-nitrobenzoic acid 10.0 mL (40.6 mmo 1) was added with 6.0 mL of thionyl chloride, and the mixture was heated under reflux at 120 ° C for 3 hours. The reaction solution was concentrated under reduced pressure. did. 30.0 ml of ethanol was added to the residue, followed by 6.8 g (48.7 mmo 1) of aluminum salt, and the mixture was heated and stirred at 160 for 5 hours. A saturated aqueous solution of ammonium chloride was added, the reaction solution was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1), and 8.3 g (yield: 61%) of (2-promo-5-ditrophenyl) (phenyl) methanone was obtained. Obtained as a yellow oil.

_{^ NMR (CDC 1 3) δ} : 3. 90 (3Η, s), 6. 97 (. 2H, d, J = 9 0Hz), 7. 77 (2H, d, J = 9. 0Hz), 7. 85 (2H, d, J = 9.5Hz), 8.16—8.20 (2H, m)

 FAB-MS (/ e): 336/338 [M + H] +

To a solution of 2.60 g (7.73 mmo 1) of (2-promo 5-ditrophenyl) methanone obtained in step 1 in dimethylformamide (30 m 1), t-butyl N— {2-methyl— To the mixture was added 3.0 g (11.4 mmo 1) of potassium carbonate and 2.09 g (15. lmmo 1) of potassium carbonate, and the mixture was heated with stirring at 120 ° C. for 2 hours. A saturated aqueous solution of ammonium chloride was added, and the reaction solution was extracted with ethyl acetate.The organic layer was washed with a 10% aqueous solution of hydrogen hydrogen sulfate and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. Was. To the residue was added a 4N hydrogen chloride 1,4-dioxane solution (10.0 ml), the mixture was stirred at room temperature overnight, and the reaction solution was concentrated under reduced pressure. 2,6-Lutidine (20.0 ml) was added to the residue, and concentrated hydrochloric acid (10.0 ml) was added. After the addition was completed, the mixture was azeotroped for 3 hours and distilled under reduced pressure. The residue was collected with a saturated aqueous sodium hydrogen carbonate solution, and the solution was extracted twice with ethyl acetate. The collected extract was washed with a saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give 3-isopropyl-17-nitro-5-phenyl-2,3-dihydro-1,4-benzothiazepine. 1.65 g (yield: 60%) was obtained as a pale yellow oil.

_{^ NMR (CDC 1 3) δ} :. 0. 95 (3H, d, J = 6. 7Hz), 1. 0 5 (3H, d, J = 6. 6Hz), 1. 95-2 10 (1 H , M), 2.89-2.99 (1H, m), 3.42 (1H, dd, J = l 1.2, 12.0 Hz), 3.62 (1H, dd, J = 3.7 , 11.2Hz), 3.84 (3H, s), 6.90 (2H, d, J = 8.9Hz), 7.52 (2H, d, J = 8.9Hz), 7.76 (1H, d, J = 8.3Hz), 7.99 (1H, d, J = 2.6Hz), 8.19 (1H, dd, J = 2.6, 8.3Hz)

 FAB-MS (m / e): 357 [M + H] +

 3-58- (2-nitro) -5-phenyl-2,3-dihydro-1,4-monobenzothiazepine obtained in Step 2 1.58 g (4.43 mmo 1) of tetrahydrofuran solution in 10 m 1 To this was added a solution of trifluoroacetic acid (3.0 ml), and 30% aqueous hydrogen peroxide (1.0 ml) was added at a temperature of about O :. After the addition was completed, the mixture was stirred at room temperature overnight, treated with a 10% aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution, extracted twice with ethyl acetate, and the combined extracts were washed with a saturated aqueous sodium chloride solution. Dry and concentrate under reduced pressure. 4N Hydrogen chloride 1,4-dioxane solution (10.0 ml) was added to the residue, and 288 mg of zinc powder was gradually added at a temperature of about O. The mixture was stirred overnight at room temperature, treated with saturated aqueous sodium bicarbonate and filtered through celite. The mixture was extracted twice with ethyl acetate, and the combined extracts were washed with a saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. Silica gel obtained residue

-(Hexane: ethyl acetate = 1: 1) Papermaking, 3-isopropyl one 7-nitro-one 5-phenyl 2, 3, 4, 5, Tetora Hidoro Iff one 1 lambda ^6, 4-benzothiazepine - 1, 1-dione Jiasutereo mer a (408 mg) and b (53 Omg) as pale yellow oily product diastereomer a

