WO2014017093A1 - Benzene ring-fused, nitrogen-containing 5-membered heterocyclic compound or pharmacologically acceptable salt thereof - Google Patents

Benzene ring-fused, nitrogen-containing 5-membered heterocyclic compound or pharmacologically acceptable salt thereof Download PDF

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WO2014017093A1
WO2014017093A1 PCT/JP2013/004520 JP2013004520W WO2014017093A1 WO 2014017093 A1 WO2014017093 A1 WO 2014017093A1 JP 2013004520 W JP2013004520 W JP 2013004520W WO 2014017093 A1 WO2014017093 A1 WO 2014017093A1
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group
methyl
thiazol
benzo
pyrazole
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PCT/JP2013/004520
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French (fr)
Japanese (ja)
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茂樹 瀬戸
健太郎 楳井
麻生 谷岡
田谷　和也
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杏林製薬株式会社
キッセイ薬品工業株式会社
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    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • the present invention relates to a benzene ring condensed nitrogen-containing 5-membered heterocyclic compound having an EP 1 receptor antagonistic action, or a pharmacologically acceptable salt thereof.
  • OABs overactive bladder syndrome
  • OABs are diseases defined as "symptom syndrome requiring urgency of urine, usually accompanied by frequent urination and nocturia. Imminent urinary incontinence is not essential.” is there.
  • anticholinergic drugs are first-line drugs for the treatment of OABs.
  • anticholinergic drugs need to be used with sufficient consideration for antimuscarinic effects such as dry mouth and residual urine, and are not necessarily effective for all patients (for example, non-patent literature). 1).
  • development of a therapeutic agent having a mechanism different from that of an anticholinergic agent is desired (see, for example, Non-Patent Document 1).
  • EP 1 there are four subtypes of receptors for PGE 2 , EP 2 , EP 3 and EP 4 .
  • the EP 1 receptor is present in the lung, skeletal muscle, kidney collecting duct and the like in addition to the bladder and urothelium (see, for example, Non-Patent Document 2).
  • it is expected that therapeutic agents for a desired disease can be developed by changing the selectivity of the PGE 2 receptor subtype and the target organ or target tissue of the drug.
  • Patent Document 1 discloses a benzofuran derivative represented by the chemical structural formula (A) as a compound having an EP 1 receptor antagonistic action.
  • R 1 represents a hydrogen atom, a halogen atom or the like
  • R 2a represents a hydrogen atom or the like
  • R 2b represents a C 1-4 alkyl group (straight or branched chain having 1 to 4 carbon atoms).
  • R 2c represents a hydrogen atom or the like
  • R 3 represents a group represented by the following general formula (B) or the like.
  • R 4 represents a carboxy group or the like.
  • Patent Document 2 discloses a compound represented by the chemical structural formula (C) as a compound having an EP 1 receptor antagonistic action.
  • R 1 represents a hydrogen atom, a halogen atom or the like
  • R 2 represents a thienyl group or the like
  • R 3 represents a group represented by the following general formula (B) or the like.
  • R 4 represents a carboxy group or the like.
  • An object of the present invention is to provide a novel compound having an EP 1 receptor antagonistic action.
  • the gist of the present invention is as follows.
  • the benzene ring condensed nitrogen-containing 5-membered heterocyclic ring containing Y 1 and Y 2 and having R 2 , R 3 , R 4 , R 5 and Y 3 bonded thereto is represented by the following a) to d):
  • A is a group selected from the group consisting of e) to i) below:
  • A is a group selected from the group consisting of the following e), f), h) and i), wherein the nitrogen-containing 5-membered benzene ring is described in [1] A heterocyclic compound or a pharmacologically acceptable salt thereof.
  • R a , W 1 , W 2 , W 3 , and W 4 are as defined above.
  • R a has the same meaning as described above.
  • R 1 is —C ( ⁇ O) —OZ 1
  • Z 1 is a hydrogen atom or a C 1-6 alkyl group
  • R 1 is —C ( ⁇ O ) -NHSO 2 Z 2 , wherein Z 2 is a C 1-6 alkyl group, the benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a compound thereof according to any one of [1] to [5] Pharmacologically acceptable salt.
  • R 3 is selected from the group consisting of the following A), B), C), F), G), H), J), K), and M).
  • R 2 is a group selected from the group consisting of the following aa1), bb), cc), dd), ee1), ff1), gg1) and hh1). Benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of [1] to [7].
  • R a has the same meaning as described above.
  • R 3 is substituted with a hydrogen atom, a halogen atom, a C 2-8 alkenyl group, a C 1-7 alkanoyl group, or two independent C 1-6 alkyl groups.
  • the benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or the drug thereof according to any one of [1] to [10], which is an amino group, a C 1-6 alkoxy group, or a halo C 1-6 alkoxy group Physically acceptable salt.
  • R 2 is a group selected from the group consisting of the following bb1), cc), dd), gg2) and hh2), [1] to [11] The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of the above.
  • bb1) C 3-6 cycloalkyl group whose ring is substituted with one C 1-6 alkyl group cc) C 2-6 alkenyl group dd) C 5-8 cycloalkenyl group gg2) two independent C 1 1- Amino groups substituted with 6 alkyl groups hh2) 4-7 membered cyclic amino groups
  • the benzene ring condensed nitrogen-containing 5-membered heterocyclic ring is a ring selected from the group consisting of the following a), b) and d): [1] to [12 ]
  • R 2 , R 3 , R 4 , R 5 and Y 3 are as defined above.
  • R 2 , R 3 , R 4 , R 5 and Y 3 are as defined above.
  • the compound represented by the general formula (I) is: 1-[[6-bromo-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[6-chloro-2- (diethylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[6-Chloro-2- (5-methyl-3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazo
  • a medicament comprising the benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of [1] to [15].
  • An EP 1 receptor antagonist comprising the benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [15].
  • a benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a drug thereof according to any one of the above [1] to [15], for producing a medicament for preventing or treating lower urinary tract symptoms The use of a physically acceptable salt.
  • a benzene ring-fused nitrogen-containing 5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [15] for use in the prevention or treatment of lower urinary tract symptoms Salt.
  • a novel compound having an EP 1 receptor antagonistic action can be provided.
  • This embodiment relates to a benzene ring condensed nitrogen-containing 5-membered heterocyclic compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof.
  • the benzene ring condensed nitrogen-containing 5-membered heterocyclic ring containing Y 1 and Y 2 and having R 2 , R 3 , R 4 , R 5 and Y 3 bonded thereto is represented by the following a) to d):
  • A is a group selected from the group consisting of e) to i) below:
  • the bond marked with (*) bonded to Y 3, represents a bond with (**) attached to bond R 1.
  • “Independently” and “independently” mean that they may be the same or different between two or more substituents that may be present. Of course, Z 2 and Z 3 may be the same or different.
  • Halogen atom includes fluorine atom, chlorine atom, bromine atom and iodine atom.
  • C 1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms.
  • Examples of the C 1-6 alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, and 1-methylbutyl.
  • 2-methylbutyl group 1,2-dimethylpropyl group, hexyl group, isohexyl group and the like.
  • halo C 1-6 alkyl group means a C 1-6 alkyl group substituted with 1 to 5 same or different halogen atoms.
  • examples of the halo C 1-6 alkyl group include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 2-chloroethyl group, a 2,2-difluoroethyl group, and a 1,1-difluoroethyl group.
  • a fluoromethyl group, a difluoromethyl group, and a trifluoromethyl group are mentioned.
  • C 1-6 alkylene means a divalent straight chain or branched saturated hydrocarbon chain having 1 to 6 carbon atoms.
  • C 1-6 alkylene for example, —CH 2 —, — (CH 2 ) 2 —, —CH (CH 3 ) —, — (CH 2 ) 3 —, —CH (CH 3 ) CH 2 —, —CH 2 CH (CH 3 ) —, —CH (CH 2 CH 3 ) —, —C (CH 3 ) 2 —, — (CH 2 ) 4 —, —CH (CH 3 ) — (CH 2 ) 2 —, — (CH 2 ) 2 —CH (CH 3 ) —, —CH (CH 2 CH 3 ) —CH 2 —, —C (CH 3 ) 2 CH 2 —, —CH 2 —C (CH 3 ) 2 —, — CH (CH 3 ) —CH (CH 3 ) —, — (CH 2 —
  • the “C 2-6 alkenyl group” means a straight or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms having at least one double bond.
  • Examples of the C 2-6 alkenyl group include a vinyl group, 2-propenyl group, 1-propenyl group, 1-buten-1-yl group, 1-buten-2-yl group, 1-buten-3-yl group, 1-buten-4-yl group, 2-buten-1-yl group, 2-buten-2-yl group, 1-penten-1-yl group, 1-penten-2-yl group, 1-pentene-3 -Yl group, 2-penten-1-yl group, 2-penten-2-yl group, 2-penten-3-yl group, 1-hexen-1-yl group, 1-hexen-2-yl group, -Hexen-3-yl group, 2-methyl-1-propen-1-yl group and the like.
  • the “C 2-8 alkenyl group” means a straight or branched unsaturated hydrocarbon group having 2 to 8 carbon atoms having at least one double bond.
  • Examples of the C 2-8 alkenyl group include a vinyl group, 2-propenyl group, 1-propenyl group, 1-buten-1-yl group, 1-buten-2-yl group, 1-buten-3-yl group, 1-buten-4-yl group, 2-buten-1-yl group, 2-buten-2-yl group, 1-penten-1-yl group, 1-penten-2-yl group, 1-pentene-3 -Yl group, 2-penten-1-yl group, 2-penten-2-yl group, 2-penten-3-yl group, 1-hexen-1-yl group, 1-hexen-2-yl group, -Hexen-3-yl group, 1-hepten-1-yl group, 1-octen-1-yl group, 2-methyl-1-propen-1-yl group and the like.
  • the “C 1-6 alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms.
  • Examples of the C 1-6 alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, an isobutoxy group, a butoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, and a hexyloxy group.
  • a methoxy group and an ethoxy group are mentioned.
  • halo C 1-6 alkoxy group means a C 1-6 alkoxy group substituted with 1 to 5 same or different halogen atoms.
  • examples of the halo C 1-6 alkoxy group include a monofluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a 2-fluoroethoxy group, a 2-chloroethoxy group, a 2,2-difluoroethoxy group, and a 1,1-difluoro group.
  • Ethoxy group 1,2-difluoroethoxy group, 2,2,2-trifluoroethoxy group, 1,1,2,2,2-pentafluoroethoxy group, 2,2,2-trichloroethoxy group, 3-fluoro Propoxy group, 2-fluoropropoxy group, 1-fluoropropoxy group, 3,3-difluoropropoxy group, 2,2-difluoropropoxy group, 1,1-difluoropropoxy group, 4-fluorobutoxy group, 5-fluoropentyloxy Group, 6-fluorohexyloxy group and the like.
  • a monofluoromethoxy group, a difluoromethoxy group, and a trifluoromethoxy group are mentioned.
  • the “(C 1-6 alkoxy) carbonyl group” means a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms.
  • (C 1-6 alkoxy) carbonyl group includes, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, isobutoxycarbonyl group, butoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group , A pentyloxycarbonyl group, a hexyloxycarbonyl group, and the like.
  • a methoxycarbonyl group and a tert-butoxycarbonyl group are used.
  • C 1-6 alkoxy C 1-6 alkyl group means a C 1-6 alkyl group substituted with a linear or branched alkoxy group having 1 to 6 carbon atoms.
  • Examples of the C 1-6 alkoxy C 1-6 alkyl group include a methoxymethyl group, an ethoxyethyl group, a propoxymethyl group, and an isopropoxymethyl group.
  • C 1-6 alkylenedioxy group means a group represented by —O— (C 1-6 alkyl) -O—.
  • a methylenedioxy group, an ethylenedioxy group, a propylenedioxy group, etc. are mentioned.
  • the “C 1-7 alkanoyl group” means an acyl group derived from a linear or branched aliphatic carboxylic acid having 1 to 7 carbon atoms.
  • Examples of the C 1-7 alkanoyl group include formyl group, acetyl group, propanoyl group, butanoyl group, pentanoyl group, hexanoyl group and the like.
  • C 1-6 alkylsulfanyl group means a group represented by (C 1-6 alkyl) -S—.
  • Examples of the C 1-6 alkylsulfanyl group include a methylsulfanyl group, an ethylsulfanyl group, a propylsulfanyl group, an isopropylsulfanyl group, a butylsulfanyl group, an isobutylsulfanyl group, a sec-butylsulfanyl group, a pentylsulfanyl group, and a hexylsulfanyl group.
  • C 7-10 aralkyl group means an alkyl group having 1 to 4 carbon atoms substituted with a phenyl group.
  • Examples of the C 7-10 aralkyl group include benzyl group, phenethyl group, 1-phenylethyl group, 3-phenylpropyl group, 4-phenylbutyl group and the like.
  • the “C 7-10 aralkyloxy group” means an alkoxy group having 1 to 4 carbon atoms substituted with a phenyl group.
  • Examples of the C 7-10 aralkyloxy group include a benzyloxy group, a phenethyloxy group, a 1-phenylethyloxy group, a 3-phenylpropyloxy group, and a 4-phenylbutyloxy group.
  • the “C 4-10 heteroaralkyl group” means an alkyl group having 1 to 4 carbon atoms substituted with a heteroaryl group.
  • Examples of the C 4-10 heteroaralkyl group include a 2-furanylmethyl group, a 3-furanylmethyl group, a 2-pyridylmethyl group, and the like.
  • the “C 4-6 heterocycloalkyl group” means an alkyl group having 1 to 4 carbon atoms substituted with a saturated heterocyclic group.
  • Examples of the C 4-6 heterocycloalkyl group include a 2-tetrahydrofuranylmethyl group, a 3-tetrahydrofuranylmethyl group, a 2-pyrrolidinylmethyl group, and the like.
  • the “C 3-6 cycloalkyl group” means a monocyclic saturated alicyclic hydrocarbon group having 3 to 6 carbon atoms.
  • Examples of the C 3-6 cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • C 3-6 cycloalkyl group in which the ring is substituted with one C 1-6 alkyl group refers to the above C 3-6 cycloalkyl group in which the ring is substituted with the above C 1-6 alkyl group.
  • Examples of the C 3-6 cycloalkyl group in which the ring is substituted with one C 1-6 alkyl group include a 1-methylcyclopropyl group, a 1-ethylcyclopropyl group, a 1-methylcyclobutyl group, and a 2-methylcyclo Examples include a butyl group, 1-methylcyclopentyl group, 2-methylcyclopentyl group, 1-methylcyclohexyl group, 2-methylcyclohexyl group and the like.
  • a 1-methylcyclopropyl group and a 1-ethylcyclopropyl group are preferable, and a 1-methylcyclopropyl group is more preferable.
  • the “C 5-8 cycloalkenyl group” means a monocyclic unsaturated alicyclic hydrocarbon group having 5 to 8 carbon atoms.
  • Examples of the C 5-8 cycloalkenyl group include a cyclopenten-1-yl group, a cyclohexen-1-yl group, a cyclohepten-1-yl group, and a cycloocten-1-yl group.
  • the “aryl group” means, for example, an aromatic hydrocarbon group having 6 to 14 carbon atoms such as a phenyl group, an indenyl group, a naphthyl group, a phenanthrenyl group, or an anthracenyl group.
  • a “C 6-10 aryl group” which means an aromatic hydrocarbon group having 6 to 10 carbon atoms. Examples of the C 6-10 aryl group include a phenyl group, an indenyl group, and a naphthyl group.
  • Heterocyclic group means a 5- to 7-membered heterocyclic group containing 1 to 4 atoms selected from a sulfur atom, an oxygen atom, and a nitrogen atom.
  • heterocyclic groups include furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl Group, thiadiazolyl group, pyranyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group and other aromatic heterocyclic groups, pyrrolinyl group, imidazolinyl group, pyrazolinyl group, dihydropyranyl group, dihydrothiopyranyl group, dihydropyridyl group And unsaturated
  • heterocyclic group When the “heterocyclic group” is a condensed cyclic group, a monocyclic or condensed heterocyclic group and a cyclic group other than the heterocyclic ring may be condensed.
  • the heterocyclic group in which the heterocyclic group and other cyclic group other than the heterocyclic ring are condensed include, for example, an isobenzofuranyl group, a benzoxazolyl group, a benzoisoxazolyl group, a benzothiazolyl group, a benzo Isothiazolyl group, chromenyl group, chromanonyl group, xanthenyl group, phenoxathiinyl group, indolizinyl group, isoindolidinyl group, indolyl group, indazolyl group, purinyl group, quinolidinyl group, isoquinolyl group, quinolyl group, phthalazinyl group, Examples thereof include
  • the “branched C 3-6 alkyl group” means a branched alkyl group having 3 to 6 carbon atoms.
  • Examples of branched C 3-6 alkyl groups include, for example, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group 1,2-dimethylpropyl group, 1-ethylpropyl group, isohexyl group and the like.
  • Preferred are isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, 1-ethylpropyl group and the like.
  • the “5-membered aromatic heterocyclic group” means a 5-membered aromatic group containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom in the ring.
  • 5-membered aromatic heterocyclic groups include furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1 , 3,4-oxadiazolyl group, 1,2,4-oxadiazolyl group and the like.
  • 6-membered aromatic heterocyclic group means a 6-membered aromatic group containing 1 to 4 nitrogen atoms in the ring.
  • examples of the 6-membered aromatic heterocyclic group include a pyridyl group, a pyrimidyl group, a pyrazinyl group, and a pyridazinyl group.
  • the “acidic 5-membered heterocyclic group” means a 5-membered ring containing a nitrogen atom bonded to an acidic proton in the ring or a 5-membered nitrogen-containing heterocyclic ring having a phenolic hydroxyl group.
  • Examples of the acidic 5-membered heterocyclic group include groups selected from the group consisting of 5-membered nitrogen-containing heterocyclic groups having the following structures.
  • a group selected from the group consisting of a 5-membered nitrogen-containing heterocyclic group having the structure shown below is exemplified.
  • C 1-6 alkyl group substituted by a 6-membered aliphatic cyclic amino group means a linear or branched alkyl group having 1 to 6 carbon atoms and substituted by a morpholino group or piperidino group. To do.
  • Examples of the C 1-6 alkyl group substituted with a 6-membered aliphatic cyclic amino group include, for example, morpholinomethyl group, piperidinoethyl group, 1-morpholinoethyl group, 1-piperidinoethyl group, 2-morpholinoethyl group, 2-piperidinoethyl group Etc.
  • the benzene ring condensed nitrogen-containing 5-membered heterocyclic ring containing Y 1 and Y 2 and to which R 2 , R 3 , R 4 , R 5 and Y 3 are bonded is preferably from the following a), b) and d):
  • the benzene ring condensed nitrogen-containing 5-membered heterocyclic ring is more preferably a ring represented by the following a).
  • A preferably a group represented by e) wherein W 1 is CH or a nitrogen atom, a group represented by f) wherein W 2 is an oxygen atom or a sulfur atom, a group represented by h), and One of W 3 and W 4 is a nitrogen atom, and the other is a group represented by i), which is CH or a nitrogen atom.
  • R a is as defined above, and is preferably a hydrogen atom or a C 1-6 alkyl group. More preferably, A is a group selected from the group consisting of the following e1), f1), h) and i1).
  • R a is preferably a hydrogen atom or a C 1-6 alkyl group.
  • the bond marked with (*) bonded to Y 3, represents a bond with (**) attached to bond R 1.
  • R a is attached, even more preferably a group R a is represented as e1) a C 1-6 alkyl group, a group R a is represented as e1) a hydrogen atom, R a is hydrogen group represented by an atom f1), a group a group R a is represented as h) is a hydrogen atom, R a is represented as i1) a hydrogen atom.
  • R a is a group represented by e1) wherein R 1 is a C 1-6 alkyl group, R a is a group represented by f1) wherein H is a hydrogen atom, R a is hydrogen It is a group represented as i1) which is an atom.
  • R a is bonded, particularly preferred are a group represented by e1) in which R a is a C 1-6 alkyl group and a group represented by f1) in which R a is a hydrogen atom.
  • Y 3 is preferably C 1-6 alkylene such as methylene, —O— or —S—, more preferably C 1-6 alkylene, and particularly preferably methylene.
  • R 1 is preferably —C ( ⁇ O) —OZ 1 , —C ( ⁇ O) —NHSO 2 Z 2 or an acidic 5-membered heterocyclic group, and more preferably R 1 is —C ( ⁇ O). —OZ 1 , —C ( ⁇ O) —NHSO 2 Z 2 or a tetrazolyl group. Furthermore, when R 1 is —C ( ⁇ O) —OZ 1 , Z 1 is a hydrogen atom or a C 1-6 alkyl group, and R 1 is —C ( ⁇ O) —NHSO 2 Z 2 In some cases, Z 2 is preferably a C 1-6 alkyl group.
  • R 2 is preferably a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 2-6 alkenyl group, C 5-8 , which is unsubstituted or substituted with one C 1-6 alkyl group. It consists of a cycloalkenyl group, a phenyl group that is unsubstituted or independently substituted with 1 to 5 halogen atoms, a 6-membered aromatic heterocyclic group, a C 1-6 alkyl group, and a C 2-6 alkenyl group.
  • R 2 more preferably C 3-6 branched alkyl, unsubstituted or one C 1-6 alkyl group a C 3-6 cycloalkyl group which ring is substituted, C 2-6 alkenyl group, A C 5-8 cycloalkenyl group, a phenyl group, a pyridyl group, an amino group substituted with two independent C 1-6 alkyls, and a 4- to 7-membered cyclic amino group.
  • R 2 is more preferably a C 3-6 cycloalkyl group, a C 2-6 alkenyl group, a C 5-8 cycloalkenyl group in which the ring is substituted with one C 1-6 alkyl group, two independent groups An amino group substituted with a C 1-6 alkyl group of 4 to 7-membered cyclic amino group.
  • R 2 is particularly preferably a vinyl group, 2-propenyl group, 1-isobutenyl group, 1-cyclopentenyl group, 1-methylcyclopropyl group, dimethylamino group, methyl (ethyl) amino group, diethylamino group, ethyl ( n-propyl) amino group, di (n-propyl) amino group, phenyl group, pyridyl group, pyrrolidin-1-yl group, piperidin-1-yl group, morpholin-4-yl group, thiomorpholin-4-yl group 3,6-dihydropyridin-1 (2H) -yl group.
  • R 3 is preferably a hydrogen atom, a halogen atom, a cyano group, a C 2-8 alkenyl group, a C 1-7 alkanoyl group, an amino group which is unsubstituted or substituted with 1 or 2 C 1-6 alkyl groups , C 1-6 alkoxy group, halo C 1-6 alkoxy group, 5-membered aromatic heterocyclic group.
  • R 3 is a hydrogen atom, a halogen atom, a C 2-8 alkenyl group, a C 1-7 alkanoyl group, an amino group substituted with two C 1-6 alkyl groups, a C 1-6 alkoxy group, A halo C 1-6 alkoxy group; R 3 is more preferably a hydrogen atom, fluorine atom, chlorine atom, bromine atom, cyano group, vinyl group, 2-propenyl group, acetyl group, dimethylamino group, methoxy group or trifluoromethoxy group.
  • R 4 is preferably a hydrogen atom or a halogen atom, and more preferably a hydrogen atom.
  • R 5 is preferably a hydrogen atom or a halogen atom, more preferably a hydrogen atom.
  • the pharmacologically acceptable salt of Compound (I) means a salt of Compound (I) with a pharmaceutically acceptable non-toxic base or acid (for example, an inorganic or organic base and an inorganic or organic acid). Salts derived from non-toxic bases of pharmaceutically acceptable compounds (I) include aluminum, ammonium, calcium, copper, ferrous, ferric, lithium, magnesium, manganese, manganite, potassium and sodium, etc.
  • Salts with inorganic bases are ammonium, calcium, manganese, potassium and sodium salts or primary, secondary, tertiary amines, substituted amines (eg naturally occurring substituted amines)
  • Organic bases such as cyclic amines and basic ion exchange resins (for example, arginine, betaine, caffeine, choline, N, N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, Ethylenediamine, N-ethylmorpholine, N-ethylpipe Lysine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, tripropylamine, tripropylamine, trome
  • Examples of the salt derived from a pharmaceutically acceptable non-toxic acid of compound (I) include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid, or acetic acid, maleic acid, fumaric acid, succinic acid and lactic acid. And salts with organic acids such as malic acid, tartaric acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid and palmitic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid, or acetic acid, maleic acid, fumaric acid, succinic acid and lactic acid.
  • salts with organic acids such as malic acid, tartaric acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid and palmitic acid.
  • the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof may exist as a hydrate or a solvate.
  • Arbitrary hydrates and solvates formed by the benzene ring condensed nitrogen-containing 5-membered heterocyclic compound represented by the general formula (I) or a salt thereof including the preferred compounds specifically described above are: These are all included in the scope of the present invention.
  • Solvents that can form solvates include methanol, ethanol, 2-propanol, acetone, ethyl acetate, dichloromethane, diisopropyl ether, and the like.
  • the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof may have an optically active substance, a stereoisomer, or a rotational isomer in addition to the racemate.
  • the compound (I) of the present embodiment or a pharmaceutically acceptable salt thereof may have a proton tautomer.
  • EP 1 receptor antagonism means an action of inhibiting the binding of prostaglandin E 2 (PGE 2 ) to prostaglandin E receptor 1 (EP 1 receptor).
  • EP 1 receptor antagonism decreases the amount of calcium inflow into the cell and decreases or suppresses the intracellular calcium concentration. As a result, effects such as smooth muscle relaxation and sensory nerve stimulation inhibitory action are induced by the EP 1 receptor antagonistic action.
  • EP 1 receptor antagonism, bladder, causing the urothelium like, LUTS useful in the treatment or prevention of symptoms among others OABs like.
  • the EP 1 receptor antagonism can be evaluated by the potency of inhibiting calcium influx into cells due to the stimulating action of PGE 2 on the EP 1 receptor.
  • This efficacy can be evaluated by an in vitro test or an in vivo test according to “Pharmacological Test Examples” described in JP-A-2008-214224.
  • Compound (I) of the present embodiment can be produced by various synthesis methods. Next, a typical production method of the compound (I) of this embodiment will be described.
  • Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 and A are as defined above;
  • L 1 represents a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group or the like;
  • 1 represents a C 1-6 alkyl group or a C 7-10 aralkyl group.
  • Step 1-1 This step is a step for producing compound (Ia) by reacting compound (1) with compound (2).
  • Compound (Ia) can be produced, for example, by reacting compound (1) and compound (2) in the presence of a base in a solvent.
  • the solvent include N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, a mixed solvent thereof and the like.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux temperature, preferably 0 ° C. to 30 ° C.
  • an inorganic base such as sodium hydride, potassium carbonate or sodium carbonate, or an organic base such as triethylamine, N, N-diisopropylethylamine or pyridine can be used.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 1-2 This step is a step of producing compound (Ib) by hydrolyzing the ester moiety of compound (Ia).
  • Compound (Ib) can be produced, for example, by reacting compound (Ia) with a base in a solvent.
  • the solvent include tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, propanol, 2-propanol, butanol, water, a mixed solvent thereof and the like.
  • the reaction temperature is usually 0 ° C. to solvent reflux temperature.
  • the base used include alkali metal salts such as potassium hydroxide and sodium hydroxide.
  • reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Compound (2) can be a commercially available product, or can be produced according to other methods described in the literature or a method analogous thereto.
  • Compound (1) can be obtained, for example, by any one of the following methods a, b, c, d, e, and f.
  • R 2 , R 3 , R 4 , R 5 and L 1 are as defined above; L 2 represents a chlorine atom, a bromine atom or the like.
  • Step 1a-1 This step is a step of producing compound (5) by a condensation reaction between compound (3) and compound (4).
  • Compound (5) can be produced, for example, by reacting compound (3) with compound (4) in a solvent in the presence or absence of a base.
  • the solvent include N, N-dimethylformamide, dichloromethane, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like.
  • the base to be used potassium carbonate, sodium carbonate, triethylamine, N, N-diisopropylethylamine or the like can be used.
  • the reaction temperature is usually from ⁇ 78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 20 ° C.
  • reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • the compound (3) and compound (4) used at this process can use a commercial item, and can also manufacture them according to the method of other literature description, or the method according to them.
  • Step 1a-2 This step is a step of producing compound (6) from compound (5).
  • Compound (6) can be produced, for example, by reacting compound (5) with a compound serving as a sulfur source such as Lawesson's reagent in a solvent.
  • the solvent include toluene, dichloromethane, N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like.
  • the reaction temperature is usually from ⁇ 78 ° C. to the solvent reflux temperature, preferably 20 to 150 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 1a-3 This step is a step of producing compound (7) from compound (6).
  • Compound (7) can be produced, for example, by cyclizing compound (6) in the presence of a base in a solvent.
  • the solvent include N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, 2-propanol, a mixed solvent thereof and the like.
  • the base used include 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), potassium carbonate, Sodium carbonate, cesium carbonate, sodium acetate and the like can be used.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux temperature, preferably 20 ° C. to 100 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 1a-4 This step is a step of producing compound (1a) having the above structure among compounds (1) from compound (7).
  • Compound (1a) can be produced, for example, by brominating compound (7) with N-bromosuccinimide in a solvent when L 1 is a bromine atom.
  • benzoyl peroxide, azobisisobutyronitrile and the like can be added as a radical initiator.
  • the solvent include carbon tetrachloride, chloroform, dichloromethane, N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, 2-propanol, and mixed solvents thereof.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux temperature, preferably 20 ° C. to 150 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • R 2 , R 3 , R 4 , R 5 and L 1 are as defined above;
  • L 3 represents a chlorine atom, a bromine atom, an iodine atom, etc .;
  • L 4 is a hydrogen atom,
  • B (OH) 2 Q represents NH 4 or the like.
  • Step 1b-1 This step is a step of producing compound (10) by reaction of compound (8) with compound (9).
  • Compound (10) can be produced, for example, by reacting compound (8) and compound (9) in the presence of bromine in an acetic acid solvent.
  • the reaction temperature is usually from ⁇ 20 ° C. to solvent reflux temperature, preferably 0 ° C. to 20 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • the compound (8) and compound (9) used at this process can use a commercial item, and can also manufacture them according to the method of other literature description, or the method according to them.
  • Step 1b-2 This step is a step for producing the compound (11) by introducing a tert-butoxycarbonyl group into the amino group of the compound (10).
  • Compound (11) can be produced, for example, by reacting di-tert-butyl dicarbonate with compound (10) in a solvent or without using a solvent.
  • the solvent used in the reaction include 1,4-dioxane, tetrahydrofuran, methanol, ethanol, 2-propanol, N, N-dimethylformamide, a mixed solvent thereof and the like.
  • a base when a base is used in this reaction, triethylamine, N, N-diisopropylethylamine, pyridine and the like can be used.
  • the reaction temperature is usually from ⁇ 20 ° C. to the solvent reflux temperature, preferably 0 ° C. to 150 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3
  • Step 1b-3 This step is a step for producing a compound (12) by converting a bromine atom of the compound (11) into a hydroxymethyl group.
  • Compound (12) can be produced, for example, by converting the bromine atom of compound (11) into a lithium salt, Grignard reagent or the like in a solvent and then reacting with paraformaldehyde or the like.
  • the solvent used include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, a mixed solvent thereof and the like.
  • the reagent used when preparing the lithium salt include n-butyllithium, sec-butyllithium, lithium diisopropylamide and the like.
  • Examples of the reagent used when the Grignard reagent is used include isopropylmagnesium chloride, isopropylmagnesium chloride lithium chloride complex, and metallic magnesium.
  • the reaction temperature can usually be carried out at -78 ° C to 50 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Compound (12) was prepared by treating a lithium salt of Compound (11) or a Grignard reagent with N, N-dimethylformamide or the like to introduce a formyl group, and then removing the obtained compound having a formyl group in the presence of a solvent.
  • the solvent used include methanol, water, ethanol, tetrahydrofuran, and mixed solvents thereof.
  • the reaction temperature is usually from ⁇ 78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 100 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 1b-4 This step is a step for producing the compound (13) by removing the tert-butoxycarbonyl group of the compound (12).
