WO2011055770A1 - Fused heterocyclic compound - Google Patents

Fused heterocyclic compound Download PDF

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WO2011055770A1
WO2011055770A1 PCT/JP2010/069654 JP2010069654W WO2011055770A1 WO 2011055770 A1 WO2011055770 A1 WO 2011055770A1 JP 2010069654 W JP2010069654 W JP 2010069654W WO 2011055770 A1 WO2011055770 A1 WO 2011055770A1
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group
optionally substituted
compound
halogen atoms
substituents selected
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PCT/JP2010/069654
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French (fr)
Japanese (ja)
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浩通 杉本
伸行 根来
俊樹 村田
健太郎 力丸
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武田薬品工業株式会社
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Priority to JP2011539392A priority Critical patent/JPWO2011055770A1/en
Publication of WO2011055770A1 publication Critical patent/WO2011055770A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/04Anorexiants; Antiobesity agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a condensed heterocyclic compound having a GPR119 agonist activity and useful for the prevention and treatment of diabetes, obesity and the like.
  • Diabetes is one of the metabolic diseases characterized by high blood glucose levels resulting from abnormal sugar metabolism. This disease is broadly classified into type 1 diabetes, also called insulin dependent diabetes or IDDM, and type 2 diabetes, also called non-insulin dependent diabetes or NIDDM. Diabetes not only causes microvascular complications (eg diabetic retinopathy, diabetic neuropathy, diabetic nephropathy) but also macrovascular disorders (eg arteriosclerosis, cardiovascular disease, myocardial infarction) ) Risk factor.
  • IDDM insulin dependent diabetes
  • NIDDM non-insulin dependent diabetes
  • GPR119 is a G protein-coupled receptor that is strongly expressed in pancreatic ⁇ cells and has recently been reported to function as a blood glucose sensor that promotes insulin secretion depending on the sugar concentration in the blood (Non-patent Document). 1). Therefore, GPR119 has attracted attention as a new target molecule for the treatment of diabetes.
  • GPR119 is also expressed in the intestinal tract of humans and mice, and the GPR119 agonist is glucagon-like peptide-1 (GLP-1) and glucose-dependent insulin secretion stimulating polypeptide (glucose) in mice.
  • GLP-1 glucagon-like peptide-1
  • glucose glucose-dependent insulin secretion stimulating polypeptide
  • GIP -dependent insulinotropic peptidepolypeptide secretion
  • a compound having a GPR119 agonistic action is useful for the prevention and treatment of diabetes, obesity and the like.
  • one of A and B is nitrogen, the other is CR 1 , W and Y are independently a bond, C 1-3 alkyl or C 2-3 alkenyl, and X is CH 2 , O, S, CH (OH), etc.
  • G represents CHR 3 , N—C (O) OR 4 , N—C (O) NR 4 R 5, etc.
  • R 1 represents a hydrogen atom, a halogen atom, Cyano
  • R 2 is a hydrogen atom or C 1-4 alkyl
  • R 3 is C 3-6 alkyl
  • R 4 is C 1-8 alkyl, C 2-8 alkenyl, etc.
  • R 5 is ,
  • R 6 is a hydrogen atom, a halogen atom, cyano
  • R 8 is a hydrogen atom, a halogen atom, cyano, etc.
  • R 11 is a halogen atom or hydroxy
  • a and B independently represent optionally substituted C 1-3 alkylene, D represents O, S, S (O), S (O) 2 , CR 2 R 3 or NR 2 , E is N, C, CR 4 ; V 1 is a bond, optionally substituted C 1-3 alkylene; V 2 is a bond, optionally substituted C 3- 6 cycloalkylene or optionally substituted C 1-3 alkylene, W is NR 5 , O, S, S (O), S (O) 2 or absent, Q is NR 6 , O, S, S (O) or S (O) 2 , X is N or CR 7 , Y is N or CR 8 , Ar 1 is optionally substituted aryl or optionally substituted Heteroaryl, R 2 represents aryl, heteroaryl, carboxy and the like. ] (Refer patent document 2).
  • the R 1 represents a hydrogen atom, an optionally substituted C 1-6 alkyl, or an optionally substituted C 1-6 acyl
  • R 2 and R 3 independently represent a hydrogen atom, a halogen atom, Hydroxy, optionally substituted C 1-6 alkyl, or optionally substituted C 1-6 alkoxy
  • R 4 is a hydrogen atom, a halogen atom, hydroxy, cyano, nitro, trifluoromethyl, C 1 -6 alkyl or C 1-6 alkoxy
  • Y is O, N (R 5 ) or CH 2
  • R 5 is a hydrogen atom or C 1-6 alkyl
  • a, b and c are independently 1 represents an integer of 1 to 3
  • d represents an integer of 0 to 2
  • f and g independently represent an integer of 0 to 2
  • f + g represents an integer of 1 to 3.
  • R 1 is optionally substituted with a specific substituent, C 1-6 Amino optionally substituted with alkyl, C 3-7 cycloalkyl, C 2-6 alkynyl or C 2-6 alkenyl, or C 1-6 alkyl, R 2 represents a halogen atom, hydroxy, C 1-6 alkyl or C 1-6 alkoxy, R 3 is halogen atom, C 1-6 alkyl, C 1-6 alkoxy such as, R 4 and R 5 are independently hydrogen atom, halogen atom, C 1- 6 alkyl, C 1-6 alkoxy and the like, R 6 represents —C (O) OR 6a , —C (O) —R 6b and the like, R 7 represents a hydrogen atom, a halogen atom or C 1-6 alkyl. Show. ] (Refer patent document 4). (4) Formula:
  • Ring P represents a further substituted 6-membered aromatic ring
  • Ring Q is a 6-membered aromatic ring which may be further substituted
  • a 1 represents CR 4a R 4b (R 4a and R 4b each independently represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted group.
  • NR 4c (wherein R 4c represents a hydrogen atom or an optionally substituted hydrocarbon group), O, S, SO, or SO 2 ;
  • L 1 represents an optionally substituted C 1-5 alkylene group;
  • L 2 represents a bond or an optionally substituted C 1-3 alkylene group;
  • L 3 and L 4 independently represent an optionally substituted C 1-3 alkylene group;
  • R 1 is (1) represents a hydrogen atom, a halogen atom, a cyano group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted hydroxy group, or (2)
  • a 1 is CR 4a R 4b , R 1 and R 4a and / or R 4b together with the adjacent carbon atom form an optionally substituted 4- to 8-membered ring.
  • R 1 and R 4c together with the adjacent carbon and nitrogen atoms form an optionally substituted 4- to 8-membered nitrogen-containing heterocycle.
  • R 2 represents a hydrogen atom, a cyano group, or an optionally substituted hydrocarbon group
  • R 3a represents the formula: —CO—SR A1 (wherein R A1 represents an optionally substituted hydrocarbon) A group or a heterocyclic group which may be substituted) or a 5- or 6-membered aromatic ring group which may be substituted. ] (Refer patent document 5).
  • Endocrinology 148 (6), 2601-2609, 2007 Endocrinology, 149 (5), 2038-47, 2008 Keystone Symposium 2008, Isle and Beta Cell Biology, Poster Abstract, 102, P.M. 58
  • Ring A represents a 6-membered aromatic ring which may be further substituted
  • R 1 represents a halogen atom, a cyano group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted amino group, or an acyl group
  • R 2 represents a cyano group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an acyl group
  • X 1 represents an optionally substituted linear C 2-3 alkylene group
  • X 2 represents a bond, optionally substituted NH, S, SO, SO 2 , CO, or O
  • X 3 is a bond, an optionally substituted linear C 1-2 alkylene group
  • Y 1 and Y 2 are independently an optionally substituted linear C 1-3 alkylene Indicates a group.
  • Compound (I) has an excellent GPR119 agonistic action, is useful for the prevention and treatment of diabetes, obesity and the like, and has an excellent medicinal effect. Found for the first time to have. Based on this knowledge, the present inventors have conducted intensive studies and completed the present invention.
  • Compound (I) has a GPR119 agonistic action, is useful for the prevention and treatment of diabetes, obesity and the like, and has an excellent medicinal effect.
  • halogen atom in the present specification means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom unless otherwise specified.
  • C 1-6 alkyl group means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethyl unless otherwise specified. It means propyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
  • the “C 1-6 alkoxy group” in the present specification means methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like unless otherwise specified.
  • the “C 1-6 alkoxy-carbonyl group” in the present specification means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl and the like, unless otherwise specified.
  • C 1-6 alkyl-carbonyl group in the present specification means acetyl, propanoyl, butanoyl, isobutanoyl, pentanoyl, isopentanoyl, hexanoyl and the like, unless otherwise specified.
  • Ring A represents a 6-membered aromatic ring which may be further substituted.
  • Examples of the “6-membered aromatic ring” in the “optionally substituted 6-membered aromatic ring” represented by ring A include benzene, pyridine, pyridazine, pyrimidine, pyrazine, triazine and the like. Preferred are benzene, pyridine, pyridazine, pyrimidine, pyrazine and the like, and more preferred are benzene, pyridine, pyrimidine and the like.
  • the “6-membered aromatic ring” in the “optionally substituted 6-membered aromatic ring” represented by ring A has 1 to 3 substituents at substitutable positions in addition to the R 1 group.
  • a substituent for example, (1) a C 3-10 cycloalkyl group (eg, cyclopropyl, cyclohexyl); (2) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and (d) a C 6- optionally substituted with 1 to 3 substituents selected from halogen atoms.
  • a C 3-10 cycloalkyl group eg, cyclopropyl, cyclohexyl
  • (2) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and (d) a C 6- optionally substituted with 1 to 3 substituents selected from hal
  • aryl groups eg, phenyl, naphthyl
  • (3) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, and (d) an aromatic complex which may be substituted with 1 to 3 substituents selected from halogen atoms.
  • a cyclic group (eg, thienyl, furyl, pyridyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl); (4) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, (d) a non-aromatic heterocyclic group (eg, tetrahydrofuryl, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, piperazinyl) optionally substituted by 1 to 3 substituents selected from halogen atoms and (e) oxo groups ); (5) (a) a C 1-6 alkyl group which may be substituted with 1 to 3
  • a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl) optionally substituted by 1 to 3 substituents selected from: (8) a C 1-6 alkylsulfonyl group which may be substituted with 1 to 3 halogen atoms (eg, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl); (9) a carbamoyl group optionally mono- or di-substituted with a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms; (10) a thiocarbamoyl group optionally mono- or di-substituted with a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms; (11) a sulfamoyl group optionally mono- or disubstituted with a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms; (12
  • 1-6 alkyl groups (33) (a) a halogen atom, (b) a carboxy group, (c) a hydroxy group, (d) a C 1-6 alkoxy-carbonyl group, (e) a C 1-6 alkoxy group, and (f) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted.
  • 2-6 alkenyl groups (eg, ethenyl, 1-propenyl); (34) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group, and (d) a C 7-13 aralkyl group (eg, benzyl) optionally substituted with 1 to 3 substituents selected from halogen atoms; Etc. When there are two or more substituents, each substituent may be the same or different.
  • Ring A is preferably (1) hydroxy group; (2) Halogen atoms (eg, fluorine atoms, chlorine atoms); (3) a C 3-10 cycloalkoxy group optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, and (b) a C 1-6 alkoxy group; (4) (a) a halogen atom, (b) a carboxy group, (c) a hydroxy group, (d) a C 1-6 alkoxy-carbonyl group, (e) a C 1-6 alkoxy group, and (f) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted.
  • Halogen atoms eg, fluorine atoms, chlorine atoms
  • C 3-10 cycloalkoxy group optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, and (b) a C 1-6 alk
  • 1-6 alkyl groups (eg, methyl); (5) (a) a halogen atom, (b) a carboxy group, (c) a hydroxy group, (d) a C 1-6 alkoxy-carbonyl group, (e) a C 1-6 alkoxy group, and (f) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted.
  • 1-6 alkoxy groups eg, methoxy
  • Benzene, pyridine, pyridazine, pyrimidine, pyrazine preferably benzene, pyridine, pyrimidine
  • pyrazine preferably benzene, pyridine, pyrimidine
  • Ring A is more preferably (1) Halogen atoms (eg, fluorine atoms, chlorine atoms); (2) a C 1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms; and (3) a C 1-6 alkoxy group (eg, methoxy) optionally substituted by 1 to 3 halogen atoms; Benzene, pyridine, pyrimidine (preferably benzene) and the like, each of which may be further substituted with 1 to 3 substituents selected from
  • R 1 represents a halogen atom, a cyano group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted amino group, or an acyl group.
  • Examples of the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R 1 include a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, C 3 -10 cycloalkyl group, C 3-10 cycloalkenyl group, C 4-10 cycloalkadienyl group, C 6-14 aryl group, C 7-13 aralkyl group, C 8-13 arylalkenyl group and the like can be mentioned.
  • examples of the C 1-10 alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1 , 1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and the like.
  • Examples of the C 2-10 alkenyl group include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1 -Pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like.
  • Examples of the C 2-10 alkynyl group include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1 -Hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like.
  • Examples of the C 3-10 cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3 2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] decyl, adamantyl and the like. Can be mentioned.
  • Examples of the C 3-10 cycloalkenyl group include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like.
  • Examples of the C 4-10 cycloalkadienyl group include 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl, and the like. .
  • C 3-10 cycloalkyl group, C 3-10 cycloalkenyl group and C 4-10 cycloalkadienyl group may each form a condensed ring group with a benzene ring, and such a condensed ring group Examples thereof include indanyl, dihydronaphthyl, tetrahydronaphthyl, fluorenyl and the like.
  • Examples of the C 6-14 aryl group include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like.
  • Examples of the C 7-13 aralkyl group include benzyl, phenethyl, naphthylmethyl, biphenylylmethyl and the like.
  • Examples of the C 8-13 arylalkenyl group include styryl and the like.
  • the C 1-10 alkyl group, C 2-10 alkenyl group, and C 2-10 alkynyl group exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R 1 can be substituted. It may have 1 to 3 substituents at various positions.
  • a substituent for example, (1) a C 3-10 cycloalkyl group (eg, cyclopropyl, cyclohexyl); (2) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and (d) a C 6- optionally substituted with 1 to 3 substituents selected from halogen atoms.
  • a C 3-10 cycloalkyl group eg, cyclopropyl, cyclohexyl
  • (2) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and (d) a C 6- optionally substituted with 1 to 3 substituents selected from hal
  • aryl groups eg, phenyl, naphthyl
  • (3) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, and (d) an aromatic complex which may be substituted with 1 to 3 substituents selected from halogen atoms.
  • a cyclic group (eg, thienyl, furyl, pyridyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl); (4) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (b) a hydroxy group, (c) a C 1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, (d) a non-aromatic heterocyclic group (eg, tetrahydrofuryl, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, piperazinyl) optionally substituted by 1 to 3 substituents selected from halogen atoms and (e) oxo groups ); (5) (a) a C 1-6 alkyl group which may be substituted with 1 to 3
  • the dienyl group, C 6-14 aryl group, C 7-13 aralkyl group and C 8-13 arylalkenyl group may have 1 to 3 substituents at substitutable positions. Examples of such a substituent include the same substituents as those of the “6-membered aromatic ring” in the “optionally substituted 6-membered aromatic ring” represented by ring A. When there are two or more substituents, each substituent may be the same or different.
  • the “optionally substituted hydrocarbon group” represented by R 1 is preferably An optionally substituted C 1-6 alkyl group, more preferably (1) a halogen atom, (2) a carboxy group, (3) a C 1-6 alkoxy-carbonyl group, and (4) a C 1-6 alkyl group which may be substituted with 1 to 3 substituents selected from amino groups which may be mono- or di-substituted with a C 1-6 alkyl group.
  • heterocyclic group in the “optionally substituted heterocyclic group” represented by R 1 include an aromatic heterocyclic group and a non-aromatic heterocyclic group.
  • examples of the aromatic heterocyclic group include 4 to 7 members (preferably 5 or 5) containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituent atom.
  • examples of the condensed aromatic heterocyclic group include a ring corresponding to the 4- to 7-membered monocyclic aromatic heterocyclic group and a 5- or 6-membered aromatic heterocyclic ring containing 1 or 2 nitrogen atoms.
  • Furyl eg, 2-furyl, 3-furyl
  • thienyl eg, 2-thienyl, 3-thienyl
  • pyridyl eg, 2-pyridyl, 3-pyridyl, 4-pyridyl
  • pyrimidinyl eg, 2-pyrimidinyl
  • 5-pyrimidinyl pyridazinyl
  • pyridazinyl eg, 3-pyridazinyl, 4-pyridazinyl
  • pyrazinyl eg, 2-pyrazinyl
  • pyrrolyl eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl
  • imidazolyl Eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl
  • pyrazolyl eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl
  • thiazolyl e
  • non-aromatic heterocyclic group examples include 4 to 7 members (preferably 5 or 6 members) containing 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms in addition to carbon atoms as ring constituent atoms.
  • Monocyclic non-aromatic heterocyclic group and condensed non-aromatic heterocyclic group examples include a ring corresponding to the 4- to 7-membered monocyclic non-aromatic heterocyclic group, and a 5- or 6-membered aromatic containing 1 or 2 nitrogen atoms.
  • 1 or 2 rings selected from a heterocycle (eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine), a 5-membered aromatic heterocycle containing one sulfur atom (eg, thiophene) and a benzene ring
  • a heterocycle eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine
  • a 5-membered aromatic heterocycle containing one sulfur atom eg, thiophene
  • benzene ring examples thereof include a group derived from a condensed ring and a group obtained by partial saturation of the group.
  • a non-aromatic heterocyclic group Pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl), piperidinyl (eg, piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), morpholinyl (eg, morpholino), thiomorpholinyl (eg, thiomorpholino), piperazinyl (eg, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl), hexamethyleneiminyl (eg, hexamethyleneimin-1-yl), oxazolidinyl (eg, oxazolidine-2-yl), thiazolidinyl (eg, thiazolidin-2-yl) ), Imidazolidinyl (eg, imidazolidin-2-yl, imidazolidin-3-yl), oxazolinyl (eg,
  • heterocyclic group in the “optionally substituted heterocyclic group” represented by R 1 may have 1 to 3 substituents at substitutable positions. Examples of such a substituent include the same substituents as those of the “6-membered aromatic ring” in the “optionally substituted 6-membered aromatic ring” represented by ring A.
  • an oxo group is further included as a substituent. When there are two or more substituents, each substituent may be the same or different.
  • the “optionally substituted heterocyclic group” represented by R 1 is preferably (1) (a) a C 1-6 alkyl group, (b) a hydroxy group, (c) a C 1-6 alkoxy group, and (d) an aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from a halogen atom; (2) (a) a C 1-6 alkyl group, (b) a hydroxy group, (c) a C 1-6 alkoxy group, (d) a halogen atom, and (e) a non-aromatic heterocyclic group (eg, pyrrolidinyl) optionally substituted with 1 to 3 substituents selected from an oxo group; Etc.
  • a non-aromatic heterocyclic group eg, pyrrolidinyl
  • Examples of the “optionally substituted amino group” represented by R 1 include 1 or 2 selected from a hydrocarbon group that may be substituted, a heterocyclic group that may be substituted, an acyl group, and the like. And an amino group which may be substituted with the above substituent. When there are two substituents, each substituent may be the same or different.
  • hydrocarbon group” in the “optionally substituted hydrocarbon group” exemplified as the “substituent” in the “optionally substituted amino group” represented by R 1 is 1 to You may have three substituents. Examples of such a substituent include the same substituents that the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R 1 may have. When there are two or more substituents, each substituent may be the same or different.
  • heterocyclic group in the “optionally substituted heterocyclic group” exemplified as the “substituent” in the “optionally substituted amino group” represented by R 1 is 1 to You may have three substituents. Examples of such a substituent include the same substituents that the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R 1 may have. When there are two or more substituents, each substituent may be the same or different.
  • the “optionally substituted amino group” represented by R 1 is preferably (1) a C 1-6 alkyl group; and (2) a C 1-6 alkoxy-carbonyl group; An amino group which may be mono- or di-substituted with a substituent selected from
  • Examples of the “acyl group” represented by R 1 include, for example, the formula: —COR A1 , —CO—OR A1 , —SO 3 R A1 , —SO 2 R A1 , —SOR A1 , —CO—NR A2 R B2 , —CS—NR A2 R B2 , —SO 2 NR A2 R B2 [wherein R A1 represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group.
  • R A2 and R B2 independently represent a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or R A2 and R B2 together with an adjacent nitrogen atom Form an optionally substituted nitrogen-containing heterocycle], and the like.
  • the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R A1 , R A2 or R B2 may have 1 to 3 substituents at substitutable positions. Examples of such a substituent include the same substituents that the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R 1 may have. When there are two or more substituents, each substituent may be the same or different.
  • heterocyclic group in the “optionally substituted heterocyclic group” represented by R A1 , R A2 or R B2 , for example, in the “optionally substituted heterocyclic group” represented by R 1
  • R A1 , R A2 or R B2 for example, in the “optionally substituted heterocyclic group” represented by R 1
  • R 1 The same thing as a “heterocyclic group” is mentioned.
  • the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R A1 , R A2 or R B2 may have 1 to 3 substituents at substitutable positions. Examples of such a substituent include the same substituents that the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R 1 may have. When there are two or more substituents, each substituent may be the same or different.
  • the “nitrogen-containing heterocycle” in the “optionally substituted nitrogen-containing heterocycle” formed by R A2 and R B2 together with the adjacent nitrogen atom is, for example, at least one nitrogen other than a carbon atom as a ring-constituting atom.
  • examples thereof include a 5- to 7-membered nitrogen-containing heterocyclic ring which contains an atom and may further contain 1 or 2 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom.
  • Specific examples of the nitrogen-containing heterocyclic ring include pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine and the like.
  • the “nitrogen-containing heterocycle” may have 1 to 3 substituents at substitutable positions.
  • substituents include the same substituents that the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R 1 may have.
  • each substituent may be the same or different.
  • the “acyl group” represented by R 1 is preferably (1) formyl group; (2) (a) a halogen atom, (b) a C 6-14 aryl group, (c) a C 1-6 alkoxy group, and (d) a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl) optionally substituted with 1 to 3 substituents selected from a heterocyclic group; (3) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, and (b) a C 6-14 aryl group; (4) A sulfamoyl group which may be mono- or di-substituted with a substituent selected from C 1-6 alkyl groups optionally substituted with 1 to 3 halogen atoms (eg, methylsulfamoyl, dimethylsulfato) Famoyl); (5)
  • R 1 is preferably (1) Halogen atom (eg, bromine atom); (2) (a) a halogen atom, (b) a carboxy group, (c) a C 1-6 alkoxy-carbonyl group, and (d) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted with a C 1-6 alkyl group; (3) (a) a C 1-6 alkyl group, (b) a hydroxy group, (c) a C 1-6 alkoxy group, and (d) an aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from halogen atoms (preferably a 5- or 6-membered aromatic heterocyclic group Ring group); (4) (a) a C 1-6 alkyl group, (b) a hydroxy group, (c) a C 1-6 alkoxy group, (d) a non-aromatic heterocyclic group (preferably a 4- to 7-membered non
  • a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl) optionally substituted by 1 to 3 substituents selected from: (8) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, and (b) a C 6-14 aryl group; (9) A sulfamoyl group which may be mono- or di-substituted with a substituent selected from C 1-6 alkyl groups which may be substituted with 1 to 3 halogen atoms (eg, methylsulfamoyl, dimethylsulfato) Famoyl); (10) a non-aromatic heterocyclic sulfonyl group optionally substituted with 1 to 3 substituents selected from C 1-6 alkyl groups optionally substituted with 1 to 3 halogen atoms (preferably A 4- to 7-membered non-aro
  • R 1 is more preferably (1) halogen atom (eg, bromine atom); (2) a carboxy group; (3) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (b) optionally substituted with 1 to 3 substituents selected from an oxo group A non-aromatic heterocyclic group (preferably a 5- or 6-membered non-aromatic heterocyclic group) (eg, pyrrolidinyl); (4) a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl) optionally substituted with 1 to 3 halogen atoms; (5) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl) optionally substituted by 1 to 3 halogen atoms; (6) a sulfamoyl group (eg, methylsulfamoyl, dimethylsulfamoyl) optionally mono- or di-substit
  • R 2 represents a cyano group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an acyl group.
  • Examples of the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R 2 include “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R 1. The same thing is mentioned.
  • the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R 2 may have 1 to 3 substituents at substitutable positions. Examples of such a substituent include the same substituents that the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R 1 may have. When there are two or more substituents, each substituent may be the same or different.
  • the “optionally substituted hydrocarbon group” represented by R 2 is preferably An optionally substituted C 1-6 alkyl group, more preferably (a) a halogen atom, (b) a carboxy group, (c) a C 1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl), and (d) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted with a C 1-6 alkyl group (eg, methyl) Etc.
  • C 1-6 alkyl group more preferably (a) a halogen atom, (b) a carboxy group, (c) a C 1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl), and (d) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted with a C 1-6 alkyl group (e
  • heterocyclic group in the “optionally substituted heterocyclic group” represented by R 2
  • heterocyclic group in the “optionally substituted heterocyclic group” represented by R 1. The same thing is mentioned.
  • heterocyclic group” in the “optionally substituted heterocyclic group” represented by R 2 may have 1 to 3 substituents at substitutable positions. Examples of such a substituent include the same substituents that the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R 1 may have. When there are two or more substituents, each substituent may be the same or different.
  • the “optionally substituted heterocyclic group” represented by R 2 is preferably (1) (a) a C 1-6 alkyl group (eg, ethyl, propyl), (b) a hydroxy group, (c) a C 1-6 alkoxy group, and (d) an aromatic heterocyclic group (eg, pyrimidinyl) optionally substituted with 1 to 3 substituents selected from halogen atoms; (2) (a) a C 1-6 alkyl group (eg, isopropyl), (b) a hydroxy group, (c) a C 1-6 alkoxy group, (d) a halogen atom, and (e) a non-aromatic heterocyclic group (eg, dihydrooxazolyl) optionally substituted with 1 to 3 substituents selected from an oxo group; Etc.
  • a C 1-6 alkyl group eg, ethyl, propyl
  • a hydroxy group e.g, a C
  • Examples of the “acyl group” represented by R 2 include the same “acyl group” represented by R 1 .
  • the “acyl group” represented by R 2 is preferably (1) (a) a halogen atom, (b) a C 6-14 aryl group, (c) a C 1-6 alkoxy group, and (d) a C 1-6 alkoxy-carbonyl group optionally substituted with 1 to 3 substituents selected from heterocyclic groups (eg, isopropylcarbonyl, tert- Butylcarbonyl); (2) (a) a halogen atom, (b) a C 1-6 alkyl group (eg, methyl, propyl, tert-butyl), (c) a C 6-14 aryl group, (d) a C 1-6 alkoxy group, and (e) a heterocyclic group (eg, pyridazinyl) A carbamoyl group which may be mono- or di-substituted with a substituent selected from: (3) (a) a C 1-6 alkyl group, and (b) a non-aromatic
  • R 2 is preferably (1) (a) a halogen atom, (b) a carboxy group, (c) a C 1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl), and (d) a C 1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted with C 1-6 alkyl group; (2) (a) a C 1-6 alkyl group (eg, ethyl, propyl), (b) a hydroxy group, (c) a C 1-6 alkoxy group, and (d) an aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from halogen atoms (preferably a 5- or 6-membered aromatic heterocyclic group Ring group) (eg, pyrimidinyl); (3) (a) a C 1-6 alkyl group (eg, isopropyl), (b) a hydroxy group, (c) a
  • a C 1-6 alkoxy-carbonyl group (eg, isopropylcarbonyl, tert-butylcarbonyl) optionally substituted with 1 to 3 substituents selected from: (5) (a) a halogen atom, (b) a C 1-6 alkyl group (eg, methyl, propyl, tert-butyl), (c) a C 6-14 aryl group, (d) a C 1-6 alkoxy group, and (e) a heterocyclic group (preferably a 4- to 7-membered heterocyclic group) (eg, pyridazinyl)
  • a carbamoyl group which may be mono- or di-substituted with a substituent selected from: (6) (a) a C 1-6 alkyl group, and (b) a non-aromatic heterocyclic oxycarbonyl group (preferably a 4- to 7-membered non-aromatic heterocyclic oxycarbonyl group) which may be substitute
  • R 2 is more preferably (1) (a) a halogen atom, and (b) C 1-6 alkoxy - carbonyl group (e.g., ethoxycarbonyl) 1 to 3 substituents optionally substituted by a C 1-6 alkyl group selected from (Eg, methyl); (2) an aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from (a) a halogen atom and (b) a C 1-6 alkyl group (eg, ethyl, propyl) (preferably Is a 5- or 6-membered aromatic heterocyclic group) (eg, pyrimidinyl); (3) Non-aromatic optionally substituted by 1 to 3 substituents selected from (a) a halogen atom, (b) a C 1-6 alkyl group (eg, isopropyl), and (c) an oxo group A heterocyclic group (preferably a 5- or 6-membered non-aromatic heterocyclic group) (eg,
  • X 1 represents an optionally substituted linear C 2-3 alkylene group.
  • linear C 2-3 alkylene group in the "optionally substituted linear C 2-3 alkylene group” represented by X 1, ethylene and trimethylene.
  • X 1 is preferably (1) a halogen atom; (2) hydroxy group; (3) a C 1-6 alkoxy group; (4) C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms (eg, methyl); And ethylene, trimethylene and the like, each of which may be substituted with 1 to 3 substituents selected from the above.
  • X 1 is more preferably (1) a halogen atom; (2) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms (eg, methyl); And ethylene, trimethylene and the like, each of which may be substituted with 1 to 3 substituents selected from
  • X 2 represents a bond, optionally substituted NH, S, SO, SO 2 , CO, or O.
  • NH in “NH which may be substituted” represented by X 2 may have one substituent.
  • substituents include the same substituents as those of the “6-membered aromatic ring” in the “optionally substituted 6-membered aromatic ring” represented by ring A.
  • the “optionally substituted NH” represented by X 2 is preferably (1) (a) a cyano group, and (b) 1 to 3 halogen atoms (eg, fluorine atoms) C 1-6 alkyl (eg, methyl, propyl) optionally substituted with 1 to 3 substituents selected from: (2) a C 1-6 alkyl-carbonyl group (eg, acetyl) optionally substituted by 1 to 3 halogen atoms; (3) a C 1-6 alkoxy-carbonyl group; (4) C 1-6 alkylsulfonyl group (eg, methylsulfonyl); NH which may be substituted with, and the like.
  • halogen atoms eg, fluorine atoms
  • C 1-6 alkyl eg, methyl, propyl
  • substituents selected from: (2) a C 1-6 alkyl-carbonyl group (eg, acetyl) optionally substituted by 1 to 3
  • X 2 is preferably (1) Bond hands; (2) O; (3) (a) (i) a cyano group, and (ii) 1 to 3 halogen atoms (eg, fluorine atoms) C 1-6 alkyl (eg, methyl, propyl) optionally substituted with 1 to 3 substituents selected from: (B) a C 1-6 alkyl-carbonyl group (eg acetyl) optionally substituted by 1 to 3 halogen atoms; (C) a C 1-6 alkoxy-carbonyl group; and (d) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl); NH optionally substituted with Etc.
  • halogen atoms eg, fluorine atoms
  • C 1-6 alkyl eg, methyl, propyl
  • substituents selected from: (B) a C 1-6 alkyl-carbonyl group (eg acetyl) optionally substitute
  • X 2 is more preferably (1) Bond hands; (2) O; (3) C 1-6 optionally substituted with 1 to 3 substituents selected from (a) (i) cyano group, and (ii) 1 to 3 halogen atoms (eg, fluorine atom) Alkyl (eg, methyl, propyl), (b) a C 1-6 alkyl-carbonyl group (eg, acetyl), or (c) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl); NH etc. which may be substituted with
  • X 3 represents a bond or a linear C 1-2 alkylene group which may be substituted.
  • linear C 1-2 alkylene group of the "substituted linear C 1-2 may be an alkylene group" represented by X 3, include methylene and ethylene.
  • X 3 is preferably (1) Bond hands; (2) (a) a halogen atom; and (b) C 1-6 alkyl; Methylene optionally substituted with 1 to 3 substituents selected from: Etc.
  • X 3 is more preferably a bond, methylene or the like.
  • Y 1 and Y 2 independently represent an optionally substituted linear C 1-3 alkylene group.
  • linear C 1-3 alkylene group in the “optionally substituted linear C 1-3 alkylene group” represented by Y 1 or Y 2, methylene, ethylene and trimethylene.
  • linear C 1-3 alkylene group of the "optionally substituted linear C 1-3 alkylene group” is substituted for 3 to 1 at substitutable positions It may have a group.
  • substituents include the same substituents as those of the “6-membered aromatic ring” in the “optionally substituted 6-membered aromatic ring” represented by ring A, an oxo group, and the like. When there are two or more substituents, each substituent may be the same or different.
  • Y 1 and Y 2 are preferably independently (1) a halogen atom; (2) a C 1-6 alkyl group; (3) an oxo group; And methylene, ethylene and the like, each of which may be substituted with 1 to 3 substituents selected from the above.
  • Y 1 and Y 2 are independently methylene, ethylene and the like.
  • Y 1 is more preferably methylene, ethylene or the like.
  • Y 2 is more preferably ethylene or the like.
  • Ring A is (1) a hydroxy group, (2) halogen atoms (eg, fluorine atoms, chlorine atoms), (3) a C 3-10 cycloalkoxy group optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, and (b) a C 1-6 alkoxy group, (4) (a) a halogen atom, (b) a carboxy group, (c) a hydroxy group, (d) a C 1-6 alkoxy-carbonyl group, (e) a C 1-6 alkoxy group, and (f) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted.
  • halogen atoms eg, fluorine atoms, chlorine atoms
  • C 3-10 cycloalkoxy group optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, and (b) a C 1-6
  • a 1-6 alkyl group (eg, methyl), and (5) (a) a halogen atom, (b) a carboxy group, (c) a hydroxy group, (d) a C 1-6 alkoxy-carbonyl group, (e) a C 1-6 alkoxy group, and (f) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted.
  • R 1 is (1) halogen atoms (eg, bromine atoms), (2) (a) a halogen atom, (b) a carboxy group, (c) a C 1-6 alkoxy-carbonyl group, and (d) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted with a C 1-6 alkyl group, (3) (a) a C 1-6 alkyl group, (b) a hydroxy group, (c) a C 1-6 alkoxy group, and (d) an aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from halogen atoms, (4) (a) a C
  • Ring A is (1) a hydroxy group, (2) halogen atoms (eg, fluorine atoms, chlorine atoms), (3) a C 3-10 cycloalkoxy group optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, and (b) a C 1-6 alkoxy group, (4) (a) a halogen atom, (b) a carboxy group, (c) a hydroxy group, (d) a C 1-6 alkoxy-carbonyl group, (e) a C 1-6 alkoxy group, and (f) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted.
  • halogen atoms eg, fluorine atoms, chlorine atoms
  • C 3-10 cycloalkoxy group optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, and (b) a C 1-6
  • a 1-6 alkyl group (eg, methyl), and (5) (a) a halogen atom, (b) a carboxy group, (c) a hydroxy group, (d) a C 1-6 alkoxy-carbonyl group, (e) a C 1-6 alkoxy group, and (f) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted.
  • R 1 is (1) halogen atoms (eg, bromine atoms), (2) (a) a halogen atom, (b) a carboxy group, (c) a C 1-6 alkoxy-carbonyl group, and (d) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted with a C 1-6 alkyl group, (3) (a) a C 1-6 alkyl group, (b) a hydroxy group, (c) a C 1-6 alkoxy group, and (d) a 5- or 6-membered aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from halogen atoms,
  • R 1 is (1) halogen atoms (eg, bromine atoms), (2) (a) a halogen atom, (b) a carboxy group, (c) a C 1-6 alkoxy-carbonyl group, and (d) a C 1-6 alkyl
  • Ring A is (1) halogen atom (eg, fluorine atom, chlorine atom), (2) a C 1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms, and (3) C 1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms (eg, methoxy) Benzene, pyridine, or pyrimidine (preferably benzene), each of which may be further substituted with 1 to 3 substituents selected from:
  • R 1 is (1) halogen atoms (eg, bromine atoms), (2) a carboxy group, (3) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (b) optionally substituted with 1 to 3 substituents selected from an oxo group
  • Non-aromatic heterocyclic groups eg, pyrrolidinyl
  • (4) a C 1-6 alkoxy-carbonyl group eg, methoxycarbonyl
  • X 1 is (1) a halogen atom, and (2) C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms (eg, methyl) Ethylene or trimethylene, each of which may be substituted with 1 to 3 substituents selected from:
  • X 2 is, (1) Joining hands, (2) O or (3) C 1-6 optionally substituted with 1 to 3 substituents selected from (a) (i) cyano group, and (ii) 1 to 3 halogen atoms (eg, fluorine atom) Alkyl (eg, methyl, propyl), (b) C 1-6 alkyl-carbonyl group (eg, acety
  • Ring A is (1) halogen atom (eg, fluorine atom, chlorine atom), (2) a C 1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms, and (3) C 1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms (eg, methoxy) Benzene, pyridine, or pyrimidine (preferably benzene), each of which may be further substituted with 1 to 3 substituents selected from:
  • R 1 is (1) halogen atoms (eg, bromine atoms), (2) a carboxy group, (3) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (b) optionally substituted with 1 to 3 substituents selected from an oxo group A 5- or 6-membered non-aromatic heterocyclic group (eg, pyrrolidinyl), (4) a C 1-6 alkoxy-carbonyl group (eg,
  • the salt of the compound represented by formula (I) is preferably a pharmacologically acceptable salt.
  • a salt with an inorganic base examples include a salt with an inorganic base, a salt with an organic base, and a salt with an inorganic acid. Salts, salts with organic acids, salts with basic or acidic amino acids, and the like.
  • the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt; ammonium salt and the like.
  • the salt with an organic base include trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, benzylamine, And salts with dicyclohexylamine, N, N-dibenzylethylenediamine and the like.
  • salt with inorganic acid examples include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfonic acid And salts with p-toluenesulfonic acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like.
  • salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
  • Compound (I) may be labeled with an isotope (eg, 3 H, 11 C, 14 C, 18 F, 35 S, 125 I) or the like.
  • Compound (I) may be a solvate (for example, an anhydride) or a solvate (for example, a hydrate).
  • a deuterium converter obtained by converting 1 H into 2 H (D) is also encompassed in compound (I).
  • the prodrug of the compound (I) is a compound that is converted to the compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, the compound (I) ), A compound that undergoes hydrolysis or the like due to gastric acid or the like and changes to compound (I).
  • the prodrug of compound (I) is a compound that changes to compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Drug Development”, Volume 7, Molecular Design, pages 163 to 198. It may be.
  • Compound (I) can be produced by a method known per se, for example, schemes 1 to 15 shown below or a method analogous thereto.
  • the starting compound may be used as a salt, and as such a salt, those exemplified as the salt of the compound represented by the formula (I) are used.
  • the solvent used in the reaction in each of the following schemes is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • aromatic hydrocarbons such as benzene, toluene and xylene; hexane Aliphatic hydrocarbons such as heptane; ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane; ketones such as acetone and 2-butanone; acetonitrile, pro Nitriles such as pionitrile; esters such as ethyl acetate, isopropyl acetate and tert-butyl acetate; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidinone; 3-dimethyl-2-imidazolidinone, etc.
  • Alcohols such as methanol, ethanol, isopropanol and tert-butanol; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; sulfoxides such as dimethyl sulfoxide; water and the like It is done. These solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually carried out below the boiling point of the above-mentioned solvent at ⁇ 100 to 250 ° C., but depending on the case, the reaction may be carried out at a temperature above the boiling point of the solvent using pressure resistant reaction conditions or the like.
  • the reaction time is usually 0.5 to 100 hours.
  • ring A, R 1 , R 2 , X 1 , X 2 , X 3 , Y 1 and Y 2 are as defined above.
  • Compound (I) can be produced, for example, according to the method shown in Scheme 1 or a method analogous thereto.
  • Z 1 represents a leaving group (for example, a halogen atom, —OSO 2 Me, —OSO 2 (4-tolyl), etc.).
  • compound (II) and compound (III) are coupled using, for example, triphosgene as a condensing agent in the presence of a base (eg, pyridine, 2,6-lutidine, triethylamine, diisopropylethylamine, etc.).
  • a base eg, pyridine, 2,6-lutidine, triethylamine, diisopropylethylamine, etc.
  • Compound (I) can be produced, for example, by reacting compound (II) with compound (IIIa) usually in the presence of a base.
  • Compound (I) can also be produced by reacting compound (II) with compound (IV) in the presence of a carbonate such as potassium carbonate or cesium carbonate.
  • a carbonate such as potassium carbonate or cesium carbonate.
  • Compound (II) can be produced by the methods shown in schemes 3 to 4 described later, methods known per se, or methods analogous thereto.
  • Compound (III) can be produced by the method shown in Schemes 5 to 7 described later, a method known per se, or a method analogous thereto.
  • Compound (IIIa) and compound (IV) can be produced from compound (III) according to a method known per se or a method analogous thereto.
  • Compound (I-1), Compound (I-2), Compound (I-3), Compound (I-4), Compound (I-5a) and Compound (I-) in which R 2 of Compound (I) is variously converted 5b) can be produced, for example, according to the method shown in Scheme 2 in which compound (Ia) is used as a raw material and compound (V) is used as an intermediate, or a method analogous thereto.
  • P a for example, tert- butoxycarbonyl, benzyloxycarbonyl, the protecting group of the amino group, such as benzyl, R 3 and R 4 independently the same groups as R A1
  • Ar is substituted
  • An optionally substituted C 6-14 aryl group eg, phenyl
  • an optionally substituted C 6-14 heteroaryl group eg, pyridyl, pyrimidinyl, oxadiazolyl
  • R 5a and R 5b are independently R 6 represents a group similar to R A2 or R B2
  • R 6 represents a group similar to the “optionally substituted hydrocarbon group” represented by R 2 .
  • R 6a and R 6b are independently a C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, pentyl, tert-pentyl), a C 6-14 aryl group ( Eg, phenyl) or a C 6-14 heteroaryl group (eg, pyridyl, pyrimidinyl, oxadiazolyl), Z 2 and Z 3 are independently the same groups as those exemplified as leaving groups (eg, Z 1) ).
  • a C 1-6 alkyl group eg, methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, pentyl, tert-pentyl
  • a C 6-14 aryl group Eg, phenyl
  • P a is for example, benzyloxycarbonyl, the case such as benzyl, these protecting groups are, for example, palladium / carbon, can be deprotected by using hydrogenation, or acid using a palladium hydroxide / carbon.
  • P a, for example tert- butoxycarbonyl, when such as a benzyloxycarbonyl, can be deprotected by using for example trifluoroacetic acid, an acid such as hydrochloric acid.
  • Compound (I-1) is usually prepared by using, for example, a coupling reagent (eg, triphosgene, CDI (1,1′-carbonyldiimidazole)) to produce alcohol (R 3 OH) and compound (V). It can be prepared by coupling in the presence of a base or by acylating compound (V) with chloroformate (R 3 OCOCl).
  • a coupling reagent eg, triphosgene, CDI (1,1′-carbonyldiimidazole)
  • Compound (I-2) is, for example, 4- (4,6-dimethoxy-1,3,5-triazine- Using a coupling reagent such as 2-yl) -4-methyl-morpholinium chloride, 1-ethyl-3-dimethylaminopropylcarbodiimide, 2-methyl-6-nitrobenzoic anhydride, the carboxylic acid (R 4 COOH) and compound (V) can be coupled in the presence of a base, if necessary, or can be prepared by acylating compound (V) with acyl chloride (R 4 COCl).
  • a coupling reagent such as 2-yl) -4-methyl-morpholinium chloride, 1-ethyl-3-dimethylaminopropylcarbodiimide, 2-methyl-6-nitrobenzoic anhydride
  • the carboxylic acid (R 4 COOH) and compound (V) can be coupled in the presence of a base, if necessary, or can be prepared by acylating compound (V) with
  • Compound (I-3) is, for example, an aryl halide or aryl sulfonate (Ar—Z 2 ) and compound (V), usually in the presence of a base and appropriately with a palladium catalyst or a copper catalyst as necessary.
  • a method known per se in the presence of a ligand for example, Organic Letters (Org. Lett.) Vol. 2, p. 1101 (2000), Journal of the American Chemical Society (J. Am. Chem. Soc.), No. 128. Vol. 8742 (2006) or Organic Process Research and Development (Org. Process Res. Dev.) Vol. 12, 480 (2008), etc. Can be manufactured by ringing.
  • Compound (I-4) is prepared by, for example, using a coupling reagent (eg, triphosgene, CDI (1,1′-carbonyldiimidazole)) to convert amine (R 5a R 5b NH) and compound (V) Usually, it can be prepared by coupling in the presence of a base or acylating compound (V) with carbamoyl chloride (R 5a R 5b NCOCl).
  • a coupling reagent eg, triphosgene, CDI (1,1′-carbonyldiimidazole)
  • Compound (I-5a) can be produced, for example, by alkylating compound (V) with an alkyl halide or alkyl sulfonate (R 6 -Z 3 ) and a base.
  • Compound (I-5b) is prepared, for example, by using aldehyde or ketone (R 6a -CO—R 6b ) and a suitable reducing agent (for example, sodium triacetoxyborohydride, picoline-borane complex, etc.) It can manufacture by performing reductive amination of.
  • Compound (Ia) can be produced by the method shown in the above-mentioned scheme 1 or schemes 8 to 11 described later, or a method analogous thereto.
  • Compound (II-1) in which R 1 of compound (II) is hydrogen, Compound (II-2) that is an alkylthio group, Compound (II-3) that is an alkylsulfinyl group, and Compound (II) that is an alkylsulfonyl group -4) can be produced, for example, according to the method shown in scheme 3 using compound (II-1a) as a raw material or a method analogous thereto.
  • P b is an amino-protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, etc.
  • R 7 is the same group as R A1
  • Z 4 is a leaving group (eg, Z 1 The same groups as illustrated).
  • Compound (II-1) can be obtained, for example, by reacting compound (II-1a) with a suitable reducing agent (for example, sodium cyanoborohydride-acetic acid, triethylsilane-trifluoroacetic acid, etc.) or palladium / It can be produced by subjecting it to conditions such as catalytic reduction using carbon, palladium hydroxide / carbon and the like.
  • a suitable reducing agent for example, sodium cyanoborohydride-acetic acid, triethylsilane-trifluoroacetic acid, etc.
  • palladium / It can be produced by subjecting it to conditions such as catalytic reduction using carbon, palladium hydroxide / carbon and the like.
  • bromine and potassium thiocyanate are allowed to act on the compound (II-1), followed by a base such as an aqueous sodium hydroxide solution, and then an alkyl halide or an alkyl sulfonate (R 7- Z 4 ) can be produced.
  • Compound (II-2a) is usually pyridine, triethylamine or N, N′-dimethyl relative to compound (II-2) when P b is, for example, benzyloxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl or the like.
  • P b is, for example, benzyloxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl or the like.
  • presence of a base such as aminopyridine, may be prepared by the action of such chloroformate esters and di carbonic acid diester corresponding to P b.
  • Compound (II-1a) can be produced according to a method known per se.
  • Compound (II) is a method similar to the reduction of compound (II-1a) from compound (II-1a) shown in scheme 3 to compound (II-1) as shown in scheme 4, for example. Or according to a method equivalent thereto.
  • Compound (II-a) can be produced according to a method known per se.
  • R 8a is a C 1-6 alkyl group (eg, methyl, ethyl, tert-butyl) or C 7-10 aralkyl group (eg, benzyl), and R 9a is a C 1-6 alkyl group (eg, benzyl).
  • Methyl, ethyl, tert-butyl C 1-6 alkoxy group (eg, methoxy, ethoxy, isopropoxy) or an optionally substituted amino group (eg, acetylamino, benzyloxyamino, tert-butoxycarbonylamino)
  • R 9ba , R 9bb and R 9c independently represent an optionally substituted C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, trifluoromethyl).
  • Compound (III-1c) was obtained by subjecting compound (III-1a) to conditions known per se, for example, the method described in Chemical Review (Chem. Rev.), 89, 863 (1989) or the like.
  • the carbon is increased by a method to obtain the compound (III-1b), and then catalytic reduction (eg, hydrogen-palladium / carbon, hydrogen-platinum oxide, hydrogen-palladium hydroxide / carbon, hydrogen-palladium / carbon ethylenediamine complex), etc. It can manufacture by reducing on condition.
  • Compound (III-1) is an appropriate reducing agent (for example, sodium borohydride, sodium borohydride-calcium chloride, sodium borohydride-lithium chloride, lithium aluminum hydride, etc.) relative to compound (III-1c) ) Can be produced.
  • an appropriate reducing agent for example, sodium borohydride, sodium borohydride-calcium chloride, sodium borohydride-lithium chloride, lithium aluminum hydride, etc.
  • Compound (III-2) can be produced by reacting compound (III-1c) with an organometallic reagent corresponding to R 9b (eg, a Grignard reagent or an alkyl lithium reagent).
  • organometallic reagent corresponding to R 9b eg, a Grignard reagent or an alkyl lithium reagent.
  • Compound (III-3) acts on compound (III-3a) produced from compound (III-1) with an organometallic reagent corresponding to R 9c (eg, Grignard reagent or alkyllithium reagent). Can be manufactured.
  • R 9c eg, Grignard reagent or alkyllithium reagent
  • R 9c is trifluoromethyl, for example, the method described in Journal of the American Chemical Society, Vol. 111, page 393 (1989), or the like It can be manufactured by a method or the like.
  • Compound (III-3a), which is a starting compound of compound (III-3), is obtained by subjecting compound (III-1) to conditions known per se, for example, Journal of Organic Chemistry (J. Org. Chem.) Vol. 48, It can be produced by oxidation by the method described in page 4155 (1983) or synthesis page 639 (1994), or a method analogous thereto.
  • Compound (III-1a) can be produced according to a method known per se.
  • R 8b represents the same group as R 8a
  • R 9d represents the same group as R 9a
  • R 9ea , R 9eb and R 9f independently represent the same groups as R 9b and R 9c .
  • Compound (III-4b) can be obtained by using conditions known per se, for example, a coupling reagent (eg, CDI (1,1′-carbonyldiimidazole), 1-ethyl-3-dimethylaminopropylcarbodiimide, etc.) (III-4a) and N, O-dimethylhydroxylamine can be usually produced by coupling in the presence of a base.
  • a coupling reagent eg, CDI (1,1′-carbonyldiimidazole), 1-ethyl-3-dimethylaminopropylcarbodiimide, etc.
  • N, O-dimethylhydroxylamine can be usually produced by coupling in the presence of a base.
  • Compound (III-4c) can be produced by a method known per se, for example, the method described in Tetrahedron Letters Vol. 22, p. 3815 (1981) or the like or a method analogous thereto. -4b).
  • Compound (III-4a) can be produced according to a method known per se.
  • Compound (III-7) wherein X 1 -X 2 of compound (III) is —CH 2 CHR 10 X 2a — can be produced, for example, according to the method shown in Scheme 7 or a method analogous thereto.
  • X 2a represents optionally substituted NH, S, SO, SO 2 or O
  • R 8c represents the same group as R 8a
  • R 10 represents the same group as R 9a
  • Z 5 represents A leaving group (eg, a group similar to that exemplified as Z 1 ) is shown.
  • Compound (III-7b) can be produced under conditions known per se, for example, by alkylating compound (III-7a) with an ester (R 10 CHZ 5 COOR 7c ) usually in the presence of a base.
  • Compound (III-7) can be produced, for example, by a method similar to the method for producing compound (III-1) from compound (III-1c) shown in Scheme 5.
  • Compound (III-7a) can be produced according to a method known per se.
  • P c is an amino-protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, etc.
  • R 11 is an amino group substituent (for example, “optionally substituted” represented by X 2 And the same groups as those exemplified as the substituent in “NH”.
  • Compound (VII) can be produced, for example, according to the same method as shown in scheme 1 or a method analogous thereto.
  • Compound (VIII) in the same manner as the deprotection of P a shown in Scheme 2, a protecting group P c of the compound (VII) can be prepared by deprotecting.
  • Compound (I-6) is prepared, for example, by combining compound (VIII) and compound (III-1a) with an appropriate reducing agent (for example, sodium triacetoxyborohydride, picoline-borane complex, hydrogen-palladium / carbon, etc.). It can manufacture by performing reductive amination using.
  • an appropriate reducing agent for example, sodium triacetoxyborohydride, picoline-borane complex, hydrogen-palladium / carbon, etc.
  • Compound (I-7) is compound (I-1), compound (I-2), compound (I-3) from compound (V) shown in scheme 2 using compound (I-6) as a starting compound.
  • the compound can be produced by introducing R 11 according to a method similar to the method for producing the compound (I-4) and the compound (I-5) or a method analogous thereto.
  • Compound (II) can be produced by the methods shown in the above-mentioned schemes 3 to 4, or a method known per se, or a method analogous thereto.
  • Compound (I-8) wherein X 2 of compound (I) is X 2b can be produced, for example, according to the method shown in Scheme 9 or a method analogous thereto.
  • X 2b represents optionally substituted NH, S, SO, SO 2 or O
  • Z 6 represents a leaving group (eg, the same group as exemplified as Z 1 ).
  • Compound (X) can be produced, for example, according to a method similar to the method shown in Scheme 1 or a method analogous thereto.
  • Compound (I-8) is produced, for example, by alkylating compound (XI) with compound (X) usually in the presence of a base (eg, sodium hydride, potassium tert-butoxide). be able to.
  • a base eg, sodium hydride, potassium tert-butoxide
  • Compound (II) can be produced by the methods shown in the above-mentioned schemes 3 to 4, or a method known per se, or a method analogous thereto.
  • the compound (I-9) in which R 1 of the compound (I) is COOR 8d , the compound (I-10) in which COOH is COOH, and the compound (I-11) in which CONR 12a R 12b is used can be prepared, for example, by the method shown in Scheme 10. Or according to a method according to these methods.
  • R 8d represents the same group as R 8a
  • R 12a and R 12b independently represent the same group as R A2 or R B2 .
  • Compound (I-10) is obtained by, for example, hydrolyzing compound (I-9) with a base (eg, potassium hydroxide aqueous solution, sodium hydroxide aqueous solution, lithium hydroxide aqueous solution) or an acid (eg, hydrochloric acid, sulfuric acid).
  • a base eg, potassium hydroxide aqueous solution, sodium hydroxide aqueous solution, lithium hydroxide aqueous solution
  • an acid eg, hydrochloric acid, sulfuric acid.
  • Compound (I-11) is a method for producing compound (I-2) from compound (V) shown in Scheme 2 using compound (I-10) and amine (R 12a R 12b NH) as starting compounds. It can be produced according to a similar method or a method analogous thereto.
  • Compound (I-9) can be produced by the methods shown in the above-mentioned schemes 1 and 2, schemes 8 to 9, or schemes 13 to 15 described later, or a method analogous thereto.
  • R 1 of compound (I) is SO 2 NR 13a R 13b
  • R 13a and R 13b independently represent the same group as R A2 or R B2 .
  • Compound (I-12a) can be produced, for example, by reacting compound (XII) with chlorosulfonic acid.
  • Compound (I-12) was prepared by reacting compound (I-12a) with an amine (R 13a R 13b NH) and converting the resulting compound from compound (V) to compound (I-1) shown in Scheme 2.
  • Compound (XII) can be produced by the methods shown in the above-mentioned schemes 1 and 2, schemes 8 to 9, or schemes 13 to 15 described later, or a method analogous thereto.
  • R 1 of compound (I) is R 14a R 14b N
  • R 14a and R 14b are the same groups as R A2 or R B2
  • Z 7 is a leaving group (eg, a halogen atom or —OSO 2 CF 3 , —OSO 2 (4-tolyl), etc.). Show.
  • Compound (I-14) is prepared by, for example, compound (I-13) and an amine compound (R 14a R 14b NH) usually in the presence of a base, in the presence of a palladium catalyst or a copper catalyst, and an appropriate ligand.
  • a method known per se for example, Organic Letters, Vol. 2, 1101, 2000), Journal of the American Chemical Society, Vol. 128, 8742. Page (2006) or organic process research and development (Org. Process Res. Dev.) Vol. 12, page 480 (2008), etc. Can be manufactured by.
  • Compound (I-13) can be produced by the methods shown in the above-mentioned schemes 1 and 2, schemes 8 to 9, or schemes 13 to 15 described later, or a method analogous thereto.
  • R 15 represents a C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, tert-butyl) or a C 6-10 aryl group (eg, phenyl, pyridyl, pyrimidinyl).
  • Compound (I-15) is produced from compound (XIIIa) via compound (XIIIb) by a method known per se (for example, the method described in WO2007 / 061661 or a method analogous thereto). It can be produced by reacting the obtained compound (XIII) with compound (V).
  • the compound (V) can be produced by the method shown in the above-mentioned scheme 2 or a method analogous thereto.
  • Compound (I-16) can be produced, for example, according to the method shown in Scheme 14 or a method analogous thereto.
  • R 16 represents the same group as R 15 .
  • Compound (XIV) can be obtained by reacting trimethylsilylmethyl azide with triphenylphosphine and carbon disulfide (for example, Journal of Organic Chemistry (J. Org. Chem.) 52, 1027 (1987)). Described method) or a method similar thereto.
  • Compound (I-16) can be synthesized with compound (V) by a method known per se (for example, the method described in Heterocycles Vol. 45, page 1405 (1997)) or a method analogous thereto. It can be produced from compound (XIV) via compound (I-16a).
  • the compound (V) can be produced by the method shown in the above-mentioned scheme 2 or a method analogous thereto.
  • R 17 is a C 1-6 alkyl group (eg, methyl, ethyl, propyl, propyl, isopropyl, tert-butyl) C 5-10 aryl group (eg, oxadiazolyl, tetrazolyl, triazolyl, pyrazolyl, phenyl, pyridyl, Pyrimidinyl), cyano, or halogen
  • R 18 represents a group similar to R A2 or R B2
  • Z 8 represents a leaving group (eg, a group similar to those exemplified as Z 1 ).
  • Compound (XVI) can be produced, for example, by reacting compound (XV) with phenyl chloroformate in the presence of a base such as pyridine.
  • Compound (I-17) can be produced by reacting compound (V) with compound (XVI) usually in the presence of a base.
  • Compound (I-18) can be produced by alkylating compound (I-17) with compound (R 18 -Z 7 ) and a base.
  • the compound (V) can be produced by the method shown in the above-mentioned scheme 2 or a method analogous thereto.
  • a protective group generally used in peptide chemistry or the like is introduced into these groups.
  • the target compound can be obtained by removing the protecting group as necessary after the reaction.
  • Examples of the protecting group for amino group include formyl group, C 1-6 alkyl-carbonyl group, C 1-6 alkoxy-carbonyl group, benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), C 7-14 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), trityl group, phthaloyl group, N, N-dimethylaminomethylene group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, Dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl groups (eg, 1-allyl) and the like. These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkoxy group and a
  • Examples of the protecting group for the carboxyl group include a C 1-6 alkyl group, a C 7-11 aralkyl group (eg, benzyl), a phenyl group, a trityl group, a substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl groups (eg, 1-allyl) and the like. These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkoxy group and a nitro group.
  • Examples of the protecting group for the hydroxy group include a C 1-6 alkyl group, a phenyl group, a trityl group, a C 7-10 aralkyl group (eg, benzyl), a formyl group, a C 1-6 alkyl-carbonyl group, a benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert -Butyldiethylsilyl), C 2-6 alkenyl group (eg, 1-allyl) and the like. These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkyl group, a C
  • Examples of the protecting group for the carbonyl group include cyclic acetals (eg, 1,3-dioxane), acyclic acetals (eg, di-C 1-6 alkylacetal) and the like.
  • Examples of the protecting group for the mercapto group include a C 1-6 alkyl group, a phenyl group, a trityl group, a C 7-10 aralkyl group (eg, benzyl), a C 1-6 alkyl-carbonyl group, a benzoyl group, a C 7- 10 aralkyl-carbonyl group (eg, benzylcarbonyl), C 1-6 alkoxy-carbonyl group, C 6-14 aryloxy-carbonyl group (eg, phenyloxycarbonyl), C 7-14 aralkyloxy-carbonyl group (eg, Benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), 2-tetrahydropyranyl group, C 1-6 alkylamino-carbonyl group (eg, methylaminocarbonyl, ethylaminocarbonyl) and the like. These groups may be substituted with 1 to 3 substituents selected
  • the method for removing the protecting group described above can be carried out according to a method known per se, for example, the method described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (1980). . Specifically, acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (eg, trimethylsilyl iodide, trimethylsilyl bromide), etc. are used. And a reduction method.
  • a method known per se for example, the method described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (1980). . Specifically, acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsily
  • the compound of the present invention obtained by each of the above production methods can be isolated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution, chromatography and the like. Moreover, each raw material compound used in each of the above production methods can be isolated and purified by the same known means as described above. On the other hand, you may use these raw material compounds as a reaction mixture as it is as a raw material for the next step without isolation.
  • compound (I) contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compound (I), and are synthesized by known synthesis methods and separation methods, respectively. Can be obtained as a single product.
  • compound (I) has an optical isomer, the optical isomer resolved from the compound is also encompassed in compound (I).
  • Compound (I) may be a crystal. Crystals of compound (I) (hereinafter sometimes abbreviated as crystals of the present invention) can be produced by crystallization by applying a crystallization method known per se to compound (I). In the present specification, the melting point is measured using, for example, a trace melting point measuring device (Yanako, MP-500D type or Buchi, B-545 type) or a DSC (differential scanning calorimetry) apparatus (SEIKO, EXSTAR6000). Mean melting point. In general, the melting point may vary depending on measurement equipment, measurement conditions, and the like. The crystal in the present specification may be a crystal exhibiting a value different from the melting point described in the present specification as long as it is within a normal error range.
  • the crystals of the present invention are excellent in physicochemical properties (eg, melting point, solubility, stability) and biological properties (eg, pharmacokinetics (absorbability, distribution, metabolism, excretion), expression of medicinal properties), and are extremely useful as pharmaceuticals. Useful.
  • Compound (I) or a prodrug thereof (hereinafter, sometimes simply abbreviated as the compound of the present invention) has low toxicity and should be used as it is or mixed with a pharmacologically acceptable carrier to form a pharmaceutical composition.
  • a pharmaceutical composition e.g, a preventive or therapeutic agent for various diseases described below for mammals (eg, humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys).
  • the pharmacologically acceptable carrier various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations , Solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents and the like. If necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.
  • excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light
  • excipients include anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminate metasilicate.
  • lubricant examples include magnesium stearate, calcium stearate, talc and colloidal silica.
  • Preferred examples of the binder include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxy Examples include propylmethylcellulose and polyvinylpyrrolidone.
  • disintegrant examples include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, and low-substituted hydroxypropyl cellulose.
  • Suitable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. Is mentioned.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; polyvinyl alcohol, polyvinylpyrrolidone , Hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, and polyoxyethylene hydrogenated castor oil.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate
  • polyvinyl alcohol, polyvinylpyrrolidone Hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,
  • Preferable examples of the isotonic agent include sodium chloride, glycerin, D-mannitol, D-sorbitol and glucose.
  • buffer solutions of phosphate, acetate, carbonate, citrate and the like Preferable examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like.
  • a preferred example of the soothing agent is benzyl alcohol.
  • Preferable examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.
  • Preferable examples of the antioxidant include sulfite and ascorbate.
  • the colorant examples include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2, etc.), water-insoluble lake dyes (Eg, the aluminum salt of the water-soluble edible tar dye) and natural dyes (eg, ⁇ -carotene, chlorophyll, bengara).
  • water-soluble edible tar dyes eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2, etc.
  • water-insoluble lake dyes Eg, the aluminum salt of the water-soluble edible tar dye
  • natural dyes eg, ⁇ -carotene, chlorophyll, bengara
  • Suitable examples of sweeteners include saccharin sodium, dipotassium glycyrrhizinate, aspartame, and stevia.
  • the medicament containing the compound of the present invention can be used alone or mixed with a pharmacologically acceptable carrier according to a method known per se as a method for producing a pharmaceutical preparation (eg, a method described in the Japanese Pharmacopoeia).
  • tablets including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.
  • pills powders, granules, capsules (including soft capsules and microcapsules), troches Agent, syrup, solution, emulsion, suspension, controlled release formulation (eg, immediate release formulation, sustained release formulation, sustained release microcapsule), aerosol, film agent (eg, orally disintegrating film, Oral mucosa adhesive film), injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), drip, transdermal preparation, ointment, lotion, patch, sitting Suppositories (eg, rectal suppositories) Vaginal suppositories), pellets,
  • the pharmaceutical composition can be produced by a method commonly used in the field of pharmaceutical technology, for example, a method described in the Japanese Pharmacopoeia.
  • the content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention, etc., but is, for example, about 0.1 to 100% by weight.
  • an oral preparation When manufacturing an oral preparation, it may be coated for the purpose of taste masking, enteric solubility or sustainability, if necessary.
  • coating base used for coating examples include sugar coating base, water-soluble film coating base, enteric film coating base and sustained-release film coating base.
  • sucrose is used, and one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.
  • water-soluble film coating base examples include cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name) ], Synthetic polymers such as polyvinylpyrrolidone; polysaccharides such as pullulan.
  • enteric film coating bases include cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name) ] Acrylic acid polymers such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)], methacrylic acid copolymer S [Eudragit S (trade name)]; natural products such as shellac.
  • cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate
  • methacrylic acid copolymer L (Eudragit L (trade name) ]
  • Acrylic acid polymers such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)], methacrylic acid copolymer
  • sustained-release film coating base examples include cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit Acrylic polymer such as NE (trade name)].
  • cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit Acrylic polymer such as NE (trade name)].
  • the above-mentioned coating bases may be used by mixing two or more of them in an appropriate ratio. Moreover, you may use light-shielding agents, such as a titanium oxide, ferric oxide, etc. in the case of coating.
  • the compound of the present invention has low toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity), few side effects, and mammals (eg, humans, cows, horses, dogs, cats, Monkeys, mice, rats) can be used as preventive or therapeutic agents for various diseases described later, or as diagnostic agents.
  • toxicity eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity
  • mammals eg, humans, cows, horses, dogs, cats, Monkeys, mice, rats
  • the compound of the present invention has an excellent GPR119 agonistic action.
  • GPR119 agonist activates GPR119 expressed in pancreatic ⁇ cells to promote insulin secretion, and activates GPR119 expressed in the intestinal tract to secrete glucagon-like peptide-1 (GLP-1) To promote. That is, the compound of the present invention has a blood glucose lowering action, an insulin secretion promoting action, a GLP-1 secretion promoting action and a pancreatic ⁇ -cell protecting action.
  • the compound of the present invention may have a glucose-dependent insulinotropic polypeptide (GIP) secretion promoting action, a peptide YY (PYY) secretion promoting action, an antifeedant action, and a glucagon secretion inhibiting action.
  • GIP glucose-dependent insulinotropic polypeptide
  • PYY peptide YY
  • the compound of the present invention can be used as a GPR119 agonist.
  • the compound of the present invention can be used as a prophylactic or therapeutic agent for a disease state or disease in which GPR119 is involved.
  • the compound of the present invention includes, for example, a preventive / therapeutic agent for diabetes (eg, type 1 diabetes, type 2 diabetes, gestational diabetes, obesity type diabetes), insulin secretagogue, GLP-1 secretagogue, pancreatic ⁇ cell protective agent, It can be used as a GIP secretion promoter, a PYY secretion promoter, a prophylactic / therapeutic agent for glucose intolerance [IGT (Impaired Glucose Tolerance)], and a transition inhibitor from glucose intolerance to diabetes.
  • a preventive / therapeutic agent for diabetes eg, type 1 diabetes, type 2 diabetes, gestational diabetes, obesity type diabetes
  • insulin secretagogue e.g., GLP-1 secretagogue
  • pancreatic ⁇ cell protective agent e.g, pancreatic ⁇ cell protective agent
  • GIP secretion promoter e.g, type 1 diabetes, type 2 diabetes, gestational diabetes, obesity type diabetes
  • PYY secretion promoter e.g
  • the compounds of the present invention are obesity, hyperlipidemia (eg, hypertriglyceridemia, hypercholesterolemia, high LDL cholesterolemia, low HDL cholesterolemia, postprandial hyperlipidemia), hypertension, heart failure, diabetes Complications [eg, neuropathy, nephropathy, diabetic retinopathy, diabetic cardiomyopathy, cataract, macrovascular disorder, osteopenia, diabetic hyperosmolar coma, infection (eg, respiratory infection, urine] Tract infection, digestive tract infection, skin soft tissue infection, lower limb infection), diabetic gangrene, xerostomia, hearing loss, cerebrovascular disorder, peripheral blood circulation disorder], metabolic syndrome (Japan Society of Obesity in 2005) According to the diagnostic criteria in Japanese reported by et al., Metabolic syndrome means that the waist circumference is 85 cm for men and 90 cm or more for women, and systolic blood pressure is 130 or more or diastolic blood pressure is 85 mm.
  • Metabolic syndrome means that the waist circumference is 85
  • g or more, neutral triglyceride 150 mg / dl or more or HDLc less than 40 mg / dl, and fasting blood glucose level (glucose concentration in venous plasma) is 2 mg or more among 3 items. It can be used as a preventive / therapeutic agent.
  • diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or higher, and a 75 g oral glucose tolerance test (75 gOGTT) 2-hour value (glucose concentration in venous plasma) of 200 mg / dl or higher.
  • 75 gOGTT 75 g oral glucose tolerance test
  • a fasting blood glucose level (glucose concentration in venous plasma) is less than 110 mg / dl or a 75 g oral glucose tolerance test (75 g OGTT) 2 hour value (glucose concentration in venous plasma) is 140 mg / dl.
  • a state that is not “a state indicating less than dl” (normal type) is referred to as a “boundary type”.
  • diabetes is a diabetes-like symptom (polyuria, heavy drinking, overeating, overwork, weight loss, foggy vision, growth disorder), and anytime blood glucose level (glucose concentration in venous plasma) It is a state in which 200 mg / dl or more, fasting blood glucose level (glucose concentration in venous plasma) is 126 mg / dl or more, and 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) is 200 mg / dl or more. .
  • diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or higher, or a 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) of 200 mg / dl or higher. It is the state which shows.
  • glucose intolerance is a fasting blood glucose level (glucose concentration in venous plasma) of less than 126 mg / dl, and a 2-hour value of 75 g oral glucose tolerance test (glucose concentration in venous plasma). Is a state showing 140 mg / dl or more and less than 200 mg / dl. Furthermore, according to the report of ADA, the state where the fasting blood glucose level (glucose concentration in venous plasma) is 110 mg / dl or more and less than 126 mg / dl is called IFG (Impaired Fasting Glucose).
  • the IFG is a state in which the 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) is less than 140 mg / dl as IFG (Impaired Fasting Glycemia). Call.
  • the compound of the present invention is also used as a prophylactic / therapeutic agent for diabetes, borderline type, glucose intolerance, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glycemia) determined by the above-mentioned new criteria. Furthermore, the compound of the present invention has a boundary type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) or IFG (Impaired Fasting Glycemia). ) To diabetes can also be prevented.
  • the compounds of the present invention include, for example, cognitive impairment, osteoporosis, cachexia (eg, cancer cachexia, tuberculosis cachexia, diabetic cachexia, hematological cachexia, endocrine cachexia, infectious cachexia) Or cachexia due to acquired immune deficiency syndrome), fatty liver, polycystic ovary syndrome, kidney disease (eg, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage kidney) Disease), muscular dystrophy, myocardial infarction, angina pectoris, cerebrovascular disorder (eg, cerebral infarction, stroke), insulin resistance syndrome, syndrome X, hyperinsulinemia, sensory disturbance in hyperinsulinemia, tumor (eg, leukemia) , Breast cancer, prostate cancer, skin cancer), irritable bowel syndrome, acute or chronic diarrhea, inflammatory disease (eg, arteriosclerosis (eg, atherosclerosis), rhe
  • the compound of the present invention can also be used to improve symptoms such as peptic ulcer, acute or chronic gastritis, biliary dyskinesia, abdominal pain associated with cholecystitis, nausea, vomiting and upper abdominal discomfort.
  • the compound of the present invention has a pancreatic ⁇ -cell protective action, it can be used to improve the prognosis at the time of islet transplantation.
  • the compound of the present invention reduces visceral fat, suppresses visceral fat accumulation, improves glucose metabolism, improves lipid metabolism, improves insulin resistance, suppresses oxidized LDL production, improves lipoprotein metabolism, improves coronary metabolism, prevents cardiovascular complications It is also used for treatment, prevention and treatment of heart failure complications, blood remnant reduction, anovulation prevention and treatment, hirsutism prevention and treatment, hyperandrogenemia prevention and treatment, etc.
  • the compound of the present invention is also used for secondary prevention and progression suppression of the various diseases described above (eg, cardiovascular events such as myocardial infarction).
  • cardiovascular events such as myocardial infarction
  • the dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptom, etc.
  • the dose is usually about 0.01 to 100 mg / kg body weight. It is preferably 0.05 to 30 mg / kg body weight, more preferably 0.1 to 10 mg / kg body weight, still more preferably 0.3 to 5 mg / kg body weight, and this amount is once to 3 times a day. It is desirable to administer.
  • the compound of the present invention comprises a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, an antihypertensive agent, an antiobesity agent, a diuretic agent, a chemotherapeutic agent, an immunotherapeutic agent, an antithrombotic agent, a therapeutic agent for osteoporosis, It can be used in combination with a drug (hereinafter abbreviated as a concomitant drug) such as a dementia agent, an erectile dysfunction improving agent, a urinary incontinence / frequent urination therapeutic agent, or a dysuria therapeutic agent.
  • a concomitant drug such as a dementia agent, an erectile dysfunction improving agent, a urinary incontinence / frequent urination therapeutic agent, or a dysuria therapeutic agent.
  • concomitant drugs may be low molecular compounds, high molecular proteins, polypeptides, antibodies, or vaccines.
  • the administration timing of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference.
  • the dosage form is not particularly limited as long as the compound of the present invention and the concomitant drug are combined.
  • Examples of such dosage forms include: (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, (2) Simultaneous administration by the same route of administration of two preparations obtained by separately formulating the compound of the present invention and a concomitant drug, (3) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug at the same administration route with a time difference, (4) Simultaneous administration by different administration routes of two kinds of preparations obtained by separately formulating the compound of the present invention and a concomitant drug, (5) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug at different time intervals in different administration routes (for example, administration in the order of the compound of the present invention and the concomitant drug, or Administration in reverse order) Etc.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like.
  • the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.
  • insulin preparations eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations genetically engineered using Escherichia coli and yeast; insulin zinc; protamine insulin zinc; insulin Fragment or derivative (eg, INS-1), oral insulin preparation
  • insulin resistance improving agent eg, pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone or a salt thereof (preferably maleate)
  • Metaglidasen AMG-131, Balaglitazone, MBX-2044, Riboglitazone, Aleglitazar, Chiglitazar, Lobeglitazone, PLX-204, PN-2034 GFT-505, THR-0921, WO2007 / 013694, WO2007 / 018314, WO2008 / 093639 or WO2008 / 0997 94
  • ⁇ -glucosidase inhibitors eg, voglibose, acar
  • Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors (eg, tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat (AS-3201), ridressat), neurotrophic factor and its increase drug (Eg, NGF, NT-3, BDNF, neurotrophin production / secretion promoter described in WO01 / 14372 (eg, 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5- [3- (2-Methylphenoxy) propyl] oxazole), compounds described in WO2004 / 039365), PKC inhibitors (eg, ruboxistaurin mesylate), AGE inhibitors (eg, ALT946, N-Fe) Nasyl thiazolium bromide (ALT766), EXO-226, pyridoline (Pyridorin), pyridoxamine), GABA receptor agonist (eg,
  • HMG-CoA reductase inhibitors eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or salts thereof (eg, sodium salt, calcium salt)
  • Squalene synthase inhibitors eg, compounds described in pamphlet of WO97 / 10224, such as N-[[(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro-5 -(2,3-dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid) , Fibrate compounds (eg, bezafibrate, clofibrate, simfibrate, clinofibrate), anion exchange resins (eg,
  • antihypertensive agent examples include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril, etc.), angiotensin II antagonists (eg, candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan, irbesartan, tasosartan , Olmesartan, olmesartan, medoxomil, azilsartan, azilsartan, medoxomil, etc.), calcium antagonists (eg, manidipine, nifedipine, amlodipine, nicardipine, amlodipine, sinodidipine, etc.), ⁇ -blockers (eg, metoprolol, atenolol, propranolol, propranolol) Pindolol), clonidine and
  • anti-obesity agents include monoamine uptake inhibitors (eg, phentermine, sibutramine, mazindol, floxetine, tesofensin), serotonin 2C receptor agonists ( Eg, lorcaserin), serotonin 6 receptor antagonist, histamine H3 receptor, GABA modulator (eg, topiramate), neuropeptide Y antagonist (eg, Berneperit), cannabinoid receptor antagonist (eg, rimonabant, taranaban) , Ghrelin antagonist, ghrelin receptor antagonist, ghrelin acylase inhibitor, opioid receptor antagonist (eg, GSK-1521498), orexin receptor antagonist, melanocortin 4 receptor agonist, 11 ⁇ -hydroxysteroid dehydrogenase inhibitor Drugs (eg, AZD-4017), pancreatic lipase inhibitors (eg, orlistat, cetilistat), ⁇ 3 agonists (eg, N-5984), diacylg
  • diuretic examples include, for example, xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine), thiazide preparations (eg, etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide).
  • xanthine derivatives eg, sodium salicylate theobromine, calcium salicylate theobromine
  • thiazide preparations eg, etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide.
  • Ventilhydrochlorothiazide penfluthiazide, poly-5thiazide, methiclotiazide, etc.
  • anti-aldosterone preparations eg, spironolactone, triamterene, etc.
  • carbonic anhydrase inhibitors eg, acetazolamide, etc.
  • chlorobenzenesulfonamide preparations eg, , Chlorthalidone, mefluside, indapamide, etc.
  • azosemide isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like.
  • chemotherapeutic agents include alkylating agents (eg, cyclophosphamide, ifosfamide), antimetabolites (eg, methotrexate, 5-fluorouracil and derivatives thereof), anticancer antibiotics (eg, mitomycin, adriamycin) Plant-derived anticancer agents (eg, vincristine, vindesine, taxol), cisplatin, carboplatin, etoposide and the like. Of these, 5-fluorouracil derivatives such as furtulon or neoflutulon are preferred.
  • alkylating agents eg, cyclophosphamide, ifosfamide
  • antimetabolites eg, methotrexate, 5-fluorouracil and derivatives thereof
  • anticancer antibiotics eg, mitomycin, adriamycin
  • Plant-derived anticancer agents eg, vincristine, vindesine, taxol
  • cisplatin carb
  • immunotherapeutic agents include microorganisms or bacterial components (eg, muramyl dipeptide derivatives, picibanil), polysaccharides having immunopotentiating activity (eg, lentinan, schizophyllan, krestin), and cytokines obtained by genetic engineering techniques (eg, , Interferon, interleukin (IL)), colony stimulating factor (eg, granulocyte colony stimulating factor, erythropoietin) and the like, and interleukins such as IL-1, IL-2 and IL-12 are preferred.
  • microorganisms or bacterial components eg, muramyl dipeptide derivatives, picibanil
  • polysaccharides having immunopotentiating activity eg, lentinan, schizophyllan, krestin
  • cytokines obtained by genetic engineering techniques (eg, , Interferon, interleukin (IL)
  • colony stimulating factor eg, granulocyte colony stimulating
  • Antithrombotic agents include, for example, heparin (eg, heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium) sodium)), warfarin (eg, warfarin potassium), antithrombin drugs (eg, aragatroban, dabigatran), FXa inhibitors (eg, rivaroxaban, apixaban, edoxaban, YM150, WO02 / 06234, WO2004 / 048363, WO2005 / 030740, WO2005 / 058823 or WO2005 / 113504, thrombolytic agents (eg, urokinase, tisokinase,reteplase, nateplase) ), Monteplase, pamitepase, platelet aggregation inhibitor (eg, ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cil
  • osteoporosis therapeutic agents examples include alfacalcidol, calcitriol, elcatonin, salmon calcitonin salmon, estriol, ipriflavone, risedronate disodium (risedronate) disodium), pamidronate disodium, alendronate sodium hydrate, incadronate disodium, and the like.
  • anti-dementia agent examples include tacrine, donepezil, rivastigmine, galanthamine and the like.
  • the erectile dysfunction ameliorating agent examples include apomorphine and sildenafil citrate.
  • urinary incontinence / frequent urination therapeutic agent examples include flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride and the like.
  • dysuria therapeutic agent examples include acetylcholinesterase inhibitors (eg, distigmine).
  • Concomitant drugs include drugs that have been shown to improve cachexia in animal models and clinically, ie cyclooxygenase inhibitors (eg, indomethacin), progesterone derivatives (eg, megesterol acetate), carbohydrate steroids (eg, Dexamethasone), metoclopramide drugs, tetrahydrocannabinol drugs, fat metabolism improvers (eg, eicosapentaenoic acid), growth hormone, IGF-1, or cachexia-inducing factors TNF- ⁇ , LIF, IL -6, an antibody against Oncostatin M, and the like.
  • cyclooxygenase inhibitors eg, indomethacin
  • progesterone derivatives eg, megesterol acetate
  • carbohydrate steroids eg, Dexamethasone
  • metoclopramide drugs etrahydrocannabinol drugs
  • fat metabolism improvers eg, eico
  • the concomitant drugs include nerve regeneration promoters (eg, Y-128, VX-853, prosaptide), antidepressants (eg, desipramine, amitriptyline, imipramine), antiepileptic drugs (eg, lamotrigine), antiarrhythmic drugs (Eg, mexiletine), acetylcholine receptor ligand (eg, ABT-594), endothelin receptor antagonist (eg, ABT-627), monoamine uptake inhibitor (eg, tramadol), narcotic analgesic (eg, morphine) GABA receptor agonist (eg, gabapentin), ⁇ 2 receptor agonist (eg, clonidine), local analgesic (eg, capsaicin), anxiolytic (eg, benzodiazepine), dopamine agonist (eg, apomorphine), Midazolam, ketoconazole, etc. are also mentioned.
  • nerve regeneration promoters eg, Y-128,
  • the combination drug is preferably an insulin preparation, an insulin resistance improving agent, a dipeptidyl peptidase IV inhibitor, an ⁇ -glucosidase inhibitor, a biguanide agent, an insulin secretagogue (preferably a sulfonylurea agent), a GLP-1 receptor agonist Etc.
  • Two or more of the above concomitant drugs may be used in combination at an appropriate ratio.
  • the amount of each agent can be reduced within a safe range in consideration of the opposite effect of those agents.
  • the insulin resistance ameliorating agent, dipeptidyl peptidase IV inhibitor, ⁇ -glucosidase inhibitor, biguanide insulin secretagogue and GLP-1 receptor agonist can be reduced from the usual dose.
  • the adverse effects that would be caused by these agents can be safely prevented.
  • the dosage of diabetic complications, hyperlipidemia, antihypertensives can be reduced, and as a result, adverse effects that would be caused by these agents can be effectively prevented.
  • Root temperature in the following examples usually indicates about 10 ° C. to about 35 ° C. Solvents used in chromatography indicate volume%, and others indicate weight%. Proton NMR spectra that cannot be confirmed broadly, such as OH and NH protons, are not described in the data.
  • Melting point measuring instrument Sayanagimoto micro melting point measuring instrument, or Büch melting point measuring instrument B-545 type.
  • a molecular ion peak is observed, but in the case of a compound having a tert-butoxycarbonyl group (-Boc), a peak from which the tert-butoxycarbonyl group or tert-butyl group is eliminated should be observed as a fragment ion. There is also. In the case of a compound having a hydroxyl group (—OH), a peak from which H 2 O is eliminated may be observed as a fragment ion. In the case of a salt, a free molecular ion peak or a fragment ion peak is usually observed.
  • Example 1 2- [1- (tert-Butoxycarbonyl) piperidin-4-yl] ethyl 5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylate (A) tert-butyl 4- ⁇ 2-[(methylsulfonyl) oxy] ethyl ⁇ piperidine-1-carboxylate tert-butyl 4- (2-hydroxyethyl) piperidine-1-carboxylate (0.115 g) and triethylamine ( 0.11 mL) in ethyl acetate (10 mL) was ice-cooled, methanesulfonyl chloride (0.063 g) was added, and the mixture was stirred for 1 hr.
  • Example 2 5- (Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 3- [1- (tert-butoxycarbonyl) piperidin-4-yl] propyl (A) tert-butyl 4- ⁇ 3-[(methylsulfonyl) oxy] propyl ⁇ piperidine-1-carboxylate tert-butyl 4- (3-hydroxypropyl) piperidine-1-carboxylate (0.450 g) and triethylamine ( 0.39 mL) in ethyl acetate (20 mL) was ice-cooled, methanesulfonyl chloride (0.16 mL) was added, and the mixture was stirred for 1 hr.
  • Example 3 2- [1- (tert-Butoxycarbonyl) piperidin-4-yl] ethyl 5-bromo-2,3-dihydro-1H-indole-1-carboxylate 5-bromoindoline (0.198 g) and triethylamine ( To a solution of 0.21 mL) in ethyl acetate (10 mL), triphosgene (0.386 g) was added dropwise under ice cooling, and the mixture was stirred for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Example 6 5- (2-Oxopyrrolidin-1-yl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- ⁇ 1-[(tetrahydrofuran-3-yloxy) carbonyl] piperidin-4-yl ⁇
  • Triphosgene (0.0556 g) and pyridine (0.046 mL) were added to an ether (5 mL) solution of ethyl 3-hydroxytetrahydrofuran (0.046 mL) under ice cooling, and the mixture was stirred for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure.
  • Example 7 (2-Oxopyrrolidin-1-yl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- [1- (2-ethoxy-2-oxoethyl) piperidin-4-yl] Ethyl 5- (2-oxopyrrolidin-1-yl) -2,3-dihydro-1H-indole-1-carboxylate 2- (piperidin-4-yl) ethyl (0.100 g), ethyl bromoacetate (0.031 mL) , And a suspension of potassium carbonate (0.077 g) in N, N-dimethylformamide (3 mL) was stirred at 80 ° C. overnight.
  • reaction mixture was added to water and extracted with ethyl acetate.
  • organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (0.090 g) as a colorless oil.
  • Example 8 5- (2-Oxopyrrolidin-1-yl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- ⁇ 1- [tert-butyl (methyl) carbamoyl] piperidin-4-yl ⁇
  • pyridine 0.135 mL
  • N-methyl-tert-butylamine 0.2 mL
  • the reaction solution was concentrated under reduced pressure, and diethyl ether was added to the residue.
  • Example 9 5- (2-oxopyrrolidin-1-yl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- ⁇ 1- [5- (1-methylethyl) -4,5-dihydro -1,3-oxazol-2-yl] piperidin-4-yl ⁇ ethyl (A) 5- (2-Oxopyrrolidin-1-yl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- ⁇ 1-[(Z)-(methylsulfanyl) ⁇ [(trimethylsilyl) methyl ] Imino ⁇ methyl] piperidine-4- Il ⁇ ethyl trimethylsilylmethyl azide (0.500 g) and triphenylphosphine (1.02 g) in carbon disulfide (4 mL) were stirred at room temperature for 2 hours.
  • reaction solution was filtered, and the filtrate was concentrated under reduced pressure.
  • the residue was dissolved in tetrahydrofuran (100 mL), and methyl 2,3-dihydro-1H-indole-5-carboxylate (1.18 g) and N, N-diisopropylethylamine (2.32 mL) were added to this solution at room temperature. Stir for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 11 1-( ⁇ 2- [1- (tert-butoxycarbonyl) piperidin-4-yl] ethoxy ⁇ carbonyl) -2,3-dihydro-1H-indole-5-carboxylic acid 2,3-dihydro-1H -Indole-1,5-dicarboxylic acid 5-methyl 1- ⁇ 2- [1- (tert-butoxycarbonyl) piperidin-4-yl] ethyl ⁇ (1.72 g) in methanol (8 mL) and tetrahydrofuran (16 mL) To the mixed solution was added 1 M aqueous sodium hydroxide solution (8 mL), and the mixture was stirred at 50 ° C. for 3 hr.
  • Example 12 2- [1- (tert-Butoxycarbonyl) piperidin-4-yl] propyl 5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid
  • A 4- (2-Ethoxy-1-methyl-2-oxoethylidene) piperidine-1-carboxylate tert-butyl 2-phosphonopropionate triethyl (13.9 mL) in tetrahydrofuran (80 mL) was ice-cooled.
  • Sodium hydride oil, 60%, 2.60 g was added in small portions and stirred for 1 hour under a nitrogen atmosphere.
  • reaction solution was filtered, and the filtrate was concentrated under reduced pressure.
  • the residue was dissolved in tetrahydrofuran (30 mL), and 5- (methylsulfonyl) -2,3-dihydro-1H-indole (0.395 g) and N, N-diisopropylethylamine (1.05 mL) were added to this solution at room temperature. Stir for 20 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 13 2- ⁇ 1-[(1-Methylethoxy) carbonyl] piperidin-4-yl ⁇ propyl 5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid (A) 5- (Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- (piperidin-4-yl) propyl hydrochloride 5- (methylsulfonyl) -2,3-dihydro-1H -Indole-1-carboxylic acid 2- [1- (tert-butoxycarbonyl) piperidin-4-yl] propyl (1.32 g) was added to 4 M hydrogen chloride / ethyl acetate (20 mL) solution, and the mixture was stirred at room temperature for 20 hours.
  • Example 14 5- (Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- [1- (5-propylpyrimidin-2-yl) piperidin-4-yl] propyl 5- (methyl Sulfonyl) -2,3-dihydro-1H-indole-1-carboxylate 2- [1- (tert-butoxycarbonyl) piperidin-4-yl] propyl (0.470 g) was added to trifluoroacetic acid (2 mL), Stir at room temperature for 24 hours.
  • reaction mixture was concentrated under reduced pressure, the residue was dissolved in 1-methyl-2-pyrrolidinone (2 mL), 2-chloro-5-propylpyrimidine (0.189 g) and cesium carbonate (1.64 g) were added, and nitrogen atmosphere was added. The mixture was stirred at 70 ° C. for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 15 2- [1- (Pyridazin-3-ylcarbamoyl) piperidin-4-yl] propyl 5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid
  • Phenylpyridazin-3-ylcarbamate Phenyl chloroformate (1.66 mL) was added to a mixture of 3-aminopyridazine (1.14 g) and pyridine (1.17 mL) in tetrahydrofuran (10 mL) and acetonitrile (15 mL). The mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere.
  • Example 16 2- (1- [Methyl (pyridazin-3-yl) carbamoyl] piperidin-4-yl ⁇ propyl 5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylate 5- ( Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylate 2- [1- (pyridazin-3-ylcarbamoyl) piperidin-4-yl] propyl (0.170 g) was converted to N, N-dimethylformamide ( 1 mL), sodium hydride (60%, oily, 0.017 g) was added, and the mixture was stirred at room temperature for 30 min under a nitrogen atmosphere.
  • Example 17 The compound of Example 17 was synthesized by the same method as in Example 16.
  • Example 18 7-Fluoro-5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- [1- (tert-butoxycarbonyl) piperidin-4-yl] propyl (A) 7-Fluoro-2,3-dihydro-1H-indole To a solution of 7-fluoroindole (20.0 g) in acetic acid (60 mL), sodium cyanoborohydride (18.7 g) was added little by little, and Stir for hours. The reaction mixture was added to 2M aqueous sodium hydroxide solution (1500 mL) and extracted with dichloromethane.
  • the extract was washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the residue was dissolved in dichloromethane (60 mL), metachloroperbenzoic acid (65%, 8.8 g) was added under ice-cooling, and the mixture was stirred for 1 hr.
  • a 10% aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was extracted with dichloromethane.
  • the extract was washed successively with aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • reaction solution was filtered, and the filtrate was concentrated under reduced pressure.
  • the residue was dissolved in tetrahydrofuran (60 mL), and 7-fluoro-5- (methylsulfonyl) -2,3-dihydro-1H-indole hydrochloride (0.861 g) and N, N-diisopropylethylamine (2.09 g) were dissolved in this solution. mL) was added and stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 33 7-Fluoro-5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- [1- (5-propylpyrimidin-2-yl) piperidin-4-yl] propyl (A) 7-fluoro-5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylate 2- (piperidin-4-yl) propyl hydrochloride 7-fluoro-5- (methylsulfonyl) -2,3-Dihydro-1H-indole-1-carboxylic acid 2- [1- (tert-butoxycarbonyl) piperidin-4-yl] propyl (1.01 g) in 4 M hydrogen chloride / ethyl acetate (20 mL) solution And stirred at room temperature for 20 hours.
  • Example 34 The compound of Example 34 was synthesized by the same method as in Example 33.
  • Example 35 7-Methyl-5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- ⁇ 1-[(1-methylethoxy) carbonyl] piperidin-4-yl ⁇ ethyl 7 2-Methyl-5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylate 2- [1- (tert-butoxycarbonyl) piperidin-4-yl] ethyl (0.268 g) in trifluoroacetic acid (1 mL) and stirred at room temperature for 3 hours.
  • Example 45 5- [Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 4- [1- (tert-butoxycarbonyl) piperidin-4-yl] butyl (A) 4- (4-Ethoxy-4-oxobutyl) piperidine-1-carboxylate tert-butyl (2E) -4- (diethoxyphosphoryl) but-2-enoic acid ethyl ester (10.0 g) in tetrahydrofuran (40 mL ) Sodium hydride (oil, 60%, 1.60 g) was added to the solution and stirred at 0 ° C. for 30 minutes.
  • A 4- (4-Ethoxy-4-oxobutyl) piperidine-1-carboxylate tert-butyl (2E) -4- (diethoxyphosphoryl) but-2-enoic acid ethyl ester (10.0 g) in tetrahydrofur
  • Example 46 5- [Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 3- [1- (tert-butoxycarbonyl) piperidin-4-yl] butyl (A) 4- [methoxy (methyl) carbamoyl] piperidine-1-carboxylic acid tert-butyl 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (10.0 g) in tetrahydrofuran (120 mL) 1'-Carbonyldiimidazole (12.7 g) was added in small portions and stirred at room temperature for 2 hours.
  • reaction solution was filtered, and the filtrate was concentrated under reduced pressure.
  • the residue was dissolved in tetrahydrofuran (10 mL), and 5- (methylsulfonyl) -2,3-dihydro-1H-indole (0.197 g) and N, N-diisopropylethylamine (0.871 mL) were added to this solution at room temperature. Stir for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 48 2- ⁇ [1- (tert-Butoxycarbonyl) piperidin-4-yl] amino ⁇ ethyl 5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylate (2-hydroxyethyl ) Tert-butyl carbamate (2.42 g) and triphosgene (1.48 g)
  • a diethyl ether (90 mL) solution of pyridine (1.23 mL) in diethyl ether (10 mL) was added dropwise at ⁇ 40 ° C. under a nitrogen atmosphere. Stir. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure.
  • the obtained solid was added to 4 M hydrogen chloride / ethyl acetate (30 mL) solution, and the mixture was stirred at room temperature for 4 hr.
  • the reaction solution was concentrated under reduced pressure, and the resulting solid was washed with ethyl acetate to obtain a pale pink solid.
  • a mixture of the obtained solid, tert-butyl 4-oxopiperidine-1-carboxylate (2.99 g), and triethylamine (2.09 mL) in methanol (50 mL) was stirred at room temperature for 1.5 hr.
  • Example 49 The compound of Example 49 was synthesized by the same method as in Example 48.
  • Example 50 2-([1- (tert-Butoxycarbonyl) piperidin-4-yl] (propyl) amino ⁇ ethyl 5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylate 5- (Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylate 2- ⁇ [1- (tert-butoxycarbonyl) piperidin-4-yl] amino ⁇ ethyl (0.351 g) and potassium carbonate (0.135 g 1-iodopropane (0.110 mL) was added to a suspension of N, N-dimethylformamide (2 mL) and stirred at 70 ° C.
  • Example 55 5- (Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylate 2- ⁇ acetyl [1- (tert-butoxycarbonyl) piperidin-4-yl] amino ⁇ ethyl 5- (methyl Sulfonyl) -2,3-dihydro-1H-indole-1-carboxylate 2- ⁇ [1- (tert-butoxycarbonyl) piperidin-4-yl] amino ⁇ ethyl (0.234 g) in a solution of pyridine (1 mL) Acetic anhydride (0.071 mL) was added dropwise, and the mixture was stirred at room temperature for 2 days under a nitrogen atmosphere.
  • Example 56 5- (Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- ⁇ [1- (tert-butoxycarbonyl) piperidin-4-yl] (methylsulfonyl) amino ⁇ ethyl 5 -(Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylate 2- ⁇ [1- (tert-butoxycarbonyl) piperidin-4-yl] amino ⁇ ethyl (0.234 g) and N, N- Methanesulfonyl chloride (0.047 mL) was added dropwise to a solution of diisopropylethylamine (0.131 mL) in tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 2 days under a nitrogen atmosphere.
  • Example 57 5- (Pyrrolidin-1-ylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- [1- (tert-butoxycarbonyl) piperidin-4-yl] ethyl
  • A 2,3-Dihydro-1H-indole-1-carboxylic acid 2- ⁇ 1-[(1-methylethoxy) carbonyl] piperidin-4-yl ⁇ ethyl
  • the title compound is the same as in Example 10, Step B. It was synthesized by the method.
  • the reaction mixture was cooled to room temperature, poured slowly into ice water, and extracted with ethyl acetate. The organic phase was separated and washed twice with water, then with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a pale yellow oil. Pyrrolidine (1.5 mL) was added to a solution of the obtained oil in tetrahydrofuran (15 mL), and the mixture was stirred at room temperature for 15 min and concentrated under reduced pressure.
  • Table 1 shows the structural formulas, chemical names and measured values of MS of the example compounds.
  • Test example 1 Evaluation of human GPR119 agonist activity using an increase in intracellular cAMP concentration as an index
  • Primer 1 5′-GCGTCGACATGGAATCATTTTTCTCATTTGG-3 ′ (SEQ ID NO: 1)
  • Primer 2 5′-GCCGCTAGCTTAGCCATCAAACTCTGAGCT-3 ′ (SEQ ID NO: 2)
  • PCR was performed using Pyrobest DNA polymerase (Takara Bio).
  • the obtained PCR product was cloned into pUC118 (Takara Bio). After confirming the base sequence, it was digested with restriction enzymes Sal I and Nhe I.
  • the obtained DNA fragment was similarly digested with Sal I and Nhe I, an animal cell expression vector pAKKO-111H (Biochem. Biophys. Acta, Hinuma, S. et al., 1219, 251-259 (1994)).
  • the plasmid was inserted into the same plasmid as pAKKO-1.111H) to prepare an expression plasmid pAKKO-111H / hGPR119.
  • Zeocin-U 5'-GGATCCAGGCAGGCAGAAGTATG-3 ' (SEQ ID NO: 3)
  • Zeocine-L 5'-GTCGACGAGACATGATAAGATACATTG ATG-3 ′ (SEQ ID NO: 4)
  • the obtained PCR product was inserted into pCR-BluntII (Invitrogen).
  • a fragment containing the Zeocine resistance gene obtained by cleaving with restriction enzymes Sal I and BamH I from this plasmid was inserted into plasmid pGL3 (R2.2) -Basic Vector (Promega) that was also digested with Sal I and BamHI.
  • a Zeocin resistant plasmid pGL3 (R2.2) / Zeocin-Basic Vector was prepared.
  • a reporter plasmid in which four cAMP responsive elements (CRE) were linked in tandem was prepared using the following 5′-terminal phosphorylated synthetic DNA.
  • CRE-Upper 5'-CAGCCTGACGTCAGAGAGCCTGGACGTCAGAGAGCCTGACGTCAGAGAGCCTGACGTCAGAGTCGACACGGGGAACTCTAGAGGGTATATAAGCTT-3 '(SEQ ID NO: 5)
  • CRE-Lower 5′-AGCTTATATACCCCTTAGAGTCTCCCGCTGTCGCACTCTGACGTCAGGCTCCTCTGACGTCAGGCCTCTGACGTCAGGCCTCTGACGTCAGGCCTCTGACGTCAGGCTGCTGTACC-3 ′ (SEQ ID NO: 6)
  • a DNA fragment containing the CRE sequence obtained by extension with KOD polymerase was inserted into pCR-BluntII to obtain pCR-BluntII-CRE.
  • reporter plasmid pGL3 (R2.2) / Zeocin-CRE-luc was prepared.
  • CRE-luc / CHO (dhfr-) cells a strain in which the expression of luciferase was induced, CRE-luc / CHO (dhfr-) cells.
  • 15 ⁇ g of the plasmid pAKKO-111H / hGPR119 obtained in (1) and 5 ⁇ g of pcDNA3.1 (Invitrogen) were added to 1 ⁇ 10 7 CRE-luc / CHO (dhfr-) cells in the same manner as described above.
  • electroporation was performed under a voltage of 250 mV and a capacitance of 950 ⁇ F.
  • geneticin (Wako Pure Chemical Industries) is suspended in a medium containing 500 ⁇ g / mL, diluted to 250 cells / well, seeded in a 96-well plate, and placed in a CO 2 incubator at 37 ° C. Geneticin-resistant transformants were obtained by culturing.
  • hGPR119 / CRE-luc / CHO (dhfr-) cells were seeded in a 384-well white plate (NUNC) to 1 ⁇ 10 4 cells / well, and 10% fetal bovine serum, 100 U / mL penicillin In a MEM ⁇ (Minimum essential medium alpha) medium containing 100 ⁇ g / mL streptomycin and 500 ⁇ g / mL geneticin, the cells were cultured overnight in a CO 2 incubator at 37 ° C.
  • NUNC 384-well white plate
  • Luciferase activity in the presence of 10 ⁇ M N- [4- (methylsulfonyl) phenyl] -5-nitro-6- ⁇ 4- [4- (trifluoromethoxy) phenoxy] piperidin-1-yl ⁇ pyrimidin-4-amine GPR119 agonist activity was calculated using 100% of luciferase activity when DMSO was added instead of the test compound as 0%, and an increase in intracellular cAMP concentration as an index. The results are shown in Table 2.
  • the compound of the present invention has an excellent GPR119 agonistic action.
  • Formulation Example 1 (Manufacture of capsules) 1) 30 mg of the compound of Example 1 2) Fine powder cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg 60 mg total 1), 2), 3) and 4) are mixed and filled into gelatin capsules.
  • Formulation Example 2 (Manufacture of tablets) 1) 30 g of the compound of Example 1 2) Lactose 50 g 3) Corn starch 15 g 4) Carboxymethylcellulose calcium 44 g 5) Magnesium stearate 1 g 1000 tablets total 140 g The total amount of 1), 2), and 3) and 30 g of 4) are kneaded with water, vacuum dried, and sized. 14 g of 4) and 1 g of 5) are mixed with the sized powder, and tableted with a tableting machine. In this way, 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.
  • the compound of the present invention has a GPR119 agonistic action and is useful for prevention / treatment of obesity, diabetes and the like.
  • This application is based on patent application No. 2009-254568 filed in Japan, the contents of which are incorporated in full herein.