_{^{X HNMR (CDC 1 3) δ}} : 0. 95 (. 3Η, d, J = 6 8Hz), 0. 9 5 (3H, d, J = 6. 8Hz), 1. 70- 1. 81 (1 H , m), 3.01 (1H, dd, J = 11.4, 14.OHz), 3.37 (1H, dd, J = 2.3, 14.OHz), 3.44 (1H, ddd, J = 2.2, 5.0, 11.4 Hz), 3.85 (3H, s), 5.71 (1H, s), 5.88 (1H, d, J = 2.3 Hz), 6 .51 (1H, dd, J = 2.3, 8.4 Hz), 6.94 (2H, d, J = 8.6 Hz), 7.31 (1H, d, J = 8.6 Hz), 7. 88 (1H, d, J = 8.4Hz)

 FAB-MS (m / e): 361 [M + H] +

Ge stereomer b

_{^{X HNMR (CDC 1 3) 6}} : 0. 93 (3H, d, J = 6. 8Hz), 0. 9 7 (3H, d, J = 6. 7Hz), 1. 85 - 1. 99 (1H, m), 2.90—3.00 (lH, m), 3.30-3.40 (2H, m), 3.82 (3H, s), 5.73 (1H, s), 6.08 (1H, d, J = 2.4Hz), 6.61 (1H, dd, J = 2.4, 8.5Hz), 6.90 (2H, d, J = 8.6Hz), 7 26 (1H, d, J = 8.6Hz), 7.89 (1H, d, J = 8.5Hz)

 FAB-MS (m / e): 361 [M + H] +

 The physical constants of the compound obtained in the same manner as in Example 117 are shown below. Example 118

Preparation of Compound Example 1157

Diastereomer a (A r: 7-N02-Ph; R ¹ : H; R ² : H; R ³ P r; R ⁴ : H; R ⁵ : 4-MeO-Ph; n = 0) _{^ NMR (CDC 1 3) δ} : 0. 95 (3H, d, J = 6. 8Hz), 0. 9 6 (3H, d, J = 6. 8Hz), 1. 65 - 1. 78 (lH, m), 2.49 (IH, dd, J = 10.3, 13.9 Hz), 2.98 (1H, dd, J = 2.2, 13.9 Hz), 3.06 (1 H, m) , 3.86 (3H, s), 5.48 (IH, s), 6.97 (2H, d, J = 8.8 Hz), 7.33 (2H, d, J = 8.8 Hz), 7.49 (1H, d, J = 2.5Hz), 7.75 (1H, d, J = 8.4Hz), 7.92 (IH, dd, J = 2.5, 8.4Hz)

FAB-MS (m / e): 359 [M + H] +

Jiasutereoma b (A r: 7-N02 -Ph; R X: H; R 2: H;: l - P r; R 4: H; R 5: 4-MeO-P; n = 0)

_{aHNMR (CDC 1 3) (5} :. 0. 93 (3H, d, J = 6. 7Hz), 0. 9 5 (3H, d, J = 6 7Hz), 1. 90- 2. 10 (1 H , m), 2.75-2.85 (IH, m), 2.90-3.05 (2H, m), 3.84 (3H, s), 5.64 (IH, s), 6. 93 (2H, d, J = 8.8 Hz), 7.25 (2H, d, J = 8.8 Hz), 7.58 (IH, d, J = 8.5 Hz), 7.63 (IH, d, J = 2.3Hz), 7.93 (1H, dd, J = 2.3, 8.5Hz)

FAB-MS (m / e): 359 [M + H] ⁺ Example 119

Preparation of Compound Example 1159

Jiasutereoma a (Ar: 7- N3- Pt R ^ HR ^ HR 3: i -P r; R 4: H; R 5: 4-MeO-Ph; n = 2)

_{XHNMR (CDC 1 3) δ 0.} 96 (3 H, d, J = 6. 8Hz), 0. 9 6 (3H, d, J = 6. 8Hz), 1. 70- 1. 82 (1 H, m), 3.05 (IH, dd, J = 11.8, 14.OHz), 3.41 (1H, dd, J = 2.0, 14.OHz), 3.48 (1H, ddd, J = 2.0, 5.0, 11.8 Hz), 3.85 (3H, s), 5.73 (1H, s), 6.31 (IH, d, J = 2.4 Hz), 6. 96 (2H, d, J = 8.5Hz), 7.03 (2H , dd, J = 2.4, 8.4Hz), 7.29 (2H, d, J = 8.5Hz), 8.12 (1H, d, J = 8.4Hz)

FAB-MS (m / e): 384 [M + H] ⁺

Jiasutereoma b (Ar: T-NS- P i R ^ H j R 'i H j R 3: i one ^{P r; R 4: H;} R 5: 4-MeO-Ph; n = 2)