  • Compound (13) can be produced, for example, by treating compound (12) with an appropriate acid in a solvent or without using a solvent.
  • the solvent used for the reaction include dichloromethane, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, a mixed solvent thereof and the like.
  • As the acid used trifluoroacetic acid, hydrogen chloride and the like can be used.
  • the reaction temperature is usually from ⁇ 20 ° C. to solvent reflux temperature, preferably 0 ° C. to 50 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 1b-5 This step is a step for producing a compound (13) by converting a bromine atom of the compound (10) into a hydroxymethyl group. This step can be performed according to the above-mentioned method b and step 1b-3.
  • Step 1b-6 This step is a step for producing a compound (14) by converting the amino group of the compound (13) into an appropriate leaving group (L 3 ).
  • Compound (14) can be produced, for example, by reacting compound (13) with potassium iodide, sodium nitrite and the like in the presence of an acid in a solvent when L 3 is an iodine atom.
  • the solvent used in the reaction include acetonitrile, water, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, 2-propanol, N, N-dimethylformamide, acetic acid, and mixed solvents thereof.
  • the acid used in this reaction examples include p-toluenesulfonic acid, acetic acid, hydrochloric acid, trifluoroacetic acid and the like.
  • the reaction temperature is usually from ⁇ 50 ° C. to the solvent reflux temperature, preferably from ⁇ 20 ° C. to 100 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 1b-7 This step is a step for producing a compound (16) by reacting the compound (14) with the compound (15) and substituting L 3 with R 2 .
  • Compound (16) can be produced by replacing L 3 of compound (14) with R 2 which is a substituted amino group by a nucleophilic substitution reaction.
  • This reaction proceeds by reacting compound (14) with compound (15), which is an appropriate substituted amine, in a solvent or without using a solvent. In this reaction, an excess amount of a substituted amine can be used or a base can be allowed to coexist to supplement the acid produced during the reaction.
  • Examples of the solvent used include tetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, ethanol, propanol, N, N-dimethylformamide, dimethyl sulfoxide, water, and mixed solvents thereof. Can do.
  • Examples of the coexisting base include triethylamine, N, N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine and the like.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux temperature, preferably 0 ° C. to 150 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Compound (16) can be produced by replacing L 3 of compound (14) with R 2 which is an aryl group by Suzuki coupling reaction.
  • This reaction proceeds, for example, in the presence of a base using compound (14) and arylboronic acid in a solvent and a palladium reagent as a catalyst.
  • the solvent used include tetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, ethanol, propanol, N, N-dimethylformamide, dimethyl sulfoxide, water, and mixed solvents thereof.
  • solvent include tetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, ethanol, propanol, N, N-dimethylformamide, dimethyl sulfoxide, water, and mixed solvents thereof.
  • Examples of the palladium catalyst to be used include dichlorobis (triphenylphosphine) palladium (II), tetrakis (triphenylphosphine) palladium (0), and the like.
  • Examples of the base used include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, triethylamine, N, N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine and the like. Is mentioned.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux temperature, preferably 0 ° C. to solvent reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 1b-8 This step is a step for producing the compound (1a) by converting the hydroxyl group of the compound (16) into an appropriate leaving group (L 1 ).
  • Compound (1a) can be produced, for example, by reacting carbon tetrabromide with compound (16) in the presence of triphenylphosphine or the like in a solvent when L 1 is a bromine atom.
  • the solvent used for the reaction include tetrahydrofuran, dichloromethane, chloroform, a mixed solvent thereof and the like.
  • the reaction temperature can usually be carried out at ⁇ 50 ° C. to solvent reflux temperature, preferably 0 ° C. to 100 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • R 2 , R 3 , R 4 , R 5 , L 1 and L 2 are as defined above.
  • Step 1c-1 This step is a step of producing compound (18) by a condensation reaction between compound (17) and compound (4). This step can be performed according to the above-mentioned method a, step 1a-1. Moreover, the compound (17) used at this process can use a commercial item, and can also manufacture it according to the method of other literature description, or the method according to them.
  • Step 1c-2 This step is a step of producing compound (19) from compound (18). This step can be performed according to the above-mentioned method a, step 1a-2.
  • Step 1c-3 This step is a step of producing compound (20) from compound (19). This step can be performed according to the above-mentioned method a, step 1a-3.
  • Step 1c-4 This step is a step of producing compound (1b) having the above structure among compounds (1) from compound (20). This step can be performed according to the above-mentioned method a, step 1a-4.
  • R 2 , R 3 , R 4 , R 5 , L 1 and L 2 are as defined above;
  • Q 2 represents a C 1-6 alkyl group or a C 7-10 aralkyl group.
  • Step 1d-1 This step is a step of producing compound (22) by a condensation reaction between compound (21) and compound (4). This step can be performed according to the above-mentioned method a, step 1a-1. Moreover, the compound (21) used at this process can use a commercial item, and can also manufacture it according to the method of other literature description, or the method according to them.
  • Step 1d-2 This step is a step of producing compound (23) from compound (22). This step can be performed according to the above-mentioned method a, step 1a-2.
  • Step 1d-3 This step is a step of producing compound (24) from compound (23). This step can be performed according to the above-mentioned method a, step 1a-3.
  • Step 1d-4 This step is a step of producing compound (25) from compound (24).
  • Compound (25) can be produced, for example, by reducing the alkoxycarbonyl group of compound (24) to a hydroxymethyl group using lithium aluminum hydride, lithium borohydride or the like in a solvent.
  • the solvent used include tetrahydrofuran, diethyl ether, a mixed solvent thereof and the like.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux temperature, and it is preferably carried out at ⁇ 20 ° C. to 100 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 1d-5 This step is a step for producing the compound (1b) by converting the hydroxyl group of the compound (25) into an appropriate leaving group (L 1 ). This step can be performed according to the above-mentioned method b, step 1b-8.
  • R 2 , R 3 , R 4 , R 5 , L 1 , L 2 , L 3 and L 4 are as defined above.
  • Step 1e-1 This step is a step of producing compound (27) from compound (26) and compound (4).
  • Compound (27) is obtained by, for example, treating a cyclization precursor obtained by a condensation reaction of compound (26) and compound (4) in a solvent according to the above method a, step 1a-1 with an appropriate acid.
  • the solvent used include xylene, toluene, benzene, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like.
  • the acid used in this reaction include p-toluenesulfonic acid, acetic acid, hydrochloric acid, trifluoroacetic acid and the like.
  • the reaction temperature is usually from ⁇ 20 ° C.
  • reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • the compound (26) used at this process can use a commercial item, and can also manufacture it according to the method of other literature description, or the method according to them.
  • Step 1e-2 This step is a step for producing a compound (28) by converting a bromine atom of the compound (27) into a formyl group.
  • Compound (28) is produced, for example, by converting the bromine atom of compound (27) into a lithium salt, Grignard reagent, or the like in a solvent and then reacting with a compound serving as a formyl source such as N, N-dimethylformamide. can do.
  • the solvent used include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, a mixed solvent thereof and the like.
  • Examples of the reagent used when preparing the lithium salt include n-butyllithium, sec-butyllithium, lithium diisopropylamide and the like.
  • Examples of the reagent used when the Grignard reagent is used include isopropylmagnesium chloride, isopropylmagnesium chloride lithium chloride complex, and metallic magnesium.
  • the reaction temperature can usually be carried out at -78 ° C to 50 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 1e-3 This step is a step for producing a compound (29) by converting a formyl group of the compound (28) into a hydroxymethyl group.
  • Compound (29) can be produced, for example, by reducing compound (28) with sodium borohydride, lithium aluminum hydride, lithium borohydride or the like in the presence of a solvent.
  • the solvent used include methanol, water, ethanol, tetrahydrofuran, and mixed solvents thereof.
  • the reaction temperature is usually from ⁇ 78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 100 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 1e-4 This step is a step of producing a compound (1c) having the above structure among the compounds (1) by converting the hydroxyl group of the compound (29) into an appropriate leaving group (L 1 ). This step can be performed according to the above-mentioned method b, step 1b-8.
  • Step 1e-5 This step is a step of producing compound (30) from compound (26).
  • Compound (30) can be produced, for example, by reacting compound (26) with cyanogen bromide in a solvent.
  • the solvent used include ethanol, 2-propanol, tetrahydrofuran, 1,4-dioxane, a mixed solvent thereof and the like.
  • the reaction temperature is usually from ⁇ 20 ° C. to the solvent reflux temperature, preferably 0 ° C. to 30 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 1e-6 This step is a step for producing the compound (31) by introducing a tert-butoxycarbonyl group into the amino group of the compound (30). This step can be performed according to the above-mentioned method b and step 1b-2.
  • Step 1e-7 This step is a step for producing a compound (32) by converting a bromine atom of the compound (31) into a formyl group. This step can be performed according to the above-mentioned e method and step 1e-2.
  • Step 1e-8 This step is a step for producing a compound (33) by converting a formyl group of the compound (32) into a hydroxymethyl group. This step can be performed according to the above-mentioned e method and step 1e-3.
  • Step 1e-9 This step is a step for producing the compound (34) by converting the amino group produced by removing the tert-butoxycarbonyl group of the compound (33) into an appropriate leaving group (L 3 ).
  • This step can be performed according to the above-mentioned method b, step 1b-4 and step 1b-6.
  • Step 1e-10 This step is a step for producing a compound (29) by reacting the compound (34) with the compound (15) and substituting L 3 with R 2 .
  • This step can be carried out according to the above-mentioned method b, step 1b-7.
  • R 2 , R 3 , R 4 , R 5 , L 1 , L 2 and Q 2 are as defined above.
  • Step 1f-1 This step is a step of producing compound (36) from compound (35) and compound (4). This step can be carried out according to the above-mentioned e method and step 1e-1. Moreover, the compound (35) used at this process can use a commercial item, and can also manufacture it according to the method of other literature description, or the method according to them.
  • Step 1f-2 This step is a step of producing compound (37) from compound (36). This step can be carried out according to the above-mentioned method d, step 1d-4.
  • Step 1f-3 This step is a step of producing a compound (1d) having the above structure among the compounds (1) by converting the hydroxyl group of the compound (37) into an appropriate leaving group (L 1 ). This process It can be carried out according to the above-mentioned method b, step 1b-8.
  • R 2 , R 3 , R 4 , R 5 , L 1 , L 3 , L 4 , Q, Q 1 , Q 2 and A are as defined above;
  • L 5 is a bromine atom, an iodine atom, ZnBr , ZnCl and the like;
  • L 6 represents a bromine atom, an iodine atom and the like.
  • Step 2-1 This step is a step of producing compound (10) by reaction of compound (8) with compound (9). This step can be performed according to the above-mentioned method b and step 1b-1.
  • Step 2-2 is a step for producing the compound (11) by introducing a tert-butoxycarbonyl group into the amino group of the compound (10). This step can be performed according to the above-mentioned method b and step 1b-2.
  • Step 2-3a This step is a step for producing a compound (39) by a coupling reaction of the compound (11) and the compound (38).
  • Compound (39) can be produced, for example, by converting the bromine atom of compound (11) into a lithium salt, Grignard reagent, or the like in a solvent and then reacting with compound (38).
  • the solvent used include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, a mixed solvent thereof and the like.
  • the reagent used when preparing the lithium salt include n-butyllithium, sec-butyllithium, lithium diisopropylamide and the like.
  • Examples of the reagent used when the Grignard reagent is used include isopropylmagnesium chloride, isopropylmagnesium chloride lithium chloride complex, and metallic magnesium.
  • the reaction temperature can usually be ⁇ 78 ° C. to 50 ° C., preferably ⁇ 20 ° C. to 50 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 2-3b This step is a step for producing the compound (40) by replacing the hydroxy group of the compound (39) with a hydrogen atom.
  • Compound (40) can be produced, for example, by reacting phosphorus tribromide with compound (39) in a solvent or in the absence of a solvent. Examples of the solvent used include chloroform.
  • the reaction temperature is usually from ⁇ 78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 100 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 2-3c This step is a step of producing compound (40) by a coupling reaction between compound (11) and compound (41).
  • Compound (40) can be produced, for example, by utilizing a Negishi coupling reaction between compound (11) and compound (41) in a solvent.
  • the solvent used include tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, a mixed solvent thereof and the like.
  • the reaction temperature is usually from ⁇ 78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 50 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 2-3d This step is a step of producing compound (43) from compound (11) and compound (42).
  • Compound (43) is obtained by, for example, reacting a compound obtained by converting the bromine atom of compound (11) into a lithium salt or a Grignard reagent or the like according to the aforementioned method b, step 1b-3 in a solvent and reacting with compound (42). Thereafter, the obtained compound can be produced by treating with an appropriate acid.
  • the solvent used include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, a mixed solvent thereof and the like.
  • the acid used include hydrochloric acid.
  • the reaction temperature can usually be carried out at -78 ° C to 50 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 2-3e This step is a step for producing compound (40) by Suzuki coupling reaction of compound (43) and compound (44).
  • Compound (40) can be produced, for example, by reacting compound (43) and compound (44) in a solvent and using a palladium reagent as a catalyst in the presence of a base.
  • the solvent used include tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, a mixed solvent thereof and the like.
  • Examples of the palladium catalyst to be used include dichlorobis (triphenylphosphine) palladium (II), tetrakis (triphenylphosphine) palladium (0), and the like.
  • Examples of the base used include triethylamine, N, N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine and the like.
  • reaction temperature is usually from ⁇ 78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 20 ° C.
  • reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 2-3f This step is a step for producing a compound (12) by converting a bromine atom of the compound (11) into a hydroxymethyl group. This step can be performed according to the above-mentioned method b and step 1b-3.
  • This step is a step for producing a compound (45) by converting the hydroxyl group of the compound (12) into an appropriate leaving group (L 1 ).
  • This step can be performed according to the above-mentioned method b, step 1b-8.
  • Step 2-3h This step is a step of producing compound (40) by reacting compound (45) with compound (2). This step can be performed according to the above-mentioned method A, step 1-1.
  • Step 2-4 is a step for producing the compound (46) by removing the tert-butoxycarbonyl group of the compound (40). This step can be performed according to the above-mentioned method b and step 1b-4.
  • Step 2-5 This step is a step of producing compound (47) by a coupling reaction between compound (10) and compound (38). This step can be performed according to the above-mentioned method B, step 2-3a.
  • Step 2-6 This step is a step for producing the compound (46) by replacing the hydroxy group of the compound (47) with a hydrogen atom. This step can be performed according to the above-mentioned Method B and Step 2-3b.
  • Step 2-7 This step is a step for producing the compound (48) by converting the amino group of the compound (46) into an appropriate leaving group (L 3 ). This step can be performed according to the above-mentioned method b, step 1b-6.
  • Step 2-8 This step is a step for producing compound (Ic) by reacting compound (48) with compound (15) and substituting L 3 with R 2 .
  • This step can be carried out according to the above-mentioned method b, step 1b-7.
  • Step 2-9 This step is a step of producing compound (Id) by hydrolyzing the ester moiety of compound (Ic). This step can be performed according to the above-mentioned Method A, Step 1-2.
  • Y 1 , Y 2 , R 2 , R 4 , R 5 , A and Q 1 are as defined above;
  • Q 3 and Q 4 are a hydrogen atom and a C 1-6 alkyl group (bonded together to form a ring
  • R 3a represents a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 1-7 alkanoyl group, a cyano group, or the like.
  • Step 3-1 This step is a step of producing compound (If) by substituting the bromine atom of compound (Ie) with R 3a .
  • Compound (If) can be produced, for example, by reacting compound (Ie) with compound (49) in a solvent and using a palladium reagent as a catalyst in the presence of a base.
  • the solvent used include tetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, ethanol, propanol, N, N-dimethylformamide, dimethyl sulfoxide, water, and mixed solvents thereof. Can do.
  • Examples of the palladium catalyst to be used include dichlorobis (triphenylphosphine) palladium (II), tetrakis (triphenylphosphine) palladium (0), and the like.
  • Examples of the base used include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, triethylamine, N, N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine and the like. Is mentioned.
  • reaction temperature is usually from ⁇ 78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 100 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Compound (Ie) can be produced according to Method A or Method B.
  • Step 3-2 This step is a step of producing compound (Ig) by hydrolyzing the ester moiety of compound (If). This step can be performed according to the above-mentioned Method A, Step 1-2.
  • Method D Among the compounds (I), the following compound (Ih) can be produced, for example, by Method D described below.
  • Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , A and Z 2 are as defined above.
  • Step 4-1 This step is a step of producing compound (Ih) by a condensation reaction between compound (Ib) and compound (50).
  • Compound (Ih) can be produced, for example, by reacting compound (Ib) with compound (50) in the presence of a condensing agent in the presence or absence of a base in a solvent.
  • the solvent include N, N-dimethylformamide, dichloromethane, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like.
  • Examples of the condensing agent used include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), dicyclohexylcarbodiimide (DCC), 2- (1H-7-azabenzotriazol-1-yl) -1 1,3,3-tetramethyluronium hexafluorophosphate metanaminium (HATU) and the like.
  • EDCI 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • DCC dicyclohexylcarbodiimide
  • 4-dimethylaminopyridine, pyridine, 1-hydroxybenzotriazole (HOBT) or the like can also be used as a reaction accelerator.
  • Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 and A are as defined above.
  • Step 5-1 This step is a step of producing compound (51) from compound (Ib).
  • Compound (51) can be produced, for example, by reacting compound (Ib) with a compound serving as an amine source such as ammonium chloride in the presence of a condensing agent in a solvent in the presence or absence of a base.
  • a compound serving as an amine source such as ammonium chloride
  • the solvent include N, N-dimethylformamide, dichloromethane, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like.
  • Examples of the condensing agent used include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), dicyclohexylcarbodiimide (DCC), 2- (1H-7-azabenzotriazol-1-yl) -1 1,3,3-tetramethyluronium hexafluorophosphate metanaminium (HATU) and the like.
  • EDCI 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • DCC dicyclohexylcarbodiimide
  • 4-dimethylaminopyridine, pyridine, 1-hydroxybenzotriazole (HOBT) or the like can also be used as a reaction accelerator.
  • Step 5-2 This step is a step of producing compound (52) by dehydration reaction of compound (51).
  • Compound (52) can be produced, for example, by reacting compound (51) with thionyl chloride, phosphorus oxychloride or the like in a solvent.
  • the solvent include N, N-dimethylformamide, dichloromethane, 1,4-dioxane, tetrahydrofuran, toluene, a mixed solvent thereof and the like.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 5-3 is a step for producing a compound (Ii) by converting a nitrile group of the compound (52) into a tetrazolyl group.
  • Compound (Ii) can be produced, for example, by reacting compound (52) with sodium azide or the like in a solvent.
  • the solvent include N, N-dimethylformamide, water, dichloromethane, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like.
  • zinc bromide, ammonium chloride, silver nitrate, acetic acid, etc. can be added as needed.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux temperature, preferably 20 ° C. to solvent reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • the pharmacologically acceptable salt of compound (I) of this embodiment can be produced according to a conventional method using compound (I) of this embodiment.
  • a protective group when required depending on the type of functional group, it can be carried out by appropriately combining the introduction and desorption operations according to a conventional method.
  • a protective group For the type, introduction, and elimination of protecting groups, see, for example, Theodora W. Green & Peter G. M. The methods described in Wuts, “Green's Protective Groups in Organic Synthesis”, fourth edition, Wiley-Interscience, 2006 can be mentioned.
  • the intermediate used for producing the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof may be isolated and purified by means well known to those skilled in the art, if necessary. It can be isolated and purified by certain solvent extraction, crystallization, recrystallization, chromatography, preparative high performance liquid chromatography, and the like.
  • the pharmaceutical containing the compound (I) of this embodiment or a pharmacologically acceptable salt thereof The pharmaceutical containing the compound (I) of this embodiment or a pharmacologically acceptable salt thereof as an active ingredient
  • dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, solutions, ointments, suppositories, patches, sublinguals, etc. It is administered orally or parenterally.
  • These medicaments are prepared by a known method according to the dosage form, as an active ingredient, compound (I) of the present embodiment or a pharmacologically acceptable salt thereof, a pharmacologically acceptable additive, It can comprise as a pharmaceutical composition containing this.
  • Additives contained in the pharmaceutical composition include excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stable agents.
  • An agent, a solubilizing agent, etc. can be mentioned.
  • the pharmaceutical composition comprises the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof and an appropriate additive appropriately mixed, or the compound (I) or a pharmacologically acceptable salt thereof. It can be prepared by diluting and dissolving with additives. Further, when used in combination with drugs other than the EP 1 receptor antagonist, simultaneously or separately each of active ingredients, it can be prepared by formulating the same manner as described above.
  • Compound (I) or a pharmacologically acceptable salt of the present embodiment is an EP 1 receptor antagonistic confirmation test, etc. Shows strong EP 1 receptor antagonism. Therefore, the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof can suppress or decrease the intracellular calcium concentration. Therefore, the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof is based on the EP 1 receptor antagonism confirmation test, and is a disease caused by activation of EP 1 receptor by PGE 2 stimulation. It can be used for the treatment, prevention, or suppression of symptoms.
  • Examples of the disease or symptom that activates the EP 1 receptor by PGE 2 stimulation include lower urinary tract symptoms (LUTS), inflammatory diseases, painful diseases, osteoporosis, cancer and the like. Therefore, the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof is used for the treatment, prevention or suppression of lower urinary tract symptoms (LUTS), inflammatory diseases, painful diseases, osteoporosis, cancer and the like. Can be used for Here, the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof is preferably used for the treatment or prevention of LUTS, inflammatory disease or pain disease, and lower urinary tract symptoms More preferably it is used for the treatment or prevention of (LUTS).
  • the pharmaceutical composition containing the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof as an active ingredient has a disease or symptom caused by activation of EP 1 receptor by PGE 2 stimulating action. It can be used as a therapeutic or prophylactic agent.
  • the pharmaceutical composition containing the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof as an active ingredient includes lower urinary tract symptoms (LUTS), inflammatory diseases, pain diseases, It can be used as a therapeutic or prophylactic agent for diseases or symptoms such as osteoporosis and cancer.
  • the pharmaceutical composition according to the present embodiment is preferably used as a therapeutic or prophylactic agent for LUTS, inflammatory disease or pain disease, and more preferably used as a therapeutic or prophylactic agent for LUTS. preferable.
  • Examples of the causative diseases of lower urinary tract symptoms include overactive bladder (OAB), prostatic hypertrophy (BPH), cystitis such as interstitial cystitis, prostatitis and the like.
  • OAB overactive bladder
  • BPH prostatic hypertrophy
  • cystitis such as interstitial cystitis, prostatitis and the like.
  • “Lower urinary tract symptoms” means, for example, urine storage symptoms, urination symptoms, and post-urination symptoms.
  • the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof is preferably used for the treatment or prevention of urinary retention symptoms.
  • bladder perception such as increased perception, decreased bladder perception, lack of bladder perception, and nonspecific bladder perception.
  • Compound (I) or a pharmacologically acceptable salt thereof according to this embodiment includes urinary urgency, daytime frequent urination, nocturia, urge urinary incontinence, mixed urinary incontinence, enuresis, nocturia, increased bladder perception Alternatively, it is preferably used for treatment or prevention of nonspecific bladder perception.
  • the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof is used for the treatment or prevention of urgency, daytime frequent urination, nocturia, urinary urinary incontinence or increased bladder perception. Used for.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof is particularly preferable for the treatment or prevention of OABs.
  • Compound (I) of the present embodiment or a pharmacologically acceptable salt thereof, or a combination thereof Compound (I) of the present embodiment or a pharmaceutically acceptable salt thereof is an EP 1 receptor antagonist It can also be used in combination with at least one kind of drug other than
  • Examples of the drug that can be used in combination with the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof include overactive bladder (OAB) and prostatic hypertrophy having a mechanism of action different from that of the EP 1 receptor antagonist.
  • OAB overactive bladder
  • prostatic hypertrophy having a mechanism of action different from that of the EP 1 receptor antagonist.
  • therapeutic agents for cystitis (BPH), cystitis such as interstitial cystitis, prostatitis and the like include interstitial cystitis, prostatitis and the like.
  • anticholinergic agents ⁇ 1 antagonists, ⁇ agonists, 5 ⁇ -reductase inhibitors, PDE inhibitors, progesterone hormones, antidiuretics, smooth muscle direct acting agents or tricyclic antidepressants.
  • the drug used in combination with the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof is specifically exemplified as follows. However, the contents of the present invention are not limited to these. In addition, specific compounds include free forms thereof and other pharmacologically acceptable salts.
  • anticholinergic agent examples include oxybutynin, propiverine, solifenacin, torte mouth gin, imidafenacin, temiverine, darifenacin, fesoterodine, trospium, propantelin and the like.
  • ⁇ 1 antagonist examples include urapidil, naphthopidyl, tamsulosin, silodosin, prazosin, terazosin, alfuzosin, doxazosin, CR-2991, feduxin and the like.
  • ⁇ agonists examples include mirabegron, KUC-7383, KRP-204, SM-350300, TRK-380, amibegron, clenbuterol, SAR-150640, sorabegron and the like.
  • 5 ⁇ -reductase inhibitors examples include dutasteride, TF-505, finasteride, and izonsteride.
  • PDE inhibitor means a phosphodiesterase inhibitor, and examples thereof include tadalafil, vardenafil, sildenafil, avanafil, UK-369003, T-0156, AKP-002, etazolate and the like.
  • acetylcholinesterase inhibitor examples include distigmine, donepezil, Z-338, rivastigmine, ganstigmine, BGC-20-1259, galantamine, itopride, NP-61, SPH-1286, tolserine, ZT-1 and the like.
  • anti-androgen examples include guestnolone, oxendron, bicalutamide, BMS-641988, CB-03-01, CH-489789, flutamide, MDV-3100, nilutamide, TAK-700, YM-580 and the like.
  • progesterone hormones include chromazinone and allylestrenol.
  • LH-RH analog means a gonadotropin releasing hormone analog. Gonadotropin releasing hormone may also be referred to as luteinizing hormone releasing hormone.
  • AEZS-108 buserelin, deslorelin, goserelin, histrelin, leuprorelin, lutropin, nafarelin, triptorelin, AEZS-019, cetrorelix, degarelix, elagorix, ganilelex, ozarelix, PTD-634, TAK-385, Taverix 448, TAK-683 and the like.
  • neurokinin inhibitor examples include KRP-103, aprepitant, AV-608, Casopitant, CP-122721, DNK-333, fosprepitant, LY-686017, netpitant, olbepitant, lolapitant, TA-5538, T-2328, Vestipitant, AZD-2624, Z-501, 1144814, MEN-15596, MEN-11420, SAR-102779, SAR-102279, Saleduant, SSR-241586, and the like.
  • antidiuretic examples include desmopressin, VA-106483 and the like.
  • calcium channel blockers include amlodipine, cilnidipine, puffer piverine, temiverine, PD-299685, alanidipine, azelnidipine, balnidipine, benidipine, bevantolol, clevidipine, CYC-381, diltiazem, efonidipine, fasudil, felodipine, gabamil Examples include isradipine, lacidipine, lercanidipine, lomerizine, manidipine, MEM-1003, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, SB-751689, verapamil, YM-58483, and ziconotide.
  • “Smooth muscle direct acting drugs” include flavoxate and the like.
  • Tricyclic antidepressants include imipramine, clomipramine, amitriptyline, and the like.
  • Examples of the “potassium channel modulator” include nicorandil, NIP-141, NS-4591, NS-1643, andlast, diazoxide, ICA-105665, minoxidil, pinacidil, tirisolol, VRX-698 and the like.
  • sodium channel blocker examples include bepridil, dronedarone, propafenone, safinamide, SUN-N8075, SMP-986, 1014802, 552-02, A-803467, brivaracetam, cibenzoline, eslicarbazepine, F-15845, flecainide Phosphenytoin, lacosamide, lamotrigine, levobupivacaine, M-58373, mexiletine, moracidin, nerispyridine, NW-3509, oxcarbazepine, pilsicainide, pirmenol, propafenone, NW-1029, ropivacaine, vanacarant, etc. it can.
  • H 1 blocker examples include acribastine, alcaftadine, bepotastine, bilastine, cetirizine, desloratadine, ebastine, efletirizine, epinastine, fexofenadine, GSK-835726, levocabastine, levocetirizine, loratadine, mequitadine, mizolastine, NBI-7, 43 -1869, terfenadine, UCB-35440, vapitadine, YM-344484, diphenhydramine, chlorpheniramine and the like.
  • “Serotonin reuptake inhibitors” include UCB-46331, 424887, AD-337, BGC-20-1259, BMS-505130, citalopram, dapoxetine, desvenlafaxine, DOV-102673, DOV-216303, DOV-21947 , Duloxetine, escitalopram, F-2695, F-98214-TA, fluoxetine, fluvoxamine, IDN-5491, milnacipran, minaprine, NS-2359, NSD-644, paroxetine, PF-184298, SD-726, SEP-225289 , SEP-227162, SEP-228425, SEP-228432, sertraline, sibutramine, tesofensin, tramadol, trazodone, UCB-46331, venlafa Singh, mention may be made Birazodon, the WAY-426, WF-516 and the like.
  • Examples of “norepinephrine reuptake inhibitors” include AD-337, desvenlafaxine, DOV-102677, DOV-216303, DOV-21947, duloxetine, F-2695, F-98214-TA, milnacipran, NS-2359 , NSD-644, PF-184298, SD-726, SEP-225289, SEP-227162, SEP-228425, SEP-228432, Sibutramine, Tesofensin, Tramadol, Venlafaxine, Bupropion, Radafaxin, Atomoxetine, DDP-225, LY -2216684, nevogramin, NRI-193, reboxetine, tapentadol, WAY-256805, WAY-260022, and the like.
  • Examples of the “dopamine reuptake inhibitor” include DOV-102777, DOV-216303, DOV-21947, IDN-5491, NS-2359, NSD-644, SEP-225289, SEP-228425, SEP-228432, sibutramine, tesofensin, Examples thereof include tramadol, brasofensin, bupropion, NS-27100, radafaxin, safinamide and the like.
  • GABA agonists include retigabine, eszopiclone, indipron, pagok mouth, SEP-225441, acamprosate, baclofen, AZD-7325, BL-1020, brotizolam, DP-VPA, progabide, propofol, topiramate, zopiclone EVT-201, AZD-3043, ganaxolone, NS-11394, albaclofen, AZD-3355, GS-39783, ADX-71441, ADX-71943, and the like.
  • TRPV1 modulators include force psaicin, resiniferatoxin, DE-096, GRC-6611, AMG-8562, JTS-653, SB-705498, A-4256619, A-784168, ABT-102, AMG- 628, AZD-1386, JNJ-17203212, NGD-8243, PF-386486, SAR-115740, SB-784243, and the like.
  • Endothelin antagonists include SB-234551, ACT-064992, ambrisentan, atrasentan, bosentan, clazosentan, darsentan, fundsentan, S-0139, TA-0201, TBC-3711, dibotentane, BMS-509701, PS -433540 and the like.
  • Examples of the “5-HT 1A antagonist” include espindolol, lecozotan, lurasidone, E-2110, REC-0206, SB-649915, WAY-426, WF-516 and the like.
  • ⁇ 1 agonist examples include CM-2236, armodafinil, midodrine, modafinil and the like.
  • Opioid agonists include morphine, TRK-130, DPI-125, DPI-3290, fentanyl, LIF-301, loperamide, loperamide oxide, remifentanil, tapentadol, WY-16225, oxycodone, PTI-202, PTI-721 ADL-5747, ADL-5589, DPI-221, DPI-353, IPP-102199, SN-11, ADL-10-0101, ADL-10-0116, asimadoline, buprenorphine, CR-665, CR-845, eptazosin Nalbuphine, nalflaphine, pentazocine, XEN-0548, W-212393, ZP-120, nalmefene and the like.
  • P 2 X antagonist examples include A-740003, AZ-1157312, AZD-9056, GSK-14482160, GSK-31481A and the like.