Abstract

Disclosed is a compound represented by formula (I) or a salt thereof, which has an GPR119 agonist action and is useful for prevention and treatment of diabetes, obesity and the like. (In the formula, the symbols are as defined in the description.)

Description

縮合複素環化合物Fused heterocyclic compounds
 本発明は、GPR119アゴニスト作用を有し、糖尿病、肥満症等の予防・治療に有用な縮合複素環化合物に関する。 The present invention relates to a condensed heterocyclic compound having a GPR119 agonist activity and useful for the prevention and treatment of diabetes, obesity and the like.
[発明の背景]
 糖尿病は、糖代謝異常の結果生じる血糖高値を特徴とする代謝性疾患の一つである。この疾患は、インスリン依存性糖尿病もしくはIDDMとも呼ばれる1型糖尿病と、インスリン非依存性糖尿病またはNIDDMとも呼ばれる2型糖尿病とに大きく分類される。糖尿病は微小血管性の合併症(例:糖尿病性網膜症、糖尿病性神経障害、糖尿病性腎症)の原因となるばかりでなく、大血管障害(例:動脈硬化症、心血管疾患、心筋梗塞)のリスク要因でもある。
[Background of the invention]
Diabetes is one of the metabolic diseases characterized by high blood glucose levels resulting from abnormal sugar metabolism. This disease is broadly classified into type 1 diabetes, also called insulin dependent diabetes or IDDM, and type 2 diabetes, also called non-insulin dependent diabetes or NIDDM. Diabetes not only causes microvascular complications (eg diabetic retinopathy, diabetic neuropathy, diabetic nephropathy) but also macrovascular disorders (eg arteriosclerosis, cardiovascular disease, myocardial infarction) ) Risk factor.
 GPR119は、膵臓β細胞に強く発現するG蛋白質共役型受容体であり、近年、血中の糖濃度に依存してインスリン分泌を促す血糖センサーとして機能していることが報告された(非特許文献1参照)。そのため、GPR119は新たな糖尿病治療の標的分子として注目されている。 GPR119 is a G protein-coupled receptor that is strongly expressed in pancreatic β cells and has recently been reported to function as a blood glucose sensor that promotes insulin secretion depending on the sugar concentration in the blood (Non-patent Document). 1). Therefore, GPR119 has attracted attention as a new target molecule for the treatment of diabetes.
 また、GPR119はヒトおよびマウスの腸管にも発現しており、GPR119作動薬がマウスにおいてグルカゴン様ペプチド-1(glucagon-like peptide-1:GLP-1)及びグルコース依存性インスリン分泌刺激ポリペプチド(glucose-dependent insulinotropic polypeptide:GIP)分泌を促進すること、(非特許文献2参照)、GPR119作動薬がマウスにおいてペプチドYY(PYY)やグルカゴン分泌を促進することも報告されている(非特許文献3)。 GPR119 is also expressed in the intestinal tract of humans and mice, and the GPR119 agonist is glucagon-like peptide-1 (GLP-1) and glucose-dependent insulin secretion stimulating polypeptide (glucose) in mice. -dependent insulinotropic peptidepolypeptide (GIP) secretion (see Non-Patent Document 2), GPR119 agonists have also been reported to promote peptide YY (PYY) and glucagon secretion in mice (Non-Patent Document 3). .
 従って、GPR119アゴニスト作用を有する化合物は、糖尿病、肥満症等の予防および治療に有用である。 Therefore, a compound having a GPR119 agonistic action is useful for the prevention and treatment of diabetes, obesity and the like.
 一方、以下の化合物が報告されている。 On the other hand, the following compounds have been reported.
(1)式: (1) Formula:
Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-C000002
[式中、AおよびBは、一方が窒素を、他方がCRを、WおよびYは、独立して、結合手、C1-3アルキルまたはC2-3アルケニルを、Xは、CH、O、S、CH(OH)等を、Gは、CHR、 N-C(O)OR、 N-C(O)NR等を、Rは、水素原子、ハロゲン原子、シアノ等を、Rは、水素原子またはC1-4アルキルを、Rは、C3-6アルキルを、Rは、C1-8アルキル、C2-8アルケニル等を、Rは、ハロゲン原子またはC1-4アルキルを、Rは、水素原子、ハロゲン原子、シアノ等を、Rは、水素原子、ハロゲン原子、シアノ等を、R11は、ハロゲン原子またはヒドロキシを、dは0ないし3の整数を、eは1ないし5の整数(但し、d+eは2ないし5の整数を示す)を、fは0ないし2の整数を示す。]
で表される化合物(特許文献1参照)。
[In the formula, one of A and B is nitrogen, the other is CR 1 , W and Y are independently a bond, C 1-3 alkyl or C 2-3 alkenyl, and X is CH 2 , O, S, CH (OH), etc., G represents CHR 3 , N—C (O) OR 4 , N—C (O) NR 4 R 5, etc., R 1 represents a hydrogen atom, a halogen atom, Cyano, R 2 is a hydrogen atom or C 1-4 alkyl, R 3 is C 3-6 alkyl, R 4 is C 1-8 alkyl, C 2-8 alkenyl, etc., R 5 is , A halogen atom or C 1-4 alkyl, R 6 is a hydrogen atom, a halogen atom, cyano, etc., R 8 is a hydrogen atom, a halogen atom, cyano, etc., R 11 is a halogen atom or hydroxy, d Is an integer from 0 to 3, e is an integer from 1 to 5 (where d + e is an integer from 2 to 5) ), F represents an integer of 0 to 2. ]
The compound represented by (refer patent document 1).
(2)式: (2) Formula:
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000003
[式中、AおよびBは、独立して、置換されていてもよいC1-3アルキレンを、Dは、O、S、S(O)、S(O)、CRまたはNRを、Eは、N、C、CRを、Vは、結合手、置換されていてもよいC1-3アルキレンを、Vは、結合手、置換されていてもよいC3-6シクロアルキレンまたは置換されていてもよいC1-3アルキレンを、Wは、NR、O、S、S(O)、S(O)または存在せず、Qは、NR、O、S、S(O)またはS(O)を、Xは、NまたはCRを、Yは、NまたはCRを、Arは、置換されていてもよいアリールまたは置換されていてもよいヘテロアリールを、Rは、アリール、ヘテロアリール、カルボキシ等を示す。]
で表される化合物(特許文献2参照)。
[Wherein A and B independently represent optionally substituted C 1-3 alkylene, D represents O, S, S (O), S (O) 2 , CR 2 R 3 or NR 2 , E is N, C, CR 4 ; V 1 is a bond, optionally substituted C 1-3 alkylene; V 2 is a bond, optionally substituted C 3- 6 cycloalkylene or optionally substituted C 1-3 alkylene, W is NR 5 , O, S, S (O), S (O) 2 or absent, Q is NR 6 , O, S, S (O) or S (O) 2 , X is N or CR 7 , Y is N or CR 8 , Ar 1 is optionally substituted aryl or optionally substituted Heteroaryl, R 2 represents aryl, heteroaryl, carboxy and the like. ]
(Refer patent document 2).
(3)式: (3) Formula:
Figure JPOXMLDOC01-appb-C000004

[式中、Aは
Figure JPOXMLDOC01-appb-C000004

[Where A is
Figure JPOXMLDOC01-appb-C000005

または
Figure JPOXMLDOC01-appb-C000005

Or
Figure JPOXMLDOC01-appb-C000006

を、
は、水素原子、置換されていてもよいC1-6アルキル、または置換されていてもよいC1-6アシルを、RおよびRは、独立して、水素原子、ハロゲン原子、ヒドロキシ、置換されていてもよいC1-6アルキル、または置換されていてもよいC1-6アルコキシを、Rは、水素原子、ハロゲン原子、ヒドロキシ、シアノ、ニトロ、トリフルオロメチル、C1-6アルキルまたはC1-6アルコキシを、Yは、O、N(R)またはCHを、Rは、水素原子またはC1-6アルキルを、a,bおよびcは、独立して、1ないし3の整数を、dは0ないし2の整数を、fおよびgは、独立して、0ないし2の整数で、かつ、f+gは1ないし3の整数を示す。]
で表される化合物(特許文献3参照)。
Figure JPOXMLDOC01-appb-C000006

The
R 1 represents a hydrogen atom, an optionally substituted C 1-6 alkyl, or an optionally substituted C 1-6 acyl, R 2 and R 3 independently represent a hydrogen atom, a halogen atom, Hydroxy, optionally substituted C 1-6 alkyl, or optionally substituted C 1-6 alkoxy, R 4 is a hydrogen atom, a halogen atom, hydroxy, cyano, nitro, trifluoromethyl, C 1 -6 alkyl or C 1-6 alkoxy, Y is O, N (R 5 ) or CH 2 , R 5 is a hydrogen atom or C 1-6 alkyl, a, b and c are independently 1 represents an integer of 1 to 3, d represents an integer of 0 to 2, f and g independently represent an integer of 0 to 2, and f + g represents an integer of 1 to 3. ]
The compound represented by (refer patent document 3).
(4)式: (4) Formula:
Figure JPOXMLDOC01-appb-C000007

[式中、pは1または2を、mは0ないし3の整数を、nは0ないし4の整数を、Rは、特定の置換基でそれぞれ置換されていてもよい、C1-6アルキル、C3-7シクロアルキル、C2-6アルキニルまたはC2-6アルケニル、もしくはC1-6アルキルで置換されていてもよいアミノを、Rは、ハロゲン原子、ヒドロキシ、C1-6アルキルまたはC1-6アルコキシを、Rは、ハロゲン原子、C1-6アルキル、C1-6アルコキシ等を、RおよびRは、独立して、水素原子、ハロゲン原子、C1-6アルキル、C1-6アルコキシ等を、Rは、-C(O)OR6a、-C(O)-R6b等を、Rは、水素原子、ハロゲン原子またはC1-6アルキルを示す。]
で表される化合物(特許文献4参照)。
(4)式:
Figure JPOXMLDOC01-appb-C000007

[Wherein, p is 1 or 2, m is an integer of 0 to 3, n is an integer of 0 to 4, and R 1 is optionally substituted with a specific substituent, C 1-6 Amino optionally substituted with alkyl, C 3-7 cycloalkyl, C 2-6 alkynyl or C 2-6 alkenyl, or C 1-6 alkyl, R 2 represents a halogen atom, hydroxy, C 1-6 alkyl or C 1-6 alkoxy, R 3 is halogen atom, C 1-6 alkyl, C 1-6 alkoxy such as, R 4 and R 5 are independently hydrogen atom, halogen atom, C 1- 6 alkyl, C 1-6 alkoxy and the like, R 6 represents —C (O) OR 6a , —C (O) —R 6b and the like, R 7 represents a hydrogen atom, a halogen atom or C 1-6 alkyl. Show. ]
(Refer patent document 4).
(4) Formula:
Figure JPOXMLDOC01-appb-C000008

[式中、環Pは、さらに置換された6員芳香環を;
環Qは、さらに置換されていてもよい6員芳香環を;
は、CR4a4b(R4aおよびR4bは、独立して、水素原子、置換されていてもよい炭化水素基、置換されていてもよい複素環基、または置換されていてもよいヒドロキシ基を示す)、NR4c(R4cは、水素原子、または置換されていてもよい炭化水素基を示す)、O、S、SO、またはSOを;
は、置換されていてもよいC1-5アルキレン基を;
は、結合手、または置換されていてもよいC1-3アルキレン基を;
およびLは、独立して、置換されていてもよいC1-3アルキレン基を;
は、
(1)水素原子、ハロゲン原子、シアノ基、置換されていてもよい炭化水素基、置換されていてもよい複素環基、または置換されていてもよいヒドロキシ基を示すか、あるいは、
(2)AがCR4a4bである場合、RとR4aおよび/またはR4bとは隣接する炭素原子と一緒になって、置換されていてもよい4ないし8員環を形成してもよく、または、
(3)AがNR4cである場合、RとR4cとは隣接する炭素原子および窒素原子と一緒になって、置換されていてもよい4ないし8員の含窒素複素環を形成してもよく;
は、水素原子、シアノ基、または置換されていてもよい炭化水素基を;および
3aは、式:-CO-SRA1(式中、RA1は、置換されていてもよい炭化水素基、または置換されていてもよい複素環基を示す)で表される基または置換されていてもよい5または6員芳香環基を示す。]
で表される化合物(特許文献5参照)。
Figure JPOXMLDOC01-appb-C000008

[Wherein ring P represents a further substituted 6-membered aromatic ring;
Ring Q is a 6-membered aromatic ring which may be further substituted;
A 1 represents CR 4a R 4b (R 4a and R 4b each independently represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted group. NR 4c (wherein R 4c represents a hydrogen atom or an optionally substituted hydrocarbon group), O, S, SO, or SO 2 ;
L 1 represents an optionally substituted C 1-5 alkylene group;
L 2 represents a bond or an optionally substituted C 1-3 alkylene group;
L 3 and L 4 independently represent an optionally substituted C 1-3 alkylene group;
R 1 is
(1) represents a hydrogen atom, a halogen atom, a cyano group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an optionally substituted hydroxy group, or
(2) When A 1 is CR 4a R 4b , R 1 and R 4a and / or R 4b together with the adjacent carbon atom form an optionally substituted 4- to 8-membered ring. Or
(3) When A 1 is NR 4c , R 1 and R 4c together with the adjacent carbon and nitrogen atoms form an optionally substituted 4- to 8-membered nitrogen-containing heterocycle. May be;
R 2 represents a hydrogen atom, a cyano group, or an optionally substituted hydrocarbon group; and R 3a represents the formula: —CO—SR A1 (wherein R A1 represents an optionally substituted hydrocarbon) A group or a heterocyclic group which may be substituted) or a 5- or 6-membered aromatic ring group which may be substituted. ]
(Refer patent document 5).
WO2006/067531号パンフレットWO2006 / 067531 pamphlet WO2005/007647号パンフレットWO2005 / 007647 pamphlet WO2009/071677号パンフレットWO2009 / 071677 pamphlet WO2009/051119号パンフレットWO2009 / 051119 pamphlet WO2010/095663号パンフレットWO2010 / 095663 pamphlet
 GPR119アゴニスト作用を有し、糖尿病、肥満症等の予防・治療に有用であり、かつ優れた薬効を有する化合物の開発が望まれている。 Development of a compound having a GPR119 agonist activity, useful for the prevention and treatment of diabetes, obesity and the like, and having an excellent medicinal effect is desired.
 本発明者らは、式 We have the formula
Figure JPOXMLDOC01-appb-C000009