_{^{: HNMR (CDC 1 3) δ}} : 0. 94 (3H, d, J = 6. 7Hz), 0. 9 8 (3H, d, J = 6. 7Hz), 1. 90- 2. 05 (lH, m), 2.95 — 3.04 (lH, m), 3.35-3.50 (2H, m), 3.82 (3H, s), 5.76 (1H, s), 6.54 (1H, d, J = 2.2Hz), 6.92 (2H, d, J = 8.6Hz), 7.09 (1H, dd, J = 2.2, 8.5Hz), 7.23 (2H, d, J = 8.6Hz), 8.13 (1H, d, J = 8.5Hz)

 FAB-MS (m / e): 387 [M + H] + Example 120

Preparation of compound examples 1 164 (Ar: y-MeO -P i R ^ H ^^ H i R 3: i -P r; R 4: H; R 5: Ph; n = 0)

_{^{X HNMR (CDC 1 3) (}} 5: 0. 94 (3H, d, J = 6. 8Hz), 0. 9 5 (3H, d, J = 6. 8Hz), 1. 55- 1. 75 (1 H, m), 2.38 (1H, dd, J = 10.8, 13.8 Hz), 2.84 (1H, dd, J = 2.1, 13.8 Hz), 3.00-3.08 (1H, m), 3.58 (3H, s), 5.66 (1H, s), 6.14 (1H, d, J = 2.7Hz), 6.62 (1H, dd, J = 2.7, 8.3Hz), 7.25-745 (5H, m), 7.56 (1H, d, J = 8.3Hz)

 FAB-MS (m / e): 3 14 [M + H] + Example 121

Preparation of Compound Example 1279

Diastereomer a (Ar: 3, 4-Py ri dy l; R ^ HJR ^ HJR ³ : I -P r; R ⁴ : H; R ⁵ : Ph; n = 0)

_{iHNMR (CDC 1 3) δ:} 0. 96 (3H, d, J = 6. 8Hz), 0. 9 7 (3H, d, J = 6. 7Hz), 1. 67- 1. 80 (1 H, m), 2.46 (1H, dd, J = 10.5, 14.1 Hz), 2.98 (1H, dd, J = 2.1, 14.1 Hz), 3.10 (1H, ddd, J = l. 9, 4. 9, 10.5 Hz), 5.54 (1H, s), 6.64 (1 H, d, J = 6.0 Hz), 7.35 -7.46 ( 5H, m), 8.21 (1H, d, J = 6. OHz), 8.78 (1H, s)

 FAB-MS (mZe): 285 [M + H] +

Jiasutereoma b (Ar: 3, 4- Py ri dy l; R 1: H; R 2: H; R 3: i -P r; R 4: H; R 5: Ph; n = 0)

_{^{X HNMR (CDC 1 3) δ}} : 0. 94 (3H, d, J = 6. 8Hz), 0. 9

5 (3H, d, J = 6.6Hz), 2.00-2.12 (1H, m), 2.75-2.85 (1H, m), 2.95—3.00 (2H, m), 5.64 (1H, s), 6.80 (1H, d, J = 5.9 Hz), 7.28-7.43 (5H, m), 8.23 (1H, d, J = 5.9Hz), 8.66 (1 H, s)

 FAB-MS (m / e): 285 [M + H] + Example 122

Preparation of Compound Example 128 1

Jiasutereoma a (Ar: 3, 4- Py ri dy l; R 1: H; R 2: H; R 3: i -P r; R 4: H; R 5: 4-PhCH2O-P; n = 0)

_{XHNMR (CDC 1 3) (5} : 0. 95 (3H, d, J = 6. 9Hz), 0. 9

6 (3H, d, J = 6.9 Hz), 1.65-1.80 (lH, m), 2.45 (1H, dd, J = 10.4, 14. OHz), 2.94 (1 H, dd, J = 2

0, 14. OHz), 3.10 (1H, ddd, J = 2.0, 4.9, 10.4Hz), 5.10 (2H, s), 5.46 (1H, s), 6.69 (1H, d, J = 5.9Hz), 7.04 (1H, d, J = 8.7Hz), 7.29—7.47 (5H, m), 7.28 (1H , D, J = 8.7 Hz), 8.22 (1H, d, J = 5.9 Hz), 8.76 (1H, s)

 FAB-MS (m / e): 391 [M + H] +

Diastereomer b (Ar: 3, 4-Py ri dy 1; R ¹ : H; R ² : H; R ³ : i-P r; R ⁴ : H; R ⁵ : 4-PhCH20-Ph; n = 0 )

_{XHNMR (CDC 1 3) d:} 0. 95 (3H, d, J = 5. 7Hz), 0. 9

5 (3H, d, J = 5.7 Hz), 1.98—2.10 (1H, m), 2.71 -2.82 (lH, m), 2.95—3.00 (2H, m), 5.08 (2H, s), 5.58 (1H, s), 6.82 (1H, d, J = 5.8 Hz), 7.00 (2H, d, J = 8.7 Hz) ), 7.10 (2H, d, J = 8.7Hz), 7.25-7.43 (5H, m), 8.23 (1H, d, J = 5.8Hz), 8.