  • COX inhibitor means a cyclooxygenase inhibitor such as aceclofenac, ST-679, aspirin, bromfenac, dexketoprofen, flurbiprofen, FYO-750, ibuprofen, ketoprofen, ketorolac, lycoferon, lornoxicam, loxoprofen, LT -NS001, diclofenac, mofezolac, nabumetone, naproxen, oxaprozin, piroxicam, pranoprofen, suprofen, tenoxicam, thiaprofenic acid, tolfenamic acid, zaltoprofen, 644784, ABT-963, ajulemic acid, apricoxib, celecoxib, citricoxib, citricoxib Lumiracoxib, meloxicam, nimesulide, parecoxib, RO-26-21 8, it can be mentioned valdecoxib
  • Examples of the “ ⁇ agonist” include ANAVEX-27-1041, PRS-013, SA-4503, ANAVEX-2-73, silamesine, ANAVEX-7-1037, ANAVEX-1-41, and the like.
  • muscle agonists examples include AC-260584, cevimeline, MCD-386, NGX-267, NGX-292, subcomerin, pilocarpine, bethanechol and the like.
  • the present invention is selected from the following 1) to 5) Any one method of administration is included. 1) Simultaneous administration with combination drug, 2) As separate formulations, co-administration by the same route of administration, 3) As separate formulations, co-administration by different routes of administration, 4) Administration at different times by the same route of administration as separate formulations, or 5) Administration at different times by different routes of administration as separate formulations Also at different times as separate formulations as in 4) or 5)
  • the administration order of the compound (I) of the present invention and the above drug is not particularly limited.
  • the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof can be used as an additive effect in preventing or treating the above diseases by using one or more of the above drugs in appropriate combination.
  • the above advantageous effects can be obtained.
  • the medicament according to this embodiment can be used systemically or locally, orally or parenterally (nasal, pulmonary, intravenous, rectal, subcutaneous, intramuscular, transdermal). Can be administered via the skin).
  • the dose of compound (I) of the present embodiment is determined by the patient's age, sex, It is determined as appropriate according to body weight, disease, degree of treatment, and the like.
  • an adult with a body weight of 60 kg
  • the daily dose as an oral preparation is preferably 6 to 540 mg / body, more preferably 18 to 180 mg / body.
  • parenteral administration it can be appropriately administered once or in several divided doses in the range of about 0.01 to 300 mg per day for an adult.
  • the daily dose as a parenteral preparation is preferably 1 to 100 mg / body, more preferably 6 to 60 mg / body.
  • the dose of the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof can be reduced according to the dose of a drug other than the EP 1 receptor antagonist.
  • Methyl 5-chloro-2-[(1-methylcyclopropylcarbonyl) amino] benzoate To a solution of methyl 2-amino-5-chlorobenzoate (2.50 g) in dichloromethane (20 mL) under an argon atmosphere, 0 Triethylamine (8.5 mL) and 1-methylcyclopropanecarboxylic acid chloride (2.37 g) were added at 0 ° C. to prepare a reaction solution. The reaction was stirred at 0 ° C. for 5 hours. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate.
  • the reaction solution was cooled to 0 ° C., water and a saturated aqueous sodium hydrogen carbonate solution were added to adjust the pH of the reaction solution to 11, and the mixture was extracted with ethyl acetate.
  • the residue obtained by distilling off the solvent was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (5.0 mL) was added at room temperature to obtain a second reaction solution.
  • the second reaction was stirred at room temperature for 24 hours.
  • the second reaction solution was poured into a 1 mol / L aqueous potassium carbonate solution (100 mL), and the precipitated solid was collected by filtration to give the title compound as colorless crystals (1.37 g).
  • Reference Examples 15-2 to 15-7 The corresponding compounds of Reference Examples 15-2 to 15-7 were obtained in the same manner as in Reference Example 15-1, using the corresponding aldehyde compounds. Their structures and spectral data are shown in Tables 7 and 8.
  • Reference Examples 16-2 to 16-14 The corresponding compounds of Reference Examples 16-2 to 16-14 were obtained in the same manner as in Reference Example 16-1, using the corresponding amino form. Their structures and spectral data are shown in Tables 9-11.
  • the first reaction solution was ice-cooled, and an aqueous hydrogen chloride solution (1.0 mol / L, 300 mL) was added for extraction.
  • the organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate.
  • dichloromethane 450 mL
  • trifluoroacetic acid 200 mL
  • the second reaction solution was stirred at room temperature for 2 hours.
  • acetic acid (200 mL) and ethyl 2,4-dioxoheptanoate (16.0 mL) were added to the residue to obtain a third reaction solution.
  • Examples 1-2 to 1-182 The following Examples 1-2 to 1-182 were obtained in the same manner as in Example 1-1 using the corresponding esters. Their structures and spectral data are shown in Tables 17-63.
  • the second reaction solution was then stirred for 3 hours under ice cooling.
  • the 2nd reaction liquid was diluted with ethanol (1 mL), and after adding sodium hydroxide aqueous solution (2 mol / L, 1.0 mL), it stirred at room temperature for 2 hours.
  • reaction solution was stirred at 80 ° C. for 2 hours, and then stirred at 150 ° C. for 3 hours.
  • 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified using silica gel column chromatography (ethyl acetate) to obtain the title compound as a yellow liquid (18 mg).
  • reaction was stirred at room temperature for 2 hours.
  • Examples 7-2 to 7-9 The following compounds of Examples 7-2 to 7-9 were obtained in the same manner as in Example 7-1 using the corresponding chloromethyl compounds. Their structures and spectral data are shown in Tables 64-66.
  • Examples 8-2 to 8-4 The following compounds of Examples 8-2 to 8-4 were obtained in the same manner as in Example 8-1, using the corresponding methyl compound. Their structures and spectral data are shown in Table 67.
  • Examples 9-2 and 9-3 The corresponding compounds of Examples 9-2 and 9-3 were obtained in the same manner as Example 9-1 using the corresponding bromomethyl compounds. Their structure and spectral data are shown in Table 68.
  • reaction solution was stirred at room temperature for 0.5 hour, p-toluenesulfonic acid monohydrate (460 mg) was added, and the mixture was stirred at room temperature for 5 minutes.
  • reaction mixture was stirred at room temperature for 0.5 hour, p-toluenesulfonic acid monohydrate (230 mg) was added, and the mixture was heated to reflux for 5 hours.
  • Examples 11-2 to 11-93 The following compounds of Examples 11-2 to 11-93 were obtained in the same manner as Example 11-1 using the corresponding halogen compounds. Their structures and spectral data are shown in Tables 69-93.
  • reaction solution was subjected to a reaction at 90 ° C. for 1 hour using a microwave (CEM, 150 W).
  • Example 12-2 to 12-33 Using the corresponding halogen compounds, the following compounds of Examples 12-2 to 12-33 were obtained in the same manner as in Example 12-1. Their structures and spectral data are shown in Tables 94-101.
  • Examples 13-2 to 13-23 The following compounds of Examples 13-2 to 13-23 were obtained in the same manner as in Example 13-1, using the corresponding halogen compounds. Their structures and spectral data are shown in Tables 102-109.
  • reaction solution was subjected to a reaction for 40 minutes at 80 ° C. using a microwave (CEM, 150 W).
  • Example 18-2 to 18-4 The following compounds of Examples 18-2 to 18-4 were obtained in the same manner as in Example 18-1, using the corresponding halogen compound. Their structure and spectral data are shown in Table 110.
  • EP 1 receptor antagonism confirmation test (1) Preparation of rat EP 1 expression vector Using Rat Kidney BD Marathon-Ready cDNA (Nippon Becton Dickinson Co., Ltd.) as a template, forward primer and SEQ ID NO: 2 The first PCR was performed using KOD-Plus-Ver2.0 (Toyobo Co., Ltd.) using the indicated reverse primer. Furthermore, using this amplification product as a template, the forward primer shown in SEQ ID NO: 3 and the reverse primer shown in SEQ ID NO: 4 were used, and a second PCR was performed in the same manner.
  • the amplification product obtained by the second PCR was incorporated into a vector (pcDNA3.1 D / V5-His-TOPO (registered trademark), Invitrogen Corporation).
  • a vector pcDNA3.1 D / V5-His-TOPO (registered trademark), Invitrogen Corporation.
  • the vector incorporating this amplification product was introduced into E. coli (One-shot TOP10 competent cell, Invitrogen) and transformed.
  • the transformed E. coli was cultured on LB agar medium for 1 day. After culture, colonies were selected and cultured in LB liquid medium containing 50 ⁇ g / mL ampicillin. After culture, the vector was purified using QIAprep Spin Miniprep Kit (Qiagen).
  • C0S-1 cell culture COS-1 cells (Dainippon Sumitomo Pharma) are penicillin-streptomycin solution (Invitrogen Corporation, final concentration: benzylpenicillin) as an antibiotic. 100 U / mL; 100 ⁇ g / mL as streptomycin), D-MEM liquid medium (high concentration, MEM non-essential amino acid (Invitrogen Corporation, final concentration 0.1 mM)) and fetal bovine serum (MoregateBiotech, final concentration: 10%) Using glucose and L-glutamine, Invitrogen Corporation), the cells were cultured in an incubator under 5% CO 2 gas conditions at 37 ° C. until they reached confluence.
  • penicillin-streptomycin solution Invitrogen Corporation, final concentration: benzylpenicillin
  • D-MEM liquid medium high concentration, MEM non-essential amino acid (Invitrogen Corporation, final concentration 0.1 mM)
  • fetal bovine serum (MoregateBiotech, final concentration:
  • This resuspended cell suspension was poly D-lysine coated 96 well microplate (BD BioCoat (registered trademark), Nippon Becton Dickinson Co., Ltd.) in each well 5 ⁇ 10 4 cells / liquid medium 100 ⁇ L / Well in a liquid medium so that it becomes a well, 100 ⁇ L of this cell preparation was dispensed into each well and seeded. After seeding, the cells were cultured at 37 ° C. in an incubator under 5% CO 2 gas conditions. When the cells for introduction of the rat EP 1 expression vector were adhered (about 2 hours after seeding), the rat EP 1 expression vector was introduced by the following procedure.
  • Rats EP 1 expression vector was diluted with 200 ng / 25 [mu] L / to be well OPTI-MEM (R) I Reduced-Serum Medium (Invitrogen Corporation).
  • OPTI-MEM registered trademark I Reduced-Serum Medium (Invitrogen Corp.) to 0.5 ⁇ L / 25 ⁇ L / well and incubated at room temperature for 5 minutes. .
  • rat EP 1 expression vector and diluted Lipofectamine 2000 were mixed and incubated at room temperature for 30 minutes for complex formation of rat EP 1 expression vector / Lipofectamine 2000. After incubation for 30 minutes, the rat EP 1 expression vector / Lipofectamine 2000 complex was dispensed into the rat EP 1 expression vector introduction cells at 50 ⁇ L / well. The cells into which the complex of rat EP 1 expression vector / Lipofectamine 2000 was dispensed were cultured at 37 ° C. for 24 hours in an incubator under 5% CO 2 gas conditions. After culturing for 24 hours, this cell was used as a rat EP 1 receptor-expressing cell to measure intracellular calcium concentration.
  • Pluronic F-127 (Invitrogen Corporation) was mixed with a fluorescent calcium indicator (Fluo 4-AM (Dojindo Laboratories)) to a final concentration of 0.0004%, then assay buffer was added, and 4 ⁇ mol / L Fluo 4 -An AM solution was prepared. 100 ⁇ L of this solution was added to each well and incubated in an incubator at 37 ° C. for 90 minutes. Thereafter, all the cell supernatant was aspirated, and 100 ⁇ L of assay buffer containing 2.5 mM probenecid was added to each well. After incubation in the incubator for 15 minutes, the intracellular calcium concentration was measured.
  • fluorescent calcium indicator Fluo 4-AM (Dojindo Laboratories)
  • the intracellular calcium concentration was measured as a fluorescence signal using FlexStation (registered trademark) (manufactured by Molecular Devices). Twenty seconds after the start of reading the fluorescence signal, 50 ⁇ L of each test compound (final concentration: 0.1 nM to 10 ⁇ M) diluted with the assay buffer was added to each well, and the fluorescence signal was measured for 60 seconds. Then added 50 ⁇ L prostaglandin E 2 buffer solution to each well (final concentration 10 nM), was measured for 60 seconds the fluorescence signal. In the method shown above, the fluorescence signal obtained when prostaglandin E 2 was added when assay buffer was added instead of the test compound was obtained when 100% of the test signal and prostaglandin E 2 were not added. The signal obtained was 0%. The concentration showing 50% inhibition from the dose-response curve of the test compound was taken as the IC 50 value. The IC 50 values of the obtained test compounds are shown in Table I below.
  • the skin of the left thigh was incised, the femoral artery was exposed and peeled, and an arterial catheter filled with 200 heparin units / mL heparin was inserted 15 mm.
  • the left femoral incision layer was closed with surgical adhesive.
  • the skin of the right thigh was incised to expose the femoral artery and ligated after peeling.
  • the drug was administered intravenously, the right femoral vein was exposed and peeled, and a venous catheter was inserted.
  • the right femoral incision layer was closed with surgical adhesive.
  • a midline incision was made in the abdomen to expose the ureters on both sides, and after ligation, the kidney side was cut.
  • Two Michel hemostatic forceps were applied to the top of the bladder at an interval of about 3 mm, an incision was made between them, a bladder catheter was inserted 5 mm therefrom, and a purse-string suture was performed. After the abdominal incision layer was sutured, the penis was exposed and ligated. A midline incision was made in the neck, the trachea was exposed, the incision was made, and the distal side was ligated. The tip of the Eppendorf tip was placed under the trachea, and the trachea was slightly lifted to secure the airway.
  • the compound of the present invention has a strong EP 1 receptor antagonism, it is useful as a therapeutic or prophylactic agent for diseases or symptoms caused by the activation of EP 1 receptor by the stimulating action of PGE 2 . Among them, it is useful as a therapeutic agent or preventive agent for lower urinary tract symptoms (LUTS), particularly overactive bladder syndrome (OABs).
  • LUTS lower urinary tract symptoms
  • OABs overactive bladder syndrome
  • SEQ ID NO: 1 is the sequence of the forward primer (5 ′ primer) used to amplify the DNA of SEQ ID NO: 5.
  • SEQ ID NO: 2 is the sequence of the reverse primer (3 ′ primer) used to amplify the DNA of SEQ ID NO: 5.
  • SEQ ID NO: 3 is the sequence of the forward primer (5 ′ primer) used to amplify the DNA of SEQ ID NO: 5.
  • SEQ ID NO: 4 is the sequence of the reverse primer (3 ′ primer) used to amplify the DNA of SEQ ID NO: 5.
  • SEQ ID NO: 5> SEQ ID NO: 5 is a DNA sequence for expressing the rat EP1 receptor amplified using the primers of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4.

Abstract

[Problem] To provide a novel compound having EP1 receptor antagonist activity, or a pharmacologically acceptable salt thereof. [Solution] A benzene ring-fused, nitrogen-containing 5-membered heterocyclic compound indicated by general formula (I) or a pharmacologically acceptable salt thereof was found to have powerful EP1 receptor antagonist activity. The compound (I) or a pharmacologically acceptable salt thereof is effective as a therapeutic medication or preventative medication for lower urinary tract symptoms (LUTS), for example, and overactive bladder syndrome (OABs), etc., in particular. In addition, the compound (I) or a pharmacologically acceptable salt thereof is highly useful in the treatment, prevention, or suppression of a variety of conditions involving EP1 receptors, in addition to lower urinary tract symptoms (LUTS) (e.g., inflammatory conditions, painful conditions, osteoporosis, cancer, etc.).

Description

ベンゼン環縮合含窒素５員複素環式化合物、またはその薬理学的に許容される塩Benzene ring condensed nitrogen-containing 5-membered heterocyclic compound, or pharmacologically acceptable salt thereof
　本発明は、ＥＰ１受容体拮抗作用を有するベンゼン環縮合含窒素５員複素環式化合物、またはその薬理学的に許容される塩に関する。 The present invention relates to a benzene ring condensed nitrogen-containing 5-membered heterocyclic compound having an EP 1 receptor antagonistic action, or a pharmacologically acceptable salt thereof.
　高齢化社会・ストレス社会の進展に伴い、下部尿路機能障害（ＬＵＴＤ）の患者数が増加している。ＬＵＴＤとは蓄尿障害と排尿障害の総称であり、ＬＵＴＤから発症する症状が下部尿路症状（ＬＵＴＳ）である。ＬＵＴＳの１つとして、過活動膀胱症候群（ＯＡＢｓ）がある。ＯＡＢｓは一般に過活動膀胱（ＯＡＢ）と呼ばれることもある。いずれにせよ、ＯＡＢｓは、「尿意切迫感を必須とした症状症候群であり、通常は頻尿と夜間頻尿を伴うものである。切迫性尿失禁は必須でない。」と定義されている疾患である。ＯＡＢｓに伴うこれらの症状は、仕事、日常生活、精神活動等の生活全般に支障をきたし、生活の質（ＱＯＬ）を低下させる。現在、ＯＡＢｓの治療薬としては、抗コリン薬が第一選択薬である。しかし、抗コリン薬は口渇や残尿のような抗ムスカリン様作用にも十分に配慮して使用する必要がある上、必ずしもすべての患者に対して有効とは限らない（例えば、非特許文献１参照）。このような状況下、抗コリン薬とは異なるメカニズムの治療薬の開発が望まれている（例えば、非特許文献１参照）。 With the progress of aging society and stress society, the number of patients with lower urinary tract dysfunction (LUTD) is increasing. LUTD is a general term for urinary storage disorder and dysuria, and the symptoms that develop from LUTD are lower urinary tract symptoms (LUTS). One type of LUTS is overactive bladder syndrome (OABs). OABs are also sometimes referred to as overactive bladder (OAB). In any case, OABs are diseases defined as "symptom syndrome requiring urgency of urine, usually accompanied by frequent urination and nocturia. Imminent urinary incontinence is not essential." is there. These symptoms associated with OABs interfere with overall life such as work, daily life, and mental activity, and lower the quality of life (QOL). Currently, anticholinergic drugs are first-line drugs for the treatment of OABs. However, anticholinergic drugs need to be used with sufficient consideration for antimuscarinic effects such as dry mouth and residual urine, and are not necessarily effective for all patients (for example, non-patent literature). 1). Under such circumstances, development of a therapeutic agent having a mechanism different from that of an anticholinergic agent is desired (see, for example, Non-Patent Document 1).
  近年、ＬＵＴＳ、特にＯＡＢｓにおいて、尿路上皮の役割が注目されている。ＬＵＴＳにおいても尿路上皮細胞では、種々の化学伝達物質が放出され、膀胱知覚神経終末の受容体を介して、排尿反射を引き起こす事が明らかになってきた。中でも、化学伝達物質の1つであるプロスタグランジンＥ２（ＰＧＥ２）は尿路上皮における求心性神経（特にＣ線維）のプロスタグランジンＥ受容体１（ＥＰ１受容体）に結合することにより排尿反射を亢進させる。また、ＰＧＥ２は膀胱平滑筋に存在するＥＰ１受容体に結合することにより膀胱を収縮させる。実際に、ＥＰ１受容体拮抗薬が、ＰＧＥ２による排尿反射の亢進および求心性神経活動の亢進の何れをも抑制することが報告されている（例えば、非特許文献２および非特許文献３参照）。これらから、ＰＧＥ２がＥＰ１受容体を介して膀胱平滑筋の収縮および膀胱知覚神経の亢進に関与していると示唆される。さらに、ＥＰ１受容体拮抗薬は残尿量を増加させること無く、膀胱容量を増加させることも報告されている（例えば非特許文献４参照）。 In recent years, the role of urothelium has attracted attention in LUTS, especially in OABs. Also in LUTS, it has been clarified that various chemical mediators are released in urothelial cells and cause a micturition reflex through a receptor of bladder sensory nerve endings. Among them, prostaglandin E 2 (PGE 2 ), one of chemical transmitters, binds to prostaglandin E receptor 1 (EP 1 receptor) of afferent nerve (especially C fiber) in urothelium. Increases the micturition reflex. PGE 2 also contracts the bladder by binding to the EP 1 receptor present in bladder smooth muscle. In fact, it has been reported that an EP 1 receptor antagonist suppresses both the enhancement of micturition reflex and the enhancement of afferent nerve activity by PGE 2 (see, for example, Non-Patent Document 2 and Non-Patent Document 3). ). These suggest that PGE 2 is involved in bladder smooth muscle contraction and bladder sensory nerve enhancement via the EP 1 receptor. Furthermore, EP 1 receptor antagonists have also been reported to increase bladder capacity without increasing residual urine volume (see, for example, Non-Patent Document 4).
　ＰＧＥ２の受容体としては、ＥＰ１のほか、ＥＰ２、ＥＰ３およびＥＰ４の４つのサブタイプが存在する。ＥＰ１受容体は、膀胱および尿路上皮のほか、肺、骨格筋および腎集合管等に存在する（例えば、非特許文献２参照）。然るに、ＰＧＥ２受容体サブタイプの選択性、薬物の標的臓器や標的組織を変えることにより、所望の疾患に対する治療薬を開発することができると期待される。 In addition to EP 1 , there are four subtypes of receptors for PGE 2 , EP 2 , EP 3 and EP 4 . The EP 1 receptor is present in the lung, skeletal muscle, kidney collecting duct and the like in addition to the bladder and urothelium (see, for example, Non-Patent Document 2). However, it is expected that therapeutic agents for a desired disease can be developed by changing the selectivity of the PGE 2 receptor subtype and the target organ or target tissue of the drug.
　特許文献１にはＥＰ１受容体拮抗作用を有する化合物として化学構造式（Ａ）で表されるベンゾフラン誘導体が開示されている。 Patent Document 1 discloses a benzofuran derivative represented by the chemical structural formula (A) as a compound having an EP 1 receptor antagonistic action.
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000001
式（Ａ）中、Ｒ１は水素原子、ハロゲン原子等を表し、Ｒ２ａは水素原子等を表し、Ｒ２ｂはＣ１－４アルキル基（炭素数１～４の直鎖の又は分枝鎖のアルキル基）等を表し、Ｒ２ｃは水素原子等を表し、Ｒ３は下記一般式（Ｂ）で表される基等を表す。 In formula (A), R 1 represents a hydrogen atom, a halogen atom or the like, R 2a represents a hydrogen atom or the like, R 2b represents a C 1-4 alkyl group (straight or branched chain having 1 to 4 carbon atoms). R 2c represents a hydrogen atom or the like, and R 3 represents a group represented by the following general formula (B) or the like.
Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-C000002
式（Ｂ）中、Ｒ４はカルボキシ基等を表す。 In formula (B), R 4 represents a carboxy group or the like.
　また、特許文献２にはＥＰ１受容体拮抗作用を有する化合物として化学構造式（Ｃ）で表される化合物が開示されている。 Patent Document 2 discloses a compound represented by the chemical structural formula (C) as a compound having an EP 1 receptor antagonistic action.
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000003
式（Ｃ）中、Ｒ１は水素原子、ハロゲン原子等を表し、Ｒ２はチエニル基等を表し、Ｒ３は下記一般式（Ｂ）で表される基等を表す。 In formula (C), R 1 represents a hydrogen atom, a halogen atom or the like, R 2 represents a thienyl group or the like, and R 3 represents a group represented by the following general formula (B) or the like.
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
式（Ｂ）中、Ｒ４はカルボキシ基等を表す。 In formula (B), R 4 represents a carboxy group or the like.
　しかし、この化合物は、本発明化合物とは基本化学構造式が異なっている。なお、このような化合物は、本願請求項には含有されないことは言うまでもない。 However, this compound is different in basic chemical structural formula from the compound of the present invention. In addition, it cannot be overemphasized that such a compound is not contained in a claim of this application.
国際公開第２００７／１１３２８９号International Publication No. 2007/113289 国際公開第２００８／０９８９７８号International Publication No. 2008/098978
　現在、前記した種々の病態に対する予防及び治療薬として、優れたＥＰ１受容体拮抗作用を有し、かつ副作用が少ない等の点からも十分に満足できる医薬品となり得る化合物は見出されていない。 At present, no compound has been found as a prophylactic and therapeutic agent for the various pathologies described above, which can be a sufficiently satisfactory pharmaceutical from the viewpoint of having excellent EP 1 receptor antagonism and few side effects.
　本発明の目的は、ＥＰ１受容体拮抗作用を有する新規な化合物を提供することにある。 An object of the present invention is to provide a novel compound having an EP 1 receptor antagonistic action.
　本発明者らは、鋭意研究を行った結果、下記一般式（Ｉ）で表されるベンゼン環縮合含窒素5員複素環式化合物（以下、化合物（Ｉ）という場合がある）またはその薬理学的に許容される塩が強力なＥＰ１受容体拮抗作用を有することを見出し、本発明を完成した。 As a result of intensive studies, the present inventors have found that a benzene ring condensed nitrogen-containing 5-membered heterocyclic compound represented by the following general formula (I) (hereinafter sometimes referred to as compound (I)) or a pharmacology thereof. The present invention was completed by finding that a chemically acceptable salt has a strong EP 1 receptor antagonistic action.
　即ち、本発明の要旨は、以下の通りである。 That is, the gist of the present invention is as follows.
〔１〕　下記一般式（Ｉ）で表されるベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。 [1] A benzene ring condensed nitrogen-containing 5-membered heterocyclic compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof.
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
式（Ｉ）中、Ｙ１およびＹ２を含み、Ｒ２、Ｒ３、Ｒ４、Ｒ５およびＹ３が結合するベンゼン環縮合含窒素５員複素環は、以下のａ）～d）からなる群から選択される環であり； The benzene ring condensed nitrogen-containing 5-membered heterocyclic ring containing Y 1 and Y 2 and having R 2 , R 3 , R 4 , R 5 and Y 3 bonded thereto is represented by the following a) to d): A ring selected from the group consisting of;
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
Ａは、以下のｅ）～ｉ）からなる群から選択される基であり； A is a group selected from the group consisting of e) to i) below:
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
　Ｒａは、水素原子、ハロゲン原子またはＣ１－６アルキル基であり；
　Ｗ１は、ＣＨまたは窒素原子であり；
　Ｗ２は、酸素原子または硫黄原子であり；
　Ｗ３およびＷ４は、一方が窒素原子であり、他方がＣＨまたは窒素原子であり；
　Ｙ３は、Ｃ１－６アルキレン、－Ｏ－、－Ｓ－または－ＮＲｂ－であり；
　Ｒｂは、水素原子、Ｃ１－６アルキル基または（Ｃ１－６アルコキシ）カルボニル基であり；
　Ｒ１は、以下のｊ）～ｏ）からなる群から選択される基であり；
ｊ）－Ｃ（＝Ｏ）－ＯＺ１
ｋ）－Ｃ（＝Ｏ）－ＮＨＳＯ２Ｚ２
ｌ）－Ｃ（＝Ｏ）－ＮＨＯＨ
ｍ）－Ｃ（＝Ｏ）－ＮＨＣＮ
ｎ）－ＮＨ－Ｃ（＝Ｏ）－Ｚ３
ｏ）酸性５員ヘテロ環基
　Ｚ１は、水素原子、Ｃ１－６アルキル基またはＣ７－１０アラルキル基であり；
　Ｚ２およびＺ３は、以下のｐ）～ｔ）からなる群から選択される基であり；
ｐ）Ｃ１－６アルキル基
ｑ）ハロＣ１－６アルキル基
ｒ）Ｃ３－６シクロアルキル基
ｓ）非置換またはハロゲン原子、Ｃ１－６アルキル基、ハロＣ１－６アルキル基およびＣ１－６アルコキシ基からなる群から独立して選択される１～５個の基で環が置換されるアリール基
ｔ）複素環基
Ｒ２は、以下のａａ）～ｌｌ）からなる群から選択される基であり；
ａａ）Ｃ１－６アルキル基またはＣ１－６アルコキシＣ１－６アルキル基
ｂｂ）非置換または１つのＣ１－６アルキル基で環が置換されるＣ３－６シクロアルキル基
ｃｃ）Ｃ２－６アルケニル基
ｄｄ）Ｃ５－８シクロアルケニル基
ｅｅ）非置換またはハロゲン原子、Ｃ１－６アルコキシ基およびＣ７－１０アラルキルオキシ基からなる群から独立して選択される１～５個の基で環が置換されるフェニル基
ｆｆ）複素環基
ｇｇ）非置換またはＣ１－６アルキル基、Ｃ２－６アルケニル基、Ｃ１－６アルコキシＣ１－６アルキル基、Ｃ４－６ヘテロシクロアルキル基およびＣ４－１０ヘテロアラルキル基から独立して選択される１個または２個の基で置換されるアミノ基
ｈｈ）非置換またはＣ１－６アルキル基、およびＣ１－６アルキレンジオキシ基からなる群から独立して選択される１～３個の基で環が置換される４～７員の環状アミノ基
ｉｉ）Ｃ１－６アルコキシ基
ｊｊ）Ｃ７－１０アラルキル基
ｋｋ）Ｃ１－６アルキルスルファニル基
ｌｌ）６員の脂肪族環状アミノ基で置換されるＣ１－６アルキル基
　Ｒ３は、以下のＡ）～Ｎ）からなる群から選択される基であり；
Ａ）水素原子
Ｂ）ハロゲン原子
Ｃ）シアノ基
Ｄ）ニトロ基
Ｅ）Ｃ３－６シクロアルキル基またはＣ５－８シクロアルケニル基
Ｆ）Ｃ２－８アルケニル基
Ｇ）Ｃ１－７アルカノイル基
Ｈ）非置換または独立した１もしくは２個のＣ１－６アルキル基で置換されるアミノ基
Ｉ）Ｃ１－６アルキル基
Ｊ）Ｃ１－６アルコキシ基
Ｋ）ハロＣ１－６アルコキシ基
Ｌ）非置換またはハロゲン原子、Ｃ１－６アルキル基およびＣ１－６アルコキシ基からなる群から独立して選択される１～５個の基で環が置換されるフェニル基
Ｍ）５員環の芳香族複素環基
Ｎ）カルボキシル基
　Ｒ4およびＲ５は、それぞれ独立して、水素原子またはハロゲン原子を表す。（＊）を付された結合はＹ３と結合し、（＊＊）を付された結合はＲ１と結合することを表す。 R a is a hydrogen atom, a halogen atom or a C 1-6 alkyl group;
W 1 is CH or a nitrogen atom;
W 2 is an oxygen atom or a sulfur atom;
One of W 3 and W 4 is a nitrogen atom, and the other is CH or a nitrogen atom;
Y 3 is C 1-6 alkylene, —O—, —S— or —NR b —;
R b is a hydrogen atom, a C 1-6 alkyl group or a (C 1-6 alkoxy) carbonyl group;
R 1 is a group selected from the group consisting of j) to o) below:
j) -C (= O) -OZ 1
k) —C (═O) —NHSO 2 Z 2
l) —C (═O) —NHOH
m) —C (═O) —NHCN
n) —NH—C (═O) —Z 3
o) an acidic 5-membered heterocyclic group Z 1 is a hydrogen atom, a C 1-6 alkyl group or a C 7-10 aralkyl group;
Z 2 and Z 3 are groups selected from the group consisting of p) to t) below;
p) C 1-6 alkyl group q) halo C 1-6 alkyl group r) C 3-6 cycloalkyl group s) unsubstituted or halogen atom, C 1-6 alkyl group, halo C 1-6 alkyl group and C Aryl group wherein the ring is substituted with 1 to 5 groups independently selected from the group consisting of 1-6 alkoxy groups t) heterocyclic group R 2 is selected from the group consisting of aa) to ll) below A group to be
aa) a C 1-6 alkyl group or a C 1-6 alkoxy C 1-6 alkyl group bb) a C 3-6 cycloalkyl group cc) C 2 which is unsubstituted or substituted with one C 1-6 alkyl group -6 alkenyl groups dd) C 5-8 cycloalkenyl groups ee) unsubstituted or independently selected from the group consisting of halogen atoms, C 1-6 alkoxy groups and C 7-10 aralkyloxy groups Phenyl group in which the ring is substituted ff) heterocyclic group gg) unsubstituted or C 1-6 alkyl group, C 2-6 alkenyl group, C 1-6 alkoxy C 1-6 alkyl group, C 4-6 hetero one or amino groups hh is substituted with two groups) unsubstituted or C 1-6 alkyl groups independently selected from cycloalkyl group and C 4-10 heteroaralkyl group, and a C 1-6 Al Dioxy 4-7 membered cyclic amino group, ii ring with one to three groups independently selected from the group consisting of group is substituted) C 1-6 alkoxy group jj) C 7-10 aralkyl group kk ) A C 1-6 alkylsulfanyl group ll) a C 1-6 alkyl group R 3 substituted with a 6-membered aliphatic cyclic amino group is a group selected from the group consisting of A) to N) below;
A) hydrogen atom B) halogen atom C) cyano group D) nitro group E) C 3-6 cycloalkyl group or C 5-8 cycloalkenyl group F) C 2-8 alkenyl group G) C 1-7 alkanoyl group H ) Amino group which is unsubstituted or substituted by 1 or 2 independent C 1-6 alkyl groups I) C 1-6 alkyl group J) C 1-6 alkoxy group K) Halo C 1-6 alkoxy group L) Unsubstituted or phenyl group in which the ring is substituted with 1 to 5 groups independently selected from the group consisting of halogen atoms, C 1-6 alkyl groups and C 1-6 alkoxy groups M) 5-membered aromatic Group heterocyclic group N) carboxyl group R 4 and R 5 each independently represents a hydrogen atom or a halogen atom. The bond marked with (*) bonded to Y 3, represents a bond with (**) attached to bond R 1.