 (I)
Figure JPOXMLDOC01-appb-C000009

(I)
[式中、
環Aは、さらに置換されていてもよい6員芳香環を;
は、ハロゲン原子、シアノ基、置換されていてもよい炭化水素基、置換されていてもよい複素環基、置換されていてもよいアミノ基、またはアシル基を;
は、シアノ基、置換されていてもよい炭化水素基、置換されていてもよい複素環基、またはアシル基を;
は、置換されていてもよい直鎖状C2-3アルキレン基を;
は、結合手、置換されていてもよいNH、S、SO、SO、CO、またはOを;
は、結合手、置換されていてもよい直鎖状C1-2アルキレン基を;および
およびYは、独立して、置換されていてもよい直鎖状C1-3アルキレン基を示す。]
で表される化合物またはその塩[以下、化合物(I)と称する場合がある]が、優れたGPR119アゴニスト作用を有し、糖尿病、肥満症等の予防・治療に有用であり、かつ優れた薬効を有することを初めて見いだした。この知見に基づいて、本発明者らは、鋭意研究を行い、本発明を完成するに至った。
[Where:
Ring A represents a 6-membered aromatic ring which may be further substituted;
R 1 represents a halogen atom, a cyano group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted amino group, or an acyl group;
R 2 represents a cyano group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an acyl group;
X 1 represents an optionally substituted linear C 2-3 alkylene group;
X 2 represents a bond, optionally substituted NH, S, SO, SO 2 , CO, or O;
X 3 is a bond, an optionally substituted linear C 1-2 alkylene group; and Y 1 and Y 2 are independently an optionally substituted linear C 1-3 alkylene Indicates a group. ]
Or a salt thereof [hereinafter sometimes referred to as Compound (I)] has an excellent GPR119 agonistic action, is useful for the prevention and treatment of diabetes, obesity and the like, and has an excellent medicinal effect. Found for the first time to have. Based on this knowledge, the present inventors have conducted intensive studies and completed the present invention.
 即ち、本発明は、
[1]化合物(I);
[2]Xが、結合手または置換されていてもよいCHである、上記[1]記載の化合物またはその塩;
[3]環Aが、
(1)ハロゲン原子、
(2)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基、および
(3)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ基
から選ばれる1ないし3個の置換基でそれぞれさらに置換されていてもよい、ベンゼン、ピリジン、またはピリミジンである、上記[1]または[2]記載の化合物またはその塩;
[4]Rが、
(1)ハロゲン原子、
(2)カルボキシ基、
(3)(a)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基、および(b)オキソ基から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環基、
(4)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ-カルボニル基、
(5)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキルスルホニル基、
(6)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基でモノまたはジ置換されていてもよいスルファモイル基、または
(7)(a)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基、および(b)オキソ基から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環スルホニル基である、上記[1]~[3]のいずれか1記載の化合物またはその塩;
[5]Rが、
(1)(a)ハロゲン原子、および(b)C1-6アルコキシ-カルボニル基から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基、
(2)(a)ハロゲン原子、および(b)C1-6アルキル基から選ばれる1ないし3個の置換基で置換されていてもよい芳香族複素環基、
(3)(a)ハロゲン原子、(b)C1-6アルキル基、および(c)オキソ基から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環基、
(4)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ-カルボニル基、
(5)(a)C1-6アルキル基、および(b)複素環基から選ばれる置換基でモノまたはジ置換されていてもよいカルバモイル基、または
(6)(a)C1-6アルキル基、および(b)オキソ基から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環オキシカルボニル基である、上記[1]~[4]のいずれか1記載の化合物またはその塩;
[6]Xが、
(1)ハロゲン原子、および
(2)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル
から選ばれる1ないし3個の置換基でそれぞれ置換されていてもよい、エチレンまたはトリメチレンである、上記[1]~[5]のいずれか1記載の化合物またはその塩;
[7]Xが、
(1)結合手、
(2)O、または
(3)(a)(i)シアノ基、および(ii)1ないし3個のハロゲン原子から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル、 
   (b)C1-6アルキル-カルボニル基、 または
   (c)C1-6アルキルスルホニル基
で置換されていてもよいNHである、上記[1]~[6]のいずれか1記載の化合物またはその塩;
[8]Xが、結合手またはメチレンである、上記[1]~[7]のいずれか1記載の化合物またはその塩;
[9]YおよびYが、独立して、メチレンまたはエチレンである、上記[1]~[8]のいずれか1記載の化合物またはその塩;
[10]環Aが、
(1)ハロゲン原子、
(2)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基、および
(3)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ基
から選ばれる1ないし3個の置換基でそれぞれさらに置換されていてもよい、ベンゼン、ピリジン、またはピリミジンであり;
が、
(1)ハロゲン原子、
(2)カルボキシ基、
(3)(a)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基、および(b)オキソ基から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環基、
(4)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ-カルボニル基、
(5)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキルスルホニル基、
(6)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基でモノまたはジ置換されていてもよいスルファモイル基、または
(7)(a)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基、および(b)オキソ基から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環スルホニル基であり;
が、
(1)(a)ハロゲン原子、および(b)C1-6アルコキシ-カルボニル基から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基、
(2)(a)ハロゲン原子、および(b)C1-6アルキル基から選ばれる1ないし3個の置換基で置換されていてもよい芳香族複素環基、
(3)(a)ハロゲン原子、(b)C1-6アルキル基、および(c)オキソ基から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環基、
(4)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ-カルボニル基、
(5)(a)C1-6アルキル基、および(b)複素環基から選ばれる置換基でモノまたはジ置換されていてもよいカルバモイル基、または
(6)(a)C1-6アルキル基、および(b)オキソ基から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環オキシカルボニル基であり;
が、
(1)ハロゲン原子、および
(2)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル
から選ばれる1ないし3個の置換基でそれぞれ置換されていてもよい、エチレンまたはトリメチレンであり;
が、
(1)結合手、
(2)O、または
(3)(a)(i)シアノ基、および(ii)1ないし3個のハロゲン原子から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル、 
   (b)C1-6アルキル-カルボニル基、 または
   (c)C1-6アルキルスルホニル基
で置換されていてもよいNHであり;
が、結合手またはメチレンであり;および
およびYが、独立して、メチレンまたはエチレンである、上記[1]~[9]のいずれか1記載の化合物またはその塩;
[11]5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸 2-[1-(5-プロピルピリミジン-2-イル)ピペリジン-4-イル]プロピルまたはその塩;
[12]7-フルオロ-5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-[1-(5-プロピルピリミジン-2-イル)ピペリジン-4-イル]プロピルまたはその塩;
[13]上記[1]~[12]のいずれか1記載の化合物もしくはその塩またはそのプロドラッグを含む、医薬;
[14]インスリン分泌促進剤である、上記[13]記載の医薬;
[15]グルカゴン様ペプチド‐1分泌促進剤である、上記[13]記載の医薬;
[16]GPR119作動薬である、上記[13]記載の医薬;
[17]糖尿病の予防または治療剤である、上記[13]記載の医薬;
[18]肥満症の予防または治療剤である、上記[13]記載の医薬;
[19]上記[1]~[12]のいずれか1記載の化合物もしくはその塩またはそのプロドラッグを哺乳動物に有効量投与することを特徴とする、該哺乳動物における糖尿病の予防または治療方法;
[20]上記[1]~[12]のいずれか1記載の化合物もしくはその塩またはそのプロドラッグを哺乳動物に有効量投与することを特徴とする、該哺乳動物における肥満症の予防または治療方法;
[21]糖尿病の予防または治療剤を製造するための、上記[1]~[12]のいずれか1記載の化合物もしくはその塩またはそのプロドラッグの使用;
[22]肥満症の予防または治療剤を製造するための、上記[1]~[12]のいずれか1記載の化合物もしくはその塩またはそのプロドラッグの使用;
[23]上記[1]~[12]のいずれか1記載の化合物またはその塩のプロドラッグ;
等に関する。
That is, the present invention
[1] Compound (I);
[2] The compound or a salt thereof according to the above [1], wherein X 3 is a bond or optionally substituted CH 2 ;
[3] Ring A is
(1) a halogen atom,
(2) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, and
(3) With benzene, pyridine, or pyrimidine, each of which may be further substituted with 1 to 3 substituents selected from C 1-6 alkoxy groups optionally substituted with 1 to 3 halogen atoms A compound or salt thereof according to [1] or [2] above;
[4] R 1 is
(1) a halogen atom,
(2) a carboxy group,
(3) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (b) optionally substituted with 1 to 3 substituents selected from an oxo group Non-aromatic heterocyclic group,
(4) a C 1-6 alkoxy-carbonyl group optionally substituted with 1 to 3 halogen atoms,
(5) a C 1-6 alkylsulfonyl group which may be substituted with 1 to 3 halogen atoms,
(6) a sulfamoyl group optionally mono- or disubstituted with a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, or
(7) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (b) optionally substituted with 1 to 3 substituents selected from an oxo group The compound or the salt thereof according to any one of the above [1] to [3], which is a non-aromatic heterocyclic sulfonyl group;
[5] R 2 is
(1) (a) a halogen atom, and (b) C 1-6 alkoxy - 1 to 3 substituents optionally substituted by a C 1-6 alkyl group selected from a carbonyl group,
(2) an aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, and (b) a C 1-6 alkyl group,
(3) a non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, (b) a C 1-6 alkyl group, and (c) an oxo group,
(4) a C 1-6 alkoxy-carbonyl group optionally substituted with 1 to 3 halogen atoms,
(5) a carbamoyl group optionally mono- or disubstituted with a substituent selected from (a) a C 1-6 alkyl group, and (b) a heterocyclic group, or
(6) The above-mentioned [1], which is a non-aromatic heterocyclic oxycarbonyl group optionally substituted with 1 to 3 substituents selected from (a) a C 1-6 alkyl group and (b) an oxo group ] To [4] or a salt thereof;
[6] X 1 is
(1) a halogen atom, and
(2) The above [1], which is ethylene or trimethylene, each of which may be substituted with 1 to 3 substituents selected from C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms ] To [5] or a salt thereof;
[7] X 2 is
(1) Joining hands,
(2) O or
(3) (a) (i) a cyano group, and (ii) C 1-6 alkyl optionally substituted with 1 to 3 substituents selected from 1 to 3 halogen atoms,
(b) a C 1-6 alkyl-carbonyl group, or (c) NH, which may be substituted with a C 1-6 alkylsulfonyl group, or a compound according to any one of [1] to [6] above, Its salt;
[8] The compound or salt thereof according to any one of [1] to [7] above, wherein X 3 is a bond or methylene;
[9] The compound or a salt thereof according to any one of [1] to [8] above, wherein Y 1 and Y 2 are independently methylene or ethylene;
[10] Ring A is
(1) a halogen atom,
(2) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, and
(3) With benzene, pyridine, or pyrimidine, each of which may be further substituted with 1 to 3 substituents selected from C 1-6 alkoxy groups optionally substituted with 1 to 3 halogen atoms Yes;
R 1 is
(1) a halogen atom,
(2) a carboxy group,
(3) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (b) optionally substituted with 1 to 3 substituents selected from an oxo group Non-aromatic heterocyclic group,
(4) a C 1-6 alkoxy-carbonyl group optionally substituted with 1 to 3 halogen atoms,
(5) a C 1-6 alkylsulfonyl group which may be substituted with 1 to 3 halogen atoms,
(6) a sulfamoyl group optionally mono- or disubstituted with a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, or
(7) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (b) optionally substituted with 1 to 3 substituents selected from an oxo group A non-aromatic heterocyclic sulfonyl group;
R 2 is
(1) (a) a halogen atom, and (b) C 1-6 alkoxy - 1 to 3 substituents optionally substituted by a C 1-6 alkyl group selected from a carbonyl group,
(2) an aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, and (b) a C 1-6 alkyl group,
(3) a non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, (b) a C 1-6 alkyl group, and (c) an oxo group,
(4) a C 1-6 alkoxy-carbonyl group optionally substituted with 1 to 3 halogen atoms,
(5) a carbamoyl group optionally mono- or disubstituted with a substituent selected from (a) a C 1-6 alkyl group, and (b) a heterocyclic group, or
(6) (a) a non-aromatic heterocyclic oxycarbonyl group which may be substituted with 1 to 3 substituents selected from (a) a C 1-6 alkyl group and (b) an oxo group;
X 1 is
(1) a halogen atom, and
(2) ethylene or trimethylene, each optionally substituted with 1 to 3 substituents selected from C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms;
X 2 is,
(1) Joining hands,
(2) O or
(3) (a) (i) a cyano group, and (ii) C 1-6 alkyl optionally substituted with 1 to 3 substituents selected from 1 to 3 halogen atoms,
(b) a C 1-6 alkyl-carbonyl group, or (c) NH optionally substituted with a C 1-6 alkylsulfonyl group;
The compound or a salt thereof according to any one of the above [1] to [9], wherein X 3 is a bond or methylene; and Y 1 and Y 2 are independently methylene or ethylene;
[11] 5- [Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- [1- (5-propylpyrimidin-2-yl) piperidin-4-yl] propyl or a salt thereof;
[12] 7-Fluoro-5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- [1- (5-propylpyrimidin-2-yl) piperidin-4-yl] propyl Or a salt thereof;
[13] A medicament comprising the compound according to any one of [1] to [12] above or a salt thereof or a prodrug thereof;
[14] The medicament according to [13] above, which is an insulin secretion promoter;
[15] The medicament according to [13] above, which is a glucagon-like peptide-1 secretion promoter;
[16] The medicament according to [13] above, which is a GPR119 agonist;
[17] The medicament according to [13] above, which is a preventive or therapeutic agent for diabetes;
[18] The medicament according to [13] above, which is an agent for preventing or treating obesity;
[19] A method for preventing or treating diabetes in a mammal, comprising administering to the mammal an effective amount of the compound according to any one of [1] to [12] above or a salt thereof, or a prodrug thereof;
[20] A method for preventing or treating obesity in a mammal, comprising administering an effective amount of the compound according to any one of [1] to [12] above or a salt thereof or a prodrug thereof to the mammal. ;
[21] Use of the compound according to any one of [1] to [12] above, or a salt thereof, or a prodrug thereof for the manufacture of an agent for preventing or treating diabetes;
[22] Use of the compound according to any one of [1] to [12] above, or a salt thereof, or a prodrug thereof for the manufacture of a prophylactic or therapeutic agent for obesity;
[23] A prodrug of the compound or a salt thereof according to any one of [1] to [12] above;
Etc.
 化合物(I)は、GPR119アゴニスト作用を有し、糖尿病、肥満症等の予防・治療に有用であり、かつ優れた薬効を有する。 Compound (I) has a GPR119 agonistic action, is useful for the prevention and treatment of diabetes, obesity and the like, and has an excellent medicinal effect.
[発明の詳細な説明]
 以下、式(I)中の各記号の定義について詳述する。
 本明細書中の「ハロゲン原子」は、特に断りのない限り、フッ素原子、塩素原子、臭素原子、ヨウ素原子を意味する。
 本明細書中の「C1-6アルキル基」は、特に断りのない限り、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec-ブチル、tert-ブチル、ペンチル、イソペンチル、ネオペンチル、1-エチルプロピル、ヘキシル、イソヘキシル、1,1-ジメチルブチル、2,2-ジメチルブチル、3,3-ジメチルブチル、2-エチルブチル等を意味する。
Detailed Description of the Invention
Hereinafter, the definition of each symbol in formula (I) will be described in detail.
The “halogen atom” in the present specification means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom unless otherwise specified.
In the present specification, “C 1-6 alkyl group” means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethyl unless otherwise specified. It means propyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
 本明細書中の「C1-6アルコキシ基」は、特に断りのない限り、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、sec-ブトキシ、tert-ブトキシ等を意味する。
 本明細書中の「C1-6アルコキシ-カルボニル基」は、特に断りのない限り、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、tert-ブトキシカルボニル等を意味する。
 本明細書中の「C1-6アルキル-カルボニル基」は、特に断りのない限り、アセチル、プロパノイル、ブタノイル、イソブタノイル、ペンタノイル、イソペンタノイル、ヘキサノイル等を意味する。
The “C 1-6 alkoxy group” in the present specification means methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like unless otherwise specified.
The “C 1-6 alkoxy-carbonyl group” in the present specification means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl and the like, unless otherwise specified.
The “C 1-6 alkyl-carbonyl group” in the present specification means acetyl, propanoyl, butanoyl, isobutanoyl, pentanoyl, isopentanoyl, hexanoyl and the like, unless otherwise specified.
 環Aは、さらに置換されていてもよい6員芳香環を示す。 Ring A represents a 6-membered aromatic ring which may be further substituted.
 環Aで示される「置換されていてもよい6員芳香環」における「6員芳香環」としては、ベンゼン、ピリジン、ピリダジン、ピリミジン、ピラジン、トリアジン等が挙げられる。好ましくは、ベンゼン、ピリジン、ピリダジン、ピリミジン、ピラジン等であり、より好ましくは、ベンゼン、ピリジン、ピリミジン等である。 Examples of the “6-membered aromatic ring” in the “optionally substituted 6-membered aromatic ring” represented by ring A include benzene, pyridine, pyridazine, pyrimidine, pyrazine, triazine and the like. Preferred are benzene, pyridine, pyridazine, pyrimidine, pyrazine and the like, and more preferred are benzene, pyridine, pyrimidine and the like.
 環Aで示される「置換されていてもよい6員芳香環」における「6員芳香環」は、R基に加えて、置換可能な位置に1ないし3個の置換基を有する。 The “6-membered aromatic ring” in the “optionally substituted 6-membered aromatic ring” represented by ring A has 1 to 3 substituents at substitutable positions in addition to the R 1 group.
 このような置換基としては、例えば、
(1)C3-10シクロアルキル基(例、シクロプロピル、シクロヘキシル);
(2)(a)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基、
   (b)ヒドロキシ基、
   (c)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ基、および
   (d)ハロゲン原子
から選ばれる1ないし3個の置換基で置換されていてもよいC6-14アリール基(例、フェニル、ナフチル);
(3)(a)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基、
   (b)ヒドロキシ基、
   (c)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ基、および
   (d)ハロゲン原子
から選ばれる1ないし3個の置換基で置換されていてもよい芳香族複素環基(例、チエニル、フリル、ピリジル、ピラゾリル、イミダゾリル、テトラゾリル、オキサゾリル、チアゾリル、オキサジアゾリル、チアジアゾリル);
(4)(a)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基、
   (b)ヒドロキシ基、
   (c)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ基、
   (d)ハロゲン原子、および
   (e)オキソ基
から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環基(例、テトラヒドロフリル、モルホリニル、チオモルホリニル、ピペリジニル、ピロリジニル、ピペラジニル);
(5)(a)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基、
   (b)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル-カルボニル基、
   (c)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ-カルボニル基、
   (d)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキルスルホニル基(例、メチルスルホニル)、
   (e)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基でモノまたはジ置換されていてもよいカルバモイル基、および
   (f)芳香族複素環基(例、チエニル、フリル、ピリジル、ピラゾリル、イミダゾリル、テトラゾリル、オキサゾリル、チアゾリル、オキサジアゾリル、チアジアゾリル)
から選ばれる置換基でモノまたはジ置換されていてもよいアミノ基;
(6)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル-カルボニ
ル基;
(7)(a)ハロゲン原子、
   (b)C1-6アルコキシ基、
   (c)C6-14アリール基(例、フェニル)、および
   (d)複素環基(例、テトラヒドロフリル)
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルコキシ-カルボニル基(例、メトキシカルボニル);
(8)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキルスルホニル
基(例、メチルスルホニル、エチルスルホニル、イソプロピルスルホニル);
(9)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基でモノま
たはジ置換されていてもよいカルバモイル基;
(10)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基でモノまたはジ置換されていてもよいチオカルバモイル基;
(11)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基でモノまたはジ置換されていてもよいスルファモイル基;
(12)カルボキシ基;
(13)ヒドロキシ基;
(14)(a)ハロゲン原子、
   (b)カルボキシ基、
   (c)C1-6アルコキシ基、
   (d)1ないし3個のC6-14アリール基(例、フェニル)で置換されていてもよ
いC1-6アルコキシ-カルボニル基、
   (e)C1-6アルキル基およびC1-6アルコキシ-カルボニル基から選ばれる置
換基でモノまたはジ置換されていてもよいアミノ基、
   (f)複素環基(例、テトラヒドロフリル)、および
   (g)C3-10シクロアルキル基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルコキシ基;
(15)1ないし3個のハロゲン原子で置換されていてもよいC2-6アルケニルオキシ基(例、エテニルオキシ);
(16)C7-13アラルキルオキシ基(例、ベンジルオキシ);
(17)C6-14アリールオキシ基(例、フェニルオキシ、ナフチルオキシ);
(18)C1-6アルキル-カルボニルオキシ基(例、アセチルオキシ、tert-ブチルカルボニルオキシ);
(19)(a)ハロゲン原子、および
   (b)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基
から選ばれる1ないし3個の置換基で置換されていてもよいC6-14アリール-カルボニル基(例、ベンゾイル);
(20)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環カルボニル基(例、ピロリジニルカルボニル、モルホリニルカルボニル);
(21)メルカプト基;
(22)(a)ハロゲン原子、および
   (b)C1-6アルコキシ-カルボニル基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキルチオ基(例、メチルチオ、エチルチオ);
(23)C7-13アラルキルチオ基(例、ベンジルチオ);
(24)C6-14アリールチオ基(例、フェニルチオ、ナフチルチオ);
(25)シアノ基;
(26)ニトロ基;
(27)ハロゲン原子(例、フッ素原子、塩素原子、臭素原子);
(28)C1-3アルキレンジオキシ基;
(29)C1-3アルキレンオキシ基(例、メチレンオキシ、エチレンオキシ);
(30)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基から選ばれる1ないし3個の置換基で置換されていてもよい芳香族複素環カルボニル基(例、ピラゾリルカルボニル、ピラジニルカルボニル、イソキサゾリルカルボニル、ピリジルカルボニル、チアゾリルカルボニル);
(31)(a)ハロゲン原子(例、フッ素原子)、および
   (b)C1-6アルコキシ基(例、メトキシ)
から選ばれる1ないし3個の置換基で置換されていてもよいC3-10シクロアルコキシ基(例、シクロプロポキシ、シクロペンチルオキシ);
(32)(a)ハロゲン原子、
   (b)カルボキシ基、
   (c)ヒドロキシ基、
   (d)C1-6アルコキシ-カルボニル基、
   (e)C1-6アルコキシ基、および
   (f)C1-6アルキル基でモノまたはジ置換されていてもよいアミノ基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基;
(33)(a)ハロゲン原子、
   (b)カルボキシ基、
   (c)ヒドロキシ基、
   (d)C1-6アルコキシ-カルボニル基、
   (e)C1-6アルコキシ基、および
   (f)C1-6アルキル基でモノまたはジ置換されていてもよいアミノ基
から選ばれる1ないし3個の置換基で置換されていてもよいC2-6アルケニル基(例、エテニル、1-プロペニル);
(34)(a)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基、
   (b)ヒドロキシ基、
   (c)C1-6アルコキシ基、および
   (d)ハロゲン原子
から選ばれる1ないし3個の置換基で置換されていてもよいC7-13アラルキル基(例、ベンジル);
等が挙げられる。置換基が2個以上である場合、各置換基は同一でも異なっていてもよい。
As such a substituent, for example,
(1) a C 3-10 cycloalkyl group (eg, cyclopropyl, cyclohexyl);
(2) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C 1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and (d) a C 6- optionally substituted with 1 to 3 substituents selected from halogen atoms. 14 aryl groups (eg, phenyl, naphthyl);
(3) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C 1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, and (d) an aromatic complex which may be substituted with 1 to 3 substituents selected from halogen atoms. A cyclic group (eg, thienyl, furyl, pyridyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl);
(4) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C 1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms,
(d) a non-aromatic heterocyclic group (eg, tetrahydrofuryl, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, piperazinyl) optionally substituted by 1 to 3 substituents selected from halogen atoms and (e) oxo groups );
(5) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms,
(b) a C 1-6 alkyl-carbonyl group optionally substituted by 1 to 3 halogen atoms,
(c) a C 1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 halogen atoms,
(d) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl) optionally substituted with 1 to 3 halogen atoms,
(e) a carbamoyl group optionally mono- or di-substituted with a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (f) an aromatic heterocyclic group (eg, thienyl, Furyl, pyridyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl)
An amino group which may be mono- or di-substituted with a substituent selected from:
(6) a C 1-6 alkyl-carbonyl group optionally substituted with 1 to 3 halogen atoms;
(7) (a) a halogen atom,
(b) a C 1-6 alkoxy group,
(c) a C 6-14 aryl group (eg, phenyl), and (d) a heterocyclic group (eg, tetrahydrofuryl).
A C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl) optionally substituted by 1 to 3 substituents selected from:
(8) a C 1-6 alkylsulfonyl group which may be substituted with 1 to 3 halogen atoms (eg, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl);
(9) a carbamoyl group optionally mono- or di-substituted with a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms;
(10) a thiocarbamoyl group optionally mono- or di-substituted with a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms;
(11) a sulfamoyl group optionally mono- or disubstituted with a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms;
(12) a carboxy group;
(13) a hydroxy group;
(14) (a) a halogen atom,
(b) a carboxy group,
(c) a C 1-6 alkoxy group,
(d) a C 1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 C 6-14 aryl groups (eg, phenyl),
(e) an amino group which may be mono- or di-substituted with a substituent selected from a C 1-6 alkyl group and a C 1-6 alkoxy-carbonyl group,
(f) a heterocyclic group (eg, tetrahydrofuryl), and (g) a C 1-6 alkoxy group that may be substituted with 1 to 3 substituents selected from a C 3-10 cycloalkyl group;
(15) a C 2-6 alkenyloxy group (eg, ethenyloxy) optionally substituted by 1 to 3 halogen atoms;
(16) C 7-13 aralkyloxy group (eg, benzyloxy);
(17) C 6-14 aryloxy group (eg, phenyloxy, naphthyloxy);
(18) C 1-6 alkyl-carbonyloxy group (eg, acetyloxy, tert-butylcarbonyloxy);
(19) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, and (b) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms A C 6-14 aryl-carbonyl group (eg, benzoyl);
(20) a non-aromatic heterocyclic carbonyl group optionally substituted with 1 to 3 substituents selected from C 1-6 alkyl groups optionally substituted with 1 to 3 halogen atoms (eg, Pyrrolidinylcarbonyl, morpholinylcarbonyl);
(21) mercapto group;
(22) a C 1-6 alkylthio group (eg, methylthio, ethylthio) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, and (b) a C 1-6 alkoxy-carbonyl group );
(23) C 7-13 aralkylthio group (eg, benzylthio);
(24) C 6-14 arylthio group (eg, phenylthio, naphthylthio);
(25) a cyano group;
(26) a nitro group;
(27) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom);
(28) a C 1-3 alkylenedioxy group;
(29) C 1-3 alkyleneoxy group (eg, methyleneoxy, ethyleneoxy);
(30) an aromatic heterocyclic carbonyl group optionally substituted with 1 to 3 substituents selected from C 1-6 alkyl groups optionally substituted with 1 to 3 halogen atoms (eg, pyrazolyl) Carbonyl, pyrazinylcarbonyl, isoxazolylcarbonyl, pyridylcarbonyl, thiazolylcarbonyl);
(31) (a) a halogen atom (eg, fluorine atom), and (b) a C 1-6 alkoxy group (eg, methoxy)
A C 3-10 cycloalkoxy group (eg, cyclopropoxy, cyclopentyloxy) optionally substituted with 1 to 3 substituents selected from:
(32) (a) a halogen atom,
(b) a carboxy group,
(c) a hydroxy group,
(d) a C 1-6 alkoxy-carbonyl group,
(e) a C 1-6 alkoxy group, and (f) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted. 1-6 alkyl groups;
(33) (a) a halogen atom,
(b) a carboxy group,
(c) a hydroxy group,
(d) a C 1-6 alkoxy-carbonyl group,
(e) a C 1-6 alkoxy group, and (f) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted. 2-6 alkenyl groups (eg, ethenyl, 1-propenyl);
(34) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C 1-6 alkoxy group, and (d) a C 7-13 aralkyl group (eg, benzyl) optionally substituted with 1 to 3 substituents selected from halogen atoms;
Etc. When there are two or more substituents, each substituent may be the same or different.
 環Aは、好ましくは、
(1)ヒドロキシ基;
(2)ハロゲン原子(例、フッ素原子、塩素原子);
(3)(a)ハロゲン原子、および
   (b)C1-6アルコキシ基
から選ばれる1ないし3個の置換基で置換されていてもよいC3-10シクロアルコキシ基;
(4)(a)ハロゲン原子、
   (b)カルボキシ基、
   (c)ヒドロキシ基、
   (d)C1-6アルコキシ-カルボニル基、
   (e)C1-6アルコキシ基、および
   (f)C1-6アルキル基でモノまたはジ置換されていてもよいアミノ基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基(例、メチル);
(5)(a)ハロゲン原子、
   (b)カルボキシ基、
   (c)ヒドロキシ基、
   (d)C1-6アルコキシ-カルボニル基、
   (e)C1-6アルコキシ基、および
   (f)C1-6アルキル基でモノまたはジ置換されていてもよいアミノ基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルコキシ基(例、メトキシ);
等から選ばれる1ないし3個の置換基でそれぞれ置換されていてもよい、ベンゼン、ピリジン、ピリダジン、ピリミジン、ピラジン(好ましくは、ベンゼン、ピリジン、ピリミジン)等である。
Ring A is preferably
(1) hydroxy group;
(2) Halogen atoms (eg, fluorine atoms, chlorine atoms);
(3) a C 3-10 cycloalkoxy group optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, and (b) a C 1-6 alkoxy group;
(4) (a) a halogen atom,
(b) a carboxy group,
(c) a hydroxy group,
(d) a C 1-6 alkoxy-carbonyl group,
(e) a C 1-6 alkoxy group, and (f) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted. 1-6 alkyl groups (eg, methyl);
(5) (a) a halogen atom,
(b) a carboxy group,
(c) a hydroxy group,
(d) a C 1-6 alkoxy-carbonyl group,
(e) a C 1-6 alkoxy group, and (f) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted. 1-6 alkoxy groups (eg, methoxy);
Benzene, pyridine, pyridazine, pyrimidine, pyrazine (preferably benzene, pyridine, pyrimidine) and the like, each of which may be substituted with 1 to 3 substituents selected from the above.
 環Aは、より好ましくは、
(1)ハロゲン原子(例、フッ素原子、塩素原子);
(2)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基(例、メチル)、および;
(3)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ基(例、メトキシ);
から選ばれる1ないし3個の置換基でそれぞれさらに置換されていてもよい、ベンゼン、ピリジン、ピリミジン(好ましくは、ベンゼン)等である。
Ring A is more preferably
(1) Halogen atoms (eg, fluorine atoms, chlorine atoms);
(2) a C 1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms; and
(3) a C 1-6 alkoxy group (eg, methoxy) optionally substituted by 1 to 3 halogen atoms;
Benzene, pyridine, pyrimidine (preferably benzene) and the like, each of which may be further substituted with 1 to 3 substituents selected from
 Rは、ハロゲン原子、シアノ基、置換されていてもよい炭化水素基、置換されていてもよい複素環基、置換されていてもよいアミノ基、またはアシル基を示す。 R 1 represents a halogen atom, a cyano group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted amino group, or an acyl group.
 Rで示される「置換されていてもよい炭化水素基」における「炭化水素基」としては、例えば、C1-10アルキル基、C2-10アルケニル基、C2-10アルキニル基、C3-10シクロアルキル基、C3-10シクロアルケニル基、C4-10シクロアルカジエニル基、C6-14アリール基、C7-13アラルキル基、C8-13アリールアルケニル基等が挙げられる。 Examples of the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R 1 include a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 2-10 alkynyl group, C 3 -10 cycloalkyl group, C 3-10 cycloalkenyl group, C 4-10 cycloalkadienyl group, C 6-14 aryl group, C 7-13 aralkyl group, C 8-13 arylalkenyl group and the like can be mentioned.
 ここで、C1-10アルキル基としては、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec-ブチル、tert-ブチル、ペンチル、イソペンチル、ネオペンチル、1-エチルプロピル、ヘキシル、イソヘキシル、1,1-ジメチルブチル、2,2-ジメチルブチル、3,3-ジメチルブチル、2-エチルブチル、ヘプチル、オクチル、ノニル、デシル等が挙げられる。 Here, examples of the C 1-10 alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1 , 1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and the like.
 C2-10アルケニル基としては、例えば、エテニル、1-プロペニル、2-プロペニル、2-メチル-1-プロペニル、1-ブテニル、2-ブテニル、3-ブテニル、3-メチル-2-ブテニル、1-ペンテニル、2-ペンテニル、3-ペンテニル、4-ペンテニル、4-メチル-3-ペンテニル、1-ヘキセニル、3-ヘキセニル、5-ヘキセニル、1-ヘプテニル、1-オクテニル等が挙げられる。 Examples of the C 2-10 alkenyl group include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1 -Pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like.
 C2-10アルキニル基としては、例えば、エチニル、1-プロピニル、2-プロピニル、1-ブチニル、2-ブチニル、3-ブチニル、1-ペンチニル、2-ペンチニル、3-ペンチニル、4-ペンチニル、1-ヘキシニル、2-ヘキシニル、3-ヘキシニル、4-ヘキシニル、5-ヘキシニル、1-ヘプチニル、1-オクチニル等が挙げられる。 Examples of the C 2-10 alkynyl group include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1 -Hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like.
 C3-10シクロアルキル基としては、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、ビシクロ[2.2.1]ヘプチル、ビシクロ[2.2.2]オクチル、ビシクロ[3.2.1]オクチル、ビシクロ[3.2.2]ノニル、ビシクロ[3.3.1]ノニル、ビシクロ[4.2.1]ノニル、ビシクロ[4.3.1]デシル、アダマンチル等が挙げられる。 Examples of the C 3-10 cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3 2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] decyl, adamantyl and the like. Can be mentioned.
 C3-10シクロアルケニル基としては、例えば、2-シクロペンテン-1-イル、3-シクロペンテン-1-イル、2-シクロヘキセン-1-イル、3-シクロヘキセン-1-イル等が挙げられる。 Examples of the C 3-10 cycloalkenyl group include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like.
 C4-10シクロアルカジエニル基としては、例えば、2,4-シクロペンタジエン-1-イル、2,4-シクロヘキサジエン-1-イル、2,5-シクロヘキサジエン-1-イル等が挙げられる。 Examples of the C 4-10 cycloalkadienyl group include 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl, and the like. .
 上記のC3-10シクロアルキル基、C3-10シクロアルケニル基およびC4-10シクロアルカジエニル基は、それぞれベンゼン環と縮合環基を形成していてもよく、このような縮合環基としては、例えば、インダニル、ジヒドロナフチル、テトラヒドロナフチル、フルオレニル等が挙げられる。 The above C 3-10 cycloalkyl group, C 3-10 cycloalkenyl group and C 4-10 cycloalkadienyl group may each form a condensed ring group with a benzene ring, and such a condensed ring group Examples thereof include indanyl, dihydronaphthyl, tetrahydronaphthyl, fluorenyl and the like.
 C6-14アリール基としては、例えば、フェニル、ナフチル、アントリル、フェナントリル、アセナフチレニル、ビフェニリル等が挙げられる。 Examples of the C 6-14 aryl group include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl and the like.
 C7-13アラルキル基としては、例えば、ベンジル、フェネチル、ナフチルメチル、ビフェニリルメチル等が挙げられる。
 C8-13アリールアルケニル基としては、例えば、スチリル等が挙げられる。
Examples of the C 7-13 aralkyl group include benzyl, phenethyl, naphthylmethyl, biphenylylmethyl and the like.
Examples of the C 8-13 arylalkenyl group include styryl and the like.
 Rで示される「置換されていてもよい炭化水素基」における「炭化水素基」として例示した、C1-10アルキル基、C2-10アルケニル基およびC2-10アルキニル基は、置換可能な位置に1ないし3個の置換基を有していてもよい。 The C 1-10 alkyl group, C 2-10 alkenyl group, and C 2-10 alkynyl group exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R 1 can be substituted. It may have 1 to 3 substituents at various positions.
 このような置換基としては、例えば、
(1)C3-10シクロアルキル基(例、シクロプロピル、シクロヘキシル);
(2)(a)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基、
   (b)ヒドロキシ基、
   (c)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ基、および
   (d)ハロゲン原子
から選ばれる1ないし3個の置換基で置換されていてもよいC6-14アリール基(例、フェニル、ナフチル);
(3)(a)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基、
   (b)ヒドロキシ基、
   (c)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ基、および
   (d)ハロゲン原子
から選ばれる1ないし3個の置換基で置換されていてもよい芳香族複素環基(例、チエニル、フリル、ピリジル、ピラゾリル、イミダゾリル、テトラゾリル、オキサゾリル、チアゾリル、オキサジアゾリル、チアジアゾリル);
(4)(a)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基、
   (b)ヒドロキシ基、
   (c)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ基、
   (d)ハロゲン原子、および
   (e)オキソ基
から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環基(例、テトラヒドロフリル、モルホリニル、チオモルホリニル、ピペリジニル、ピロリジニル、ピペラジニル);
(5)(a)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基、
   (b)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル-カルボニル基、
   (c)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ-カルボニル基、
   (d)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキルスルホニル基(例、メチルスルホニル)、
   (e)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基でモノまたはジ置換されていてもよいカルバモイル基、および
   (f)芳香族複素環基(例、チエニル、フリル、ピリジル、ピラゾリル、イミダゾリル、テトラゾリル、オキサゾリル、チアゾリル、オキサジアゾリル、チアジアゾリル)
から選ばれる置換基でモノまたはジ置換されていてもよいアミノ基;
(6)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル-カルボニ
ル基;
(7)(a)ハロゲン原子、
   (b)C1-6アルコキシ基、
   (c)C6-14アリール基(例、フェニル)、および
   (d)複素環基(例、テトラヒドロフリル)
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルコキシ-カルボニル基;
(8)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキルスルホニル
基(例、メチルスルホニル、エチルスルホニル、イソプロピルスルホニル);
(9)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基でモノま
たはジ置換されていてもよいカルバモイル基;
(10)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基でモノまたはジ置換されていてもよいチオカルバモイル基;
(11)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基でモノまたはジ置換されていてもよいスルファモイル基;
(12)カルボキシ基;
(13)ヒドロキシ基;
(14)(a)ハロゲン原子、
   (b)カルボキシ基、
   (c)C1-6アルコキシ基、
   (d)1ないし3個のC6-14アリール基(例、フェニル)で置換されていてもよ
いC1-6アルコキシ-カルボニル基、
   (e)C1-6アルキル基およびC1-6アルコキシ-カルボニル基から選ばれる置
換基でモノまたはジ置換されていてもよいアミノ基、
   (f)複素環基(例、テトラヒドロフリル)、および
   (g)C3-10シクロアルキル基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルコキシ基;
(15)1ないし3個のハロゲン原子で置換されていてもよいC2-6アルケニルオキシ基(例、エテニルオキシ);
(16)C7-13アラルキルオキシ基(例、ベンジルオキシ);
(17)C6-14アリールオキシ基(例、フェニルオキシ、ナフチルオキシ);
(18)C1-6アルキル-カルボニルオキシ基(例、アセチルオキシ、tert-ブチルカルボニルオキシ);
(19)(a)ハロゲン原子、および
   (b)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基
から選ばれる1ないし3個の置換基で置換されていてもよいC6-14アリール-カルボニル基(例、ベンゾイル);
(20)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環カルボニル基(例、ピロリジニルカルボニル、モルホリニルカルボニル);
(21)メルカプト基;
(22)(a)ハロゲン原子、および
   (b)C1-6アルコキシ-カルボニル基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキルチオ基(例、メチルチオ、エチルチオ);
(23)C7-13アラルキルチオ基(例、ベンジルチオ);
(24)C6-14アリールチオ基(例、フェニルチオ、ナフチルチオ);
(25)シアノ基;
(26)ニトロ基;
(27)ハロゲン原子(例、フッ素原子、塩素原子);
(28)C1-3アルキレンジオキシ基;
(29)C1-3アルキレンオキシ基(例、メチレンオキシ、エチレンオキシ);
(30)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基から選ばれる1ないし3個の置換基で置換されていてもよい芳香族複素環カルボニル基(例、ピラゾリルカルボニル、ピラジニルカルボニル、イソキサゾリルカルボニル、ピリジルカルボニル、チアゾリルカルボニル);
(31)(a)ハロゲン原子(例、フッ素原子)、および
   (b)C1-6アルコキシ基(例、メトキシ)
から選ばれる1ないし3個の置換基で置換されていてもよいC3-10シクロアルコキシ基(例、シクロプロポキシ、シクロペンチルオキシ);
等が挙げられる。置換基が2個以上である場合、各置換基は同一でも異なっていてもよい。
As such a substituent, for example,
(1) a C 3-10 cycloalkyl group (eg, cyclopropyl, cyclohexyl);
(2) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C 1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms, and (d) a C 6- optionally substituted with 1 to 3 substituents selected from halogen atoms. 14 aryl groups (eg, phenyl, naphthyl);
(3) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C 1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, and (d) an aromatic complex which may be substituted with 1 to 3 substituents selected from halogen atoms. A cyclic group (eg, thienyl, furyl, pyridyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl);
(4) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms,
(b) a hydroxy group,
(c) a C 1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms,
(d) a non-aromatic heterocyclic group (eg, tetrahydrofuryl, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, piperazinyl) optionally substituted by 1 to 3 substituents selected from halogen atoms and (e) oxo groups );
(5) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms,
(b) a C 1-6 alkyl-carbonyl group optionally substituted by 1 to 3 halogen atoms,
(c) a C 1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 halogen atoms,
(d) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl) optionally substituted with 1 to 3 halogen atoms,
(e) a carbamoyl group optionally mono- or di-substituted with a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (f) an aromatic heterocyclic group (eg, thienyl, Furyl, pyridyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl)
An amino group which may be mono- or di-substituted with a substituent selected from:
(6) a C 1-6 alkyl-carbonyl group optionally substituted with 1 to 3 halogen atoms;
(7) (a) a halogen atom,
(b) a C 1-6 alkoxy group,
(c) a C 6-14 aryl group (eg, phenyl), and (d) a heterocyclic group (eg, tetrahydrofuryl).
A C 1-6 alkoxy-carbonyl group optionally substituted with 1 to 3 substituents selected from:
(8) a C 1-6 alkylsulfonyl group which may be substituted with 1 to 3 halogen atoms (eg, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl);
(9) a carbamoyl group optionally mono- or di-substituted with a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms;
(10) a thiocarbamoyl group optionally mono- or di-substituted with a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms;
(11) a sulfamoyl group optionally mono- or disubstituted with a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms;
(12) a carboxy group;
(13) a hydroxy group;
(14) (a) a halogen atom,
(b) a carboxy group,
(c) a C 1-6 alkoxy group,
(d) a C 1-6 alkoxy-carbonyl group optionally substituted by 1 to 3 C 6-14 aryl groups (eg, phenyl),
(e) an amino group which may be mono- or di-substituted with a substituent selected from a C 1-6 alkyl group and a C 1-6 alkoxy-carbonyl group,
(f) a heterocyclic group (eg, tetrahydrofuryl), and (g) a C 1-6 alkoxy group that may be substituted with 1 to 3 substituents selected from a C 3-10 cycloalkyl group;
(15) a C 2-6 alkenyloxy group (eg, ethenyloxy) optionally substituted by 1 to 3 halogen atoms;
(16) C 7-13 aralkyloxy group (eg, benzyloxy);
(17) C 6-14 aryloxy group (eg, phenyloxy, naphthyloxy);
(18) C 1-6 alkyl-carbonyloxy group (eg, acetyloxy, tert-butylcarbonyloxy);
(19) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, and (b) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms A C 6-14 aryl-carbonyl group (eg, benzoyl);
(20) a non-aromatic heterocyclic carbonyl group optionally substituted with 1 to 3 substituents selected from C 1-6 alkyl groups optionally substituted with 1 to 3 halogen atoms (eg, Pyrrolidinylcarbonyl, morpholinylcarbonyl);
(21) mercapto group;
(22) a C 1-6 alkylthio group (eg, methylthio, ethylthio) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, and (b) a C 1-6 alkoxy-carbonyl group );
(23) C 7-13 aralkylthio group (eg, benzylthio);
(24) C 6-14 arylthio group (eg, phenylthio, naphthylthio);
(25) a cyano group;
(26) a nitro group;
(27) halogen atoms (eg, fluorine atoms, chlorine atoms);
(28) a C 1-3 alkylenedioxy group;
(29) C 1-3 alkyleneoxy group (eg, methyleneoxy, ethyleneoxy);
(30) an aromatic heterocyclic carbonyl group optionally substituted with 1 to 3 substituents selected from C 1-6 alkyl groups optionally substituted with 1 to 3 halogen atoms (eg, pyrazolyl) Carbonyl, pyrazinylcarbonyl, isoxazolylcarbonyl, pyridylcarbonyl, thiazolylcarbonyl);
(31) (a) a halogen atom (eg, fluorine atom), and (b) a C 1-6 alkoxy group (eg, methoxy)
A C 3-10 cycloalkoxy group (eg, cyclopropoxy, cyclopentyloxy) optionally substituted with 1 to 3 substituents selected from:
Etc. When there are two or more substituents, each substituent may be the same or different.
 また、Rで示される「置換されていてもよい炭化水素基」における「炭化水素基」として例示した、C3-10シクロアルキル基、C3-10シクロアルケニル基、C4-10シクロアルカジエニル基、C6-14アリール基、C7-13アラルキル基およびC8-13アリールアルケニル基は、置換可能な位置に1ないし3個の置換基を有していてもよい。このような置換基としては、例えば、環Aで示される「置換されていてもよい6員芳香環」における「6員芳香環」が有する置換基と同様のものが挙げられる。置換基が2個以上である場合、各置換基は同一でも異なっていてもよい。 In addition, the C 3-10 cycloalkyl group, the C 3-10 cycloalkenyl group, the C 4-10 cycloalkenyl exemplified as the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R 1 The dienyl group, C 6-14 aryl group, C 7-13 aralkyl group and C 8-13 arylalkenyl group may have 1 to 3 substituents at substitutable positions. Examples of such a substituent include the same substituents as those of the “6-membered aromatic ring” in the “optionally substituted 6-membered aromatic ring” represented by ring A. When there are two or more substituents, each substituent may be the same or different.
 Rで示される「置換されていてもよい炭化水素基」は、好ましくは、
置換されていてもよいC1-6アルキル基であり、より好ましくは、
(1)ハロゲン原子、
(2)カルボキシ基、
(3)C1-6アルコキシ-カルボニル基、および
(4)C1-6アルキル基でモノまたはジ置換されていてもよいアミノ基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基
等である。
The “optionally substituted hydrocarbon group” represented by R 1 is preferably
An optionally substituted C 1-6 alkyl group, more preferably
(1) a halogen atom,
(2) a carboxy group,
(3) a C 1-6 alkoxy-carbonyl group, and
(4) a C 1-6 alkyl group which may be substituted with 1 to 3 substituents selected from amino groups which may be mono- or di-substituted with a C 1-6 alkyl group.
 Rで示される「置換されていてもよい複素環基」における「複素環基」としては、芳香族複素環基および非芳香族複素環基が挙げられる。 Examples of the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R 1 include an aromatic heterocyclic group and a non-aromatic heterocyclic group.
 ここで、芳香族複素環基としては、例えば、環構成原子として炭素原子以外に酸素原子、硫黄原子および窒素原子から選ばれるヘテロ原子を1ないし4個含有する4ないし7員(好ましくは5または6員)の単環式芳香族複素環基および縮合芳香族複素環基が挙げられる。該縮合芳香族複素環基としては、例えば、これら4ないし7員の単環式芳香族複素環基に対応する環と、1または2個の窒素原子を含む5または6員の芳香族複素環(例、ピロール、イミダゾール、ピラゾール、ピラジン、ピリジン、ピリミジン)、1個の硫黄原子を含む5員の芳香族複素環(例、チオフェン)およびベンゼン環から選ばれる1または2個が縮合した環から誘導される基等が挙げられる。 Here, examples of the aromatic heterocyclic group include 4 to 7 members (preferably 5 or 5) containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituent atom. 6-membered) monocyclic aromatic heterocyclic group and condensed aromatic heterocyclic group. Examples of the condensed aromatic heterocyclic group include a ring corresponding to the 4- to 7-membered monocyclic aromatic heterocyclic group and a 5- or 6-membered aromatic heterocyclic ring containing 1 or 2 nitrogen atoms. (Eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine) From a ring in which 1 or 2 selected from a 5-membered aromatic heterocycle containing one sulfur atom (eg, thiophene) and a benzene ring are condensed Examples include groups to be derived.
 芳香族複素環基の好適な例としては、
フリル(例、2-フリル、3-フリル)、チエニル(例、2-チエニル、3-チエニル)、ピリジル(例、2-ピリジル、3-ピリジル、4-ピリジル)、ピリミジニル(例、2-ピリミジニル、4-ピリミジニル、5-ピリミジニル)、ピリダジニル(例、3-ピリダジニル、4-ピリダジニル)、ピラジニル(例、2-ピラジニル)、ピロリル(例、1-ピロリル、2-ピロリル、3-ピロリル)、イミダゾリル(例、1-イミダゾリル、2-イミダゾリル、4-イミダゾリル、5-イミダゾリル)、ピラゾリル(例、1-ピラゾリル、3-ピラゾリル、4-ピラゾリル)、チアゾリル(例、2-チアゾリル、4-チアゾリル、5-チアゾリル)、イソチアゾリル(例、3-イソチアゾリル、4-イソチアゾリル、5-イソチアゾリル)、オキサゾリル(例、2-オキサゾリル、4-オキサゾリル、5-オキサゾリル)、イソオキサゾリル(例、3-イソオキサゾリル、4-イソオキサゾリル、5-イソオキサゾリル)、オキサジアゾリル(例、1,2,4-オキサジアゾール-5-イル、1,3,4-オキサジアゾール-2-イル)、チアジアゾリル(例、1,3,4-チアジアゾール-2-イル)、トリアゾリル(例、1,2,4-トリアゾール-1-イル、1,2,4-トリアゾール-3-イル、1,2,3-トリアゾール-1-イル、1,2,3-トリアゾール-2-イル、1,2,3-トリアゾール-4-イル)、テトラゾリル(例、テトラゾール-1-イル、テトラゾール-5-イル)、トリアジニル(例、1,2,4-トリアジン-1-イル、1,2,4-トリアジン-3-イル)等の単環式芳香族複素環基;
キノリル(例、2-キノリル、3-キノリル、4-キノリル、6-キノリル)、イソキノリル(例、3-イソキノリル)、キナゾリル(例、2-キナゾリル、4-キナゾリル)、キノキサリル(例、2-キノキサリル、6-キノキサリル)、ベンゾフラニル(例、2-ベンゾフラニル、3-ベンゾフラニル)、ベンゾチエニル(例、2-ベンゾチエニル、3-ベンゾチエニル)、ベンズオキサゾリル(例、2-ベンズオキサゾリル)、ベンズイソオキサゾリル(例、7-ベンズイソオキサゾリル)、ベンゾチアゾリル(例、2-ベンゾチアゾリル)、ベンズイミダゾリル(例、ベンズイミダゾール-1-イル、ベンズイミダゾール-2-イル、ベンズイミダゾール-5-イル)、ベンゾトリアゾリル(例、1H-1,2,3-ベンゾトリアゾール-5-イル)、インドリル(例、インドール-1-イル、インドール-2-イル、インドール-3-イル、インドール-5-イル)、インダゾリル(例、1H-インダゾール-3-イル)、ピロロピラジニル(例、1H-ピロロ[2,3-b]ピラジン-2-イル、1H-ピロロ[2,3-b]ピラジン-6-イル)、イミダゾピリジニル(例、1H-イミダゾ[4,5-b]ピリジン-2-イル、1H-イミダゾ[4,5-c]ピリジン-2-イル、2H-イミダゾ[1,2-a]ピリジン-3-イル)、チエノピリジニル(例、チエノ[2,3-b]ピリジン-3-イル)、イミダゾピラジニル(例、1H-イミダゾ[4,5-b]ピラジン-2-イル)、ピラゾロピリジニル(例、1H-ピラゾロ[4,3-c]ピリジン-3-イル)、ピラゾロチエニル(例、2H-ピラゾロ[3,4-b]チオフェン-2-イル)、ピラゾロトリアジニル(例、ピラゾロ[5,1-c][1,2,4]トリアジン-3-イル)、ピリドピリジニル(例、ピリド[2,3-b]ピリジン-3-イル)、チエノピリジル(例、チエノ[2,3-b]ピリジン-3-イル)等の縮合芳香族複素環基;
等が挙げられる。
As preferable examples of the aromatic heterocyclic group,
Furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (eg, 2-pyrimidinyl) 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (eg, 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (eg, 2-pyrazinyl), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (Eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), thiazolyl (eg, 2-thiazolyl, 4-thiazolyl, 5 -Thiazolyl), isothiazolyl (eg, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl) Oxazolyl (eg, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (eg, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (eg, 1,2,4-oxadiazole-5- Yl, 1,3,4-oxadiazol-2-yl), thiadiazolyl (eg, 1,3,4-thiadiazol-2-yl), triazolyl (eg, 1,2,4-triazol-1-yl), 1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl), tetrazolyl (Eg, tetrazol-1-yl, tetrazol-5-yl), triazinyl (eg, 1,2,4-triazin-1-yl, 1,2,4-tri 3-yl) monocyclic aromatic heterocyclic group and the like;
Quinolyl (eg, 2-quinolyl, 3-quinolyl, 4-quinolyl, 6-quinolyl), isoquinolyl (eg, 3-isoquinolyl), quinazolyl (eg, 2-quinazolyl, 4-quinazolyl), quinoxalyl (eg, 2-quinoxalyl) , 6-quinoxalyl), benzofuranyl (eg, 2-benzofuranyl, 3-benzofuranyl), benzothienyl (eg, 2-benzothienyl, 3-benzothienyl), benzoxazolyl (eg, 2-benzoxazolyl), Benzisoxazolyl (eg, 7-benzisoxazolyl), benzothiazolyl (eg, 2-benzothiazolyl), benzimidazolyl (eg, benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-5- Yl), benzotriazolyl (eg, 1H-1,2,3-benzotriazo Ruyl-5-yl), indolyl (eg, indol-1-yl, indol-2-yl, indol-3-yl, indol-5-yl), indazolyl (eg, 1H-indazol-3-yl), pyrrolopyrazinyl (Eg, 1H-pyrrolo [2,3-b] pyrazin-2-yl, 1H-pyrrolo [2,3-b] pyrazin-6-yl), imidazopyridinyl (eg, 1H-imidazo [4,5 -B] pyridin-2-yl, 1H-imidazo [4,5-c] pyridin-2-yl, 2H-imidazo [1,2-a] pyridin-3-yl), thienopyridinyl (eg, thieno [2, 3-b] pyridin-3-yl), imidazopyrazinyl (eg, 1H-imidazo [4,5-b] pyrazin-2-yl), pyrazolopyridinyl (eg, 1H-pyrazolo [4,3 -C] pyridine-3-i ), Pyrazolothienyl (eg, 2H-pyrazolo [3,4-b] thiophen-2-yl), pyrazolotriazinyl (eg, pyrazolo [5,1-c] [1,2,4] triazine-3- Yl), pyridopyridinyl (eg, pyrido [2,3-b] pyridin-3-yl), thienopyridyl (eg, thieno [2,3-b] pyridin-3-yl) and the like;
Etc.
 非芳香族複素環基としては、例えば、環構成原子として炭素原子以外に酸素原子、硫黄原子および窒素原子から選ばれるヘテロ原子を1ないし4個含有する4ないし7員(好ましくは5または6員)の単環式非芳香族複素環基および縮合非芳香族複素環基が挙げられる。該縮合非芳香族複素環基としては、例えば、これら4ないし7員の単環式非芳香族複素環基に対応する環と、1または2個の窒素原子を含む5または6員の芳香族複素環(例、ピロール、イミダゾール、ピラゾール、ピラジン、ピリジン、ピリミジン)、1個の硫黄原子を含む5員の芳香族複素環(例、チオフェン)およびベンゼン環から選ばれる1または2個の環が縮合した環から誘導される基、ならびに該基の部分飽和により得られる基等が挙げられる。 Examples of the non-aromatic heterocyclic group include 4 to 7 members (preferably 5 or 6 members) containing 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms in addition to carbon atoms as ring constituent atoms. ) Monocyclic non-aromatic heterocyclic group and condensed non-aromatic heterocyclic group. Examples of the condensed non-aromatic heterocyclic group include a ring corresponding to the 4- to 7-membered monocyclic non-aromatic heterocyclic group, and a 5- or 6-membered aromatic containing 1 or 2 nitrogen atoms. 1 or 2 rings selected from a heterocycle (eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine), a 5-membered aromatic heterocycle containing one sulfur atom (eg, thiophene) and a benzene ring Examples thereof include a group derived from a condensed ring and a group obtained by partial saturation of the group.
 非芳香族複素環基の好適な例としては、
ピロリジニル(例、1-ピロリジニル、2-ピロリジニル)、ピペリジニル(例、ピペリジノ、2-ピペリジニル、3-ピペリジニル、4-ピペリジニル)、モルホリニル(例、モルホリノ)、チオモルホリニル(例、チオモルホリノ)、ピペラジニル(例、1-ピペラジニル、2-ピペラジニル、3-ピペラジニル)、ヘキサメチレンイミニル(例、ヘキサメチレンイミン-1-イル)、オキサゾリジニル(例、オキサゾリジン-2-イル)、チアゾリジニル(例、チアゾリジン-2-イル)、イミダゾリジニル(例、イミダゾリジン-2-イル、イミダゾリジン-3-イル)、オキサゾリニル(例、オキサゾリン-2-イル)、チアゾリニル(例、チアゾリン-2-イル)、イミダゾリニル(例、イミダゾリン-2-イル、イミダゾリン-3-イル)、ジオキソリル(例、1,3-ジオキソール-4-イル)、ジオキソラニル(例、1,3-ジオキソラン-4-イル)、ジヒドロオキサジアゾリル(例、4,5-ジヒドロ-1,2,4-オキサジアゾール-3-イル)、ピラニル(例、4-ピラニル)、テトラヒドロピラニル(例、2-テトラヒドロピラニル、3-テトラヒドロピラニル、4-テトラヒドロピラニル)、チオピラニル(例、4-チオピラニル)、テトラヒドロチオピラニル(例、2-テトラヒドロチオピラニル、3-テトラヒドロチオピラニル、4-テトラヒドロチオピラニル)、テトラヒドロフリル(例、テトラヒドロフラン-3-イル、テトラヒドロフラン-2-イル)、ピラゾリジニル(例、ピラゾリジン-1-イル、ピラゾリジン-3-イル)、ピラゾリニル(例、ピラゾリン-1-イル)、テトラヒドロピリミジニル(例、テトラヒドロピリミジン-1-イル)、ジヒドロトリアゾリル(例、2,3-ジヒドロ-1H-1,2,3-トリアゾール-1-イル)、テトラヒドロトリアゾリル(例、2,3,4,5-テトラヒドロ-1H-1,2,3-トリアゾール-1-イル)等の単環式非芳香族複素環基;
ジヒドロインドリル(例、2,3-ジヒドロ-1H-インドール-1-イル)、ジヒドロイソインドリル(例、1,3-ジヒドロ-2H-イソインドール-2-イル)、ジヒドロベンゾフラニル(例、2,3-ジヒドロ-1-ベンゾフラン-5-イル)、ジヒドロベンゾジオキシニル(例、2,3-ジヒドロ-1,4-ベンゾジオキシニル)、ジヒドロベンゾジオキセピニル(例、3,4-ジヒドロ-2H-1,5-ベンゾジオキセピニル)、テトラヒドロベンゾフラニル(例、4,5,6,7-テトラヒドロ-1-ベンゾフラン-3-イル)、クロメニル(例、4H-クロメン-2-イル、2H-クロメン-3-イル)、ジヒドロクロメニル(例、3,4-ジヒドロ-2H-クロメン-2-イル)、ジヒドロキノリニル(例、1,2-ジヒドロキノリン-4-イル)、テトラヒドロキノリニル(例、1,2,3,4-テトラヒドロキノリン-4-イル)、ジヒドロイソキノリニル(例、1,2-ジヒドロイソキノリン-4-イル)、テトラヒドロイソキノリニル(例、1,2,3,4-テトラヒドロイソキノリン-4-イル)、ジヒドロフタラジニル(例、1,4-ジヒドロフタラジン-4-イル)等の縮合非芳香族複素環基;
等が挙げられる。
As a suitable example of a non-aromatic heterocyclic group,
Pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl), piperidinyl (eg, piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), morpholinyl (eg, morpholino), thiomorpholinyl (eg, thiomorpholino), piperazinyl (eg, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl), hexamethyleneiminyl (eg, hexamethyleneimin-1-yl), oxazolidinyl (eg, oxazolidine-2-yl), thiazolidinyl (eg, thiazolidin-2-yl) ), Imidazolidinyl (eg, imidazolidin-2-yl, imidazolidin-3-yl), oxazolinyl (eg, oxazolin-2-yl), thiazolinyl (eg, thiazoline-2-yl), imidazolinyl (eg, imidazoline-2 -Ill, imidazoline 3-yl), dioxolyl (eg, 1,3-dioxol-4-yl), dioxolanyl (eg, 1,3-dioxolan-4-yl), dihydrooxadiazolyl (eg, 4,5-dihydro-1, 2,4-oxadiazol-3-yl), pyranyl (eg, 4-pyranyl), tetrahydropyranyl (eg, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl), thiopyranyl (eg, 4-thiopyranyl), tetrahydrothiopyranyl (eg, 2-tetrahydrothiopyranyl, 3-tetrahydrothiopyranyl, 4-tetrahydrothiopyranyl), tetrahydrofuryl (eg, tetrahydrofuran-3-yl, tetrahydrofuran-2- Yl), pyrazolidinyl (eg, pyrazolidin-1-yl, pyrazolidin-3-yl), pyra Linyl (eg, pyrazolin-1-yl), tetrahydropyrimidinyl (eg, tetrahydropyrimidin-1-yl), dihydrotriazolyl (eg, 2,3-dihydro-1H-1,2,3-triazol-1-yl) ), Monocyclic non-aromatic heterocyclic groups such as tetrahydrotriazolyl (eg 2,3,4,5-tetrahydro-1H-1,2,3-triazol-1-yl);
Dihydroindolyl (eg, 2,3-dihydro-1H-indol-1-yl), dihydroisoindolyl (eg, 1,3-dihydro-2H-isoindol-2-yl), dihydrobenzofuranyl (eg, 2,3-dihydro-1-benzofuran-5-yl), dihydrobenzodioxinyl (eg, 2,3-dihydro-1,4-benzodioxinyl), dihydrobenzodioxepinyl (eg, 3 , 4-dihydro-2H-1,5-benzodioxepinyl), tetrahydrobenzofuranyl (eg, 4,5,6,7-tetrahydro-1-benzofuran-3-yl), chromenyl (eg, 4H- Chromen-2-yl, 2H-chromen-3-yl), dihydrochromenyl (eg, 3,4-dihydro-2H-chromen-2-yl), dihydroquinolinyl (eg, 1,2-dihydro) Roquinolin-4-yl), tetrahydroquinolinyl (eg, 1,2,3,4-tetrahydroquinolin-4-yl), dihydroisoquinolinyl (eg, 1,2-dihydroisoquinolin-4-yl), Condensed non-aromatic heterocycles such as tetrahydroisoquinolinyl (eg, 1,2,3,4-tetrahydroisoquinolin-4-yl), dihydrophthalazinyl (eg, 1,4-dihydrophthalazin-4-yl) A ring group;
Etc.
 Rで示される「置換されていてもよい複素環基」における「複素環基」は、置換可能な位置に1ないし3個の置換基を有していてもよい。このような置換基としては、例えば、環Aで示される「置換されていてもよい6員芳香環」における「6員芳香環」が有する置換基と同様のものが挙げられる。また該複素環基が「非芳香族複素環基」である場合、置換基としてオキソ基がさらに含まれる。置換基が2個以上である場合、各置換基は同一でも異なっていてもよい。 The “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R 1 may have 1 to 3 substituents at substitutable positions. Examples of such a substituent include the same substituents as those of the “6-membered aromatic ring” in the “optionally substituted 6-membered aromatic ring” represented by ring A. When the heterocyclic group is a “non-aromatic heterocyclic group”, an oxo group is further included as a substituent. When there are two or more substituents, each substituent may be the same or different.
 Rで示される「置換されていてもよい複素環基」は、好ましくは、
(1)(a)C1-6アルキル基、
   (b)ヒドロキシ基、
   (c)C1-6アルコキシ基、および
   (d)ハロゲン原子
から選ばれる1ないし3個の置換基で置換されていてもよい芳香族複素環基;
(2)(a)C1-6アルキル基、
   (b)ヒドロキシ基、
   (c)C1-6アルコキシ基、
   (d)ハロゲン原子、および
   (e)オキソ基
から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環基(例、ピロリジニル);
等である。
The “optionally substituted heterocyclic group” represented by R 1 is preferably
(1) (a) a C 1-6 alkyl group,
(b) a hydroxy group,
(c) a C 1-6 alkoxy group, and (d) an aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from a halogen atom;
(2) (a) a C 1-6 alkyl group,
(b) a hydroxy group,
(c) a C 1-6 alkoxy group,
(d) a halogen atom, and (e) a non-aromatic heterocyclic group (eg, pyrrolidinyl) optionally substituted with 1 to 3 substituents selected from an oxo group;
Etc.
 Rで示される「置換されていてもよいアミノ基」としては、例えば、置換されていてもよい炭化水素基、置換されていてもよい複素環基、アシル基等から選ばれる1または2個の置換基で置換されていてもよいアミノ基が挙げられる。置換基が2個である場合、各置換基は同一でも異なっていてもよい。 Examples of the “optionally substituted amino group” represented by R 1 include 1 or 2 selected from a hydrocarbon group that may be substituted, a heterocyclic group that may be substituted, an acyl group, and the like. And an amino group which may be substituted with the above substituent. When there are two substituents, each substituent may be the same or different.
 Rで示される「置換されていてもよいアミノ基」における「置換基」として例示した、「置換されていてもよい炭化水素基」における「炭化水素基」としては、例えば、Rで示される「置換されていてもよい炭化水素基」における「炭化水素基」と同様のものが挙げられる。 Exemplified as the "substituent" in the "optionally substituted amino group" represented by R 1, as "hydrocarbon group" of the "optionally substituted hydrocarbon group", for example, represented by R 1 And the same as the “hydrocarbon group” in the “optionally substituted hydrocarbon group”.
 Rで示される「置換されていてもよいアミノ基」における「置換基」として例示した、「置換されていてもよい炭化水素基」における「炭化水素基」は、置換可能な位置に1ないし3個の置換基を有していてもよい。このような置換基としては、例えば、Rで示される「置換されていてもよい炭化水素基」における「炭化水素基」が有していてもよい置換基と同様のものが挙げられる。置換基が2個以上である場合、各置換基は同一でも異なっていてもよい。 The “hydrocarbon group” in the “optionally substituted hydrocarbon group” exemplified as the “substituent” in the “optionally substituted amino group” represented by R 1 is 1 to You may have three substituents. Examples of such a substituent include the same substituents that the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R 1 may have. When there are two or more substituents, each substituent may be the same or different.
 Rで示される「置換されていてもよいアミノ基」における「置換基」として例示した、「置換されていてもよい複素環基」における「複素環基」としては、例えば、Rで示される「置換されていてもよい複素環基」における「複素環基」と同様のものが挙げられる。 Exemplified as the "substituent" in the "optionally substituted amino group" represented by R 1, a "heterocyclic group" of the "optionally substituted heterocyclic group", for example, represented by R 1 And the same as the “heterocyclic group” in the “optionally substituted heterocyclic group”.
 Rで示される「置換されていてもよいアミノ基」における「置換基」として例示した、「置換されていてもよい複素環基」における「複素環基」は、置換可能な位置に1ないし3個の置換基を有していてもよい。このような置換基としては、例えば、Rで示される「置換されていてもよい複素環基」における「複素環基」が有していてもよい置換基と同様のものが挙げられる。置換基が2個以上である場合、各置換基は同一でも異なっていてもよい。 The “heterocyclic group” in the “optionally substituted heterocyclic group” exemplified as the “substituent” in the “optionally substituted amino group” represented by R 1 is 1 to You may have three substituents. Examples of such a substituent include the same substituents that the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R 1 may have. When there are two or more substituents, each substituent may be the same or different.
 Rで示される「置換されていてもよいアミノ基」における「置換基」として例示した「アシル基」としては、後述のRで示される「アシル基」と同様のものが挙げられる。 Exemplified as the "substituent" in the "optionally substituted amino group" represented by R 1 "acyl group" include those similar to the "acyl group" represented by R 1 described later.
 Rで示される「置換されていてもよいアミノ基」は、好ましくは、
(1)C1-6アルキル基;および
(2)C1-6アルコキシ-カルボニル基;
から選ばれる置換基でモノまたはジ置換されていてもよいアミノ基等である。
The “optionally substituted amino group” represented by R 1 is preferably
(1) a C 1-6 alkyl group; and (2) a C 1-6 alkoxy-carbonyl group;
An amino group which may be mono- or di-substituted with a substituent selected from
 Rで示される「アシル基」としては、例えば、式:-CORA1、-CO-ORA1、-SOA1、-SOA1、-SORA1、-CO-NRA2B2、-CS-NRA2B2、-SONRA2B2[式中、RA1は、水素原子、置換されていてもよい炭化水素基または置換されていてもよい複素環基を示す。RA2およびRB2は、独立して、水素原子、置換されていてもよい炭化水素基または置換されていてもよい複素環基を示すか、あるいはRA2およびRB2は、隣接する窒素原子と共に置換されていてもよい含窒素複素環を形成する]で表される基等が挙げられる。 Examples of the “acyl group” represented by R 1 include, for example, the formula: —COR A1 , —CO—OR A1 , —SO 3 R A1 , —SO 2 R A1 , —SOR A1 , —CO—NR A2 R B2 , —CS—NR A2 R B2 , —SO 2 NR A2 R B2 [wherein R A1 represents a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group. R A2 and R B2 independently represent a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or R A2 and R B2 together with an adjacent nitrogen atom Form an optionally substituted nitrogen-containing heterocycle], and the like.
 RA1、RA2またはRB2で示される「置換されていてもよい炭化水素基」における「炭化水素基」としては、例えば、Rで示される「置換されていてもよい炭化水素基」における「炭化水素基」と同様のものが挙げられる。 As the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R A1 , R A2 or R B2 , for example, in the “optionally substituted hydrocarbon group” represented by R 1 The same thing as a "hydrocarbon group" is mentioned.
 RA1、RA2またはRB2で示される「置換されていてもよい炭化水素基」における「炭化水素基」は、置換可能な位置に1ないし3個の置換基を有していてもよい。このような置換基としては、例えば、Rで示される「置換されていてもよい炭化水素基」における「炭化水素基」が有していてもよい置換基と同様のものが挙げられる。置換基が2個以上である場合、各置換基は同一でも異なっていてもよい。 The “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R A1 , R A2 or R B2 may have 1 to 3 substituents at substitutable positions. Examples of such a substituent include the same substituents that the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R 1 may have. When there are two or more substituents, each substituent may be the same or different.
 RA1、RA2またはRB2で示される「置換されていてもよい複素環基」における「複素環基」としては、例えば、Rで示される「置換されていてもよい複素環基」における「複素環基」と同様のものが挙げられる。 As the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R A1 , R A2 or R B2 , for example, in the “optionally substituted heterocyclic group” represented by R 1 The same thing as a "heterocyclic group" is mentioned.
 RA1、RA2またはRB2で示される「置換されていてもよい複素環基」における「複素環基」は、置換可能な位置に1ないし3個の置換基を有していてもよい。このような置換基としては、例えば、Rで示される「置換されていてもよい複素環基」における「複素環基」が有していてもよい置換基と同様のものが挙げられる。置換基が2個以上である場合、各置換基は同一でも異なっていてもよい。 The “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R A1 , R A2 or R B2 may have 1 to 3 substituents at substitutable positions. Examples of such a substituent include the same substituents that the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R 1 may have. When there are two or more substituents, each substituent may be the same or different.
 RA2およびRB2が隣接する窒素原子と共に形成する「置換されていてもよい含窒素複素環」における「含窒素複素環」としては、例えば、環構成原子として炭素原子以外に少なくとも1個の窒素原子を含み、さらに酸素原子、硫黄原子および窒素原子から選ばれるヘテロ原子を1または2個含んでいてもよい5ないし7員の含窒素複素環が挙げられる。該含窒素複素環の具体例としては、ピロリジン、イミダゾリジン、ピラゾリジン、ピペリジン、ピペラジン、モルホリン、チオモルホリン等が挙げられる。 The “nitrogen-containing heterocycle” in the “optionally substituted nitrogen-containing heterocycle” formed by R A2 and R B2 together with the adjacent nitrogen atom is, for example, at least one nitrogen other than a carbon atom as a ring-constituting atom. Examples thereof include a 5- to 7-membered nitrogen-containing heterocyclic ring which contains an atom and may further contain 1 or 2 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. Specific examples of the nitrogen-containing heterocyclic ring include pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine and the like.