65 (1H, s)

 FAB-MS (m / e): 39 1 [M + H] + Example 123

Preparation of Compound Example 1288

Jiasutereoma a (Ar: 2, 3- Py ri dy l; R ^ H j R 'r H j R 3: i - P r; R 4: H; R 5: P; n = 0)

_{NMR (CDC 1 3) 6:} 0. 97 (3H, d, J = 6. 4Hz), 0. 9

7 (3H, d, J = 6.4Hz), 1.70-1.80 (1H, m), 2.64 (1H, dd, J = 9.8, 14.1Hz), 3.01 (1H, dd, J = 2.

1, 14.1 Hz), 3.02-3.12 (1H, m), 5.44 (1H, s), 6.85 (1H, dd, J = 2.0, 7.9Hz), 6 95 (1H, dd, J = 4.8, 7.9Hz), 7.30-7.43 (5H, m), 8.29 (1H, dd, J = 2.0, 4.8Hz)

 FAB-MS (m / e): 285 [M + H] +

Jiasutereoma b (Ar: 2, 3- Py ri dy l; R ^ HJR 'IHIR 3: i -P r; R 4: H; R 5: P h; n = 0)

_{^{X HNMR (CDC 1 3) 6}} : 0. 94 (3H, d, J = 6. 2Hz), 0. 9 6 (3H, d, J = 6. 6Hz), 1. 86- 2. 01 (1 H , m), 2.80 — 2.90 (1H, m), 3.05-3.11 (2H, m), 5.56 (1H, s), 6.92-6.96 (2H, m), 7.28-7 . 42 (5H, m), 8.28-8.30 (1H, m)

 FAB-MS (m / e): 285 [M + H] + Example 124

Preparation of compound examples 1291 (Ar: 5, e- Py ri dy ^ R ^ HR ^ H; R 3:. I - P r; R 4: H; R 5: Ph; n = 0)

_{^ NMR (CDC 1 3) (} 5: 0. 97 (3H, d, J = 6. 8Hz), 0. 9 8 (3H, d, J = 6. 7Hz), 1. 65- 1. 80 (1 H, m), 2.48 (1H, dd, J = l 0.8, 14.1 Hz), 2.95—3.05 (2H, m), 5.68 (1H, s), 7.02 (1H, dd, J = 4.7, 7.6Hz), 7.27 -7. 46 (5H, m), 7.88 (1H, dd, J = 1. 7, 7.7Hz), 8.32 (1H, dd, J = l. 7, 4.8Hz)

 FAB-MS (mZe): 285 [M + H] + Formulation example

 Formulation examples of the compound of the present invention are shown below, but the formulation of the compound of the present invention is not limited to the present formulation example.

Formulation example 1

 Compound Example 1116 Compound 45 (parts)

 Heavy magnesium oxide 15

 Lactose 75

Into a powder or fine-grained powder of 350 m or less. This powder was placed in a forcepsell container to form a forcepsefle. Formulation example 2

 Compound Example 1116 Compound 45 (parts)

Starch 15 Lactose 1 6

 Crystalline cellulose 2 1

 Polyvinyl alcohol 3

 Distilled water 3 0

Was uniformly mixed, crushed and granulated, dried, and then sieved to obtain granules having a size of 141 to 1177ΠΙ. Formulation example 3

 After preparing granules in the same manner as in Formulation Example 2, 96 parts of the granules were added with 4 parts of calcium stearate and compression-molded to prepare tablets having a diameter of 10 mm. Formulation example 4

 To 90 parts of the granules obtained by the method of Formulation Example 2, 10 parts of crystalline cellulose and 3 parts of calcium stearate were added, and the mixture was compression-molded into tablets having a diameter of 8 mm. A sugar-coated tablet was prepared by adding a precipitated calcium carbonate mixed suspension. Industrial applicability

 Since the benzothiazepine derivative of the compound of the present invention exhibits an activity of exhibiting a high blood GLP-1 concentration, it is useful as a therapeutic agent for diabetes, a preventive agent for chronic complications of diabetes, or an antiobesity agent.