〔２〕　前記一般式（Ｉ）中、Ａが、以下のｅ）、ｆ）、ｈ）およびｉ）からなる群から選択される基である、〔１〕記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。 [2] In the general formula (I), A is a group selected from the group consisting of the following e), f), h) and i), wherein the nitrogen-containing 5-membered benzene ring is described in [1] A heterocyclic compound or a pharmacologically acceptable salt thereof.
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
Ｒａ、Ｗ１、Ｗ２、Ｗ３、Ｗ４は前述と同義である。（＊）を付された結合はＹ３と結合し、（＊＊）を付された結合はＲ１と結合することを表す。 R a , W 1 , W 2 , W 3 , and W 4 are as defined above. The bond marked with (*) bonded to Y 3, represents a bond with (**) attached to bond R 1.
〔３〕　前記一般式（Ｉ）中、Ａが、以下のｅ１）、ｆ１）、ｈ）およびｉ１）からなる群から選択される基である、〔１〕または〔２〕に記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。 [3] The benzene ring according to [1] or [2], wherein A in the general formula (I) is a group selected from the group consisting of e1), f1), h) and i1) below: A condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof.
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
Ｒａは前述と同義である。（＊）を付された結合はＹ３と結合し、（＊＊）を付された結合はＲ１と結合することを表す。 R a has the same meaning as described above. The bond marked with (*) bonded to Y 3, represents a bond with (**) attached to bond R 1.
〔４〕　前記一般式（Ｉ）中、Ｒａが水素原子またはＣ１－６アルキル基である、〔１〕～〔３〕のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。 [4] The benzene ring condensed nitrogen-containing 5-membered heterocycle according to any one of [1] to [3], wherein R a is a hydrogen atom or a C 1-6 alkyl group in the general formula (I) Formula compound or pharmacologically acceptable salt thereof.
〔５〕　前記一般式（Ｉ）中、Ｙ３がメチレン、－Ｏ－または－Ｓ－である、〔１〕～〔４〕のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。 [5] The benzene ring condensed nitrogen-containing 5-membered heterocycle according to any one of [1] to [4], wherein Y 3 in the general formula (I) is methylene, —O— or —S— Formula compound or pharmacologically acceptable salt thereof.
〔６〕　前記一般式（Ｉ）中、Ｒ１が－Ｃ（＝Ｏ）－ＯＺ１である場合にＺ１が水素原子またはＣ１－６アルキル基であり、Ｒ１が－Ｃ（＝Ｏ）－ＮＨＳＯ２Ｚ２である場合にＺ２がＣ１－６アルキル基である、〔１〕～〔５〕のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。 [6] In the general formula (I), when R 1 is —C (═O) —OZ 1 , Z 1 is a hydrogen atom or a C 1-6 alkyl group, and R 1 is —C (═O ) -NHSO 2 Z 2 , wherein Z 2 is a C 1-6 alkyl group, the benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a compound thereof according to any one of [1] to [5] Pharmacologically acceptable salt.
〔７〕　前記一般式（Ｉ）中、Ｒ３が、以下のＡ）、Ｂ）、Ｃ）、Ｆ）、Ｇ）、Ｈ）、Ｊ）、Ｋ）およびＭ）からなる群から選択される基である、〔１〕～〔６〕のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。
Ａ）水素原子
Ｂ）ハロゲン原子
Ｃ）シアノ基
Ｆ）Ｃ２－８アルケニル基
Ｇ）Ｃ１－７アルカノイル基
H）非置換または独立した１もしくは２個のＣ１－６アルキル基で置換されるアミノ基
Ｊ）Ｃ１－６アルコキシ基
Ｋ）ハロＣ１－６アルコキシ基
Ｍ）５員環の芳香族複素環基 [7] In the general formula (I), R 3 is selected from the group consisting of the following A), B), C), F), G), H), J), K), and M). A benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [6], which is a group.
A) hydrogen atom B) halogen atom C) cyano group F) C 2-8 alkenyl group G) C 1-7 alkanoyl group
H) Amino group unsubstituted or substituted by 1 or 2 independent C 1-6 alkyl groups J) C 1-6 alkoxy group K) Halo C 1-6 alkoxy group M) 5-membered aromatic heterocycle Ring group
〔８〕　前記一般式（Ｉ）中、Ｒ２が、以下のａａ１）、ｂｂ）、ｃｃ）、ｄｄ）、ｅｅ１）、ｆｆ１）、ｇｇ１）およびｈｈ１）からなる群から選択される基である、〔１〕～〔７〕のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。
ａａ１）Ｃ１－６アルキル基
ｂｂ）非置換または１つのＣ１－６アルキル基で環が置換されるＣ３－６シクロアルキル基
ｃｃ）Ｃ２－６アルケニル基
ｄｄ）Ｃ５－８シクロアルケニル基
ｅｅ１）非置換または独立した１～５個のハロゲン原子で環が置換されるフェニル基
ｆｆ１）６員環の芳香族複素環基
ｇｇ１）Ｃ１－６アルキル基およびＣ２－６アルケニル基からなる群から独立して選択される１個または２個の基で置換されるアミノ基
ｈｈ１）非置換または独立した１～３個のＣ１－６アルキル基で環が置換される４～７員の環状アミノ基 [8] In the general formula (I), R 2 is a group selected from the group consisting of the following aa1), bb), cc), dd), ee1), ff1), gg1) and hh1). Benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of [1] to [7].
aa1) C 1-6 alkyl group bb) C 3-6 cycloalkyl group cc) C 2-6 alkenyl group dd) C 5-8 cycloalkenyl which is unsubstituted or substituted with one C 1-6 alkyl group The group ee1) a phenyl group which is unsubstituted or independently substituted with 1 to 5 halogen atoms ff1) a 6-membered aromatic heterocyclic group gg1) from a C 1-6 alkyl group and a C 2-6 alkenyl group An amino group hh1 substituted with one or two groups independently selected from the group consisting of 4 to 7 members whose ring is substituted by unsubstituted or independent 1 to 3 C 1-6 alkyl groups Cyclic amino group of
〔９〕　前記一般式（Ｉ）中、Ａが、以下のｅ１）またはｆ１）として表される基である、〔１〕～〔８〕のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。 [9] The benzene ring condensed nitrogen-containing 5 according to any one of [1] to [8], wherein A in the general formula (I) is a group represented by the following e1) or f1): A membered heterocyclic compound or a pharmacologically acceptable salt thereof.
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
Ｒａは前述と同義である。（＊）を付された結合はＹ３と結合し、（＊＊）を付された結合はＲ１と結合することを表す。 R a has the same meaning as described above. The bond marked with (*) bonded to Y 3, represents a bond with (**) attached to bond R 1.
〔１０〕　前記一般式（Ｉ）中、Ｙ３がメチレンである、〔１〕～〔９〕のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。 [10] The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound according to any one of [1] to [9], wherein Y 3 in the general formula (I) is methylene, or a pharmacologically thereof Acceptable salt.
〔１１〕　前記一般式（Ｉ）中、Ｒ３が、水素原子、ハロゲン原子、Ｃ２－８アルケニル基、Ｃ１－７アルカノイル基、独立した２個のＣ１－６アルキル基で置換されるアミノ基、Ｃ１－６アルコキシ基、またはハロＣ１－６アルコキシ基である、〔１〕～〔１０〕のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。 [11] In the general formula (I), R 3 is substituted with a hydrogen atom, a halogen atom, a C 2-8 alkenyl group, a C 1-7 alkanoyl group, or two independent C 1-6 alkyl groups. The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or the drug thereof according to any one of [1] to [10], which is an amino group, a C 1-6 alkoxy group, or a halo C 1-6 alkoxy group Physically acceptable salt.
〔１２〕　前記一般式（Ｉ）中、Ｒ２が、以下のｂｂ１）、ｃｃ）、ｄｄ）、ｇｇ２）およびｈｈ２）からなる群から選択される基である、〔１〕～〔１１〕のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。
ｂｂ１）１つのＣ１－６アルキル基で環が置換されるＣ３－６シクロアルキル基
ｃｃ）Ｃ２－６アルケニル基
ｄｄ）Ｃ５－８シクロアルケニル基
ｇｇ２）独立した２個のＣ１－６アルキル基で置換されるアミノ基
ｈｈ２）４～７員の環状アミノ基 [12] In the above general formula (I), R 2 is a group selected from the group consisting of the following bb1), cc), dd), gg2) and hh2), [1] to [11] The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of the above.
bb1) C 3-6 cycloalkyl group whose ring is substituted with one C 1-6 alkyl group cc) C 2-6 alkenyl group dd) C 5-8 cycloalkenyl group gg2) two independent C 1 1- Amino groups substituted with 6 alkyl groups hh2) 4-7 membered cyclic amino groups
〔１３〕　前記一般式（Ｉ）中、前記ベンゼン環縮合含窒素５員複素環が、以下のａ）、ｂ）およびｄ）からなる群から選択される環である、〔１〕～〔１２〕のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。 [13] In the general formula (I), the benzene ring condensed nitrogen-containing 5-membered heterocyclic ring is a ring selected from the group consisting of the following a), b) and d): [1] to [12 ] The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of the above.
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｙ３は前述と同義である。 R 2 , R 3 , R 4 , R 5 and Y 3 are as defined above.
〔１４〕　前記一般式（Ｉ）中、前記ベンゼン環縮合含窒素５員複素環が、以下のａ）として表される環である、〔１〕～〔１３〕のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。 [14] The general formula (I), wherein the benzene ring condensed nitrogen-containing 5-membered heterocycle is a ring represented by the following a), according to any one of [1] to [13] A benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof.
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｙ３は前述と同義である。 R 2 , R 3 , R 4 , R 5 and Y 3 are as defined above.
〔１５〕　前記一般式（Ｉ）で表される化合物が、
１－［［６－ブロモ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（ジエチルアミノ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（５－メチル－３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（１－プロペン－２－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－ビニルベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
６－クロロ－４－［［５－メチル－３－（１Ｈ－テトラゾール－５－イル）－１Ｈ－ピラゾール－１－イル］メチル］－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール、
１－［［５－クロロ－２－（１－メチルシクロプロピル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［（６－クロロ－２－フェニルベンゾ［ｄ］チアゾール－４－イル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［５－クロロ－２－（３－クロロフェニル）ベンゾ［ｄ］オキサゾール－７－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－フルオロベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－（トリフルオロメトキシ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（ピペリジン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（モルホリン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（ピロリジン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（ジメチルアミノ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（チオモルホリン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（ｃｉｓ－２，６－ジメチルモルホリン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（４－メチル－３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－メトキシベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（ピリジン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（２－メチル－１－プロペン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－（ジメチルアミノ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
５－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］オキシ］フラン－２－カルボン酸、
５－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］チオ］フラン－２－カルボン酸、または
１－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］オキサゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸である、〔１〕記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。 [15] The compound represented by the general formula (I) is:
1-[[6-bromo-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (diethylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-Chloro-2- (5-methyl-3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3 -carboxylic acid,
1-[[6-chloro-2- (1-propen-2-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (3,6-dihydropyridin-1 (2H) -yl) -6-vinylbenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
6-Chloro-4-[[5-methyl-3- (1H-tetrazol-5-yl) -1H-pyrazol-1-yl] methyl] -2- (3,6-dihydropyridin-1 (2H) -yl ) Benzo [d] thiazole,
1-[[5-chloro-2- (1-methylcyclopropyl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[(6-chloro-2-phenylbenzo [d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[5-chloro-2- (3-chlorophenyl) benzo [d] oxazol-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (3,6-dihydropyridin-1 (2H) -yl) -6-fluorobenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6- (trifluoromethoxy) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3 -carboxylic acid,
1-[[2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (piperidin-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (pyrrolidin-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (dimethylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (thiomorpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (cis-2,6-dimethylmorpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-Chloro-2- (4-methyl-3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3 -carboxylic acid,
1-[[2- (3,6-dihydropyridin-1 (2H) -yl) -6-methoxybenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (pyridin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (2-methyl-1-propen-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6- (dimethylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3- carboxylic acid,
5-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] oxy] furan-2-carboxylic acid,
5-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] thio] furan-2-carboxylic acid, or 1-[[6- [1] is chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] oxazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid A nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof.
〔１６〕　前記〔１〕～〔１５〕のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩を含有する医薬。 [16] A medicament comprising the benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of [1] to [15].
〔１７〕　前記〔１〕～〔１５〕のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩を含有するＥＰ１受容体拮抗薬。 [17] An EP 1 receptor antagonist comprising the benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [15].
〔１８〕　前記〔１〕～〔１５〕のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩を含有する下部尿路症状の治療または予防薬。 [18] Treatment of lower urinary tract symptoms comprising the benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or the pharmaceutically acceptable salt thereof according to any one of [1] to [15] Preventive drugs.
〔１９〕　前記〔１〕～〔１５〕のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩を患者に投与することを含む下部尿路症状の治療または予防方法。 [19] Lower urine comprising administering to a patient the benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of [1] to [15] How to treat or prevent tract symptoms.
〔２０〕　下部尿路症状の予防または治療用の医薬を製造するための、前記〔１〕～〔１５〕のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩の使用。 [20] A benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a drug thereof according to any one of the above [1] to [15], for producing a medicament for preventing or treating lower urinary tract symptoms The use of a physically acceptable salt.
〔２１〕　下部尿路症状の予防または治療に使用するための、〔１〕～〔１５〕のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。
  [21] A benzene ring-fused nitrogen-containing 5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [15] for use in the prevention or treatment of lower urinary tract symptoms Salt.
　本発明によれば、ＥＰ１受容体拮抗作用を有する新規な化合物を提供することができる。 According to the present invention, a novel compound having an EP 1 receptor antagonistic action can be provided.
　以下に、本実施形態の化合物（Ｉ）を詳細に説明する。
　以下において、一般式が有する官能基の定義については、すでに記載した定義を引用してその説明を省略することがある。引用している定義は、以下に記載する実施形態の説明中に記載した定義を指しており、先行技術として記載した化合物が有する官能基についての定義を引用するものではないことは、当然に理解できる。 Hereinafter, the compound (I) of the present embodiment will be described in detail.
In the following, the definition of the functional group of the general formula may be omitted with reference to the definition already described. It should be understood that the definitions cited refer to the definitions described in the description of the embodiments described below, and do not refer to the definitions of the functional groups of the compounds described as the prior art. it can.
　本実施形態は、下記一般式（Ｉ）で表されるベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩に関する。 This embodiment relates to a benzene ring condensed nitrogen-containing 5-membered heterocyclic compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof.
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
式（Ｉ）中、Ｙ１およびＹ２を含み、Ｒ２、Ｒ３、Ｒ４、Ｒ５およびＹ３が結合するベンゼン環縮合含窒素５員複素環は、以下のａ）～d）からなる群から選択される環であり； The benzene ring condensed nitrogen-containing 5-membered heterocyclic ring containing Y 1 and Y 2 and having R 2 , R 3 , R 4 , R 5 and Y 3 bonded thereto is represented by the following a) to d): A ring selected from the group consisting of;
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
Ａは、以下のｅ）～ｉ）からなる群から選択される基であり； A is a group selected from the group consisting of e) to i) below:
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
　Ｒａは、水素原子、ハロゲン原子またはＣ１－６アルキル基であり；
　Ｗ１は、ＣＨまたは窒素原子であり；
　Ｗ２は、酸素原子または硫黄原子であり；
　Ｗ３およびＷ４は、一方が窒素原子であり、他方がＣＨまたは窒素原子であり；
　Ｙ３は、Ｃ１－６アルキレン、－Ｏ－、－Ｓ－または－ＮＲｂ－であり；
　Ｒｂは、水素原子、Ｃ１－６アルキル基または（Ｃ１－６アルコキシ）カルボニル基であり；
　Ｒ１は、以下のｊ）～ｏ）からなる群から選択される基であり；
ｊ）－Ｃ（＝Ｏ）－ＯＺ１
ｋ）－Ｃ（＝Ｏ）－ＮＨＳＯ２Ｚ２
ｌ）－Ｃ（＝Ｏ）－ＮＨＯＨ
ｍ）－Ｃ（＝Ｏ）－ＮＨＣＮ
ｎ）－ＮＨ－Ｃ（＝Ｏ）－Ｚ３
ｏ）酸性５員ヘテロ環基
　Ｚ１は、水素原子、Ｃ１－６アルキル基またはＣ７－１０アラルキル基であり；
　Ｚ２およびＺ３は、以下のｐ）～ｔ）からなる群から選択される基であり；
ｐ）Ｃ１－６アルキル基
ｑ）ハロＣ１－６アルキル基
ｒ）Ｃ３－６シクロアルキル基
ｓ）非置換またはハロゲン原子、Ｃ１－６アルキル基、ハロＣ１－６アルキル基およびＣ１－６アルコキシ基からなる群から独立して選択される１～５個の基で環が置換されるアリール基
ｔ）複素環基
Ｒ２は、以下のａａ）～ｌｌ）からなる群から選択される基であり；
ａａ）Ｃ１－６アルキル基またはＣ１－６アルコキシＣ１－６アルキル基
ｂｂ）非置換または１つのＣ１－６アルキル基で環が置換されるＣ３－６シクロアルキル基
ｃｃ）Ｃ２－６アルケニル基
ｄｄ）Ｃ５－８シクロアルケニル基
ｅｅ）非置換またはハロゲン原子、Ｃ１－６アルコキシ基およびＣ７－１０アラルキルオキシ基からなる群から独立して選択される１～５個の基で環が置換されるフェニル基
ｆｆ）複素環基
ｇｇ）非置換またはＣ１－６アルキル基、Ｃ２－６アルケニル基、Ｃ１－６アルコキシＣ１－６アルキル基、Ｃ４－６ヘテロシクロアルキル基およびＣ４－１０ヘテロアラルキル基から独立して選択される１個または２個の基で置換されるアミノ基
ｈｈ）非置換またはＣ１－６アルキル基、およびＣ１－６アルキレンジオキシ基からなる群から独立して選択される１～３個の基で環が置換される４～７員の環状アミノ基
ｉｉ）Ｃ１－６アルコキシ基
ｊｊ）Ｃ７－１０アラルキル基
ｋｋ）Ｃ１－６アルキルスルファニル基
ｌｌ）６員の脂肪族環状アミノ基で置換されるＣ１－６アルキル基
　Ｒ３は、以下のＡ）～Ｎ）からなる群から選択される基であり；
Ａ）水素原子
Ｂ）ハロゲン原子
Ｃ）シアノ基
Ｄ）ニトロ基
Ｅ）Ｃ３－６シクロアルキル基またはＣ５－８シクロアルケニル基
Ｆ）Ｃ２－８アルケニル基
Ｇ）Ｃ１－７アルカノイル基
Ｈ）非置換または独立した１もしくは２個のＣ１－６アルキル基で置換されるアミノ基
Ｉ）Ｃ１－６アルキル基
Ｊ）Ｃ１－６アルコキシ基
Ｋ）ハロＣ１－６アルコキシ基
Ｌ）非置換またはハロゲン原子、Ｃ１－６アルキル基およびＣ１－６アルコキシ基からなる群から独立して選択される１～５個の基で環が置換されるフェニル基
Ｍ）５員環の芳香族複素環基
Ｎ）カルボキシル基
　Ｒ4およびＲ５は、それぞれ独立して、水素原子またはハロゲン原子を表す。（＊）を付された結合はＹ３と結合し、（＊＊）を付された結合はＲ１と結合することを表す。
　なお、「独立して」および「独立した」とは、存在し得る２個以上の置換基の間でそれらが同一でも異なっていてもよいことを意味している。
　また、当然ながら、Ｚ２とＺ３とは、同一でも異なっていてもよい。 R a is a hydrogen atom, a halogen atom or a C 1-6 alkyl group;
W 1 is CH or a nitrogen atom;
W 2 is an oxygen atom or a sulfur atom;
One of W 3 and W 4 is a nitrogen atom, and the other is CH or a nitrogen atom;
Y 3 is C 1-6 alkylene, —O—, —S— or —NR b —;
R b is a hydrogen atom, a C 1-6 alkyl group or a (C 1-6 alkoxy) carbonyl group;
R 1 is a group selected from the group consisting of j) to o) below:
j) -C (= O) -OZ 1
k) —C (═O) —NHSO 2 Z 2
l) —C (═O) —NHOH
m) —C (═O) —NHCN
n) —NH—C (═O) —Z 3
o) an acidic 5-membered heterocyclic group Z 1 is a hydrogen atom, a C 1-6 alkyl group or a C 7-10 aralkyl group;
Z 2 and Z 3 are groups selected from the group consisting of p) to t) below;
p) C 1-6 alkyl group q) halo C 1-6 alkyl group r) C 3-6 cycloalkyl group s) unsubstituted or halogen atom, C 1-6 alkyl group, halo C 1-6 alkyl group and C Aryl group wherein the ring is substituted with 1 to 5 groups independently selected from the group consisting of 1-6 alkoxy groups t) heterocyclic group R 2 is selected from the group consisting of aa) to ll) below A group to be
aa) a C 1-6 alkyl group or a C 1-6 alkoxy C 1-6 alkyl group bb) a C 3-6 cycloalkyl group cc) C 2 which is unsubstituted or substituted with one C 1-6 alkyl group -6 alkenyl groups dd) C 5-8 cycloalkenyl groups ee) unsubstituted or independently selected from the group consisting of halogen atoms, C 1-6 alkoxy groups and C 7-10 aralkyloxy groups Phenyl group in which the ring is substituted ff) heterocyclic group gg) unsubstituted or C 1-6 alkyl group, C 2-6 alkenyl group, C 1-6 alkoxy C 1-6 alkyl group, C 4-6 hetero one or amino groups hh is substituted with two groups) unsubstituted or C 1-6 alkyl groups independently selected from cycloalkyl group and C 4-10 heteroaralkyl group, and a C 1-6 Al Dioxy 4-7 membered cyclic amino group, ii ring with one to three groups independently selected from the group consisting of group is substituted) C 1-6 alkoxy group jj) C 7-10 aralkyl group kk ) A C 1-6 alkylsulfanyl group ll) a C 1-6 alkyl group R 3 substituted with a 6-membered aliphatic cyclic amino group is a group selected from the group consisting of A) to N) below;
A) hydrogen atom B) halogen atom C) cyano group D) nitro group E) C 3-6 cycloalkyl group or C 5-8 cycloalkenyl group F) C 2-8 alkenyl group G) C 1-7 alkanoyl group H ) Amino group which is unsubstituted or substituted by 1 or 2 independent C 1-6 alkyl groups I) C 1-6 alkyl group J) C 1-6 alkoxy group K) Halo C 1-6 alkoxy group L) Unsubstituted or phenyl group in which the ring is substituted with 1 to 5 groups independently selected from the group consisting of halogen atoms, C 1-6 alkyl groups and C 1-6 alkoxy groups M) 5-membered aromatic Group heterocyclic group N) carboxyl group R 4 and R 5 each independently represents a hydrogen atom or a halogen atom. The bond marked with (*) bonded to Y 3, represents a bond with (**) attached to bond R 1.
“Independently” and “independently” mean that they may be the same or different between two or more substituents that may be present.
Of course, Z 2 and Z 3 may be the same or different.
　「ハロゲン原子」としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられる。 “Halogen atom” includes fluorine atom, chlorine atom, bromine atom and iodine atom.
　「Ｃ１－６アルキル基」とは、炭素数１～６の直鎖の又は分枝鎖のアルキル基を意味する。Ｃ１－６アルキル基として、例えば、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基、ペンチル基、イソペンチル基、ネオペンチル基、１－メチルブチル基、２－メチルブチル基、１，２－ジメチルプロピル基、ヘキシル基、イソヘキシル基等が挙げられる。 “C 1-6 alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms. Examples of the C 1-6 alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, and 1-methylbutyl. Group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group and the like.
　「ハロＣ１－６アルキル基」とは、１～５個の同種または異種のハロゲン原子で置換されたＣ１－６アルキル基を意味する。ハロＣ１－６アルキル基として、例えば、フルオロメチル基、ジフルオロメチル基、トリフルオロメチル基、２－フルオロエチル基、２－クロロエチル基、２，２－ジフルオロエチル基、１，１－ジフルオロエチル基、１，２－ジフルオロエチル基、２，２，２－トリフルオロエチル基、１，１，２，２，２－ペンタフルオロエチル基、２，２，２－トリクロロエチル基、３－フルオロプロピル基、２－フルオロプロピル基、１－フルオロプロピル基、３，３－ジフルオロプロピル基、２，２－ジフルオロプロピル基、１，１－ジフルオロプロピル基、４－フルオロブチル基、５－フルオロペンチル基、６－フルオロヘキシル基、２，２，２－トリフルオロ－１－トリフルオロメチルエチル等が挙げられる。好ましくは、フルオロメチル基、ジフルオロメチル基、トリフルオロメチル基が挙げられる。 The “halo C 1-6 alkyl group” means a C 1-6 alkyl group substituted with 1 to 5 same or different halogen atoms. Examples of the halo C 1-6 alkyl group include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 2-chloroethyl group, a 2,2-difluoroethyl group, and a 1,1-difluoroethyl group. 1,2-difluoroethyl group, 2,2,2-trifluoroethyl group, 1,1,2,2,2-pentafluoroethyl group, 2,2,2-trichloroethyl group, 3-fluoropropyl group 2-fluoropropyl group, 1-fluoropropyl group, 3,3-difluoropropyl group, 2,2-difluoropropyl group, 1,1-difluoropropyl group, 4-fluorobutyl group, 5-fluoropentyl group, 6 -Fluorohexyl group, 2,2,2-trifluoro-1-trifluoromethylethyl and the like. Preferably, a fluoromethyl group, a difluoromethyl group, and a trifluoromethyl group are mentioned.
　「Ｃ１－６アルキレン」とは、炭素数１～６の２価の直鎖または分枝鎖状の飽和炭化水素鎖を意味する。Ｃ１－６アルキレンとして、例えば、－ＣＨ２－、－（ＣＨ２）２－、－ＣＨ（ＣＨ３）－、－（ＣＨ２）３－、－ＣＨ（ＣＨ３）ＣＨ２－、－ＣＨ２ＣＨ（ＣＨ３）－、－ＣＨ（ＣＨ２ＣＨ３）－、－Ｃ（ＣＨ３）２－、－（ＣＨ２）４－、－ＣＨ（ＣＨ３）－（ＣＨ２）２－、－（ＣＨ２）２－ＣＨ（ＣＨ３）－、－ＣＨ（ＣＨ２ＣＨ３）－ＣＨ２－、－Ｃ（ＣＨ３）２ＣＨ２－、－ＣＨ２－Ｃ（ＣＨ３）２－、－ＣＨ（ＣＨ３）－ＣＨ（ＣＨ３）－、－（ＣＨ２）５－、－ＣＨ（ＣＨ３）－（ＣＨ２）３－、－Ｃ（ＣＨ３）２ＣＨ２ＣＨ２－、－（ＣＨ２）６－、－Ｃ（ＣＨ３）２－（ＣＨ２）３－等が挙げられる。好ましくは、－ＣＨ２－等が挙げられる。なお、本明細書中、－ＣＨ２－をメチレンと称する場合がある。 “C 1-6 alkylene” means a divalent straight chain or branched saturated hydrocarbon chain having 1 to 6 carbon atoms. As C 1-6 alkylene, for example, —CH 2 —, — (CH 2 ) 2 —, —CH (CH 3 ) —, — (CH 2 ) 3 —, —CH (CH 3 ) CH 2 —, —CH 2 CH (CH 3 ) —, —CH (CH 2 CH 3 ) —, —C (CH 3 ) 2 —, — (CH 2 ) 4 —, —CH (CH 3 ) — (CH 2 ) 2 —, — (CH 2 ) 2 —CH (CH 3 ) —, —CH (CH 2 CH 3 ) —CH 2 —, —C (CH 3 ) 2 CH 2 —, —CH 2 —C (CH 3 ) 2 —, — CH (CH 3 ) —CH (CH 3 ) —, — (CH 2 ) 5 —, —CH (CH 3 ) — (CH 2 ) 3 —, —C (CH 3 ) 2 CH 2 CH 2 —, — ( CH 2 ) 6 —, —C (CH 3 ) 2 — (CH 2 ) 3 — and the like. Preferably, —CH 2 — and the like are mentioned. In the present specification, —CH 2 — may be referred to as methylene.
　「Ｃ２－６アルケニル基」とは、少なくとも１個の二重結合を有する、直鎖または分岐鎖上の炭素数２～６個の不飽和炭化水素基を意味する。Ｃ２－６アルケニル基として、例えば、ビニル基、２－プロペニル基、１－プロペニル基、１－ブテン－１－イル基、１－ブテン－２－イル基、１－ブテン－３－イル基、１－ブテン－４－イル基、２－ブテン－１－イル基、２－ブテン－２－イル基、１－ペンテン－１－イル基、１－ペンテン－２－イル基、１－ペンテン－３－イル基、２－ペンテン－１－イル基、２－ペンテン－２－イル基、２－ペンテン－３－イル基、１－ヘキセン－１－イル基、１－ヘキセン－２－イル基、１－ヘキセン－３－イル基、２－メチル－１－プロペン－１－イル基等が挙げられる。 The “C 2-6 alkenyl group” means a straight or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms having at least one double bond. Examples of the C 2-6 alkenyl group include a vinyl group, 2-propenyl group, 1-propenyl group, 1-buten-1-yl group, 1-buten-2-yl group, 1-buten-3-yl group, 1-buten-4-yl group, 2-buten-1-yl group, 2-buten-2-yl group, 1-penten-1-yl group, 1-penten-2-yl group, 1-pentene-3 -Yl group, 2-penten-1-yl group, 2-penten-2-yl group, 2-penten-3-yl group, 1-hexen-1-yl group, 1-hexen-2-yl group, -Hexen-3-yl group, 2-methyl-1-propen-1-yl group and the like.
　「Ｃ２－８アルケニル基」とは、少なくとも１個の二重結合を有する、直鎖または分岐鎖上の炭素数２～８個の不飽和炭化水素基を意味する。Ｃ２－８アルケニル基として、例えば、ビニル基、２－プロペニル基、１－プロペニル基、１－ブテン－１－イル基、１－ブテン－２－イル基、１－ブテン－３－イル基、１－ブテン－４－イル基、２－ブテン－１－イル基、２－ブテン－２－イル基、１－ペンテン－１－イル基、１－ペンテン－２－イル基、１－ペンテン－３－イル基、２－ペンテン－１－イル基、２－ペンテン－２－イル基、２－ペンテン－３－イル基、１－ヘキセン－１－イル基、１－ヘキセン－２－イル基、１－ヘキセン－３－イル基、１－ヘプテン－１－イル基、１－オクテン－１－イル基、２－メチル－１－プロペン－１－イル基等が挙げられる。 The “C 2-8 alkenyl group” means a straight or branched unsaturated hydrocarbon group having 2 to 8 carbon atoms having at least one double bond. Examples of the C 2-8 alkenyl group include a vinyl group, 2-propenyl group, 1-propenyl group, 1-buten-1-yl group, 1-buten-2-yl group, 1-buten-3-yl group, 1-buten-4-yl group, 2-buten-1-yl group, 2-buten-2-yl group, 1-penten-1-yl group, 1-penten-2-yl group, 1-pentene-3 -Yl group, 2-penten-1-yl group, 2-penten-2-yl group, 2-penten-3-yl group, 1-hexen-1-yl group, 1-hexen-2-yl group, -Hexen-3-yl group, 1-hepten-1-yl group, 1-octen-1-yl group, 2-methyl-1-propen-1-yl group and the like.