 該「含窒素複素環」は、置換可能な位置に1ないし3個の置換基を有していてもよい。このような置換基としては、例えば、Rで示される「置換されていてもよい複素環基」における「複素環基」が有していてもよい置換基と同様のものが挙げられる。置換基が2個以上である場合、各置換基は同一でも異なっていてもよい。 The “nitrogen-containing heterocycle” may have 1 to 3 substituents at substitutable positions. Examples of such a substituent include the same substituents that the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R 1 may have. When there are two or more substituents, each substituent may be the same or different.
 Rで示される「アシル基」は、好ましくは、
(1)ホルミル基;
(2)(a)ハロゲン原子、
  (b)C6-14アリール基、
  (c)C1-6アルコキシ基、および
  (d)複素環基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルコキシ-カルボニル基(例、メトキシカルボニル);
(3)(a)ハロゲン原子、および
  (b)C6-14アリール基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキルスルホニル基(例、メチルスルホニル);
(4)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基から選ばれ
る置換基でモノまたはジ置換されていてもよいスルファモイル基(例、メチルスルファモイル、ジメチルスルファモイル);
(5)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基から選ばれ
る1ないし3個の置換基で置換されていてもよい非芳香族複素環スルホニル基(例、ピロリジノスルホニル、モルホリノスルホニル);
等が挙げられる。
The “acyl group” represented by R 1 is preferably
(1) formyl group;
(2) (a) a halogen atom,
(b) a C 6-14 aryl group,
(c) a C 1-6 alkoxy group, and (d) a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl) optionally substituted with 1 to 3 substituents selected from a heterocyclic group;
(3) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, and (b) a C 6-14 aryl group;
(4) A sulfamoyl group which may be mono- or di-substituted with a substituent selected from C 1-6 alkyl groups optionally substituted with 1 to 3 halogen atoms (eg, methylsulfamoyl, dimethylsulfato) Famoyl);
(5) a non-aromatic heterocyclic sulfonyl group optionally substituted with 1 to 3 substituents selected from C 1-6 alkyl groups optionally substituted with 1 to 3 halogen atoms (eg, Pyrrolidinosulfonyl, morpholinosulfonyl);
Etc.
 Rは、好ましくは、
(1)ハロゲン原子(例、臭素原子);
(2)(a)ハロゲン原子、
(b)カルボキシ基、
(c)C1-6アルコキシ-カルボニル基、および
(d)C1-6アルキル基でモノまたはジ置換されていてもよいアミノ基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基;
(3)(a)C1-6アルキル基、
   (b)ヒドロキシ基、
   (c)C1-6アルコキシ基、および
   (d)ハロゲン原子
から選ばれる1ないし3個の置換基で置換されていてもよい芳香族複素環基(好ましくは、5または6員の芳香族複素環基);
(4)(a)C1-6アルキル基、
   (b)ヒドロキシ基、
   (c)C1-6アルコキシ基、
   (d)ハロゲン原子、および
   (e)オキソ基
から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環基(好ましくは、4ないし7員の非芳香族複素環基)(例、ピロリジニル);
(5)(a)C1-6アルキル基;および
   (b)C1-6アルコキシ-カルボニル基; 
から選ばれる置換基でモノまたはジ置換されていてもよいアミノ基;
(6)ホルミル基;
(7)(a)ハロゲン原子、
  (b)C6-14アリール基、
  (c)C1-6アルコキシ基、および
  (d)複素環基(好ましくは、4ないし7員の複素環基)
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルコキシ-カルボニル基(例、メトキシカルボニル);
(8)(a)ハロゲン原子、および
  (b)C6-14アリール基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキルスルホニル基(例、メチルスルホニル);
(9)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基から選ば
れる置換基でモノまたはジ置換されていてもよいスルファモイル基(例、メチルスルファモイル、ジメチルスルファモイル);
(10)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環スルホニル基(好ましくは、4ないし7員の非芳香族複素環スルホニル基)(例、ピロリジノスルホニル、モルホリノスルホニル);
等である。
R 1 is preferably
(1) Halogen atom (eg, bromine atom);
(2) (a) a halogen atom,
(b) a carboxy group,
(c) a C 1-6 alkoxy-carbonyl group, and
(d) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted with a C 1-6 alkyl group;
(3) (a) a C 1-6 alkyl group,
(b) a hydroxy group,
(c) a C 1-6 alkoxy group, and (d) an aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from halogen atoms (preferably a 5- or 6-membered aromatic heterocyclic group Ring group);
(4) (a) a C 1-6 alkyl group,
(b) a hydroxy group,
(c) a C 1-6 alkoxy group,
(d) a non-aromatic heterocyclic group (preferably a 4- to 7-membered non-aromatic heterocyclic group) optionally substituted with 1 to 3 substituents selected from a halogen atom and (e) an oxo group ) (Eg, pyrrolidinyl);
(5) (a) a C 1-6 alkyl group; and (b) a C 1-6 alkoxy-carbonyl group;
An amino group which may be mono- or di-substituted with a substituent selected from:
(6) formyl group;
(7) (a) a halogen atom,
(b) a C 6-14 aryl group,
(c) a C 1-6 alkoxy group, and (d) a heterocyclic group (preferably a 4- to 7-membered heterocyclic group).
A C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl) optionally substituted by 1 to 3 substituents selected from:
(8) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, and (b) a C 6-14 aryl group;
(9) A sulfamoyl group which may be mono- or di-substituted with a substituent selected from C 1-6 alkyl groups which may be substituted with 1 to 3 halogen atoms (eg, methylsulfamoyl, dimethylsulfato) Famoyl);
(10) a non-aromatic heterocyclic sulfonyl group optionally substituted with 1 to 3 substituents selected from C 1-6 alkyl groups optionally substituted with 1 to 3 halogen atoms (preferably A 4- to 7-membered non-aromatic heterocyclic sulfonyl group) (eg, pyrrolidinosulfonyl, morpholinosulfonyl);
Etc.
 Rは、より好ましくは、
(1)ハロゲン原子(例、臭素原子);
(2)カルボキシ基;
(3)(a)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基、および(b)オキソ基から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環基(好ましくは、5または6員の非芳香族複素環基)(例、ピロリジニル);、
(4)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ-カルボニル基(例、メトキシカルボニル);
(5)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキルスルホニル基(例、メチルスルホニル);
(6)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基でモノまたはジ置換されていてもよいスルファモイル基(例、メチルスルファモイル、ジメチルスルファモイル);
(7)(a)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基、および(b)オキソ基から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環スルホニル基(好ましくは、5または6員の非芳香族複素環スルホニル基)(例、ピロリジノスルホニル、モルホリノスルホニル);
等である。
R 1 is more preferably
(1) halogen atom (eg, bromine atom);
(2) a carboxy group;
(3) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (b) optionally substituted with 1 to 3 substituents selected from an oxo group A non-aromatic heterocyclic group (preferably a 5- or 6-membered non-aromatic heterocyclic group) (eg, pyrrolidinyl);
(4) a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl) optionally substituted with 1 to 3 halogen atoms;
(5) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl) optionally substituted by 1 to 3 halogen atoms;
(6) a sulfamoyl group (eg, methylsulfamoyl, dimethylsulfamoyl) optionally mono- or di-substituted with a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms;
(7) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (b) optionally substituted with 1 to 3 substituents selected from an oxo group A non-aromatic heterocyclic sulfonyl group (preferably a 5- or 6-membered non-aromatic heterocyclic sulfonyl group) (eg, pyrrolidinosulfonyl, morpholinosulfonyl);
Etc.
 Rは、シアノ基、置換されていてもよい炭化水素基、置換されていてもよい複素環基、またはアシル基を示す。 R 2 represents a cyano group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an acyl group.
 Rで示される「置換されていてもよい炭化水素基」における「炭化水素基」としては、例えば、Rで示される「置換されていてもよい炭化水素基」における「炭化水素基」と同様のものが挙げられる。 Examples of the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R 2 include “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R 1. The same thing is mentioned.
 Rで示される「置換されていてもよい炭化水素基」における「炭化水素基」は、置換可能な位置に1ないし3個の置換基を有していてもよい。このような置換基としては、例えば、Rで示される「置換されていてもよい炭化水素基」における「炭化水素基」が有していてもよい置換基と同様のものが挙げられる。置換基が2個以上である場合、各置換基は同一でも異なっていてもよい。 The “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R 2 may have 1 to 3 substituents at substitutable positions. Examples of such a substituent include the same substituents that the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R 1 may have. When there are two or more substituents, each substituent may be the same or different.
 Rで示される「置換されていてもよい炭化水素基」は、好ましくは、
置換されていてもよいC1-6アルキル基であり、より好ましくは、
(a)ハロゲン原子、
(b)カルボキシ基、
(c)C1-6アルコキシ-カルボニル基(例、エトキシカルボニル)、および
(d)C1-6アルキル基でモノまたはジ置換されていてもよいアミノ基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基(例、メチル)
等である。
The “optionally substituted hydrocarbon group” represented by R 2 is preferably
An optionally substituted C 1-6 alkyl group, more preferably
(a) a halogen atom,
(b) a carboxy group,
(c) a C 1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl), and
(d) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted with a C 1-6 alkyl group (eg, methyl)
Etc.
 Rで示される「置換されていてもよい複素環基」における「複素環基」としては、例えば、Rで示される「置換されていてもよい複素環基」における「複素環基」と同様のものが挙げられる。 Examples of the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R 2 include “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R 1. The same thing is mentioned.
 Rで示される「置換されていてもよい複素環基」における「複素環基」は、置換可能な位置に1ないし3個の置換基を有していてもよい。このような置換基としては、例えば、Rで示される「置換されていてもよい複素環基」における「複素環基」が有していてもよい置換基と同様のものが挙げられる。置換基が2個以上である場合、各置換基は同一でも異なっていてもよい。 The “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R 2 may have 1 to 3 substituents at substitutable positions. Examples of such a substituent include the same substituents that the “heterocyclic group” in the “optionally substituted heterocyclic group” represented by R 1 may have. When there are two or more substituents, each substituent may be the same or different.
 Rで示される「置換されていてもよい複素環基」は、好ましくは、
(1)(a)C1-6アルキル基(例、エチル、プロピル)、
   (b)ヒドロキシ基、
   (c)C1-6アルコキシ基、および
   (d)ハロゲン原子
から選ばれる1ないし3個の置換基で置換されていてもよい芳香族複素環基(例、ピリミジニル);
(2)(a)C1-6アルキル基(例、イソプロピル)、
   (b)ヒドロキシ基、
   (c)C1-6アルコキシ基、
   (d)ハロゲン原子、および
   (e)オキソ基
から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環基(例、ジヒドロオキサゾリル);
等である。
The “optionally substituted heterocyclic group” represented by R 2 is preferably
(1) (a) a C 1-6 alkyl group (eg, ethyl, propyl),
(b) a hydroxy group,
(c) a C 1-6 alkoxy group, and (d) an aromatic heterocyclic group (eg, pyrimidinyl) optionally substituted with 1 to 3 substituents selected from halogen atoms;
(2) (a) a C 1-6 alkyl group (eg, isopropyl),
(b) a hydroxy group,
(c) a C 1-6 alkoxy group,
(d) a halogen atom, and (e) a non-aromatic heterocyclic group (eg, dihydrooxazolyl) optionally substituted with 1 to 3 substituents selected from an oxo group;
Etc.
 Rで示される「アシル基」としては、例えば、Rで示される「アシル基」と同様のものが挙げられる。 Examples of the “acyl group” represented by R 2 include the same “acyl group” represented by R 1 .
 Rで示される「アシル基」は、好ましくは、
(1)(a)ハロゲン原子、
  (b)C6-14アリール基、
  (c)C1-6アルコキシ基、および
  (d)複素環基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルコキシ-カルボニル基(例、イソプロピルカルボニル、tert-ブチルカルボニル);
(2)(a)ハロゲン原子、
  (b)C1-6アルキル基(例、メチル、プロピル、tert-ブチル)、
(c)C6-14アリール基、
  (d)C1-6アルコキシ基、および
  (e)複素環基(例、ピリダジニル)
から選ばれる置換基でモノまたはジ置換されていてもよいカルバモイル基;
(3)(a)C1-6アルキル基、および
(b)オキソ基
から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環オキシカルボニル基(例、テトラヒドロフラニルオキシカルボニル);
等が挙げられる。
The “acyl group” represented by R 2 is preferably
(1) (a) a halogen atom,
(b) a C 6-14 aryl group,
(c) a C 1-6 alkoxy group, and (d) a C 1-6 alkoxy-carbonyl group optionally substituted with 1 to 3 substituents selected from heterocyclic groups (eg, isopropylcarbonyl, tert- Butylcarbonyl);
(2) (a) a halogen atom,
(b) a C 1-6 alkyl group (eg, methyl, propyl, tert-butyl),
(c) a C 6-14 aryl group,
(d) a C 1-6 alkoxy group, and (e) a heterocyclic group (eg, pyridazinyl)
A carbamoyl group which may be mono- or di-substituted with a substituent selected from:
(3) (a) a C 1-6 alkyl group, and
(b) a non-aromatic heterocyclic oxycarbonyl group (eg, tetrahydrofuranyloxycarbonyl) which may be substituted with 1 to 3 substituents selected from oxo groups;
Etc.
 Rは、好ましくは、
(1)(a)ハロゲン原子、
(b)カルボキシ基、
(c)C1-6アルコキシ-カルボニル基(例、エトキシカルボニル)、および
(d)C1-6アルキル基でモノまたはジ置換されていてもよいアミノ基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基(例、メチル);
(2)(a)C1-6アルキル基(例、エチル、プロピル)、
   (b)ヒドロキシ基、
   (c)C1-6アルコキシ基、および
   (d)ハロゲン原子
から選ばれる1ないし3個の置換基で置換されていてもよい芳香族複素環基(好ましくは、5または6員の芳香族複素環基)(例、ピリミジニル);
(3)(a)C1-6アルキル基(例、イソプロピル)、
   (b)ヒドロキシ基、
   (c)C1-6アルコキシ基、
   (d)ハロゲン原子、および
   (e)オキソ基
から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環基(好ましくは、4ないし7員の非芳香族複素環基)(例、ジヒドロオキサゾリル);
(4)(a)ハロゲン原子、
  (b)C6-14アリール基、
  (c)C1-6アルコキシ基、および
  (d)複素環基(好ましくは、4ないし7員の複素環基)
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルコキシ-カルボニル基(例、イソプロピルカルボニル、tert-ブチルカルボニル);
(5)(a)ハロゲン原子、
  (b)C1-6アルキル基(例、メチル、プロピル、tert-ブチル)、
(c)C6-14アリール基、
  (d)C1-6アルコキシ基、および
  (e)複素環基(好ましくは、4ないし7員の複素環基)(例、ピリダジニル)
から選ばれる置換基でモノまたはジ置換されていてもよいカルバモイル基;
(6)(a)C1-6アルキル基、および
(b)オキソ基
から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環オキシカルボニル基(好ましくは、4ないし7員の非芳香族複素環オキシカルボニル基)(例、テトラヒドロフラニルオキシカルボニル);
等である。
R 2 is preferably
(1) (a) a halogen atom,
(b) a carboxy group,
(c) a C 1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl), and
(d) a C 1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted with C 1-6 alkyl group;
(2) (a) a C 1-6 alkyl group (eg, ethyl, propyl),
(b) a hydroxy group,
(c) a C 1-6 alkoxy group, and (d) an aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from halogen atoms (preferably a 5- or 6-membered aromatic heterocyclic group Ring group) (eg, pyrimidinyl);
(3) (a) a C 1-6 alkyl group (eg, isopropyl),
(b) a hydroxy group,
(c) a C 1-6 alkoxy group,
(d) a non-aromatic heterocyclic group (preferably a 4- to 7-membered non-aromatic heterocyclic group) which may be substituted with 1 to 3 substituents selected from a halogen atom and (e) an oxo group ) (Eg, dihydrooxazolyl);
(4) (a) a halogen atom,
(b) a C 6-14 aryl group,
(c) a C 1-6 alkoxy group, and (d) a heterocyclic group (preferably a 4- to 7-membered heterocyclic group).
A C 1-6 alkoxy-carbonyl group (eg, isopropylcarbonyl, tert-butylcarbonyl) optionally substituted with 1 to 3 substituents selected from:
(5) (a) a halogen atom,
(b) a C 1-6 alkyl group (eg, methyl, propyl, tert-butyl),
(c) a C 6-14 aryl group,
(d) a C 1-6 alkoxy group, and (e) a heterocyclic group (preferably a 4- to 7-membered heterocyclic group) (eg, pyridazinyl)
A carbamoyl group which may be mono- or di-substituted with a substituent selected from:
(6) (a) a C 1-6 alkyl group, and
(b) a non-aromatic heterocyclic oxycarbonyl group (preferably a 4- to 7-membered non-aromatic heterocyclic oxycarbonyl group) which may be substituted with 1 to 3 substituents selected from oxo groups (examples) , Tetrahydrofuranyloxycarbonyl);
Etc.
 Rは、より好ましくは、
(1)(a)ハロゲン原子、および(b)C1-6アルコキシ-カルボニル基(例、エトキシカルボニル)から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基(例、メチル);
(2)(a)ハロゲン原子、および(b)C1-6アルキル基(例、エチル、プロピル)から選ばれる1ないし3個の置換基で置換されていてもよい芳香族複素環基(好ましくは、5または6員の芳香族複素環基)(例、ピリミジニル);
(3)(a)ハロゲン原子、(b)C1-6アルキル基(例、イソプロピル)、および(c)オキソ基から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環基(好ましくは、5または6員の非芳香族複素環基)(例、ジヒドロオキサゾリル);
(4)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ-カルボニル基(例、イソプロピルカルボニル、tert-ブチルカルボニル);
(5)(a)C1-6アルキル基(例、メチル、プロピル、tert-ブチル)、および(b)複素環基(好ましくは、5または6員の複素環基)(例、ピリダジニル)から選ばれる置換基でモノまたはジ置換されていてもよいカルバモイル基;
(6)(a)C1-6アルキル基、および(b)オキソ基から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環オキシカルボニル基(好ましくは、5または6員の非芳香族複素環オキシカルボニル基)(例、テトラヒドロフラニルオキシカルボニル);
等である。
R 2 is more preferably
(1) (a) a halogen atom, and (b) C 1-6 alkoxy - carbonyl group (e.g., ethoxycarbonyl) 1 to 3 substituents optionally substituted by a C 1-6 alkyl group selected from (Eg, methyl);
(2) an aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from (a) a halogen atom and (b) a C 1-6 alkyl group (eg, ethyl, propyl) (preferably Is a 5- or 6-membered aromatic heterocyclic group) (eg, pyrimidinyl);
(3) Non-aromatic optionally substituted by 1 to 3 substituents selected from (a) a halogen atom, (b) a C 1-6 alkyl group (eg, isopropyl), and (c) an oxo group A heterocyclic group (preferably a 5- or 6-membered non-aromatic heterocyclic group) (eg, dihydrooxazolyl);
(4) a C 1-6 alkoxy-carbonyl group (eg, isopropylcarbonyl, tert-butylcarbonyl) optionally substituted by 1 to 3 halogen atoms;
(5) From (a) a C 1-6 alkyl group (eg, methyl, propyl, tert-butyl) and (b) a heterocyclic group (preferably a 5- or 6-membered heterocyclic group) (eg, pyridazinyl) A carbamoyl group optionally mono- or di-substituted with a selected substituent;
(6) a non-aromatic heterocyclic oxycarbonyl group which is optionally substituted with 1 to 3 substituents selected from (a) a C 1-6 alkyl group and (b) an oxo group (preferably 5 or A 6-membered non-aromatic heterocyclic oxycarbonyl group) (eg, tetrahydrofuranyloxycarbonyl);
Etc.
 Xは、置換されていてもよい直鎖状C2-3アルキレン基を示す。 X 1 represents an optionally substituted linear C 2-3 alkylene group.
 Xで示される「置換されていてもよい直鎖状C2-3アルキレン基」における「直鎖状C2-3アルキレン基」としては、エチレンおよびトリメチレンが挙げられる。 As "linear C 2-3 alkylene group" in the "optionally substituted linear C 2-3 alkylene group" represented by X 1, ethylene and trimethylene.
 Xで示される「置換されていてもよい直鎖状C2-3アルキレン基」における「直鎖状C2-3アルキレン基」は、置換可能な位置に1ないし3個の置換基を有していてもよい。このような置換基としては、例えば、環Aで示される「置換されていてもよい6員芳香環」における「6員芳香環」が有する置換基と同様のものが挙げられる。置換基が2個以上である場合、各置換基は同一でも異なっていてもよい。 Represented by X 1 "linear C 2-3 alkylene group" of the "optionally substituted linear C 2-3 alkylene group" have a 1 to 3 substituents at substitutable position You may do it. Examples of such a substituent include the same substituents as those of the “6-membered aromatic ring” in the “optionally substituted 6-membered aromatic ring” represented by ring A. When there are two or more substituents, each substituent may be the same or different.
 Xは、好ましくは、
(1)ハロゲン原子;
(2)ヒドロキシ基;
(3)C1-6アルコキシ基;
(4)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル(例、メチ
ル);
等から選ばれる1ないし3個の置換基でそれぞれ置換されていてもよい、エチレン、トリメチレン等である。
X 1 is preferably
(1) a halogen atom;
(2) hydroxy group;
(3) a C 1-6 alkoxy group;
(4) C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms (eg, methyl);
And ethylene, trimethylene and the like, each of which may be substituted with 1 to 3 substituents selected from the above.
 Xは、より好ましくは、
(1)ハロゲン原子;
(2)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基(例、メチル);
から選ばれる1ないし3個の置換基でそれぞれ置換されていてもよい、エチレン、トリメチレン等である。
X 1 is more preferably
(1) a halogen atom;
(2) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms (eg, methyl);
And ethylene, trimethylene and the like, each of which may be substituted with 1 to 3 substituents selected from
 Xは、結合手、置換されていてもよいNH、S、SO、SO、CO、またはOを示す。 X 2 represents a bond, optionally substituted NH, S, SO, SO 2 , CO, or O.
 Xで示される「置換されていてもよいNH」における「NH」は、1個の置換基を有していてもよい。このような置換基としては、例えば、環Aで示される「置換されていてもよい6員芳香環」における「6員芳香環」が有する置換基と同様のものが挙げられる。 “NH” in “NH which may be substituted” represented by X 2 may have one substituent. Examples of such a substituent include the same substituents as those of the “6-membered aromatic ring” in the “optionally substituted 6-membered aromatic ring” represented by ring A.
 Xで示される「置換されていてもよいNH」は、好ましくは、
(1)(a)シアノ基、および
   (b)1ないし3個のハロゲン原子(例、フッ素原子)
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル(例、メチル、プロピル); 
(2)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル-カルボニ
ル基(例、アセチル); 
(3)C1-6アルコキシ-カルボニル基;
(4)C1-6アルキルスルホニル基(例、メチルスルホニル); 
等で置換されていてもよいNHである。
The “optionally substituted NH” represented by X 2 is preferably
(1) (a) a cyano group, and (b) 1 to 3 halogen atoms (eg, fluorine atoms)
C 1-6 alkyl (eg, methyl, propyl) optionally substituted with 1 to 3 substituents selected from:
(2) a C 1-6 alkyl-carbonyl group (eg, acetyl) optionally substituted by 1 to 3 halogen atoms;
(3) a C 1-6 alkoxy-carbonyl group;
(4) C 1-6 alkylsulfonyl group (eg, methylsulfonyl);
NH which may be substituted with, and the like.
 Xは、好ましくは、
(1)結合手;
(2)O;
(3)(a)(i)シアノ基、および
    (ii)1ないし3個のハロゲン原子(例、フッ素原子)
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル(例、メチル、プロピル); 
(b)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル-カルボニ
ル基(例、アセチル); 
(c)C1-6アルコキシ-カルボニル基; および
(d)C1-6アルキルスルホニル基(例、メチルスルホニル); 
で置換されていてもよいNH;
等である。
X 2 is preferably
(1) Bond hands;
(2) O;
(3) (a) (i) a cyano group, and (ii) 1 to 3 halogen atoms (eg, fluorine atoms)
C 1-6 alkyl (eg, methyl, propyl) optionally substituted with 1 to 3 substituents selected from:
(B) a C 1-6 alkyl-carbonyl group (eg acetyl) optionally substituted by 1 to 3 halogen atoms;
(C) a C 1-6 alkoxy-carbonyl group; and (d) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl);
NH optionally substituted with
Etc.
 Xは、より好ましくは、
(1)結合手;
(2)O;
(3)(a)(i)シアノ基、および(ii)1ないし3個のハロゲン原子(例、フッ素原子)から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル(例、メチル、プロピル)、 
   (b)C1-6アルキル-カルボニル基(例、アセチル)、 または
   (c)C1-6アルキルスルホニル基(例、メチルスルホニル);
で置換されていてもよいNH等である。
X 2 is more preferably
(1) Bond hands;
(2) O;
(3) C 1-6 optionally substituted with 1 to 3 substituents selected from (a) (i) cyano group, and (ii) 1 to 3 halogen atoms (eg, fluorine atom) Alkyl (eg, methyl, propyl),
(b) a C 1-6 alkyl-carbonyl group (eg, acetyl), or (c) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl);
NH etc. which may be substituted with
 Xは、結合手、置換されていてもよい直鎖状C1-2アルキレン基を示す。 X 3 represents a bond or a linear C 1-2 alkylene group which may be substituted.
 Xで示される「置換されていてもよい直鎖状C1-2アルキレン基」における「直鎖状C1-2アルキレン基」としては、メチレンおよびエチレンが挙げられる。 As "linear C 1-2 alkylene group" of the "substituted linear C 1-2 may be an alkylene group" represented by X 3, include methylene and ethylene.
 Xで示される「置換されていてもよい直鎖状C1-2アルキレン基」における「直鎖状C1-2アルキレン基」は、置換可能な位置に1ないし3個の置換基を有していてもよい。このような置換基としては、例えば、環Aで示される「置換されていてもよい6員芳香環」における「6員芳香環」が有する置換基と同様のものが挙げられる。置換基が2個以上である場合、各置換基は同一でも異なっていてもよい。 Represented by X 3 "linear C 1-2 alkylene group" of the "optionally substituted linear C 1-2 alkylene group" have a 1 to 3 substituents at substitutable position You may do it. Examples of such a substituent include the same substituents as those of the “6-membered aromatic ring” in the “optionally substituted 6-membered aromatic ring” represented by ring A. When there are two or more substituents, each substituent may be the same or different.
 Xは、好ましくは、
(1)結合手;
(2)(a)ハロゲン原子;および
(b)C1-6アルキル;
から選ばれる1ないし3個の置換基で置換されていてもよいメチレン;
等である。
X 3 is preferably
(1) Bond hands;
(2) (a) a halogen atom; and
(b) C 1-6 alkyl;
Methylene optionally substituted with 1 to 3 substituents selected from:
Etc.
 Xは、より好ましくは、結合手、メチレン等である。 X 3 is more preferably a bond, methylene or the like.
 YおよびYは、独立して、置換されていてもよい直鎖状C1-3アルキレン基を示す。 Y 1 and Y 2 independently represent an optionally substituted linear C 1-3 alkylene group.
 YまたはYで示される「置換されていてもよい直鎖状C1-3アルキレン基」における「直鎖状C1-3アルキレン基」としては、メチレン、エチレンおよびトリメチレンが挙げられる。 As "linear C 1-3 alkylene group" in the "optionally substituted linear C 1-3 alkylene group" represented by Y 1 or Y 2, methylene, ethylene and trimethylene.
 YまたはYで示される「置換されていてもよい直鎖状C1-3アルキレン基」における「直鎖状C1-3アルキレン基」は、置換可能な位置に1ないし3個の置換基を有していてもよい。このような置換基としては、例えば、環Aで示される「置換されていてもよい6員芳香環」における「6員芳香環」が有する置換基と同様のもの、オキソ基等が挙げられる。置換基が2個以上である場合、各置換基は同一でも異なっていてもよい。 Represented by Y 1 or Y 2 "linear C 1-3 alkylene group" of the "optionally substituted linear C 1-3 alkylene group" is substituted for 3 to 1 at substitutable positions It may have a group. Examples of such a substituent include the same substituents as those of the “6-membered aromatic ring” in the “optionally substituted 6-membered aromatic ring” represented by ring A, an oxo group, and the like. When there are two or more substituents, each substituent may be the same or different.
 YおよびYは、好ましくは、独立して、
(1)ハロゲン原子;
(2)C1-6アルキル基;
(3)オキソ基;
等から選ばれる1ないし3個の置換基でそれぞれ置換されていてもよい、メチレン、エチレン等である。
Y 1 and Y 2 are preferably independently
(1) a halogen atom;
(2) a C 1-6 alkyl group;
(3) an oxo group;
And methylene, ethylene and the like, each of which may be substituted with 1 to 3 substituents selected from the above.
 YおよびYは、独立して、メチレン、エチレン等である。 Y 1 and Y 2 are independently methylene, ethylene and the like.
 Yは、さらに好ましくは、メチレン、エチレン等である。
 Yは、さらに好ましくは、エチレン等である。
Y 1 is more preferably methylene, ethylene or the like.
Y 2 is more preferably ethylene or the like.
 化合物(I)の好適な例としては、以下の化合物が挙げられる。
[化合物A]
環Aが、
(1)ヒドロキシ基、
(2)ハロゲン原子(例、フッ素原子、塩素原子)、
(3)(a)ハロゲン原子、および
   (b)C1-6アルコキシ基
から選ばれる1ないし3個の置換基で置換されていてもよいC3-10シクロアルコキシ基、
(4)(a)ハロゲン原子、
   (b)カルボキシ基、
   (c)ヒドロキシ基、
   (d)C1-6アルコキシ-カルボニル基、
   (e)C1-6アルコキシ基、および
   (f)C1-6アルキル基でモノまたはジ置換されていてもよいアミノ基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基(例、メチル)、および
(5)(a)ハロゲン原子、
   (b)カルボキシ基、
   (c)ヒドロキシ基、
   (d)C1-6アルコキシ-カルボニル基、
   (e)C1-6アルコキシ基、および
   (f)C1-6アルキル基でモノまたはジ置換されていてもよいアミノ基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルコキシ基(例、メトキシ)、
から選ばれる1ないし3個の置換基でそれぞれ置換されていてもよい、ベンゼン、ピリジン、ピリダジン、ピリミジンまたはピラジン(好ましくは、ベンゼン、ピリジン、ピリミジン)であり;
が、
(1)ハロゲン原子(例、臭素原子)、
(2)(a)ハロゲン原子、
(b)カルボキシ基、
(c)C1-6アルコキシ-カルボニル基、および
(d)C1-6アルキル基でモノまたはジ置換されていてもよいアミノ基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基、
(3)(a)C1-6アルキル基、
   (b)ヒドロキシ基、
   (c)C1-6アルコキシ基、および
   (d)ハロゲン原子
から選ばれる1ないし3個の置換基で置換されていてもよい芳香族複素環基、
(4)(a)C1-6アルキル基、
   (b)ヒドロキシ基、
   (c)C1-6アルコキシ基、
   (d)ハロゲン原子、および
   (e)オキソ基
から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環基(例、ピロリジニル)、
(5)(a)C1-6アルキル基;および
   (b)C1-6アルコキシ-カルボニル基; 
から選ばれる置換基でモノまたはジ置換されていてもよいアミノ基、
(6)ホルミル基、
(7)(a)ハロゲン原子、
  (b)C6-14アリール基、
  (c)C1-6アルコキシ基、および
  (d)複素環基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルコキシ-カルボニル基(例、メトキシカルボニル)、
(8)(a)ハロゲン原子、および
  (b)C6-14アリール基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキルスルホニル基(例、メチルスルホニル)、
(9)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基から選ば
れる置換基でモノまたはジ置換されていてもよいスルファモイル基(例、メチルスルファモイル、ジメチルスルファモイル)、または
(10)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環スルホニル基(例、ピロリジノスルホニル、モルホリノスルホニル)であり;
が、
(1)(a)ハロゲン原子、
(b)カルボキシ基、
(c)C1-6アルコキシ-カルボニル基(例、エトキシカルボニル)、および
(d)C1-6アルキル基でモノまたはジ置換されていてもよいアミノ基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基(例、メチル)、
(2)(a)C1-6アルキル基(例、エチル、プロピル)、
   (b)ヒドロキシ基、
   (c)C1-6アルコキシ基、および
   (d)ハロゲン原子
から選ばれる1ないし3個の置換基で置換されていてもよい芳香族複素環基(例、ピリミジニル)、
(3)(a)C1-6アルキル基(例、イソプロピル)、
   (b)ヒドロキシ基、
   (c)C1-6アルコキシ基、
   (d)ハロゲン原子、および
   (e)オキソ基
から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環基(例、ジヒドロオキサゾリル)、
(4)(a)ハロゲン原子、
  (b)C6-14アリール基、
  (c)C1-6アルコキシ基、および
  (d)複素環基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルコキシ-カルボニル基(例、イソプロピルカルボニル、tert-ブチルカルボニル)、
(5)(a)ハロゲン原子、
  (b)C1-6アルキル基(例、メチル、プロピル、tert-ブチル)、
(c)C6-14アリール基、
  (d)C1-6アルコキシ基、および
  (e)複素環基(例、ピリダジニル)
から選ばれる置換基でモノまたはジ置換されていてもよいカルバモイル基、または
(6)(a)C1-6アルキル基、および
(b)オキソ基
から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環オキシカルボニル基(例、テトラヒドロフラニルオキシカルボニル)であり;
が、
(1)ハロゲン原子、
(2)ヒドロキシ基、
(3)C1-6アルコキシ基、および
(4)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル(例、メチ
ル)
から選ばれる1ないし3個の置換基でそれぞれ置換されていてもよい、エチレンまたはトリメチレンであり;
が、
(1)結合手、
(2)O、または
(3)(a)(i)シアノ基、および
    (ii)1ないし3個のハロゲン原子(例、フッ素原子)
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル(例、メチル、プロピル)、
(b)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル-カルボニ
ル基(例、アセチル)、
(c)C1-6アルコキシ-カルボニル基、および
(d)C1-6アルキルスルホニル基(例、メチルスルホニル) 
で置換されていてもよいNHであり;
が、
(1)結合手、または
(2)(a)ハロゲン原子、および
(b)C1-6アルキル
から選ばれる1ないし3個の置換基で置換されていてもよいメチレンであり;
およびYが、独立して、
(1)ハロゲン原子、
(2)C1-6アルキル基、および
(3)オキソ基
から選ばれる1ないし3個の置換基でそれぞれ置換されていてもよい、メチレンまたはエチレンである、
化合物(I)。
Preferable examples of compound (I) include the following compounds.
[Compound A]
Ring A is
(1) a hydroxy group,
(2) halogen atoms (eg, fluorine atoms, chlorine atoms),
(3) a C 3-10 cycloalkoxy group optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, and (b) a C 1-6 alkoxy group,
(4) (a) a halogen atom,
(b) a carboxy group,
(c) a hydroxy group,
(d) a C 1-6 alkoxy-carbonyl group,
(e) a C 1-6 alkoxy group, and (f) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted. A 1-6 alkyl group (eg, methyl), and (5) (a) a halogen atom,
(b) a carboxy group,
(c) a hydroxy group,
(d) a C 1-6 alkoxy-carbonyl group,
(e) a C 1-6 alkoxy group, and (f) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted. 1-6 alkoxy groups (eg, methoxy),
Benzene, pyridine, pyridazine, pyrimidine or pyrazine (preferably benzene, pyridine, pyrimidine) each optionally substituted by 1 to 3 substituents selected from:
R 1 is
(1) halogen atoms (eg, bromine atoms),
(2) (a) a halogen atom,
(b) a carboxy group,
(c) a C 1-6 alkoxy-carbonyl group, and
(d) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted with a C 1-6 alkyl group,
(3) (a) a C 1-6 alkyl group,
(b) a hydroxy group,
(c) a C 1-6 alkoxy group, and (d) an aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from halogen atoms,
(4) (a) a C 1-6 alkyl group,
(b) a hydroxy group,
(c) a C 1-6 alkoxy group,
(d) a halogen atom, and (e) a non-aromatic heterocyclic group (eg, pyrrolidinyl) optionally substituted with 1 to 3 substituents selected from an oxo group,
(5) (a) a C 1-6 alkyl group; and (b) a C 1-6 alkoxy-carbonyl group;
An amino group which may be mono- or di-substituted with a substituent selected from:
(6) formyl group,
(7) (a) a halogen atom,
(b) a C 6-14 aryl group,
(c) a C 1-6 alkoxy group, and (d) a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl) optionally substituted with 1 to 3 substituents selected from a heterocyclic group,
(8) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, and (b) a C 6-14 aryl group,
(9) A sulfamoyl group which may be mono- or di-substituted with a substituent selected from C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms (eg, methylsulfamoyl, dimethylsulfato) Famoyl), or (10) a non-aromatic heterocycle optionally substituted with 1 to 3 substituents selected from C 1-6 alkyl groups optionally substituted with 1 to 3 halogen atoms A sulfonyl group (eg, pyrrolidinosulfonyl, morpholinosulfonyl);
R 2 is
(1) (a) a halogen atom,
(b) a carboxy group,
(c) a C 1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl), and
(d) a C 1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted with a C 1-6 alkyl group,
(2) (a) a C 1-6 alkyl group (eg, ethyl, propyl),
(b) a hydroxy group,
(c) a C 1-6 alkoxy group, and (d) an aromatic heterocyclic group (eg, pyrimidinyl) optionally substituted with 1 to 3 substituents selected from halogen atoms,
(3) (a) a C 1-6 alkyl group (eg, isopropyl),
(b) a hydroxy group,
(c) a C 1-6 alkoxy group,
(d) a halogen atom, and (e) a non-aromatic heterocyclic group (eg, dihydrooxazolyl) optionally substituted with 1 to 3 substituents selected from an oxo group,
(4) (a) a halogen atom,
(b) a C 6-14 aryl group,
(c) a C 1-6 alkoxy group, and (d) a C 1-6 alkoxy-carbonyl group optionally substituted with 1 to 3 substituents selected from a heterocyclic group (eg, isopropylcarbonyl, tert- Butylcarbonyl),
(5) (a) a halogen atom,
(b) a C 1-6 alkyl group (eg, methyl, propyl, tert-butyl),
(c) a C 6-14 aryl group,
(d) a C 1-6 alkoxy group, and (e) a heterocyclic group (eg, pyridazinyl)
A carbamoyl group which may be mono- or di-substituted with a substituent selected from: (6) (a) a C 1-6 alkyl group, and
(b) a non-aromatic heterocyclic oxycarbonyl group (eg, tetrahydrofuranyloxycarbonyl) optionally substituted with 1 to 3 substituents selected from oxo groups;
X 1 is
(1) halogen atom,
(2) hydroxy group,
(3) C 1-6 alkoxy group, and (4) 1 to 3 halogen atoms optionally substituted by a C 1-6 alkyl (e.g., methyl)
Ethylene or trimethylene, each of which may be substituted with 1 to 3 substituents selected from:
X 2 is,
(1) join hands,
(2) O, or (3) (a) (i) a cyano group, and (ii) 1 to 3 halogen atoms (eg, fluorine atoms)
C 1-6 alkyl (eg, methyl, propyl) optionally substituted with 1 to 3 substituents selected from:
(B) a C 1-6 alkyl-carbonyl group (eg, acetyl) optionally substituted with 1 to 3 halogen atoms,
(C) a C 1-6 alkoxy-carbonyl group, and (d) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl)
NH optionally substituted with
X 3 is
(1) a bond, or (2) (a) a halogen atom, and
(b) methylene optionally substituted with 1 to 3 substituents selected from C 1-6 alkyl;
Y 1 and Y 2 are independently
(1) halogen atom,
(2) methylene or ethylene, each optionally substituted with 1 to 3 substituents selected from a C 1-6 alkyl group and (3) an oxo group,
Compound (I).
[化合物B]
環Aが、
(1)ヒドロキシ基、
(2)ハロゲン原子(例、フッ素原子、塩素原子)、
(3)(a)ハロゲン原子、および
   (b)C1-6アルコキシ基
から選ばれる1ないし3個の置換基で置換されていてもよいC3-10シクロアルコキシ基、
(4)(a)ハロゲン原子、
   (b)カルボキシ基、
   (c)ヒドロキシ基、
   (d)C1-6アルコキシ-カルボニル基、
   (e)C1-6アルコキシ基、および
   (f)C1-6アルキル基でモノまたはジ置換されていてもよいアミノ基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基(例、メチル)、および
(5)(a)ハロゲン原子、
   (b)カルボキシ基、
   (c)ヒドロキシ基、
   (d)C1-6アルコキシ-カルボニル基、
   (e)C1-6アルコキシ基、および
   (f)C1-6アルキル基でモノまたはジ置換されていてもよいアミノ基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルコキシ基(例、メトキシ)、
から選ばれる1ないし3個の置換基でそれぞれ置換されていてもよい、ベンゼン、ピリジン、ピリダジン、ピリミジンまたはピラジン(好ましくは、ベンゼン、ピリジン、ピリミジン)であり;
が、
(1)ハロゲン原子(例、臭素原子)、
(2)(a)ハロゲン原子、
(b)カルボキシ基、
(c)C1-6アルコキシ-カルボニル基、および
(d)C1-6アルキル基でモノまたはジ置換されていてもよいアミノ基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基、
(3)(a)C1-6アルキル基、
   (b)ヒドロキシ基、
   (c)C1-6アルコキシ基、および
   (d)ハロゲン原子
から選ばれる1ないし3個の置換基で置換されていてもよい5または6員の芳香族複素環基、
(4)(a)C1-6アルキル基、
   (b)ヒドロキシ基、
   (c)C1-6アルコキシ基、
   (d)ハロゲン原子、および
   (e)オキソ基
から選ばれる1ないし3個の置換基で置換されていてもよい4ないし7員の非芳香族複素環基(例、ピロリジニル)、
(5)(a)C1-6アルキル基;および
   (b)C1-6アルコキシ-カルボニル基; 
から選ばれる置換基でモノまたはジ置換されていてもよいアミノ基、
(6)ホルミル基、
(7)(a)ハロゲン原子、
  (b)C6-14アリール基、
  (c)C1-6アルコキシ基、および
  (d)4ないし7員の複素環基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルコキシ-カルボニル基(例、メトキシカルボニル)、
(8)(a)ハロゲン原子、および
  (b)C6-14アリール基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキルスルホニル基(例、メチルスルホニル)、
(9)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基から選ば
れる置換基でモノまたはジ置換されていてもよいスルファモイル基(例、メチルスルファモイル、ジメチルスルファモイル)、または
(10)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基から選ばれる1ないし3個の置換基で置換されていてもよい4ないし7員の非芳香族複素環スルホニル基(例、ピロリジノスルホニル、モルホリノスルホニル)であり;
が、
(1)(a)ハロゲン原子、
(b)カルボキシ基、
(c)C1-6アルコキシ-カルボニル基(例、エトキシカルボニル)、および
(d)C1-6アルキル基でモノまたはジ置換されていてもよいアミノ基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基(例、メチル)、
(2)(a)C1-6アルキル基(例、エチル、プロピル)、
   (b)ヒドロキシ基、
   (c)C1-6アルコキシ基、および
   (d)ハロゲン原子
から選ばれる1ないし3個の置換基で置換されていてもよい5または6員の芳香族複素環基(例、ピリミジニル)、
(3)(a)C1-6アルキル基(例、イソプロピル)、
   (b)ヒドロキシ基、
   (c)C1-6アルコキシ基、
   (d)ハロゲン原子、および
   (e)オキソ基
から選ばれる1ないし3個の置換基で置換されていてもよい4ないし7員の非芳香族複素環基(例、ジヒドロオキサゾリル)、
(4)(a)ハロゲン原子、
  (b)C6-14アリール基、
  (c)C1-6アルコキシ基、および
  (d)4ないし7員の複素環基
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルコキシ-カルボニル基(例、イソプロピルカルボニル、tert-ブチルカルボニル)、
(5)(a)ハロゲン原子、
  (b)C1-6アルキル基(例、メチル、プロピル、tert-ブチル)、
(c)C6-14アリール基、
  (d)C1-6アルコキシ基、および
  (e)4ないし7員の複素環基(例、ピリダジニル)
から選ばれる置換基でモノまたはジ置換されていてもよいカルバモイル基、または
(6)(a)C1-6アルキル基、および
(b)オキソ基
から選ばれる1ないし3個の置換基で置換されていてもよい4ないし7員の非芳香族複素環オキシカルボニル基(例、テトラヒドロフラニルオキシカルボニル)であり;
が、
(1)ハロゲン原子、
(2)ヒドロキシ基、
(3)C1-6アルコキシ基、および
(4)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル(例、メチ
ル)
から選ばれる1ないし3個の置換基でそれぞれ置換されていてもよい、エチレンまたはトリメチレンであり;
が、
(1)結合手、
(2)O、または
(3)(a)(i)シアノ基、および
    (ii)1ないし3個のハロゲン原子(例、フッ素原子)
から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル(例、メチル、プロピル)、
(b)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル-カルボニ
ル基(例、アセチル)、
(c)C1-6アルコキシ-カルボニル基、および
(d)C1-6アルキルスルホニル基(例、メチルスルホニル) 
で置換されていてもよいNHであり;
が、
(1)結合手、または
(2)(a)ハロゲン原子、および
(b)C1-6アルキル
から選ばれる1ないし3個の置換基で置換されていてもよいメチレンであり;
およびYが、独立して、
(1)ハロゲン原子、
(2)C1-6アルキル基、および
(3)オキソ基
から選ばれる1ないし3個の置換基でそれぞれ置換されていてもよい、メチレンまたはエチレンである、
化合物(I)。
[Compound B]
Ring A is
(1) a hydroxy group,
(2) halogen atoms (eg, fluorine atoms, chlorine atoms),
(3) a C 3-10 cycloalkoxy group optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, and (b) a C 1-6 alkoxy group,
(4) (a) a halogen atom,
(b) a carboxy group,
(c) a hydroxy group,
(d) a C 1-6 alkoxy-carbonyl group,
(e) a C 1-6 alkoxy group, and (f) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted. A 1-6 alkyl group (eg, methyl), and (5) (a) a halogen atom,
(b) a carboxy group,
(c) a hydroxy group,
(d) a C 1-6 alkoxy-carbonyl group,
(e) a C 1-6 alkoxy group, and (f) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted. 1-6 alkoxy groups (eg, methoxy),
Benzene, pyridine, pyridazine, pyrimidine or pyrazine (preferably benzene, pyridine, pyrimidine) each optionally substituted by 1 to 3 substituents selected from:
R 1 is
(1) halogen atoms (eg, bromine atoms),
(2) (a) a halogen atom,
(b) a carboxy group,
(c) a C 1-6 alkoxy-carbonyl group, and
(d) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted with a C 1-6 alkyl group,
(3) (a) a C 1-6 alkyl group,
(b) a hydroxy group,
(c) a C 1-6 alkoxy group, and (d) a 5- or 6-membered aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from halogen atoms,
(4) (a) a C 1-6 alkyl group,
(b) a hydroxy group,
(c) a C 1-6 alkoxy group,
(d) a halogen atom, and (e) a 4- to 7-membered non-aromatic heterocyclic group (eg, pyrrolidinyl) optionally substituted with 1 to 3 substituents selected from oxo groups,
(5) (a) a C 1-6 alkyl group; and (b) a C 1-6 alkoxy-carbonyl group;
An amino group which may be mono- or di-substituted with a substituent selected from:
(6) formyl group,
(7) (a) a halogen atom,
(b) a C 6-14 aryl group,
(c) a C 1-6 alkoxy group, and (d) a C 1-6 alkoxy-carbonyl group optionally substituted with 1 to 3 substituents selected from 4- to 7-membered heterocyclic groups (eg, Methoxycarbonyl),
(8) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, and (b) a C 6-14 aryl group,
(9) A sulfamoyl group which may be mono- or di-substituted with a substituent selected from C 1-6 alkyl groups which may be substituted with 1 to 3 halogen atoms (eg, methylsulfamoyl, dimethylsulfato) Famoyl), or (10) 4 to 7 membered optionally substituted with 1 to 3 substituents selected from C 1-6 alkyl groups optionally substituted with 1 to 3 halogen atoms A non-aromatic heterocyclic sulfonyl group (eg, pyrrolidinosulfonyl, morpholinosulfonyl);
R 2 is
(1) (a) a halogen atom,
(b) a carboxy group,
(c) a C 1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl), and
(d) a C 1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted with a C 1-6 alkyl group,
(2) (a) a C 1-6 alkyl group (eg, ethyl, propyl),
(b) a hydroxy group,
(c) a C 1-6 alkoxy group, and (d) a 5- or 6-membered aromatic heterocyclic group (eg, pyrimidinyl) optionally substituted with 1 to 3 substituents selected from halogen atoms,
(3) (a) a C 1-6 alkyl group (eg, isopropyl),
(b) a hydroxy group,
(c) a C 1-6 alkoxy group,
(d) a halogen atom, and (e) a 4- to 7-membered non-aromatic heterocyclic group (eg, dihydrooxazolyl) optionally substituted with 1 to 3 substituents selected from oxo groups,
(4) (a) a halogen atom,
(b) a C 6-14 aryl group,
(c) a C 1-6 alkoxy group, and (d) a C 1-6 alkoxy-carbonyl group optionally substituted with 1 to 3 substituents selected from 4- to 7-membered heterocyclic groups (eg, Isopropylcarbonyl, tert-butylcarbonyl),
(5) (a) a halogen atom,
(b) a C 1-6 alkyl group (eg, methyl, propyl, tert-butyl),
(c) a C 6-14 aryl group,
(d) a C 1-6 alkoxy group, and (e) a 4- to 7-membered heterocyclic group (eg, pyridazinyl)
A carbamoyl group which may be mono- or di-substituted with a substituent selected from: (6) (a) a C 1-6 alkyl group, and
(b) a 4- to 7-membered non-aromatic heterocyclic oxycarbonyl group (eg, tetrahydrofuranyloxycarbonyl) optionally substituted with 1 to 3 substituents selected from oxo groups;
X 1 is
(1) halogen atom,
(2) hydroxy group,
(3) C 1-6 alkoxy group, and (4) 1 to 3 halogen atoms optionally substituted by a C 1-6 alkyl (e.g., methyl)
Ethylene or trimethylene, each of which may be substituted with 1 to 3 substituents selected from:
X 2 is,
(1) join hands,
(2) O, or (3) (a) (i) a cyano group, and (ii) 1 to 3 halogen atoms (eg, fluorine atoms)
C 1-6 alkyl (eg, methyl, propyl) optionally substituted with 1 to 3 substituents selected from:
(B) a C 1-6 alkyl-carbonyl group (eg, acetyl) optionally substituted with 1 to 3 halogen atoms,
(C) a C 1-6 alkoxy-carbonyl group, and (d) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl)
NH optionally substituted with
X 3 is
(1) a bond, or (2) (a) a halogen atom, and
(b) methylene optionally substituted with 1 to 3 substituents selected from C 1-6 alkyl;
Y 1 and Y 2 are independently
(1) halogen atom,
(2) methylene or ethylene, each optionally substituted with 1 to 3 substituents selected from a C 1-6 alkyl group and (3) an oxo group,
Compound (I).
[化合物C]
 環Aが、
(1)ハロゲン原子(例、フッ素原子、塩素原子)、
(2)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基(例、メチル)、および
(3)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ基(例、メトキシ)
から選ばれる1ないし3個の置換基でそれぞれさらに置換されていてもよい、ベンゼン、ピリジン、またはピリミジン(好ましくは、ベンゼン)であり;
が、
(1)ハロゲン原子(例、臭素原子)、
(2)カルボキシ基、
(3)(a)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基、および(b)オキソ基から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環基(例、ピロリジニル)、
(4)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ-カルボニル基(例、メトキシカルボニル)、
(5)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキルスルホニル基(例、メチルスルホニル)、
(6)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基でモノまたはジ置換されていてもよいスルファモイル基(例、メチルスルファモイル、ジメチルスルファモイル)、または
(7)(a)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基、および(b)オキソ基から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環スルホニル基(例、ピロリジノスルホニル、モルホリノスルホニル)であり;
が、
(1)(a)ハロゲン原子、および(b)C1-6アルコキシ-カルボニル基(例、エトキシカルボニル)から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基(例、メチル)、
(2)(a)ハロゲン原子、および(b)C1-6アルキル基(例、エチル、プロピル)から選ばれる1ないし3個の置換基で置換されていてもよい芳香族複素環基(例、ピリミジニル)、
(3)(a)ハロゲン原子、(b)C1-6アルキル基(例、イソプロピル)、および(c)オキソ基から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環基(例、ジヒドロオキサゾリル)、
(4)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ-カルボニル基(例、イソプロピルカルボニル、tert-ブチルカルボニル)、
(5)(a)C1-6アルキル基(例、メチル、プロピル、tert-ブチル)、および(b)複素環基(例、ピリダジニル)から選ばれる置換基でモノまたはジ置換されていてもよいカルバモイル基、または
(6)(a)C1-6アルキル基、および(b)オキソ基から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環オキシカルボニル基(例、テトラヒドロフラニルオキシカルボニル)であり;
が、
(1)ハロゲン原子、および
(2)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル(例、メチル)
から選ばれる1ないし3個の置換基でそれぞれ置換されていてもよい、エチレンまたはトリメチレンであり;
が、
(1)結合手、
(2)O、または
(3)(a)(i)シアノ基、および(ii)1ないし3個のハロゲン原子(例、フッ素原子)から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル(例、メチル、プロピル)、 
   (b)C1-6アルキル-カルボニル基(例、アセチル)、 または
   (c)C1-6アルキルスルホニル基(例、メチルスルホニル)
で置換されていてもよいNHであり; 
が、結合手またはメチレンであり;および
およびYが、独立して、メチレンまたはエチレンである、化合物(I)。
[Compound C]
Ring A is
(1) halogen atom (eg, fluorine atom, chlorine atom),
(2) a C 1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms, and
(3) C 1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms (eg, methoxy)
Benzene, pyridine, or pyrimidine (preferably benzene), each of which may be further substituted with 1 to 3 substituents selected from:
R 1 is
(1) halogen atoms (eg, bromine atoms),
(2) a carboxy group,
(3) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (b) optionally substituted with 1 to 3 substituents selected from an oxo group Non-aromatic heterocyclic groups (eg, pyrrolidinyl),
(4) a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl) optionally substituted with 1 to 3 halogen atoms,
(5) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl) optionally substituted with 1 to 3 halogen atoms,
(6) a sulfamoyl group (eg, methylsulfamoyl, dimethylsulfamoyl) optionally mono- or disubstituted with a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, or
(7) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (b) optionally substituted with 1 to 3 substituents selected from an oxo group A non-aromatic heterocyclic sulfonyl group (eg, pyrrolidinosulfonyl, morpholinosulfonyl);
R 2 is
(1) (a) a halogen atom, and (b) C 1-6 alkoxy - carbonyl group (e.g., ethoxycarbonyl) 1 to 3 substituents optionally substituted by a C 1-6 alkyl group selected from (Eg, methyl),
(2) an aromatic heterocyclic group (eg, optionally substituted with 1 to 3 substituents selected from (a) a halogen atom and (b) a C 1-6 alkyl group (eg, ethyl, propyl) , Pyrimidinyl),
(3) Non-aromatic optionally substituted by 1 to 3 substituents selected from (a) a halogen atom, (b) a C 1-6 alkyl group (eg, isopropyl), and (c) an oxo group A heterocyclic group (eg, dihydrooxazolyl),
(4) a C 1-6 alkoxy-carbonyl group (eg, isopropylcarbonyl, tert-butylcarbonyl) optionally substituted with 1 to 3 halogen atoms,
(5) It may be mono- or di-substituted with a substituent selected from (a) a C 1-6 alkyl group (eg, methyl, propyl, tert-butyl) and (b) a heterocyclic group (eg, pyridazinyl). A good carbamoyl group, or
(6) a non-aromatic heterocyclic oxycarbonyl group (eg, tetrahydrofuranyloxy) which may be substituted with 1 to 3 substituents selected from (a) a C 1-6 alkyl group and (b) an oxo group Carbonyl);
X 1 is
(1) a halogen atom, and
(2) C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms (eg, methyl)
Ethylene or trimethylene, each of which may be substituted with 1 to 3 substituents selected from:
X 2 is,
(1) Joining hands,
(2) O or
(3) C 1-6 optionally substituted with 1 to 3 substituents selected from (a) (i) cyano group, and (ii) 1 to 3 halogen atoms (eg, fluorine atom) Alkyl (eg, methyl, propyl),
(b) C 1-6 alkyl-carbonyl group (eg, acetyl), or (c) C 1-6 alkylsulfonyl group (eg, methylsulfonyl)
NH optionally substituted with
Compound (I), wherein X 3 is a bond or methylene; and Y 1 and Y 2 are independently methylene or ethylene.
[化合物D]
 環Aが、
(1)ハロゲン原子(例、フッ素原子、塩素原子)、
(2)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基(例、メチル)、および
(3)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ基(例、メトキシ)
から選ばれる1ないし3個の置換基でそれぞれさらに置換されていてもよい、ベンゼン、ピリジン、またはピリミジン(好ましくは、ベンゼン)であり;
が、
(1)ハロゲン原子(例、臭素原子)、
(2)カルボキシ基、
(3)(a)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基、および(b)オキソ基から選ばれる1ないし3個の置換基で置換されていてもよい5または6員の非芳香族複素環基(例、ピロリジニル)、
(4)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ-カルボニル基(例、メトキシカルボニル)、
(5)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキルスルホニル基(例、メチルスルホニル)、
(6)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基でモノまたはジ置換されていてもよいスルファモイル基(例、メチルスルファモイル、ジメチルスルファモイル)、または
(7)(a)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基、および(b)オキソ基から選ばれる1ないし3個の置換基で置換されていてもよい5または6員の非芳香族複素環スルホニル基(例、ピロリジノスルホニル、モルホリノスルホニル)であり;
が、
(1)(a)ハロゲン原子、および(b)C1-6アルコキシ-カルボニル基(例、エトキシカルボニル)から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基(例、メチル)、
(2)(a)ハロゲン原子、および(b)C1-6アルキル基(例、エチル、プロピル)から選ばれる1ないし3個の置換基で置換されていてもよい5または6員の芳香族複素環基(例、ピリミジニル)、
(3)(a)ハロゲン原子、(b)C1-6アルキル基(例、イソプロピル)、および(c)オキソ基から選ばれる1ないし3個の置換基で置換されていてもよい5または6員の非芳香族複素環基(例、ジヒドロオキサゾリル)、
(4)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ-カルボニル基(例、イソプロピルカルボニル、tert-ブチルカルボニル)、
(5)(a)C1-6アルキル基(例、メチル、プロピル、tert-ブチル)、および(b)5または6員の複素環基(例、ピリダジニル)から選ばれる置換基でモノまたはジ置換されていてもよいカルバモイル基、または
(6)(a)C1-6アルキル基、および(b)オキソ基から選ばれる1ないし3個の置換基で置換されていてもよい5または6員の非芳香族複素環オキシカルボニル基(例、テトラヒドロフラニルオキシカルボニル)であり;
が、
(1)ハロゲン原子、および
(2)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル(例、メチル)
から選ばれる1ないし3個の置換基でそれぞれ置換されていてもよい、エチレンまたはトリメチレンであり;
が、
(1)結合手、
(2)O、または
(3)(a)(i)シアノ基、および(ii)1ないし3個のハロゲン原子(例、フッ素原子)から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル(例、メチル、プロピル)、 
   (b)C1-6アルキル-カルボニル基(例、アセチル)、 または
   (c)C1-6アルキルスルホニル基(例、メチルスルホニル)
で置換されていてもよいNHであり; 
が、結合手またはメチレンであり;および
およびYが、独立して、メチレンまたはエチレンである、化合物(I)。
[Compound D]
Ring A is
(1) halogen atom (eg, fluorine atom, chlorine atom),
(2) a C 1-6 alkyl group (eg, methyl) optionally substituted with 1 to 3 halogen atoms, and
(3) C 1-6 alkoxy group optionally substituted with 1 to 3 halogen atoms (eg, methoxy)
Benzene, pyridine, or pyrimidine (preferably benzene), each of which may be further substituted with 1 to 3 substituents selected from:
R 1 is
(1) halogen atoms (eg, bromine atoms),
(2) a carboxy group,
(3) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (b) optionally substituted with 1 to 3 substituents selected from an oxo group A 5- or 6-membered non-aromatic heterocyclic group (eg, pyrrolidinyl),
(4) a C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl) optionally substituted with 1 to 3 halogen atoms,
(5) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl) optionally substituted with 1 to 3 halogen atoms,
(6) a sulfamoyl group (eg, methylsulfamoyl, dimethylsulfamoyl) optionally mono- or disubstituted with a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, or
(7) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (b) optionally substituted with 1 to 3 substituents selected from an oxo group A 5- or 6-membered non-aromatic heterocyclic sulfonyl group (eg, pyrrolidinosulfonyl, morpholinosulfonyl);
R 2 is
(1) (a) a halogen atom, and (b) C 1-6 alkoxy - carbonyl group (e.g., ethoxycarbonyl) 1 to 3 substituents optionally substituted by a C 1-6 alkyl group selected from (Eg, methyl),
(2) 5- or 6-membered aromatic optionally substituted by 1 to 3 substituents selected from (a) a halogen atom and (b) a C 1-6 alkyl group (eg, ethyl, propyl) A heterocyclic group (eg, pyrimidinyl),
(3) optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, (b) a C 1-6 alkyl group (eg, isopropyl), and (c) an oxo group Member non-aromatic heterocyclic groups (eg, dihydrooxazolyl),
(4) a C 1-6 alkoxy-carbonyl group (eg, isopropylcarbonyl, tert-butylcarbonyl) optionally substituted with 1 to 3 halogen atoms,
(5) mono or di substituents selected from (a) C 1-6 alkyl groups (eg, methyl, propyl, tert-butyl) and (b) 5 or 6 membered heterocyclic groups (eg, pyridazinyl) An optionally substituted carbamoyl group, or
(6) a 5- or 6-membered non-aromatic heterocyclic oxycarbonyl group which may be substituted with 1 to 3 substituents selected from (a) a C 1-6 alkyl group and (b) an oxo group ( Eg, tetrahydrofuranyloxycarbonyl);
X 1 is
(1) a halogen atom, and
(2) C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms (eg, methyl)
Ethylene or trimethylene, each of which may be substituted with 1 to 3 substituents selected from:
X 2 is,
(1) Joining hands,
(2) O or
(3) C 1-6 optionally substituted with 1 to 3 substituents selected from (a) (i) cyano group, and (ii) 1 to 3 halogen atoms (eg, fluorine atom) Alkyl (eg, methyl, propyl),
(b) C 1-6 alkyl-carbonyl group (eg, acetyl), or (c) C 1-6 alkylsulfonyl group (eg, methylsulfonyl)
NH optionally substituted with
Compound (I), wherein X 3 is a bond or methylene; and Y 1 and Y 2 are independently methylene or ethylene.
[化合物E]
・5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸 2-[1-(5-プロピルピリミジン-2-イル)ピペリジン-4-イル]プロピルまたはその塩。
・7-フルオロ-5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-[1-(5-プロピルピリミジン-2-イル)ピペリジン-4-イル]プロピルまたはその塩。
[Compound E]
5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- [1- (5-propylpyrimidin-2-yl) piperidin-4-yl] propyl or a salt thereof.
7-fluoro-5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- [1- (5-propylpyrimidin-2-yl) piperidin-4-yl] propyl or its salt.
 式(I)で表される化合物の塩としては、薬理学的に許容される塩が好ましく、このような塩としては、例えば、無機塩基との塩、有機塩基との塩、無機酸との塩、有機酸との塩、塩基性または酸性アミノ酸との塩等が挙げられる。 The salt of the compound represented by formula (I) is preferably a pharmacologically acceptable salt. Examples of such a salt include a salt with an inorganic base, a salt with an organic base, and a salt with an inorganic acid. Salts, salts with organic acids, salts with basic or acidic amino acids, and the like.
 無機塩基との塩の好適な例としては、ナトリウム塩、カリウム塩等のアルカリ金属塩;カルシウム塩、マグネシウム塩等のアルカリ土類金属塩;アルミニウム塩;アンモニウム塩等が挙げられる。 Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt; ammonium salt and the like.
 有機塩基との塩の好適な例としては、トリメチルアミン、トリエチルアミン、ピリジン、ピコリン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、トロメタミン[トリス(ヒドロキシメチル)メチルアミン]、tert-ブチルアミン、シクロヘキシルアミン、ベンジルアミン、ジシクロヘキシルアミン、N,N-ジベンジルエチレンジアミン等との塩が挙げられる。 Preferable examples of the salt with an organic base include trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris (hydroxymethyl) methylamine], tert-butylamine, cyclohexylamine, benzylamine, And salts with dicyclohexylamine, N, N-dibenzylethylenediamine and the like.
 無機酸との塩の好適な例としては、塩酸、臭化水素酸、硝酸、硫酸、リン酸等との塩が挙げられる。 Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
 有機酸との塩の好適な例としては、ギ酸、酢酸、トリフルオロ酢酸、フタル酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、メタンスルホン酸、ベンゼンスルホン酸、p-トルエンスルホン酸等との塩が挙げられる。 Preferable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfonic acid And salts with p-toluenesulfonic acid and the like.
 塩基性アミノ酸との塩の好適な例としては、アルギニン、リジン、オルニチン等との塩が挙げられる。 Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like.
 酸性アミノ酸との塩の好適な例としては、アスパラギン酸、グルタミン酸等との塩が挙げられる。 Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
 化合物(I)は、同位元素(例、3H、11C、14C、18F、35S、125I)等で標識されていてもよい。
 また、化合物(I)は、無溶媒和物(例えば、無水物)であっても、溶媒和物(例えば、水和物)であってもよい。
 さらに、HをH(D)に変換した重水素変換体も、化合物(I)に包含される。
Compound (I) may be labeled with an isotope (eg, 3 H, 11 C, 14 C, 18 F, 35 S, 125 I) or the like.
Compound (I) may be a solvate (for example, an anhydride) or a solvate (for example, a hydrate).
Further, a deuterium converter obtained by converting 1 H into 2 H (D) is also encompassed in compound (I).
 化合物(I)のプロドラッグとは、生体内における生理条件下で酵素や胃酸等による反応により化合物(I)に変換する化合物、すなわち酵素的に酸化、還元、加水分解等を起こして化合物(I)に変化する化合物、胃酸等により加水分解等を起こして化合物(I)に変化する化合物である。 The prodrug of the compound (I) is a compound that is converted to the compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, the compound (I) ), A compound that undergoes hydrolysis or the like due to gastric acid or the like and changes to compound (I).
 化合物(I)のプロドラッグとしては、
化合物(I)のアミノ基がアシル化、アルキル化またはリン酸化された化合物(例、化合物(I)のアミノ基がエイコサノイル化、アラニル化、ペンチルアミノカルボニル化、(5-メチル-2-オキソ-1,3-ジオキソレン-4-イル)メトキシカルボニル化、テトラヒドロフラニル化、ピロリジルメチル化、ピバロイルオキシメチル化またはtert-ブチル化された化合物);
化合物(I)のヒドロキシ基がアシル化、アルキル化、リン酸化またはホウ酸化された化合物(例、化合物(I)のヒドロキシ基がアセチル化、パルミトイル化、プロパノイル化、ピバロイル化、サクシニル化、フマリル化、アラニル化またはジメチルアミノメチルカルボニル化された化合物);
化合物(I)のカルボキシル基がエステル化またはアミド化された化合物(例、化合物(I)のカルボキシル基がエチルエステル化、フェニルエステル化、カルボキシメチルエステル化、ジメチルアミノメチルエステル化、ピバロイルオキシメチルエステル化、エトキシカルボニルオキシエチルエステル化、フタリジルエステル化、(5-メチル-2-オキソ-1,3-ジオキソレン-4-イル)メチルエステル化、シクロヘキシルオキシカルボニルエチルエステル化またはメチルアミド化された化合物)
等が挙げられる。これらの化合物は自体公知の方法によって化合物(I)から製造することができる。
As a prodrug of compound (I),
Compounds wherein the amino group of compound (I) is acylated, alkylated or phosphorylated (eg, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo- 1,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated compounds);
Compounds in which the hydroxy group of compound (I) is acylated, alkylated, phosphorylated or borated (eg, hydroxy group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated Alanylated or dimethylaminomethylcarbonylated compounds);
Compounds in which the carboxyl group of compound (I) is esterified or amidated (eg, the carboxyl group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxy Methyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification or methylamidation Compound)
Etc. These compounds can be produced from compound (I) by a method known per se.
 また、化合物(I)のプロドラッグは、広川書店1990年刊「医薬品の開発」第7巻分子設計163頁から198頁に記載されているような、生理的条件で化合物(I)に変化するものであってもよい。 In addition, the prodrug of compound (I) is a compound that changes to compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Drug Development”, Volume 7, Molecular Design, pages 163 to 198. It may be.
 以下、化合物(I)の製造法について説明する。
 化合物(I)は、自体公知の方法、例えば以下に示すスキーム1~15あるいはこれらに準ずる方法により製造することができる。なお、以下の各スキームにおいて、原料化合物は塩として用いてもよく、このような塩としては、式(I)で表される化合物の塩として例示したものが用いられる。以下の各スキームにおける反応で使用する溶媒としては、反応を阻害せず、出発物質をある程度溶解するものであれば特に限定されないが、例えば、ベンゼン、トルエン、キシレン等の芳香族炭化水素類;ヘキサン、ヘプタン等の脂肪族炭化水素類;ジエチルエーテル、ジイソプロピルエーテル、tert-ブチルメチルエーテル、テトラヒドロフラン、ジオキサン、1,2-ジメトキシエタン等のエーテル類;アセトン、2-ブタノン等のケトン類;アセトニトリル、プロピオニトリル等のニトリル類;酢酸エチル、酢酸イソプロピル、酢酸tert-ブチル等のエステル類;N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、1-メチル-2-ピロリジノン等のアミド類;1,3-ジメチル-2-イミダゾリジノン等のイミド類;例えばメタノール、エタノール、イソプロパノール、tert-ブタノール等のアルコール類;クロロホルム、ジクロロメタン、1,2-ジクロロエタン、四塩化炭素等のハロゲン化炭化水素類;ジメチルスルホキシド等のスルホキシド類;水等が挙げられる。これらの溶媒は、適宜の割合で混合して用いてもよい。反応温度は、通常、-100~250℃の前記した溶媒の沸点以下で行われるが、場合によって、耐圧反応条件等を用いて、溶媒の沸点以上の温度で反応を行っても良い。反応時間は、通常、0.5時間~100時間である。ここで、以下のスキームの式中、環A、R、R、X、X、X、YおよびYは前記と同意義を示す。
Hereafter, the manufacturing method of compound (I) is demonstrated.
Compound (I) can be produced by a method known per se, for example, schemes 1 to 15 shown below or a method analogous thereto. In each of the following schemes, the starting compound may be used as a salt, and as such a salt, those exemplified as the salt of the compound represented by the formula (I) are used. The solvent used in the reaction in each of the following schemes is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, aromatic hydrocarbons such as benzene, toluene and xylene; hexane Aliphatic hydrocarbons such as heptane; ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane; ketones such as acetone and 2-butanone; acetonitrile, pro Nitriles such as pionitrile; esters such as ethyl acetate, isopropyl acetate and tert-butyl acetate; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidinone; 3-dimethyl-2-imidazolidinone, etc. Alcohols such as methanol, ethanol, isopropanol and tert-butanol; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; sulfoxides such as dimethyl sulfoxide; water and the like It is done. These solvents may be mixed and used at an appropriate ratio. The reaction temperature is usually carried out below the boiling point of the above-mentioned solvent at −100 to 250 ° C., but depending on the case, the reaction may be carried out at a temperature above the boiling point of the solvent using pressure resistant reaction conditions or the like. The reaction time is usually 0.5 to 100 hours. Here, in the formulas of the following schemes, ring A, R 1 , R 2 , X 1 , X 2 , X 3 , Y 1 and Y 2 are as defined above.
[スキーム1] [Scheme 1]
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
 化合物(I)は例えば、スキーム1に示した方法、またはこれらに準ずる方法に従って製造することができる。ここで、Zは脱離基(例えば、ハロゲン原子または-OSOMe、-OSO(4-トリル)など)を示す。本法では、塩基(例えば、ピリジン、2,6-ルチジン、トリエチルアミン、ジイソプロピルエチルアミンなど)存在下、縮合剤として、例えばトリホスゲンなどを用いて、化合物(II)と化合物(III)をカップリングさせることによって製造することができる。また、化合物(I)は、例えば、通常、塩基存在下、化合物(II)と化合物(IIIa)を反応させることによって製造することができる。また、化合物(I)は、例えば炭酸カリウムや炭酸セシウムなどの炭酸塩存在下、化合物(II)と化合物(IV)を反応させることによっても製造することができる。
 なお、化合物(II)は後述するスキーム3~4に示した方法または自体公知の方法、あるいはこれらに準ずる方法によって製造することができる。化合物(III)は後述するスキーム5~7に示した方法または自体公知の方法、あるいはこれらに準ずる方法によって製造することができる。化合物(IIIa)および化合物(IV)は化合物(III)から自体公知の方法、またはこれに準ずる方法に従って製造することができる。
Compound (I) can be produced, for example, according to the method shown in Scheme 1 or a method analogous thereto. Here, Z 1 represents a leaving group (for example, a halogen atom, —OSO 2 Me, —OSO 2 (4-tolyl), etc.). In this method, compound (II) and compound (III) are coupled using, for example, triphosgene as a condensing agent in the presence of a base (eg, pyridine, 2,6-lutidine, triethylamine, diisopropylethylamine, etc.). Can be manufactured by. Compound (I) can be produced, for example, by reacting compound (II) with compound (IIIa) usually in the presence of a base. Compound (I) can also be produced by reacting compound (II) with compound (IV) in the presence of a carbonate such as potassium carbonate or cesium carbonate.