Claims

General formula [I] of

[Wherein, R ¹ and R ² are the same or different and each is a hydrogen atom, a C ₃ alkyl group, R ³ is a hydrogen atom, a Ci—Ce alkyl group (excluding an n-butyl group), R ⁴ is a hydrogen atom, a hydroxyl group, (: _1- (: ₃ alkyl group, box R ⁵ is a hydrogen atom, azide group, amino group, carpamoyl group, rubamoylamino group, rubamoyloxy group, hlupoxyl group, cyano group, sulfamoyl group, sulfo group, nitro group, halogen atom, hydroxy group, formyl group, formyl group Amino group, cyclic saturated or unsaturated C ₃ -C ₉ aliphatic group, aralkyl group, N-aralkylamino group, N, N-diaralkylamino group, aralkyloxy group, aralkylcarbonyl group, N-aralkyl force Rubamoyl group, aryl group, N-arylamino group, N, N-diarylamino group, aryloxy group, arylsulfonyl group, arylsulfonyloxy group, N-arylsulfonylamino group, N-alpha Li one Le sulfonyl § amino C "C ₆ Arukiruamino group, N- § Li one Rusuruhoniruami yc _x -c ₁₀ alkyl Power Rubamoiru group, N- § Li -. Le sulfonyl § Mino one c ₆ alkoxy Cal Poni group, § Li one Rusurufamoiru group, § reel sulfamoyl Okishi group, § reel sulfamoyl (^ primary alkyl force Rubamoiru group, § Li one Rusurufamoiru 0 t—C ₆ alkoxycarbonyl group, N—aryl carbamoyl group, aroyl group, alkoxy group, N—aroyl group, N— (N—aroylamino) C xC ₁₀ alkyl rubamoyl group, N—aroylamino Ci—C ₆ alkoxycarbonyl group, C ₂ —C ₆ alkanoyl group, C ₂ —C ₆ alkanoyloxy group, N—C ₂ One C ₆ alkanoylamino group, N, N-di C ₂ —C ₆ alkanoylamino group, one N C ₆ alkylamino group, one N, N-di C ₆ alkylamino group, NC! -0 ₁₀ alkyl force Rubamoiru group, N, N-di - Ci one C _{1 ()} alkyl force Rubamoi Le group, N- C ₂ - C ₆ alkenyl carbamoylmethyl group, N, N-di-C ₂ - _<6 Aruke carbamoylmethyl group, N-amido (^ — (^ 0 alkylcarbamoyl group, N— Ci— C 6 alkoxy C ^ —C ₁₀ alkyl group rubamoyl group, N-Cj-Cg alkoxycarbonyl 1 C ₁₀ alkyl group rubamoyl group, N-Ci -Cg alkoxy force Ruponirua amino C j one C E ₀ alkyl force Rubamoiru group, N-C i one C ₆ alkoxy force Ruponirua amino C E - C ₆ alkoxycarbonyl group, one C ₆ alkylthio group, N - C 'C ₆ alkyl a sulfamoyl group, N, N-di - A C ₆ alkylsulfamoyl group, c, -c ₆ A ! Kirusurufiniru group, c - c ₆ alkylsulfonyl group, _c: -c ₆ alkoxy groups, one c ₆ alkoxycarbonyl group, amino - c ₆ alkoxy Karuponiru group, N-C ₃ - ₆ cycloalkyl § amino group, N, N-di-C ₃ - C ₆ cycloalkylamino group, C ₃ - C ₆ cycloalkyl O alkoxy group, N - C ₃ - C ₆ cyclo alkyl force Rubamoiru group, N, N-di-C ₃ - Ji ₆ 1 to 5 hetero atoms per ring system selected from the group consisting of a cycloalkyl group and a 5- or 6-membered heterocyclic group, a nitrogen atom, an oxygen atom and a sulfur atom. 1 to 3 hetero-ring group and may be substituted with the substituent, linear or saturated or unsaturated branched C having - C ₉ aliphatic groups, C one C ₆ alkoxy group , One C ₆ alkylthio group, N— one C ₆ alkylamino group, N — A C ₆ alkyl group having an optionally substituted substituent selected from the group consisting of C ₆ alkyl group rubamoyl groups and N-Ci-C ₆ alkylthio group rubamoyl groups; 7-Ci 5-carbon aromatic ring group or 5- or 6-membered heterocyclic group or 1 to 3 ring atoms having 1 to 5 hetero atoms per ring system selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom A heteroaromatic group (excluding a 5- or 6-membered heterocyclic group) ), Ar represents a hydrogen atom, an azide group, an amino group, a rubamoyl group, a rubamoylamino group, a rubamoyloxy group, a lipoxyl group, a cyano group, a sulfamoyl group, a sulfo group, a nitro group, a halogen atom, a hydroxy group, a formyl group, Formylamino group, cyclic saturated or unsaturated C ₃ -C ₉ aliphatic group, aralkyl