WO2011055770A1 - Composé à hétérocycle condensé - Google Patents

Composé à hétérocycle condensé 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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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/ja
Publication of WO2011055770A1 publication Critical patent/WO2011055770A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic 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
    • C07D401/02—Heterocyclic 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
    • C07D401/12—Heterocyclic 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic 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
    • C07D401/14—Heterocyclic 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic 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
    • C07D403/12—Heterocyclic 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic 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
    • C07D405/14—Heterocyclic 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic 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

L'invention concerne un composé représenté par la formule (I) ou un sel de celui-ci, qui a une action agoniste de GPR119 et est utile pour la prévention et le traitement du diabète, de l'obésité et similaires. (Dans la formule, les symboles sont tels que définis dans la description).
PCT/JP2010/069654 2009-11-06 2010-11-05 Composé à hétérocycle condensé WO2011055770A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012170867A1 (fr) 2011-06-09 2012-12-13 Rhizen Pharmaceuticals Sa Nouveaux composes utilises comme modulateurs de gpr-119
US8410089B2 (en) 2009-02-18 2013-04-02 Takeda Pharmaceutical Company Limited Fused heterocyclic ring compound
WO2014011926A1 (fr) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comportant des statines, des biguanides et d'autres agents pour réduire un risque cardiométabolique
CN115448871A (zh) * 2022-08-30 2022-12-09 中国药科大学 一种盐酸替罗非班的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004067509A1 (fr) * 2003-01-31 2004-08-12 Sanwa Kagaku Kenkyusho Co., Ltd. Composé inhibant la dipeptidyl peptidase iv
JP2005511557A (ja) * 2001-10-26 2005-04-28 エフ．ホフマン−ラ　ロシュ　アーゲー ジペプチジルペプチダーゼｉｖインヒビターとしてのｎ−置換ピロリジン誘導体
WO2009071677A1 (fr) * 2007-12-05 2009-06-11 Biovitrum Ab (Publ) Nouveaux composés iii

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005511557A (ja) * 2001-10-26 2005-04-28 エフ．ホフマン−ラ　ロシュ　アーゲー ジペプチジルペプチダーゼｉｖインヒビターとしてのｎ−置換ピロリジン誘導体
WO2004067509A1 (fr) * 2003-01-31 2004-08-12 Sanwa Kagaku Kenkyusho Co., Ltd. Composé inhibant la dipeptidyl peptidase iv
WO2009071677A1 (fr) * 2007-12-05 2009-06-11 Biovitrum Ab (Publ) Nouveaux composés iii

Cited By (4)

* Cited by examiner, † Cited by third party
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 (fr) 2011-06-09 2012-12-13 Rhizen Pharmaceuticals Sa Nouveaux composes utilises comme modulateurs de gpr-119
WO2014011926A1 (fr) 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comportant des statines, des biguanides et d'autres agents pour réduire un risque cardiométabolique
CN115448871A (zh) * 2022-08-30 2022-12-09 中国药科大学 一种盐酸替罗非班的制备方法

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