Compound (II) can be produced by the methods shown in schemes 3 to 4 described later, methods known per se, or methods analogous thereto. Compound (III) can be produced by the method shown in Schemes 5 to 7 described later, a method known per se, or a method analogous thereto. Compound (IIIa) and compound (IV) can be produced from compound (III) according to a method known per se or a method analogous thereto.
[スキーム2] [Scheme 2]
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
 化合物(I)のRを種々変換した化合物(I-1)、化合物(I-2)、化合物(I-3)、化合物(I-4)、化合物(I-5a)および化合物(I-5b)は、例えばスキーム2に示した、化合物(Ia)を原料とし、化合物(V)を中間体として経る方法、またはこれらに準ずる方法に従って製造することができる。ここで、Pは例えば、tert-ブトキシカルボニル、ベンジルオキシカルボニル、ベンジルなどのアミノ基の保護基を、RおよびRは、独立して、RA1と同様の基を、Arは置換されていてもよいC6-14アリール基(例、フェニル)または置換されていてもよいC6-14ヘテロアリール基(例、ピリジル、ピリミジニル、オキサジアゾリル)を、R5aおよびR5bは独立して、RA2またはRB2と同様の基を、RはRで示される「置換されていてもよい炭化水素基」と同様の基を示す。R6aおよびR6bは独立して、C1-6アルキル基(例、メチル、エチル、プロピル、イソプロピル、イソブチル、tert-ブチル、シクロプロピル、ペンチル、tert-ペンチル)、C6-14アリール基(例、フェニル)またはC6-14ヘテロアリール基(例、ピリジル、ピリミジニル、オキサジアゾリル)を、ZおよびZは、独立して、脱離基(例、Zとして例示したものと同様の基)を示す。 Compound (I-1), Compound (I-2), Compound (I-3), Compound (I-4), Compound (I-5a) and Compound (I-) in which R 2 of Compound (I) is variously converted 5b) can be produced, for example, according to the method shown in Scheme 2 in which compound (Ia) is used as a raw material and compound (V) is used as an intermediate, or a method analogous thereto. Here, P a, for example, tert- butoxycarbonyl, benzyloxycarbonyl, the protecting group of the amino group, such as benzyl, R 3 and R 4 independently the same groups as R A1, Ar is substituted An optionally substituted C 6-14 aryl group (eg, phenyl) or an optionally substituted C 6-14 heteroaryl group (eg, pyridyl, pyrimidinyl, oxadiazolyl), R 5a and R 5b are independently R 6 represents a group similar to R A2 or R B2, and R 6 represents a group similar to the “optionally substituted hydrocarbon group” represented by R 2 . R 6a and R 6b are independently a C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, cyclopropyl, pentyl, tert-pentyl), a C 6-14 aryl group ( Eg, phenyl) or a C 6-14 heteroaryl group (eg, pyridyl, pyrimidinyl, oxadiazolyl), Z 2 and Z 3 are independently the same groups as those exemplified as leaving groups (eg, Z 1) ).
 Pが例えば、ベンジルオキシカルボニル、ベンジルなどの場合、これら保護基は、例えばパラジウム/炭素、水酸化パラジウム/炭素などを用いた水素添加、または酸を用いることによって脱保護することができる。Pが例えばtert-ブトキシカルボニル、ベンジルオキシカルボニルなどの時、例えばトリフルオロ酢酸、塩酸などの酸を用いることによって脱保護することができる。 P a is for example, benzyloxycarbonyl, the case such as benzyl, these protecting groups are, for example, palladium / carbon, can be deprotected by using hydrogenation, or acid using a palladium hydroxide / carbon. P a, for example tert- butoxycarbonyl, when such as a benzyloxycarbonyl, can be deprotected by using for example trifluoroacetic acid, an acid such as hydrochloric acid.
 化合物(I-1)は、例えば、カップリング試薬(例、トリホスゲン、CDI(1,1’-カルボニルジイミダゾール))を用いて、アルコール(ROH)と化合物(V)とを、通常、塩基の存在下でカップリングさせるか、または、クロロギ酸エステル(ROCOCl)を用いて化合物(V)をアシル化することによって製造できる。 Compound (I-1) is usually prepared by using, for example, a coupling reagent (eg, triphosgene, CDI (1,1′-carbonyldiimidazole)) to produce alcohol (R 3 OH) and compound (V). It can be prepared by coupling in the presence of a base or by acylating compound (V) with chloroformate (R 3 OCOCl).
 化合物(I-2)は、例えば、4-(4,6-ジメトキシ-1,3,5-トリアジン-
2-イル)-4-メチル-モルホリニウムクロリド、1-エチル-3-ジメチルアミノプ
ロピルカルボジイミド、2-メチル-6-ニトロ安息香酸無水物などのカップリング試薬を用いて、カルボン酸(RCOOH)と化合物(V)とを、必要に応じて塩基の存在下でカップリングさせるか、または、アシルクロリド(RCOCl)を用いて化合物(V)をアシル化することによって製造できる。
Compound (I-2) is, for example, 4- (4,6-dimethoxy-1,3,5-triazine-
Using a coupling reagent such as 2-yl) -4-methyl-morpholinium chloride, 1-ethyl-3-dimethylaminopropylcarbodiimide, 2-methyl-6-nitrobenzoic anhydride, the carboxylic acid (R 4 COOH) and compound (V) can be coupled in the presence of a base, if necessary, or can be prepared by acylating compound (V) with acyl chloride (R 4 COCl).
 化合物(I-3)は、例えば、ハロゲン化アリールまたはアリールスルホナート(Ar-Z)と化合物(V)とを、通常、塩基の存在下、必要に応じてパラジウム触媒や銅触媒と適切な配位子の存在させる自体公知の方法(例えば、オーガニックレターズ(Org.Lett.)第2巻、1101頁(2000年)、ジャーナルオブザアメリカンケミカルソシエティ(J.Am.Chem.Soc.)第128巻、8742頁(2006年)またはオーガニックプロセスリサーチアンドディベロップメント(Org.Process Res.Dev.)第12巻、480頁(2008年)などに記載の方法あるいはこれに準じた方法等)で、カップリングさせることによって製造できる。 Compound (I-3) is, for example, an aryl halide or aryl sulfonate (Ar—Z 2 ) and compound (V), usually in the presence of a base and appropriately with a palladium catalyst or a copper catalyst as necessary. A method known per se in the presence of a ligand (for example, Organic Letters (Org. Lett.) Vol. 2, p. 1101 (2000), Journal of the American Chemical Society (J. Am. Chem. Soc.), No. 128. Vol. 8742 (2006) or Organic Process Research and Development (Org. Process Res. Dev.) Vol. 12, 480 (2008), etc. Can be manufactured by ringing.
 化合物(I-4)は、例えば、カップリング試薬(例、トリホスゲン、CDI(1,1’-カルボニルジイミダゾール))を用いて、アミン(R5a5bNH)と化合物(V)とを、通常、塩基の存在下でカップリングさせるか、または、カルバモイルクロリド(R5a5bNCOCl)を用いて化合物(V)をアシル化することによって製造できる。 Compound (I-4) is prepared by, for example, using a coupling reagent (eg, triphosgene, CDI (1,1′-carbonyldiimidazole)) to convert amine (R 5a R 5b NH) and compound (V) Usually, it can be prepared by coupling in the presence of a base or acylating compound (V) with carbamoyl chloride (R 5a R 5b NCOCl).
 化合物(I-5a)は、例えば、アルキルハライドまたはアルキルスルホナート(R-Z)および塩基を用いて化合物(V)をアルキル化することによって製造できる。
 化合物(I-5b)は、例えば、アルデヒドまたはケトン(R6a-CO-R6b)および適当な還元剤(例えば、トリアセトキシ水素化ホウ素ナトリウム、ピコリン-ボラン錯体など)を用いて化合物(V)の還元アミノ化を行うことによって製造できる。
Compound (I-5a) can be produced, for example, by alkylating compound (V) with an alkyl halide or alkyl sulfonate (R 6 -Z 3 ) and a base.
Compound (I-5b) is prepared, for example, by using aldehyde or ketone (R 6a -CO—R 6b ) and a suitable reducing agent (for example, sodium triacetoxyborohydride, picoline-borane complex, etc.) It can manufacture by performing reductive amination of.
 なお、化合物(Ia)は前記したスキーム1または後述するスキーム8~11に示した方法、またはこれらに準ずる方法によって製造することができる。 Compound (Ia) can be produced by the method shown in the above-mentioned scheme 1 or schemes 8 to 11 described later, or a method analogous thereto.
[スキーム3] [Scheme 3]
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
 化合物(II)のRが水素である化合物(II-1)、アルキルチオ基である化合物(II-2)、アルキルスルフィニル基である化合物(II-3)、およびアルキルスルホニル基である化合物(II-4)は、例えばスキーム3に示した、化合物(II-1a)を原料とする方法、またはこれらに準ずる方法に従って製造することができる。ここで、Pは例えば、tert-ブトキシカルボニル、ベンジルオキシカルボニル、ベンジルなどのアミノ基の保護基を、RはRA1と同様の基を、Zは脱離基(例、Zとして例示したものと同様の基)を示す。 Compound (II-1) in which R 1 of compound (II) is hydrogen, Compound (II-2) that is an alkylthio group, Compound (II-3) that is an alkylsulfinyl group, and Compound (II) that is an alkylsulfonyl group -4) can be produced, for example, according to the method shown in scheme 3 using compound (II-1a) as a raw material or a method analogous thereto. Here, P b is an amino-protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, etc., R 7 is the same group as R A1 , Z 4 is a leaving group (eg, Z 1 The same groups as illustrated).
 化合物(II-1)は、例えば、化合物(II-1a)に、適当な還元剤(例えば、シアノ水素化ホウ素ナトリウム-酢酸、トリエチルシラン-トリフルオロ酢酸など)を作用させるか、または、パラジウム/炭素、水酸化パラジウム/炭素などを用いた接触還元などの条件に付すことによって、製造することができる。 Compound (II-1) can be obtained, for example, by reacting compound (II-1a) with a suitable reducing agent (for example, sodium cyanoborohydride-acetic acid, triethylsilane-trifluoroacetic acid, etc.) or palladium / It can be produced by subjecting it to conditions such as catalytic reduction using carbon, palladium hydroxide / carbon and the like.
 化合物(II-2)は、例えば、化合物(II-1)に対し、臭素およびチオシアン酸カリウムを作用させ、ついで、水酸化ナトリウム水溶液などの塩基を作用させ、ついでアルキルハライドまたはアルキルスルホナート(R-Z)を作用させることによって製造できる。 In the compound (II-2), for example, bromine and potassium thiocyanate are allowed to act on the compound (II-1), followed by a base such as an aqueous sodium hydroxide solution, and then an alkyl halide or an alkyl sulfonate (R 7- Z 4 ) can be produced.
 化合物(II-2a)は、Pが例えば、ベンジルオキシカルボニル、tert-ブトキシカルボニル、ベンジルオキシカルボニルなどの場合、化合物(II-2)に対し、通常、ピリジン、トリエチルアミンまたはN,N’-ジメチルアミノピリジンなどの塩基存在下、Pに対応するクロロギ酸エステルやジ炭酸ジエステルなどを作用させることによって製造することができる。 Compound (II-2a) is usually pyridine, triethylamine or N, N′-dimethyl relative to compound (II-2) when P b is, for example, benzyloxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl or the like. presence of a base such as aminopyridine, may be prepared by the action of such chloroformate esters and di carbonic acid diester corresponding to P b.
 化合物(II-3)および化合物(II-4)は、化合物(II-2a)に対し、メタクロロ安息香過酸、過酸化水素、などの酸化剤を作用させ、スキーム2に示したPの脱保護と同様にしてPを脱保護することによって製造することができる。 The compound (II-3) and compound (II-4), relative to the compound (II-2a), meta benzoic peracid, by the action of an oxidizing agent hydrogen peroxide, etc., for P a shown in Scheme 2 de It may be prepared by deprotection of P b protection and in the same manner.
 なお、化合物(II-1a)は、自体公知の方法に従って製造することができる。 Compound (II-1a) can be produced according to a method known per se.
[スキーム4] [Scheme 4]
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
 化合物(II)は、例えばスキーム4に示したように、化合物(II-a)に対し、スキーム3で示した化合物(II-1a)から、化合物(II-1)への還元と同様の方法、またはこれに準ずる方法に従って製造することができる。 Compound (II) is a method similar to the reduction of compound (II-1a) from compound (II-1a) shown in scheme 3 to compound (II-1) as shown in scheme 4, for example. Or according to a method equivalent thereto.
 なお、化合物(II-a)は、自体公知の方法に従って製造することができる。 Compound (II-a) can be produced according to a method known per se.
[スキーム5] [Scheme 5]
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
 化合物(III)のX-X-Xが-CHCHR9a-である化合物(III-1)、-CR9b9bCHR9a-である化合物(III-2)、-CHR9cCHR9a-である化合物(III-3)は、例えばスキーム5に示したように、化合物(III-1a)を原料化合物とする方法、またはこれらに準ずる方法に従って製造することができる。ここで、R8aはC1-6アルキル基(例、メチル、エチル、tert-ブチル)またはC7-10アラルキル基(例、ベンジル)を、R9aは、C1-6アルキル基(例、メチル、エチル、tert-ブチル)、C1-6アルコキシ基(例、メトキシ、エトキシ、イソプロポキシ)または置換されていてもよいアミノ基(例、アセチルアミノ、ベンジルオキシアミノ、tert-ブトキシカルボニルアミノ)を、R9ba、R9bbおよびR9cは独立して、置換されていてもよいC1-6アルキル基(例、メチル、エチル、プロピル、イソプロピル、トリフルオロメチル)を示す。 Compound (III- 1 ) in which X 1 -X 2 -X 3 of Compound (III) is —CH 2 CHR 9a —, Compound (III-2) in which —CR 9b R 9b CHR 9a — is —CHR 9c CHR 9a - a is compound (III-3), for example as shown in scheme 5, it can be prepared according to a method analogous compound (III-1a) a method for the starting compounds or to,. Here, R 8a is a C 1-6 alkyl group (eg, methyl, ethyl, tert-butyl) or C 7-10 aralkyl group (eg, benzyl), and R 9a is a C 1-6 alkyl group (eg, benzyl). Methyl, ethyl, tert-butyl), C 1-6 alkoxy group (eg, methoxy, ethoxy, isopropoxy) or an optionally substituted amino group (eg, acetylamino, benzyloxyamino, tert-butoxycarbonylamino) R 9ba , R 9bb and R 9c independently represent an optionally substituted C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, trifluoromethyl).
 化合物(III-1c)は、化合物(III-1a)を自体公知の条件、例えば、ケミカルレビュー(Chem.Rev.)第89巻、863頁(1989年)などに記載の方法あるいはこれに準じた方法等で増炭して化合物(III-1b)とし、ついで接触還元(例、水素-パラジウム/炭素、水素-酸化白金、水素-水酸化パラジウム/炭素、水素-パラジウム/炭素エチレンジアミン錯体)などの条件で還元を行うこと製造することがで
きる。
Compound (III-1c) was obtained by subjecting compound (III-1a) to conditions known per se, for example, the method described in Chemical Review (Chem. Rev.), 89, 863 (1989) or the like. The carbon is increased by a method to obtain the compound (III-1b), and then catalytic reduction (eg, hydrogen-palladium / carbon, hydrogen-platinum oxide, hydrogen-palladium hydroxide / carbon, hydrogen-palladium / carbon ethylenediamine complex), etc. It can manufacture by reducing on condition.
 化合物(III-1)は、化合物(III-1c)に対し、適当な還元剤(例えば、水素化ホウ素ナトリウム、水素化ホウ素ナトリウム-塩化カルシウム、水素化ホウ素ナトリウム-塩化リチウム、水素化アルミニウムリチウムなど)を作用させることで製造することができる。 Compound (III-1) is an appropriate reducing agent (for example, sodium borohydride, sodium borohydride-calcium chloride, sodium borohydride-lithium chloride, lithium aluminum hydride, etc.) relative to compound (III-1c) ) Can be produced.
 化合物(III-2)は、化合物(III-1c)に対し、R9bに対応する有機金属試薬(例えば、グリニャール反応剤またはアルキルリチウム試薬など)を作用させることで製造することができる。 Compound (III-2) can be produced by reacting compound (III-1c) with an organometallic reagent corresponding to R 9b (eg, a Grignard reagent or an alkyl lithium reagent).
 化合物(III-3)は、例えば、化合物(III-1)から製造した化合物(III-3a)に対し、R9cに対応する有機金属試薬(例えば、グリニャール反応剤またはアルキルリチウム試薬など)を作用させることで製造することができる。また、R9cがトリフルオロメチルの場合、例えば、ジャーナルオブザアメリカンケミカルソシエティ(J.Am.Chem.Soc.)第111巻、393頁(1989年)などに記載の方法、あるいはこれに準じた方法等によって製造することができる。化合物(III-3)の原料化合物である化合物(III-3a)は、化合物(III-1)を、自体公知の条件、例えば、ジャーナルオブオーガニックケミストリー(J.Org.Chem.)第48巻、4155頁(1983年)またはシンセシス(Synthesis) 639頁 (1994年)などに記載の方法あるいはこれらに準じた方法等によって酸化することで製造することができる。 Compound (III-3), for example, acts on compound (III-3a) produced from compound (III-1) with an organometallic reagent corresponding to R 9c (eg, Grignard reagent or alkyllithium reagent). Can be manufactured. When R 9c is trifluoromethyl, for example, the method described in Journal of the American Chemical Society, Vol. 111, page 393 (1989), or the like It can be manufactured by a method or the like. Compound (III-3a), which is a starting compound of compound (III-3), is obtained by subjecting compound (III-1) to conditions known per se, for example, Journal of Organic Chemistry (J. Org. Chem.) Vol. 48, It can be produced by oxidation by the method described in page 4155 (1983) or synthesis page 639 (1994), or a method analogous thereto.
 なお、化合物(III-1a)は、自体公知の方法に従って製造することができる。 Compound (III-1a) can be produced according to a method known per se.
[スキーム6] [Scheme 6]
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
 化合物(III)のX-X-Xが、-CHCHCHR9d-である化合物(III-4)、-CR9e9eCHCHR9d-である化合物(III-5)および-CHR9eCHCHR9d-である化合物(III-6)は、例えばスキーム6に示したように、化合物(III-4a)から製造できる化合物(III-4c)を原料化合物として、スキーム5と同様の方法、またはこれらに準ずる方法に従って製造することができる。ここで、R8bはR8aと同様の基を、R9dはR9aと同様の基を、R9ea、R9ebおよびR9fは独立して、R9bおよびR9cと同様の基を示す。 Compound (III-4) in which X 1 -X 2 -X 3 of Compound (III) is —CH 2 CH 2 CHR 9d —, Compound (III-5) in which —CR 9e R 9e CH 2 CHR 9d — Compound (III-6), which is —CHR 9e CH 2 CHR 9d —, is prepared by using, as a starting compound, Compound (III-4c) that can be produced from Compound (III-4a) as shown in Scheme 6, for example. It can be produced according to a method similar to or a method analogous thereto. Here, R 8b represents the same group as R 8a , R 9d represents the same group as R 9a, and R 9ea , R 9eb and R 9f independently represent the same groups as R 9b and R 9c .
 化合物(III-4b)は、自体公知の条件、例えば、カップリング試薬(例、CDI(1,1’-カルボニルジイミダゾール)、1-エチル-3-ジメチルアミノプロピルカルボジイミドなど)を用いて、化合物(III-4a)とN,O-ジメチルヒドロキシルアミンとを、通常、塩基の存在下でカップリングさせることによって製造できる。化合物(III-4c)は、自体公知の条件、例えば、テトラヘドロンレターズ(Tetrahedron Let.)第22巻、3815頁(1981年)などに記載の方法あるいはこれに準じた方法等によって、化合物(III-4b)から製造できる。 Compound (III-4b) can be obtained by using conditions known per se, for example, a coupling reagent (eg, CDI (1,1′-carbonyldiimidazole), 1-ethyl-3-dimethylaminopropylcarbodiimide, etc.) (III-4a) and N, O-dimethylhydroxylamine can be usually produced by coupling in the presence of a base. Compound (III-4c) can be produced by a method known per se, for example, the method described in Tetrahedron Letters Vol. 22, p. 3815 (1981) or the like or a method analogous thereto. -4b).
 なお、化合物(III-4a)は、自体公知の方法に従って製造することができる。 Compound (III-4a) can be produced according to a method known per se.
[スキーム7] [Scheme 7]
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
 化合物(III)のX-Xが-CHCHR102a-である化合物(III-7)は、例えばスキーム7に示した方法、またはこれらに準ずる方法に従って製造することができる。
ここで、X2aは、置換されていても良いNH、S、SO、SOまたはOを、R8cはR8aと同様の基を、R10はR9aと同様の基を、Zは脱離基(例、Zとして例示したものと同様の基)を示す。
Compound (III-7) wherein X 1 -X 2 of compound (III) is —CH 2 CHR 10 X 2a — can be produced, for example, according to the method shown in Scheme 7 or a method analogous thereto.
Here, X 2a represents optionally substituted NH, S, SO, SO 2 or O, R 8c represents the same group as R 8a , R 10 represents the same group as R 9a, and Z 5 represents A leaving group (eg, a group similar to that exemplified as Z 1 ) is shown.
 化合物(III-7b)は、自体公知の条件、例えば、化合物(III-7a)を、通常、塩基の存在下で、エステル(R10CHZCOOR7c)を用いてアルキル化することによって製造できる。化合物(III-7)は、例えば、スキーム5で示した、化合物(III-1c)から化合物(III-1)を製造する方法と同様の方法等によって製造できる。 Compound (III-7b) can be produced under conditions known per se, for example, by alkylating compound (III-7a) with an ester (R 10 CHZ 5 COOR 7c ) usually in the presence of a base. . Compound (III-7) can be produced, for example, by a method similar to the method for producing compound (III-1) from compound (III-1c) shown in Scheme 5.
 なお、化合物(III-7a)は、自体公知の方法に従って製造することができる。 Compound (III-7a) can be produced according to a method known per se.
[スキーム8] [Scheme 8]
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
 化合物(I)のX-XがNHである化合物(I-6)、NR11である化合物(I-7)は、例えばスキーム8に示した方法、またはこれらに準ずる方法に従って製造することができる。ここで、Pは例えば、tert-ブトキシカルボニル、ベンジルオキシカルボニル、ベンジルなどのアミノ基の保護基を、R11はアミノ基の置換基(例えば、Xで示される「置換されていてもよいNH」における置換基として例示したものと同様の基)を示す。 Compound (I-6) in which X 2 -X 3 of Compound (I) is NH and Compound (I-7) in which NR 11 is NR 11 should be produced, for example, according to the method shown in Scheme 8 or a method analogous thereto. Can do. Here, P c is an amino-protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, etc., and R 11 is an amino group substituent (for example, “optionally substituted” represented by X 2 And the same groups as those exemplified as the substituent in “NH”.
 化合物(VII)は、例えば、スキーム1で示した方法と同様の方法、またはこれらに準ずる方法に従って製造することができる。化合物(VIII)は、スキーム2に示したPの脱保護と同様にして、化合物(VII)の保護基Pを脱保護することによって製造することができる。化合物(I-6)は、例えば、化合物(VIII)と化合物(III-1a)を、適当な還元剤(例えば、トリアセトキシ水素化ホウ素ナトリウム、ピコリン-ボラン錯体、水素-パラジウム/炭素など)を用いて還元アミノ化を行うことによっ
て製造できる。化合物(I-7)は、化合物(I-6)を原料化合物として、スキーム2で示した化合物(V)から、化合物(I-1)、化合物(I-2)、化合物(I-3)、化合物(I-4)および化合物(I-5)を製造する方法と同様の方法、またはこれらに準ずる方法に従ってR11を導入することで、製造することができる。
Compound (VII) can be produced, for example, according to the same method as shown in scheme 1 or a method analogous thereto. Compound (VIII), in the same manner as the deprotection of P a shown in Scheme 2, a protecting group P c of the compound (VII) can be prepared by deprotecting. Compound (I-6) is prepared, for example, by combining compound (VIII) and compound (III-1a) with an appropriate reducing agent (for example, sodium triacetoxyborohydride, picoline-borane complex, hydrogen-palladium / carbon, etc.). It can manufacture by performing reductive amination using. Compound (I-7) is compound (I-1), compound (I-2), compound (I-3) from compound (V) shown in scheme 2 using compound (I-6) as a starting compound. The compound can be produced by introducing R 11 according to a method similar to the method for producing the compound (I-4) and the compound (I-5) or a method analogous thereto.
 なお、化合物(II)は前記したスキーム3~4に示した方法、または自体公知の方法、あるいはこれらに準ずる方法によって製造することができる。 Compound (II) can be produced by the methods shown in the above-mentioned schemes 3 to 4, or a method known per se, or a method analogous thereto.
[スキーム9] [Scheme 9]
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
 化合物(I)のXがX2bである化合物(I-8)は、例えばスキーム9に示した方法、またはこれらに準ずる方法に従って製造することができる。ここで、X2bは、置換されていてもよいNH、S、SO、SOまたはOを、Zは脱離基(例、Zとして例示したものと同様の基)を、それぞれ示す。 Compound (I-8) wherein X 2 of compound (I) is X 2b can be produced, for example, according to the method shown in Scheme 9 or a method analogous thereto. Here, X 2b represents optionally substituted NH, S, SO, SO 2 or O, and Z 6 represents a leaving group (eg, the same group as exemplified as Z 1 ).
 化合物(X)は、例えば、スキーム1で示した方法と同様の方法、またはこれらに準ずる方法に従って製造することができる。化合物(I-8)は、例えば、化合物(XI)を、通常、塩基(例、水素化ナトリウム、カリウムtert-ブトキシド)の存在下で、化合物(X)を用いてアルキル化することによって製造することができる。 Compound (X) can be produced, for example, according to a method similar to the method shown in Scheme 1 or a method analogous thereto. Compound (I-8) is produced, for example, by alkylating compound (XI) with compound (X) usually in the presence of a base (eg, sodium hydride, potassium tert-butoxide). be able to.
 なお、化合物(II)は前記したスキーム3~4に示した方法、または自体公知の方法、あるいはこれらに準ずる方法によって製造することができる。 Compound (II) can be produced by the methods shown in the above-mentioned schemes 3 to 4, or a method known per se, or a method analogous thereto.
[スキーム10] [Scheme 10]
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
 化合物(I)のRがCOOR8dである化合物(I-9)、COOHである化合物(I-10)およびCONR12a12bである化合物(I-11)は、例えばスキーム10に示した方法、またはこれらに準ずる方法に従って製造することができる。ここで、R8dはR8aと同様の基を、R12aおよびR12bは独立して、RA2またはRB2と同様の基を示す。 The compound (I-9) in which R 1 of the compound (I) is COOR 8d , the compound (I-10) in which COOH is COOH, and the compound (I-11) in which CONR 12a R 12b is used can be prepared, for example, by the method shown in Scheme 10. Or according to a method according to these methods. Here, R 8d represents the same group as R 8a, and R 12a and R 12b independently represent the same group as R A2 or R B2 .
 化合物(I-10)は、例えば、化合物(I-9)を、塩基(例、水酸化カリウム水溶液、水酸化ナトリウム水溶液、水酸化リチウム水溶液)または酸(例、塩酸、硫酸)によって加水分解することで製造することができる。化合物(I-11)は、化合物(I-10)およびアミン(R12a12bNH)を原料化合物として、スキーム2で示した、化合物(V)から化合物(I-2)を製造する方法と同様の方法、またはこれらに準ずる方法に従って製造することができる。 Compound (I-10) is obtained by, for example, hydrolyzing compound (I-9) with a base (eg, potassium hydroxide aqueous solution, sodium hydroxide aqueous solution, lithium hydroxide aqueous solution) or an acid (eg, hydrochloric acid, sulfuric acid). Can be manufactured. Compound (I-11) is a method for producing compound (I-2) from compound (V) shown in Scheme 2 using compound (I-10) and amine (R 12a R 12b NH) as starting compounds. It can be produced according to a similar method or a method analogous thereto.
 なお、化合物(I-9)は、前記したスキーム1~2、スキーム8~9または後述するスキーム13~15に示した方法、またはこれらに準ずる方法によって製造することができる。 Compound (I-9) can be produced by the methods shown in the above-mentioned schemes 1 and 2, schemes 8 to 9, or schemes 13 to 15 described later, or a method analogous thereto.
[スキーム11] [Scheme 11]
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
 化合物(I)のRがSONR13a13bである化合物(I-12)は、例えばスキーム11に示した方法、またはこれらに準ずる方法に従って製造することができる。ここで、R13aおよびR13bは独立して、RA2またはRB2と同様の基を示す。 Compound (I-12) wherein R 1 of compound (I) is SO 2 NR 13a R 13b can be produced, for example, according to the method shown in Scheme 11 or a method analogous thereto. Here, R 13a and R 13b independently represent the same group as R A2 or R B2 .
 化合物(I-12a)は、例えば、化合物(XII)に、クロロスルホン酸を作用させることで製造することができる。化合物(I-12)は、化合物(I-12a)にアミン(R13a13bNH)を作用させ、得られた化合物を、スキーム2で示した、化合物(V)から化合物(I-1)、化合物(I-2)、化合物(I-3)、化合物(I-4)および化合物(I-5)を製造する方法と同様の方法、またはこれらに準ずる方法に従ってRを導入することで、製造することができる。 Compound (I-12a) can be produced, for example, by reacting compound (XII) with chlorosulfonic acid. Compound (I-12) was prepared by reacting compound (I-12a) with an amine (R 13a R 13b NH) and converting the resulting compound from compound (V) to compound (I-1) shown in Scheme 2. Introducing R 2 according to a method similar to the method for producing Compound (I-2), Compound (I-3), Compound (I-4) and Compound (I-5), or a method analogous thereto Can be manufactured.
 なお、化合物(XII)は、前記したスキーム1~2、スキーム8~9または後述するスキーム13~15に示した方法、またはこれらに準ずる方法によって製造することができる。 Compound (XII) can be produced by the methods shown in the above-mentioned schemes 1 and 2, schemes 8 to 9, or schemes 13 to 15 described later, or a method analogous thereto.
[スキーム12] [Scheme 12]
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
 化合物(I)のRがR14a14bNである化合物(I-14)は、例えばスキーム12に示した方法、またはこれらに準ずる方法に従って製造することができる。ここで、R14aおよびR14bは、RA2またはRB2と同様の基を、Zは脱離基(例、ハロゲン原子または-OSOCF、-OSO(4-トリル)など)を示す。 Compound (I-14) wherein R 1 of compound (I) is R 14a R 14b N can be produced, for example, according to the method shown in Scheme 12 or a method analogous thereto. Here, R 14a and R 14b are the same groups as R A2 or R B2, and Z 7 is a leaving group (eg, a halogen atom or —OSO 2 CF 3 , —OSO 2 (4-tolyl), etc.). Show.
 化合物(I-14)は、例えば、化合物(I-13)とアミン化合物(R14a14bNH)とを、通常、塩基の存在下、パラジウム触媒や銅触媒と適切な配位子の存在下カップリングさせる自体公知の方法(例えば、オーガニックレターズ(Org.Lett.)第2巻、1101頁(2000年)、ジャーナルオブザアメリカンケミカルソシエティ(J.Am.Chem.Soc.)第128巻、8742頁(2006年)またはオーガニックプロセスリサーチアンドディベロップメント(Org.Process Res.Dev.)第12巻、480頁(2008年)などに記載の方法あるいはこれらに準じた方法等)で、カップリングさせることによって製造することができる。 Compound (I-14) is prepared by, for example, compound (I-13) and an amine compound (R 14a R 14b NH) usually in the presence of a base, in the presence of a palladium catalyst or a copper catalyst, and an appropriate ligand. A method known per se (for example, Organic Letters, Vol. 2, 1101, 2000), Journal of the American Chemical Society, Vol. 128, 8742. Page (2006) or organic process research and development (Org. Process Res. Dev.) Vol. 12, page 480 (2008), etc. Can be manufactured by.
 なお、化合物(I-13)は、前記したスキーム1~2、スキーム8~9または後述するスキーム13~15に示した方法、またはこれらに準ずる方法によって製造することができる。 Compound (I-13) can be produced by the methods shown in the above-mentioned schemes 1 and 2, schemes 8 to 9, or schemes 13 to 15 described later, or a method analogous thereto.
[スキーム13] [Scheme 13]
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
 化合物(I)のRR 2 of compound (I) is
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
 である化合物(I-15)は、例えばスキーム13に示した方法、またはこれらに準ずる方法に従って製造することができる。ここで、R15は、C1-6アルキル基(例、メチル、エチル、プロピル、イソプロピル、tert-ブチル)またはC6-10アリール基(例、フェニル、ピリジル、ピリミジニル)を示す。 Compound (I-15) can be produced, for example, according to the method shown in Scheme 13 or a method analogous thereto. Here, R 15 represents a C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, tert-butyl) or a C 6-10 aryl group (eg, phenyl, pyridyl, pyrimidinyl).
 化合物(I-15)は、自体公知の方法(例えば、WO2007/061661に記載の方法あるいはこれに準じた方法等)で、化合物(XIIIa)から化合物(XIIIb)を経て化合物(XIII)を製造し、得られた化合物(XIII)と化合物(V)を反応させることで製造することができる。 Compound (I-15) is produced from compound (XIIIa) via compound (XIIIb) by a method known per se (for example, the method described in WO2007 / 061661 or a method analogous thereto). It can be produced by reacting the obtained compound (XIII) with compound (V).
 なお、化合物(V)は前記したスキーム2に示した方法、またはこれらに準ずる方法によって製造することができる。 The compound (V) can be produced by the method shown in the above-mentioned scheme 2 or a method analogous thereto.
[スキーム14] [Scheme 14]
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
 化合物(I)のRR 2 of compound (I) is
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
 である化合物(I-16)は、例えばスキーム14に示した方法、またはこれらに準ずる方法に従って製造することができる。ここで、R16はR15と同様の基を示す。 Compound (I-16) can be produced, for example, according to the method shown in Scheme 14 or a method analogous thereto. Here, R 16 represents the same group as R 15 .
 化合物(XIV)は、トリメチルシリルメチルアジドとトリフェニルホスフィンおよび二硫化炭素を反応させる自体公知の方法(例えば、ジャーナルオブオーガニックケミストリー(J.Org.Chem.)第52巻、1027頁(1987年)に記載の方法)またはこれに準じた方法等で製造することができる。化合物(I-16)は、自体公知の方法(例えば、ヘテロサイクルズ(Heterocycles)第45巻、1405頁(1997年)に記載の方法)またはこれに準じた方法等で、化合物(V)と化合物(XIV)から、化合物(I-16a)を経て製造することができる。 Compound (XIV) can be obtained by reacting trimethylsilylmethyl azide with triphenylphosphine and carbon disulfide (for example, Journal of Organic Chemistry (J. Org. Chem.) 52, 1027 (1987)). Described method) or a method similar thereto. Compound (I-16) can be synthesized with compound (V) by a method known per se (for example, the method described in Heterocycles Vol. 45, page 1405 (1997)) or a method analogous thereto. It can be produced from compound (XIV) via compound (I-16a).
 なお、化合物(V)は前記したスキーム2に示した方法、またはこれらに準ずる方法によって製造することができる。 The compound (V) can be produced by the method shown in the above-mentioned scheme 2 or a method analogous thereto.
[スキーム15] [Scheme 15]
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
 化合物(I)のRR 2 of compound (I) is
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
 である化合物(I-17)、および Compound (I-17), and
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
 である化合物(I-18)は、例えばスキーム15に示した方法、またはこれらに準ずる方法に従って製造することができる。ここで、R17はC1-6アルキル基(例、メチル、エチル、プロピル、プロピル、イソプロピル、tert-ブチル)C5-10アリール基(例、オキサジアゾリル、テトラゾリル、トリアゾリル、ピラゾリル、フェニル、ピリジル、ピリミジニル)、シアノ、またはハロゲンを、R18はRA2またはRB2と同様の基を、Zは脱離基(例、Zとして例示したものと同様の基)を示す。 Compound (I-18) can be produced, for example, according to the method shown in Scheme 15 or a method analogous thereto. Here, R 17 is a C 1-6 alkyl group (eg, methyl, ethyl, propyl, propyl, isopropyl, tert-butyl) C 5-10 aryl group (eg, oxadiazolyl, tetrazolyl, triazolyl, pyrazolyl, phenyl, pyridyl, Pyrimidinyl), cyano, or halogen, R 18 represents a group similar to R A2 or R B2, and Z 8 represents a leaving group (eg, a group similar to those exemplified as Z 1 ).
 化合物(XVI)は、例えば、化合物(XV)に対し、通常、ピリジンなどの塩基の存在下、クロロギ酸フェニルを反応させることで製造することができる。化合物(I-17)は、化合物(V)と化合物(XVI)を、通常、塩基の存在下で反応させることで製造することができる。化合物(I-18)は、化合物(R18-Z)および塩基を用いて、化合物(I-17)をアルキル化することによって製造することができる。 Compound (XVI) can be produced, for example, by reacting compound (XV) with phenyl chloroformate in the presence of a base such as pyridine. Compound (I-17) can be produced by reacting compound (V) with compound (XVI) usually in the presence of a base. Compound (I-18) can be produced by alkylating compound (I-17) with compound (R 18 -Z 7 ) and a base.
 なお、化合物(V)は前記したスキーム2に示した方法、またはこれらに準ずる方法によって製造することができる。 The compound (V) can be produced by the method shown in the above-mentioned scheme 2 or a method analogous thereto.
 前記の各反応において、原料化合物が置換基としてアミノ基、カルボキシル基、ヒドロキシ基、カルボニル基またはメルカプト基を有する場合、これらの基にペプチド化学等で一般的に用いられるような保護基が導入されていてもよく、反応後に必要に応じて保護基を除去することにより目的化合物を得ることができる。 In each of the above reactions, when the raw material compound has an amino group, carboxyl group, hydroxy group, carbonyl group or mercapto group as a substituent, a protective group generally used in peptide chemistry or the like is introduced into these groups. The target compound can be obtained by removing the protecting group as necessary after the reaction.
 アミノ基の保護基としては、例えば、ホルミル基、C1-6アルキル-カルボニル基、C1-6アルコキシ-カルボニル基、ベンゾイル基、C7-10アラルキル-カルボニル基(例、ベンジルカルボニル)、C7-14アラルキルオキシ-カルボニル基(例、ベンジルオキシカルボニル、9-フルオレニルメトキシカルボニル)、トリチル基、フタロイル基、N,N-ジメチルアミノメチレン基、置換シリル基(例、トリメチルシリル、トリエチルシリル、ジメチルフェニルシリル、tert-ブチルジメチルシリル、tert-ブチルジエチルシリル)、C2-6アルケニル基(例、1-アリル)等が挙げられる。これらの基は、ハロゲン原子、C1-6アルコキシ基およびニトロ基から選ばれる1ないし3個の置換基で置換されていてもよい。 Examples of the protecting group for amino group include formyl group, C 1-6 alkyl-carbonyl group, C 1-6 alkoxy-carbonyl group, benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), C 7-14 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), trityl group, phthaloyl group, N, N-dimethylaminomethylene group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, Dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl groups (eg, 1-allyl) and the like. These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkoxy group and a nitro group.
 カルボキシル基の保護基としては、例えば、C1-6アルキル基、C7-11アラルキル基(例、ベンジル)、フェニル基、トリチル基、置換シリル基(例、トリメチルシリル、トリエチルシリル、ジメチルフェニルシリル、tert-ブチルジメチルシリル、tert-ブチルジエチルシリル)、C2-6アルケニル基(例、1-アリル)等が挙げられる。これらの基は、ハロゲン原子、C1-6アルコキシ基およびニトロ基から選ばれる1ないし3個の置換基で置換されていてもよい。 Examples of the protecting group for the carboxyl group include a C 1-6 alkyl group, a C 7-11 aralkyl group (eg, benzyl), a phenyl group, a trityl group, a substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl groups (eg, 1-allyl) and the like. These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkoxy group and a nitro group.
 ヒドロキシ基の保護基としては、例えば、C1-6アルキル基、フェニル基、トリチル基、C7-10アラルキル基(例、ベンジル)、ホルミル基、C1-6アルキル-カルボニル基、ベンゾイル基、C7-10アラルキル-カルボニル基(例、ベンジルカルボニル)、2-テトラヒドロピラニル基、2-テトラヒドロフラニル基、置換シリル基(例、トリメチルシリル、トリエチルシリル、ジメチルフェニルシリル、tert-ブチルジメチルシリル、tert-ブチルジエチルシリル)、C2-6アルケニル基(例、1-アリル)等が挙げられる。これらの基は、ハロゲン原子、C1-6アルキル基、C1-6アルコキシ基またはニトロ基から選ばれる1ないし3個の置換基で置換されていてもよい。 Examples of the protecting group for the hydroxy group include a C 1-6 alkyl group, a phenyl group, a trityl group, a C 7-10 aralkyl group (eg, benzyl), a formyl group, a C 1-6 alkyl-carbonyl group, a benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert -Butyldiethylsilyl), C 2-6 alkenyl group (eg, 1-allyl) and the like. These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group or a nitro group.
 カルボニル基の保護基としては、例えば、環状アセタール(例、1,3-ジオキサン)、非環状アセタール(例、ジ-C1-6アルキルアセタール)等が挙げられる。 Examples of the protecting group for the carbonyl group include cyclic acetals (eg, 1,3-dioxane), acyclic acetals (eg, di-C 1-6 alkylacetal) and the like.
 メルカプト基の保護基としては、例えば、C1-6アルキル基、フェニル基、トリチル基、C7-10アラルキル基(例、ベンジル)、C1-6アルキル-カルボニル基、ベンゾイル基、C7-10アラルキル-カルボニル基(例、ベンジルカルボニル)、C1-6アルコキシ-カルボニル基、C6-14アリールオキシ-カルボニル基(例、フェニルオキシカルボニル)、C7-14アラルキルオキシ-カルボニル基(例、ベンジルオキシカルボニル、9-フルオレニルメトキシカルボニル)、2-テトラヒドロピラニル基、C1-6アルキルアミノ-カルボニル基(例、メチルアミノカルボニル、エチルアミノカルボニル)等が挙げられる。これらの基は、ハロゲン原子、C1-6アルキル基、C1-6アルコキシ基またはニトロ基から選ばれる1ないし3個の置換基で置換されていてもよい。 Examples of the protecting group for the mercapto group include a C 1-6 alkyl group, a phenyl group, a trityl group, a C 7-10 aralkyl group (eg, benzyl), a C 1-6 alkyl-carbonyl group, a benzoyl group, a C 7- 10 aralkyl-carbonyl group (eg, benzylcarbonyl), C 1-6 alkoxy-carbonyl group, C 6-14 aryloxy-carbonyl group (eg, phenyloxycarbonyl), C 7-14 aralkyloxy-carbonyl group (eg, Benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), 2-tetrahydropyranyl group, C 1-6 alkylamino-carbonyl group (eg, methylaminocarbonyl, ethylaminocarbonyl) and the like. These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group or a nitro group.
 上記した保護基の除去方法は、自体公知の方法、例えば、プロテクティブ グループス イン オーガニック シンセシス(Protective Groups in Organic Synthesis)、John Wiley and Sons刊(1980)に記載の方法等に準じて行うことができる。具体的には、酸、塩基、紫外光、ヒドラジン、フェニルヒドラジン、N-メチルジチオカルバミン酸ナトリウム、テトラブチルアンモニウムフルオリド、酢酸パラジウム、トリアルキルシリルハライド(例、トリメチルシ
リルヨージド、トリメチルシリルブロミド)等を使用する方法、還元法等が挙げられる。
The method for removing the protecting group described above can be carried out according to a method known per se, for example, the method described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (1980). . Specifically, acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (eg, trimethylsilyl iodide, trimethylsilyl bromide), etc. are used. And a reduction method.
 上記の各製造法により得られる本発明化合物は、濃縮、減圧濃縮、溶媒抽出、晶出、再結晶、転溶、クロマトグラフィー等の公知の手段により単離精製することができる。また、上記の各製造法において用いられる各原料化合物は、前記と同様の公知の手段によって単離精製することができる。一方、これら原料化合物を単離することなく、そのまま反応混合物として、次の工程の原料として用いてもよい。 The compound of the present invention obtained by each of the above production methods can be isolated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolution, chromatography and the like. Moreover, each raw material compound used in each of the above production methods can be isolated and purified by the same known means as described above. On the other hand, you may use these raw material compounds as a reaction mixture as it is as a raw material for the next step without isolation.
 化合物(I)が、光学異性体、立体異性体、位置異性体、回転異性体を含有する場合には、これらも化合物(I)として含有されるとともに、自体公知の合成手法、分離手法によりそれぞれを単品として得ることができる。例えば、化合物(I)に光学異性体が存在する場合には、該化合物から分割された光学異性体も化合物(I)に包含される。 When compound (I) contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compound (I), and are synthesized by known synthesis methods and separation methods, respectively. Can be obtained as a single product. For example, when compound (I) has an optical isomer, the optical isomer resolved from the compound is also encompassed in compound (I).
 化合物(I)は、結晶であってもよい。
 化合物(I)の結晶(以下、本発明の結晶と略記することがある)は、化合物(I)に自体公知の結晶化法を適用して、結晶化することによって製造することができる。
 本明細書中、融点は、例えば、微量融点測定器(ヤナコ、MP-500D型またはBuchi、B-545型)またはDSC(示差走査熱量分析)装置(SEIKO、EXSTAR6000)等を用いて測定される融点を意味する。
 一般に、融点は、測定機器、測定条件等によって変動する場合がある。本明細書中の結晶は、通常の誤差範囲内であれば、本明細書に記載の融点と異なる値を示す結晶であってもよい。
 本発明の結晶は、物理化学的性質(例、融点、溶解度、安定性)および生物学的性質(例、体内動態(吸収性、分布、代謝、排泄)、薬効発現)に優れ、医薬として極めて有用である。
Compound (I) may be a crystal.
Crystals of compound (I) (hereinafter sometimes abbreviated as crystals of the present invention) can be produced by crystallization by applying a crystallization method known per se to compound (I).
In the present specification, the melting point is measured using, for example, a trace melting point measuring device (Yanako, MP-500D type or Buchi, B-545 type) or a DSC (differential scanning calorimetry) apparatus (SEIKO, EXSTAR6000). Mean melting point.
In general, the melting point may vary depending on measurement equipment, measurement conditions, and the like. The crystal in the present specification may be a crystal exhibiting a value different from the melting point described in the present specification as long as it is within a normal error range.
The crystals of the present invention are excellent in physicochemical properties (eg, melting point, solubility, stability) and biological properties (eg, pharmacokinetics (absorbability, distribution, metabolism, excretion), expression of medicinal properties), and are extremely useful as pharmaceuticals. Useful.
 化合物(I)またはそのプロドラッグ(以下、単に本発明化合物と略記することがある)は、毒性が低く、そのまま、または薬理学的に許容し得る担体等と混合して医薬組成物とすることにより、哺乳動物(例、ヒト、マウス、ラット、ウサギ、イヌ、ネコ、ウシ、ウマ、ブタ、サル)に対して、後述する各種疾患の予防または治療剤として用いることができる。 Compound (I) or a prodrug thereof (hereinafter, sometimes simply abbreviated as the compound of the present invention) has low toxicity and should be used as it is or mixed with a pharmacologically acceptable carrier to form a pharmaceutical composition. Thus, it can be used as a preventive or therapeutic agent for various diseases described below for mammals (eg, humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys).
 ここで、薬理学的に許容し得る担体としては、製剤素材として慣用の各種有機あるいは無機担体物質が用いられ、固形製剤における賦形剤、滑沢剤、結合剤、崩壊剤;液状製剤における溶剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤、無痛化剤等として配合される。また必要に応じて、防腐剤、抗酸化剤、着色剤、甘味剤等の製剤添加物を用いることもできる。 Here, as the pharmacologically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations , Solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents and the like. If necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.
 賦形剤の好適な例としては、乳糖、白糖、D-マンニトール、D-ソルビトール、デンプン、α化デンプン、デキストリン、結晶セルロース、低置換度ヒドロキシプロピルセルロース、カルボキシメチルセルロースナトリウム、アラビアゴム、プルラン、軽質無水ケイ酸、合成ケイ酸アルミニウム、メタケイ酸アルミン酸マグネシウムが挙げられる。 Preferable examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light Examples thereof include anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminate metasilicate.
 滑沢剤の好適な例としては、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、コロイドシリカが挙げられる。 Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc and colloidal silica.
 結合剤の好適な例としては、α化デンプン、ショ糖、ゼラチン、アラビアゴム、メチルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム、結晶セルロース、白糖、D-マンニトール、トレハロース、デキストリン、プルラン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドンが挙げられる。 Preferred examples of the binder include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxy Examples include propylmethylcellulose and polyvinylpyrrolidone.
 崩壊剤の好適な例としては、乳糖、白糖、デンプン、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム、軽質無水ケイ酸、低置換度ヒドロキシプロピルセルロースが挙げられる。 Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, and low-substituted hydroxypropyl cellulose.
 溶剤の好適な例としては、注射用水、生理的食塩水、リンゲル液、アルコール、プロピレングリコール、ポリエチレングリコール、ゴマ油、トウモロコシ油、オリーブ油、綿実油が挙げられる。 Suitable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil.
 溶解補助剤の好適な例としては、ポリエチレングリコール、プロピレングリコール、D-マンニトール、トレハロース、安息香酸ベンジル、エタノール、トリスアミノメタン、コレステロール、トリエタノールアミン、炭酸ナトリウム、クエン酸ナトリウム、サリチル酸ナトリウム、酢酸ナトリウムが挙げられる。 Preferable examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. Is mentioned.
 懸濁化剤の好適な例としては、ステアリルトリエタノールアミン、ラウリル硫酸ナトリウム、ラウリルアミノプロピオン酸、レシチン、塩化ベンザルコニウム、塩化ベンゼトニウム、モノステアリン酸グリセリン等の界面活性剤;ポリビニルアルコール、ポリビニルピロリドン、カルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース等の親水性高分子;ポリソルベート類、ポリオキシエチレン硬化ヒマシ油が挙げられる。 Suitable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; polyvinyl alcohol, polyvinylpyrrolidone , Hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, and polyoxyethylene hydrogenated castor oil.
 等張化剤の好適な例としては、塩化ナトリウム、グリセリン、D-マンニトール、D-ソルビトール、ブドウ糖が挙げられる。 Preferable examples of the isotonic agent include sodium chloride, glycerin, D-mannitol, D-sorbitol and glucose.
 緩衝剤の好適な例としては、リン酸塩、酢酸塩、炭酸塩、クエン酸塩等の緩衝液が挙げられる。
 無痛化剤の好適な例としては、ベンジルアルコールが挙げられる。
Preferable examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like.
A preferred example of the soothing agent is benzyl alcohol.
 防腐剤の好適な例としては、パラオキシ安息香酸エステル類、クロロブタノール、ベンジルアルコール、フェネチルアルコール、デヒドロ酢酸、ソルビン酸が挙げられる。
 抗酸化剤の好適な例としては、亜硫酸塩、アスコルビン酸塩等が挙げられる。
Preferable examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.
Preferable examples of the antioxidant include sulfite and ascorbate.
 着色剤の好適な例としては、水溶性食用タール色素(例、食用赤色2号および3号、食用黄色4号および5号、食用青色1号および2号等の食用色素)、水不溶性レーキ色素(例、前記水溶性食用タール色素のアルミニウム塩)、天然色素(例、β-カロチン、クロロフィル、ベンガラ)が挙げられる。 Preferred examples of the colorant include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2, etc.), water-insoluble lake dyes (Eg, the aluminum salt of the water-soluble edible tar dye) and natural dyes (eg, β-carotene, chlorophyll, bengara).
 甘味剤の好適な例としては、サッカリンナトリウム、グリチルリチン酸二カリウム、アスパルテーム、ステビアが挙げられる。 Suitable examples of sweeteners include saccharin sodium, dipotassium glycyrrhizinate, aspartame, and stevia.
 本発明化合物を含有する医薬は、医薬製剤の製造法として自体公知の方法(例、日本薬局方記載の方法等)に従って、本発明化合物を単独で、または薬理学的に許容される担体と混合して、例えば錠剤(糖衣錠、フィルムコーティング錠、舌下錠、口腔内崩壊錠、バッカル錠等を含む)、丸剤、散剤、顆粒剤、カプセル剤(ソフトカプセル剤、マイクロカプセル剤を含む)、トローチ剤、シロップ剤、液剤、乳剤、懸濁剤、放出制御製剤(例、速放性製剤、徐放性製剤、徐放性マイクロカプセル剤)、エアゾール剤、フィルム剤(例、口腔内崩壊フィルム、口腔粘膜貼付フィルム)、注射剤(例、皮下注射剤、静脈内注射剤、筋肉内注射剤、腹腔内注射剤)、点滴剤、経皮吸収型製剤、軟膏剤、ローション剤、貼付剤、坐剤(例、肛門坐剤、膣坐剤)、ペレット、経鼻剤、経肺剤(吸入剤)、点眼剤等として、経口的または非経口的(例、静脈内、筋肉内、皮下、臓器内、鼻腔内、皮内、点眼、脳内、直腸内、膣内、腹腔内、腫瘍内部、腫瘍の近位等への投与および直接的な病巣への投与)に安全に投与することができる。 The medicament containing the compound of the present invention can be used alone or mixed with a pharmacologically acceptable carrier according to a method known per se as a method for producing a pharmaceutical preparation (eg, a method described in the Japanese Pharmacopoeia). For example, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (including soft capsules and microcapsules), troches Agent, syrup, solution, emulsion, suspension, controlled release formulation (eg, immediate release formulation, sustained release formulation, sustained release microcapsule), aerosol, film agent (eg, orally disintegrating film, Oral mucosa adhesive film), injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), drip, transdermal preparation, ointment, lotion, patch, sitting Suppositories (eg, rectal suppositories) Vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, etc., orally or parenterally (eg, intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, Ophthalmic, intracerebral, intrarectal, intravaginal, intraperitoneal, intratumoral, proximal to the tumor, etc. and direct administration to the lesion).
 医薬組成物は、製剤技術分野において慣用の方法、例えば、日本薬局方に記載の方法等により製造することができる。 The pharmaceutical composition can be produced by a method commonly used in the field of pharmaceutical technology, for example, a method described in the Japanese Pharmacopoeia.
 なお、医薬組成物中の本発明化合物の含量は、剤形、本発明化合物の投与量等により異なるが、例えば、約0.1~100重量%である。 The content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention, etc., but is, for example, about 0.1 to 100% by weight.
 経口剤を製造する際には、必要により、味のマスキング、腸溶性あるいは持続性を目的として、コーティングを行ってもよい。 When manufacturing an oral preparation, it may be coated for the purpose of taste masking, enteric solubility or sustainability, if necessary.
 コーティングに用いられるコーティング基剤としては、例えば、糖衣基剤、水溶性フィルムコーティング基剤、腸溶性フィルムコーティング基剤、徐放性フィルムコーティング基剤が挙げられる。 Examples of the coating base used for coating include sugar coating base, water-soluble film coating base, enteric film coating base and sustained-release film coating base.
 糖衣基剤としては、白糖が用いられ、さらに、タルク、沈降炭酸カルシウム、ゼラチン、アラビアゴム、プルラン、カルナバロウ等から選ばれる1種または2種以上を併用してもよい。 As the sugar coating base, sucrose is used, and one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.
 水溶性フィルムコーティング基剤としては、例えば、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシエチルセルロース、メチルヒドロキシエチルセルロース等のセルロース系高分子;ポリビニルアセタールジエチルアミノアセテート、アミノアルキルメタアクリレートコポリマーE〔オイドラギットE(商品名)〕、ポリビニルピロリドン等の合成高分子;プルラン等の多糖類が挙げられる。 Examples of the water-soluble film coating base include cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name) ], Synthetic polymers such as polyvinylpyrrolidone; polysaccharides such as pullulan.
 腸溶性フィルムコーティング基剤としては、例えば、ヒドロキシプロピルメチルセルロース フタレート、ヒドロキシプロピルメチルセルロース アセテートサクシネート、カルボキシメチルエチルセルロース、酢酸フタル酸セルロース等のセルロース系高分子;メタアクリル酸コポリマーL〔オイドラギットL(商品名)〕、メタアクリル酸コポリマーLD〔オイドラギットL-30D55(商品名)〕、メタアクリル酸コポリマーS〔オイドラギットS(商品名)〕等のアクリル酸系高分子;セラック等の天然物が挙げられる。 Examples of enteric film coating bases include cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name) ] Acrylic acid polymers such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)], methacrylic acid copolymer S [Eudragit S (trade name)]; natural products such as shellac.
 徐放性フィルムコーティング基剤としては、例えば、エチルセルロース等のセルロース系高分子;アミノアルキルメタアクリレートコポリマーRS〔オイドラギットRS(商品名)〕、アクリル酸エチル-メタクリル酸メチル共重合体懸濁液〔オイドラギットNE(商品名)〕等のアクリル酸系高分子が挙げられる。 Examples of the sustained-release film coating base include cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit Acrylic polymer such as NE (trade name)].
 上記したコーティング基剤は、その2種以上を適宜の割合で混合して用いてもよい。また、コーティングの際に、例えば、酸化チタン、三二酸化鉄等のような遮光剤を用いてもよい。 The above-mentioned coating bases may be used by mixing two or more of them in an appropriate ratio. Moreover, you may use light-shielding agents, such as a titanium oxide, ferric oxide, etc. in the case of coating.
 本発明化合物は、毒性(例、急性毒性、慢性毒性、遺伝毒性、生殖毒性、心毒性、癌原性)が低く、副作用も少なく、哺乳動物(例えば、ヒト、ウシ、ウマ、イヌ、ネコ、サル、マウス、ラット)に対し、後述する各種疾患の予防または治療剤、または診断薬として用いることができる。 The compound of the present invention has low toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity), few side effects, and mammals (eg, humans, cows, horses, dogs, cats, Monkeys, mice, rats) can be used as preventive or therapeutic agents for various diseases described later, or as diagnostic agents.
 本発明化合物は、優れたGPR119アゴニスト作用を有する。
 GPR119アゴニストは、膵臓β細胞に発現したGPR119を活性化してインスリン分泌を促進させ、また、腸管に発現したGPR119を活性化してグルカゴン様ペプチド-1(glucagon-like peptide-1: GLP-1)分泌を促進させる。すなわち、本発明
化合物は、血糖低下作用、インスリン分泌促進作用、GLP-1分泌促進作用および膵臓β細胞の保護作用を有する。
 また、本発明化合物は、グルコース依存性インスリン分泌刺激ポリペプチド(glucose-dependent insulinotropic polypeptide: GIP)分泌促進作用およびペプチドYY(PYY)分泌促進作用、摂食抑制作用、グルカゴン分泌抑制作用を有しうる。
The compound of the present invention has an excellent GPR119 agonistic action.
GPR119 agonist activates GPR119 expressed in pancreatic β cells to promote insulin secretion, and activates GPR119 expressed in the intestinal tract to secrete glucagon-like peptide-1 (GLP-1) To promote. That is, the compound of the present invention has a blood glucose lowering action, an insulin secretion promoting action, a GLP-1 secretion promoting action and a pancreatic β-cell protecting action.
In addition, the compound of the present invention may have a glucose-dependent insulinotropic polypeptide (GIP) secretion promoting action, a peptide YY (PYY) secretion promoting action, an antifeedant action, and a glucagon secretion inhibiting action. .
 本発明化合物は、GPR119作動薬として用いることができる。
 本発明化合物は、GPR119が関与する病態または疾患の予防または治療剤として用いることができる。
The compound of the present invention can be used as a GPR119 agonist.
The compound of the present invention can be used as a prophylactic or therapeutic agent for a disease state or disease in which GPR119 is involved.
 本発明化合物は、例えば、糖尿病(例、1型糖尿病、2型糖尿病、妊娠糖尿病、肥満型糖尿病)の予防・治療剤、インスリン分泌促進剤、GLP-1分泌促進剤、膵臓β細胞保護剤、GIP分泌促進剤、PYY分泌促進剤、耐糖能不全[IGT(Impaired Glucose Tolerance)]の予防・治療剤、および耐糖能不全から糖尿病への移行抑制剤として用いることができる。 The compound of the present invention includes, for example, a preventive / therapeutic agent for diabetes (eg, type 1 diabetes, type 2 diabetes, gestational diabetes, obesity type diabetes), insulin secretagogue, GLP-1 secretagogue, pancreatic β cell protective agent, It can be used as a GIP secretion promoter, a PYY secretion promoter, a prophylactic / therapeutic agent for glucose intolerance [IGT (Impaired Glucose Tolerance)], and a transition inhibitor from glucose intolerance to diabetes.
 本発明化合物は、肥満症、高脂血症(例、高トリグリセリド血症、高コレステロール血症、高LDLコレステロール血症、低HDLコレステロール血症、食後高脂血症)、高血圧症、心不全、糖尿病性合併症[例、神経障害、腎症、糖尿病性網膜症、糖尿病性心筋症、白内障、大血管障害、骨減少症、糖尿病性高浸透圧昏睡、感染症(例、呼吸器感染症、尿路感染症、消化器感染症、皮膚軟部組織感染症、下肢感染症)、糖尿病性壊疽、口腔乾燥症、聴覚の低下、脳血管障害、末梢血行障害]、メタボリックシンドローム(2005年に日本肥満学会等で報告された日本人における診断基準によると、メタボリックシンドロームとは、腹囲が男性85cm、女性90cm以上を有し、かつ、収縮期血圧130以上または拡張期血圧85mmHg以上、中性トリグリセリド150mg/dl以上またはHDLc40mg/dl未満、および、空腹時血糖値(静脈血漿におけるグルコース濃度)が110mg/dl以上、の3項目のうち2項目以上を有する場合を呼ぶ。)等の予防・治療剤として用いることができる。 The compounds of the present invention are obesity, hyperlipidemia (eg, hypertriglyceridemia, hypercholesterolemia, high LDL cholesterolemia, low HDL cholesterolemia, postprandial hyperlipidemia), hypertension, heart failure, diabetes Complications [eg, neuropathy, nephropathy, diabetic retinopathy, diabetic cardiomyopathy, cataract, macrovascular disorder, osteopenia, diabetic hyperosmolar coma, infection (eg, respiratory infection, urine] Tract infection, digestive tract infection, skin soft tissue infection, lower limb infection), diabetic gangrene, xerostomia, hearing loss, cerebrovascular disorder, peripheral blood circulation disorder], metabolic syndrome (Japan Society of Obesity in 2005) According to the diagnostic criteria in Japanese reported by et al., Metabolic syndrome means that the waist circumference is 85 cm for men and 90 cm or more for women, and systolic blood pressure is 130 or more or diastolic blood pressure is 85 mm. g or more, neutral triglyceride 150 mg / dl or more or HDLc less than 40 mg / dl, and fasting blood glucose level (glucose concentration in venous plasma) is 2 mg or more among 3 items. It can be used as a preventive / therapeutic agent.
 糖尿病の判定基準については、1999年に日本糖尿病学会から判定基準が報告されている。 Regarding the criteria for determining diabetes, the criteria was reported in 1999 by the Japan Diabetes Society.
 この報告によれば、糖尿病とは、空腹時血糖値(静脈血漿におけるグルコース濃度)が126mg/dl以上、75g経口ブドウ糖負荷試験(75gOGTT)2時間値(静脈血漿におけるグルコース濃度)が200mg/dl以上、随時血糖値(静脈血漿におけるグルコース濃度)が200mg/dl以上のいずれかを示す状態である。また、上記糖尿病に該当せず、かつ、「空腹時血糖値(静脈血漿におけるグルコース濃度)が110mg/dl未満または75g経口ブドウ糖負荷試験(75gOGTT)2時間値(静脈血漿におけるグルコース濃度)が140mg/dl未満を示す状態」(正常型)でない状態を、「境界型」と呼ぶ。 According to this report, diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or higher, and a 75 g oral glucose tolerance test (75 gOGTT) 2-hour value (glucose concentration in venous plasma) of 200 mg / dl or higher. This is a state in which the blood glucose level (glucose concentration in venous plasma) is at least 200 mg / dl as needed. In addition, it does not correspond to the above-mentioned diabetes, and “a fasting blood glucose level (glucose concentration in venous plasma) is less than 110 mg / dl or a 75 g oral glucose tolerance test (75 g OGTT) 2 hour value (glucose concentration in venous plasma) is 140 mg / dl. A state that is not “a state indicating less than dl” (normal type) is referred to as a “boundary type”.
 また、糖尿病の判定基準については、1997年にADA(米国糖尿病学会)から、1998年にWHOから、判定基準が報告されている。 In addition, as for the criteria for determining diabetes, the criteria were reported from ADA (American Diabetes Association) in 1997 and from WHO in 1998.
 ADAの報告によれば、糖尿病とは、糖尿病様症状(多尿、多飲、過食、過労、体重減少、霧視、成長障害)を呈し、かつ、随時血糖値(静脈血漿におけるグルコース濃度)が200mg/dl以上、空腹時血糖値(静脈血漿におけるグルコース濃度)が126mg/dl以上、75g経口ブドウ糖負荷試験2時間値(静脈血漿におけるグルコース濃度)が200mg/dl以上のいずれかを示す状態である。WHOの報告によれば、糖尿病とは、空腹時血糖値(静脈血漿におけるグルコース濃度)が126mg/dl以上、または、75g経口ブドウ糖負荷試験2時間値(静脈血漿におけるグルコース濃度)が200mg/dl以上を示す状態である。 According to ADA reports, diabetes is a diabetes-like symptom (polyuria, heavy drinking, overeating, overwork, weight loss, foggy vision, growth disorder), and anytime blood glucose level (glucose concentration in venous plasma) It is a state in which 200 mg / dl or more, fasting blood glucose level (glucose concentration in venous plasma) is 126 mg / dl or more, and 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) is 200 mg / dl or more. . According to WHO reports, diabetes is a fasting blood glucose level (glucose concentration in venous plasma) of 126 mg / dl or higher, or a 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) of 200 mg / dl or higher. It is the state which shows.
 また、上記報告によれば、耐糖能不全とは、空腹時血糖値(静脈血漿におけるグルコース濃度)が126mg/dl未満であり、かつ、75g経口ブドウ糖負荷試験2時間値(静脈血漿におけるグルコース濃度)が140mg/dl以上200mg/dl未満を示す状態である。さらに、ADAの報告によれば、空腹時血糖値(静脈血漿におけるグルコース濃度)が110mg/dl以上126mg/dl未満の状態をIFG(Impaired Fasting Glucose)と呼ぶ。一方、WHOの報告によれば、該IFG(Impaired Fasting Glucose)のうち、75g経口ブドウ糖負荷試験2時間値(静脈血漿におけるグルコース濃度)が140mg/dl未満である状態をIFG(Impaired Fasting Glycemia)と呼
ぶ。
According to the above report, glucose intolerance is a fasting blood glucose level (glucose concentration in venous plasma) of less than 126 mg / dl, and a 2-hour value of 75 g oral glucose tolerance test (glucose concentration in venous plasma). Is a state showing 140 mg / dl or more and less than 200 mg / dl. Furthermore, according to the report of ADA, the state where the fasting blood glucose level (glucose concentration in venous plasma) is 110 mg / dl or more and less than 126 mg / dl is called IFG (Impaired Fasting Glucose). On the other hand, according to the report of WHO, the IFG (Impaired Fasting Glucose) is a state in which the 75 g oral glucose tolerance test 2 hour value (glucose concentration in venous plasma) is less than 140 mg / dl as IFG (Impaired Fasting Glycemia). Call.
 本発明化合物は、上記した新たな判定基準により決定される糖尿病、境界型、耐糖能不全、IFG(Impaired Fasting Glucose)およびIFG(Impaired Fasting Glycemia)の予防・治療剤としても用いられる。さらに、本発明化合物は、境界型、耐糖能不全
、IFG(Impaired Fasting Glucose)またはIFG(Impaired Fasting Glycemia
)から糖尿病への進展を防止することもできる。
The compound of the present invention is also used as a prophylactic / therapeutic agent for diabetes, borderline type, glucose intolerance, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glycemia) determined by the above-mentioned new criteria. Furthermore, the compound of the present invention has a boundary type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) or IFG (Impaired Fasting Glycemia).
) To diabetes can also be prevented.
 本発明化合物は、例えば、認知障害、骨粗鬆症、悪液質(例、癌性悪液質、結核性悪液質、糖尿病性悪液質、血液疾患性悪液質、内分泌疾患性悪液質、感染症性悪液質または後天性免疫不全症候群による悪液質)、脂肪肝、多嚢胞性卵巣症候群、腎臓疾患(例、糖尿病性ネフロパシー、糸球体腎炎、糸球体硬化症、ネフローゼ症候群、高血圧性腎硬化症、末期腎臓疾患)、筋ジストロフィー、心筋梗塞、狭心症、脳血管障害(例、脳梗塞、脳卒中)、インスリン抵抗性症候群、シンドロームX、高インスリン血症、高インスリン血症における知覚障害、腫瘍(例、白血病、乳癌、前立腺癌、皮膚癌)、過敏性腸症候群、急性または慢性下痢、炎症性疾患(例、動脈硬化症(例、アテローム性動脈硬化症)、慢性関節リウマチ、変形性脊椎炎、変形性関節炎、腰痛、痛風、手術外傷後の炎症、腫脹、神経痛、咽喉頭炎、膀胱炎、肝炎(非アルコール性脂肪性肝炎を含む)、肺炎、膵炎、炎症性大腸疾患、潰瘍性大腸炎、慢性閉塞性肺疾患(COPD))、内臓肥満症候群、足潰瘍、セプシス、乾癬等の予防・治療剤としても用いることができる。 The compounds of the present invention include, for example, cognitive impairment, osteoporosis, cachexia (eg, cancer cachexia, tuberculosis cachexia, diabetic cachexia, hematological cachexia, endocrine cachexia, infectious cachexia) Or cachexia due to acquired immune deficiency syndrome), fatty liver, polycystic ovary syndrome, kidney disease (eg, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage kidney) Disease), muscular dystrophy, myocardial infarction, angina pectoris, cerebrovascular disorder (eg, cerebral infarction, stroke), insulin resistance syndrome, syndrome X, hyperinsulinemia, sensory disturbance in hyperinsulinemia, tumor (eg, leukemia) , Breast cancer, prostate cancer, skin cancer), irritable bowel syndrome, acute or chronic diarrhea, inflammatory disease (eg, arteriosclerosis (eg, atherosclerosis), rheumatoid arthritis, osteoarthritis spondylitis Osteoarthritis, low back pain, gout, post-traumatic inflammation, swelling, neuralgia, sore throat, cystitis, hepatitis (including non-alcoholic steatohepatitis), pneumonia, pancreatitis, inflammatory bowel disease, ulcerative colitis , Chronic obstructive pulmonary disease (COPD), visceral obesity syndrome, foot ulcer, sepsis, psoriasis and the like.
 また、本発明化合物は、消化性潰瘍、急性または慢性胃炎、胆道ジスキネジアー、胆のう炎等に伴う腹痛、悪心、嘔吐、上腹部不快感等の症状の改善等にも用いることができる。 The compound of the present invention can also be used to improve symptoms such as peptic ulcer, acute or chronic gastritis, biliary dyskinesia, abdominal pain associated with cholecystitis, nausea, vomiting and upper abdominal discomfort.
 本発明化合物は、膵β細胞保護作用を有することから、膵島移植時の予後改善に用いることができる。 Since the compound of the present invention has a pancreatic β-cell protective action, it can be used to improve the prognosis at the time of islet transplantation.
 本発明化合物は、内臓脂肪の減少、内臓脂肪蓄積の抑制、糖代謝改善、脂質代謝改善、インスリン抵抗性改善、酸化LDL産生抑制、リポタンパク代謝改善、冠動脈代謝改善、心血管合併症の予防・治療、心不全合併症の予防・治療、血中レムナント低下、無排卵症の予防・治療、多毛症の予防・治療、高アンドロゲン血症の予防・治療等にも用いられる。 The compound of the present invention reduces visceral fat, suppresses visceral fat accumulation, improves glucose metabolism, improves lipid metabolism, improves insulin resistance, suppresses oxidized LDL production, improves lipoprotein metabolism, improves coronary metabolism, prevents cardiovascular complications It is also used for treatment, prevention and treatment of heart failure complications, blood remnant reduction, anovulation prevention and treatment, hirsutism prevention and treatment, hyperandrogenemia prevention and treatment, etc.
 本発明化合物は、上記した各種疾患(例、心筋梗塞等の心血管イベント)の2次予防および進展抑制にも用いられる。 The compound of the present invention is also used for secondary prevention and progression suppression of the various diseases described above (eg, cardiovascular events such as myocardial infarction).
 本発明化合物の投与量は、投与対象、投与ルート、対象疾患、症状等によっても異なるが、例えば、成人の糖尿病患者に経口投与する場合、通常1回量として約0.01~100mg/kg体重、好ましくは0.05~30mg/kg体重、より好ましくは0.1~10mg/kg体重であり、さらに好ましくは0.3~5mg/kg体重であり、この量を1日1回~3回投与するのが望ましい。 The dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptom, etc. For example, when orally administered to an adult diabetic patient, the dose is usually about 0.01 to 100 mg / kg body weight. It is preferably 0.05 to 30 mg / kg body weight, more preferably 0.1 to 10 mg / kg body weight, still more preferably 0.3 to 5 mg / kg body weight, and this amount is once to 3 times a day. It is desirable to administer.
 本発明化合物は、糖尿病治療剤、糖尿病性合併症治療剤、高脂血症治療剤、降圧剤、抗肥満剤、利尿剤、化学療法剤、免疫療法剤、抗血栓剤、骨粗鬆症治療剤、抗痴呆剤、勃起不全改善剤、尿失禁・頻尿治療剤、排尿困難治療剤等の薬剤(以下、併用薬剤と略記する)と組み合わせて用いることができる。これらの併用薬剤は、低分子化合物であってもよく、また高分子の蛋白、ポリペプチド、抗体であるか、あるいはワクチン等であってもよい。
 本発明化合物および併用薬剤の投与時期は限定されず、これらを投与対象に対し、同時に投与してもよいし、時間差をおいて投与してもよい。
 投与形態としては、特に限定されず、本発明化合物と併用薬剤が組み合わされていればよい。このような投与形態としては、例えば、
(1)本発明化合物と併用薬剤とを同時に製剤化して得られる単一の製剤の投与、
(2)本発明化合物と併用薬剤とを別々に製剤化して得られる2種の製剤の同一投与経路での同時投与、
(3)本発明化合物と併用薬剤とを別々に製剤化して得られる2種の製剤の同一投与経路での時間差をおいての投与、
(4)本発明化合物と併用薬剤とを別々に製剤化して得られる2種の製剤の異なる投与経路での同時投与、
(5)本発明化合物と併用薬剤とを別々に製剤化して得られる2種の製剤の異なる投与経路での時間差をおいての投与(例えば、本発明化合物および併用薬剤の順序での投与、あるいは逆の順序での投与)
等が挙げられる。