group, N-ara Alkylamino group, N, N-diaralkylamino group, aralkyloxy group, aralkylcarbonyl group, N-aralkyl rubamoyl group, aryl group, N-arylamino group, N, N-diarylamino group, aryloxy group, arylsulphoni Alkyl group, arylsulfonylamoxy group, N-arylsulfonylamino group, N-arylsulfonylamino d-C ₆ alkylamino group, N-arylsulfonylamino C. N-arylsulfonylamino-1-C ₆ alkoxy Cal Poni group, § Li one Rusurufamoiru group, § reel sulfamoyl Ruokishi group, § Li one Rusurufamoiru C E - C E. Alkyl rubamoyl group, arylsulfamoyl C _ C ₆ alkoxycarbonyl group, N-arylcarbamoyl group, aroyl group, alkoxy group, N-aroyl group, N— (N-aroylamino) C ₁ -C ₁ 0 Alkyl rubamoyl group, N-aroylamino 1 C ₆ alkoxyl ruponyl group, C ₂ — C ₆ alkanoyl group, C ₂ _ C ₆ alkylyloxy group, NC ₂ — C ₆ alkanoylamino group, N, N— Di-C ₂ —C ₆ alkanoylamino group, N—C-C ₆ alkylamino group, N, N—di C 丄 —C ₆ alkylamino group, N—Ci-Cio alkyl rubamoyl group, N, N— Gee one C _{1 ()} alkyl carba model I le group, N- C ₂ - C ₆ alkenyl carbamoylmethyl group, N, N- di - C ₂ - C ₆ alkenyl carbamoylmethyl group, N- amino Ji chromatography. Alkyl rubamoyl group, NC, -C ₆ alkoxy C _x 1 C! 0 Alkyl Lubamoyl group, N—C ₁ -C ₆ Alkoxy Luponyl CC ₁₀ Alkyl Lubamoyl, N-Cj-Ce Alkoxy Lupamine Lumino Ci 1 C ₁₀ Alkyl Lubamoyl, NC.-Cg Alkoxycarbo Ruamino C _t one C ₆ alkoxycarbonyl group, (: ₁ - ○ ₆ Arukiruchio group, NC _x one C ₆ alkylsulfamoyl group, N, N-di-CI- Ce alkyl sulfamoyl Le group, C ₁ one C ₆ alkylsulfinyl group, C ₆ alkylsulfonyl group, C ₁ C ₆ alkoxy group, C! C ₆ alkoxycarbonyl group, amino (^ C ₆ alkoxycarbonyl group, N—C ₃ — C ₆ cycloalkylamino group, N, N-di - C ₃ - C ₆ cycloalkylamino group, C ₃ - C ₆ cycloalkyl O alkoxy group, NC ₃ -C ₆ cycloalkyl force Rubamoiru group, N, N-di C ₃ - or the group consisting of C ₆ cycloalkyl carba model I le radical Substituents selected, 5 or 6 membered heterocyclic group, the nitrogen atom, to 1 per ring system heteroatoms selected from the group consisting of oxygen radicals and sulfur atoms 5 A straight-chain or branched-chain saturated or unsaturated C ₁ -C ₉ aliphatic group, which may be substituted with a mono- to tricyclic heteroaromatic group or the substituent, Ci-C ₆ alkoxy group, (: E one C ₆ alkylthio group, N-CI- Ce alkylamino group, N-- C ₆ alkyl force Rubamoiru group, N - is selected from C "group from C ₆ alkylthio force Rubamoiru group ing substituted good carbon aromatic ring group which may have a group 1 to 3 rings of the C ₇ - ₅ carbon aromatic ring group or a 5- or 6-membered heterocyclic group, or a nitrogen atom, from the group consisting of an oxygen atom and a sulfur atom A bicyclic to tricyclic fused heteroaromatic group having 1 to 5 heteroatoms per ring system (excluding a 5- or 6-membered heterocyclic group), and n is an integer of 0-2 Or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein R ¹ and R ² are both hydrogen atoms. 3. The compound according to claim 1, wherein R ³ is a C ₂ _C ₆ alkyl group (excluding an n-butyl group). 4. The compound according to claim 1, wherein R ⁴ is a hydrogen atom or a Ci—Cs alkyl group. 5. In R ⁵ , the carbon aromatic ring group is a phenyl group or a naphthyl group, and the substituent of the carbon aromatic ring group which may have a substituent is a hydrogen atom, an azide group, an amino group, or a carbamoyl group. Group, carbamoylamino group, carbamoyloxy group, propyloxyl group, cyano group, nitro group, halogen atom, hydroxy group, cyclic saturated or unsaturated C ₃ -C ₉ aliphatic group, aralkyl group, N —Aralkylamino group, aralkyloxy group, aralkylcarbonyl group, N-aralkyl rubamoyl group, aryl group, N-arylamino group, aryloxy group, arylsulfonyl group, 7arylsulfonyloxy