　「Ｃ１－６アルコキシ基」とは、炭素数１～６の直鎖の又は分枝鎖のアルコキシ基を意味する。Ｃ１－６アルコキシ基として、例えば、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、イソブトキシ基、ブトキシ基、ｓｅｃ－ブトキシ基、ｔｅｒｔ－ブトキシ基、ペンチルオキシ基、ヘキシルオキシ基等が挙げられる。好ましくは、メトキシ基、エトキシ基が挙げられる。 The “C 1-6 alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms. Examples of the C 1-6 alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, an isobutoxy group, a butoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, and a hexyloxy group. . Preferably, a methoxy group and an ethoxy group are mentioned.
　「ハロＣ１－６アルコキシ基」とは、１～５個の同種または異種のハロゲン原子で置換されたＣ１－６アルコキシ基を意味する。ハロＣ１－６アルコキシ基として、例えば、モノフルオロメトキシ基、ジフルオロメトキシ基、トリフルオロメトキシ基、２－フルオロエトキシ基、２－クロロエトキシ基、２，２－ジフルオロエトキシ基、１，１－ジフルオロエトキシ基、１，２－ジフルオロエトキシ基、２，２，２－トリフルオロエトキシ基、１，１，２，２，２－ペンタフルオロエトキシ基、２，２，２－トリクロロエトキシ基、３－フルオロプロポキシ基、２－フルオロプロポキシ基、１－フルオロプロポキシ基、３，３－ジフルオロプロポキシ基、２，２－ジフルオロプロポキシ基、１，１－ジフルオロプロポキシ基、４－フルオロブトキシ基、５－フルオロペンチルオキシ基、６－フルオロヘキシルオキシ基等が挙げられる。好ましくは、モノフルオロメトキシ基、ジフルオロメトキシ基、トリフルオロメトキシ基が挙げられる。 The “halo C 1-6 alkoxy group” means a C 1-6 alkoxy group substituted with 1 to 5 same or different halogen atoms. Examples of the halo C 1-6 alkoxy group include a monofluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a 2-fluoroethoxy group, a 2-chloroethoxy group, a 2,2-difluoroethoxy group, and a 1,1-difluoro group. Ethoxy group, 1,2-difluoroethoxy group, 2,2,2-trifluoroethoxy group, 1,1,2,2,2-pentafluoroethoxy group, 2,2,2-trichloroethoxy group, 3-fluoro Propoxy group, 2-fluoropropoxy group, 1-fluoropropoxy group, 3,3-difluoropropoxy group, 2,2-difluoropropoxy group, 1,1-difluoropropoxy group, 4-fluorobutoxy group, 5-fluoropentyloxy Group, 6-fluorohexyloxy group and the like. Preferably, a monofluoromethoxy group, a difluoromethoxy group, and a trifluoromethoxy group are mentioned.
　「（Ｃ１－６アルコキシ）カルボニル基」とは、炭素数１～６の直鎖の又は分枝鎖のアルコキシカルボニル基を意味する。（Ｃ１－６アルコキシ）カルボニル基として、例えば、メトキシカルボニル基、エトキシカルボニル基、プロポキシカルボニル基、イソプロポキシカルボニル基、イソブトキシカルボニル基、ブトキシカルボニル基、ｓｅｃ－ブトキシカルボニル基、ｔｅｒｔ－ブトキシカルボニル基、ペンチルオキシカルボニル基、ヘキシルオキシカルボニル基等が挙げられる。好ましくは、メトキシカルボニル基、ｔｅｒｔ－ブトキシカルボニル基が挙げられる。 The “(C 1-6 alkoxy) carbonyl group” means a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms. (C 1-6 alkoxy) carbonyl group includes, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, isobutoxycarbonyl group, butoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group , A pentyloxycarbonyl group, a hexyloxycarbonyl group, and the like. Preferably, a methoxycarbonyl group and a tert-butoxycarbonyl group are used.
　「Ｃ１－６アルコキシＣ１－６アルキル基」とは、炭素数１～６の直鎖の又は分枝鎖のアルコキシ基で置換されたＣ１－６アルキル基を意味する。Ｃ１－６アルコキシＣ１－６アルキル基として、例えば、メトキシメチル基、エトキシエチル基、プロポキシメチル基、イソプロポキシメチル基が挙げられる。 The “C 1-6 alkoxy C 1-6 alkyl group” means a C 1-6 alkyl group substituted with a linear or branched alkoxy group having 1 to 6 carbon atoms. Examples of the C 1-6 alkoxy C 1-6 alkyl group include a methoxymethyl group, an ethoxyethyl group, a propoxymethyl group, and an isopropoxymethyl group.
　「Ｃ１－６アルキレンジオキシ基」とは、－Ｏ－（Ｃ１－６アルキル）－Ｏ－で表される基を意味する。例えば、メチレンジオキシ基、エチレンジオキシ基、プロピレンジオキシ基等が挙げられる。 The “C 1-6 alkylenedioxy group” means a group represented by —O— (C 1-6 alkyl) -O—. For example, a methylenedioxy group, an ethylenedioxy group, a propylenedioxy group, etc. are mentioned.
　「Ｃ１－７アルカノイル基」とは炭素原子１～７個を有する直鎖状または分岐鎖状の脂肪族カルボン酸から誘導されるアシル基を意味する。Ｃ１－７アルカノイル基として、例えば、ホルミル基、アセチル基、プロパノイル基、ブタノイル基、ペンタノイル基、ヘキサノイル基等が挙げられる。 The “C 1-7 alkanoyl group” means an acyl group derived from a linear or branched aliphatic carboxylic acid having 1 to 7 carbon atoms. Examples of the C 1-7 alkanoyl group include formyl group, acetyl group, propanoyl group, butanoyl group, pentanoyl group, hexanoyl group and the like.
　「Ｃ１－６アルキルスルファニル基」とは、（Ｃ１－６アルキル）－Ｓ－で表される基を意味する。Ｃ１－６アルキルスルファニル基として、例えば、メチルスルファニル基、エチルスルファニル基、プロピルスルファニル基、イソプロピルスルファニル基、ブチルスルファニル基、イソブチルスルファニル基、ｓｅｃ－ブチルスルファニル基、ペンチルスルファニル基、ヘキシルスルファニル基等が挙げられる。 The “C 1-6 alkylsulfanyl group” means a group represented by (C 1-6 alkyl) -S—. Examples of the C 1-6 alkylsulfanyl group include a methylsulfanyl group, an ethylsulfanyl group, a propylsulfanyl group, an isopropylsulfanyl group, a butylsulfanyl group, an isobutylsulfanyl group, a sec-butylsulfanyl group, a pentylsulfanyl group, and a hexylsulfanyl group. Can be mentioned.
　「Ｃ７－１０アラルキル基」とは、フェニル基で置換された炭素数１～４個のアルキル基を意味する。Ｃ７－１０アラルキル基として、例えば、ベンジル基、フェネチル基、１－フェニルエチル基、３－フェニルプロピル基、４－フェニルブチル基等が挙げられる。 “C 7-10 aralkyl group” means an alkyl group having 1 to 4 carbon atoms substituted with a phenyl group. Examples of the C 7-10 aralkyl group include benzyl group, phenethyl group, 1-phenylethyl group, 3-phenylpropyl group, 4-phenylbutyl group and the like.
　「Ｃ７－１０アラルキルオキシ基」とは、フェニル基で置換された炭素数１～４個のアルコキシ基を意味する。Ｃ７－１０アラルキルオキシ基として、例えば、ベンジルオキシ基、フェネチルオキシ基、１－フェニルエチルオキシ基、３－フェニルプロピルオキシ基、４－フェニルブチルオキシ基等が挙げられる。 The “C 7-10 aralkyloxy group” means an alkoxy group having 1 to 4 carbon atoms substituted with a phenyl group. Examples of the C 7-10 aralkyloxy group include a benzyloxy group, a phenethyloxy group, a 1-phenylethyloxy group, a 3-phenylpropyloxy group, and a 4-phenylbutyloxy group.
　「Ｃ４－１０ヘテロアラルキル基」とは、ヘテロアリール基で置換された炭素数１～４個のアルキル基を意味する。Ｃ４－１０ヘテロアラルキル基として、例えば、２－フラニルメチル基、３－フラニルメチル基、２－ピリジルメチル基等が挙げられる。 The “C 4-10 heteroaralkyl group” means an alkyl group having 1 to 4 carbon atoms substituted with a heteroaryl group. Examples of the C 4-10 heteroaralkyl group include a 2-furanylmethyl group, a 3-furanylmethyl group, a 2-pyridylmethyl group, and the like.
　「Ｃ４－６ヘテロシクロアルキル基」とは、飽和複素環基で置換された炭素数１～４個のアルキル基を意味する。Ｃ４－６ヘテロシクロアルキル基として、例えば、２－テトラヒドロフラニルメチル基、３－テトラヒドロフラニルメチル基、２－ピロリジニルメチル基等が挙げられる。 The “C 4-6 heterocycloalkyl group” means an alkyl group having 1 to 4 carbon atoms substituted with a saturated heterocyclic group. Examples of the C 4-6 heterocycloalkyl group include a 2-tetrahydrofuranylmethyl group, a 3-tetrahydrofuranylmethyl group, a 2-pyrrolidinylmethyl group, and the like.
　「Ｃ３－６シクロアルキル基」とは、炭素数３～６個の単環性飽和脂環式炭化水素基を意味する。Ｃ３－６シクロアルキル基として、例えば、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基が挙げられる。 The “C 3-6 cycloalkyl group” means a monocyclic saturated alicyclic hydrocarbon group having 3 to 6 carbon atoms. Examples of the C 3-6 cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
　「１つのＣ１－６アルキル基で環が置換されるＣ３－６シクロアルキル基」とは、上記Ｃ１－６アルキル基で環が置換された上記Ｃ３－６シクロアルキル基をいう。１つのＣ１－６アルキル基で環が置換されるＣ３－６シクロアルキル基として、例えば、1-メチルシクロプロピル基、１-エチルシクロプロピル基、1-メチルシクロブチル基、２-メチルシクロブチル基、1-メチルシクロペンチル基、２-メチルシクロペンチル基、1-メチルシクロヘキシル基、２-メチルシクロヘキシル基等が挙げられる。好ましくは、1-メチルシクロプロピル基、1-エチルシクロプロピル基であり、より好ましくは、1-メチルシクロプロピル基である。 The “C 3-6 cycloalkyl group in which the ring is substituted with one C 1-6 alkyl group” refers to the above C 3-6 cycloalkyl group in which the ring is substituted with the above C 1-6 alkyl group. Examples of the C 3-6 cycloalkyl group in which the ring is substituted with one C 1-6 alkyl group include a 1-methylcyclopropyl group, a 1-ethylcyclopropyl group, a 1-methylcyclobutyl group, and a 2-methylcyclo Examples include a butyl group, 1-methylcyclopentyl group, 2-methylcyclopentyl group, 1-methylcyclohexyl group, 2-methylcyclohexyl group and the like. A 1-methylcyclopropyl group and a 1-ethylcyclopropyl group are preferable, and a 1-methylcyclopropyl group is more preferable.
　「Ｃ５－８シクロアルケニル基」とは、炭素数５～８個の単環性不飽和脂環式炭化水素基を意味する。Ｃ５－８シクロアルケニル基として、例えば、シクロペンテン－１－イル基、シクロヘキセン－１－イル基、シクロヘプテン－１－イル基、シクロオクテン－１－イル基等が挙げられる。 The “C 5-8 cycloalkenyl group” means a monocyclic unsaturated alicyclic hydrocarbon group having 5 to 8 carbon atoms. Examples of the C 5-8 cycloalkenyl group include a cyclopenten-1-yl group, a cyclohexen-1-yl group, a cyclohepten-1-yl group, and a cycloocten-1-yl group.
　「アリール基」とは、例えば、フェニル基、インデニル基、ナフチル基、フェナンスレニル基、アントラセニル基のような炭素数６～１４個の芳香族炭化水素基を意味する。好ましくは「Ｃ６－１０アリール基」であり、これは炭素数６～１０個の芳香族炭化水素基を意味する。Ｃ６－１０アリール基として、例えば、フェニル基、インデニル基、ナフチル基が挙げられる。 The “aryl group” means, for example, an aromatic hydrocarbon group having 6 to 14 carbon atoms such as a phenyl group, an indenyl group, a naphthyl group, a phenanthrenyl group, or an anthracenyl group. Preferred is a “C 6-10 aryl group”, which means an aromatic hydrocarbon group having 6 to 10 carbon atoms. Examples of the C 6-10 aryl group include a phenyl group, an indenyl group, and a naphthyl group.
　「複素環基」としては、硫黄原子、酸素原子、窒素原子の中から選ばれた１～４個の原子を含む５～７員複素環基を意味する。複素環基として、例えば、フリル基、チエニル基、ピロリル基、アゼピニル基、ピラゾリル基、イミダゾリル基、オキサゾリル基、イソキサゾリル基、チアゾリル基、イソチアゾリル基、１，２，３－オキサジアゾリル基、トリアゾリル基、テトラゾリル基、チアジアゾリル基、ピラニル基、ピリジル基、ピリダジニル基、ピリミジニル基、ピラジニル基等の芳香族複素環基、ピロリニル基、イミダゾリニル基、ピラゾリニル基、ジヒドロピラニル基、ジヒドロチオピラニル基、ジヒドロピリジル基等の不飽和複素環基、及びモルホリニル基、チオモルホリニル基、ピロリジニル基、ピペリジニル基、ピペラジニル基、テトラヒドロフラニル基等の飽和複素環基を挙げることができる。なお、上記「複素環基」は、縮合環式である場合、単環式または縮合環式の複素環基と複素環以外の他の環式基とが縮環していてもよい。複素環基と複素環以外の他の環式基とが縮環している複素環基として、例えば、イソベンゾフラニル基、ベンゾオキサゾリル基、ベンゾイソオキサゾリル基、ベンゾチアゾリル基、ベンゾイソチアゾリル基、クロメニル基、クロマノニル基、キサンテニル基、フェノキサチイニル基、インドリジニル基、イソインドリジニル基、インドリル基、インダゾリル基、プリニル基、キノリジニル基、イソキノリル基、キノリル基、フタラジニル基、ナフチリジニル基、キノキサリニル基、キナゾリニル基、カルバゾリル基、カルボリニル基、アクリジニル基、イソインドリニル基等を挙げることができる。 “Heterocyclic group” means a 5- to 7-membered heterocyclic group containing 1 to 4 atoms selected from a sulfur atom, an oxygen atom, and a nitrogen atom. Examples of heterocyclic groups include furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl Group, thiadiazolyl group, pyranyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group and other aromatic heterocyclic groups, pyrrolinyl group, imidazolinyl group, pyrazolinyl group, dihydropyranyl group, dihydrothiopyranyl group, dihydropyridyl group And unsaturated heterocyclic groups such as morpholinyl group, thiomorpholinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, tetrahydrofuranyl group and the like. When the “heterocyclic group” is a condensed cyclic group, a monocyclic or condensed heterocyclic group and a cyclic group other than the heterocyclic ring may be condensed. Examples of the heterocyclic group in which the heterocyclic group and other cyclic group other than the heterocyclic ring are condensed include, for example, an isobenzofuranyl group, a benzoxazolyl group, a benzoisoxazolyl group, a benzothiazolyl group, a benzo Isothiazolyl group, chromenyl group, chromanonyl group, xanthenyl group, phenoxathiinyl group, indolizinyl group, isoindolidinyl group, indolyl group, indazolyl group, purinyl group, quinolidinyl group, isoquinolyl group, quinolyl group, phthalazinyl group, Examples thereof include a naphthyridinyl group, a quinoxalinyl group, a quinazolinyl group, a carbazolyl group, a carbolinyl group, an acridinyl group, and an isoindolinyl group.
　「分枝鎖のＣ３－６アルキル基」とは、炭素数３～６個の分枝鎖状のアルキル基を意味する。分枝鎖のＣ３－６アルキル基として、例えば、イソプロピル基、イソブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基、イソペンチル基、ネオペンチル基、ｔｅｒｔ－ペンチル基、１－メチルブチル基、２－メチルブチル基、１，２－ジメチルプロピル基、１－エチルプロピル基、イソヘキシル基等が挙げられる。好ましくは、イソプロピル基、イソブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基、１－エチルプロピル基等が挙げられる。 The “branched C 3-6 alkyl group” means a branched alkyl group having 3 to 6 carbon atoms. Examples of branched C 3-6 alkyl groups include, for example, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group 1,2-dimethylpropyl group, 1-ethylpropyl group, isohexyl group and the like. Preferred are isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, 1-ethylpropyl group and the like.
　「５員環の芳香族複素環基」とは、酸素原子、窒素原子および硫黄原子から選択される１～４個のヘテロ原子を環内に含む５員環の芳香族基を意味する。５員環の芳香族複素環基として、例えば、フリル基、ピロリル基、チエニル基、イミダゾリル基、ピラゾリル基、１，２，４－トリアゾリル基、イソチアゾリル基、イソオキサゾリル基、オキサゾリル基、チアゾリル基、１，３，４－オキサジアゾリル基、１，２，４－オキサジアゾリル基等が挙げられる。 The “5-membered aromatic heterocyclic group” means a 5-membered aromatic group containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom in the ring. Examples of 5-membered aromatic heterocyclic groups include furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1 , 3,4-oxadiazolyl group, 1,2,4-oxadiazolyl group and the like.
　「６員環の芳香族複素環基」とは、１～４個の窒素原子を環内に含む６員環の芳香族基を意味する。６員環の芳香族複素環基として、例えば、ピリジル基、ピリミジル基、ピラジニル基、ピリダジニル基等が挙げられる。 “6-membered aromatic heterocyclic group” means a 6-membered aromatic group containing 1 to 4 nitrogen atoms in the ring. Examples of the 6-membered aromatic heterocyclic group include a pyridyl group, a pyrimidyl group, a pyrazinyl group, and a pyridazinyl group.
　「非置換またはＣ１－６アルキル基およびＣ１－６アルキレンジオキシ基からなる群から独立して選択される１～３個の基で環が置換される４～７員の環状アミノ基」としては、例えば以下にその構造を示す環状アミノ基からなる群から選ばれる基等が挙げられる。 “Unsubstituted or 4- to 7-membered cyclic amino group in which the ring is substituted with 1 to 3 groups independently selected from the group consisting of a C 1-6 alkyl group and a C 1-6 alkylenedioxy group” Examples thereof include groups selected from the group consisting of cyclic amino groups having the following structures.
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
　「酸性５員ヘテロ環基」とは、酸性プロトンと結合している窒素原子を環内に含む５員環、またはフェノール性水酸基を有する５員環の含窒素ヘテロ環を意味する。酸性５員ヘテロ環基として、例えば、以下にその構造を示す５員環の含窒素ヘテロ環基からなる群から選択される基が挙げられる。 The “acidic 5-membered heterocyclic group” means a 5-membered ring containing a nitrogen atom bonded to an acidic proton in the ring or a 5-membered nitrogen-containing heterocyclic ring having a phenolic hydroxyl group. Examples of the acidic 5-membered heterocyclic group include groups selected from the group consisting of 5-membered nitrogen-containing heterocyclic groups having the following structures.
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
　好ましくは、以下にその構造を示す５員環の含窒素ヘテロ環基からなる群から選択される基が挙げられる。 Preferably, a group selected from the group consisting of a 5-membered nitrogen-containing heterocyclic group having the structure shown below is exemplified.
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
　更に好ましくは、以下にその構造を示す５－テトラゾリル基である。 More preferably, it is a 5-tetrazolyl group whose structure is shown below.
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
　「６員の脂肪族環状アミノ基で置換されるＣ１－６アルキル基」とは、モルホリノ基またはピペリジノ基で置換された炭素数１～６の直鎖の又は分枝鎖のアルキル基を意味する。６員の脂肪族環状アミノ基で置換されるＣ１－６アルキル基として、例えば、モルホリノメチル基、ピペリジノエチル基、１－モルホリノエチル基、１－ピペリジノエチル基、２－モルホリノエチル基、２－ピペリジノエチル基等が挙げられる。 “C 1-6 alkyl group substituted by a 6-membered aliphatic cyclic amino group” means a linear or branched alkyl group having 1 to 6 carbon atoms and substituted by a morpholino group or piperidino group. To do. Examples of the C 1-6 alkyl group substituted with a 6-membered aliphatic cyclic amino group include, for example, morpholinomethyl group, piperidinoethyl group, 1-morpholinoethyl group, 1-piperidinoethyl group, 2-morpholinoethyl group, 2-piperidinoethyl group Etc.
　本実施形態の化合物（Ｉ）またはその薬理学的に許容される塩において、好ましい置換基は次の通りである。 In the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof, preferred substituents are as follows.
　Ｙ１およびＹ２を含み、Ｒ２、Ｒ３、Ｒ４、Ｒ５およびＹ３が結合するベンゼン環縮合含窒素５員複素環は、好ましくは、以下のａ）、ｂ）およびｄ）からなる群から選択される環である。 The benzene ring condensed nitrogen-containing 5-membered heterocyclic ring containing Y 1 and Y 2 and to which R 2 , R 3 , R 4 , R 5 and Y 3 are bonded is preferably from the following a), b) and d): A ring selected from the group consisting of
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
　当該ベンゼン環縮合含窒素５員複素環として、更に好ましくは以下のａ）として表される環である。 The benzene ring condensed nitrogen-containing 5-membered heterocyclic ring is more preferably a ring represented by the following a).
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
　Ａとして、好ましくは、Ｗ１がＣＨまたは窒素原子であるｅ）として表される基、Ｗ２が酸素原子または硫黄原子であるｆ）として表される基、ｈ）として表される基、およびＷ３およびＷ４の一方が窒素原子であり、他方がＣＨまたは窒素原子であるｉ）として表される基である。なお、Ａがｅ）、ｆ）、ｈ）またはｉ）として表される基である場合に、Ｒａは前述と同義であり、好ましくは水素原子またはＣ１－６アルキル基である。
　Ａとして更に好ましくは、以下のｅ１）、ｆ１）、ｈ）およびｉ１）からなる群から選択される基である。Ａがｅ１）、ｆ１）、ｈ）またはｉ１）として表される基であるとき、Ｒａは好ましくは水素原子またはＣ１－６アルキル基である。 As A, preferably a group represented by e) wherein W 1 is CH or a nitrogen atom, a group represented by f) wherein W 2 is an oxygen atom or a sulfur atom, a group represented by h), and One of W 3 and W 4 is a nitrogen atom, and the other is a group represented by i), which is CH or a nitrogen atom. When A is a group represented by e), f), h) or i), R a is as defined above, and is preferably a hydrogen atom or a C 1-6 alkyl group.
More preferably, A is a group selected from the group consisting of the following e1), f1), h) and i1). When A is a group represented as e1), f1), h) or i1), R a is preferably a hydrogen atom or a C 1-6 alkyl group.
Figure JPOXMLDOC01-appb-C000022
（＊）を付された結合はＹ３と結合し、（＊＊）を付された結合はＲ１と結合することを表す。
Figure JPOXMLDOC01-appb-C000022
The bond marked with (*) bonded to Y 3, represents a bond with (**) attached to bond R 1.
　Ｒａが結合するＡに関し、より更に好ましくはＲａがＣ１－６アルキル基であるe１）として表される基、Ｒａが水素原子であるe１）として表される基、Ｒａが水素原子であるｆ１）として表される基、Ｒａが水素原子であるｈ）として表される基、Ｒａが水素原子であるi１）として表される基である。
　Ｒａが結合するＡに関し、一層更に好ましくはＲａがＣ１－６アルキル基であるe１）として表される基、Ｒａが水素原子であるｆ１）として表される基、Ｒａが水素原子であるi１）として表される基である。
　Ｒａが結合するＡに関し、特に好ましくは、ＲａがＣ１－６アルキル基であるe１）として表される基、Ｒａが水素原子であるｆ１）として表される基である。 Relates A which R a is attached, even more preferably a group R a is represented as e1) a C 1-6 alkyl group, a group R a is represented as e1) a hydrogen atom, R a is hydrogen group represented by an atom f1), a group a group R a is represented as h) is a hydrogen atom, R a is represented as i1) a hydrogen atom.
With respect to A to which R a is bonded, even more preferably, R a is a group represented by e1) wherein R 1 is a C 1-6 alkyl group, R a is a group represented by f1) wherein H is a hydrogen atom, R a is hydrogen It is a group represented as i1) which is an atom.
With respect to A to which R a is bonded, particularly preferred are a group represented by e1) in which R a is a C 1-6 alkyl group and a group represented by f1) in which R a is a hydrogen atom.
　Ｙ３は、好ましくはメチレンなどのＣ１－６アルキレン、－Ｏ－または－Ｓ－であり、更に好ましくはＣ１－６アルキレンであり、特に好ましくはメチレンである。 Y 3 is preferably C 1-6 alkylene such as methylene, —O— or —S—, more preferably C 1-6 alkylene, and particularly preferably methylene.
　Ｒ１は、好ましくは－Ｃ（＝Ｏ）－ＯＺ１、－Ｃ（＝Ｏ）－ＮＨＳＯ２Ｚ２又は酸性５員ヘテロ環基であり、更に好ましくは、Ｒ１は－Ｃ（＝Ｏ）－ＯＺ１、－Ｃ（＝Ｏ）－ＮＨＳＯ２Ｚ２又はテトラゾリル基である。さらにまた、Ｒ１が－Ｃ（＝Ｏ）－ＯＺ１である場合に、Ｚ１は水素原子またはＣ１－６アルキル基であり、Ｒ１が－Ｃ（＝Ｏ）－ＮＨＳＯ２Ｚ２である場合に、Ｚ２はＣ１－６アルキル基であることが好ましい。 R 1 is preferably —C (═O) —OZ 1 , —C (═O) —NHSO 2 Z 2 or an acidic 5-membered heterocyclic group, and more preferably R 1 is —C (═O). —OZ 1 , —C (═O) —NHSO 2 Z 2 or a tetrazolyl group. Furthermore, when R 1 is —C (═O) —OZ 1 , Z 1 is a hydrogen atom or a C 1-6 alkyl group, and R 1 is —C (═O) —NHSO 2 Z 2 In some cases, Z 2 is preferably a C 1-6 alkyl group.
　Ｒ２は、好ましくは、Ｃ１－６アルキル基、非置換または１つのＣ１－６アルキル基で環が置換されるＣ３－６シクロアルキル基、Ｃ２－６アルケニル基、Ｃ５－８シクロアルケニル基、非置換または独立した１～５個のハロゲン原子で環が置換されるフェニル基、６員環の芳香族複素環基、Ｃ１－６アルキル基およびＣ２－６アルケニル基からなる群から独立して選択される１個または２個の基で置換されるアミノ基、あるいは非置換または独立した１～３個のＣ１－６アルキル基で環が置換される４～７員の環状アミノ基である。
　Ｒ２として、更に好ましくは分枝鎖のＣ３－６アルキル基、非置換または１つのＣ１－６アルキル基で環が置換されるＣ３－６シクロアルキル基、Ｃ２－６アルケニル基、Ｃ５－８シクロアルケニル基、フェニル基、ピリジル基、独立した２個のＣ１－６アルキルで置換されるアミノ基、４～７員の環状アミノ基である。
　Ｒ２として、より更に好ましくは、１つのＣ１－６アルキル基で環が置換されるＣ３－６シクロアルキル基、Ｃ２－６アルケニル基、Ｃ５－８シクロアルケニル基、独立した２個のＣ１－６アルキル基で置換されるアミノ基、４～７員の環状アミノ基である。
　Ｒ２として、特に好ましくは、ビニル基、２－プロペニル基、１－イソブテニル基、１－シクロペンテニル基、１－メチルシクロプロピル基、ジメチルアミノ基、メチル（エチル）アミノ基、ジエチルアミノ基、エチル（ｎ－プロピル）アミノ基、ジ（ｎ－プロピル）アミノ基、フェニル基、ピリジル基、ピロリジン－１－イル基、ピペリジン－１－イル基、モルホリン－４－イル基、チオモルホリン－４－イル基、３，６－ジヒドロピリジン－１（２Ｈ）－イル基である。 R 2 is preferably a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 2-6 alkenyl group, C 5-8 , which is unsubstituted or substituted with one C 1-6 alkyl group. It consists of a cycloalkenyl group, a phenyl group that is unsubstituted or independently substituted with 1 to 5 halogen atoms, a 6-membered aromatic heterocyclic group, a C 1-6 alkyl group, and a C 2-6 alkenyl group. An amino group substituted with one or two groups independently selected from the group, or a 4-7 membered ring substituted with unsubstituted or independent 1-3 C 1-6 alkyl groups It is a cyclic amino group.
As R 2, more preferably C 3-6 branched alkyl, unsubstituted or one C 1-6 alkyl group a C 3-6 cycloalkyl group which ring is substituted, C 2-6 alkenyl group, A C 5-8 cycloalkenyl group, a phenyl group, a pyridyl group, an amino group substituted with two independent C 1-6 alkyls, and a 4- to 7-membered cyclic amino group.
R 2 is more preferably a C 3-6 cycloalkyl group, a C 2-6 alkenyl group, a C 5-8 cycloalkenyl group in which the ring is substituted with one C 1-6 alkyl group, two independent groups An amino group substituted with a C 1-6 alkyl group of 4 to 7-membered cyclic amino group.
R 2 is particularly preferably a vinyl group, 2-propenyl group, 1-isobutenyl group, 1-cyclopentenyl group, 1-methylcyclopropyl group, dimethylamino group, methyl (ethyl) amino group, diethylamino group, ethyl ( n-propyl) amino group, di (n-propyl) amino group, phenyl group, pyridyl group, pyrrolidin-1-yl group, piperidin-1-yl group, morpholin-4-yl group, thiomorpholin-4-yl group 3,6-dihydropyridin-1 (2H) -yl group.
　Ｒ３は、好ましくは、水素原子、ハロゲン原子、シアノ基、Ｃ２－８アルケニル基、Ｃ１－７アルカノイル基、非置換または１もしくは２個のＣ１－６アルキル基で置換されるアミノ基、Ｃ１－６アルコキシ基、ハロＣ１－６アルコキシ基、５員環の芳香族複素環基である。
　Ｒ３として更に好ましくは、水素原子、ハロゲン原子、Ｃ２－８アルケニル基、Ｃ１－７アルカノイル基、２個のＣ１－６アルキル基で置換されるアミノ基、Ｃ１－６アルコキシ基、ハロＣ１－６アルコキシ基である。
　Ｒ３としてより更に好ましくは、水素原子、フッ素原子、塩素原子、臭素原子、シアノ基、ビニル基、２－プロペニル基、アセチル基、ジメチルアミノ基、メトキシ基、トリフルオロメトキシ基である。 R 3 is preferably a hydrogen atom, a halogen atom, a cyano group, a C 2-8 alkenyl group, a C 1-7 alkanoyl group, an amino group which is unsubstituted or substituted with 1 or 2 C 1-6 alkyl groups , C 1-6 alkoxy group, halo C 1-6 alkoxy group, 5-membered aromatic heterocyclic group.
More preferably, R 3 is a hydrogen atom, a halogen atom, a C 2-8 alkenyl group, a C 1-7 alkanoyl group, an amino group substituted with two C 1-6 alkyl groups, a C 1-6 alkoxy group, A halo C 1-6 alkoxy group;
R 3 is more preferably a hydrogen atom, fluorine atom, chlorine atom, bromine atom, cyano group, vinyl group, 2-propenyl group, acetyl group, dimethylamino group, methoxy group or trifluoromethoxy group.
　Ｒ４は、好ましくは水素原子、ハロゲン原子であり、更に好ましくは水素原子である。 R 4 is preferably a hydrogen atom or a halogen atom, and more preferably a hydrogen atom.