The compound of the present invention comprises a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, an antihypertensive agent, an antiobesity agent, a diuretic agent, a chemotherapeutic agent, an immunotherapeutic agent, an antithrombotic agent, a therapeutic agent for osteoporosis, It can be used in combination with a drug (hereinafter abbreviated as a concomitant drug) such as a dementia agent, an erectile dysfunction improving agent, a urinary incontinence / frequent urination therapeutic agent, or a dysuria therapeutic agent. These concomitant drugs may be low molecular compounds, high molecular proteins, polypeptides, antibodies, or vaccines.
The administration timing of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference.
The dosage form is not particularly limited as long as the compound of the present invention and the concomitant drug are combined. Examples of such dosage forms include:
(1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug,
(2) Simultaneous administration by the same route of administration of two preparations obtained by separately formulating the compound of the present invention and a concomitant drug,
(3) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug at the same administration route with a time difference,
(4) Simultaneous administration by different administration routes of two kinds of preparations obtained by separately formulating the compound of the present invention and a concomitant drug,
(5) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug at different time intervals in different administration routes (for example, administration in the order of the compound of the present invention and the concomitant drug, or Administration in reverse order)
Etc.
 併用薬剤の投与量は、臨床上用いられている用量を基準として適宜選択することができる。また、本発明化合物と併用薬剤の配合比は、投与対象、投与ルート、対象疾患、症状、組み合わせ等により適宜選択することができる。例えば、投与対象がヒトである場合、本発明化合物1重量部に対し、併用薬剤を0.01~100重量部用いればよい。 The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.
 糖尿病治療剤としては、例えば、インスリン製剤(例、ウシ、ブタの膵臓から抽出された動物インスリン製剤;大腸菌、イーストを用い遺伝子工学的に合成したヒトインスリン製剤;インスリン亜鉛;プロタミンインスリン亜鉛;インスリンのフラグメントまたは誘導体(例、INS-1)、経口インスリン製剤)、インスリン抵抗性改善剤(例、ピオグリタ
ゾンまたはその塩(好ましくは、塩酸塩)、ロシグリタゾンまたはその塩(好ましくは、マレイン酸塩)、メタグリダセン(Metaglidasen)、AMG-131、バラグリタゾン(Balaglitazone)、MBX-2044、リボグリタゾン(Rivoglitazone)、アレグリタザール(Aleglitazar)、チグリタザール(Chiglitazar)、ロベグリタゾン(Lobeglitazone)、PLX-204、PN-2034、GFT-505、THR-0921、WO2007/013694、WO2007/018314、WO2008/093639またはWO2008/099794記載の化合物)、α-グルコシダーゼ阻害剤(例、ボグリボース、アカルボース、ミグリトール、エミグリテート)、ビグアナイド剤(例、メトホルミン、ブホルミンまたはそれらの塩(例、塩酸塩、フマル酸塩、コハク酸塩))、インスリン分泌促進剤(例、スルホニルウレア剤(例、トルブタミド、グリベンクラミド、グリクラジド、クロルプロパミド、トラザミド、アセトヘキサミド、グリクロピラミド、グリメピリド、グリピザイド、グリブゾール)、レパグリニド、ナテグリニド、ミチグリニドまたはそのカルシウム塩水和物)、ジペプチジルペプチダーゼIV阻害剤(例、アログリプチン(Alogliptin)またはその塩(好ましくは、安息香酸塩)、ヴィルダグリプチン(Vildagliptin)、シタグリプチン(Sitagliptin)、サクサグリプチン(Saxagliptin)、BI1356、GRC8200
、MP-513、PF-00734200、PHX1149、SK-0403、ALS2-0426、TA-6666、TS-021、KRP-104、2-[[6-[(3R)-3-アミノ-1-ピペリジニル]-3,4-ジヒドロ-3-メチル-2,4-ジオキソ-1(2H)-ピリミジニル]メチル]-4-フルオロベンゾニトリルまたはその塩)、β3アゴニスト(例、N-5984)、GPR40アゴニスト(例、WO2004/041266、WO2004/106276、WO2005/063729、WO2005/063725、WO2005/087710、WO2005/095338、WO2007/013689またはWO2008/001931記載の化合物)、GLP-1受容体アゴニスト(例、GLP-1、GLP-1MR剤、リラグルチド(Liraglutide)、エキセナチド(Exenatide)、AVE-0010、BIM-51077、Aib(8,35)hGLP-1(7,37)NH2、CJC-1131、Albiglutide)、アミリンアゴニスト(例、プラムリンチド)、ホスホチロシンホスファターゼ阻害剤(例、バナジン酸ナトリウム)、糖新生阻害剤(例、グリコーゲンホスホリラーゼ阻害剤、グルコース-6-ホスファターゼ阻害剤、グルカゴン拮抗剤、FBPase阻
害薬)、SGLT2(sodium-glucose cotransporter 2)阻害剤(例、Dapagliflozin、AVE2268、TS-033、YM543、TA-7284、Remogliflozin、ASP1941)、SGLT1阻害薬、11β-ヒドロキ
システロイドデヒドロゲナーゼ阻害薬(例、BVT-3498、INCB-13739)、アジポネクチンまたはその作動薬、IKK阻害薬(例、AS-2868)、レプチン抵抗性改善薬、ソマトスタチン受容体作動薬、グルコキナーゼ活性化薬(例、Piragliatin、AZD1656、AZD6370、TTP-355、WO2006/112549、WO2007/028135、WO2008/047821、WO2008/050821、WO2008/136428またはWO2008/156757記載の化合物)、GIP(Glucose-dependent insulinotropic peptide)、GPR119アゴニスト(例、PSN821、MBX-2982、APD597)、FGF21、FGFアナログ等が挙げられる。
Examples of the therapeutic agent for diabetes include, for example, insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations genetically engineered using Escherichia coli and yeast; insulin zinc; protamine insulin zinc; insulin Fragment or derivative (eg, INS-1), oral insulin preparation), insulin resistance improving agent (eg, pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone or a salt thereof (preferably maleate), Metaglidasen, AMG-131, Balaglitazone, MBX-2044, Riboglitazone, Aleglitazar, Chiglitazar, Lobeglitazone, PLX-204, PN-2034 GFT-505, THR-0921, WO2007 / 013694, WO2007 / 018314, WO2008 / 093639 or WO2008 / 0997 94), α-glucosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate), biguanides (eg, metformin, buformin or salts thereof (eg, hydrochloride, fumarate, succinate)) , Insulin secretagogues (eg, sulfonylureas (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybazole), repaglinide, nateglinide, mitiglinide or its calcium salt hydrate Product), dipeptidyl peptidase IV inhibitor (eg, alogliptin or a salt thereof (preferably benzoate), vildagliptin, sitagliptin, saxagliptin) (Saxagliptin), BI1356, GRC8200
, MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, TA-6666, TS-021, KRP-104, 2-[[6-[(3R) -3-Amino-1-piperidinyl] -3,4-dihydro-3-methyl-2,4-dioxo-1 (2H) -pyrimidinyl] methyl] -4-fluorobenzonitrile or a salt thereof), β3 agonist (eg, N-5984), GPR40 agonist ( Examples, compounds described in WO2004 / 041266, WO2004 / 106276, WO2005 / 063729, WO2005 / 063725, WO2005 / 087710, WO2005 / 095338, WO2007 / 013689 or WO2008 / 001931), GLP-1 receptor agonists (eg, GLP-1 , GLP-1MR agent, liraglutide (liraglutide), exenatide (exenatide), AVE-0010, BIM-51077, Aib (8,35) hGLP-1 (7,37) NH 2, CJC-1131, Albiglutide), amylin agonists (Eg, pramlintide), phosphotyrosine phosphatase inhibitor (eg, sodium vanadate), gluconeogenesis inhibitor (eg, glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor) Glucagon antagonist, FBPase inhibitor), SGLT2 (sodium-glucose cotransporter 2) inhibitor (eg, Dapagliflozin, AVE2268, TS-033, YM543, TA-7284, Remogliflozin, ASP1941), SGLT1 inhibitor, 11β-hydroxysteroid dehydrogenase Inhibitors (eg, BVT-3498, INCB-13739), adiponectin or agonists thereof, IKK inhibitors (eg, AS-2868), leptin resistance improvers, somatostatin receptor agonists, glucokinase activators (eg, , Piragliatin, AZD1656, AZD6370, TTP-355, WO2006 / 112549, WO2007 / 028135, WO2008 / 047821, WO2008 / 050821, WO2008 / 136428 or WO2008 / 156757), GIP (Glucose-dependent insulinotropic peptide), GPR119 agonist (Eg, PSN821, MBX-2982, APD597), FGF21, FGF analogs and the like.
 糖尿病性合併症治療剤としては、例えば、アルドース還元酵素阻害剤(例、トルレスタット、エパルレスタット、ゾポルレスタット、フィダレスタット、CT-112、ラニレスタット(AS-3201)、リドレスタット)、神経栄養因子およびその増加薬(例、NGF、NT-3、BDNF、WO01/14372に記載のニューロトロフィン産生・分泌促進剤(例、4-(4-クロロフェニ
ル)-2-(2-メチル-1-イミダゾリル)-5-[3-(2-メチルフェノキシ)プロピル]オキサゾール)、WO2004/039365記載の化合物)、PKC阻害剤(例、ルボキシスタウリン メシレート(ruboxistaurin mesylate))、AGE阻害剤(例、ALT946、N-フェナシルチアゾリウム ブロ
マイド(ALT766)、EXO-226、ピリドリン(Pyridorin)、ピリドキサミン)、GABA受容体作動薬(例、ギャバペンチン、プレギャバリン)、セロトニン・ノルアドレナリン再取込み阻害薬(例、デュロキセチン)、ナトリウムチャンネル阻害薬(例、ラコサミド)、活性酸素消去薬(例、チオクト酸)、脳血管拡張剤(例、チアプリド、メキシレチン)、ソマトスタチン受容体作動薬(例、BIM23190)、アポトーシスシグナルレギュレーティングキナーゼ-1(ASK-1)阻害薬等が挙げられる。
Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors (eg, tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat (AS-3201), ridressat), neurotrophic factor and its increase drug (Eg, NGF, NT-3, BDNF, neurotrophin production / secretion promoter described in WO01 / 14372 (eg, 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5- [3- (2-Methylphenoxy) propyl] oxazole), compounds described in WO2004 / 039365), PKC inhibitors (eg, ruboxistaurin mesylate), AGE inhibitors (eg, ALT946, N-Fe) Nasyl thiazolium bromide (ALT766), EXO-226, pyridoline (Pyridorin), pyridoxamine), GABA receptor agonist (eg, gabapentin, pregabalin), serotonin and noradrenaline retake Inhibitors (eg, duloxetine), sodium channel inhibitors (eg, lacosamide), active oxygen scavengers (eg, thioctic acid), cerebral vasodilators (eg, thiaprid, mexiletine), somatostatin receptor agonists (eg, BIM23190), apoptosis signal regulating kinase-1 (ASK-1) inhibitor and the like.
 高脂血症治療剤としては、例えば、HMG-CoA還元酵素阻害剤(例、プラバスタチン、シ
ンバスタチン、ロバスタチン、アトルバスタチン、フルバスタチン、ロスバスタチン、ピタバスタチンまたはそれらの塩(例、ナトリウム塩、カルシウム塩))、スクアレン合成酵素阻害剤(例、WO97/10224号パンフレットに記載の化合物、例えば、N-[[(3R,5S)-1-(3-アセトキシ-2,2-ジメチルプロピル)-7-クロロ-5-(2,3-ジメトキシフェニル)-2-オキソ-1,2,3,5-テトラヒドロ-4,1-ベンゾオキサゼピン-3-イル]アセチル]ピペリジン-4-酢酸)
、フィブラート系化合物(例、ベザフィブラート、クロフィブラート、シムフィブラート、クリノフィブラート)、陰イオン交換樹脂(例、コレスチラミン)、プロブコール、ニコチン酸系薬剤(例、ニコモール(nicomol)、ニセリトロール(niceritrol)、ナイア
スパン(niaspan))、イコサペント酸エチル、植物ステロール(例、ソイステロール(soysterol)、ガンマオリザノール(γ-oryzanol))、コレステロール吸収阻害剤 (例、ゼチア)、CETP阻害剤(例、ダルセトラピブ(dalcetrapib)、アナセトラピブ(anacetrapib))、ω-3脂肪酸製剤(例、ω-3-acid ethyl esters 90)等が挙げられる。
Examples of therapeutic agents for hyperlipidemia include HMG-CoA reductase inhibitors (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or salts thereof (eg, sodium salt, calcium salt)), Squalene synthase inhibitors (eg, compounds described in pamphlet of WO97 / 10224, such as N-[[(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro-5 -(2,3-dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid)
, Fibrate compounds (eg, bezafibrate, clofibrate, simfibrate, clinofibrate), anion exchange resins (eg, cholestyramine), probucol, nicotinic acid drugs (eg, nicomol, niceritrol), Niaspan, ethyl icosapentate, plant sterols (eg, soysterol, gamma-oryzanol), cholesterol absorption inhibitors (eg, zetia), CETP inhibitors (eg, dalcetrapib) , Anacetrapib), omega-3 fatty acid preparations (eg, omega-3-acid ethyl esters 90), and the like.
 降圧剤としては、例えば、アンジオテンシン変換酵素阻害剤(例、カプトプリル、エナラプリル、デラプリルなど)、アンジオテンシンII拮抗剤(例、カンデサルタン シレキセチル、カンデサルタン、ロサルタン、ロサルタン カリウム、エプロサルタン、バルサルタン、テルミサルタン、イルベサルタン、タソサルタン、オルメサルタン、オルメサルタン メドキソミル、アジルサルタン、アジルサルタン メドキソミルなど)、カルシウム拮抗剤(例、マニジピン、ニフェジピン、アムロジピン、エホニジピン、ニカルジピン、アムロジピン、シニルジピンなど)、βブロッカー(例、メトプロロール、アテノロール、プロプラノロール、カルベジロール、ピンドロールなど)、クロニジン等が挙げられる。 Examples of the antihypertensive agent include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril, etc.), angiotensin II antagonists (eg, candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan, irbesartan, tasosartan , Olmesartan, olmesartan, medoxomil, azilsartan, azilsartan, medoxomil, etc.), calcium antagonists (eg, manidipine, nifedipine, amlodipine, nicardipine, amlodipine, sinodidipine, etc.), β-blockers (eg, metoprolol, atenolol, propranolol, propranolol) Pindolol), clonidine and the like.
 抗肥満剤としては、例えば、モノアミン取り込み阻害薬(例、フェンテルミン、シブトラミン、マジンドール、フロキセチン、テソフェンシン)、セロトニン2C受容体作動薬(
例、ロルカセリン)、セロトニン6受容体拮抗薬、ヒスタミンH3受容体、GABA調節薬(例、トピラメイト)、ニューロペプチドY拮抗薬(例、ベルネペリット)、カンナビノイド受容体拮抗薬(例、リモナバン、タラナバン)、グレリン拮抗薬、グレリン受容体拮抗薬、グレリンアシル化酵素阻害薬、オピオイド受容体拮抗薬(例、GSK-1521498)、オレキシ
ン受容体拮抗薬、メラノコルチン4受容体作動薬、11β-ヒドロキシステロイドデヒドロゲナーゼ阻害薬(例、AZD-4017)、膵リパーゼ阻害薬(例、オルリスタット、セティリスタット(cetilistat))、β3アゴニスト(例、N-5984)、ジアシルグリセロールアシルト
ランスフェラーゼ1(DGAT1)阻害薬、アセチルCoAカルボキシラーゼ(ACC)阻害薬、ステアリン酸CoA脱飽和酵素阻害、ミクロソームトリグリセリド転送蛋白阻害薬(例、R-256918)、Na-グルコース共輸送担体阻害薬(例、JNJ-28431754、レモグリフロジン)、NFκ
阻害(例、HE-3286)、PPARアゴニスト(例、GFT-505、DRF-11605)、ホスホチロシンホ
スファターゼ阻害剤(例、バナジン酸ナトリウム、トロダスケミン(Trodusquemin))、GPR119作動薬(例、PSN-821、MBX-2982、APD597)、グルコキナーゼ活性化薬(例、AZD-1656)、レプチン、レプチン誘導体(例、メトレレプチン)、CNTF(毛様体神経栄養因子
)、BDNF(脳由来神経栄養因子)、コレシストキニンアゴニスト、グルカゴン様ペプチド-1(GLP-1)製剤(例、ウシ、ブタの膵臓から抽出された動物GLP-1製剤;大腸菌、イーストを用い遺伝子工学的に合成したヒトGLP-1製剤;GLP-1のフラグメントまたは誘導体(例、エクセナチド、リラグルチド))、アミリン製剤(例、プラムリンタイド、AC-2307)
、ニューロペプチドYアゴニスト(例、PYY3-36、PYY3-36の誘導体、オビネプタイド、TM-30339、TM-30335)、オキシントモジュリン製剤:FGF21製剤(例、ウシ、ブタの膵臓から抽出された動物FGF21製剤;大腸菌、イーストを用い遺伝子工学的に合成したヒトFGF21製剤;FGF21のフラグメントまたは誘導体))、摂食抑制薬(例、P-57)等が挙げられる。
Examples of anti-obesity agents include monoamine uptake inhibitors (eg, phentermine, sibutramine, mazindol, floxetine, tesofensin), serotonin 2C receptor agonists (
Eg, lorcaserin), serotonin 6 receptor antagonist, histamine H3 receptor, GABA modulator (eg, topiramate), neuropeptide Y antagonist (eg, Berneperit), cannabinoid receptor antagonist (eg, rimonabant, taranaban) , Ghrelin antagonist, ghrelin receptor antagonist, ghrelin acylase inhibitor, opioid receptor antagonist (eg, GSK-1521498), orexin receptor antagonist, melanocortin 4 receptor agonist, 11β-hydroxysteroid dehydrogenase inhibitor Drugs (eg, AZD-4017), pancreatic lipase inhibitors (eg, orlistat, cetilistat), β3 agonists (eg, N-5984), diacylglycerol acyltransferase 1 (DGAT1) inhibitors, acetyl CoA carboxylase (ACC) inhibitor, stearate CoA desaturase inhibition, microsomal triglycerides Transfer protein inhibitor (eg, R-256918), Na-glucose co-transport carrier inhibitor (eg, JNJ-28431754, remogliflozin), NFκ
Inhibition (eg, HE-3286), PPAR agonist (eg, GFT-505, DRF-11605), phosphotyrosine phosphatase inhibitor (eg, sodium vanadate, Trodusquemin), GPR119 agonist (eg, PSN-821, MBX-2982, APD597), glucokinase activator (eg, AZD-1656), leptin, leptin derivative (eg, metreleptin), CNTF (ciliary neurotrophic factor), BDNF (brain-derived neurotrophic factor), kore Cystkinin agonist, glucagon-like peptide-1 (GLP-1) preparation (eg, animal GLP-1 preparation extracted from bovine and porcine pancreas; human GLP-1 preparation synthesized by genetic engineering using Escherichia coli and yeast; GLP-1 fragments or derivatives (eg, exenatide, liraglutide), amylin preparations (eg, pramlintide, AC-2307)
, Neuropeptide Y agonist (eg, PYY3-36, derivatives of PYY3-36, obineptide, TM-30339, TM-30335), oxyntomodulin preparation: FGF21 preparation (eg, animal FGF21 extracted from bovine, porcine pancreas) Preparations; human FGF21 preparations synthesized by genetic engineering using Escherichia coli and yeast; fragments or derivatives of FGF21)), antifeedants (eg, P-57) and the like.
 利尿剤としては、例えば、利尿剤としては、例えば、キサンチン誘導体(例、サリチル酸ナトリウムテオブロミン、サリチル酸カルシウムテオブロミンなど)、チアジド系製剤(例、エチアジド、シクロペンチアジド、トリクロルメチアジド、ヒドロクロロチアジド、ヒドロフルメチアジド、ベンチルヒドロクロロチアジド、ペンフルチアジド、ポリ5チアジド、メチクロチアジドなど)、抗アルドステロン製剤(例、スピロノラクトン、トリアムテレンなど)、炭酸脱水酵素阻害剤(例、アセタゾラミドなど)、クロルベンゼンスルホンアミド系製剤(例、クロルタリドン、メフルシド、インダパミドなど)、アゾセミド、イソソルビド、エタクリン酸、ピレタニド、ブメタニド、フロセミドなどが挙げられる。 Examples of the diuretic include, for example, xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine), thiazide preparations (eg, etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide). , Ventilhydrochlorothiazide, penfluthiazide, poly-5thiazide, methiclotiazide, etc.), anti-aldosterone preparations (eg, spironolactone, triamterene, etc.), carbonic anhydrase inhibitors (eg, acetazolamide, etc.), chlorobenzenesulfonamide preparations (eg, , Chlorthalidone, mefluside, indapamide, etc.), azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like.
 化学療法剤としては、例えば、アルキル化剤(例、サイクロフォスファミド、イフォスファミド)、代謝拮抗剤(例、メソトレキセート、5-フルオロウラシルおよびその誘導体)、抗癌性抗生物質(例、マイトマイシン、アドリアマイシン)、植物由来抗癌剤(例、ビンクリスチン、ビンデシン、タキソール)、シスプラチン、カルボプラチン、エトポシド等が挙げられる。なかでも5-フルオロウラシル誘導体であるフルツロンあるいはネオフルツロン等が好ましい。
 免疫療法剤としては、例えば、微生物または細菌成分(例、ムラミルジペプチド誘導体、ピシバニール)、免疫増強活性のある多糖類(例、レンチナン、シゾフィラン、クレスチン)、遺伝子工学的手法で得られるサイトカイン(例、インターフェロン、インターロイキン(IL))、コロニー刺激因子(例、顆粒球コロニー刺激因子、エリスロポエチン)等が挙げられ、なかでもIL-1、IL-2、IL-12等のインターロイキンが好ましい。
Examples of chemotherapeutic agents include alkylating agents (eg, cyclophosphamide, ifosfamide), antimetabolites (eg, methotrexate, 5-fluorouracil and derivatives thereof), anticancer antibiotics (eg, mitomycin, adriamycin) Plant-derived anticancer agents (eg, vincristine, vindesine, taxol), cisplatin, carboplatin, etoposide and the like. Of these, 5-fluorouracil derivatives such as furtulon or neoflutulon are preferred.
Examples of immunotherapeutic agents include microorganisms or bacterial components (eg, muramyl dipeptide derivatives, picibanil), polysaccharides having immunopotentiating activity (eg, lentinan, schizophyllan, krestin), and cytokines obtained by genetic engineering techniques (eg, , Interferon, interleukin (IL)), colony stimulating factor (eg, granulocyte colony stimulating factor, erythropoietin) and the like, and interleukins such as IL-1, IL-2 and IL-12 are preferred.
 抗血栓剤としては、例えば、ヘパリン(例、ヘパリンナトリウム、ヘパリンカルシウム、エノキサパリンナトリウム(enoxaparin sodium)、ダルテパリンナトリウム(dalteparin
sodium))、ワルファリン(例、ワルファリンカリウム)、抗トロンビン薬(例、アルガトロバン(aragatroban)、ダビガトラン(dabigatran))、FXa阻害薬(例、リバロキサバン(rivaroxaban)、アピキサバン(apixaban)、エドキサバン(edoxaban)、YM150、WO02/06234、WO2004/048363、WO2005/030740、WO2005/058823またはWO2005/113504記載の化合物)、血栓溶解薬(例、ウロキナーゼ(urokinase)、チソキナーゼ(tisokinase)、アルテプラー
ゼ(alteplase)、ナテプラーゼ(nateplase)、モンテプラーゼ(monteplase)、パミテプラーゼ(pamiteplase))、血小板凝集抑制薬(例、塩酸チクロピジン(ticlopidine hydrochloride)、クロピドグレル、プラスグレル、E5555、SHC530348、シロスタゾール(cilostazol)、イコサペント酸エチル、ベラプロストナトリウム(beraprost sodium)、塩酸サルポグレラート(sarpogrelate hydrochloride))等が挙げられる。
 骨粗鬆症治療剤としては、例えば、アルファカルシドール(alfacalcidol)、カルシトリオール(calcitriol)、エルカトニン(elcatonin)、サケカルシトニン(calcitonin salmon)、エストリオール(estriol)、イプリフラボン(ipriflavone)、リセドロン酸二ナトリウム(risedronate disodium)、パミドロン酸二ナトリウム(pamidronate disodium)、アレンドロン酸ナトリウム水和物(alendronate sodium hydrate)、インカドロン酸二ナトリウム(incadronate disodium)等が挙げられる。
 抗痴呆剤としては、例えば、タクリン(tacrine)、ドネペジル(donepezil)、リバスチグミン(rivastigmine)、ガランタミン(galanthamine)等が挙げられる。
 勃起不全改善剤としては、例えば、アポモルフィン(apomorphine)、クエン酸シルデ
ナフィル(sildenafil citrate)等が挙げられる。
 尿失禁・頻尿治療剤としては、例えば、塩酸フラボキサート(flavoxate hydrochloride)、塩酸オキシブチニン(oxybutynin hydrochloride)、塩酸プロピベリン(propiverine hydrochloride)等が挙げられる。
 排尿困難治療剤としては、例えば、アセチルコリンエステラーゼ阻害薬(例、ジスチグミン)等が挙げられる。
Antithrombotic agents include, for example, heparin (eg, heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium)
sodium)), warfarin (eg, warfarin potassium), antithrombin drugs (eg, aragatroban, dabigatran), FXa inhibitors (eg, rivaroxaban, apixaban, edoxaban, YM150, WO02 / 06234, WO2004 / 048363, WO2005 / 030740, WO2005 / 058823 or WO2005 / 113504, thrombolytic agents (eg, urokinase, tisokinase, alteplase, nateplase) ), Monteplase, pamitepase, platelet aggregation inhibitor (eg, ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, ethyl icosapentate, beraprost sodium) , Sarpogrelate hydrochloride) and the like .
Examples of osteoporosis therapeutic agents include alfacalcidol, calcitriol, elcatonin, salmon calcitonin salmon, estriol, ipriflavone, risedronate disodium (risedronate) disodium), pamidronate disodium, alendronate sodium hydrate, incadronate disodium, and the like.
Examples of the anti-dementia agent include tacrine, donepezil, rivastigmine, galanthamine and the like.
Examples of the erectile dysfunction ameliorating agent include apomorphine and sildenafil citrate.
Examples of the urinary incontinence / frequent urination therapeutic agent include flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride and the like.
Examples of the dysuria therapeutic agent include acetylcholinesterase inhibitors (eg, distigmine).
 また、併用薬剤としては、動物モデルや臨床で悪液質改善作用が認められている薬剤、すなわち、シクロオキシゲナーゼ阻害剤(例、インドメタシン)、プロゲステロン誘導体(例、メゲステロールアセテート)、糖質ステロイド(例、デキサメサゾン)、メトクロプラミド系薬剤、テトラヒドロカンナビノール系薬剤、脂肪代謝改善剤(例、エイコサペンタエン酸)、成長ホルモン、IGF-1、あるいは悪液質を誘導する因子であるTNF-α、LIF、IL-6、オンコスタチンMに対する抗体等も挙げられる。 Concomitant drugs include drugs that have been shown to improve cachexia in animal models and clinically, ie cyclooxygenase inhibitors (eg, indomethacin), progesterone derivatives (eg, megesterol acetate), carbohydrate steroids (eg, Dexamethasone), metoclopramide drugs, tetrahydrocannabinol drugs, fat metabolism improvers (eg, eicosapentaenoic acid), growth hormone, IGF-1, or cachexia-inducing factors TNF-α, LIF, IL -6, an antibody against Oncostatin M, and the like.
 さらに、併用薬剤としては、神経再生促進薬(例、Y-128、VX-853、prosaptide)、抗うつ薬(例、デシプラミン、アミトリプチリン、イミプラミン)、抗てんかん薬(例、ラモトリジン)、抗不整脈薬(例、メキシレチン)、アセチルコリン受容体リガンド(例、ABT-594)、エンドセリン受容体拮抗薬(例、ABT-627)、モノアミン取り込み阻害薬(例、トラマドル)、麻薬性鎮痛薬(例、モルヒネ)、GABA受容体作動薬(例、ギャバペンチン)、α2受容体作動薬(例、クロニジン)、局所鎮痛薬(例、カプサイシン)、抗不安薬(例、ベンゾジアゼピン)、ドーパミン作動薬(例、アポモルフィン)、ミダゾラム、ケトコナゾール等も挙げられる。 Further, the concomitant drugs include nerve regeneration promoters (eg, Y-128, VX-853, prosaptide), antidepressants (eg, desipramine, amitriptyline, imipramine), antiepileptic drugs (eg, lamotrigine), antiarrhythmic drugs (Eg, mexiletine), acetylcholine receptor ligand (eg, ABT-594), endothelin receptor antagonist (eg, ABT-627), monoamine uptake inhibitor (eg, tramadol), narcotic analgesic (eg, morphine) GABA receptor agonist (eg, gabapentin), α2 receptor agonist (eg, clonidine), local analgesic (eg, capsaicin), anxiolytic (eg, benzodiazepine), dopamine agonist (eg, apomorphine), Midazolam, ketoconazole, etc. are also mentioned.
 併用薬剤は、好ましくは、インスリン製剤、インスリン抵抗性改善剤、ジペプチジルペプチダーゼIV阻害剤、α-グルコシダーゼ阻害剤、ビグアナイド剤、インスリン分泌促進剤(好ましくは、スルホニルウレア剤)、GLP-1受容体アゴニスト等である。
 上記併用薬剤は、2種以上を適宜の割合で組み合わせて用いてもよい。
The combination drug is preferably an insulin preparation, an insulin resistance improving agent, a dipeptidyl peptidase IV inhibitor, an α-glucosidase inhibitor, a biguanide agent, an insulin secretagogue (preferably a sulfonylurea agent), a GLP-1 receptor agonist Etc.
Two or more of the above concomitant drugs may be used in combination at an appropriate ratio.
 本発明化合物が併用薬剤と組み合せて使用される場合には、お互いの剤の量は、それらの剤の反対効果を考えて安全な範囲内で低減できる。特に、インスリン抵抗性改善剤、ジペプチジルペプチダーゼIV阻害剤、α-グルコシダーゼ阻害剤、ビグアナイド剤インスリン分泌促進剤およびGLP-1受容体アゴニストは、通常の投与量よりも低減できる。従って、これらの剤により引き起こされるであろう反対効果は安全に防止できる。それに加えて、糖尿病合併症治療剤、高脂血症治療剤、降圧剤の投与量は低減でき、その結果これらの剤により引き起こされるであろう反対効果は効果的に防止できる。 When the compound of the present invention is used in combination with a concomitant drug, the amount of each agent can be reduced within a safe range in consideration of the opposite effect of those agents. In particular, the insulin resistance ameliorating agent, dipeptidyl peptidase IV inhibitor, α-glucosidase inhibitor, biguanide insulin secretagogue and GLP-1 receptor agonist can be reduced from the usual dose. Thus, the adverse effects that would be caused by these agents can be safely prevented. In addition, the dosage of diabetic complications, hyperlipidemia, antihypertensives can be reduced, and as a result, adverse effects that would be caused by these agents can be effectively prevented.
 本発明は、更に以下の実施例、試験例および製剤例によって詳しく説明されるが、これらは本発明を限定するものではなく、また本発明の範囲を逸脱しない範囲で変化させてもよい。 The present invention is further described in detail by the following examples, test examples and formulation examples, but these are not intended to limit the present invention, and may be changed without departing from the scope of the present invention.
 以下の実施例中の「室温」は通常約 10 ℃ないし約 35 ℃を示す。
 クロマトグラフィーで用いられる溶媒は体積%を、その他は重量%を示す。
 プロトンNMRスペクトルで、OHやNHプロトンなどブロードで確認できないものについて
はデータに記載していない。
“Room temperature” in the following examples usually indicates about 10 ° C. to about 35 ° C.
Solvents used in chromatography indicate volume%, and others indicate weight%.
Proton NMR spectra that cannot be confirmed broadly, such as OH and NH protons, are not described in the data.
 その他の本文中で用いられている略号は下記の意味を示す。
s: シングレット(singlet)
d: ダブレット(doublet)
t: トリプレット(triplet)
q: クァルテット(quartet)
m: マルチプレット(multiplet)
br: ブロード(broad)
J: カップリング定数(coupling constant)
Hz: ヘルツ(Hertz)
CDCl3: 重クロロホルム
DMSO-d6: 重ジメチルスルホキシド
1H NMR: プロトン核磁気共鳴
Other abbreviations used in the text have the following meanings.
s: singlet
d: doublet
t: triplet
q: quartet
m: multiplet
br: broad
J: coupling constant
Hz: Hertz
CDCl 3 : Deuterated chloroform
DMSO-d 6 : Heavy dimethyl sulfoxide
1 H NMR: proton nuclear magnetic resonance
 以下の実施例において、融点、核磁気共鳴スペクトル(NMR)およびマススペクトル(MS)
は以下の条件により測定した。
In the following examples, melting point, nuclear magnetic resonance spectrum (NMR) and mass spectrum (MS)
Was measured under the following conditions.
融点測定機器: 柳本微量融点測定器、またはビュッヒ社 融点測定器 B-545型。 Melting point measuring instrument: Sayanagimoto micro melting point measuring instrument, or Büch melting point measuring instrument B-545 type.
NMR測定機器: バリアン社 Varian Gemini 300(300MHz)、ブルカー・バイオスピン社 AVANCE 300。 NMR measuring instrument: Varian Gemini 300 (300 MHz), Bruker Biospin AVANCE 300
MS測定機器: ウオーターズ社 ZQ2000、カラム: SHISEIDO CAPCELLPAK C18 UG120 1.5 mm I.D.×35 mm S-3μm、溶媒: A液0.05%トリフルオロ酢酸含有水、B液0.04%トリフルオロ酢酸含有アセトニトリル、グラジエントサイクル: 0.00分(A液/B液 = 90/10)、0.01分(A液/B液 = 90/10)、2.00分(A液/B液 = 5/95)、2.75分(A液/B液 = 5/95)、2.76分(A液/B液 = 90/10)、3.45分(A液/B液 = 90/10)、流速: 0.5 mL/min、検出法: UV 220 nm、イオン化法: ESI positive。または、MS測定機器: アジレント社 G6100、カラム: ZORBAX Extend-C18 Rapid Resolution HT 3.0×30 mm 1.8 micron 600 bar、溶媒: A液0.01 M酢酸アンモニウム含有水、B液 0.01 M酢酸アンモニウム含有アセトニトリル、グラジエントサイクル: 0.00分(A液/B液 = 90/10)、0.20分(A液/B液 = 90/10)、1.50分(A液/B液 = 0/100)、2.00分(A液/B液 = 90/10)、流速: 1.2 mL/min、検出法: UV 220 nm、イオン化法: ESI positiveあるいはESI negative。データは実測値を記載した。通常、分子イオンピークが観測されるが、tert-ブトキシカルボニル基(-Boc)を有する化合物の場合、フラグメントイオンとして、tert-ブトキシカルボニル基あるいはtert-ブチル基が脱離したピークが観測されることもある。また、水酸基(-OH)を有する化合物の場合、フラグメントイオンとして、H2Oが脱離したピークが観測されることもある。塩の場合は、通常、フリー体の分子イオンピークもしくはフラグメントイオンピークが観測される。 MS measuring instrument: Waters ZQ2000, column: SHISEIDO CAPCELLPAK C18 UG120 1.5 mm ID x 35 mm S-3 μm, solvent: A solution 0.05% trifluoroacetic acid-containing water, B solution 0.04% trifluoroacetic acid-containing acetonitrile, gradient cycle: 0.00 Minutes (A liquid / B liquid = 90/10), 0.01 minutes (A liquid / B liquid = 90/10), 2.00 minutes (A liquid / B liquid = 5/95), 2.75 minutes (A liquid / B liquid = 5/95), 2.76 minutes (A liquid / B liquid = 90/10), 3.45 minutes (A liquid / B liquid = 90/10), flow rate: 0.5 mL / min, detection method: UV 220 nm, ionization method: ESI positive. Or MS measuring instrument: Agilent G6100, column: ZORBAX Extend-C18 Rapid Resolution HT 3.0 × 30 mm 1.8 micron 600 bar, solvent: A solution 0.01 M ammonium acetate-containing water, B solution 0.01 M ammonium acetate-containing acetonitrile, gradient cycle : 0.00 minutes (A liquid / B liquid = 90/10), 0.20 minutes (A liquid / B liquid = 90/10), 1.50 minutes (A liquid / B liquid = 0/100), 2.00 minutes (A liquid / B Liquid = 90/10), flow rate: 1.2 mL / min, detection method: UV 220 nm, ionization method: ESI positive or ESI negative. The data described the measured value. Usually, a molecular ion peak is observed, but in the case of a compound having a tert-butoxycarbonyl group (-Boc), a peak from which the tert-butoxycarbonyl group or tert-butyl group is eliminated should be observed as a fragment ion. There is also. In the case of a compound having a hydroxyl group (—OH), a peak from which H 2 O is eliminated may be observed as a fragment ion. In the case of a salt, a free molecular ion peak or a fragment ion peak is usually observed.
 実施例における分取HPLCによる精製は以下の条件により行った。
機器: Waters社分取HPLCシステム、カラム: SunFire Prep C18 OBD5 μm 30×50 mm Column、溶媒: A液0.1%トリフルオロ酢酸含有水、B液 0.1%トリフルオロ酢酸含有アセトニトリル、グラジエントサイクル:0.00分(A液/B液 = 90/10)、1.20分(A液/B液 = 90/10)、5.20分(A液/B液 = 0/100)、7.00分(A液/B液 = 0/100)、7.01分(A液/B液 = 90/10)、8.50分(A液/B液 = 90/10)、流速: 70 mL/min、検出法: UV 220 nm。
または、機器: Waters社分取HPLCシステム、カラム: YMC CombiPrep ODS-A(50×20 mm.I.D S-5 μm, 12 nm)、溶媒: A液0.1%トリフルオロ酢酸含有水、B液 0.1%トリフルオロ酢酸含有アセトニトリル、グラジエントサイクル: 0.00分(A液/B液 = 90/10)、0.20分(A液/B液 = 90/10)、4.20分(A液/B液 = 0/100)、6.30分(A液/B液 = 0/100)、6.31分(A液/B
液 = 90/10)、流速: 25 mL/min、検出法: UV 220 nm。
Purification by preparative HPLC in the examples was performed under the following conditions.
Instrument: Waters preparative HPLC system, Column: SunFire Prep C18 OBD 5 μm 30 × 50 mm Column, Solvent: A solution 0.1% trifluoroacetic acid-containing water, B solution 0.1% trifluoroacetic acid-containing acetonitrile, Gradient cycle: 0.00 minutes ( A liquid / B liquid = 90/10), 1.20 minutes (A liquid / B liquid = 90/10), 5.20 minutes (A liquid / B liquid = 0/100), 7.00 minutes (A liquid / B liquid = 0 / 100), 7.01 minutes (A liquid / B liquid = 90/10), 8.50 minutes (A liquid / B liquid = 90/10), flow rate: 70 mL / min, detection method: UV 220 nm.
Or: Equipment: Waters preparative HPLC system, Column: YMC CombiPrep ODS-A (50 × 20 mm, ID S-5 μm, 12 nm), Solvent: A solution 0.1% trifluoroacetic acid-containing water, B solution 0.1% Acetonitrile with trifluoroacetic acid, gradient cycle: 0.00 minutes (liquid A / liquid B = 90/10), 0.20 minutes (liquid A / liquid B = 90/10), 4.20 minutes (liquid A / liquid B = 0/100) , 6.30 min (A liquid / B liquid = 0/100), 6.31 min (A liquid / B
Liquid = 90/10), flow rate: 25 mL / min, detection method: UV 220 nm.
実施例1 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]エチル
(A) 4-{2-[(メチルスルホニル)オキシ]エチル}ピペリジン-1-カルボン酸 tert-ブチル
 4-(2-ヒドロキシエチル)ピペリジン-1-カルボン酸 tert-ブチル(0.115 g)およびトリエチルアミン(0.11 mL)の酢酸エチル(10 mL)溶液を氷冷し、塩化メタンスルホニル(0.063 g)を加えて1時間かき混ぜた。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮して、表題化合物(0.192 g)を無色油状物として得た。
1H-NMR (300 MHz, CDCl3) δ: 1.05-1.22 (m, 2H), 1.45 (s, 9H), 1.54-1.76 (m, 5H), 2.61-2.79 (m, 2H), 3.01 (s, 3H), 3.99-4.20 (m, 2H), 4.29 (t, J = 6.4 Hz, 2H).
(B) 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]エチル 4-{2-[(メチルスルホニル)オキシ]エチル}ピペリジン-1-カルボン酸 tert-ブチル(0.468 g)、5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール(0.150 g)、炭酸カリウム(0.210 g)、およびヨウ化ナトリウム(0.114 g)のN,N-ジメチルホルムアミド(10 mL)懸濁液を、60℃で1日間かき混ぜた。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥して、減圧濃縮した。残留物を塩基性シリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=0:100~50:50)で精製し、得られた油状物をヘキサン/酢酸エチルから結晶化させて、表題化合物(0.110 g)を白色粉末として得た。
1H-NMR (300 MHz, CDCl3) δ: 1.10-1.26 (m, 2H), 1.39-1.78 (m, 14H), 2.61-2.78 (m,
2H), 3.03 (s, 3H), 3.20 (t, J = 8.5 Hz, 2H), 4.01-4.18 (m, 4H), 4.25-4.38 (m, 2H), 7.71 (s, 1H), 7.74-7.82 (m, 1H), 7.98 (br s, 1H).
Example 1 2- [1- (tert-Butoxycarbonyl) piperidin-4-yl] ethyl 5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylate
(A) tert-butyl 4- {2-[(methylsulfonyl) oxy] ethyl} piperidine-1-carboxylate tert-butyl 4- (2-hydroxyethyl) piperidine-1-carboxylate (0.115 g) and triethylamine ( 0.11 mL) in ethyl acetate (10 mL) was ice-cooled, methanesulfonyl chloride (0.063 g) was added, and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.192 g) as a colorless oil.
1 H-NMR (300 MHz, CDCl 3 ) δ: 1.05-1.22 (m, 2H), 1.45 (s, 9H), 1.54-1.76 (m, 5H), 2.61-2.79 (m, 2H), 3.01 (s , 3H), 3.99-4.20 (m, 2H), 4.29 (t, J = 6.4 Hz, 2H).
(B) 5- [Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- [1- (tert-butoxycarbonyl) piperidin-4-yl] ethyl 4- {2-[(methyl Sulfonyl) oxy] ethyl} piperidine-1-carboxylate tert-butyl (0.468 g), 5- (methylsulfonyl) -2,3-dihydro-1H-indole (0.150 g), potassium carbonate (0.210 g), and iodine A suspension of sodium chloride (0.114 g) in N, N-dimethylformamide (10 mL) was stirred at 60 ° C. for 1 day. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 0: 100-50: 50), and the resulting oil was crystallized from hexane / ethyl acetate to give the title compound (0.110 g). Obtained as a white powder.
1 H-NMR (300 MHz, CDCl 3 ) δ: 1.10-1.26 (m, 2H), 1.39-1.78 (m, 14H), 2.61-2.78 (m,
2H), 3.03 (s, 3H), 3.20 (t, J = 8.5 Hz, 2H), 4.01-4.18 (m, 4H), 4.25-4.38 (m, 2H), 7.71 (s, 1H), 7.74-7.82 (m, 1H), 7.98 (br s, 1H).
実施例2 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸 3-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]プロピル
(A) 4-{3-[(メチルスルホニル)オキシ]プロピル}ピペリジン-1-カルボン酸 tert-ブチル 4-(3-ヒドロキシプロピル)ピペリジン-1-カルボン酸 tert-ブチル(0.450 g)およびトリエチルアミン(0.39 mL)の酢酸エチル(20 mL)溶液を氷冷し、塩化メタンスルホニル(0.16 mL)を加えて1時間かき混ぜた。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮して、表題化合物(0.642 g)
を無色油状物として得た。
1H-NMR (300 MHz, CDCl3) δ: 1.02-1.18 (m, 2H), 1.30-1.51 (m, 12H), 1.60-1.71 (m,
2H), 1.72-1.84 (m, 2H), 2.59-2.75 (m, 2H), 3.01 (s, 3H), 4.00-4.16 (m, 2H), 4.22 (t, J= 6.6 Hz, 2H).
(B) 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸3-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]プロピル
 4-{3-[(メチルスルホニル)オキシ]プロピル}ピペリジン-1-カルボン酸 tert-ブチル(0.489 g)、5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール(0.150 g)、炭酸カリウム(0.210 g)、およびヨウ化ナトリウム(0.114 g)のN,N-ジメチルホルムアミド(10 mL)懸濁液を、60℃で1日間かき混ぜた。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥して、減圧濃縮した。残留物を塩基性シリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=0:100~40:60)で精製し、得られた油状物をヘキサン/酢酸エチルから結晶化させて、表題化合物(0.066 g)を白色粉末として得た。
1H-NMR (300 MHz, CDCl3) δ: 1.02-1.20 (m, 2H), 1.30-1.50 (m, 12H), 1.61-1.84 (m, 4H), 2.60-2.75 (m, 2H), 3.03 (s, 3H), 3.20 (t, J = 8.9 Hz, 2H), 3.99-4.17 (m, 4H), 4.25 (t, J= 6.2 Hz, 2H), 7.69-7.72 (m, 1H), 7.77 (dd, J = 8.7, 1.5 Hz, 1H), 7.97 (br s, 1H).
Example 2 5- (Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 3- [1- (tert-butoxycarbonyl) piperidin-4-yl] propyl
(A) tert-butyl 4- {3-[(methylsulfonyl) oxy] propyl} piperidine-1-carboxylate tert-butyl 4- (3-hydroxypropyl) piperidine-1-carboxylate (0.450 g) and triethylamine ( 0.39 mL) in ethyl acetate (20 mL) was ice-cooled, methanesulfonyl chloride (0.16 mL) was added, and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.642 g)
Was obtained as a colorless oil.
1 H-NMR (300 MHz, CDCl 3 ) δ: 1.02-1.18 (m, 2H), 1.30-1.51 (m, 12H), 1.60-1.71 (m,
2H), 1.72-1.84 (m, 2H), 2.59-2.75 (m, 2H), 3.01 (s, 3H), 4.00-4.16 (m, 2H), 4.22 (t, J = 6.6 Hz, 2H).
(B) 5- [Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 3- [1- (tert-butoxycarbonyl) piperidin-4-yl] propyl 4- {3-[(methyl Sulfonyl) oxy] propyl} piperidine-1-carboxylate tert-butyl (0.489 g), 5- (methylsulfonyl) -2,3-dihydro-1H-indole (0.150 g), potassium carbonate (0.210 g), and iodine A suspension of sodium chloride (0.114 g) in N, N-dimethylformamide (10 mL) was stirred at 60 ° C. for 1 day. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 0: 100-40: 60), and the obtained oil was crystallized from hexane / ethyl acetate to give the title compound (0.066 g). Obtained as a white powder.
1 H-NMR (300 MHz, CDCl 3 ) δ: 1.02-1.20 (m, 2H), 1.30-1.50 (m, 12H), 1.61-1.84 (m, 4H), 2.60-2.75 (m, 2H), 3.03 (s, 3H), 3.20 (t, J = 8.9 Hz, 2H), 3.99-4.17 (m, 4H), 4.25 (t, J = 6.2 Hz, 2H), 7.69-7.72 (m, 1H), 7.77 ( dd, J = 8.7, 1.5 Hz, 1H), 7.97 (br s, 1H).
実施例3 5-ブロモ-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]エチル
 5-ブロモインドリン(0.198 g)およびトリエチルアミン(0.21 mL)の酢酸エチル(10 mL)溶液に、氷冷下、トリホスゲン(0.386 g)を滴下して2時間かき混ぜた。反応液に飽和重曹水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥して、減圧濃縮した。残留物をテトラヒドロフラン(10 mL)に溶解させ、氷冷下、4-(2-ヒドロキシエチル)ピペリジン-1-カルボン酸 tert-ブチル(0.252 g)および水素化ナトリウム(油性、60%、0.052 g)を加えて、徐々に室温まで昇温しつつ、終夜かき混ぜた。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥して、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=0:100~20:80)で精製して、表題化合物(0.335 g)を無色油状物として得た。
1H-NMR (300 MHz, CDCl3) δ: 1.06-1.30 (m, 2H), 1.37-1.53 (m, 9H), 1.64-1.79 (m, 4H), 2.69 (t, J = 12.1 Hz, 2H), 3.11 (t, J = 8.7 Hz, 2H), 3.92-4.41 (m, 7H), 7.16-7.39 (m, 2H), 7.73 (s, 1H).
Example 3 2- [1- (tert-Butoxycarbonyl) piperidin-4-yl] ethyl 5-bromo-2,3-dihydro-1H-indole-1-carboxylate 5-bromoindoline (0.198 g) and triethylamine ( To a solution of 0.21 mL) in ethyl acetate (10 mL), triphosgene (0.386 g) was added dropwise under ice cooling, and the mixture was stirred for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL). Was added, and the mixture was stirred overnight while gradually warming to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 0: 100-20: 80) to give the title compound (0.335 g) as a colorless oil.
1 H-NMR (300 MHz, CDCl 3 ) δ: 1.06-1.30 (m, 2H), 1.37-1.53 (m, 9H), 1.64-1.79 (m, 4H), 2.69 (t, J = 12.1 Hz, 2H ), 3.11 (t, J = 8.7 Hz, 2H), 3.92-4.41 (m, 7H), 7.16-7.39 (m, 2H), 7.73 (s, 1H).
実施例4 5-(2-オキソピロリジン-1-イル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸 2-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]エチル 5-ブロモ-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]エチル(0.335 g)、2-ピロリドン(0.094 g)、トリス(ジベンジリデンアセトン)二パラジウム(0)(0.026 g)、5-(ジ-tert-ブチルホスフィノ)-1',3',5'-トリフェニル-1'H-[1,4']ビピラゾール(Bippyphos)(0.028 g)、およびナトリウム tert-ブトキシド(0.107 g)のtert-ブタノール(7 mL)および水(0.7 mL)混合液を、アルゴン雰囲気下、80℃で6時間かき混ぜた。反応液を冷却後、水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=20:80‐70:30)で精製して、白色固体を得た。得られた固体をヘキサン/酢酸エチルから再結晶して、表題化合物(0.236 g)を白色粉末として得た。
1H-NMR (300 MHz, CDCl3) δ: 1.07-1.28 (m, 2H), 1.46 (s, 9H), 1.54-1.80 (m, 5H), 2.07-2.27 (m, 2H), 2.47-2.81 (m, 4H), 3.14 (t, J = 8.5 Hz, 2H), 3.84 (t, J= 7.2 Hz, 2H), 3.94-4.19 (m, 4H), 4.22-4.39 (m, 2H), 7.07-7.21 (m, 1H), 7.50-7.94 (m, 2H).
Example 4 5- (2-Oxopyrrolidin-1-yl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- [1- (tert-butoxycarbonyl) piperidin-4-yl] ethyl 5- Bromo-2,3-dihydro-1H-indole-1-carboxylate 2- [1- (tert-butoxycarbonyl) piperidin-4-yl] ethyl (0.335 g), 2-pyrrolidone (0.094 g), tris (di Benzylideneacetone) dipalladium (0) (0.026 g), 5- (di-tert-butylphosphino) -1 ', 3', 5'-triphenyl-1'H- [1,4 '] bipyrazole (Bippyphos ) (0.028 g) and sodium tert-butoxide (0.107 g) in tert-butanol (7 mL) and water (0.7 mL) were stirred at 80 ° C. for 6 hours under an argon atmosphere. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 20: 80-70: 30) to give a white solid. The obtained solid was recrystallized from hexane / ethyl acetate to give the title compound (0.236 g) as a white powder.
1 H-NMR (300 MHz, CDCl 3 ) δ: 1.07-1.28 (m, 2H), 1.46 (s, 9H), 1.54-1.80 (m, 5H), 2.07-2.27 (m, 2H), 2.47-2.81 (m, 4H), 3.14 (t, J = 8.5 Hz, 2H), 3.84 (t, J = 7.2 Hz, 2H), 3.94-4.19 (m, 4H), 4.22-4.39 (m, 2H), 7.07- 7.21 (m, 1H), 7.50-7.94 (m, 2H).
実施例5 5-(2-オキソピロリジン-1-イル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸 2-{1-[5-(1-メチルエチル)-4-オキソ-4,5-ジヒドロ-1,3-オキサゾール-2-イル]ピペリジン-4-イル}エチル
(A) 2-ヒドロキシ-3-メチルブタン酸エチル
 2-ヒドロキシ-3-メチルブタン酸(1.0 g)のエタノール(50 mL)溶液に濃硫酸(0.045 mL)を加え、終夜加熱還流した。反応液を冷却後、減圧濃縮した。残留物を酢酸エチルに溶解させ、飽和重曹水および飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮して、表題化合物(0.68 g)を無色油状物として得た。
1H-NMR (300 MHz, DMSO-d6) δ: 0.83 (d, J = 8.00 Hz, 3H), 0.87 (d, J = 8.00 Hz, 3H), 1.19 (t, J = 7.19 Hz, 3H), 1.91 (dq, J = 12.12, 6.82 Hz, 1H), 3.78 (dd, J = 5.87, 5.11 Hz, 1H), 4.10 (qd, J = 7.19, 2.27 Hz, 2H), 5.21 (d, J = 6.06 Hz, 1H).(B) 2-アミノ-5-(1-メチルエチル)-1,3-オキサゾール-4(5H)-オン
 2-ヒドロキシ-3-メチルブタン酸エチル(0.68 g)およびグアニジン炭酸塩(0.838 g)のエタノール(20 mL)溶液を終夜加熱還流した。反応液を冷却後、減圧濃縮した。残留物を酢酸エチルに溶解させ、飽和重曹水および飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル)で精製して、表題化合物(0.035 g)を白色結晶として得た。
1H-NMR (300 MHz, DMSO-d6) δ: 0.80 (d, J = 7.19 Hz, 3H), 0.98 (d, J = 6.82 Hz, 3H), 1.89-2.21 (m, 1H), 4.52 (d, J = 3.79 Hz, 1H), 8.30 (br s, 2H).
(C) 5-(2-オキソピロリジン-1-イル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-(ピ
ペリジン-4-イル)エチル
 5-(2-オキソピロリジン-1-イル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]エチル(6.8 g)を氷冷したトリフルオロ酢酸(30 mL)に加え、2時間かき混ぜた。反応液に水を加え、8 M水酸化ナトリウム水溶液で塩基性にして、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残留物をヘキサン/酢酸エチルから再結晶して、表題化合物(4.40 g)を白色粉末として得た。
MS (ESI+): 358.
(D) 5-(2-オキソピロリジン-1-イル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-{1-[5-(1-メチルエチル)-4-オキソ-4,5-ジヒドロ-1,3-オキサゾール-2-イル]ピペリジン-4-イル}エチル
 5-(2-オキソピロリジン-1-イル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-(ピペリジン-4-イル)エチル(0.264 g)および2-アミノ-5-(1-メチルエチル)-1,3-オキサゾール-4(5H)-オン(0.035 g)のエタノール(3 mL)溶液をマイクロウェーブ照射下、130℃で30分間反応させた。反応液を減圧濃縮し、残留物をシリカゲルクロマトグラフィー(メタノール:酢酸エチル=0:100~10:90)で精製して、表題化合物(0.004 g)を淡黄色油状物として得た。
1H-NMR (300 MHz, CDCl3) δ: 0.89-0.98 (m, 3H), 1.05-1.14 (m, 3H), 1.53-1.79 (m, 4H), 1.89 (d, J = 12.87 Hz, 2H), 1.99-2.35 (m, 4H), 2.60 (t, J = 8.14 Hz, 2H), 2.89-3.22 (m, 4H), 3.84 (t, J = 7.19 Hz, 2H), 4.01 (t, J = 7.76 Hz, 2H), 4.15-4.38 (m, 3H), 4.44 (dd, J = 13.44, 1.70 Hz, 1H), 4.54 (d, J = 3.79 Hz, 1H), 7.10-7.23 (m, 1H), 7.58-7.88 (m, 2H).
Example 5 5- (2-oxopyrrolidin-1-yl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- {1- [5- (1-methylethyl) -4-oxo-4 , 5-Dihydro-1,3-oxazol-2-yl] piperidin-4-yl} ethyl
(A) Ethyl 2-hydroxy-3-methylbutanoate To a solution of 2-hydroxy-3-methylbutanoic acid (1.0 g) in ethanol (50 mL) was added concentrated sulfuric acid (0.045 mL), and the mixture was heated to reflux overnight. The reaction mixture was cooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.68 g) as a colorless oil.
1 H-NMR (300 MHz, DMSO-d 6 ) δ: 0.83 (d, J = 8.00 Hz, 3H), 0.87 (d, J = 8.00 Hz, 3H), 1.19 (t, J = 7.19 Hz, 3H) , 1.91 (dq, J = 12.12, 6.82 Hz, 1H), 3.78 (dd, J = 5.87, 5.11 Hz, 1H), 4.10 (qd, J = 7.19, 2.27 Hz, 2H), 5.21 (d, J = 6.06 Hz, 1H). (B) 2-Amino-5- (1-methylethyl) -1,3-oxazol-4 (5H) -one ethyl 2-hydroxy-3-methylbutanoate (0.68 g) and guanidine carbonate A solution of (0.838 g) in ethanol (20 mL) was heated to reflux overnight. The reaction mixture was cooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (0.035 g) as white crystals.
1 H-NMR (300 MHz, DMSO-d 6 ) δ: 0.80 (d, J = 7.19 Hz, 3H), 0.98 (d, J = 6.82 Hz, 3H), 1.89-2.21 (m, 1H), 4.52 ( d, J = 3.79 Hz, 1H), 8.30 (br s, 2H).
(C) 5- (2-Oxopyrrolidin-1-yl) -2,3-dihydro-1H-indole-1-carboxylate 2- (piperidin-4-yl) ethyl 5- (2-oxopyrrolidin-1- Yl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- [1- (tert-butoxycarbonyl) piperidin-4-yl] ethyl (6.8 g) in ice-cooled trifluoroacetic acid (30 mL) And stirred for 2 hours. Water was added to the reaction mixture, and the mixture was basified with 8 M aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from hexane / ethyl acetate to give the title compound (4.40 g) as a white powder.
MS (ESI +): 358.
(D) 5- (2-oxopyrrolidin-1-yl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- {1- [5- (1-methylethyl) -4-oxo-4 , 5-Dihydro-1,3-oxazol-2-yl] piperidin-4-yl} ethyl 5- (2-oxopyrrolidin-1-yl) -2,3-dihydro-1H-indole-1-carboxylic acid 2 -(Piperidin-4-yl) ethyl (0.264 g) and 2-amino-5- (1-methylethyl) -1,3-oxazol-4 (5H) -one (0.035 g) in ethanol (3 mL) Was reacted at 130 ° C. for 30 minutes under microwave irradiation. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (methanol: ethyl acetate = 0: 100 to 10:90) to give the title compound (0.004 g) as a pale yellow oil.
1 H-NMR (300 MHz, CDCl 3 ) δ: 0.89-0.98 (m, 3H), 1.05-1.14 (m, 3H), 1.53-1.79 (m, 4H), 1.89 (d, J = 12.87 Hz, 2H ), 1.99-2.35 (m, 4H), 2.60 (t, J = 8.14 Hz, 2H), 2.89-3.22 (m, 4H), 3.84 (t, J = 7.19 Hz, 2H), 4.01 (t, J = 7.76 Hz, 2H), 4.15-4.38 (m, 3H), 4.44 (dd, J = 13.44, 1.70 Hz, 1H), 4.54 (d, J = 3.79 Hz, 1H), 7.10-7.23 (m, 1H), 7.58-7.88 (m, 2H).
実施例6 5-(2-オキソピロリジン-1-イル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸 2-{1-[(テトラヒドロフラン-3-イルオキシ)カルボニル]ピペリジン-4-イル}エチル
 3-ヒドロキシテトラヒドロフラン(0.046 mL)のエーテル(5 mL)溶液にトリホスゲン(0.0556 g)およびピリジン(0.046 mL)を氷冷下で加え、1時間かき混ぜた。反応液をろ過し、ろ液を減圧濃縮した。残留物をテトラヒドロフラン(5 mL)に溶解させ、5-(2-オキソピロリジン-1-イル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸 2-(ピペリジン-4-イル)エチル(0.203 g)およびN,N-ジイソプロピルエチルアミン(0.099 mL)を加え、室温で終夜かき混ぜた。反応液を水に加え、酢酸エチルで抽出した。有機相を飽和重曹水および飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(メタノール:酢酸エチル=0:100~20:80)で精製して、表題化合物(0.036 g)を淡黄色油状物として得た。
1H-NMR (300 MHz, CDCl3) δ: 1.18 (d, J = 11.68 Hz, 2H), 1.50-1.83 (m, 5H), 1.94-2.08 (m, 1H), 2.09-2.25 (m, 3H), 2.60 (t, J = 8.10 Hz, 2H), 2.76 (t, J = 12.06 Hz, 2H), 3.14 (t, J = 8.48 Hz, 2H), 3.76-3.95 (m, 6H), 3.95-4.20 (m, 4H), 4.27 (br s, 2H), 5.25 (td, J = 4.24, 2.07 Hz, 1H), 6.99-7.23 (m, 1H), 7.34-7.91 (m, 2H).
Example 6 5- (2-Oxopyrrolidin-1-yl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- {1-[(tetrahydrofuran-3-yloxy) carbonyl] piperidin-4-yl } Triphosgene (0.0556 g) and pyridine (0.046 mL) were added to an ether (5 mL) solution of ethyl 3-hydroxytetrahydrofuran (0.046 mL) under ice cooling, and the mixture was stirred for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL) and 5- (2-oxopyrrolidin-1-yl) -2,3-dihydro-1H-indole-1-carboxylate 2- (piperidin-4-yl) ethyl ( 0.203 g) and N, N-diisopropylethylamine (0.099 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was added to water and extracted with ethyl acetate. The organic phase was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: ethyl acetate = 0: 100-20: 80) to give the title compound (0.036 g) as a pale yellow oil.
1 H-NMR (300 MHz, CDCl 3 ) δ: 1.18 (d, J = 11.68 Hz, 2H), 1.50-1.83 (m, 5H), 1.94-2.08 (m, 1H), 2.09-2.25 (m, 3H ), 2.60 (t, J = 8.10 Hz, 2H), 2.76 (t, J = 12.06 Hz, 2H), 3.14 (t, J = 8.48 Hz, 2H), 3.76-3.95 (m, 6H), 3.95-4.20 (m, 4H), 4.27 (br s, 2H), 5.25 (td, J = 4.24, 2.07 Hz, 1H), 6.99-7.23 (m, 1H), 7.34-7.91 (m, 2H).
実施例7 5-(2-オキソピロリジン-1-イル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸 2-[1-(2-エトキシ-2-オキソエチル)ピペリジン-4-イル]エチル
 5-(2-オキソピロリジン-1-イル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-(ピペリジン-4-イル)エチル(0.100 g)、ブロモ酢酸エチル(0.031 mL)、および炭酸カリウム(0.077 g)のN,N-ジメチルホルムアミド(3 mL)懸濁液を80℃で終夜かき混ぜた。反応液を水に加え、酢酸エチルで抽出した。有機相を水および飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル)で精製して、表題化合物(0.090 g)を無色油状物として得た。
1H-NMR (300 MHz, DMSO-d6) δ: 1.09-1.28 (m, 5H), 1.30-1.45 (m, 1H), 1.52-1.72 (m, 4H), 1.97-2.19 (m, 4H), 2.41-2.47 (m, 2H), 2.80 (d, J = 11.30 Hz, 2H), 3.10 (t, J = 8.67 Hz, 2H), 3.15 (s, 2H), 3.79 (t, J = 6.97 Hz, 2H), 3.95 (t, J = 8.67 Hz, 2H), 4.07 (q, J = 7.16 Hz, 2H), 4.18 (br s, 2H), 7.37 (d, J = 1.88 Hz, 1H), 7.52-7.74 (m, 2H).
Example 7 5- (2-Oxopyrrolidin-1-yl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- [1- (2-ethoxy-2-oxoethyl) piperidin-4-yl] Ethyl 5- (2-oxopyrrolidin-1-yl) -2,3-dihydro-1H-indole-1-carboxylate 2- (piperidin-4-yl) ethyl (0.100 g), ethyl bromoacetate (0.031 mL) , And a suspension of potassium carbonate (0.077 g) in N, N-dimethylformamide (3 mL) was stirred at 80 ° C. overnight. The reaction mixture was added to water and extracted with ethyl acetate. The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (0.090 g) as a colorless oil.
1 H-NMR (300 MHz, DMSO-d 6 ) δ: 1.09-1.28 (m, 5H), 1.30-1.45 (m, 1H), 1.52-1.72 (m, 4H), 1.97-2.19 (m, 4H) , 2.41-2.47 (m, 2H), 2.80 (d, J = 11.30 Hz, 2H), 3.10 (t, J = 8.67 Hz, 2H), 3.15 (s, 2H), 3.79 (t, J = 6.97 Hz, 2H), 3.95 (t, J = 8.67 Hz, 2H), 4.07 (q, J = 7.16 Hz, 2H), 4.18 (br s, 2H), 7.37 (d, J = 1.88 Hz, 1H), 7.52-7.74 (m, 2H).
実施例8 5-(2-オキソピロリジン-1-イル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸 2-{1-[tert-ブチル(メチル)カルバモイル]ピペリジン-4-イル}エチル
 トリホスゲン(0.164 g)のテトラヒドロフラン(5 mL)溶液に、氷冷下、ピリジン(0.135 mL)を加え、次いで、N-メチル-tert-ブチルアミン(0.2 mL)を加えて、室温で3日間かき混ぜた。反応液を減圧濃縮し、残留物にジエチルエーテルを加えた。析出した結晶をろ別し、ろ液を減圧濃縮した。残留物、5-(2-オキソピロリジン-1-イル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-(ピペリジン-4-イル)エチル(0.0745 g)、およびN,N-ジイソプロピルエチルアミン(0.073 mL)のテトラヒドロフラン(3 mL)溶液を室温で終夜かき混ぜた。反応液を水に加え、酢酸エチルで抽出した。有機相を飽和重曹水および飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル)で精製して、表題化合物(0.0325 g)を無色油状物として得た。
1H-NMR (300 MHz, CDCl3) δ: 1.04-1.27 (m, 2H), 1.30 (s, 9H), 1.56-1.79 (m, 6H), 2.15 (quin, J = 7.57 Hz, 2H), 2.58 (t, J = 8.14 Hz, 2H), 2.65-2.80 (m, 4H), 3.14
(t, J = 8.71 Hz, 2H), 3.73-3.88 (m, 4H), 4.02 (t, J = 8.52 Hz, 2H), 4.27 (br s, 2H), 7.16 (br s, 1H), 7.49-7.90 (m, 2H).
Example 8 5- (2-Oxopyrrolidin-1-yl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- {1- [tert-butyl (methyl) carbamoyl] piperidin-4-yl} To a solution of ethyl triphosgene (0.164 g) in tetrahydrofuran (5 mL) was added pyridine (0.135 mL) under ice-cooling, then N-methyl-tert-butylamine (0.2 mL) was added, and the mixture was stirred at room temperature for 3 days. . The reaction solution was concentrated under reduced pressure, and diethyl ether was added to the residue. The precipitated crystals were filtered off, and the filtrate was concentrated under reduced pressure. Residue, 5- (2-oxopyrrolidin-1-yl) -2,3-dihydro-1H-indole-1-carboxylate 2- (piperidin-4-yl) ethyl (0.0745 g), and N, N- A solution of diisopropylethylamine (0.073 mL) in tetrahydrofuran (3 mL) was stirred at room temperature overnight. The reaction mixture was added to water and extracted with ethyl acetate. The organic phase was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (0.0325 g) as a colorless oil.
1 H-NMR (300 MHz, CDCl 3 ) δ: 1.04-1.27 (m, 2H), 1.30 (s, 9H), 1.56-1.79 (m, 6H), 2.15 (quin, J = 7.57 Hz, 2H), 2.58 (t, J = 8.14 Hz, 2H), 2.65-2.80 (m, 4H), 3.14
(t, J = 8.71 Hz, 2H), 3.73-3.88 (m, 4H), 4.02 (t, J = 8.52 Hz, 2H), 4.27 (br s, 2H), 7.16 (br s, 1H), 7.49- 7.90 (m, 2H).
実施例9 5-(2-オキソピロリジン-1-イル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸 2-{1-[5-(1-メチルエチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]ピペリジン-4-イル}
エチル
(A) 5-(2-オキソピロリジン-1-イル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸 2-{1-[(Z)-(メチルスルファニル){[(トリメチルシリル)メチル]イミノ}メチル]ピペリジン-4-
イル}エチル
 トリメチルシリルメチルアジド(0.500 g)およびトリフェニルホスフィン(1.02 g)の二硫化炭素(4 mL)溶液を室温で2時間かき混ぜた。反応液をろ過し、ろ液を減圧濃縮した。残留物をヘキサンに溶解させ、再度ろ過した後、ろ液を減圧濃縮した。残留物および5-(2-オキソピロリジン-1-イル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-(ピペリジン-4-イル)エチル(0.2 g)のエタノール(5 mL)溶液を室温で30分間かき混ぜた。反応液にヨードメタン(0.042 mL)を加えて、さらに終夜加熱還流した。反応液を減圧濃縮し、残留物を酢酸エチルに溶解させた。その溶液を飽和重曹水および飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル)で精製して、表題化合物(0.1 g)を無色油状物として得た。
1H-NMR (300 MHz, CDCl3) δ: 0.00 (s, 9H), 1.14-1.33 (m, 3H), 1.61-1.79 (m, 4H), 2.13 (quin, J = 7.63 Hz, 2H), 2.24 (s, 3H), 2.51-2.70 (m, 4H), 3.11 (t, J = 8.67 Hz, 2H), 3.21 (s, 2H), 3.74 (d, J = 12.81 Hz, 2H), 3.81 (t, J = 6.97 Hz, 2H), 3.99 (t, J = 8.29 Hz, 2H), 4.25 (br s, 2H), 7.13 (d, J = 6.40 Hz, 1H), 7.33-7.86 (m, 2H).
(B) 5-(2-オキソピロリジン-1-イル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸 2-{1-[5-(1-メチルエチル)-4,5-ジヒドロ-1,3-オキサゾール-2-イル]ピペリジン-4-イル}エチル
 5-(2-オキソピロリジン-1-イル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸 2-{1-[(Z)-(メチルスルファニル){[(トリメチルシリル)メチル]イミノ}メチル]ピペリジン-4-イル}エチル(0.100 g)、イソブチルアルデヒド(0.035 mL)、およびフッ化セシウム(0.0353 g)のN,N-ジメチルホルムアミド(2 mL)混合液を80℃で終夜かき混ぜた。反応液を水に加え、酢酸エチルで抽出した。有機相を飽和重曹水および飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル)で精製して、表題化合物(0.0032 g)を無色油状物として得た。
1H-NMR (300 MHz, CDCl3) δ: 0.75-0.92 (m, 4H), 0.96 (d, J = 6.82 Hz, 3H), 1.49-1.90 (m, 7H), 2.15 (quin, J = 7.57 Hz, 2H), 2.60 (t, J = 8.14 Hz, 2H), 2.80 (td, J = 12.68, 2.27 Hz, 2H), 3.14 (t, J = 8.52 Hz, 2H), 3.46 (dd, J = 12.12, 7.57 Hz, 1H), 3.75 (d, J = 9.09 Hz, 1H), 3.83 (t, J = 7.00 Hz, 1H), 3.89-4.15 (m, 5H), 4.16-4.35 (m, 3H), 7.16 (br s, 1H), 7.46-7.97 (m, 2H).
Example 9 5- (2-oxopyrrolidin-1-yl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- {1- [5- (1-methylethyl) -4,5-dihydro -1,3-oxazol-2-yl] piperidin-4-yl}
ethyl
(A) 5- (2-Oxopyrrolidin-1-yl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- {1-[(Z)-(methylsulfanyl) {[(trimethylsilyl) methyl ] Imino} methyl] piperidine-4-
Il} ethyl trimethylsilylmethyl azide (0.500 g) and triphenylphosphine (1.02 g) in carbon disulfide (4 mL) were stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in hexane and filtered again, and the filtrate was concentrated under reduced pressure. Residue and 5- (2-oxopyrrolidin-1-yl) -2,3-dihydro-1H-indole-1-carboxylate 2- (piperidin-4-yl) ethyl (0.2 g) in ethanol (5 mL) The solution was stirred for 30 minutes at room temperature. To the reaction solution was added iodomethane (0.042 mL), and the mixture was further heated to reflux overnight. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (0.1 g) as a colorless oil.
1 H-NMR (300 MHz, CDCl 3 ) δ: 0.00 (s, 9H), 1.14-1.33 (m, 3H), 1.61-1.79 (m, 4H), 2.13 (quin, J = 7.63 Hz, 2H), 2.24 (s, 3H), 2.51-2.70 (m, 4H), 3.11 (t, J = 8.67 Hz, 2H), 3.21 (s, 2H), 3.74 (d, J = 12.81 Hz, 2H), 3.81 (t , J = 6.97 Hz, 2H), 3.99 (t, J = 8.29 Hz, 2H), 4.25 (br s, 2H), 7.13 (d, J = 6.40 Hz, 1H), 7.33-7.86 (m, 2H).
(B) 5- (2-oxopyrrolidin-1-yl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- {1- [5- (1-methylethyl) -4,5-dihydro -1,3-oxazol-2-yl] piperidin-4-yl} ethyl 5- (2-oxopyrrolidin-1-yl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- {1- [(Z)-(methylsulfanyl) {[(trimethylsilyl) methyl] imino} methyl] piperidin-4-yl} ethyl (0.100 g), isobutyraldehyde (0.035 mL), and cesium fluoride (0.0353 g) N, A mixture of N-dimethylformamide (2 mL) was stirred at 80 ° C. overnight. The reaction mixture was added to water and extracted with ethyl acetate. The organic phase was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (0.0032 g) as a colorless oil.
1 H-NMR (300 MHz, CDCl 3 ) δ: 0.75-0.92 (m, 4H), 0.96 (d, J = 6.82 Hz, 3H), 1.49-1.90 (m, 7H), 2.15 (quin, J = 7.57 Hz, 2H), 2.60 (t, J = 8.14 Hz, 2H), 2.80 (td, J = 12.68, 2.27 Hz, 2H), 3.14 (t, J = 8.52 Hz, 2H), 3.46 (dd, J = 12.12 , 7.57 Hz, 1H), 3.75 (d, J = 9.09 Hz, 1H), 3.83 (t, J = 7.00 Hz, 1H), 3.89-4.15 (m, 5H), 4.16-4.35 (m, 3H), 7.16 (br s, 1H), 7.46-7.97 (m, 2H).
実施例10 2,3-ジヒドロ-1H-インドール-1,5-ジカルボン酸5-メチル1-{2-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]エチル}
(A) 2,3-ジヒドロ-1H-インドール-5-カルボン酸メチル インドール-5-カルボン酸メチル(5.03 g)をトリフルオロ酢酸(70 mL)に溶解させ、氷冷下、トリエチルシラン(9.15 mL)を加えた後、室温まで昇温して24時間かき混ぜた。反応液を減圧濃縮し、残留物を水で希釈後、飽和重曹水で塩基性にして、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=25:75~75:25)で精製し、得られた固体をヘプタン/酢酸エチルで洗浄して、表題化合物(1.53 g)を淡茶色固体として得た。
MS (ESI+): 178.
(B) 2,3-ジヒドロ-1H-インドール-1,5-ジカルボン酸5-メチル 1-{2-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]エチル}
 4-(2-ヒドロキシエチル)ピペリジン-1-カルボン酸 tert-ブチル(2.29 g)およびトリホスゲン(0.989 g)のジエチルエーテル(100 mL)溶液に、窒素雰囲気下、ピリジン(0.809 mL)のジエチルエーテル(50 mL)溶液を-40℃で滴下し、滴下終了後、徐々に0℃まで昇温しつつ5時間かき混ぜた。反応液をろ過し、ろ液を減圧濃縮した。残留物をテトラヒドロフラン(100 mL)に溶解させ、この溶液に2,3-ジヒドロ-1H-インドール-5-カルボン酸メチル(1.18 g)およびN,N-ジイソプロピルエチルアミン(2.32 mL)を加え、室温で14時間かき混ぜた。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥して、減圧濃縮した。残留物を塩基性シリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=10:90~50:50)で精製し、得られた固体をヘプタン/酢酸エチルで洗浄して、表題化合物(1.78 g)を白色固体として得た。
1H-NMR (300 MHz, CDCl3) δ: 1.09-1.26 (m, 2H), 1.41-1.79 (m, 14H), 2.62-2.78 (m, 2H), 3.16 (t, J= 8.7 Hz, 2H), 3.89 (s, 3H), 4.01-4.18 (m, 4H), 4.22-4.39 (m, 2H), 7.80-7.96 (m, 3H).
Example 10 2,3-Dihydro-1H-indole-1,5-dicarboxylate 5-methyl 1- {2- [1- (tert-butoxycarbonyl) piperidin-4-yl] ethyl}
(A) Methyl 2,3-dihydro-1H-indole-5-carboxylate Methyl indole-5-carboxylate (5.03 g) was dissolved in trifluoroacetic acid (70 mL), and triethylsilane (9.15 mL) was cooled with ice. ) Was added, and the mixture was warmed to room temperature and stirred for 24 hours. The reaction mixture was concentrated under reduced pressure, the residue was diluted with water, basified with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 25: 75 to 75:25), and the obtained solid was washed with heptane / ethyl acetate to give the title compound (1.53 g) as a light brown solid. Obtained.
MS (ESI +): 178.
(B) 2,3-Dihydro-1H-indole-1,5-dicarboxylate 5-methyl 1- {2- [1- (tert-butoxycarbonyl) piperidin-4-yl] ethyl}
4- (2-Hydroxyethyl) piperidine-1-carboxylate tert-butyl (2.29 g) and triphosgene (0.989 g) in diethyl ether (100 mL) under a nitrogen atmosphere with pyridine (0.809 mL) in diethyl ether ( 50 mL) solution was added dropwise at −40 ° C., and after completion of the addition, the mixture was stirred for 5 hours while gradually warming to 0 ° C. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (100 mL), and methyl 2,3-dihydro-1H-indole-5-carboxylate (1.18 g) and N, N-diisopropylethylamine (2.32 mL) were added to this solution at room temperature. Stir for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 10: 90-50: 50), and the resulting solid was washed with heptane / ethyl acetate to give the title compound (1.78 g) as a white solid Got as.
1 H-NMR (300 MHz, CDCl 3 ) δ: 1.09-1.26 (m, 2H), 1.41-1.79 (m, 14H), 2.62-2.78 (m, 2H), 3.16 (t, J = 8.7 Hz, 2H ), 3.89 (s, 3H), 4.01-4.18 (m, 4H), 4.22-4.39 (m, 2H), 7.80-7.96 (m, 3H).
実施例11 1-({2-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]エトキシ}カルボニル)-2,3-ジヒドロ-1H-インドール-5-カルボン酸
 2,3-ジヒドロ-1H-インドール-1,5-ジカルボン酸 5-メチル1-{2-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]エチル}(1.72 g)のメタノール(8 mL)およびテトラヒドロフラン(16 mL)混合溶液に、1 M水酸化ナトリウム水溶液(8 mL)を加え、50℃で3時間かき混ぜた。反応液を減圧濃縮し、水で希釈後、1 M塩酸で中和した。析出した固体をろ取し、乾燥して、表題化合物(1.09 g)をオフホワイト色粉末として得た。
1H-NMR (300 MHz, CDCl3) δ: 1.09-1.27 (m, 2H), 1.46 (s, 9H), 1.50-1.78 (m, 5H), 2.62-2.77 (m, 2H), 3.18 (t, J = 8.7 Hz, 2H), 3.99-4.18 (m, 4H), 4.23-4.40 (m, 2H), 7.80-8.04 (m, 3H).
Example 11 1-({2- [1- (tert-butoxycarbonyl) piperidin-4-yl] ethoxy} carbonyl) -2,3-dihydro-1H-indole-5-carboxylic acid 2,3-dihydro-1H -Indole-1,5-dicarboxylic acid 5-methyl 1- {2- [1- (tert-butoxycarbonyl) piperidin-4-yl] ethyl} (1.72 g) in methanol (8 mL) and tetrahydrofuran (16 mL) To the mixed solution was added 1 M aqueous sodium hydroxide solution (8 mL), and the mixture was stirred at 50 ° C. for 3 hr. The reaction solution was concentrated under reduced pressure, diluted with water, and neutralized with 1 M hydrochloric acid. The precipitated solid was collected by filtration and dried to give the title compound (1.09 g) as an off-white powder.
1 H-NMR (300 MHz, CDCl 3 ) δ: 1.09-1.27 (m, 2H), 1.46 (s, 9H), 1.50-1.78 (m, 5H), 2.62-2.77 (m, 2H), 3.18 (t , J = 8.7 Hz, 2H), 3.99-4.18 (m, 4H), 4.23-4.40 (m, 2H), 7.80-8.04 (m, 3H).
実施例12 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]プロピル
(A) 4-(2-エトキシ-1-メチル-2-オキソエチリデン)ピペリジン-1-カルボン酸 tert-ブチル
 2-ホスホノプロピオン酸トリエチル(13.9 mL)のテトラヒドロフラン(80 mL)溶液を氷冷し、水素化ナトリウム(油性、60%、2.60 g)を少量ずつ加え、窒素雰囲気下、1時間かき混ぜた。反応液に4-オキソピペリジン-1-カルボン酸 tert-ブチル(9.96 g)のテトラヒドロフラン(25 mL)溶液を滴下し、室温まで昇温して1時間かき混ぜた。反応液に水および飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=5:95~40:60)で精製して、表題化合物(13.1 g)を無色油状物として得た。
1H-NMR (300 MHz, CDCl3) δ: 1.30 (t, J = 7.2 Hz, 3H), 1.47 (s, 9H), 1.88 (s, 3H), 2.35 (t, J = 5.9 Hz, 2H), 2.63 (t, J = 5.9 Hz, 2H), 3.38-3.53 (m, 4H), 4.20 (q, J = 7.2 Hz, 2H).
(B) 4-(2-エトキシ-1-メチル-2-オキソエチル)ピペリジン-1-カルボン酸 tert-ブチル
 4-(2-エトキシ-1-メチル-2-オキソエチリデン)ピペリジン-1-カルボン酸 tert-ブチルをメタノール (200 mL) に溶解させ、10%パラジウム/炭素(50%含水品、3.0 g)を加えて、水素雰囲気下(風船圧)、室温で5時間かき混ぜた。触媒をろ別し、ろ液を減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=5:95~30:70)で精製して、表題化合物(13.1 g)を無色油状物として得た。
1H-NMR (300 MHz, CDCl3) δ: 1.09-1.31 (m, 8H), 1.45 (s, 9H), 1.51-1.62 (m, 1H), 1.62-1.75 (m, 2H), 2.20-2.32 (m, 1H), 2.66 (t, J = 12.4 Hz, 2H), 4.01-4.23 (m, 4H).
(C) 4-(2-ヒドロキシ-1-メチルエチル)ピペリジン-1-カルボン酸 tert-ブチル
 4-(2-エトキシ-1-メチル-2-オキソエチル)ピペリジン-1-カルボン酸 tert-ブチル(13.1g)および塩化カルシウム(5.09 g)のエタノール(230 mL)の溶液を氷冷し、水素化ホウ素ナトリウム(3.47 g)を少量ずつ加え、窒素雰囲気下、徐々に室温まで昇温して、17時間かき混ぜた。反応液を氷冷し、水および10%クエン酸水溶液を注意深く加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=20:80~70:30)で精製して、表題化合物(8.84 g)を無色油状物として得た。
1H-NMR (300 MHz, CDCl3) δ: 0.91 (d, J = 6.8 Hz, 3H), 1.09-1.38 (m, 3H), 1.41-1.68 (m, 13H), 2.55-2.76 (m, 2H), 3.46-3.67 (m, 2H), 3.99-4.27 (m, 2H).
(D) 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]プロピル
 4-(2-ヒドロキシ-1-メチルエチル)ピペリジン-1-カルボン酸 tert-ブチル(0.730 g)およびトリホスゲン(0.297 g)のジエチルエーテル(30 mL)溶液に、窒素雰囲気下、ピリジン(0.243 mL)のジエチルエーテル(15 mL)溶液を-40℃で滴下し、滴下終了後、徐々に0℃まで昇温しつつ2時間かき混ぜた。反応液をろ過し、ろ液を減圧濃縮した。残留物をテトラヒドロフラン(30 mL)に溶解させ、この溶液に5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール(0.395 g)およびN,N-ジイソプロピルエチルアミン(1.05 mL)を加え、室温で20時間かき混ぜた。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥して、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=20:80~60:40)で精製し、得られた固体をヘプタン/酢酸エチルで洗浄して、表題化合物(0.470 g)を白色固体として得た。