group, N- § Li one Le sulfonyl § amino C E one C ₆ alkoxy Shikaruponiru group, § Li one Rusurufamoiru group, § Li one Rusuru sulfamoyl O alkoxy group, § Li one Luz Famoiru C ₁ one C i. Alkyl force Rubamoiru group, Arirusurufu Amoiru C _x one C ₆ alkoxy Cal Poni Le group, N- Ariru force Rubamoiru group, § b I group, Arokishi group, N- Aroiru group, C ₂ - C ₆ Arukanoiru groups, C ₂ - C ₆ Alkanyloxy, N—C ₂ —C ₆ alkanoylamino, N, N—di-C ₂ —C ₆ alkanoylamino, N—Ci—C ₆ alkylamino, N—C ₁₀ alkyl Carbamoyl group, N, N- di C i-C ^ alkyl force Rubamoiru group, N-C ₂ one C ₆ alkenyl carbamoylmethyl group, N, N- di C ₂ - C ₆ alkenyl carbamoylthiopheno Le group, N- amino Ji one C ₁₀ alkyl rubamoyl group, N— — C ₆ alkoxy C “. Alkyl rubamoyl group, N _ C ₁ — C ₆ alkoxycarbonyl C! -Ci. Alkyl rubamoyl group, C 丄 C ₆ alkylsulfinyl group , A CC ₆ alkoxy group, a C i -C g alkoxy carbonyl group, an amino C — C ₆ alkoxyl carbonyl group, an N — C ₃ — ( ₆ cycloalkylamino group, a C ₃ — ( ₆ cycloalkyloxy group , N- C ₃ - C ₆ cycloalkyl force Rubamoiru group, imidazolidinyl group, imino Dazoriniru group, tetrahydrofuranyl El group, pyrazolidinyl group, Birazoriniru group, a piperazinyl group, a piperidinyl group, pyrrolidine Group, pyrrolinyl group, morpholino group, isooxazolyl group, isothiazolyl group, imidazolyl group, oxazolyl group, oxdiazolyl group, thiazolyl group, thiadiazolyl group, chenyl group, triazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group Zolyl, pyrrolyl, pyranyl, furyl, acridinyl, isoquinolyl, isoindolyl, indazolyl, indolyl, ethylenedioxyphenyl, carbazolyl, quinazolinyl, quinoxalinyl, quinolyl, chromanyl Chromenyl group, phenanthridinyl group, phenanthrolinyl group, dibenzofuranyl group, dibenzothiophenyl group, cinnolinyl group, thonaphthenyl group, naphthyridinyl group, phenyl Dinyl group, phenaxazinyl group, benzimidazolyl group, benzoxazolyl group, benzothiazolyl group, benzotriazolyl group, benzofuranyl group, dihydrobenzofurayl group, methylenedioxyphenyl group, and 1 to 3 ring Wherein the C ₇ -C ₁₅ carbon aromatic ring group is an acenaphthylenyl group, an adamantyl group, an anthryl group, an indenyl group, a phenanthryl group, and the 5- or 6-membered heterocyclic group is an isoxazolyl group, an isothiazolyl group, Imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, chenyl, triazolyl, pyridyl, virazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyrrolyl, pyranyl, furanyl, furyl, nitrogen atom , Selected from the group consisting of oxygen and sulfur atoms 1 to chromatic 5 to 1 per ring system heteroatoms that except tricyclic heteroaromatic Hajime Tamaki (5 or 6-membered heterocyclic group. ) Is an acridinyl group , Isoquinolyl group, isoindolyl group, indazolyl group, indolyl group, indolizinyl group, ethylenedioxyphenyl group, carbazolyl group, quinazolinyl group, quinoxalinyl group, quinolyl group, chromanyl group, isochromanyl group, chromenyl group, phenanthridinyl Group, phenanthrolidyl group, dibenzofuranyl group, dibenzothiophenyl group, thonaphthenyl group, naphthidinyl group, phenazinyl group, phenaxazinyl group, phenothiazinyl group, phthalazinyl group, pteridinyl group, prinyl group, benzimidazolyl group, benzo The compound according to claim 1, which is a oxazolyl group, a benzothiazolyl group, a benzotriazolyl group, a benzofuranyl group, a dihydrobenzofuranyl group or a methylenedioxyphenyl group.  