　Ｒ５は、好ましくは水素原子、ハロゲン原子であり、更に好ましくは水素原子である。 R 5 is preferably a hydrogen atom or a halogen atom, more preferably a hydrogen atom.
　本実施形態の好ましい化合物として、例えば、
１－［（６－クロロ－２－フェニルベンゾ［ｄ］オキサゾール－４－イル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［（５－クロロ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－エチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－（プロパン－１－イル）－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－（プロパン－２－イル）－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－（２－メチルプロパン－１－イル）－１Ｈ－ピラゾール－３－カルボン酸、
１－［（６－クロロ－２－フェニルベンゾ［ｄ］チアゾール－４－イル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［（５－クロロ－２－フェニルベンゾ［ｄ］チアゾール－４－イル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
５－メチル－１－［（２－フェニルベンゾ［ｄ］チアゾール－４－イル）メチル］－１Ｈ－ピラゾール－３－カルボン酸、
１－［（７－クロロ－２－フェニルベンゾ［ｄ］チアゾール－４－イル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
５－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］フラン－２－カルボン酸、
５－［（５－クロロ－２－フェニルベンゾ［ｄ］オキサゾール－７－イル）メチル］フラン－２－カルボン酸、
５－［［５－クロロ－２－（４－クロロフェニル）ベンゾ［ｄ］オキサゾール－７－イル］メチル］フラン－２－カルボン酸、
１－［［５－クロロ－２－（３－クロロフェニル）ベンゾ［ｄ］オキサゾール－７－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［５－クロロ－２－（２－クロロフェニル）ベンゾ［ｄ］オキサゾール－７－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－フルオロベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－フルオロ－２－（ピペリジン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－フルオロ－２－（モルホリン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－フルオロ－２－（ピロリジン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（ジメチルアミノ）－６－フルオロベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（ジエチルアミノ）－６－フルオロベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
６－［［６－ブロモ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［６－ブロモ－２－（モルホリン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［６－ブロモ－２－（ジメチルアミノ）ベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［６－ブロモ－２－（ジエチルアミノ）ベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
１－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－（トリフルオロメトキシ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（ジメチルアミノ）－６－（トリフルオロメトキシ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（ジエチルアミノ）－６－（トリフルオロメトキシ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
５－メチル－１－［［２－（ピペリジン－１－イル）－６－（トリフルオロメトキシ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－１Ｈ－ピラゾール－３－カルボン酸、
５－メチル－１－［［２－（ピロリジン－１－イル）－６－（トリフルオロメトキシ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－１Ｈ－ピラゾール－３－カルボン酸、
５－メチル－１－［［２－（モルホリン－４－イル）－６－（トリフルオロメトキシ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（２，５－ジヒドロ－１Ｈ－ピロール－１－イル）－６－（トリフルオロメトキシ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（ジメチルアミノ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（ジエチルアミノ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［［２－エチル（プロピル）アミノ］ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（ジプロピルアミノ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（ジアリルアミノ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（アゼチジン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
５－メチル－１－［［２－（ピロリジン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－１Ｈ－ピラゾール－３－カルボン酸、
５－メチル－１－［［２－（ピペリジン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（アゼパン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（２，５－ジヒドロ－１Ｈ－ピロール－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
５－メチル－１－［［２－（モルホリン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（ｃｉｓ－２，６－ジメチルモルホリン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
５－メチル－１－［［２－（４－メチルピペラジン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－１Ｈ－ピラゾール－３－カルボン酸、
５－メチル－１－［［２－（チオモルホリン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（１，４－ジオキサ－８－アザスピロ［４，５］デカン－８－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－ブロモ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（ピペリジン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（モルホリン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（ピロリジン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（４－メチルピペラジン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（ジメチルアミノ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（チオモルホリン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（ジエチルアミノ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（アゼパン－１－イル）－６－クロロベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（アゼチジン－１－イル）－６－クロロベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（ｃｉｓ－２，６－ジメチルモルホリン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（１Ｈ－ピラゾール－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－［エチル（プロピル）アミノ］ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（ジアリルアミノ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（２，５－ジヒドロ－１Ｈ－ピロール－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（５－メチル－３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（３，４－ジメチル－５，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（４－メチル－３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－メトキシベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（ジメチルアミノ）－６－メトキシベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（ジエチルアミノ）－６－メトキシベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（エチル（プロピル）アミノ）－６－メトキソベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
６－［［６－クロロ－２－（ジメチルアミノ）ベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［６－クロロ－２－（ジエチルアミノ）ベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［６－クロロ－２－（ピロリジン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［６－クロロ－２－（ピペリジン－1－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［６－クロロ－２－（モルホリン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［６－クロロ－２－（チオモルホリン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［２－（アゼパン－１－イル）－６－クロロベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［６－クロロ－２－［エチル（プロピル）アミノ］ベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［６－クロロ－２－（ｃｉｓ－２，６－ジメチルモルホリン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－メトキシベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［２－（ジメチルアミノ）－６－フルオロベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［２－（ジエチルアミノ）－６－フルオロベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［２－［エチル（プロピル）アミノ］－６－フルオロベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［２－（アゼチジン－１－イル）－６－フルオロベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［６－フルオロ－２－（ピロリジン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［６－フルオロ－２－（ピペリジン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［２－（アゼパン－１－イル）－６－フルオロベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［２－（２，５－ジヒドロ－１Ｈ－ピロール－１－イル）－６－フルオロベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－フルオロベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［６－フルオロ－２－（モルホリン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［６－フルオロ－２－（チオモルホリン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
５－メチル－１－［［２－（１－プロペン－２－イル）－６－（トリフルオロメトキシ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（１－シクロヘキセン－１－イル）－６－（トリフルオロメトキシ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
５－メチル－１－［［２－（１－プロペン－２－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（２－メチル－１－プロペン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（１－シクロペンテン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（１－シクロヘキセン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（１－シクロヘプテン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（２－クロロフェニル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（３－クロロフェニル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（４－クロロフェニル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－［３－（ベンジルオキシ）フェニル］－６－クロロベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（ピリジン－３－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（ピリジン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－［２－（ベンジルオキシ）フェニル］－６－クロロベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（１－シクロヘキセン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（フェニルエチル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
（Ｅ）－１－［［６－クロロ－２－（１－ヘキセン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（１－プロペン－２－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（２－メチル－１－プロペン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（１－シクロペンテン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（１－シクロヘプテン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（３，６－ジヒドロ－２Ｈ－チオピラン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－メトキシ－２－（１－プロペン－２－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（１－シクロヘキセン－１－イル）－６－メトキシベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［（６－メトキシ－２－フェニルベンゾ［ｄ］チアゾール－４－イル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
６－［［６－クロロ－２－（１－プロペン－２－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［６－クロロ－２－（１－シクロペンテン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［６－クロロ－２－（１-シクロヘキセン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［６－クロロ－２－（１－シクロヘプテン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［６－フルオロ－２－（１－プロペン－２－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［［２－（１－シクロヘキセン－１－イル）－６－フルオロベンゾ［ｄ］チアゾール－４－イル］メチル］ピリジン－２－カルボン酸、
６－［（６－フルオロ－２－フェニルベンゾ［ｄ］チアゾール－４－イル）メチル］ピリジン－２－カルボン酸、
５－メチル－１－［［２－（モルホリン－４－イル）－６－フェニルベンゾ［ｄ］チアゾール－４－イル］メチル］－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－（２－メトキシフェニル）－２－（モルホリン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－（３－メトキシフェニル）－２－（モルホリン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－（４－メトキシフェニル）－２－（モルホリン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－（３－メチルフェニル）－２－（モルホリン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－（４－メチルフェニル）－２－（モルホリン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－（２－フルオロフェニル）－２－（モルホリン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－（３－フルオロフェニル）－２－（モルホリン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－（４－フルオロフェニル）－２－（モルホリン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－フェニルベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－（フラン－２－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－（フラン－３－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－（チオフェン－２－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－（チオフェン－３－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－ビニルベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－（１－プロペン－２－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
（Ｅ）－１－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－（１－ヘキセン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
（Ｅ）－１－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－（１－オクテン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－（１－ヘキセン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－メチルベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－アセチル－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
４－［（３－カルボキシ－５－メチル－１Ｈ－ピラゾール－１－イル）メチル］－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－６－カルボン酸、
１－［［６－シアノ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－アミノ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－（メチルアミノ）－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－（ジメチルアミノ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［［６－クロロ－２－（プロパン－２－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［（６－クロロ－２－シクロヘキシルベンゾ［ｄ］チアゾール－４－イル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
１－［（６－クロロ－２－シクロプロピルベンゾ［ｄ］チアゾール－４－イル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
６－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］オキシ］ピリジン－２－カルボン酸、
５－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］オキシ］フラン－２－カルボン酸、
６－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］アミノ］ピリジン－２－カルボン酸、
５－［（ｔｅｒｔ－ブトキシカルボニル）［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］アミノ］フラン－２－カルボン酸、
６－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］チオ］ピリジン－２－カルボン酸、
５－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］チオ］フラン－２－カルボン酸、
３－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］安息香酸、
１－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］オキサゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
６－クロロ－４－［［５－メチル－３－（１Ｈ－テトラゾール－５－イル）－１Ｈ－ピラゾール－１－イル］メチル］－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール、
３－［１－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－イル］－１、２，４－オキサジアゾール－５（４Ｈ）－チオン、
４－［１－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－イル］－３Ｈ－１，２，３，５－オキサチアジアゾール－２－オキシド、または
１－［（５－クロロ－２－（１－メチルシクロプロピル）ベンゾ［ｄ］チアゾール－４－イル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸等が例示できる。 As a preferable compound of this embodiment, for example,
1-[(6-chloro-2-phenylbenzo [d] oxazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[(5-chloro-2-phenylbenzo [d] oxazol-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-ethyl-1H-pyrazole-3-carboxylic acid,
1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5- (propan-1-yl) -1H-pyrazole -3-carboxylic acid,
1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5- (propan-2-yl) -1H-pyrazole -3-carboxylic acid,
1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5- (2-methylpropan-1-yl)- 1H-pyrazole-3-carboxylic acid,
1-[(6-chloro-2-phenylbenzo [d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[(5-chloro-2-phenylbenzo [d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
5-methyl-1-[(2-phenylbenzo [d] thiazol-4-yl) methyl] -1H-pyrazole-3-carboxylic acid,
1-[(7-chloro-2-phenylbenzo [d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
5-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] furan-2-carboxylic acid,
5-[(5-chloro-2-phenylbenzo [d] oxazol-7-yl) methyl] furan-2-carboxylic acid,
5-[[5-chloro-2- (4-chlorophenyl) benzo [d] oxazol-7-yl] methyl] furan-2-carboxylic acid,
1-[[5-chloro-2- (3-chlorophenyl) benzo [d] oxazol-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[5-chloro-2- (2-chlorophenyl) benzo [d] oxazol-7-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (3,6-dihydropyridin-1 (2H) -yl) -6-fluorobenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-fluoro-2- (piperidin-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-fluoro-2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-Fluoro-2- (pyrrolidin-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (dimethylamino) -6-fluorobenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (diethylamino) -6-fluorobenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
6-[[6-Bromo-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[6-Bromo-2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[6-Bromo-2- (dimethylamino) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[6-Bromo-2- (diethylamino) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6- (trifluoromethoxy) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3 -carboxylic acid,
1-[[2- (dimethylamino) -6- (trifluoromethoxy) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (diethylamino) -6- (trifluoromethoxy) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
5-methyl-1-[[2- (piperidin-1-yl) -6- (trifluoromethoxy) benzo [d] thiazol-4-yl] methyl] -1H-pyrazole-3-carboxylic acid,
5-methyl-1-[[2- (pyrrolidin-1-yl) -6- (trifluoromethoxy) benzo [d] thiazol-4-yl] methyl] -1H-pyrazole-3-carboxylic acid,
5-methyl-1-[[2- (morpholin-4-yl) -6- (trifluoromethoxy) benzo [d] thiazol-4-yl] methyl] -1H-pyrazole-3-carboxylic acid,
1-[[2- (2,5-Dihydro-1H-pyrrol-1-yl) -6- (trifluoromethoxy) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole- 3-carboxylic acid,
1-[[2- (dimethylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (diethylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[[2-ethyl (propyl) amino] benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (dipropylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (diallylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (azetidin-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
5-methyl-1-[[2- (pyrrolidin-1-yl) benzo [d] thiazol-4-yl] methyl] -1H-pyrazole-3-carboxylic acid,
5-methyl-1-[[2- (piperidin-1-yl) benzo [d] thiazol-4-yl] methyl] -1H-pyrazole-3-carboxylic acid,
1-[[2- (azepan-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (2,5-dihydro-1H-pyrrol-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
5-methyl-1-[[2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -1H-pyrazole-3-carboxylic acid,
1-[[2- (cis-2,6-dimethylmorpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
5-methyl-1-[[2- (4-methylpiperazin-1-yl) benzo [d] thiazol-4-yl] methyl] -1H-pyrazole-3-carboxylic acid,
5-methyl-1-[[2- (thiomorpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -1H-pyrazole-3-carboxylic acid,
1-[[2- (1,4-Dioxa-8-azaspiro [4,5] decan-8-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3- carboxylic acid,
1-[[6-bromo-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (piperidin-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (pyrrolidin-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (4-methylpiperazin-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (dimethylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (thiomorpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (diethylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (azepan-1-yl) -6-chlorobenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (azetidin-1-yl) -6-chlorobenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (cis-2,6-dimethylmorpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (1H-pyrazol-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- [ethyl (propyl) amino] benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (diallylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-Chloro-2- (2,5-dihydro-1H-pyrrol-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid ,
1-[[6-Chloro-2- (5-methyl-3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3 -carboxylic acid,
1-[[6-Chloro-2- (3,4-dimethyl-5,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole -3-carboxylic acid,
1-[[6-Chloro-2- (4-methyl-3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3 -carboxylic acid,
1-[[2- (3,6-dihydropyridin-1 (2H) -yl) -6-methoxybenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (dimethylamino) -6-methoxybenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (diethylamino) -6-methoxybenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (ethyl (propyl) amino) -6-methoxobenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
6-[[6-chloro-2- (dimethylamino) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[6-chloro-2- (diethylamino) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[6-chloro-2- (pyrrolidin-1-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[6-chloro-2- (piperidin-1-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[6-chloro-2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[6-chloro-2- (thiomorpholin-4-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[2- (azepan-1-yl) -6-chlorobenzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[6-chloro-2- [ethyl (propyl) amino] benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[6-chloro-2- (cis-2,6-dimethylmorpholin-4-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[2- (3,6-dihydropyridin-1 (2H) -yl) -6-methoxybenzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[2- (dimethylamino) -6-fluorobenzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[2- (diethylamino) -6-fluorobenzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[2- [ethyl (propyl) amino] -6-fluorobenzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[2- (azetidin-1-yl) -6-fluorobenzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[6-Fluoro-2- (pyrrolidin-1-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[6-Fluoro-2- (piperidin-1-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[2- (azepan-1-yl) -6-fluorobenzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[2- (2,5-dihydro-1H-pyrrol-1-yl) -6-fluorobenzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[2- (3,6-dihydropyridin-1 (2H) -yl) -6-fluorobenzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[6-Fluoro-2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[6-Fluoro-2- (thiomorpholin-4-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
5-methyl-1-[[2- (1-propen-2-yl) -6- (trifluoromethoxy) benzo [d] thiazol-4-yl] methyl] -1H-pyrazole-3-carboxylic acid,
1-[[2- (1-cyclohexen-1-yl) -6- (trifluoromethoxy) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
5-methyl-1-[[2- (1-propen-2-yl) benzo [d] thiazol-4-yl] methyl] -1H-pyrazole-3-carboxylic acid,
1-[[2- (2-Methyl-1-propen-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (1-cyclopenten-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (1-cyclohexen-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (1-cyclohepten-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (2-chlorophenyl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (3-chlorophenyl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (4-chlorophenyl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- [3- (benzyloxy) phenyl] -6-chlorobenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (pyridin-3-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (pyridin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- [2- (benzyloxy) phenyl] -6-chlorobenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (1-cyclohexen-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (phenylethyl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
(E) -1-[[6-Chloro-2- (1-hexen-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (1-propen-2-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (2-methyl-1-propen-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (1-cyclopenten-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-chloro-2- (1-cyclohepten-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-Chloro-2- (3,6-dihydro-2H-thiopyran-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid ,
1-[[6-methoxy-2- (1-propen-2-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (1-cyclohexen-1-yl) -6-methoxybenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[(6-methoxy-2-phenylbenzo [d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
6-[[6-chloro-2- (1-propen-2-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[6-chloro-2- (1-cyclopenten-1-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[6-chloro-2- (1-cyclohexen-1-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[6-chloro-2- (1-cyclohepten-1-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[6-Fluoro-2- (1-propen-2-yl) benzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[[2- (1-cyclohexen-1-yl) -6-fluorobenzo [d] thiazol-4-yl] methyl] pyridine-2-carboxylic acid,
6-[(6-Fluoro-2-phenylbenzo [d] thiazol-4-yl) methyl] pyridine-2-carboxylic acid,
5-methyl-1-[[2- (morpholin-4-yl) -6-phenylbenzo [d] thiazol-4-yl] methyl] -1H-pyrazole-3-carboxylic acid,
1-[[6- (2-methoxyphenyl) -2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6- (3-methoxyphenyl) -2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6- (4-methoxyphenyl) -2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6- (3-methylphenyl) -2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6- (4-methylphenyl) -2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6- (2-fluorophenyl) -2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6- (3-fluorophenyl) -2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6- (4-fluorophenyl) -2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (3,6-dihydropyridin-1 (2H) -yl) -6-phenylbenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6- (furan-2-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole -3-carboxylic acid,
1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6- (furan-3-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole -3-carboxylic acid,
1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6- (thiophen-2-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole -3-carboxylic acid,
1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6- (thiophen-3-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole -3-carboxylic acid,
1-[[2- (3,6-dihydropyridin-1 (2H) -yl) -6-vinylbenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6- (1-propen-2-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H -Pyrazole-3-carboxylic acid,
(E) -1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6- (1-hexen-1-yl) benzo [d] thiazol-4-yl] methyl] -5 -Methyl-1H-pyrazole-3-carboxylic acid,
(E) -1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6- (1-octen-1-yl) benzo [d] thiazol-4-yl] methyl] -5 -Methyl-1H-pyrazole-3-carboxylic acid,
1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6- (1-hexen-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H -Pyrazole-3-carboxylic acid,
1-[[2- (3,6-dihydropyridin-1 (2H) -yl) -6-methylbenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-acetyl-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
4-[(3-carboxy-5-methyl-1H-pyrazol-1-yl) methyl] -2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazole-6-carboxylic acid,
1-[[6-cyano-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6-amino-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[[6- (Methylamino) -2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3- carboxylic acid,
1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6- (dimethylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3- carboxylic acid,
1-[[6-chloro-2- (propan-2-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[(6-chloro-2-cyclohexylbenzo [d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
1-[(6-chloro-2-cyclopropylbenzo [d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
6-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] oxy] pyridine-2-carboxylic acid,
5-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] oxy] furan-2-carboxylic acid,
6-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] amino] pyridine-2-carboxylic acid,
5-[(tert-butoxycarbonyl) [6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] amino] furan-2-carboxylic acid,
6-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] thio] pyridine-2-carboxylic acid,
5-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] thio] furan-2-carboxylic acid,
3-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] benzoic acid,
1-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] oxazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
6-Chloro-4-[[5-methyl-3- (1H-tetrazol-5-yl) -1H-pyrazol-1-yl] methyl] -2- (3,6-dihydropyridin-1 (2H) -yl ) Benzo [d] thiazole,
3- [1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3- Yl] -1,2,4-oxadiazole-5 (4H) -thione,
4- [1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3- Yl] -3H-1,2,3,5-oxathiadiazole-2-oxide, or 1-[(5-chloro-2- (1-methylcyclopropyl) benzo [d] thiazol-4-yl) methyl] Examples include -5-methyl-1H-pyrazole-3-carboxylic acid.
　化合物（Ｉ）の薬理学的に許容される塩とは、化合物（Ｉ）と薬学上許容な非毒性塩基又は酸（例えば無機又は有機塩基及び無機又は有機酸）との塩を意味する。薬学上許容な化合物（Ｉ）の非毒性塩基から誘導される塩としては、アルミニウム、アンモニウム、カルシウム、銅、第一鉄、第二鉄、リチウム、マグネシウム、マンガン、亜マンガン酸、カリウム及びナトリウム等の無機塩基との塩（特に好ましくは、アンモニウム、カルシウム、マンガン、カリウム及びナトリウム塩が挙げられる。）、又は、第一、第二、第三アミン、置換アミン（例えば天然に存在する置換アミン）、環状アミン並びに塩基性イオン交換樹脂等の有機塩基（例えば、アルギニン、ベタイン、カフェイン、コリン、Ｎ，Ｎ’－ジベンジルエチレンジアミン、ジエチルアミン、２－ジエチルアミノエタノール、２－ジメチルアミノエタノール、エタノールアミン、エチレンジアミン、Ｎ－エチルモルホリン、Ｎ－エチルピペリジン、グルカミン、グルコサミン、ヒスチジン、ヒドラバミン、イソプロピルアミン、リジン、メチルグルカミン、モルホリン、ピペラジン、ピペリジン、ポリアミン樹脂、プロカイン、プリン、テオブロミン、トリエチルアミン、トリメチルアミン、トリプロピルアミン、トロメタミン等）と化合物（Ｉ）との塩が例示できる。
　化合物（Ｉ）の薬学上許容な非毒性酸から誘導される塩としては、例えば、塩酸、臭化水素酸、硫酸、硝酸等の無機酸、又は酢酸、マレイン酸、フマル酸、コハク酸、乳酸、リンゴ酸、酒石酸、クエン酸、メタンスルホン酸、ｐ－トルエンスルホン酸、サリチル酸、ステアリン酸、パルミチン酸等の有機酸との塩が例示できる。 The pharmacologically acceptable salt of Compound (I) means a salt of Compound (I) with a pharmaceutically acceptable non-toxic base or acid (for example, an inorganic or organic base and an inorganic or organic acid). Salts derived from non-toxic bases of pharmaceutically acceptable compounds (I) include aluminum, ammonium, calcium, copper, ferrous, ferric, lithium, magnesium, manganese, manganite, potassium and sodium, etc. Salts with inorganic bases (particularly preferred are ammonium, calcium, manganese, potassium and sodium salts) or primary, secondary, tertiary amines, substituted amines (eg naturally occurring substituted amines) Organic bases such as cyclic amines and basic ion exchange resins (for example, arginine, betaine, caffeine, choline, N, N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, Ethylenediamine, N-ethylmorpholine, N-ethylpipe Lysine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, tripropylamine, tripropylamine, tromethamine, etc.) and compound (I) And a salt thereof.
Examples of the salt derived from a pharmaceutically acceptable non-toxic acid of compound (I) include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid, or acetic acid, maleic acid, fumaric acid, succinic acid and lactic acid. And salts with organic acids such as malic acid, tartaric acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid and palmitic acid.
　さらに本実施形態の化合物（Ｉ）またはその薬理学的に許容される塩は、水和物又は溶媒和物として存在することもある。上記に具体的に記載した好ましい化合物を含めて、前記一般式（Ｉ）で表されるベンゼン環縮合含窒素5員複素環式化合物又はその塩が形成する任意の水和物及び溶媒和物は、いずれも本発明の範囲に包含される。溶媒和物を形成し得る溶媒としては、メタノール、エタノール、２－プロパノール、アセトン、酢酸エチル、ジクロロメタン、ジイソプロピルエーテル等が挙げられる。 Furthermore, the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof may exist as a hydrate or a solvate. Arbitrary hydrates and solvates formed by the benzene ring condensed nitrogen-containing 5-membered heterocyclic compound represented by the general formula (I) or a salt thereof including the preferred compounds specifically described above are: These are all included in the scope of the present invention. Solvents that can form solvates include methanol, ethanol, 2-propanol, acetone, ethyl acetate, dichloromethane, diisopropyl ether, and the like.
　また、本実施形態の化合物（Ｉ）またはその薬理学的に許容される塩には、ラセミ体の他に光学活性体、立体異性体又は回転異性体が存在することもある。また、本実施形態の化合物（Ｉ）またはその薬理学的に許容される塩には、プロトン互変異性体が存在することもある。これら光学活性体、立体異性体および回転異性体もまた、本発明の範囲に包含される。 In addition, the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof may have an optically active substance, a stereoisomer, or a rotational isomer in addition to the racemate. In addition, the compound (I) of the present embodiment or a pharmaceutically acceptable salt thereof may have a proton tautomer. These optically active isomers, stereoisomers and rotational isomers are also included in the scope of the present invention.
　本明細書において、「ＥＰ１受容体拮抗作用」とは、プロスタグランジンＥ２（ＰＧＥ２）のプロスタグランジンＥ受容体１（ＥＰ１受容体）への結合を阻害する作用を意味する。 In the present specification, “EP 1 receptor antagonism” means an action of inhibiting the binding of prostaglandin E 2 (PGE 2 ) to prostaglandin E receptor 1 (EP 1 receptor).
　ＥＰ１受容体拮抗作用は、細胞内へのカルシウム流入量を減少させ、細胞内カルシウム濃度を低下または抑制させる。この結果、ＥＰ１受容体拮抗作用により、平滑筋弛緩および知覚神経刺激抑制作用等の作用が誘導される。特に、ＥＰ１受容体拮抗作用が、膀胱、尿路上皮等において生じることにより、ＬＵＴＳ、中でもＯＡＢｓ等の症状の治療または予防に有用である。 EP 1 receptor antagonism decreases the amount of calcium inflow into the cell and decreases or suppresses the intracellular calcium concentration. As a result, effects such as smooth muscle relaxation and sensory nerve stimulation inhibitory action are induced by the EP 1 receptor antagonistic action. In particular, EP 1 receptor antagonism, bladder, causing the urothelium like, LUTS, useful in the treatment or prevention of symptoms among others OABs like.
　また、ＥＰ１受容体拮抗作用は、ＰＧＥ２のＥＰ１受容体に対する刺激作用による細胞内へのカルシウム流入を阻害する効力によって評価できる。この効力は、特開２００８－２１４２２４号記載の「薬理試験例」に準ずるｉｎ　ｖｉｔｒｏ試験またはｉｎ　ｖｉｖｏ試験によって評価することができる。 Further, the EP 1 receptor antagonism can be evaluated by the potency of inhibiting calcium influx into cells due to the stimulating action of PGE 2 on the EP 1 receptor. This efficacy can be evaluated by an in vitro test or an in vivo test according to “Pharmacological Test Examples” described in JP-A-2008-214224.
　本実施形態の化合物（Ｉ）は、種々の合成法によって製造することができる。次に、本実施形態の化合物（Ｉ）の代表的な製造法について説明する。 Compound (I) of the present embodiment can be produced by various synthesis methods. Next, a typical production method of the compound (I) of this embodiment will be described.
（Ａ法）
　化合物（Ｉ）のうち、以下に示す化合物（Ｉa）および化合物（Ｉb）は、例えば以下で説明するＡ法によって製造することができる。 (Method A)
Among the compounds (I), the following compounds (Ia) and (Ib) can be produced, for example, by Method A described below.
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
式中、Ｙ１、Ｙ２、Ｒ２、Ｒ３、Ｒ４、Ｒ５およびＡは前記と同義であり；Ｌ１は塩素原子、臭素原子、ヨウ素原子、メタンスルホニルオキシ基等を示し；Ｑ１はＣ１－６アルキル基またはＣ７－１０アラルキル基を示す。 In the formula, Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 and A are as defined above; L 1 represents a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group or the like; 1 represents a C 1-6 alkyl group or a C 7-10 aralkyl group.
工程１－１
　本工程は、化合物（１）と化合物（２）とを反応させて化合物（Ｉａ）を製造する工程である。化合物（Ｉａ）は、例えば、溶媒中、化合物（１）と化合物（２）とを塩基存在下で反応させることにより製造することができる。溶媒としては、Ｎ，Ｎ－ジメチルホルムアミド、テトラヒドロフラン、１，４－ジオキサン、それらの混合溶媒等を挙げることができる。反応温度は、通常－７８℃～溶媒還流温度で実施でき、０℃～３０℃で行うのが好ましい。用いる塩基としては、水素化ナトリウム、炭酸カリウム、炭酸ナトリウム等の無機塩基、或いはトリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、ピリジン等の有機塩基を用いることができる。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。 Step 1-1
This step is a step for producing compound (Ia) by reacting compound (1) with compound (2). Compound (Ia) can be produced, for example, by reacting compound (1) and compound (2) in the presence of a base in a solvent. Examples of the solvent include N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, a mixed solvent thereof and the like. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature, preferably 0 ° C. to 30 ° C. As the base to be used, an inorganic base such as sodium hydride, potassium carbonate or sodium carbonate, or an organic base such as triethylamine, N, N-diisopropylethylamine or pyridine can be used. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
工程１－２
　本工程は、化合物（Ｉａ）のエステル部位を加水分解することにより、化合物（Ｉｂ）を製造する工程である。化合物（Ｉｂ）は、例えば、溶媒中、化合物（Ｉａ）を塩基と反応させることにより製造することができる。溶媒としては、テトラヒドロフラン、１，４－ジオキサン、ジエチルエーテル、メタノール、エタノール、プロパノール、２－プロパノール、ブタノール、水、それらの混合溶媒等を挙げることができる。反応温度は、通常０℃～溶媒還流温度で実施できる。用いる塩基としては、例えば、水酸化カリウム、水酸化ナトリウム等のアルカリ金属塩を挙げることができる。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。
　なお、化合物（２）は、市販品を用いることができるほか、その他文献記載の方法またはそれらに準じた方法に従って製造することもできる。
　また、化合物（１）は、例えば、下記ａ法、ｂ法、ｃ法、ｄ法、ｅ法、ｆ法のいずれかの方法により得られる。 Step 1-2
This step is a step of producing compound (Ib) by hydrolyzing the ester moiety of compound (Ia). Compound (Ib) can be produced, for example, by reacting compound (Ia) with a base in a solvent. Examples of the solvent include tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, propanol, 2-propanol, butanol, water, a mixed solvent thereof and the like. The reaction temperature is usually 0 ° C. to solvent reflux temperature. Examples of the base used include alkali metal salts such as potassium hydroxide and sodium hydroxide. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
Compound (2) can be a commercially available product, or can be produced according to other methods described in the literature or a method analogous thereto.
Compound (1) can be obtained, for example, by any one of the following methods a, b, c, d, e, and f.
（ａ法） (Method a)
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
式中、Ｒ２、Ｒ３、Ｒ４、Ｒ５およびＬ１は前記と同義であり；Ｌ２は塩素原子、臭素原子等を示す。 In the formula, R 2 , R 3 , R 4 , R 5 and L 1 are as defined above; L 2 represents a chlorine atom, a bromine atom or the like.
工程１ａ－１
　本工程は、化合物（３）と化合物（４）との縮合反応により、化合物（５）を製造する工程である。化合物（５）は、例えば、溶媒中、塩基存在下又は非存在下において、化合物（３）と化合物（４）とを反応させることにより製造することができる。溶媒としては、Ｎ，Ｎ－ジメチルホルムアミド、ジクロロメタン、１，４－ジオキサン、テトラヒドロフラン、それらの混合溶媒等を挙げることができる。用いる塩基としては、炭酸カリウム、炭酸ナトリウム、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン等を用いることができる。反応温度は、通常－７８℃～溶媒還流温度で実施でき、０℃～２０℃で行うのが好ましい。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。また、本工程で用いられる化合物（３）および化合物（４）は、市販品を用いることができるほか、その他文献記載の方法またはそれらに準じた方法に従って製造することもできる。 Step 1a-1
This step is a step of producing compound (5) by a condensation reaction between compound (3) and compound (4). Compound (5) can be produced, for example, by reacting compound (3) with compound (4) in a solvent in the presence or absence of a base. Examples of the solvent include N, N-dimethylformamide, dichloromethane, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like. As the base to be used, potassium carbonate, sodium carbonate, triethylamine, N, N-diisopropylethylamine or the like can be used. The reaction temperature is usually from −78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 20 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days. Moreover, the compound (3) and compound (4) used at this process can use a commercial item, and can also manufacture them according to the method of other literature description, or the method according to them.