1H-NMR (300 MHz, CDCl3) δ: 1.00 (d, J = 6.8 Hz, 3H), 1.15-1.37 (m, 2H), 1.38-1.56 (m, 10H), 1.60-1.71 (m, 2H), 1.73-1.89 (m, 1H), 2.58-2.74 (m, 2H), 3.03 (s, 3H), 3.21 (t, J = 8.9 Hz, 2H), 4.03-4.33 (m, 6H), 7.71 (d, 1H), 7.77 (d, J = 8.3,
1.5 Hz, 1H), 7.97 (br s, 1H).
Example 12 2- [1- (tert-Butoxycarbonyl) piperidin-4-yl] propyl 5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid
(A) 4- (2-Ethoxy-1-methyl-2-oxoethylidene) piperidine-1-carboxylate tert-butyl 2-phosphonopropionate triethyl (13.9 mL) in tetrahydrofuran (80 mL) was ice-cooled. Sodium hydride (oil, 60%, 2.60 g) was added in small portions and stirred for 1 hour under a nitrogen atmosphere. To the reaction solution was added dropwise a solution of tert-butyl 4-oxopiperidine-1-carboxylate (9.96 g) in tetrahydrofuran (25 mL), and the mixture was warmed to room temperature and stirred for 1 hour. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 5: 95-40: 60) to give the title compound (13.1 g) as a colorless oil.
1 H-NMR (300 MHz, CDCl 3 ) δ: 1.30 (t, J = 7.2 Hz, 3H), 1.47 (s, 9H), 1.88 (s, 3H), 2.35 (t, J = 5.9 Hz, 2H) , 2.63 (t, J = 5.9 Hz, 2H), 3.38-3.53 (m, 4H), 4.20 (q, J = 7.2 Hz, 2H).
(B) 4- (2-ethoxy-1-methyl-2-oxoethyl) piperidine-1-carboxylic acid tert-butyl 4- (2-ethoxy-1-methyl-2-oxoethylidene) piperidine-1-carboxylic acid tert -Butyl was dissolved in methanol (200 mL), 10% palladium / carbon (50% water-containing product, 3.0 g) was added, and the mixture was stirred under a hydrogen atmosphere (balloon pressure) at room temperature for 5 hours. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 5: 95-30: 70) to give the title compound (13.1 g) as a colorless oil.
1 H-NMR (300 MHz, CDCl 3 ) δ: 1.09-1.31 (m, 8H), 1.45 (s, 9H), 1.51-1.62 (m, 1H), 1.62-1.75 (m, 2H), 2.20-2.32 (m, 1H), 2.66 (t, J = 12.4 Hz, 2H), 4.01-4.23 (m, 4H).
(C) 4- (2-hydroxy-1-methylethyl) piperidine-1-carboxylic acid tert-butyl 4- (2-ethoxy-1-methyl-2-oxoethyl) piperidine-1-carboxylic acid tert-butyl (13.1 g) and calcium chloride (5.09 g) in ethanol (230 mL) were ice-cooled, and sodium borohydride (3.47 g) was added in small portions. Stir. The reaction mixture was ice-cooled, water and 10% aqueous citric acid solution were carefully added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 20: 80-70: 30) to give the title compound (8.84 g) as a colorless oil.
1 H-NMR (300 MHz, CDCl 3 ) δ: 0.91 (d, J = 6.8 Hz, 3H), 1.09-1.38 (m, 3H), 1.41-1.68 (m, 13H), 2.55-2.76 (m, 2H ), 3.46-3.67 (m, 2H), 3.99-4.27 (m, 2H).
(D) 2- [1- (tert-Butoxycarbonyl) piperidin-4-yl] propyl 4- (2-hydroxy-1) 5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid -Methylethyl) piperidine-1-carboxylate tert-butyl (0.730 g) and triphosgene (0.297 g) in diethyl ether (30 mL) under a nitrogen atmosphere with pyridine (0.243 mL) in diethyl ether (15 mL) Was added dropwise at −40 ° C., and after completion of the dropwise addition, the mixture was stirred for 2 hours while gradually warming to 0 ° C. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL), and 5- (methylsulfonyl) -2,3-dihydro-1H-indole (0.395 g) and N, N-diisopropylethylamine (1.05 mL) were added to this solution at room temperature. Stir for 20 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 20: 80-60: 40), and the obtained solid was washed with heptane / ethyl acetate to give the title compound (0.470 g) as a white solid. It was.
1 H-NMR (300 MHz, CDCl 3 ) δ: 1.00 (d, J = 6.8 Hz, 3H), 1.15-1.37 (m, 2H), 1.38-1.56 (m, 10H), 1.60-1.71 (m, 2H ), 1.73-1.89 (m, 1H), 2.58-2.74 (m, 2H), 3.03 (s, 3H), 3.21 (t, J = 8.9 Hz, 2H), 4.03-4.33 (m, 6H), 7.71 ( d, 1H), 7.77 (d, J = 8.3,
1.5 Hz, 1H), 7.97 (br s, 1H).
実施例13 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-{1-[(1-メチルエトキシ)カルボニル]ピペリジン-4-イル}プロピル
(A) 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-(ピペリジン-4-イル)プロピル塩酸塩
 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]プロピル(1.32 g)を4 M塩化水素/酢酸エチル(20 mL)溶液に加え、室温で20時間かき混ぜた。反応液を減圧濃縮し、析出した固体を酢酸エチルで洗浄して、表題化合物(1.03 g)を白色固体として得た。
MS (ESI+): 367.
(B) 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-{1-[(1-メチルエトキシ)カルボニル]ピペリジン-4-イル}プロピル
 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-(ピペリジン-4-イル)プロピル塩酸塩(0.403 g)およびN,N-ジイソプロピルエチルアミン(0.697 mL)のテトラヒドロフラン(5 mL)の溶液に、1 Mクロロギ酸イソプロピル/トルエン(1.5 mL)溶液を加え、窒素雰囲気下、室温で17時間かき混ぜた。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=25:75~75:25)で精製し、得られた固体をヘプタン/酢酸エチルで洗浄して、表題化合物(0.425 g)を白色固体として得た。
1H-NMR (300 MHz, CDCl3) δ: 1.00 (d, J = 7.2 Hz, 3H), 1.15-1.40 (m, 8H), 1.43-1.90 (m, 4H), 2.62-2.77 (m, 2H), 3.03 (s, 3H), 3.21 (t, J = 8.7 Hz, 2H), 4.05-4.35(m, 6H), 4.83-4.99 (m, 1H), 7.66-8.11 (m, 3H).
Example 13 2- {1-[(1-Methylethoxy) carbonyl] piperidin-4-yl} propyl 5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid
(A) 5- (Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- (piperidin-4-yl) propyl hydrochloride 5- (methylsulfonyl) -2,3-dihydro-1H -Indole-1-carboxylic acid 2- [1- (tert-butoxycarbonyl) piperidin-4-yl] propyl (1.32 g) was added to 4 M hydrogen chloride / ethyl acetate (20 mL) solution, and the mixture was stirred at room temperature for 20 hours. It was. The reaction mixture was concentrated under reduced pressure, and the precipitated solid was washed with ethyl acetate to give the title compound (1.03 g) as a white solid.
MS (ESI +): 367.
(B) 5- (Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- {1-[(1-methylethoxy) carbonyl] piperidin-4-yl} propyl 5- (methylsulfonyl) ) -2,3-dihydro-1H-indole-1-carboxylate 2- (piperidin-4-yl) propyl hydrochloride (0.403 g) and N, N-diisopropylethylamine (0.697 mL) in tetrahydrofuran (5 mL) To the solution was added 1 M isopropyl chloroformate / toluene (1.5 mL) solution, and the mixture was stirred at room temperature for 17 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 25: 75 to 75:25), and the obtained solid was washed with heptane / ethyl acetate to give the title compound (0.425 g) as a white solid. It was.
1 H-NMR (300 MHz, CDCl 3 ) δ: 1.00 (d, J = 7.2 Hz, 3H), 1.15-1.40 (m, 8H), 1.43-1.90 (m, 4H), 2.62-2.77 (m, 2H ), 3.03 (s, 3H), 3.21 (t, J = 8.7 Hz, 2H), 4.05-4.35 (m, 6H), 4.83-4.99 (m, 1H), 7.66-8.11 (m, 3H).
実施例14 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-[1-(5-プロピルピリミジン-2-イル)ピペリジン-4-イル]プロピル
 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]プロピル(0.470 g)をトリフルオロ酢酸(2 mL)に加え、室温で24時間かき混ぜた。反応液を減圧濃縮し、残留物を1-メチル-2-ピロリジノン(2 mL)に溶解させ、2-クロロ-5-プロピルピリミジン(0.189 g)および炭酸セシウム(1.64 g)を加えて、窒素雰囲気下、70℃で24時間かき混ぜた。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残留物を塩基性シリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=20:80~50:50)で精製し、得られた固体をヘプタン/酢酸エチルで洗浄して、表題化合物(0.352 g)を白色固体として得た。
1H-NMR (300 MHz, CDCl3) δ: 0.92 (q, J = 7.2 Hz, 3H), 1.01 (d, J = 7.2 Hz, 3H), 1.23-1.47 (m, 2H), 1.48-1.69 (m, 3H), 1.70-1.91 (m, 3H), 2.39 (t, J = 7.5 Hz, 2H), 2.73-2.89 (m, 2H), 3.03 (s, 3H), 3.21 (t, J = 8.7 Hz, 2H), 4.03-4.18 (m, 3H), 4.21-4.35 (m, 1H), 4.71-4.84 (m, 2H), 7.70 (s, 1H), 7.78 (dd, J = 8.3, 1.9 Hz, 1H), 7.98 (br s, 1H), 8.14 (s, 2H).
Example 14 5- (Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- [1- (5-propylpyrimidin-2-yl) piperidin-4-yl] propyl 5- (methyl Sulfonyl) -2,3-dihydro-1H-indole-1-carboxylate 2- [1- (tert-butoxycarbonyl) piperidin-4-yl] propyl (0.470 g) was added to trifluoroacetic acid (2 mL), Stir at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in 1-methyl-2-pyrrolidinone (2 mL), 2-chloro-5-propylpyrimidine (0.189 g) and cesium carbonate (1.64 g) were added, and nitrogen atmosphere was added. The mixture was stirred at 70 ° C. for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 20: 80-50: 50), and the resulting solid was washed with heptane / ethyl acetate to give the title compound (0.352 g) as a white solid Got as.
1 H-NMR (300 MHz, CDCl 3 ) δ: 0.92 (q, J = 7.2 Hz, 3H), 1.01 (d, J = 7.2 Hz, 3H), 1.23-1.47 (m, 2H), 1.48-1.69 ( m, 3H), 1.70-1.91 (m, 3H), 2.39 (t, J = 7.5 Hz, 2H), 2.73-2.89 (m, 2H), 3.03 (s, 3H), 3.21 (t, J = 8.7 Hz , 2H), 4.03-4.18 (m, 3H), 4.21-4.35 (m, 1H), 4.71-4.84 (m, 2H), 7.70 (s, 1H), 7.78 (dd, J = 8.3, 1.9 Hz, 1H ), 7.98 (br s, 1H), 8.14 (s, 2H).
実施例15 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-[1-(ピリダジン-3-イルカルバモイル)ピペリジン-4-イル]プロピル
(A) ピリダジン-3-イルカルバミン酸フェニル 3-アミノピリダジン(1.14 g)およびピリジン(1.17 mL)のテトラヒドロフラン(10 mL)およびアセトニトリル(15 mL)混合液に、クロロギ酸フェニル(1.66 mL)を加え、窒素雰囲気下、室温で16時間かき混ぜた。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=40:60~100:0)で精製し、得られた固体をヘプタン/酢酸エチルで洗浄して、表題化合物(1.31 g)を淡黄色固体として得た。
MS (ESI+): 216.
(B) 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-[1-(ピリダジン-3-イルカルバモイル)ピペリジン-4-イル]プロピル
 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-(ピペリジン-4-イル)プロピル塩酸塩(0.403 g)のアセトニトリル(15 mL)懸濁液にN,N-ジイソプロピルエチルアミン(0.697 mL)およびピリダジン-3-イルカルバミン酸フェニル(0.258 g)を加え、窒素雰囲気下、室温で20時間かき混ぜた。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残留物を塩基性シリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=50:50~100:0)で精製し、得られた固体をヘプタン/酢酸エチルで洗浄して、表題化合物(0.414 g)を白色固体として得た。
1H-NMR (300 MHz, CDCl3) δ: 1.02 (d, J = 6.8 Hz, 3H), 1.27-1.50 (m, 2H), 1.53-1.69 (m, 1H), 1.74-1.94 (m, 3H), 2.83-3.00 (m, 2H), 3.03 (s, 3H), 3.22 (t, J = 8.7 Hz, 2H), 4.03-4.36 (m, 6H), 7.41 (dd, J = 9.0, 4.5 Hz, 1H), 7.68-7.85 (m, 3H), 7.99 (br s, 1H), 8.29 (d, J = 9.0 Hz, 1H), 8.83 (d, J = 3.8 Hz, 1H).
Example 15 2- [1- (Pyridazin-3-ylcarbamoyl) piperidin-4-yl] propyl 5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid
(A) Phenylpyridazin-3-ylcarbamate Phenyl chloroformate (1.66 mL) was added to a mixture of 3-aminopyridazine (1.14 g) and pyridine (1.17 mL) in tetrahydrofuran (10 mL) and acetonitrile (15 mL). The mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 40: 60-100: 0), and the resulting solid was washed with heptane / ethyl acetate to give the title compound (1.31 g) as a pale yellow solid. Obtained.
MS (ESI +): 216.
(B) 5- (Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- [1- (pyridazin-3-ylcarbamoyl) piperidin-4-yl] propyl 5- (methylsulfonyl) N, N-diisopropylethylamine (0.697 mL) to a suspension of 2- (piperidin-4-yl) propyl hydrochloride (0.403 g) in acetonitrile (15 mL) -2,3-dihydro-1H-indole-1-carboxylate ) And phenyl pyridazin-3-ylcarbamate (0.258 g) were added, and the mixture was stirred at room temperature for 20 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 50: 50-100: 0), and the resulting solid was washed with heptane / ethyl acetate to give the title compound (0.414 g) as a white solid Got as.
1 H-NMR (300 MHz, CDCl 3 ) δ: 1.02 (d, J = 6.8 Hz, 3H), 1.27-1.50 (m, 2H), 1.53-1.69 (m, 1H), 1.74-1.94 (m, 3H ), 2.83-3.00 (m, 2H), 3.03 (s, 3H), 3.22 (t, J = 8.7 Hz, 2H), 4.03-4.36 (m, 6H), 7.41 (dd, J = 9.0, 4.5 Hz, 1H), 7.68-7.85 (m, 3H), 7.99 (br s, 1H), 8.29 (d, J = 9.0 Hz, 1H), 8.83 (d, J = 3.8 Hz, 1H).
実施例16 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-{1-[メチル(ピリダジン-3-イル)カルバモイル]ピペリジン-4-イル}プロピル
 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-[1-(ピリダジン-3-イルカルバモイル)ピペリジン-4-イル]プロピル(0.170 g)をN,N-ジメチルホルムアミド(1 mL)に溶解させ、水素化ナトリウム(60%、油性、0.017 g)を加えて、窒素雰囲気下、室温で30分間かき混ぜた。反応にヨードメタン(0.065 mL)を加え、室温で27時間かき混ぜた。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥して、減圧濃縮した。残留物を塩基性シリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=50:50~100:0)で精製して、表題化合物(0.110 g)を白色固体
として得た。
1H-NMR (300 MHz, CDCl3) δ: 1.01 (d, J = 6.8 Hz, 3H), 1.19-1.43 (m, 2H), 1.48-1.90 (m, 4H), 2.57-2.91 (m, 2H), 3.03 (s, 3H), 3.21 (t, J = 8.9 Hz, 2H), 3.81 (s, 3H), 4.07-4.18 (m, 3H), 4.21-4.33 (m, 1H), 4.52-4.72 (m, 2H), 7.02 (dd, J = 9.4, 3.8 Hz, 1H), 7.66 (dd, J = 3.8, 1.9 Hz, 1H), 7.71 (s, 1H), 7.77 (dd, J = 8.3, 1.9 Hz, 1H), 7.98 (br. s., 1H), 8.26 (dd, J = 9.8, 1.9 Hz, 1H).
Example 16 2- (1- [Methyl (pyridazin-3-yl) carbamoyl] piperidin-4-yl} propyl 5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylate 5- ( Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylate 2- [1- (pyridazin-3-ylcarbamoyl) piperidin-4-yl] propyl (0.170 g) was converted to N, N-dimethylformamide ( 1 mL), sodium hydride (60%, oily, 0.017 g) was added, and the mixture was stirred at room temperature for 30 min under a nitrogen atmosphere. To the reaction was added iodomethane (0.065 mL), and the mixture was stirred at room temperature for 27 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 50: 50-100: 0) to give the title compound (0.110 g) as a white solid.
1 H-NMR (300 MHz, CDCl 3 ) δ: 1.01 (d, J = 6.8 Hz, 3H), 1.19-1.43 (m, 2H), 1.48-1.90 (m, 4H), 2.57-2.91 (m, 2H ), 3.03 (s, 3H), 3.21 (t, J = 8.9 Hz, 2H), 3.81 (s, 3H), 4.07-4.18 (m, 3H), 4.21-4.33 (m, 1H), 4.52-4.72 ( m, 2H), 7.02 (dd, J = 9.4, 3.8 Hz, 1H), 7.66 (dd, J = 3.8, 1.9 Hz, 1H), 7.71 (s, 1H), 7.77 (dd, J = 8.3, 1.9 Hz , 1H), 7.98 (br.s., 1H), 8.26 (dd, J = 9.8, 1.9 Hz, 1H).
実施例17の化合物は、実施例16と同様の方法により合成した。 The compound of Example 17 was synthesized by the same method as in Example 16.
実施例18 7-フルオロ-5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]プロピル
(A) 7-フルオロ-2,3-ジヒドロ-1H-インドール
 7-フルオロインドール(20.0 g)の酢酸(60 mL)溶液に、シアノ水素化ホウ素ナトリウム(18.7 g)を少量ずつ加え、室温で2時間かき混ぜた。反応液を2 M水酸化ナトリウム水溶液(1500 mL)に加え、ジクロロメタンで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=40:60~100:0)で精製して、表題化合物(20.0 g)を得た。
1H-NMR (300 MHz, CDCl3) δ: 3.08 (t, J = 8.4 Hz, 2H), 3.62 (t, J = 8.4 Hz, 2H), 6.62-6.66 (m, 1H), 6.78-6.83 (m, 1H), 6.90 (dd, J = 7.6, 0.4 Hz, 1H).
(B) 7-フルオロ-5-(メチルスルファニル)-2,3-ジヒドロ-1H-インドール
 チオシアン酸カリウム(14 g)のメタノール(150 mL)溶液に、ピリジン(0.243 mL)のジエチルエーテル(15 mL)溶液を窒素雰囲気下で氷冷し、臭素(3.8 mL)を滴下後、15時間かき混ぜた。反応液に7-フルオロ-2,3-ジヒドロ-1H-インドール(9.0 g)のメタノール(100 mL)溶液を加えて、室温で3時間かき混ぜた。反応液に水酸化カリウム(18.4 g)の水(120 mL)溶液を43℃以下でゆっくりと滴下し、30分間かき混ぜた。反応液を10℃に冷却し、ヨードメタン(4.1 mL)を加えて室温で30分間かき混ぜた。反応液を減圧濃縮し、水を加えてジクロロメタンで抽出した。抽出液を乾燥後、減圧濃縮し、残留物をシリカゲルカラムクロマトグラフィー(石油エーテル:ジクロロメタン=2:1~1:1)で精製して、表題化合物(2.8 g)を得た。
1H-NMR (300 MHz, CDCl3) δ: 2.42 (s, 3H), 3.05 (t, J = 8.4 Hz, 2H), 3.62 (t, J = 8.4 Hz, 2H), 6.85 (d, J = 10.8 Hz, 1H), 6.93 (s, 1H).
(C) 7-フルオロ-5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸tert-ブチル
 7-フルオロ-5-(メチルスルファニル)-2,3-ジヒドロ-1H-インドール(4.4 g)のジクロロメタン(30 mL)溶液に、二炭酸ジ-tert-ブチル(6.6 g)およびトリエチルアミン(4.3 mL)を加え、室温で48時間かき混ぜた。反応液に飽和重曹水を加え、酢酸エチルで抽出した。抽出液を順次、1 M塩酸、飽和重曹水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残留物をジクロロメタン(60 mL)に溶解させ、氷冷下、メタクロロ過安息香酸(65%、8.8 g)を加えて1時間かき混ぜた。反応液に10%亜硫酸ナトリウム水溶液を加え、ジクロロメタンで抽出した。抽出液を順次、炭酸ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥して、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=1:10~40:60)で精製して、表題化合物(4.1 g)を白色粉末として得た。
1H-NMR (300 MHz, CDCl3) δ: 1.53 (s, 9H), 3.04 (s, 3H), 3.15 (t, J = 8.4 Hz, 2H), 4.14 (t, J = 8.4 Hz, 2H), 7.26 (s, 1H), 7.52 (s, 1H).
(D) 7-フルオロ-5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール塩酸塩
  7-フルオロ-5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸tert-ブチル(4.1 g)の酢酸エチル(20 mL)溶液に、5 M塩化水素/酢酸エチル(40 mL)溶液を加え、室温で3時間かき混ぜた。析出した固体をろ取し、酢酸エチル/ジイソプロピルエーテルで洗浄して、表題化合物(3.1 g)を白色粉末として得た。
MS (ESI+): 216.
(E) 7-フルオロ-5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]プロピル
 4-(2-ヒドロキシ-1-メチルエチル)ピペリジン-1-カルボン酸 tert-ブチル(1.46 g)およびトリホスゲン(0.593 g)のジエチルエーテル(60 mL)溶液に、窒素雰囲気下、ピリジン(0.485 mL)のジエチルエーテル(30 mL)溶液を-40℃で滴下し、滴下終了後、徐々に0℃まで昇温しつつ3時間かき混ぜた。反応液をろ過し、ろ液を減圧濃縮した。残留物をテトラヒドロフラン(60 mL)に溶解させ、この溶液に7-フルオロ-5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール塩酸塩(0.861 g)およびN,N-ジイソプロピルエチルアミン(2.09 mL)を加え、室温で24時間かき混ぜた。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=20:80~70:30)で精製して、表題化合物(1.06 g)を無色油状物として得た。
1H-NMR (300 MHz, CDCl3) δ: 0.96 (d, J = 7.2 Hz, 3H), 1.13-1.36 (m, 2H), 1.40-1.86 (m, 13H), 2.56-2.75 (m, 2H), 3.05 (s, 3H), 3.19 (t, J = 8.3 Hz, 2H), 4.05-4.31 (m, 6H), 7.51-7.65 (m, 2H).
Example 18 7-Fluoro-5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- [1- (tert-butoxycarbonyl) piperidin-4-yl] propyl
(A) 7-Fluoro-2,3-dihydro-1H-indole To a solution of 7-fluoroindole (20.0 g) in acetic acid (60 mL), sodium cyanoborohydride (18.7 g) was added little by little, and Stir for hours. The reaction mixture was added to 2M aqueous sodium hydroxide solution (1500 mL) and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 40: 60-100: 0) to give the title compound (20.0 g).
1 H-NMR (300 MHz, CDCl 3 ) δ: 3.08 (t, J = 8.4 Hz, 2H), 3.62 (t, J = 8.4 Hz, 2H), 6.62-6.66 (m, 1H), 6.78-6.83 ( m, 1H), 6.90 (dd, J = 7.6, 0.4 Hz, 1H).
(B) 7-Fluoro-5- (methylsulfanyl) -2,3-dihydro-1H-indole Potassium thiocyanate (14 g) in methanol (150 mL) and pyridine (0.243 mL) in diethyl ether (15 mL) ) The solution was ice-cooled under a nitrogen atmosphere, bromine (3.8 mL) was added dropwise, and the mixture was stirred for 15 hr. A solution of 7-fluoro-2,3-dihydro-1H-indole (9.0 g) in methanol (100 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. A solution of potassium hydroxide (18.4 g) in water (120 mL) was slowly added dropwise at 43 ° C. or lower to the reaction solution, and the mixture was stirred for 30 minutes. The reaction mixture was cooled to 10 ° C., iodomethane (4.1 mL) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with dichloromethane. The extract was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: dichloromethane = 2: 1 to 1: 1) to obtain the title compound (2.8 g).
1 H-NMR (300 MHz, CDCl 3 ) δ: 2.42 (s, 3H), 3.05 (t, J = 8.4 Hz, 2H), 3.62 (t, J = 8.4 Hz, 2H), 6.85 (d, J = 10.8 Hz, 1H), 6.93 (s, 1H).
(C) tert-butyl 7-fluoro-5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylate 7-fluoro-5- (methylsulfanyl) -2,3-dihydro-1H- To a solution of indole (4.4 g) in dichloromethane (30 mL) were added di-tert-butyl dicarbonate (6.6 g) and triethylamine (4.3 mL), and the mixture was stirred at room temperature for 48 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (60 mL), metachloroperbenzoic acid (65%, 8.8 g) was added under ice-cooling, and the mixture was stirred for 1 hr. A 10% aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was washed successively with aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 10-40: 60) to give the title compound (4.1 g) as a white powder.
1 H-NMR (300 MHz, CDCl 3 ) δ: 1.53 (s, 9H), 3.04 (s, 3H), 3.15 (t, J = 8.4 Hz, 2H), 4.14 (t, J = 8.4 Hz, 2H) , 7.26 (s, 1H), 7.52 (s, 1H).
(D) 7-Fluoro-5- (methylsulfonyl) -2,3-dihydro-1H-indole hydrochloride 7-fluoro-5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid To a solution of tert-butyl (4.1 g) in ethyl acetate (20 mL) was added 5 M hydrogen chloride / ethyl acetate (40 mL) solution, and the mixture was stirred at room temperature for 3 hr. The precipitated solid was collected by filtration and washed with ethyl acetate / diisopropyl ether to give the title compound (3.1 g) as a white powder.
MS (ESI +): 216.
(E) 7-Fluoro-5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- [1- (tert-butoxycarbonyl) piperidin-4-yl] propyl 4- (2 -Hydroxy-1-methylethyl) piperidine-1-carboxylate tert-butyl (1.46 g) and triphosgene (0.593 g) in diethyl ether (60 mL) under a nitrogen atmosphere with pyridine (0.485 mL) in diethyl ether (0.485 mL) 30 mL) solution was added dropwise at −40 ° C., and after completion of the addition, the mixture was stirred for 3 hours while gradually warming to 0 ° C. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (60 mL), and 7-fluoro-5- (methylsulfonyl) -2,3-dihydro-1H-indole hydrochloride (0.861 g) and N, N-diisopropylethylamine (2.09 g) were dissolved in this solution. mL) was added and stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 20: 80-70: 30) to give the title compound (1.06 g) as a colorless oil.
1 H-NMR (300 MHz, CDCl 3 ) δ: 0.96 (d, J = 7.2 Hz, 3H), 1.13-1.36 (m, 2H), 1.40-1.86 (m, 13H), 2.56-2.75 (m, 2H ), 3.05 (s, 3H), 3.19 (t, J = 8.3 Hz, 2H), 4.05-4.31 (m, 6H), 7.51-7.65 (m, 2H).
実施例19~32の化合物は、実施例18と同様の方法により合成した。 The compounds of Examples 19 to 32 were synthesized by the same method as in Example 18.
実施例33 7-フルオロ-5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン
酸 2-[1-(5-プロピルピリミジン-2-イル)ピペリジン-4-イル]プロピル
(A) 7-フルオロ-5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-(ピペリジン-4-イル)プロピル塩酸塩
 7-フルオロ-5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]プロピル(1.01 g)を4 M塩化水素/酢酸エチル(20 mL)溶液を加え、室温で20時間かき混ぜた。反応液を減圧濃縮し、残留物を酢酸エチル/ジエチルエーテルで固化させた後、酢酸エチル/ジエチルエーテルで洗浄して、表題化合物(1.03 g)を白色固体として得た。
MS (ESI+): 385.
(B) 7-フルオロ-5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-[1-(5-プロピルピリミジン-2-イル)ピペリジン-4-イル]プロピル
 7-フルオロ-5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-(ピペリジン-4-イル)プロピル塩酸塩(0.210 g)、2-クロロ-5-プロピルピリミジン(0.094 g)および炭酸セシウム(0.407 g)の1-メチル-2-ピロリジノン(1 mL)混合液を、窒素雰囲気下、70℃で17時間かき混ぜた。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残留物を塩基性シリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=30:70~80:20)で精製し、得られた固体をヘプタン/酢酸エチルで洗浄して、表題化合物(0.212 g)を白色固体として得た。
1H-NMR (300 MHz, CDCl3) δ: 0.89-1.03 (m, 6H), 1.21-1.44 (m, 2H), 1.49-1.89 (m, 4H), 2.39 (t, J = 7.6 Hz, 2H), 2.73-2.87 (m, 2H), 3.04 (s, 3H), 3.18 (t, J = 8.3
Hz, 2H), 4.07-4.32 (m, 6H), 4.69-4.84 (m, 2H), 7.51-7.61 (m, 2H), 8.14 (s, 2H).
Example 33 7-Fluoro-5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- [1- (5-propylpyrimidin-2-yl) piperidin-4-yl] propyl
(A) 7-fluoro-5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylate 2- (piperidin-4-yl) propyl hydrochloride 7-fluoro-5- (methylsulfonyl) -2,3-Dihydro-1H-indole-1-carboxylic acid 2- [1- (tert-butoxycarbonyl) piperidin-4-yl] propyl (1.01 g) in 4 M hydrogen chloride / ethyl acetate (20 mL) solution And stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was solidified with ethyl acetate / diethyl ether and washed with ethyl acetate / diethyl ether to give the title compound (1.03 g) as a white solid.
MS (ESI +): 385.
(B) 7-Fluoro-5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- [1- (5-propylpyrimidin-2-yl) piperidin-4-yl] propyl 7-Fluoro-5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylate 2- (piperidin-4-yl) propyl hydrochloride (0.210 g), 2-chloro-5-propylpyrimidine (0.094 g) and a mixture of cesium carbonate (0.407 g) in 1-methyl-2-pyrrolidinone (1 mL) were stirred at 70 ° C. for 17 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 30: 70-80: 20), and the obtained solid was washed with heptane / ethyl acetate to give the title compound (0.212 g) as a white solid Got as.
1 H-NMR (300 MHz, CDCl 3 ) δ: 0.89-1.03 (m, 6H), 1.21-1.44 (m, 2H), 1.49-1.89 (m, 4H), 2.39 (t, J = 7.6 Hz, 2H ), 2.73-2.87 (m, 2H), 3.04 (s, 3H), 3.18 (t, J = 8.3
Hz, 2H), 4.07-4.32 (m, 6H), 4.69-4.84 (m, 2H), 7.51-7.61 (m, 2H), 8.14 (s, 2H).
実施例34の化合物は、実施例33と同様の方法により合成した。 The compound of Example 34 was synthesized by the same method as in Example 33.
実施例35 7-メチル-5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-{1-[(1-メチルエトキシ)カルボニル]ピペリジン-4-イル}エチル
 7-メチル-5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]エチル(0.268 g)をトリフルオロ酢酸(1 mL)に溶解させ、室温で3時間かき混ぜた。反応液を減圧濃縮後、残留物をテトラヒドロフラン(3 mL)に溶解させ、N,N-ジイソプロピルエチルアミン(1.00 mL)および1 Mクロロギ酸イソプロピル/トルエン溶液(0.862 mL)を加え、室温で3時間かき混ぜた。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥して、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=25:75~75:25)で精製して、表題化合物(0.129 g)を無色油状物として得た。
1H-NMR (300 MHz, CDCl3) δ: 1.08-1.32 (m, 8H), 1.48-1.79 (m, 5H), 2.35 (s, 3H), 2.63-2.82 (m, 2H), 2.94-3.18 (m, 5H), 4.01-4.38 (m, 6H), 4.85-4.97 (m, 1H), 7.59
(s, 1H), 7.63 (s, 1H).
Example 35 7-Methyl-5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- {1-[(1-methylethoxy) carbonyl] piperidin-4-yl} ethyl 7 2-Methyl-5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylate 2- [1- (tert-butoxycarbonyl) piperidin-4-yl] ethyl (0.268 g) in trifluoroacetic acid (1 mL) and stirred at room temperature for 3 hours. Concentrate the reaction solution under reduced pressure, dissolve the residue in tetrahydrofuran (3 mL), add N, N-diisopropylethylamine (1.00 mL) and 1 M isopropyl chloroformate / toluene solution (0.862 mL), and stir at room temperature for 3 hours. It was. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 25: 75-75: 25) to give the title compound (0.129 g) as a colorless oil.
1 H-NMR (300 MHz, CDCl 3 ) δ: 1.08-1.32 (m, 8H), 1.48-1.79 (m, 5H), 2.35 (s, 3H), 2.63-2.82 (m, 2H), 2.94-3.18 (m, 5H), 4.01-4.38 (m, 6H), 4.85-4.97 (m, 1H), 7.59
(s, 1H), 7.63 (s, 1H).
実施例36~44の化合物は、実施例35と同様の方法により合成した。 The compounds of Examples 36 to 44 were synthesized by the same method as in Example 35.
実施例45 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸4-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]ブチル
(A) 4-(4-エトキシ-4-オキソブチル)ピペリジン-1-カルボン酸 tert-ブチル
 (2E)-4-(ジエトキシホスホリル)ブタ-2-エン酸エチル(10.0 g)のテトラヒドロフラン(40 mL)溶液に、水素化ナトリウム(油性、60%、1.60 g)を加え、0℃で30分間かき混ぜた。この反応液に、4-オキソピペリジン-1-カルボン酸ベンジル(8.88 g)のN,N-ジメチルホルムアミド(40 mL)溶液を0℃で加えた後、反応混合物を室温で終夜かき混ぜた。反応液に水を加え、酢酸エチルで抽出した。有機相を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。ろ過操作後、ろ液を減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル: ヘキサン=5:95~1:3)に付し、無色油状物を得た。得られた油状物のテトラヒドロフラン(100 mL)溶液に、10%水酸化パラジウム/炭素(0.90 g)および二炭酸ジ-tert-ブチル(8.90 g)を加え、1気圧の水素雰囲気下、室温で終夜かき混ぜた。触媒をろ別し、ろ液を減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=0:100~50:50)に付し、表題化合物(4.28 g)を無色油状物として得た。
1H-NMR (300 MHz, CDCl3) δ: 0.94-1.18 (m, 2H), 1.19-1.32 (m, 4H), 1.45 (s, 9H), 1.57-1.76 (m, 5H), 2.28 (t, J = 7.5 Hz, 2H), 2.67 (t, J = 13.2 Hz, 2H), 3.95-4.30 (m, 5H).
(B) 4-(4-ヒドロキシブチル)ピペリジン-1-カルボン酸 tert-ブチル
 4-(4-エトキシ-4-オキソブチル)ピペリジン-1-カルボン酸 tert-ブチル(4.28 g)のテトラヒドロフラン(50 mL)溶液に、水素化ホウ素リチウム(0.660 g)を加え、室温で2日間かき混ぜた。反応液にメタノール(10 mL)および水素化ホウ素リチウム(0.660 g)を加え、室温でさらに1日間かき混ぜた。反応液に10%クエン酸水溶液を加え、酢酸エチルで抽出した。有機相を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。ろ過操作後、ろ液を減圧濃縮した。残留物を酢酸エチルに懸濁させ、シリカゲルでろ過後、ろ液を減圧濃縮して、表題化合物(2.23 g)を無色油状物として得た。
1H-NMR (300 MHz, CDCl3) δ: 0.91-1.17 (m, 2H), 1.18-1.42 (m, 4H), 1.45 (s, 9H), 1.47-1.74 (m, 4H), 2.16-2.41 (m, 1H), 2.66 (t, J = 12.2 Hz, 2H), 3.46-3.74 (m, 2H), 3.87-4.22 (m, 2H).
(C) 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸4-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]ブチル
 4-(4-ヒドロキシブチル)ピペリジン-1-カルボン酸 tert-ブチル(0.66 g)および2,6-ルチジン(0.300 mL)のジエチルエーテル(20 mL)溶液に、トリホスゲン(0.254 g)を氷冷下で加え、0℃で30分間かき混ぜた。反応液をろ過し、ろ液を減圧濃縮した。残留物をテトラヒドロフラン(20 mL)に溶解させ、この反応液に5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール(0.390 g)およびジイソプロピルエチルアミン(1.50 mL)を室温で加え、室温で終夜かき混ぜた。混合物に水を加え、酢酸エチルで抽出した。有機相を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。ろ過操作後、ろ液を減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=5:95~50:50)に付し、無色油状物を得た。得られた無色油状物を分取HPLCで精製して、表題化合物(0.31 g)を無色油状物として得た。
1H-NMR (300 MHz, CDCl3) δ: 0.86-1.18 (m, 2H), 1.18-1.43 (m, 4H), 1.45 (s, 9H), 1.62-1.88 (m, 6H), 2.67 (t, J = 12.2 Hz, 3H), 3.03 (s, 3H), 3.20 (t, J = 8.7 Hz,
2H), 3.78-4.20 (m, 2H), 4.25 (t, J = 5.8 Hz, 2H), 7.70 (s, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.97 (br s, 1H).
Example 45 5- [Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 4- [1- (tert-butoxycarbonyl) piperidin-4-yl] butyl
(A) 4- (4-Ethoxy-4-oxobutyl) piperidine-1-carboxylate tert-butyl (2E) -4- (diethoxyphosphoryl) but-2-enoic acid ethyl ester (10.0 g) in tetrahydrofuran (40 mL ) Sodium hydride (oil, 60%, 1.60 g) was added to the solution and stirred at 0 ° C. for 30 minutes. To this reaction solution, a solution of benzyl 4-oxopiperidine-1-carboxylate (8.88 g) in N, N-dimethylformamide (40 mL) was added at 0 ° C., and the reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 5: 95-1: 3) to give a colorless oil. To a solution of the obtained oil in tetrahydrofuran (100 mL), 10% palladium hydroxide / carbon (0.90 g) and di-tert-butyl dicarbonate (8.90 g) were added, and at room temperature under a hydrogen atmosphere of 1 atm overnight. Stir. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 0: 100-50: 50) to give the title compound (4.28 g) as a colorless oil.
1 H-NMR (300 MHz, CDCl 3 ) δ: 0.94-1.18 (m, 2H), 1.19-1.32 (m, 4H), 1.45 (s, 9H), 1.57-1.76 (m, 5H), 2.28 (t , J = 7.5 Hz, 2H), 2.67 (t, J = 13.2 Hz, 2H), 3.95-4.30 (m, 5H).
(B) 4- (4-hydroxybutyl) piperidine-1-carboxylic acid tert-butyl 4- (4-ethoxy-4-oxobutyl) piperidine-1-carboxylic acid tert-butyl (4.28 g) in tetrahydrofuran (50 mL) To the solution was added lithium borohydride (0.660 g), and the mixture was stirred at room temperature for 2 days. Methanol (10 mL) and lithium borohydride (0.660 g) were added to the reaction mixture, and the mixture was further stirred at room temperature for 1 day. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated under reduced pressure. The residue was suspended in ethyl acetate and filtered through silica gel. The filtrate was concentrated under reduced pressure to give the title compound (2.23 g) as a colorless oil.
1 H-NMR (300 MHz, CDCl 3 ) δ: 0.91-1.17 (m, 2H), 1.18-1.42 (m, 4H), 1.45 (s, 9H), 1.47-1.74 (m, 4H), 2.16-2.41 (m, 1H), 2.66 (t, J = 12.2 Hz, 2H), 3.46-3.74 (m, 2H), 3.87-4.22 (m, 2H).
(C) 5- [Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 4- [1- (tert-butoxycarbonyl) piperidin-4-yl] butyl 4- (4-hydroxybutyl) To a solution of tert-butyl piperidine-1-carboxylate (0.66 g) and 2,6-lutidine (0.300 mL) in diethyl ether (20 mL) was added triphosgene (0.254 g) under ice-cooling, and the mixture was stirred at 0 ° C for 30 minutes. Stir. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), and 5- (methylsulfonyl) -2,3-dihydro-1H-indole (0.390 g) and diisopropylethylamine (1.50 mL) were added to the reaction mixture at room temperature. Stir all night. Water was added to the mixture and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. After the filtration operation, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: hexane = 5: 95-50: 50) to give a colorless oil. The resulting colorless oil was purified by preparative HPLC to give the title compound (0.31 g) as a colorless oil.
1 H-NMR (300 MHz, CDCl 3 ) δ: 0.86-1.18 (m, 2H), 1.18-1.43 (m, 4H), 1.45 (s, 9H), 1.62-1.88 (m, 6H), 2.67 (t , J = 12.2 Hz, 3H), 3.03 (s, 3H), 3.20 (t, J = 8.7 Hz,
2H), 3.78-4.20 (m, 2H), 4.25 (t, J = 5.8 Hz, 2H), 7.70 (s, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.97 (br s, 1H) .
実施例46 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸3-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]ブチル
(A) 4-[メトキシ(メチル)カルバモイル]ピペリジン-1-カルボン酸 tert-ブチル
 1-(tert-ブトキシカルボニル)ピペリジン-4-カルボン酸(10.0 g)のテトラヒドロフラン(120 mL)溶液に、1,1’-カルボニルジイミダゾール(12.7 g)を少量ずつ加え、室温で2時間かき混ぜた。反応液にN,O-ジメチルヒドロキシルアミン塩酸塩(12.8 g)を加え、室温で12時間かき混ぜた。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=40:60~100:0)で精製して、表題化合物(11.0 g)を無色油状物として得た。
1H-NMR (300 MHz, CDCl3) δ: 1.46 (s, 9H), 1.63-1.78 (m, 4H), 2.67-2.90 (m, 3H), 3.19 (s, 3H), 3.71 (s, 3H), 4.02-4.26 (m, 2H).
(B) 4-アセチルピペリジン-1-カルボン酸tert-ブチル
 4-[メトキシ(メチル)カルバモイル]ピペリジン-1-カルボン酸 tert-ブチル(6.92 g)のテトラヒドロフラン(100 mL)溶液を窒素雰囲気下で氷冷し、1 M臭化メチルマグネシウム/テトラヒドロフラン(38.1 mL)溶液を滴下後、室温まで昇温して18時間かき混ぜた。反応液に水および飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=25:75~100:0)で精製して、表題化合物(5.60 g)を淡黄色油状物として得た。
1H-NMR (300 MHz, CDCl3) δ: 1.45 (s, 9H), 1.48-1.59 (m, 2H), 1.76-1.90 (m, 2H), 2.16 (s, 3H), 2.39-2.52 (m, 1H), 2.70-2.86 (m, 2H), 3.97-4.23 (m, 2H).
(C) 4-(4-エトキシ-4-オキソブタン-2-イル)ピペリジン-1-カルボン酸 tert-ブチル
  ホスホノ酢酸トリエチル(10.3 mL)のテトラヒドロフラン(80 mL)溶液を氷冷し、水素化ナトリウム(油性、60%、2.05 g)を少量ずつ加え、窒素雰囲気下、2時間かき混ぜた。反応液に4-アセチルピペリジン-1-カルボン酸 tert-ブチル(8.98 g)のテトラヒドロフラン(20 mL)溶液を滴下し、室温まで昇温して4時間かき混ぜた。反応液に水および飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残留物をエタノール(120 mL)に溶解させ、10%パラジウム/炭素(50%含水品、2.4 g)を加えて、水素雰囲気下(風船圧)、室温で20時間かき混ぜた。触媒をろ別し、ろ液を減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=5:95~50:50)で精製して、表題化合物(8.76 g)を無色油状物として得た。
1H-NMR (300 MHz, CDCl3) δ: 0.91 (d, J = 6.8 Hz, 3H), 1.08-1.41 (m, 6H), 1.45 (s, 9H), 1.53-1.64 (m, 2H), 1.83-1.99 (m, 1H), 2.03-2.16 (m, 1H), 2.36 (dd, J = 14.6, 5.1 Hz, 1H), 2.53-2.72 (m, 2H), 4.03-4.24 (m, 4H).
(D) 4-(3-ヒドロキシ-1-メチルプロピル)ピペリジン-1-カルボン酸 tert-ブチル
 4-(4-エトキシ-4-オキソブタン-2-イル)ピペリジン-1-カルボン酸 tert-ブチル(6.76 g)および塩化カルシウム(5.01 g)のエタノール(120 mL)溶液を氷冷し、水素化ホウ素ナトリウム(3.42 g)を少量ずつ加え、窒素雰囲気下、徐々に室温まで昇温しつつ、24時間かき混ぜた。反応液を氷冷し、水および10%クエン酸水溶液を注意深く加え、酢酸エチル/テトラヒドロフランで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=25:75~75:25)で精製して、表題化合物(5.60 g)を無色油状物として得た。
1H-NMR (300 MHz, CDCl3) δ: 0.87 (3H, d, J = 6.8 Hz), 1.09-1.76 (18H, m), 2.53-2.74 (2H, m), 3.58-3.79 (2H, m), 4.02-4.24 (2H, m).
(E) 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸3-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]ブチル
 4-(3-ヒドロキシ-1-メチルプロピル)ピペリジン-1-カルボン酸 tert-ブチル(0.386 g)
およびトリホスゲン(0.148 g)のジエチルエーテル(15 mL)溶液に、窒素雰囲気下、ピリジン(0.121 mL)を-10℃以下で滴下し、滴下終了後、徐々に0℃まで昇温しつつ2時間かき混ぜた。反応液をろ過し、ろ液を減圧濃縮した。残留物をテトラヒドロフラン(10 mL)に溶解させ、この溶液に5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール(0.197 g)およびN,N-ジイソプロピルエチルアミン(0.871 mL)を加え、室温で15時間かき混ぜた。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥して、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=25:75~75:25)で精製し、得られた固体をヘプタン/酢酸エチルで洗浄して、表題化合物(0.402 g)を白色固体として得た。
1H-NMR (300 MHz, CDCl3) δ: 0.93 (d, J = 6.4 Hz, 3H), 1.12-1.66 (m, 16H), 1.77-1.95 (m, 1H), 2.55-2.74 (m, 2H), 3.03 (s, 3H), 3.20 (t, J = 8.7 Hz, 2H), 4.03-4.43 (m, 6H), 7.68-7.74 (m, 1H), 7.74-7.82 (m, 1H), 7.98 (br s, 1H).
Example 46 5- [Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 3- [1- (tert-butoxycarbonyl) piperidin-4-yl] butyl
(A) 4- [methoxy (methyl) carbamoyl] piperidine-1-carboxylic acid tert-butyl 1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (10.0 g) in tetrahydrofuran (120 mL) 1'-Carbonyldiimidazole (12.7 g) was added in small portions and stirred at room temperature for 2 hours. N, O-dimethylhydroxylamine hydrochloride (12.8 g) was added to the reaction solution, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 40: 60-100: 0) to give the title compound (11.0 g) as a colorless oil.
1 H-NMR (300 MHz, CDCl 3 ) δ: 1.46 (s, 9H), 1.63-1.78 (m, 4H), 2.67-2.90 (m, 3H), 3.19 (s, 3H), 3.71 (s, 3H ), 4.02-4.26 (m, 2H).
(B) tert-butyl 4-acetylpiperidine-1-carboxylate A solution of tert-butyl 4- [methoxy (methyl) carbamoyl] piperidine-1-carboxylate (6.92 g) in tetrahydrofuran (100 mL) under a nitrogen atmosphere After cooling, a 1 M methylmagnesium bromide / tetrahydrofuran (38.1 mL) solution was added dropwise, and the mixture was warmed to room temperature and stirred for 18 hours. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 25: 75-100: 0) to give the title compound (5.60 g) as a pale yellow oil.
1 H-NMR (300 MHz, CDCl 3 ) δ: 1.45 (s, 9H), 1.48-1.59 (m, 2H), 1.76-1.90 (m, 2H), 2.16 (s, 3H), 2.39-2.52 (m , 1H), 2.70-2.86 (m, 2H), 3.97-4.23 (m, 2H).
(C) 4- (4-Ethoxy-4-oxobutan-2-yl) piperidine-1-carboxylic acid tert-butyl phosphonoacetic acid triethyl (10.3 mL) in tetrahydrofuran (80 mL) was ice-cooled and sodium hydride ( Oily, 60%, 2.05 g) was added in small portions and stirred for 2 hours under a nitrogen atmosphere. To the reaction solution was added dropwise a solution of tert-butyl 4-acetylpiperidine-1-carboxylate (8.98 g) in tetrahydrofuran (20 mL), and the mixture was warmed to room temperature and stirred for 4 hours. Water and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethanol (120 mL), 10% palladium / carbon (50% water-containing product, 2.4 g) was added, and the mixture was stirred at room temperature for 20 hours under a hydrogen atmosphere (balloon pressure). The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 5: 95-50: 50) to give the title compound (8.76 g) as a colorless oil.
1 H-NMR (300 MHz, CDCl 3 ) δ: 0.91 (d, J = 6.8 Hz, 3H), 1.08-1.41 (m, 6H), 1.45 (s, 9H), 1.53-1.64 (m, 2H), 1.83-1.99 (m, 1H), 2.03-2.16 (m, 1H), 2.36 (dd, J = 14.6, 5.1 Hz, 1H), 2.53-2.72 (m, 2H), 4.03-4.24 (m, 4H).
(D) tert-butyl 4- (3-hydroxy-1-methylpropyl) piperidine-1-carboxylate tert-butyl 4- (4-ethoxy-4-oxobutan-2-yl) piperidine-1-carboxylate (6.76 g) and calcium chloride (5.01 g) in ethanol (120 mL) are ice-cooled, sodium borohydride (3.42 g) is added in small portions, and the mixture is stirred for 24 hours while gradually warming to room temperature in a nitrogen atmosphere. It was. The reaction mixture was ice-cooled, water and 10% aqueous citric acid solution were carefully added, and the mixture was extracted with ethyl acetate / tetrahydrofuran. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 25: 75-75: 25) to give the title compound (5.60 g) as a colorless oil.
1 H-NMR (300 MHz, CDCl 3 ) δ: 0.87 (3H, d, J = 6.8 Hz), 1.09-1.76 (18H, m), 2.53-2.74 (2H, m), 3.58-3.79 (2H, m ), 4.02-4.24 (2H, m).
(E) 5- [Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 3- [1- (tert-butoxycarbonyl) piperidin-4-yl] butyl 4- (3-hydroxy-1 -Methylpropyl) piperidine-1-carboxylate tert-butyl (0.386 g)
Pyridine (0.121 mL) was added dropwise to a solution of triphosgene (0.148 g) in diethyl ether (15 mL) under a nitrogen atmosphere at -10 ° C or lower. After completion of the dropwise addition, the mixture was gradually warmed to 0 ° C and stirred for 2 hours. It was. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), and 5- (methylsulfonyl) -2,3-dihydro-1H-indole (0.197 g) and N, N-diisopropylethylamine (0.871 mL) were added to this solution at room temperature. Stir for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 25: 75-75: 25), and the obtained solid was washed with heptane / ethyl acetate to give the title compound (0.402 g) as a white solid. It was.
1 H-NMR (300 MHz, CDCl 3 ) δ: 0.93 (d, J = 6.4 Hz, 3H), 1.12-1.66 (m, 16H), 1.77-1.95 (m, 1H), 2.55-2.74 (m, 2H ), 3.03 (s, 3H), 3.20 (t, J = 8.7 Hz, 2H), 4.03-4.43 (m, 6H), 7.68-7.74 (m, 1H), 7.74-7.82 (m, 1H), 7.98 ( br s, 1H).
実施例47 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-{[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]オキシ}プロピル
(A) 4-[(1-エトキシ-1-オキソプロパン-2-イル)オキシ]ピペリジン-1-カルボン酸ベンジル 4-オキソピペリジン-1-カルボン酸ベンジル(3.00 g)のテトラヒドロフラン(200 mL)の溶液を氷冷し、水素化ナトリウム(油性、60%、0.561 g)を少量ずつ加え、1時間かき混ぜた。反応液に2-ブロモプロピオン酸エチル(2.54 g)加えて、徐々に室温まで昇温しつつ、終夜かき混ぜた。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=0:100~25:75)で精製して、表題化合物(1.40 g)を無色油状物として得た。
MS (ESI+): 336.
(B) 4-[(1-ヒドロキシプロパン-2-イル)オキシ]ピペリジン-1-カルボン酸ベンジル
 4-[(1-エトキシ-1-オキソプロパン-2-イル)オキシ]ピペリジン-1-カルボン酸ベンジル(1.40 g)および塩化カルシウム(0.925 g)のエタノール(40 mL)の溶液を氷冷し、水素化ホウ素ナトリウム(0.634 g)を少量ずつ加え、窒素雰囲気下、徐々に室温まで昇温して、20時間かき混ぜた。反応液を氷冷し、1 M塩酸を注意深く加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=0:100~60:40)で精製して、表題化合物(1.09 g)を無色油状物として得た。
MS (ESI+): 294.
(C) 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸 2-({1-[(ベンジルオキシ)カルボニル]ピペリジン-4-イル}オキシ)プロピル
 4-[(1-ヒドロキシプロパン-2-イル)オキシ]ピペリジン-1-カルボン酸ベンジル(0.527 g)およびトリホスゲン(0.178 g)のジエチルエーテル溶液を氷冷し、ピリジン(0.142 g)を滴下して、2時間かき混ぜた。反応液をろ過し、ろ液を減圧濃縮した。残留物をテトラヒドロフランに溶解させ、氷冷下、5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール(0.300 g)およびN,N-ジイソプロピルエチルアミン(0.53 mL)を加えて、室温で終夜かき混ぜた。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥して、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィーで精製して、表題化合物(0.216 g)を無色油状物として得た。
MS (ESI+): 517.
(D) 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-{[1-(tert-ブ
トキシカルボニル)ピペリジン-4-イル]オキシ}プロピル
 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-({1-[(ベンジルオキシ)カルボニル]ピペリジン-4-イル}オキシ)プロピル(0.216 g)および二炭酸ジ-tert-ブチル(0.274 g)をテトラヒドロフラン(20 mL)に溶解させ、20%水酸化パラジウム/炭素(50%含水品、0.03 g)を加え、水素雰囲気下 (風船圧)、室温で3日間かき混ぜた。触媒をろ別し、ろ液を減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィーで精製して、表題化合物(0.140 g)を無色油状物として得た。
1H-NMR (300 MHz, CDCl3) δ: 1.19-1.27 (m, 3H), 1.41-1.59 (m, 11H), 1.72-1.85 (m,
2H), 3.03 (s, 3H), 3.06-3.17 (m, 2H), 3.21 (t, J = 8.9 Hz, 2H), 3.55-3.66 (m, 1H), 3.70-3.81 (m, 2H), 3.81-3.96 (m, 1H), 4.08-4.23 (m, 4H), 7.71 (s, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.89-8.09 (m, 1H).
Example 47 2-{[1- (tert-Butoxycarbonyl) piperidin-4-yl] oxy} propyl 5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid
(A) 4-[(1-Ethoxy-1-oxopropan-2-yl) oxy] piperidine-1-carboxylate benzyl 4-oxopiperidine-1-carboxylate (3.00 g) in tetrahydrofuran (200 mL) The solution was ice-cooled and sodium hydride (oily, 60%, 0.561 g) was added in small portions and stirred for 1 hour. Ethyl 2-bromopropionate (2.54 g) was added to the reaction mixture, and the mixture was stirred overnight while gradually warming to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 0: 100-25: 75) to give the title compound (1.40 g) as a colorless oil.
MS (ESI +): 336.
(B) Benzyl 4-[(1-hydroxypropan-2-yl) oxy] piperidine-1-carboxylate 4-[(1-Ethoxy-1-oxopropan-2-yl) oxy] piperidine-1-carboxylic acid A solution of benzyl (1.40 g) and calcium chloride (0.925 g) in ethanol (40 mL) is ice-cooled, sodium borohydride (0.634 g) is added in small portions, and the temperature is gradually raised to room temperature in a nitrogen atmosphere. Stir for 20 hours. The reaction mixture was ice-cooled, 1 M hydrochloric acid was carefully added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 0: 100-60: 40) to give the title compound (1.09 g) as a colorless oil.
MS (ESI +): 294.
(C) 5- (Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 2-({1-[(benzyloxy) carbonyl] piperidin-4-yl} oxy) propyl 4-[( 1-Hydroxypropan-2-yl) oxy] piperidine-1-carboxylate benzyl (0.527 g) and triphosgene (0.178 g) in diethyl ether are ice-cooled, pyridine (0.142 g) is added dropwise, and the mixture is stirred for 2 hours. It was. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran, and 5- (methylsulfonyl) -2,3-dihydro-1H-indole (0.300 g) and N, N-diisopropylethylamine (0.53 mL) were added under ice-cooling at room temperature overnight. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.216 g) as a colorless oil.
MS (ESI +): 517.
(D) 2-([Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 2-{[1- (tert-butoxycarbonyl) piperidin-4-yl] oxy} propyl 5- (methylsulfonyl) ) -2,3-Dihydro-1H-indole-1-carboxylate 2-({1-[(benzyloxy) carbonyl] piperidin-4-yl} oxy) propyl (0.216 g) and di-tert-butyl dicarbonate (0.274 g) was dissolved in tetrahydrofuran (20 mL), 20% palladium hydroxide / carbon (50% water-containing product, 0.03 g) was added, and the mixture was stirred at room temperature for 3 days under a hydrogen atmosphere (balloon pressure). The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.140 g) as a colorless oil.
1 H-NMR (300 MHz, CDCl 3 ) δ: 1.19-1.27 (m, 3H), 1.41-1.59 (m, 11H), 1.72-1.85 (m,
2H), 3.03 (s, 3H), 3.06-3.17 (m, 2H), 3.21 (t, J = 8.9 Hz, 2H), 3.55-3.66 (m, 1H), 3.70-3.81 (m, 2H), 3.81 -3.96 (m, 1H), 4.08-4.23 (m, 4H), 7.71 (s, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.89-8.09 (m, 1H).
実施例48 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-{[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]アミノ}エチル
 (2-ヒドロキシエチル)カルバミン酸tert-ブチル(2.42 g)およびトリホスゲン(1.48 g)
のジエチルエーテル(90 mL)溶液に、窒素雰囲気下、ピリジン(1.23 mL)のジエチルエーテル(10 mL)溶液を-40℃で滴下し、滴下終了後、徐々に0℃まで昇温しつつ3時間かき混ぜた。反応液をろ過し、ろ液を減圧濃縮した。残留物をテトラヒドロフラン(100 mL)に溶解させ、この溶液に5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール(1.97 g)およびN,N-ジイソプロピルエチルアミン(5.23 mL)を加え、室温で14時間かき混ぜた。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥して、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=40:60~100:0)で精製して、白色固体を得た。得られた固体を4 M塩化水素/酢酸エチル(30 mL)溶液に加え、室温で4時間かき混ぜた。反応液を減圧濃縮し、得られた固体を酢酸エチルで洗浄して、淡桃色固体を得た。得られた固体、4-オキソピペリジン-1-カルボン酸tert-ブチル(2.99 g)、およびトリエチルアミン(2.09 mL)のメタノール(50 mL)混合液を室温で1.5時間かき混ぜた。反応液に10%パラジウム/炭素(50%含水品、1.00 g)を加え、水素雰囲気下 (風船圧)、室温で19時間かき混ぜた。触媒をろ別し、ろ液を減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=40:60~100:0)で精製し、得られた固体をヘプタン/酢酸エチルで洗浄して、表題化合物(3.89 g)を白色固体として得た。
1H-NMR (300 MHz, CDCl3) δ: 1.18-1.35 (m, 2H), 1.45 (s, 9H), 1.79-1.91 (m, 2H), 2.61-2.73 (m, 1H), 2.74-2.89 (m, 2H), 2.94-3.07 (m, 5H), 3.21 (t, J = 8.7 Hz, 2H), 3.92-4.18 (m, 4H), 4.28-4.43 (m, 2H), 7.71 (s, 1H), 7.77 (d, J = 8.3 Hz, 1H),
7.98 (br s, 1H).
Example 48 2-{[1- (tert-Butoxycarbonyl) piperidin-4-yl] amino} ethyl 5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylate (2-hydroxyethyl ) Tert-butyl carbamate (2.42 g) and triphosgene (1.48 g)
To a diethyl ether (90 mL) solution of pyridine (1.23 mL) in diethyl ether (10 mL) was added dropwise at −40 ° C. under a nitrogen atmosphere. Stir. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (100 mL), and 5- (methylsulfonyl) -2,3-dihydro-1H-indole (1.97 g) and N, N-diisopropylethylamine (5.23 mL) were added to this solution at room temperature. Stir for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 40: 60-100: 0) to give a white solid. The obtained solid was added to 4 M hydrogen chloride / ethyl acetate (30 mL) solution, and the mixture was stirred at room temperature for 4 hr. The reaction solution was concentrated under reduced pressure, and the resulting solid was washed with ethyl acetate to obtain a pale pink solid. A mixture of the obtained solid, tert-butyl 4-oxopiperidine-1-carboxylate (2.99 g), and triethylamine (2.09 mL) in methanol (50 mL) was stirred at room temperature for 1.5 hr. 10% palladium / carbon (50% water-containing product, 1.00 g) was added to the reaction solution, and the mixture was stirred at room temperature for 19 hours under a hydrogen atmosphere (balloon pressure). The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 40: 60-100: 0), and the obtained solid was washed with heptane / ethyl acetate to give the title compound (3.89 g) as a white solid. It was.
1 H-NMR (300 MHz, CDCl 3 ) δ: 1.18-1.35 (m, 2H), 1.45 (s, 9H), 1.79-1.91 (m, 2H), 2.61-2.73 (m, 1H), 2.74-2.89 (m, 2H), 2.94-3.07 (m, 5H), 3.21 (t, J = 8.7 Hz, 2H), 3.92-4.18 (m, 4H), 4.28-4.43 (m, 2H), 7.71 (s, 1H ), 7.77 (d, J = 8.3 Hz, 1H),
7.98 (br s, 1H).
実施例49の化合物は、実施例48と同様の方法により合成した。 The compound of Example 49 was synthesized by the same method as in Example 48.
実施例50 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-{[1-(tert-ブトキシカルボニル)ピペリジン-4-イル](プロピル)アミノ}エチル
 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-{[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]アミノ}エチル(0.351 g)および炭酸カリウム(0.135 g)のN,N-ジメチルホルムアミド(2 mL)懸濁液に1-ヨードプロパン(0.110 mL)を加え、窒素雰囲気下、70℃で2日間かき混ぜた。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥して、減圧濃縮した。残留物を塩基性シリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=20:80~80:20)で精製して、表題化合物(0.266 g)を無色油状物として得た。
1H-NMR (300 MHz, CDCl3) δ: 0.87 (t, J = 7.3 Hz, 3H), 1.31-1.51 (m, 13H), 1.64-1.77 (m, 2H), 2.43-2.53 (m, 2H), 2.56-2.83 (m, 5H), 3.03 (s, 3H), 3.20 (t, J = 8.9 Hz, 2H), 4.03-4.31 (m, 6H), 7.70 (s, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.97 (br s, 1H).
Example 50 2-([1- (tert-Butoxycarbonyl) piperidin-4-yl] (propyl) amino} ethyl 5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylate 5- (Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylate 2-{[1- (tert-butoxycarbonyl) piperidin-4-yl] amino} ethyl (0.351 g) and potassium carbonate (0.135 g 1-iodopropane (0.110 mL) was added to a suspension of N, N-dimethylformamide (2 mL) and stirred at 70 ° C. for 2 days under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate: hexane = 20: 80-80: 20) to give the title compound (0.266 g) as a colorless oil.
1 H-NMR (300 MHz, CDCl 3 ) δ: 0.87 (t, J = 7.3 Hz, 3H), 1.31-1.51 (m, 13H), 1.64-1.77 (m, 2H), 2.43-2.53 (m, 2H ), 2.56-2.83 (m, 5H), 3.03 (s, 3H), 3.20 (t, J = 8.9 Hz, 2H), 4.03-4.31 (m, 6H), 7.70 (s, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.97 (br s, 1H).
実施例51~54の化合物は、実施例50と同様の方法により合成した。 The compounds of Examples 51 to 54 were synthesized by the same method as in Example 50.
実施例55 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-{アセチ
ル[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]アミノ}エチル
 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-{[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]アミノ}エチル(0.234 g)のピリジン(1 mL)溶液に、無水酢酸(0.071 mL)を滴下し、窒素雰囲気下、室温で2日間かき混ぜた。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥して、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(メタノール:酢酸エチル:ヘキサン=0:50:50~0:100:0~10:90:0)で精製して、表題化合物(0.248 g)を白色非晶性粉末として得た。
1H-NMR (300 MHz, CDCl3) δ: 1.47 (s, 9H), 1.59-1.80 (m, 4H), 2.19 (s, 3H), 2.64-2.88 (m, 2H), 3.03 (s, 3H), 3.21 (q, J = 8.3 Hz, 2H), 3.56 (t, J = 6.8 Hz, 2H), 3.61-3.75 and 4.43-4.57 (m, 1H), 4.03-4.40 (m, 6H), 4.43-4.57 (m, 1H), 7.67-7.83 (m, 2H), 7.99(br s, 1H).
Example 55 5- (Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylate 2- {acetyl [1- (tert-butoxycarbonyl) piperidin-4-yl] amino} ethyl 5- (methyl Sulfonyl) -2,3-dihydro-1H-indole-1-carboxylate 2-{[1- (tert-butoxycarbonyl) piperidin-4-yl] amino} ethyl (0.234 g) in a solution of pyridine (1 mL) Acetic anhydride (0.071 mL) was added dropwise, and the mixture was stirred at room temperature for 2 days under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: ethyl acetate: hexane = 0: 50: 50-0: 100: 0-10: 90: 0) to give the title compound (0.248 g) as a white amorphous powder. Got as.
1 H-NMR (300 MHz, CDCl 3 ) δ: 1.47 (s, 9H), 1.59-1.80 (m, 4H), 2.19 (s, 3H), 2.64-2.88 (m, 2H), 3.03 (s, 3H ), 3.21 (q, J = 8.3 Hz, 2H), 3.56 (t, J = 6.8 Hz, 2H), 3.61-3.75 and 4.43-4.57 (m, 1H), 4.03-4.40 (m, 6H), 4.43- 4.57 (m, 1H), 7.67-7.83 (m, 2H), 7.99 (br s, 1H).
実施例56 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-{[1-(tert-ブトキシカルボニル)ピペリジン-4-イル](メチルスルホニル)アミノ}エチル
 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-{[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]アミノ}エチル(0.234 g)およびN,N-ジイソプロピルエチルアミン(0.131 mL)のテトラヒドロフラン(2 mL)溶液に、塩化メタンスルホニル(0.047mL)を滴下し、窒素雰囲気下、室温で2日間かき混ぜた。反応液に水を加え、酢酸エチルで抽出した。抽出液を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥して、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=30:70~100:0)で精製して、表題化合物(0.0809 g)を無色油状物として得た。
1H-NMR (300 MHz, CDCl3) δ: 1.46 (s, 9H), 1.61-1.85 (m, 4H), 2.67-2.84 (m, 2H), 2.92 (s, 3H), 3.03 (s, 3H), 3.21 (t, J = 8.7 Hz, 2H), 3.47 (t, J = 6.4 Hz, 2H), 3.70-3.84 (m, 1H), 4.07-4.45 (m, 6H), 7.71 (s, 1H), 7.78 (dd, J = 8.3, 1.9 Hz, 1H), 7.98 (br s, 1H).
Example 56 5- (Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 2-{[1- (tert-butoxycarbonyl) piperidin-4-yl] (methylsulfonyl) amino} ethyl 5 -(Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylate 2-{[1- (tert-butoxycarbonyl) piperidin-4-yl] amino} ethyl (0.234 g) and N, N- Methanesulfonyl chloride (0.047 mL) was added dropwise to a solution of diisopropylethylamine (0.131 mL) in tetrahydrofuran (2 mL), and the mixture was stirred at room temperature for 2 days under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 30: 70-100: 0) to give the title compound (0.0809 g) as a colorless oil.
1 H-NMR (300 MHz, CDCl 3 ) δ: 1.46 (s, 9H), 1.61-1.85 (m, 4H), 2.67-2.84 (m, 2H), 2.92 (s, 3H), 3.03 (s, 3H ), 3.21 (t, J = 8.7 Hz, 2H), 3.47 (t, J = 6.4 Hz, 2H), 3.70-3.84 (m, 1H), 4.07-4.45 (m, 6H), 7.71 (s, 1H) , 7.78 (dd, J = 8.3, 1.9 Hz, 1H), 7.98 (br s, 1H).
実施例57 5-(ピロリジン-1-イルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン
酸 2-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]エチル
(A) 2,3-ジヒドロ-1H-インドール-1-カルボン酸 2-{1-[(1-メチルエトキシ)カルボニル]ピペリジン-4-イル}エチル
 表題化合物は、実施例10工程Bと同様の方法により合成した。
1H NMR (300 MHz, CDCl3) δ: 1.08-1.21 (m, 3H), 1.23 (s, 3H), 1.25 (s, 3H), 1.60-1.82 (m, 4H), 2.62-2.84 (m, 2H), 3.13 (t, J = 8.7 Hz, 2H), 4.01 (t, J = 8.5 Hz, 2H), 4.07-4.22 (m, 2H), 4.28 (br s, 2H), 4.91 (m, 1H), 6.91-7.01 (m, 1H), 7.11-7.24 (m, 2H), 7.86 (br s, 1H).
(B) 5-(ピロリジン-1-イルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-[1-(tert-ブトキシカルボニル)ピペリジン-4-イル]エチル
 氷冷した塩化スルホン酸(5 mL)に2,3-ジヒドロ-1H-インドール-1-カルボン酸 2-{1-[(1-メチルエトキシ)カルボニル]ピペリジン-4-イル}エチル(1.302 g)を加え、氷冷下で15分間、室温に戻して15分間、70℃に加熱して1時間かき混ぜた。反応液を室温にまで冷却後、氷水にゆっくりと注ぎ入れ、酢酸エチルで抽出した。有機相を分離し、水で2回洗浄した後、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。ろ過操作後、ろ液を減圧濃縮し、淡黄色油状物を得た。 得られた油状物のテトラヒドロフラン(15 mL)溶液にピロリジン(1.5 mL)を加え、室温で15分間かき混ぜた後、減圧濃縮した。得られた残留物をテトラヒドロフラン(15 mL)に溶解させ、トリエチルアミン(1.0 mL)と二炭酸ジ-tert-ブチル(1.5 mL)を加え、室温で30分間かき混ぜた。その反応溶液を酢酸エチルと水で抽出した。有機相を分離し、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。ろ過操作後、ろ液を減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=20:80~50:50)で精製して、表題化合物(0.061 g)を淡黄色固体として得た。
1H NMR (300 MHz, CDCl3) δ: 1.07-1.31 (m, 3H), 1.46 (s, 9H), 1.63-1.83 (m, 8H), 2.70 (m, 2H), 3.13-3.31 (m, 6H), 4.09 (t, J = 8.7 Hz, 4H), 4.30 (t, J = 5.3 Hz, 2H), 7.61 (s, 1H), 7.64-7.74 (m, 1H), 7.96 (br s, 1H).
Example 57 5- (Pyrrolidin-1-ylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- [1- (tert-butoxycarbonyl) piperidin-4-yl] ethyl
(A) 2,3-Dihydro-1H-indole-1-carboxylic acid 2- {1-[(1-methylethoxy) carbonyl] piperidin-4-yl} ethyl The title compound is the same as in Example 10, Step B. It was synthesized by the method.
1 H NMR (300 MHz, CDCl 3 ) δ: 1.08-1.21 (m, 3H), 1.23 (s, 3H), 1.25 (s, 3H), 1.60-1.82 (m, 4H), 2.62-2.84 (m, 2H), 3.13 (t, J = 8.7 Hz, 2H), 4.01 (t, J = 8.5 Hz, 2H), 4.07-4.22 (m, 2H), 4.28 (br s, 2H), 4.91 (m, 1H) , 6.91-7.01 (m, 1H), 7.11-7.24 (m, 2H), 7.86 (br s, 1H).
(B) 2- [1- (tert-Butoxycarbonyl) piperidin-4-yl] ethyl 5- (pyrrolidin-1-ylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylate Ice-cooled chloride To 2,3-dihydro-1H-indole-1-carboxylic acid 2- {1-[(1-methylethoxy) carbonyl] piperidin-4-yl} ethyl (1.302 g) was added to sulfonic acid (5 mL) and iced. The mixture was returned to room temperature for 15 minutes under cooling, heated to 70 ° C. for 15 minutes, and stirred for 1 hour. The reaction mixture was cooled to room temperature, poured slowly into ice water, and extracted with ethyl acetate. The organic phase was separated and washed twice with water, then with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a pale yellow oil. Pyrrolidine (1.5 mL) was added to a solution of the obtained oil in tetrahydrofuran (15 mL), and the mixture was stirred at room temperature for 15 min and concentrated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (15 mL), triethylamine (1.0 mL) and di-tert-butyl dicarbonate (1.5 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction solution was extracted with ethyl acetate and water. The organic phase was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. After the filtration operation, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 20: 80-50: 50) to give the title compound (0.061 g) as a pale yellow solid.
1 H NMR (300 MHz, CDCl 3 ) δ: 1.07-1.31 (m, 3H), 1.46 (s, 9H), 1.63-1.83 (m, 8H), 2.70 (m, 2H), 3.13-3.31 (m, 6H), 4.09 (t, J = 8.7 Hz, 4H), 4.30 (t, J = 5.3 Hz, 2H), 7.61 (s, 1H), 7.64-7.74 (m, 1H), 7.96 (br s, 1H) .
 実施例58~60の化合物は、実施例57と同様の方法により合成した。 The compounds of Examples 58 to 60 were synthesized in the same manner as in Example 57.
実施例61 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-{[(3R)-1-(tert-ブトキシカルボニル)ピロリジン-3-イル]オキシ}エチル
(A) 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸 2-ブロモエチル 氷冷した5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール(3.016 g)のテトラヒドロフラン(120 mL)溶液に、クロロギ酸 2-ブロモエチル(5.29 g)のテトラヒドロフラン(10 mL)溶液を滴下し、30分間かき混ぜた。滴下終了後、室温に戻して終夜かき混ぜ、反応液に酢酸エチルと水を加えた。析出した固体をろ取し、酢酸エチルと水で洗浄後、減圧乾燥し、表題化合物(3.888 g)を無色固体として得た。
1H-NMR (300 MHz, DMSO-d6) δ: 3.15 (s, 3H), 3.20 (t, J = 8.9 Hz, 2H), 3.78 (t, J = 5.3 Hz, 2H), 4.08 (t, J = 8.7 Hz, 2H), 4.51 (t, J = 5.1 Hz, 2H), 7.65-7.98 (m, 3H).
(B) 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-{[(3R)-1-(tert-ブトキシカルボニル)ピロリジン-3-イル]オキシ}エチル
 氷冷した5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸 2-ブロモエチル(0.324 g)のN,N-ジメチルホルムアミド(6 mL)溶液に、水素化ナトリウム(油性、60%、0.060 g)を加え、室温まで昇温して2時間かき混ぜた。この反応液に(3R)-3-ヒドロキシピロリジン-1-カルボン酸 tert-ブチル(0.317 g)のN,N-ジメチルホルムアミド(2 mL)溶液を滴下し、室温で終夜かき混ぜた。反応混合物を酢酸エチルと水で抽出した。有機相を分離し、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。ろ過操作後、ろ液を濃縮した。残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル:ヘキサン=40:60~80:20)で精製し、酢酸エチル/ヘキサンで再結晶して、表題化合物(0.217 g)を無色固体として得た。
1H NMR (300 MHz, CDCl3) δ: 1.48 (s, 9H), 2.16 (br s, 2H), 3.03 (s, 3H), 3.21 (t, J = 8.7 Hz, 2H), 3.35-3.76 (m, 4H), 4.10 (t, J = 8.5 Hz, 2H), 5.40 (br s, 1H),
7.72 (s, 1H), 7.78 (d, J = 8.3 Hz, 1H), 8.00 (br s, 1H).
Example 61 2-([(3R) -1- (tert-butoxycarbonyl) pyrrolidin-3-yl] oxy} ethyl 5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid
(A) 2- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 2-bromoethyl Ice-cooled 5- (methylsulfonyl) -2,3-dihydro-1H-indole (3.016 g) To a tetrahydrofuran (120 mL) solution of 2-bromoethyl chloroformate (5.29 g) in tetrahydrofuran (10 mL) was added dropwise and stirred for 30 minutes. After completion of the dropwise addition, the mixture was returned to room temperature and stirred overnight, and ethyl acetate and water were added to the reaction solution. The precipitated solid was collected by filtration, washed with ethyl acetate and water, and dried under reduced pressure to give the title compound (3.888 g) as a colorless solid.
1 H-NMR (300 MHz, DMSO-d 6 ) δ: 3.15 (s, 3H), 3.20 (t, J = 8.9 Hz, 2H), 3.78 (t, J = 5.3 Hz, 2H), 4.08 (t, J = 8.7 Hz, 2H), 4.51 (t, J = 5.1 Hz, 2H), 7.65-7.98 (m, 3H).
(B) 2-([(3R) -1- (tert-butoxycarbonyl) pyrrolidin-3-yl] oxy} ethyl 5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid Ice To a solution of cold 5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 2-bromoethyl (0.324 g) in N, N-dimethylformamide (6 mL) was added sodium hydride (oily, 60%, 0.060 g) was added, and the mixture was warmed to room temperature and stirred for 2 hours. To this reaction solution was added dropwise a solution of tert-butyl (3R) -3-hydroxypyrrolidine-1-carboxylate (0.317 g) in N, N-dimethylformamide (2 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate and water. The organic phase was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. After the filtration operation, the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 40: 60-80: 20) and recrystallized from ethyl acetate / hexane to give the title compound (0.217 g) as a colorless solid.
1 H NMR (300 MHz, CDCl 3 ) δ: 1.48 (s, 9H), 2.16 (br s, 2H), 3.03 (s, 3H), 3.21 (t, J = 8.7 Hz, 2H), 3.35-3.76 ( m, 4H), 4.10 (t, J = 8.5 Hz, 2H), 5.40 (br s, 1H),
7.72 (s, 1H), 7.78 (d, J = 8.3 Hz, 1H), 8.00 (br s, 1H).
表1に、実施例化合物の構造式、化学名およびMSの実測値を示す。
Figure JPOXMLDOC01-appb-T000029