6. In Ar, the carbon aromatic ring group is a phenyl group or a naphthyl group And the substituent of the optionally substituted carbon aromatic ring group is a hydrogen atom, an azido group, an amino group, a carbamoyl group, a carbamoylamino group, a carbamoyloxy group, a carboxyl group, a cyano group, or a nitro group. A halogen atom, a hydroxy group, a cyclic saturated or unsaturated C ₃ -C ₉ aliphatic group, an aralkyl group, an N-aralkylamino group, an aralkyloxy group, an aralkylcarbonyl group, an N-aralkyl labamoyl group, Ariru group, N- Ariruamino group, Ariruokishi group, § Li one Rusuruhoniru group, § Li one Le sulfonyl O alkoxy group, N- § Li one Le sulfonyl § amino C E one C ₆ alkoxy Kishikaruponiru group, § Li one Rusurufamoiru group, § Li one Rusuru sulfamoyl O alkoxy group, § reel sulfamoyl 〇 ₁ one C _1Q alkyl force Rubamoiru group, Arirusuru Amoiru Ji one C ₆ alkoxy Cal Poni Le group, N- Ariru force Rubamoiru group, § Royle group, Arokishi group, N- Aroiru group, C ₂ - C ₆ Arukanoiru groups, C ₂ - C ₆ alkanoyloxy Noi Ruo alkoxy group, N- C ₂ — C ₆ alkanoylamino group, N, N—di—C ₂ —C ₆ alkanoylamino group, N—C—C ₆ alkylamino group, N—C ^ — C alkyl group, rubamoyl group, N, N- di CI- C ₁₀ alkyl force Rubamoiru group, N one C ₂ - C ₆ alkenyl carbamoylmethyl group, N, N- di - C ₂ - C ₆ Arukenirukaruba moil group, N- amino (^ - C ₁₀ alkyl force Rubamoiru Group, N— — C ₆ alkoxyl C ₁₀ alkyl rubamoyl group, N- C ₆ alkoxy carbonyl group C! -C ₁₀ alkyl rubamoyl group, C 丄 —C ₆ alkylsulfinyl group, C “C ₆ alkoxy group, C ₁ -C ₆ alkoxycarbonyl group, amino C — Cs Lucoxy Karuponiru group, N-C ₃ -〇 ₆ cycloalkylamino group, C ₃ - (3 ₆ cycloalkyl Ruokishi group, N-C ₃ -〇 ₆ cycloalkyl force Rubamoiru group, imidazolidinyl group, imidazolinyl group, tetrahydrofuranyl group, pyrazolidinyl group , Pyrazolidinyl group, piperazinyl group, piperidinyl group, pyrrolidinyl group, pyrrolinyl group, morpholino group, isooxazolyl group, isothiazolyl group, imidazolyl group, oxazolyl group, oxaziazolyl group, thiazolyl group, thiazolyl group, thiazolyl group, thiazolyl group Pyridyl group, birazinyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group, pyrrolyl group, pyranyl group, furyl group, acridinyl group, isoquinolyl group, isoindolyl group, indazolyl group, indolyl group, ethylyl Dioxyphenyl, carbazolyl, quinazolinyl, quinoxalinyl, quinolyl, chromanyl, chromenyl, phenanthridinyl, phenanthrolinyl, dibenzofuranyl, dibenzothiophenyl, cinnolinyl, thionafyl Phenyl, naphthyridinyl, phenazinyl, phenaxazinyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benzofuranyl, dihydrobenzozofuranyl, and methylenedioxyphenyl. Or a tricyclic C ₇ -C ₁₅ carbon aromatic ring group is an acenaphthylenyl group, an adamantyl group, an anthryl group, an indenyl group, or a phenanthryl group, and the 5- or 6-membered heterocyclic group is an isooxazolyl group or an isothiazolyl group. , Imidazolyl group, oxazolyl group, thiazolyl group, thiadiazolyl group, chenyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group, pyrrolyl group, pyranyl group, furyl group, nitrogen atom, oxygen atom And a tricyclic fused heteroaromatic group having 1 to 5 heteroatoms per ring system (excluding a 5- or 6-membered heterocyclic group) selected from the group consisting of , Isoquinolyl, isoindolyl, indazolyl, indolyl, indolizinyl, ethylenedioxyphenyl, carbazolyl, quinazolinyl, quinoxalinyl, quinolyl, chromanyl, isochromanyl, chromenyl, fenansuridin Group, phenanthrolidyl group, dibenzof Group, self - supplied Zochiofeniru group, Chionafuteniru group, Nafuchijiniru group, Fuenajiniru group, Hue Nakisajiniru group, Hue Roh thiazinyl group, phthalazinyl group, pteridinyl group, pre 2. The compound according to claim 1, which is a benzyl group, a benzimidazolyl group, a benzoxazolyl group, a benzothiazolyl group, a benzotriazolyl group, a benzofuranyl group, a dihydrobenzofuranyl group or a methylenedioxyphenyl group.  7. The compound according to claim 1, wherein the n force is 0 or 2.