工程１ａ－２
　本工程は、化合物（５）から、化合物（６）を製造する工程である。化合物（６）は、例えば、溶媒中、化合物（５）とローソン試薬等の硫黄源となる化合物とを反応させることにより製造することができる。溶媒としては、トルエン、ジクロロメタン、Ｎ，Ｎ－ジメチルホルムアミド、１，４－ジオキサン、テトラヒドロフラン、それらの混合溶媒等を挙げることができる。反応温度は、通常－７８℃～溶媒還流温度で実施でき、２０～１５０℃で行うのが好ましい。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。 Step 1a-2
This step is a step of producing compound (6) from compound (5). Compound (6) can be produced, for example, by reacting compound (5) with a compound serving as a sulfur source such as Lawesson's reagent in a solvent. Examples of the solvent include toluene, dichloromethane, N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like. The reaction temperature is usually from −78 ° C. to the solvent reflux temperature, preferably 20 to 150 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
工程１ａ－３
　本工程は、化合物（６）から、化合物（７）を製造する工程である。化合物（７）は、例えば、溶媒中、化合物（６）を塩基存在下で環化させることにより製造することができる。溶媒としては、Ｎ，Ｎ－ジメチルホルムアミド、１，４－ジオキサン、テトラヒドロフラン、メタノール、エタノール、２－プロパノール、それらの混合溶媒等を挙げることができる。用いる塩基としては、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（ＤＢＵ）、１，５－ジアザビシクロ［４．３．０］ノナ－５－エン（ＤＢＮ）、炭酸カリウム、炭酸ナトリウム、炭酸セシウム、酢酸ナトリウム等を用いることができる。反応温度は、通常－７８℃～溶媒還流温度で実施でき、２０℃～１００℃で行うのが好ましい。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。 Step 1a-3
This step is a step of producing compound (7) from compound (6). Compound (7) can be produced, for example, by cyclizing compound (6) in the presence of a base in a solvent. Examples of the solvent include N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, 2-propanol, a mixed solvent thereof and the like. Examples of the base used include 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), potassium carbonate, Sodium carbonate, cesium carbonate, sodium acetate and the like can be used. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature, preferably 20 ° C. to 100 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
工程１ａ－４
　本工程は、化合物（７）から、化合物（１）のうち、上記の構造を有する化合物（１ａ）を製造する工程である。化合物（１ａ）は、例えばＬ１が臭素原子の場合、溶媒中、化合物（７）をＮ－ブロモスクシンイミドで臭素化することにより製造することができる。本反応において、過酸化ベンゾイル、アゾビスイソブチロニトリル等をラジカル開始剤として添加することができる。溶媒としては、四塩化炭素、クロロホルム、ジクロロメタン、Ｎ，Ｎ－ジメチルホルムアミド、１，４－ジオキサン、テトラヒドロフラン、メタノール、エタノール、２－プロパノール、それらの混合溶媒等を挙げることができる。反応温度は、通常－７８℃～溶媒還流温度で実施でき、２０℃～１５０℃で行うのが好ましい。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。 Step 1a-4
This step is a step of producing compound (1a) having the above structure among compounds (1) from compound (7). Compound (1a) can be produced, for example, by brominating compound (7) with N-bromosuccinimide in a solvent when L 1 is a bromine atom. In this reaction, benzoyl peroxide, azobisisobutyronitrile and the like can be added as a radical initiator. Examples of the solvent include carbon tetrachloride, chloroform, dichloromethane, N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, 2-propanol, and mixed solvents thereof. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature, preferably 20 ° C. to 150 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
（ｂ法） (Method b)
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
式中、Ｒ２、Ｒ３、Ｒ４、Ｒ５およびＬ１は前記と同義であり；Ｌ３は塩素原子、臭素原子、ヨウ素原子等を示し；Ｌ４は水素原子、Ｂ（ＯＨ）２等を示し、ＱはＮＨ４等を示す。 In the formula, R 2 , R 3 , R 4 , R 5 and L 1 are as defined above; L 3 represents a chlorine atom, a bromine atom, an iodine atom, etc .; L 4 is a hydrogen atom, B (OH) 2 Q represents NH 4 or the like.
工程１ｂ－１
　本工程は、化合物（８）と化合物（９）との反応により、化合物（１０）を製造する工程である。化合物（１０）は、例えば、酢酸溶媒中、化合物（８）と化合物（９）とを臭素存在下で反応させることにより製造することができる。反応温度は、通常－２０℃～溶媒還流温度で実施でき、０℃～２０℃で行うのが好ましい。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。また、本工程で用いられる化合物（８）および化合物（９）は、市販品を用いることができるほか、その他文献記載の方法またはそれらに準じた方法に従って製造することもできる。 Step 1b-1
This step is a step of producing compound (10) by reaction of compound (8) with compound (9). Compound (10) can be produced, for example, by reacting compound (8) and compound (9) in the presence of bromine in an acetic acid solvent. The reaction temperature is usually from −20 ° C. to solvent reflux temperature, preferably 0 ° C. to 20 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days. Moreover, the compound (8) and compound (9) used at this process can use a commercial item, and can also manufacture them according to the method of other literature description, or the method according to them.
工程１ｂ－２
　本工程は、化合物（１０）のアミノ基へｔｅｒｔ－ブトキシカルボニル基を導入することにより、化合物（１１）を製造する工程である。化合物（１１）は、例えば、溶媒中或いは溶媒を用いずに、ジ－ｔｅｒｔ－ブチルジカルボネートと化合物（１０）とを反応させることにより製造することができる。反応に用いる溶媒としては、１，４－ジオキサン、テトラヒドロフラン、メタノール、エタノール、２－プロパノール、Ｎ，Ｎ－ジメチルホルムアミド、それらの混合溶媒等を挙げることができる。また、本反応において塩基を用いる場合、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、ピリジン等を用いることができる。反応温度は、通常－２０℃～溶媒還流温度で実施でき、０℃～１５０℃で行うのが好ましい。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。 Step 1b-2
This step is a step for producing the compound (11) by introducing a tert-butoxycarbonyl group into the amino group of the compound (10). Compound (11) can be produced, for example, by reacting di-tert-butyl dicarbonate with compound (10) in a solvent or without using a solvent. Examples of the solvent used in the reaction include 1,4-dioxane, tetrahydrofuran, methanol, ethanol, 2-propanol, N, N-dimethylformamide, a mixed solvent thereof and the like. Further, when a base is used in this reaction, triethylamine, N, N-diisopropylethylamine, pyridine and the like can be used. The reaction temperature is usually from −20 ° C. to the solvent reflux temperature, preferably 0 ° C. to 150 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
工程１ｂ－３
　本工程は、化合物（１１）の臭素原子をヒドロキシメチル基へ変換して、化合物（１２）を製造する工程である。化合物（１２）は、例えば、溶媒中、化合物（１１）の臭素原子を、リチウム塩やグリニャール試薬等に変換した後、パラホルムアルデヒド等と反応させることにより製造することができる。用いられる溶媒としては、テトラヒドロフラン、ジエチルエーテル、１，２－ジメトキシエタン、１，４－ジオキサン、それらの混合溶媒等を挙げることができる。リチウム塩とするときに用いられる試薬としては、ｎ－ブチルリチウム、ｓｅｃ－ブチルリチウム、リチウムジイソプロピルアミド等を挙げることができる。また、グリニャール試薬とするときに用いられる試薬としては、イソプロピルマグネシウムクロリド、イソプロピルマグネシウムクロリド塩化リチウム錯体、或いは金属マグネシウム等を挙げることが出来る。反応温度は、通常－７８℃～５０℃で実施できる。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。
　また、化合物（１２）は、化合物（１１）のリチウム塩やグリニャール試薬を、Ｎ，Ｎ－ジメチルホルムアミド等で処理してホルミル基を導入した後、得られたホルミル基を有する化合物を溶媒存在下において水素化ホウ素ナトリウム、水素化リチウムアルミニウム、水素化ホウ素リチウム等で還元することにより製造することもできる。用いられる溶媒としては、メタノール、水、エタノール、テトラヒドロフラン、それらの混合溶媒等を挙げることができる。反応温度は、通常－７８℃～溶媒還流温度で実施でき、０℃～１００℃で行うのが好ましい。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。 Step 1b-3
This step is a step for producing a compound (12) by converting a bromine atom of the compound (11) into a hydroxymethyl group. Compound (12) can be produced, for example, by converting the bromine atom of compound (11) into a lithium salt, Grignard reagent or the like in a solvent and then reacting with paraformaldehyde or the like. Examples of the solvent used include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, a mixed solvent thereof and the like. Examples of the reagent used when preparing the lithium salt include n-butyllithium, sec-butyllithium, lithium diisopropylamide and the like. Examples of the reagent used when the Grignard reagent is used include isopropylmagnesium chloride, isopropylmagnesium chloride lithium chloride complex, and metallic magnesium. The reaction temperature can usually be carried out at -78 ° C to 50 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
Compound (12) was prepared by treating a lithium salt of Compound (11) or a Grignard reagent with N, N-dimethylformamide or the like to introduce a formyl group, and then removing the obtained compound having a formyl group in the presence of a solvent. Can also be produced by reduction with sodium borohydride, lithium aluminum hydride, lithium borohydride or the like. Examples of the solvent used include methanol, water, ethanol, tetrahydrofuran, and mixed solvents thereof. The reaction temperature is usually from −78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 100 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
工程１ｂ－４
　本工程は、化合物（１２）のｔｅｒｔ－ブトキシカルボニル基を除去して、化合物（１３）を製造する工程である。化合物（１３）は、例えば、溶媒中或いは溶媒を用いずに、化合物（１２）を適当な酸で処理することにより製造することができる。反応に用いる溶媒としては、ジクロロメタン、１，４－ジオキサン、テトラヒドロフラン、メタノール、エタノール、それらの混合溶媒等を挙げることができる。用いられる酸としては、トリフルオロ酢酸、塩化水素等を用いることができる。反応温度は、通常－２０℃～溶媒還流温度で実施でき、０℃～５０℃で行うのが好ましい。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。 Step 1b-4
This step is a step for producing the compound (13) by removing the tert-butoxycarbonyl group of the compound (12). Compound (13) can be produced, for example, by treating compound (12) with an appropriate acid in a solvent or without using a solvent. Examples of the solvent used for the reaction include dichloromethane, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, a mixed solvent thereof and the like. As the acid used, trifluoroacetic acid, hydrogen chloride and the like can be used. The reaction temperature is usually from −20 ° C. to solvent reflux temperature, preferably 0 ° C. to 50 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
工程１ｂ－５
　本工程は、化合物（１０）の臭素原子をヒドロキシメチル基へ変換して、化合物（１３）を製造する工程である。本工程は、前記ｂ法、工程１ｂ－３に準じて行うことができる。 Step 1b-5
This step is a step for producing a compound (13) by converting a bromine atom of the compound (10) into a hydroxymethyl group. This step can be performed according to the above-mentioned method b and step 1b-3.
工程１ｂ－６
　本工程は、化合物（１３）のアミノ基を適当な脱離基（Ｌ３）に変換して、化合物（１４）を製造する工程である。化合物（１４）は、例えば、Ｌ３がヨウ素原子の場合、溶媒中、酸存在下において、ヨウ化カリウム及び亜硝酸ナトリウム等と化合物（１３）とを反応させることにより製造することができる。反応に用いる溶媒としては、アセトニトリル、水、１，４－ジオキサン、テトラヒドロフラン、メタノール、エタノール、２－プロパノール、Ｎ，Ｎ－ジメチルホルムアミド、酢酸、それらの混合溶媒等を挙げることができる。また、本反応において用いる酸としては、ｐ－トルエンスルホン酸、酢酸、塩酸、トリフルオロ酢酸等を挙げることができる。反応温度は、通常－５０℃～溶媒還流温度で実施でき、－２０℃～１００℃で行うのが好ましい。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。 Step 1b-6
This step is a step for producing a compound (14) by converting the amino group of the compound (13) into an appropriate leaving group (L 3 ). Compound (14) can be produced, for example, by reacting compound (13) with potassium iodide, sodium nitrite and the like in the presence of an acid in a solvent when L 3 is an iodine atom. Examples of the solvent used in the reaction include acetonitrile, water, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, 2-propanol, N, N-dimethylformamide, acetic acid, and mixed solvents thereof. Examples of the acid used in this reaction include p-toluenesulfonic acid, acetic acid, hydrochloric acid, trifluoroacetic acid and the like. The reaction temperature is usually from −50 ° C. to the solvent reflux temperature, preferably from −20 ° C. to 100 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
工程１ｂ－７
　本工程は、化合物（１４）と化合物（１５）を反応させて、Ｌ３をＲ２で置換することにより、化合物（１６）を製造する工程である。化合物（１６）は、求核置換反応により化合物（１４）のＬ３を置換アミノ基であるＲ２で置換することにより製造することができる。本反応は、溶媒中或いは溶媒を用いずに、化合物（１４）と適当な置換アミンである化合物（１５）とを反応させることにより進行する。本反応においては、反応過程で生成する酸を補足するため、過剰量の置換アミンを用いるか、或いは塩基を共存させることができる。用いられる溶媒としては、テトラヒドロフラン、１，４－ジオキサン、ジクロロメタン、１，２－ジクロロエタン、ベンゼン、トルエン、エタノール、プロパノール、Ｎ，Ｎ－ジメチルホルムアミド、ジメチルスルホキシド、水、それらの混合溶媒等を挙げることができる。共存させる塩基としては、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、ピリジン、２，６－ジメチルピリジン、２，４，６－トリメチルピリジン等が挙げられる。反応温度は、通常－７８℃～溶媒還流温度で実施でき、０℃～１５０℃で行うのが好ましい。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。 Step 1b-7
This step is a step for producing a compound (16) by reacting the compound (14) with the compound (15) and substituting L 3 with R 2 . Compound (16) can be produced by replacing L 3 of compound (14) with R 2 which is a substituted amino group by a nucleophilic substitution reaction. This reaction proceeds by reacting compound (14) with compound (15), which is an appropriate substituted amine, in a solvent or without using a solvent. In this reaction, an excess amount of a substituted amine can be used or a base can be allowed to coexist to supplement the acid produced during the reaction. Examples of the solvent used include tetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, ethanol, propanol, N, N-dimethylformamide, dimethyl sulfoxide, water, and mixed solvents thereof. Can do. Examples of the coexisting base include triethylamine, N, N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine and the like. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature, preferably 0 ° C. to 150 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
　また、化合物（１６）は、鈴木カップリング反応により化合物（１４）のＬ３をアリール基であるＲ２で置換することにより製造することができる。本反応は、例えば、化合物（１４）とアリールボロン酸を溶媒中、パラジウム試薬を触媒として、塩基存在下において進行する。用いられる溶媒としては、テトラヒドロフラン、１，４－ジオキサン、ジクロロメタン、１，２－ジクロロエタン、ベンゼン、トルエン、エタノール、プロパノール、Ｎ，Ｎ－ジメチルホルムアミド、ジメチルスルホキシド、水、それらの混合溶媒等を挙げることができる。用いられるパラジウム触媒としては、ジクロロビス（トリフェニルホスフィン）パラジウム（ＩＩ）、テトラキス（トリフェニルホスフィン）パラジウム（０）等が挙げられる。用いられる塩基としては、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム、炭酸セシウム、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、ピリジン、２，６－ジメチルピリジン、２，４，６－トリメチルピリジン等が挙げられる。反応温度は、通常－７８℃～溶媒還流温度で実施でき、０℃～溶媒還流温度で行うのが好ましい。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。 Compound (16) can be produced by replacing L 3 of compound (14) with R 2 which is an aryl group by Suzuki coupling reaction. This reaction proceeds, for example, in the presence of a base using compound (14) and arylboronic acid in a solvent and a palladium reagent as a catalyst. Examples of the solvent used include tetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, ethanol, propanol, N, N-dimethylformamide, dimethyl sulfoxide, water, and mixed solvents thereof. Can do. Examples of the palladium catalyst to be used include dichlorobis (triphenylphosphine) palladium (II), tetrakis (triphenylphosphine) palladium (0), and the like. Examples of the base used include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, triethylamine, N, N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine and the like. Is mentioned. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature, preferably 0 ° C. to solvent reflux temperature. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
工程１ｂ－８
　本工程は、化合物（１６）のヒドロキシル基を適当な脱離基（Ｌ１）に変換して、化合物（１ａ）を製造する工程である。化合物（１ａ）は、例えば、Ｌ１が臭素原子の場合、溶媒中、トリフェニルホスフィン等の存在下において、四臭化炭素と化合物（１６）とを反応させることにより製造することができる。反応に用いる溶媒としては、テトラヒドロフラン、ジクロロメタン、クロロホルム、それらの混合溶媒等を挙げることができる。反応温度は、通常－５０℃～溶媒還流温度で実施でき、０℃～１００℃で行うのが好ましい。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。 Step 1b-8
This step is a step for producing the compound (1a) by converting the hydroxyl group of the compound (16) into an appropriate leaving group (L 1 ). Compound (1a) can be produced, for example, by reacting carbon tetrabromide with compound (16) in the presence of triphenylphosphine or the like in a solvent when L 1 is a bromine atom. Examples of the solvent used for the reaction include tetrahydrofuran, dichloromethane, chloroform, a mixed solvent thereof and the like. The reaction temperature can usually be carried out at −50 ° C. to solvent reflux temperature, preferably 0 ° C. to 100 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
（ｃ法） (Method c)
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
式中、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｌ１およびＬ２は前記と同義である。 In the formula, R 2 , R 3 , R 4 , R 5 , L 1 and L 2 are as defined above.
工程１ｃ－１
　本工程は、化合物（１７）と化合物（４）との縮合反応により、化合物（１８）を製造する工程である。本工程は、前記ａ法、工程１ａ－１に準じて行うことができる。また、本工程で用いられる化合物（１７）は、市販品を用いることができるほか、その他文献記載の方法またはそれらに準じた方法に従って製造することもできる。 Step 1c-1
This step is a step of producing compound (18) by a condensation reaction between compound (17) and compound (4). This step can be performed according to the above-mentioned method a, step 1a-1. Moreover, the compound (17) used at this process can use a commercial item, and can also manufacture it according to the method of other literature description, or the method according to them.
工程１ｃ－２
　本工程は、化合物（１８）から、化合物（１９）を製造する工程である。本工程は、前記ａ法、工程１ａ－２に準じて行うことができる。 Step 1c-2
This step is a step of producing compound (19) from compound (18). This step can be performed according to the above-mentioned method a, step 1a-2.
工程１ｃ－３
　本工程は、化合物（１９）から、化合物（２０）を製造する工程である。本工程は、前記ａ法、工程１ａ－３に準じて行うことができる。 Step 1c-3
This step is a step of producing compound (20) from compound (19). This step can be performed according to the above-mentioned method a, step 1a-3.
工程１ｃ－４
　本工程は、化合物（２０）から、化合物（１）のうち、上記の構造を有する化合物（１ｂ）を製造する工程である。本工程は、前記ａ法、工程１ａ－４に準じて行うことができる。 Step 1c-4
This step is a step of producing compound (1b) having the above structure among compounds (1) from compound (20). This step can be performed according to the above-mentioned method a, step 1a-4.
（ｄ法） (Method d)
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
式中、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｌ１およびＬ２は前記と同義であり；Ｑ２はＣ１－６アルキル基またはＣ７－１０アラルキル基を示す。 In the formula, R 2 , R 3 , R 4 , R 5 , L 1 and L 2 are as defined above; Q 2 represents a C 1-6 alkyl group or a C 7-10 aralkyl group.
工程１ｄ－１
　本工程は、化合物（２１）と化合物（４）との縮合反応により、化合物（２２）を製造する工程である。本工程は、前記ａ法、工程１ａ－１に準じて行うことができる。また、本工程で用いられる化合物（２１）は、市販品を用いることができるほか、その他文献記載の方法またはそれらに準じた方法に従って製造することもできる。 Step 1d-1
This step is a step of producing compound (22) by a condensation reaction between compound (21) and compound (4). This step can be performed according to the above-mentioned method a, step 1a-1. Moreover, the compound (21) used at this process can use a commercial item, and can also manufacture it according to the method of other literature description, or the method according to them.
工程１ｄ－２
　本工程は、化合物（２２）から、化合物（２３）を製造する工程である。本工程は、前記ａ法、工程１ａ－２に準じて行うことができる。 Step 1d-2
This step is a step of producing compound (23) from compound (22). This step can be performed according to the above-mentioned method a, step 1a-2.
工程１ｄ－３
　本工程は、化合物（２３）から、化合物（２４）を製造する工程である。本工程は、前記ａ法、工程１ａ－３に準じて行うことができる。 Step 1d-3
This step is a step of producing compound (24) from compound (23). This step can be performed according to the above-mentioned method a, step 1a-3.
工程１ｄ－４
　本工程は、化合物（２４）から、化合物（２５）を製造する工程である。化合物（２５）は、例えば、溶媒中、化合物（２４）のアルコキシカルボニル基を水素化リチウムアルミニウムや水素化ホウ素リチウム等を用いてヒドロキシメチル基へ還元することにより製造することができる。用いられる溶媒としては、テトラヒドロフラン、ジエチルエーテル、それらの混合溶媒等を挙げることができる。反応温度は、通常－７８℃～溶媒還流温度で実施でき、－２０℃～１００℃で行うのが好ましい。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。 Step 1d-4
This step is a step of producing compound (25) from compound (24). Compound (25) can be produced, for example, by reducing the alkoxycarbonyl group of compound (24) to a hydroxymethyl group using lithium aluminum hydride, lithium borohydride or the like in a solvent. Examples of the solvent used include tetrahydrofuran, diethyl ether, a mixed solvent thereof and the like. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature, and it is preferably carried out at −20 ° C. to 100 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
工程１ｄ－５
　本工程は、化合物（２５）のヒドロキシル基を適当な脱離基（Ｌ１）に変換して、化合物（１ｂ）を製造する工程である。本工程は、前記ｂ法、工程１ｂ－８に準じて行うことができる。 Step 1d-5
This step is a step for producing the compound (1b) by converting the hydroxyl group of the compound (25) into an appropriate leaving group (L 1 ). This step can be performed according to the above-mentioned method b, step 1b-8.
（ｅ法） (Method e)
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
式中、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｌ１、Ｌ２、Ｌ３およびＬ４は前記と同義である。 In the formula, R 2 , R 3 , R 4 , R 5 , L 1 , L 2 , L 3 and L 4 are as defined above.
工程１ｅ－１
　本工程は、化合物（２６）と化合物（４）から、化合物（２７）を製造する工程である。化合物（２７）は、例えば、溶媒中、化合物（２６）と化合物（４）とを前記ａ法、工程１ａ－１に準じて行う縮合反応により得られる環化前駆体を、適当な酸で処理することにより製造することができる。用いられる溶媒としては、キシレン、トルエン、ベンゼン、１，４－ジオキサン、テトラヒドロフラン、それらの混合溶媒等を挙げることができる。本反応において用いる酸としては、ｐ－トルエンスルホン酸、酢酸、塩酸、トリフルオロ酢酸等を挙げることができる。反応温度は、通常－２０℃～溶媒還流温度で実施でき、０℃～２０℃で行うのが好ましい。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。また、本工程で用いられる化合物（２６）は、市販品を用いることができるほか、その他文献記載の方法またはそれらに準じた方法に従って製造することもできる。 Step 1e-1
This step is a step of producing compound (27) from compound (26) and compound (4). Compound (27) is obtained by, for example, treating a cyclization precursor obtained by a condensation reaction of compound (26) and compound (4) in a solvent according to the above method a, step 1a-1 with an appropriate acid. Can be manufactured. Examples of the solvent used include xylene, toluene, benzene, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like. Examples of the acid used in this reaction include p-toluenesulfonic acid, acetic acid, hydrochloric acid, trifluoroacetic acid and the like. The reaction temperature is usually from −20 ° C. to solvent reflux temperature, preferably 0 ° C. to 20 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days. Moreover, the compound (26) used at this process can use a commercial item, and can also manufacture it according to the method of other literature description, or the method according to them.
工程１ｅ－２
　本工程は、化合物（２７）の臭素原子をホルミル基へ変換して、化合物（２８）を製造する工程である。化合物（２８）は、例えば、溶媒中、化合物（２７）の臭素原子を、リチウム塩やグリニャール試薬等に変換した後、Ｎ，Ｎ－ジメチルホルムアミド等のホルミル源となる化合物と反応させることにより製造することができる。用いられる溶媒としては、テトラヒドロフラン、ジエチルエーテル、１，２－ジメトキシエタン、１，４－ジオキサン、それらの混合溶媒等を挙げることができる。リチウム塩とする時に用いられる試薬としては、ｎ－ブチルリチウム、ｓｅｃ－ブチルリチウム、リチウムジイソプロピルアミド等を挙げることができる。また、グリニャール試薬とする時に用いられる試薬としては、イソプロピルマグネシウムクロリド、イソプロピルマグネシウムクロリド塩化リチウム錯体、或いは金属マグネシウム等を挙げることができる。反応温度は、通常－７８℃～５０℃で実施できる。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。 Step 1e-2
This step is a step for producing a compound (28) by converting a bromine atom of the compound (27) into a formyl group. Compound (28) is produced, for example, by converting the bromine atom of compound (27) into a lithium salt, Grignard reagent, or the like in a solvent and then reacting with a compound serving as a formyl source such as N, N-dimethylformamide. can do. Examples of the solvent used include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, a mixed solvent thereof and the like. Examples of the reagent used when preparing the lithium salt include n-butyllithium, sec-butyllithium, lithium diisopropylamide and the like. Examples of the reagent used when the Grignard reagent is used include isopropylmagnesium chloride, isopropylmagnesium chloride lithium chloride complex, and metallic magnesium. The reaction temperature can usually be carried out at -78 ° C to 50 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
工程１ｅ－３
　本工程は、化合物（２８）のホルミル基をヒドロキシメチル基へ変換して、化合物（２９）を製造する工程である。化合物（２９）は、例えば、化合物（２８）を溶媒存在下において水素化ホウ素ナトリウム、水素化リチウムアルミニウム、水素化ホウ素リチウム等で還元することにより製造することができる。用いられる溶媒としては、メタノール、水、エタノール、テトラヒドロフラン、それらの混合溶媒等を挙げることができる。反応温度は、通常－７８℃～溶媒還流温度で実施でき、０℃～１００℃で行うのが好ましい。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。 Step 1e-3
This step is a step for producing a compound (29) by converting a formyl group of the compound (28) into a hydroxymethyl group. Compound (29) can be produced, for example, by reducing compound (28) with sodium borohydride, lithium aluminum hydride, lithium borohydride or the like in the presence of a solvent. Examples of the solvent used include methanol, water, ethanol, tetrahydrofuran, and mixed solvents thereof. The reaction temperature is usually from −78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 100 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
工程１ｅ－４
　本工程は、化合物（２９）のヒドロキシル基を適当な脱離基（Ｌ１）に変換して、化合物（１）のうち、上記の構造を有する化合物（１ｃ）を製造する工程である。本工程は、前記ｂ法、工程１ｂ－８に準じて行うことができる。 Step 1e-4
This step is a step of producing a compound (1c) having the above structure among the compounds (1) by converting the hydroxyl group of the compound (29) into an appropriate leaving group (L 1 ). This step can be performed according to the above-mentioned method b, step 1b-8.
工程１ｅ－５
　本工程は、化合物（２６）から、化合物（３０）を製造する工程である。化合物（３０）は、例えば、溶媒中、化合物（２６）と臭化シアンとの反応により製造することができる。用いられる溶媒としては、エタノール、２－プロパノール、テトラヒドロフラン、１，４－ジオキサン、それらの混合溶媒等を挙げることができる。反応温度は、通常－２０℃～溶媒還流温度で実施でき、０℃～３０℃で行うのが好ましい。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。 Step 1e-5
This step is a step of producing compound (30) from compound (26). Compound (30) can be produced, for example, by reacting compound (26) with cyanogen bromide in a solvent. Examples of the solvent used include ethanol, 2-propanol, tetrahydrofuran, 1,4-dioxane, a mixed solvent thereof and the like. The reaction temperature is usually from −20 ° C. to the solvent reflux temperature, preferably 0 ° C. to 30 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
工程１ｅ－６
　本工程は、化合物（３０）のアミノ基へｔｅｒｔ－ブトキシカルボニル基を導入することにより、化合物（３１）を製造する工程である。本工程は、前記ｂ法、工程１ｂ－２に準じて行うことができる。 Step 1e-6
This step is a step for producing the compound (31) by introducing a tert-butoxycarbonyl group into the amino group of the compound (30). This step can be performed according to the above-mentioned method b and step 1b-2.
工程１ｅ－７
　本工程は、化合物（３１）の臭素原子をホルミル基へ変換して、化合物（３２）を製造する工程である。本工程は、前記ｅ法、工程１ｅ－２に準じて行うことができる。 Step 1e-7
This step is a step for producing a compound (32) by converting a bromine atom of the compound (31) into a formyl group. This step can be performed according to the above-mentioned e method and step 1e-2.
工程１ｅ－８
　本工程は、化合物（３２）のホルミル基をヒドロキシメチル基へ変換して、化合物（３３）を製造する工程である。本工程は、前記ｅ法、工程１ｅ－３に準じて行うことができる。 Step 1e-8
This step is a step for producing a compound (33) by converting a formyl group of the compound (32) into a hydroxymethyl group. This step can be performed according to the above-mentioned e method and step 1e-3.
工程１ｅ－９
　本工程は、化合物（３３）のｔｅｒｔ－ブトキシカルボニル基を除去して生じたアミノ基を適当な脱離基（Ｌ３）に変換して、化合物（３４）を製造する工程である。本工程は、前記ｂ法、工程１ｂ－４および工程１ｂ－６に準じて行うことができる。 Step 1e-9
This step is a step for producing the compound (34) by converting the amino group produced by removing the tert-butoxycarbonyl group of the compound (33) into an appropriate leaving group (L 3 ). This step can be performed according to the above-mentioned method b, step 1b-4 and step 1b-6.
工程１ｅ－１０
　本工程は、化合物（３４）と化合物（１５）とを反応させて、Ｌ３をＲ２で置換することにより、化合物（２９）を製造する工程である。本工程は、前記ｂ法、工程１ｂ－７に準じて行うことができる。 Step 1e-10
This step is a step for producing a compound (29) by reacting the compound (34) with the compound (15) and substituting L 3 with R 2 . This step can be carried out according to the above-mentioned method b, step 1b-7.
（ｆ法） (Method f)
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
式中、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｌ１、Ｌ２およびＱ２は前記と同義である。 In the formula, R 2 , R 3 , R 4 , R 5 , L 1 , L 2 and Q 2 are as defined above.
工程１ｆ－１
　本工程は、化合物（３５）と化合物（４）から、化合物（３６）を製造する工程である。本工程は、前記ｅ法、工程１ｅ－１に準じて行うことができる。また、本工程で用いられる化合物（３５）は、市販品を用いることができるほか、その他文献記載の方法またはそれらに準じた方法に従って製造することもできる。 Step 1f-1
This step is a step of producing compound (36) from compound (35) and compound (4). This step can be carried out according to the above-mentioned e method and step 1e-1. Moreover, the compound (35) used at this process can use a commercial item, and can also manufacture it according to the method of other literature description, or the method according to them.
工程１ｆ－２
　本工程は、化合物（３６）から、化合物（３７）を製造する工程である。本工程は、前記ｄ法、工程１ｄ－４に準じて行うことができる。 Step 1f-2
This step is a step of producing compound (37) from compound (36). This step can be carried out according to the above-mentioned method d, step 1d-4.
工程１ｆ－３
　本工程は、化合物（３７）のヒドロキシル基を適当な脱離基（Ｌ１）に変換して、化合物（１）のうち、上記の構造を有する化合物（１ｄ）を製造する工程である。本工程は、
前記ｂ法、工程１ｂ－８に準じて行うことができる。 Step 1f-3
This step is a step of producing a compound (1d) having the above structure among the compounds (1) by converting the hydroxyl group of the compound (37) into an appropriate leaving group (L 1 ). This process
It can be carried out according to the above-mentioned method b, step 1b-8.