Figure JPOXMLDOC01-appb-I000030

Figure JPOXMLDOC01-appb-I000031
Figure JPOXMLDOC01-appb-I000032
Figure JPOXMLDOC01-appb-I000033
Figure JPOXMLDOC01-appb-I000034
Figure JPOXMLDOC01-appb-I000035
Table 1 shows the structural formulas, chemical names and measured values of MS of the example compounds.
Figure JPOXMLDOC01-appb-T000029



Figure JPOXMLDOC01-appb-I000030

Figure JPOXMLDOC01-appb-I000031
Figure JPOXMLDOC01-appb-I000032
Figure JPOXMLDOC01-appb-I000033
Figure JPOXMLDOC01-appb-I000034
Figure JPOXMLDOC01-appb-I000035
試験例1
細胞内cAMP濃度上昇を指標にしたヒトGPR119アゴニスト活性の評価
Test example 1
Evaluation of human GPR119 agonist activity using an increase in intracellular cAMP concentration as an index
(1)ヒトGPR119遺伝子の発現プラスミドの構築
 High Fidelity RNA PCR Kit(タカラバイオ)を用いて、ヒト脳mRNA(Clontech)から合成したcDNAライブラリーを鋳型とし、以下の配列の合成DNAを用いたPCRによりヒトGPR119遺伝子をクローニングした。Primer 1およびPrimer 2は、ヒトGPR119遺伝子の塩基配列情報より、Sal I、Nhe I切断部位を付加して作製した。
Primer 1:5’-GCGTCGACATGGAATCATCTTTCTCATTTGG-3’(配列番号:1)
Primer 2:5’-GCGCTAGCTTAGCCATCAAACTCTGAGCT-3’(配列番号:2)
 PCRはPyrobest DNA polymerase(タカラバイオ)を用いて実施した。得られたPCR産物をpUC118(タカラバイオ)にクローニングし、塩基配列を確認後、制限酵素Sal I、Nhe Iで消化した。得られたDNA断片を、同様にSal I、Nhe Iで消化した動物細胞発現用ベクターpAKKO-111H(Biochem.Biophys.Acta,Hinuma,S.et al.,1219,251-259(1994)記載のpAKKO-1.111Hと同一のプラスミド)へ挿入し、発現プラスミドpAKKO-111H/hGPR119を作製した。
(1) Construction of human GPR119 gene expression plasmid Using High Fidelity RNA PCR Kit (Takara Bio), cDNA library synthesized from human brain mRNA (Clontech) as a template, PCR using synthetic DNA of the following sequence The human GPR119 gene was cloned by Primer 1 and Primer 2 were prepared by adding Sal I and Nhe I cleavage sites from the base sequence information of the human GPR119 gene.
Primer 1: 5′-GCGTCGACATGGAATCATTTTTCTCATTTGG-3 ′ (SEQ ID NO: 1)
Primer 2: 5′-GCCGCTAGCTTAGCCATCAAACTCTGAGCT-3 ′ (SEQ ID NO: 2)
PCR was performed using Pyrobest DNA polymerase (Takara Bio). The obtained PCR product was cloned into pUC118 (Takara Bio). After confirming the base sequence, it was digested with restriction enzymes Sal I and Nhe I. The obtained DNA fragment was similarly digested with Sal I and Nhe I, an animal cell expression vector pAKKO-111H (Biochem. Biophys. Acta, Hinuma, S. et al., 1219, 251-259 (1994)). The plasmid was inserted into the same plasmid as pAKKO-1.111H) to prepare an expression plasmid pAKKO-111H / hGPR119.
(2)レポータープラスミドの構築
 Zeocin耐性遺伝子のクローニングは、プラスミドpcDNA3.1/Zeo(インビトロジェン)を鋳型とし、このプラスミドのZeocin耐性遺伝子の上流および下流に位置するSV40 Ori、SV40pAを含む領域の前後に制限酵素Sal I、BamH I切断部位を付加した以下の配列の合成DNAをプライマーセットに、KOD
 polymerase(東洋紡) を用いたPCRにより行った。
Zeocin-U:5 ’-GGATCCAGGCAGGCAGAAGTATG -3 ’
(配列番号:3)
Zeocine-L:5 ’-GTCGACAGACATGATAAGATACATTG
ATG-3 ’(配列番号:4)
 得られたPCR産物をpCR-BluntII(インビトロジェン)に挿入した。このプラスミドから制限酵素Sal I、BamH Iで切断することにより得たZeocine耐性遺伝子を含む断片を、同様にSal I、BamH Iで消化したプラスミドpGL3(R2.2)-Basic Vector(プロメガ)へ挿入し、Zeocin耐性プラスミドpGL3(R2.2)/Zeocin-Basic Vectorを作製した。
 cAMP応答性エレメント( CRE )が4 個タンデムに連結したレポータープラス
ミドは、以下の5’末端リン酸化合成DNAを用いて作製した。
CRE-Upper:5’-CAGCCTGACGTCAGAGAGCCTGACGTCAGAGAGCCTGACGTCAGAGAGCCTGACGTCAGAGTCGACAGCGGAGACTCTAGAGGGTATATAAGCTT-3’(配列番号:5)
CRE-Lower:5’-AGCTTATATACCCTCTAGAGTCTCCGCTGTCGACTCTGACGTCAGGCTCTCTGACGTCAGGCTCTCTGACGTCAGGCTCTCTGACGTCAGGCTGGTACC-3’(配列番号:6)
 まず、CRE-Upper、CRE-Lowerをアニーリングした後、KOD polymeraseで伸長し得られたCRE配列を含むDNA断片をpCR-BluntIIに挿入し、pCR-BluntII-CREを得た。pCR-BluntII-CREより制限酵素Kpn I、Hind IIIで切り出された断片を、同様にKpn I、Hind IIIで消化したpGL3(R2.2)/Zeocin-Basic Vectorに挿入することにより、レポータープラスミドpGL3(R2.2)/Zeocin-CRE-lucを作製した。
(2) Construction of reporter plasmid The cloning of the Zeocin resistance gene is performed using plasmid pcDNA3.1 / Zeo (Invitrogen) as a template, before and after the region containing SV40 Ori and SV40pA located upstream and downstream of the Zeocin resistance gene of this plasmid. Synthetic DNA of the following sequences with restriction enzyme Sal I and BamH I cleavage sites added to the primer set, KOD
It was performed by PCR using polymerase (Toyobo).
Zeocin-U: 5'-GGATCCAGGCAGGCAGAAGTATG-3 '
(SEQ ID NO: 3)
Zeocine-L: 5'-GTCGACGAGACATGATAAGATACATTG
ATG-3 ′ (SEQ ID NO: 4)
The obtained PCR product was inserted into pCR-BluntII (Invitrogen). A fragment containing the Zeocine resistance gene obtained by cleaving with restriction enzymes Sal I and BamH I from this plasmid was inserted into plasmid pGL3 (R2.2) -Basic Vector (Promega) that was also digested with Sal I and BamHI. A Zeocin resistant plasmid pGL3 (R2.2) / Zeocin-Basic Vector was prepared.
A reporter plasmid in which four cAMP responsive elements (CRE) were linked in tandem was prepared using the following 5′-terminal phosphorylated synthetic DNA.
CRE-Upper: 5'-CAGCCTGACGTCAGAGAGCCTGGACGTCAGAGAGCCTGACGTCAGAGAGCCTGACGTCAGAGTCGACACGGGGAACTCTAGAGGGTATATAAGCTT-3 '(SEQ ID NO: 5)
CRE-Lower: 5′-AGCTTATATACCCCTTAGAGTCTCCCGCTGTCGCACTCTGACGTCAGGCTCCTCTGACGTCAGGCTCCTCTGACGTCAGGCCTCTGACGTCAGGCTGCTGTACC-3 ′ (SEQ ID NO: 6)
First, after annealing CRE-Upper and CRE-Lower, a DNA fragment containing the CRE sequence obtained by extension with KOD polymerase was inserted into pCR-BluntII to obtain pCR-BluntII-CRE. By inserting a fragment excised from restriction enzymes Kpn I and Hind III from pCR-BluntII-CRE into pGL3 (R2.2) / Zeocin-Basic Vector similarly digested with Kpn I and Hind III, reporter plasmid pGL3 (R2.2) / Zeocin-CRE-luc was prepared.
(3)ヒトGPR119遺伝子とレポーター遺伝子のCHO(dhfr-)細胞への導入と発現細胞の取得
 10%ウシ胎児血清、100U/mLペニシリン、100μg/mLストレプトマイシン(インビトロジェン)を含むMEMα(Minimum essential medium alpha)(日研生物医学研究所)培地でCHO(dhfr-)細胞をトリプシン-EDTA(エチレンジアミン四酢酸)(インビトロジェン)処理により剥がした後、細胞をPBS(Phosphate-buffered saline)で洗浄して遠心分離(1000 rpm, 5分)し、1×10cells/mLの細胞密度でPBSに懸濁した。次に、ジーンパルサー(バイオラッド)を用いて、下記の条件に従って、DNAを細胞に導入した。すなわち、0.4cmギャップのキュベットに、1×10個の細胞、(2)で得られ、BssH IIで直鎖化したプラスミドpGL3(R2.2)/Zeocin-CRE-luc 15μg、pAKKO-111H 5μgを加え、電圧250mV、キャパシタンス950μF下でエレクトロポレーションした。その後、細胞を上記の培地に移し、24時間培養後、細胞を剥がして遠心分離し、250cells/wellとなるように希釈して96ウェルプレート(Corning)に播種して、37℃のCOインキュベーター内で培養することにより形質転換体を得た。次に、得られた形質転換体をフォルスコリンの添加により、ルシフェラーゼが発現誘導される株、CRE-luc/CHO(dhfr-)細胞を選択した。
 次に、上記と同様の方法で、1×10個のCRE-luc/CHO(dhfr-)細胞に(1)で得られたプラスミドpAKKO-111H/hGPR119 15μgとpcDNA3.1(インビトロジェン)5μgを加え、電圧250mV、キャパシタンス950μF下でエレクトロポレーションした。上記と同様に培養後、ジェネティシン(和光純薬)を500μg/mLを含む培地で懸濁し、250cells/wellとなるように希釈して96ウェルプレートに播種して、37℃のCOインキュベーター内で培養することによりジェネティシン耐性形質転換体を得た。次に、得られた形質転換体をN-[4-(メチルスルホニル)フェニル]-5-ニトロ-6-{4-[4-(トリフルオロメトキシ)フェノキシ]ピペリジン-1-イル}ピリミジン-4-アミンの添加により、ルシフェラーゼが発現誘導される株、hGPR119/CRE-luc/CHO(dhfr-)細胞を選択した。
(3) Introduction of human GPR119 gene and reporter gene into CHO (dhfr-) cells and acquisition of expressed cells ) (Nikken Biomedical Research Institute) After removing CHO (dhfr-) cells with trypsin-EDTA (ethylenediaminetetraacetic acid) (Invitrogen) treatment in a medium, the cells were washed with PBS (Phosphate-buffered saline) and centrifuged. (1000 rpm, 5 minutes) and suspended in PBS at a cell density of 1 × 10 7 cells / mL. Next, DNA was introduced into the cells using Gene Pulser (Bio-Rad) according to the following conditions. Specifically, in a 0.4 cm gap cuvette, 1 × 10 7 cells, 15 μg of plasmid pGL3 (R2.2) / Zeocin-CRE-luc obtained in (2) and linearized with BssH II, pAKKO-111H 5 μg was added and electroporated under a voltage of 250 mV and a capacitance of 950 μF. Thereafter, the cells are transferred to the above medium, cultured for 24 hours, detached, centrifuged, diluted to 250 cells / well, seeded in a 96-well plate (Corning), and a 37 ° C. CO 2 incubator. The transformant was obtained by culturing in the medium. Next, by adding forskolin to the obtained transformant, a strain in which the expression of luciferase was induced, CRE-luc / CHO (dhfr-) cells, was selected.
Next, 15 μg of the plasmid pAKKO-111H / hGPR119 obtained in (1) and 5 μg of pcDNA3.1 (Invitrogen) were added to 1 × 10 7 CRE-luc / CHO (dhfr-) cells in the same manner as described above. In addition, electroporation was performed under a voltage of 250 mV and a capacitance of 950 μF. After culturing in the same manner as described above, geneticin (Wako Pure Chemical Industries) is suspended in a medium containing 500 μg / mL, diluted to 250 cells / well, seeded in a 96-well plate, and placed in a CO 2 incubator at 37 ° C. Geneticin-resistant transformants were obtained by culturing. Next, the obtained transformant was transformed into N- [4- (methylsulfonyl) phenyl] -5-nitro-6- {4- [4- (trifluoromethoxy) phenoxy] piperidin-1-yl} pyrimidine-4 A strain in which luciferase expression is induced by addition of amine, hGPR119 / CRE-luc / CHO (dhfr-) cells, was selected.
(4)レポーターアッセイ
 hGPR119/CRE-luc/CHO(dhfr-)細胞を384ウェル白プレート(NUNC)に1×10cells/wellとなるように播種し、10%ウシ胎児血清、100U/mLペニシリン、100μg/mLストレプトマイシン、500μg/mLジェネティシンを含むMEMα(Minimum essential medium alpha)培地中で37℃のCOインキュベーター内で一晩培養した。細胞をアッセイバッファー(20mM HEPES(2-〔4-(2-ヒドロキシエチル)-1-ピペラジニル〕エタンスルホン酸)(pH7.4)(インビトロジェン)、0.1%ウシ血清アルブミン(シグマ)、100U/mLペニシリン、100μg/mLストレプトマイシンを含むMEMα培地)で1回洗浄した後、1μM濃度の被検化合物を含むアッセイバッファー40μL中で37℃のCOインキュベーター内で2時間インキュベーションした。各ウェルよりアッセイバッファーを除去後、HBSS(Hanks’ balanced salt solution)で2倍希釈したSteady-Glo(プロメガ)を25μLずつ添加し、遮光下で振盪した。30分後、Envision(パーキンエルマー)にてルシフェラーゼ活性を測定した。10μMのN-[4-(メチルスルホニル)フェニル]-5-ニトロ-6-{4-[4-(トリフルオロメトキシ)フェノキシ]ピペリジン-1-イル}ピリミジン-4-アミン存在下におけるルシフェラーゼ活性を100%、被検化合物の代わりにDMSOを添加した場合のルシフェラーゼ活性を0%として、細胞内cAMP濃度上昇を指標にGPR119アゴニスト活性を算出した。結果を表2に示す。
(4) Reporter assay hGPR119 / CRE-luc / CHO (dhfr-) cells were seeded in a 384-well white plate (NUNC) to 1 × 10 4 cells / well, and 10% fetal bovine serum, 100 U / mL penicillin In a MEMα (Minimum essential medium alpha) medium containing 100 μg / mL streptomycin and 500 μg / mL geneticin, the cells were cultured overnight in a CO 2 incubator at 37 ° C. Cells were assayed with assay buffer (20 mM HEPES (2- [4- (2-hydroxyethyl) -1-piperazinyl] ethanesulfonic acid) (pH 7.4) (Invitrogen), 0.1% bovine serum albumin (Sigma), 100 U / After washing once with MEMα medium containing mL penicillin and 100 μg / mL streptomycin), the plate was incubated for 2 hours in a CO 2 incubator at 37 ° C. in 40 μL of assay buffer containing a test compound having a concentration of 1 μM. After removing the assay buffer from each well, 25 μL of Steady-Glo (Promega) diluted 2-fold with HBSS (Hanks' balanced salt solution) was added and shaken in the dark. After 30 minutes, luciferase activity was measured with Envision (Perkin Elmer). Luciferase activity in the presence of 10 μM N- [4- (methylsulfonyl) phenyl] -5-nitro-6- {4- [4- (trifluoromethoxy) phenoxy] piperidin-1-yl} pyrimidin-4-amine GPR119 agonist activity was calculated using 100% of luciferase activity when DMSO was added instead of the test compound as 0%, and an increase in intracellular cAMP concentration as an index. The results are shown in Table 2.
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000036
 表1に示されるように、本発明化合物は優れたGPR119アゴニスト作用を有する。 As shown in Table 1, the compound of the present invention has an excellent GPR119 agonistic action.
製剤例1(カプセルの製造)
 1)実施例1の化合物                   30 mg
 2)微粉末セルロース                   10 mg
 3)乳糖                        19 mg
 4)ステアリン酸マグネシウム              1 mg
                            計 60 mg
 1)、2)、3)および4)を混合して、ゼラチンカプセルに充填する。
Formulation Example 1 (Manufacture of capsules)
1) 30 mg of the compound of Example 1
2) Fine powder cellulose 10 mg
3) Lactose 19 mg
4) Magnesium stearate 1 mg
60 mg total
1), 2), 3) and 4) are mixed and filled into gelatin capsules.
製剤例2(錠剤の製造)
 1)実施例1の化合物               30 g
 2)乳糖                     50 g
 3)トウモロコシデンプン             15 g
 4)カルボキシメチルセルロースカルシウム  44 g
 5)ステアリン酸マグネシウム            1 g
                 1000錠  計 140 g
 1)、2)、3)の全量および30gの4)を水で練合し、真空乾燥後、整粒を行う。
この整粒末に14gの4)および1gの5)を混合し、打錠機により打錠する。このようにして、1錠あたり実施例1の化合物30mgを含有する錠剤1000錠を得る。
Formulation Example 2 (Manufacture of tablets)
1) 30 g of the compound of Example 1
2) Lactose 50 g
3) Corn starch 15 g
4) Carboxymethylcellulose calcium 44 g
5) Magnesium stearate 1 g
1000 tablets total 140 g
The total amount of 1), 2), and 3) and 30 g of 4) are kneaded with water, vacuum dried, and sized.
14 g of 4) and 1 g of 5) are mixed with the sized powder, and tableted with a tableting machine. In this way, 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.
 本発明化合物は、GPR119アゴニスト作用を有し、肥満症、糖尿病等の予防・治療に有用である。
 本出願は、日本で出願された特願2009-254568を基礎としており、それらの内容は本明細書にすべて包含される。
The compound of the present invention has a GPR119 agonistic action and is useful for prevention / treatment of obesity, diabetes and the like.
This application is based on patent application No. 2009-254568 filed in Japan, the contents of which are incorporated in full herein.

Claims (22)


  1.  
    Figure JPOXMLDOC01-appb-I000001
     (I)
    [式中、
    環Aは、さらに置換されていてもよい6員芳香環を;
    は、ハロゲン原子、シアノ基、置換されていてもよい炭化水素基、置換されていてもよい複素環基、置換されていてもよいアミノ基、またはアシル基を;
    は、シアノ基、置換されていてもよい炭化水素基、置換されていてもよい複素環基、またはアシル基を;
    は、置換されていてもよい直鎖のC2-3アルキレン基を;
    は、結合手、置換されていてもよいNH、S、SO、SO、CO、またはOを;
    は、結合手、置換されていてもよい直鎖のC1-2アルキレン基を;および
    およびYは、独立して、置換されていてもよい直鎖のC1-3アルキレン基を示す。]
    で表される化合物またはその塩。
    formula
    Figure JPOXMLDOC01-appb-I000001
    (I)
    [Where:
    Ring A represents a 6-membered aromatic ring which may be further substituted;
    R 1 represents a halogen atom, a cyano group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted amino group, or an acyl group;
    R 2 represents a cyano group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, or an acyl group;
    X 1 represents an optionally substituted linear C 2-3 alkylene group;
    X 2 represents a bond, optionally substituted NH, S, SO, SO 2 , CO, or O;
    X 3 is a bond, an optionally substituted linear C 1-2 alkylene group; and Y 1 and Y 2 are independently an optionally substituted linear C 1-3 alkylene Indicates a group. ]
    Or a salt thereof.
  2. が、結合手または置換されていてもよいCHである、請求項1記載の化合物またはその塩。 The compound or a salt thereof according to claim 1, wherein X 3 is a bond or optionally substituted CH 2 .
  3. 環Aが、
    (1)ハロゲン原子、
    (2)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基、および
    (3)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ基
    から選ばれる1ないし3個の置換基でそれぞれさらに置換されていてもよい、ベンゼン、ピリジン、またはピリミジンである、請求項1記載の化合物またはその塩。
    Ring A is
    (1) a halogen atom,
    (2) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, and
    (3) With benzene, pyridine, or pyrimidine, each of which may be further substituted with 1 to 3 substituents selected from C 1-6 alkoxy groups optionally substituted with 1 to 3 halogen atoms The compound according to claim 1 or a salt thereof.
  4. が、
    (1)ハロゲン原子、
    (2)カルボキシ基、
    (3)(a)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基、および(b)オキソ基から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環基、
    (4)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ-カルボニル基、
    (5)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキルスルホニル基、
    (6)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基でモノまたはジ置換されていてもよいスルファモイル基、または
    (7)(a)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基、および(b)オキソ基から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環スルホニル基である、請求項1記載の化合物またはその塩。
    R 1 is
    (1) a halogen atom,
    (2) a carboxy group,
    (3) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (b) optionally substituted with 1 to 3 substituents selected from an oxo group Non-aromatic heterocyclic group,
    (4) a C 1-6 alkoxy-carbonyl group optionally substituted with 1 to 3 halogen atoms,
    (5) a C 1-6 alkylsulfonyl group which may be substituted with 1 to 3 halogen atoms,
    (6) a sulfamoyl group optionally mono- or disubstituted with a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, or
    (7) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (b) optionally substituted with 1 to 3 substituents selected from an oxo group The compound or its salt of Claim 1 which is a non-aromatic heterocyclic sulfonyl group.
  5. が、
    (1)(a)ハロゲン原子、および(b)C1-6アルコキシ-カルボニル基から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基、
    (2)(a)ハロゲン原子、および(b)C1-6アルキル基から選ばれる1ないし3個の置換基で置換されていてもよい芳香族複素環基、
    (3)(a)ハロゲン原子、(b)C1-6アルキル基、および(c)オキソ基から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環基、
    (4)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ-カルボニル基、
    (5)(a)C1-6アルキル基、および(b)複素環基から選ばれる置換基でモノまたはジ置換されていてもよいカルバモイル基、または
    (6)(a)C1-6アルキル基、および(b)オキソ基から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環オキシカルボニル基である、請求項1記載の化合物またはその塩。
    R 2 is
    (1) (a) a halogen atom, and (b) C 1-6 alkoxy - 1 to 3 substituents optionally substituted by a C 1-6 alkyl group selected from a carbonyl group,
    (2) an aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, and (b) a C 1-6 alkyl group,
    (3) a non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, (b) a C 1-6 alkyl group, and (c) an oxo group,
    (4) a C 1-6 alkoxy-carbonyl group optionally substituted with 1 to 3 halogen atoms,
    (5) a carbamoyl group optionally mono- or disubstituted with a substituent selected from (a) a C 1-6 alkyl group, and (b) a heterocyclic group, or
    (6) A non-aromatic heterocyclic oxycarbonyl group which may be substituted with 1 to 3 substituents selected from (a) a C 1-6 alkyl group and (b) an oxo group. Or a salt thereof.
  6. が、
    (1)ハロゲン原子、および
    (2)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル
    から選ばれる1ないし3個の置換基でそれぞれ置換されていてもよい、エチレンまたはトリメチレンである、請求項1記載の化合物またはその塩。
    X 1 is
    (1) a halogen atom, and
    (2) It is ethylene or trimethylene, each of which may be substituted with 1 to 3 substituents selected from C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms. Or a salt thereof.
  7. が、
    (1)結合手、
    (2)O、または
    (3)(a)(i)シアノ基、および(ii)1ないし3個のハロゲン原子から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル、 
       (b)C1-6アルキル-カルボニル基、 または
       (c)C1-6アルキルスルホニル基
    で置換されていてもよいNHである、請求項1記載の化合物またはその塩。
    X 2 is,
    (1) Joining hands,
    (2) O or
    (3) (a) (i) a cyano group, and (ii) C 1-6 alkyl optionally substituted with 1 to 3 substituents selected from 1 to 3 halogen atoms,
    The compound or a salt thereof according to claim 1, which is (b) a C 1-6 alkyl-carbonyl group, or (c) NH optionally substituted with a C 1-6 alkylsulfonyl group.
  8. が、結合手またはメチレンである、請求項1記載の化合物またはその塩。 The compound or a salt thereof according to claim 1, wherein X 3 is a bond or methylene.
  9. およびYが、独立して、メチレンまたはエチレンである、請求項1記載の化合物またはその塩。 The compound or a salt thereof according to claim 1, wherein Y 1 and Y 2 are independently methylene or ethylene.
  10. 環Aが、
    (1)ハロゲン原子、
    (2)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基、および
    (3)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ基
    から選ばれる1ないし3個の置換基でそれぞれさらに置換されていてもよい、ベンゼン、ピリジン、またはピリミジンであり;
    が、
    (1)ハロゲン原子、
    (2)カルボキシ基、
    (3)(a)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基、および(b)オキソ基から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環基、
    (4)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ-カルボニル基、
    (5)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキルスルホニル基、
    (6)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基でモノまたはジ置換されていてもよいスルファモイル基、または
    (7)(a)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル基、および(b)オキソ基から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環スルホニル基であり;
    が、
    (1)(a)ハロゲン原子、および(b)C1-6アルコキシ-カルボニル基から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル基、
    (2)(a)ハロゲン原子、および(b)C1-6アルキル基から選ばれる1ないし3個の置換基で置換されていてもよい芳香族複素環基、
    (3)(a)ハロゲン原子、(b)C1-6アルキル基、および(c)オキソ基から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環基、
    (4)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルコキシ-カルボニル基、
    (5)(a)C1-6アルキル基、および(b)複素環基から選ばれる置換基でモノまたはジ置換されていてもよいカルバモイル基、または
    (6)(a)C1-6アルキル基、および(b)オキソ基から選ばれる1ないし3個の置換基で置換されていてもよい非芳香族複素環オキシカルボニル基であり;
    が、
    (1)ハロゲン原子、および
    (2)1ないし3個のハロゲン原子で置換されていてもよいC1-6アルキル
    から選ばれる1ないし3個の置換基でそれぞれ置換されていてもよい、エチレンまたはトリメチレンであり;
    が、
    (1)結合手、
    (2)O、または
    (3)(a)(i)シアノ基、および(ii)1ないし3個のハロゲン原子から選ばれる1ないし3個の置換基で置換されていてもよいC1-6アルキル、 
       (b)C1-6アルキル-カルボニル基、 または
       (c)C1-6アルキルスルホニル基
    で置換されていてもよいNHであり;
    が、結合手またはメチレンであり;および
    およびYが、独立して、メチレンまたはエチレンである、請求項1記載の化合物またはその塩。
    Ring A is
    (1) a halogen atom,
    (2) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, and
    (3) With benzene, pyridine, or pyrimidine, each of which may be further substituted with 1 to 3 substituents selected from C 1-6 alkoxy groups optionally substituted with 1 to 3 halogen atoms Yes;
    R 1 is
    (1) a halogen atom,
    (2) a carboxy group,
    (3) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (b) optionally substituted with 1 to 3 substituents selected from an oxo group Non-aromatic heterocyclic group,
    (4) a C 1-6 alkoxy-carbonyl group optionally substituted with 1 to 3 halogen atoms,
    (5) a C 1-6 alkylsulfonyl group which may be substituted with 1 to 3 halogen atoms,
    (6) a sulfamoyl group optionally mono- or disubstituted with a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, or
    (7) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, and (b) optionally substituted with 1 to 3 substituents selected from an oxo group A non-aromatic heterocyclic sulfonyl group;
    R 2 is
    (1) (a) a halogen atom, and (b) C 1-6 alkoxy - 1 to 3 substituents optionally substituted by a C 1-6 alkyl group selected from a carbonyl group,
    (2) an aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, and (b) a C 1-6 alkyl group,
    (3) a non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from (a) a halogen atom, (b) a C 1-6 alkyl group, and (c) an oxo group,
    (4) a C 1-6 alkoxy-carbonyl group optionally substituted with 1 to 3 halogen atoms,
    (5) a carbamoyl group optionally mono- or disubstituted with a substituent selected from (a) a C 1-6 alkyl group, and (b) a heterocyclic group, or
    (6) (a) a non-aromatic heterocyclic oxycarbonyl group which may be substituted with 1 to 3 substituents selected from (a) a C 1-6 alkyl group and (b) an oxo group;
    X 1 is
    (1) a halogen atom, and
    (2) ethylene or trimethylene, each optionally substituted with 1 to 3 substituents selected from C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms;
    X 2 is,
    (1) Joining hands,
    (2) O or
    (3) (a) (i) a cyano group, and (ii) C 1-6 alkyl optionally substituted with 1 to 3 substituents selected from 1 to 3 halogen atoms,
    (b) a C 1-6 alkyl-carbonyl group, or (c) NH optionally substituted with a C 1-6 alkylsulfonyl group;
    The compound or a salt thereof according to claim 1, wherein X 3 is a bond or methylene; and Y 1 and Y 2 are independently methylene or ethylene.
  11. 5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸2-[1-(5-プロピルピリミジン-2-イル)ピペリジン-4-イル]プロピルまたはその塩。 5- [Methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylic acid 2- [1- (5-propylpyrimidin-2-yl) piperidin-4-yl] propyl or a salt thereof.
  12. 7-フルオロ-5-(メチルスルホニル)-2,3-ジヒドロ-1H-インドール-1-カルボン酸 2-[1-(5-プロピルピリミジン-2-イル)ピペリジン-4-イル]プロピルまたはその塩。 7-Fluoro-5- (methylsulfonyl) -2,3-dihydro-1H-indole-1-carboxylate 2- [1- (5-propylpyrimidin-2-yl) piperidin-4-yl] propyl or a salt thereof .
  13. 請求項1記載の化合物またはその塩を含む、医薬。 A medicament comprising the compound according to claim 1 or a salt thereof.
  14. インスリン分泌促進剤である、請求項13記載の医薬。 The medicament according to claim 13, which is an insulin secretagogue.
  15. グルカゴン様ペプチド‐1分泌促進剤である、請求項13記載の医薬。 The medicament according to claim 13, which is a glucagon-like peptide-1 secretion promoter.
  16. GPR119作動薬である、請求項13記載の医薬。 The medicament according to claim 13, which is a GPR119 agonist.
  17. 糖尿病の予防または治療剤である、請求項13記載の医薬。 The medicament according to claim 13, which is a prophylactic or therapeutic agent for diabetes.
  18. 肥満症の予防または治療剤である、請求項13記載の医薬。 The medicament according to claim 13, which is a prophylactic or therapeutic agent for obesity.
  19. 請求項1記載の化合物またはその塩を哺乳動物に有効量投与することを特徴とする、該哺乳動物における糖尿病の予防または治療方法。 A method for preventing or treating diabetes in a mammal, which comprises administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal.
  20. 請求項1記載の化合物またはその塩を哺乳動物に有効量投与することを特徴とする、該哺乳動物における肥満症の予防または治療方法。 A method for preventing or treating obesity in a mammal, which comprises administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal.
  21. 糖尿病の予防または治療剤を製造するための、請求項1記載の化合物またはその塩の使用。 Use of the compound according to claim 1 or a salt thereof for producing a preventive or therapeutic agent for diabetes.
  22. 肥満症の予防または治療剤を製造するための、請求項1記載の化合物またはその塩の使用。 Use of the compound according to claim 1 or a salt thereof for the manufacture of an agent for preventing or treating obesity.
PCT/JP2010/069654 2009-11-06 2010-11-05 Fused heterocyclic compound WO2011055770A1 (en)

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WO2012170867A1 (en) 2011-06-09 2012-12-13 Rhizen Pharmaceuticals Sa Novel compounds as modulators of gpr-119
US8410089B2 (en) 2009-02-18 2013-04-02 Takeda Pharmaceutical Company Limited Fused heterocyclic ring compound
WO2014011926A1 (en) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk
CN115448871A (en) * 2022-08-30 2022-12-09 中国药科大学 Preparation method of tirofiban hydrochloride

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
US8410089B2 (en) 2009-02-18 2013-04-02 Takeda Pharmaceutical Company Limited Fused heterocyclic ring compound
WO2012170867A1 (en) 2011-06-09 2012-12-13 Rhizen Pharmaceuticals Sa Novel compounds as modulators of gpr-119
WO2014011926A1 (en) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk
CN115448871A (en) * 2022-08-30 2022-12-09 中国药科大学 Preparation method of tirofiban hydrochloride

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