（Ｂ法）
　化合物（Ｉ）のうち、以下に示す化合物（Ｉｃ）および化合物（Ｉｄ）は、例えば以下で説明するＢ法によって製造することができる。 (Method B)
Of compound (I), compound (Ic) and compound (Id) shown below can be produced, for example, by Method B described below.
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
式中、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｌ１、Ｌ３、Ｌ４、Ｑ、Ｑ１、Ｑ２およびＡは前記と同義であり；Ｌ５は臭素原子、ヨウ素原子、ＺｎＢｒ、ＺｎＣｌ等を示し；Ｌ６は臭素原子、ヨウ素原子等を示す。 In the formula, R 2 , R 3 , R 4 , R 5 , L 1 , L 3 , L 4 , Q, Q 1 , Q 2 and A are as defined above; L 5 is a bromine atom, an iodine atom, ZnBr , ZnCl and the like; L 6 represents a bromine atom, an iodine atom and the like.
工程２－１
　本工程は、化合物（８）と化合物（９）との反応により、化合物（１０）を製造する工程である。本工程は、前記ｂ法、工程１ｂ－１に準じて行うことができる。 Step 2-1
This step is a step of producing compound (10) by reaction of compound (8) with compound (9). This step can be performed according to the above-mentioned method b and step 1b-1.
工程２－２
　本工程は、化合物（１０）のアミノ基へｔｅｒｔ－ブトキシカルボニル基を導入することにより、化合物（１１）を製造する工程である。本工程は、前記ｂ法、工程１ｂ－２に準じて行うことができる。 Step 2-2
This step is a step for producing the compound (11) by introducing a tert-butoxycarbonyl group into the amino group of the compound (10). This step can be performed according to the above-mentioned method b and step 1b-2.
工程２－３ａ
　本工程は、化合物（１１）と化合物（３８）とのカップリング反応により、化合物（３９）を製造する工程である。化合物（３９）は、例えば、溶媒中、化合物（１１）の臭素原子を、リチウム塩やグリニャール試薬等に変換した後、化合物（３８）と反応させることにより製造することができる。用いられる溶媒としては、テトラヒドロフラン、ジエチルエーテル、１，２－ジメトキシエタン、１，４－ジオキサン、それらの混合溶媒等を挙げることができる。リチウム塩とする時に用いられる試薬としては、ｎ－ブチルリチウム、ｓｅｃ－ブチルリチウム、リチウムジイソプロピルアミド等を挙げることができる。また、グリニャール試薬とする時に用いられる試薬としては、イソプロピルマグネシウムクロリド、イソプロピルマグネシウムクロリド塩化リチウム錯体、或いは金属マグネシウム等を挙げることができる。反応温度は、通常－７８℃～５０℃で実施でき、－２０℃～５０℃で行うのが好ましい。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。 Step 2-3a
This step is a step for producing a compound (39) by a coupling reaction of the compound (11) and the compound (38). Compound (39) can be produced, for example, by converting the bromine atom of compound (11) into a lithium salt, Grignard reagent, or the like in a solvent and then reacting with compound (38). Examples of the solvent used include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, a mixed solvent thereof and the like. Examples of the reagent used when preparing the lithium salt include n-butyllithium, sec-butyllithium, lithium diisopropylamide and the like. Examples of the reagent used when the Grignard reagent is used include isopropylmagnesium chloride, isopropylmagnesium chloride lithium chloride complex, and metallic magnesium. The reaction temperature can usually be −78 ° C. to 50 ° C., preferably −20 ° C. to 50 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
工程２－３ｂ
　本工程は、化合物（３９）のヒドロキシ基を水素原子に置換することにより、化合物（４０）を製造する工程である。化合物（４０）は、例えば、溶媒中あるいは無溶媒において、三臭化リンを化合物（３９）に作用させることにより製造することができる。用いられる溶媒としては、例えば、クロロホルム等を挙げることができる。反応温度は、通常－７８℃～溶媒還流温度で実施でき、０℃～１００℃で行うのが好ましい。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。 Step 2-3b
This step is a step for producing the compound (40) by replacing the hydroxy group of the compound (39) with a hydrogen atom. Compound (40) can be produced, for example, by reacting phosphorus tribromide with compound (39) in a solvent or in the absence of a solvent. Examples of the solvent used include chloroform. The reaction temperature is usually from −78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 100 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
工程２－３ｃ
　本工程は、化合物（１１）と化合物（４１）とのカップリング反応により、化合物（４０）を製造する工程である。化合物（４０）は、例えば、溶媒中、化合物（１１）と化合物（４１）との根岸カップリング反応等を利用することにより製造することができる。用いられる溶媒としては、テトラヒドロフラン、Ｎ，Ｎ－ジメチルホルムアミド、ジメチルスルホキシド、ジエチルエーテル、１，２－ジメトキシエタン、１，４－ジオキサン、それらの混合溶媒等を挙げることができる。反応温度は、通常－７８℃～溶媒還流温度で実施でき、０℃～５０℃で行うのが好ましい。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。 Step 2-3c
This step is a step of producing compound (40) by a coupling reaction between compound (11) and compound (41). Compound (40) can be produced, for example, by utilizing a Negishi coupling reaction between compound (11) and compound (41) in a solvent. Examples of the solvent used include tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, a mixed solvent thereof and the like. The reaction temperature is usually from −78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 50 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
工程２－３ｄ
　本工程は、化合物（１１）と化合物（４２）とから、化合物（４３）を製造する工程である。化合物（４３）は、例えば、溶媒中、化合物（１１）の臭素原子を、前記ｂ法、工程１ｂ－３に準じてリチウム塩やグリニャール試薬等に変換したものを、化合物（４２）と反応させた後、得られた化合物を適当な酸で処理することにより製造することができる。用いられる溶媒としては、テトラヒドロフラン、ジエチルエーテル、１，２－ジメトキシエタン、１，４－ジオキサン、それらの混合溶媒等を挙げることができる。用いられる酸としては、塩酸等が挙げられる。反応温度は、通常－７８℃～５０℃で実施できる。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。 Step 2-3d
This step is a step of producing compound (43) from compound (11) and compound (42). Compound (43) is obtained by, for example, reacting a compound obtained by converting the bromine atom of compound (11) into a lithium salt or a Grignard reagent or the like according to the aforementioned method b, step 1b-3 in a solvent and reacting with compound (42). Thereafter, the obtained compound can be produced by treating with an appropriate acid. Examples of the solvent used include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, a mixed solvent thereof and the like. Examples of the acid used include hydrochloric acid. The reaction temperature can usually be carried out at -78 ° C to 50 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
工程２－３ｅ
  本工程は、化合物（４３）と化合物（４４）との鈴木カップリング反応により、化合物（４０）を製造する工程である。化合物（４０）は、例えば、化合物（４３）と化合物（４４）とを溶媒中、パラジウム試薬を触媒として、塩基存在下において反応させることにより製造することができる。用いられる溶媒としては、テトラヒドロフラン、Ｎ，Ｎ－ジメチルホルムアミド、ジメチルスルホキシド、１，４－ジオキサン、ジクロロメタン、１，２－ジクロロエタン、ベンゼン、トルエン、それらの混合溶媒等を挙げることができる。用いられるパラジウム触媒としては、ジクロロビス（トリフェニルホスフィン）パラジウム（ＩＩ）、テトラキス（トリフェニルホスフィン）パラジウム（０）等が挙げられる。用いられる塩基としては、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、ピリジン、２，６－ジメチルピリジン、２，４，６－トリメチルピリジン等が挙げられる。また、リガンドとして、２，２’－ビス（ジフェニルホスフィノ）－１，１’－ビナフチル（ＢＩＮＡＰ）、２－ジシクロヘキシルホスフィノ－２’，６’－ジメトキシビフェニル（ＳＰｈｏｓ）、２－ジシクロヘキシルホスフィノ－２’，４’，６’－トリイソプロピルビフェニル（ＸＰｈｏｓ）等を用いることができる。反応温度は、通常－７８℃～溶媒還流温度で実施でき、０℃～２０℃で行うのが好ましい。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。 Step 2-3e
This step is a step for producing compound (40) by Suzuki coupling reaction of compound (43) and compound (44). Compound (40) can be produced, for example, by reacting compound (43) and compound (44) in a solvent and using a palladium reagent as a catalyst in the presence of a base. Examples of the solvent used include tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, a mixed solvent thereof and the like. Examples of the palladium catalyst to be used include dichlorobis (triphenylphosphine) palladium (II), tetrakis (triphenylphosphine) palladium (0), and the like. Examples of the base used include triethylamine, N, N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine and the like. As ligands, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (SPhos), 2-dicyclohexylphosphino -2 ', 4', 6'-triisopropylbiphenyl (XPhos) and the like can be used. The reaction temperature is usually from −78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 20 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
工程２－３ｆ
　本工程は、化合物（１１）の臭素原子をヒドロキシメチル基へ変換して、化合物（１２）を製造する工程である。本工程は、前記ｂ法、工程１ｂ－３に準じて行うことができる。 Step 2-3f
This step is a step for producing a compound (12) by converting a bromine atom of the compound (11) into a hydroxymethyl group. This step can be performed according to the above-mentioned method b and step 1b-3.
工程２－３ｇ
　本工程は、化合物（１２）のヒドロキシル基を適当な脱離基（Ｌ１）に変換して、化合物（４５）を製造する工程である。本工程は、前記ｂ法、工程１ｂ－８に準じて行うことができる。 Process 2-3g
This step is a step for producing a compound (45) by converting the hydroxyl group of the compound (12) into an appropriate leaving group (L 1 ). This step can be performed according to the above-mentioned method b, step 1b-8.
工程２－３ｈ
　本工程は、化合物（４５）と化合物（２）とを反応させて化合物（４０）を製造する工程である。本工程は、前記Ａ法、工程１－１に準じて行うことができる。 Step 2-3h
This step is a step of producing compound (40) by reacting compound (45) with compound (2). This step can be performed according to the above-mentioned method A, step 1-1.
工程２－４
　本工程は、化合物（４０）のｔｅｒｔ－ブトキシカルボニル基を除去して、化合物（４６）を製造する工程である。本工程は、前記ｂ法、工程１ｂ－４に準じて行うことができる。 Step 2-4
This step is a step for producing the compound (46) by removing the tert-butoxycarbonyl group of the compound (40). This step can be performed according to the above-mentioned method b and step 1b-4.
工程２－５
　本工程は、化合物（１０）と化合物（３８）とのカップリング反応により、化合物（４７）を製造する工程である。本工程は、前記Ｂ法、工程２－３ａに準じて行うことができる。 Step 2-5
This step is a step of producing compound (47) by a coupling reaction between compound (10) and compound (38). This step can be performed according to the above-mentioned method B, step 2-3a.
工程２－６
　本工程は、化合物（４７）のヒドロキシ基を水素原子に置換することにより、化合物（４６）を製造する工程である。本工程は、前記Ｂ法、工程２－３ｂに準じて行うことができる。 Step 2-6
This step is a step for producing the compound (46) by replacing the hydroxy group of the compound (47) with a hydrogen atom. This step can be performed according to the above-mentioned Method B and Step 2-3b.
工程２－７
　本工程は、化合物（４６）のアミノ基を適当な脱離基（Ｌ３）に変換して、化合物（４８）を製造する工程である。本工程は、前記ｂ法、工程１ｂ－６に準じて行うことができる。 Step 2-7
This step is a step for producing the compound (48) by converting the amino group of the compound (46) into an appropriate leaving group (L 3 ). This step can be performed according to the above-mentioned method b, step 1b-6.
工程２－８
　本工程は、化合物（４８）と化合物（１５）とを反応させて、Ｌ３をＲ２で置換することにより、化合物（Ｉｃ）を製造する工程である。本工程は、前記ｂ法、工程１ｂ－７に準じて行うことができる。 Step 2-8
This step is a step for producing compound (Ic) by reacting compound (48) with compound (15) and substituting L 3 with R 2 . This step can be carried out according to the above-mentioned method b, step 1b-7.
工程２－９
　本工程は、化合物（Ｉｃ）のエステル部位を加水分解することにより、化合物（Ｉｄ）を製造する工程である。本工程は、前記Ａ法、工程１－２に準じて行うことができる。 Step 2-9
This step is a step of producing compound (Id) by hydrolyzing the ester moiety of compound (Ic). This step can be performed according to the above-mentioned Method A, Step 1-2.
（Ｃ法）
　化合物（Ｉ）のうち、以下に示す化合物（Ｉｆ）および化合物（Ｉｇ）は、例えば以下で説明するＣ法によって製造することができる。 (Method C)
Of the compound (I), the following compound (If) and compound (Ig) can be produced, for example, by Method C described below.
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
式中、Ｙ１、Ｙ２、Ｒ２、Ｒ４、Ｒ５、ＡおよびＱ１は前記と同義であり；Ｑ３およびＱ４は水素原子、Ｃ１－６アルキル基（互いに結合して環を形成していてもよい）等であり；Ｒ３ａはＣ１－６アルキル基、Ｃ２－６アルケニル基、Ｃ１－７アルカノイル基、シアノ基等を示す。 In the formula, Y 1 , Y 2 , R 2 , R 4 , R 5 , A and Q 1 are as defined above; Q 3 and Q 4 are a hydrogen atom and a C 1-6 alkyl group (bonded together to form a ring R 3a represents a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 1-7 alkanoyl group, a cyano group, or the like.
工程３－１
　本工程は、化合物（Ｉｅ）の臭素原子をＲ３ａで置換することにより、化合物（Ｉｆ）を製造する工程である。化合物（Ｉｆ）は、例えば、化合物（Ｉｅ）と化合物（４９）とを溶媒中、パラジウム試薬を触媒として、塩基存在下において反応させることにより製造することができる。用いられる溶媒としては、テトラヒドロフラン、１，４－ジオキサン、ジクロロメタン、１，２－ジクロロエタン、ベンゼン、トルエン、エタノール、プロパノール、Ｎ，Ｎ－ジメチルホルムアミド、ジメチルスルホキシド、水、それらの混合溶媒等を挙げることができる。用いられるパラジウム触媒としては、ジクロロビス（トリフェニルホスフィン）パラジウム（ＩＩ）、テトラキス（トリフェニルホスフィン）パラジウム（０）等が挙げられる。用いられる塩基としては、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム、炭酸セシウム、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、ピリジン、２，６－ジメチルピリジン、２，４，６－トリメチルピリジン等が挙げられる。また、リガンドとして、２，２’－ビス（ジフェニルホスフィノ）－１，１’－ビナフチル（ＢＩＮＡＰ）、２－ジシクロヘキシルホスフィノ－２’，６’－ジメトキシビフェニル（ＳＰｈｏｓ）、２－ジシクロヘキシルホスフィノ－２’，４’，６’－トリイソプロピルビフェニル（ＸＰｈｏｓ）等を用いることができる。反応温度は、通常－７８℃～溶媒還流温度で実施でき、０℃～１００℃で行うのが好ましい。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。なお、化合物（Ｉｅ）は、前記Ａ法またはＢ法に従って製造することができる。 Step 3-1
This step is a step of producing compound (If) by substituting the bromine atom of compound (Ie) with R 3a . Compound (If) can be produced, for example, by reacting compound (Ie) with compound (49) in a solvent and using a palladium reagent as a catalyst in the presence of a base. Examples of the solvent used include tetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, ethanol, propanol, N, N-dimethylformamide, dimethyl sulfoxide, water, and mixed solvents thereof. Can do. Examples of the palladium catalyst to be used include dichlorobis (triphenylphosphine) palladium (II), tetrakis (triphenylphosphine) palladium (0), and the like. Examples of the base used include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, triethylamine, N, N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine and the like. Is mentioned. As ligands, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (SPhos), 2-dicyclohexylphosphino -2 ', 4', 6'-triisopropylbiphenyl (XPhos) and the like can be used. The reaction temperature is usually from −78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 100 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days. Compound (Ie) can be produced according to Method A or Method B.
工程３－２
　本工程は、化合物（Ｉｆ）のエステル部位を加水分解することにより、化合物（Ｉｇ）を製造する工程である。本工程は、前記Ａ法、工程１－２に準じて行うことができる。 Step 3-2
This step is a step of producing compound (Ig) by hydrolyzing the ester moiety of compound (If). This step can be performed according to the above-mentioned Method A, Step 1-2.
（Ｄ法）
　化合物（Ｉ）のうち、以下に示す化合物（Ｉｈ）は、例えば以下で説明するＤ法によって製造することができる。 (Method D)
Among the compounds (I), the following compound (Ih) can be produced, for example, by Method D described below.
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
式中、Ｙ１、Ｙ２、Ｒ２、Ｒ３、Ｒ４、Ｒ５、ＡおよびＺ２は前記と同義である。 In the formula, Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , A and Z 2 are as defined above.
工程４－１
　本工程は、化合物（Ｉｂ）と化合物（５０）との縮合反応により、化合物（Ｉｈ）を製造する工程である。化合物（Ｉｈ）は、例えば、溶媒中、塩基存在下又は非存在下において、化合物（Ｉｂ）と化合物（５０）とを縮合剤存在下で反応させることにより製造することができる。溶媒としては、Ｎ，Ｎ－ジメチルホルムアミド、ジクロロメタン、１，４－ジオキサン、テトラヒドロフラン、それらの混合溶媒等を挙げることができる。用いられる縮合剤としては、例えば、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド（ＥＤＣＩ）、ジシクロヘキシルカルボジイミド（ＤＣＣ）、２－（１Ｈ－７－アザベンゾトリアゾール－１－イル）－１，１，３，３－テトラメチルウロニウム　ヘキサフルオロホスフェート　メタナミニウム（ＨＡＴＵ）等が挙げられる。また、必要に応じて、４－ジメチルアミノピリジン、ピリジン、１－ヒドロキシベンゾトリアゾール（ＨＯＢＴ）等を反応促進剤として用いることもできる。用いる塩基としては、炭酸カリウム、炭酸ナトリウム、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン等を用いることができる。反応温度は、通常－７８℃～溶媒還流温度で実施でき、０℃～１００℃で行うのが好ましい。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。 Step 4-1
This step is a step of producing compound (Ih) by a condensation reaction between compound (Ib) and compound (50). Compound (Ih) can be produced, for example, by reacting compound (Ib) with compound (50) in the presence of a condensing agent in the presence or absence of a base in a solvent. Examples of the solvent include N, N-dimethylformamide, dichloromethane, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like. Examples of the condensing agent used include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), dicyclohexylcarbodiimide (DCC), 2- (1H-7-azabenzotriazol-1-yl) -1 1,3,3-tetramethyluronium hexafluorophosphate metanaminium (HATU) and the like. If necessary, 4-dimethylaminopyridine, pyridine, 1-hydroxybenzotriazole (HOBT) or the like can also be used as a reaction accelerator. As the base to be used, potassium carbonate, sodium carbonate, triethylamine, N, N-diisopropylethylamine or the like can be used. The reaction temperature is usually from −78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 100 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
（Ｅ法）
　化合物（Ｉ）のうち、以下に示す化合物（Ｉｉ）は、例えば以下で説明するＥ法によって製造することができる。 (E method)
Among the compounds (I), the following compound (Ii) can be produced, for example, by Method E described below.
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
式中、Ｙ１、Ｙ２、Ｒ２、Ｒ３、Ｒ４、Ｒ５およびＡは前記と同義である。 In the formula, Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 and A are as defined above.
工程５－１
　本工程は、化合物（Ｉｂ）から、化合物（５１）を製造する工程である。化合物（５１）は、例えば、溶媒中、塩基存在下又は非存在下において、化合物（Ｉｂ）とアンモニウムクロリド等のアミン源となる化合物とを縮合剤存在下で反応させることにより製造することができる。溶媒としては、Ｎ，Ｎ－ジメチルホルムアミド、ジクロロメタン、１，４－ジオキサン、テトラヒドロフラン、それらの混合溶媒等を挙げることができる。用いられる縮合剤としては、例えば、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド（ＥＤＣＩ）、ジシクロヘキシルカルボジイミド（ＤＣＣ）、２－（１Ｈ－７－アザベンゾトリアゾール－１－イル）－１，１，３，３－テトラメチルウロニウム　ヘキサフルオロホスフェート　メタナミニウム（ＨＡＴＵ）等が挙げられる。また、必要に応じて、４－ジメチルアミノピリジン、ピリジン、１－ヒドロキシベンゾトリアゾール（ＨＯＢＴ）等を反応促進剤として用いることもできる。用いる塩基としては、炭酸カリウム、炭酸ナトリウム、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン等を用いることができる。反応温度は、通常－７８℃～溶媒還流温度で実施でき、０℃～２０℃で行うのが好ましい。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。 Step 5-1
This step is a step of producing compound (51) from compound (Ib). Compound (51) can be produced, for example, by reacting compound (Ib) with a compound serving as an amine source such as ammonium chloride in the presence of a condensing agent in a solvent in the presence or absence of a base. . Examples of the solvent include N, N-dimethylformamide, dichloromethane, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like. Examples of the condensing agent used include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), dicyclohexylcarbodiimide (DCC), 2- (1H-7-azabenzotriazol-1-yl) -1 1,3,3-tetramethyluronium hexafluorophosphate metanaminium (HATU) and the like. If necessary, 4-dimethylaminopyridine, pyridine, 1-hydroxybenzotriazole (HOBT) or the like can also be used as a reaction accelerator. As the base to be used, potassium carbonate, sodium carbonate, triethylamine, N, N-diisopropylethylamine or the like can be used. The reaction temperature is usually from −78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 20 ° C. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
工程５－２
　本工程は、化合物（５１）の脱水反応により、化合物（５２）を製造する工程である。化合物（５２）は、例えば、溶媒中、化合物（５１）に塩化チオニル、オキシ塩化リン等を作用させることによって製造することができる。溶媒としては、Ｎ，Ｎ－ジメチルホルムアミド、ジクロロメタン、１，４－ジオキサン、テトラヒドロフラン、トルエン、それらの混合溶媒等を挙げることができる。反応温度は、通常－７８℃～溶媒還流温度で実施できる。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。 Step 5-2
This step is a step of producing compound (52) by dehydration reaction of compound (51). Compound (52) can be produced, for example, by reacting compound (51) with thionyl chloride, phosphorus oxychloride or the like in a solvent. Examples of the solvent include N, N-dimethylformamide, dichloromethane, 1,4-dioxane, tetrahydrofuran, toluene, a mixed solvent thereof and the like. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
工程５－３
　本工程は、化合物（５２）のニトリル基をテトラゾリル基に変換して、化合物（Ｉｉ）を製造する工程である。化合物（Ｉｉ）は、例えば、溶媒中、化合物（５２）にアジ化ナトリウム等を作用させることによって製造することができる。溶媒としては、Ｎ，Ｎ－ジメチルホルムアミド、水、ジクロロメタン、１，４－ジオキサン、テトラヒドロフラン、それらの混合溶媒等を挙げることができる。また、必要に応じて、臭化亜鉛、塩化アンモニウム、硝酸銀、酢酸等を加えることができる。反応温度は、通常－７８℃～溶媒還流温度で実施でき、２０℃～溶媒還流温度で行うのが好ましい。反応時間は用いる原料物質や溶媒、反応温度等によって異なるが、通常３０分～３日間である。 Step 5-3
This step is a step for producing a compound (Ii) by converting a nitrile group of the compound (52) into a tetrazolyl group. Compound (Ii) can be produced, for example, by reacting compound (52) with sodium azide or the like in a solvent. Examples of the solvent include N, N-dimethylformamide, water, dichloromethane, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like. Moreover, zinc bromide, ammonium chloride, silver nitrate, acetic acid, etc. can be added as needed. The reaction temperature can usually be carried out at −78 ° C. to solvent reflux temperature, preferably 20 ° C. to solvent reflux temperature. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
　本実施形態の化合物（Ｉ）の薬理学的に許容な塩は、本実施形態の化合物（Ｉ）を用い、常法に従って製造することができる。 The pharmacologically acceptable salt of compound (I) of this embodiment can be produced according to a conventional method using compound (I) of this embodiment.
　上記に示したスキームは、本実施形態の化合物（Ｉ）またはその製造中間体を製造するための方法の例示である。これらは、当業者の容易に理解され得るようなスキームへの様々な改変が可能である。 The scheme shown above is an example of a method for producing the compound (I) of the present embodiment or a production intermediate thereof. These can be variously modified into schemes that can be easily understood by those skilled in the art.
　また、官能基の種類により保護基が必要な場合は、定法に従って適宜導入および脱離の操作を組み合わせて実施することができる。保護基の種類、導入、脱離に関しては、例えば、Ｔｈｅｏｄｏｒａ　Ｗ．　Ｇｒｅｅｎｅ　＆　Ｐｅｔｅｒ　Ｇ．　Ｍ．　Ｗｕｔｓ著編、「Ｇｒｅｅｎｅ’ｓ　Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ」、ｆｏｕｒｔｈ　ｅｄｉｔｉｏｎ、Ｗｉｌｅｙ－Ｉｎｔｅｒｓｃｉｅｎｃｅ、２００６年に記載の方法を挙げることができる。 In addition, when a protective group is required depending on the type of functional group, it can be carried out by appropriately combining the introduction and desorption operations according to a conventional method. For the type, introduction, and elimination of protecting groups, see, for example, Theodora W. Green & Peter G. M. The methods described in Wuts, “Green's Protective Groups in Organic Synthesis”, fourth edition, Wiley-Interscience, 2006 can be mentioned.
　本実施形態の化合物（Ｉ）、またはその薬理学的に許容される塩を製造する為に使用される中間体は、必要に応じて、当該分野における当業者にとって周知の単離・精製手段である溶媒抽出、晶析、再結晶、クロマトグラフィー、分取高速液体クロマトグラフィー等により、単離・精製することができる。 The intermediate used for producing the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof may be isolated and purified by means well known to those skilled in the art, if necessary. It can be isolated and purified by certain solvent extraction, crystallization, recrystallization, chromatography, preparative high performance liquid chromatography, and the like.
本実施形態の化合物（Ｉ）またはその薬理学的に許容される塩を含有する医薬
  本実施形態の化合物（Ｉ）またはその薬理学的に許容される塩を有効成分として含有する医薬は、用法に応じ種々の剤形とすることができる。このような剤形としては、例えば、散剤、顆粒剤、細粒剤、ドライシロップ剤、錠剤、カプセル剤、注射剤、液剤、軟膏剤、坐剤、貼付剤、舌下剤等を挙げることができ、経口または非経口的に投与される。
　これらの医薬は、その剤形に応じて公知の手法により、有効成分としての本実施形態の化合物（Ｉ）またはその薬理学的に許容される塩と、薬理学的に許容される添加物とを含む医薬組成物として構成することができる。当該医薬組成物に含有される添加物としては、賦形剤、崩壊剤、結合剤、滑沢剤、希釈剤、緩衝剤、等張化剤、防腐剤、湿潤剤、乳化剤、分散剤、安定化剤、溶解補助剤等を挙げることができる。当該医薬品組成物は、本実施形態の化合物（Ｉ）またはその薬理学的に許容される塩と適切な添加物とを適宜混合、または化合物（Ｉ）またはその薬理学的に許容される塩を添加物で希釈・溶解することにより調剤することができる。また、ＥＰ１受容体拮抗薬以外の薬剤と組み合わせて使用する場合は、それぞれの活性成分を同時または別々に、前述と同様に製剤化することにより製造することができる。 The pharmaceutical containing the compound (I) of this embodiment or a pharmacologically acceptable salt thereof The pharmaceutical containing the compound (I) of this embodiment or a pharmacologically acceptable salt thereof as an active ingredient Various dosage forms can be obtained depending on the case. Examples of such dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, solutions, ointments, suppositories, patches, sublinguals, etc. It is administered orally or parenterally.
These medicaments are prepared by a known method according to the dosage form, as an active ingredient, compound (I) of the present embodiment or a pharmacologically acceptable salt thereof, a pharmacologically acceptable additive, It can comprise as a pharmaceutical composition containing this. Additives contained in the pharmaceutical composition include excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stable agents. An agent, a solubilizing agent, etc. can be mentioned. The pharmaceutical composition comprises the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof and an appropriate additive appropriately mixed, or the compound (I) or a pharmacologically acceptable salt thereof. It can be prepared by diluting and dissolving with additives. Further, when used in combination with drugs other than the EP 1 receptor antagonist, simultaneously or separately each of active ingredients, it can be prepared by formulating the same manner as described above.
本実施形態の化合物（Ｉ）またはその薬理学的に許容される塩の医薬用途
　本実施形態の化合物（Ｉ）またはその薬理学的に許容される塩は、ＥＰ１受容体拮抗作用確認試験等において強力なＥＰ１受容体拮抗作用を示す。ゆえに、本実施形態の化合物（Ｉ）またはその薬理学的に許容される塩は、細胞内カルシウム濃度を抑制または低下させることができる。
　よって、本実施形態の化合物（Ｉ）またはその薬理学的に許容される塩は、ＥＰ１受容体拮抗作用確認試験に基づき、ＰＧＥ２刺激作用によるＥＰ１受容体の活性化に起因する疾患もしくは症状の治療、予防、または抑制のために使用することができる。ＰＧＥ２刺激作用によるＥＰ１受容体を活性化させる疾患もしくは症状としては下部尿路症状（ＬＵＴＳ）、炎症性疾患、疼痛性疾患、骨粗鬆症、癌等が挙げられる。よって、本実施形態の化合物（Ｉ）またはその薬理学的に許容される塩は、下部尿路症状（ＬＵＴＳ）、炎症性疾患、疼痛性疾患、骨粗鬆症、癌等の治療、予防または抑制のために使用することができる。ここで、本実施形態の化合物（Ｉ）またはその薬理学的に許容される塩は、ＬＵＴＳ、炎症性疾患もしくは疼痛性疾患の治療または予防のために使用されることが好ましく、下部尿路症状（ＬＵＴＳ）の治療または予防のために使用されることがより好ましい。
　また、本実施形態の化合物（Ｉ）またはその薬理学的に許容される塩を有効成分として含有する医薬組成物は、ＰＧＥ２刺激作用によるＥＰ１受容体の活性化に起因する疾患もしくは症状の治療薬、または予防薬として使用することができる。具体的には、本実施形態の化合物（Ｉ）またはその薬理学的に許容される塩を有効成分として含有する医薬組成物は、下部尿路症状（ＬＵＴＳ）、炎症性疾患、疼痛性疾患、骨粗鬆症、癌等の疾患または症状の治療薬または予防薬として使用することができる。このうち、本実施形態に係る医薬組成物は、ＬＵＴＳ、炎症性疾患もしくは疼痛性疾患の治療薬または予防薬として使用されることが好ましく、ＬＵＴＳの治療薬または予防薬として使用されることがより好ましい。 Medicinal Use of Compound (I) or a Pharmacologically Acceptable Salt of the Present Embodiment Compound (I) or a pharmacologically acceptable salt of the present embodiment is an EP 1 receptor antagonistic confirmation test, etc. Shows strong EP 1 receptor antagonism. Therefore, the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof can suppress or decrease the intracellular calcium concentration.
Therefore, the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof is based on the EP 1 receptor antagonism confirmation test, and is a disease caused by activation of EP 1 receptor by PGE 2 stimulation. It can be used for the treatment, prevention, or suppression of symptoms. Examples of the disease or symptom that activates the EP 1 receptor by PGE 2 stimulation include lower urinary tract symptoms (LUTS), inflammatory diseases, painful diseases, osteoporosis, cancer and the like. Therefore, the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof is used for the treatment, prevention or suppression of lower urinary tract symptoms (LUTS), inflammatory diseases, painful diseases, osteoporosis, cancer and the like. Can be used for Here, the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof is preferably used for the treatment or prevention of LUTS, inflammatory disease or pain disease, and lower urinary tract symptoms More preferably it is used for the treatment or prevention of (LUTS).
In addition, the pharmaceutical composition containing the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof as an active ingredient has a disease or symptom caused by activation of EP 1 receptor by PGE 2 stimulating action. It can be used as a therapeutic or prophylactic agent. Specifically, the pharmaceutical composition containing the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof as an active ingredient includes lower urinary tract symptoms (LUTS), inflammatory diseases, pain diseases, It can be used as a therapeutic or prophylactic agent for diseases or symptoms such as osteoporosis and cancer. Among these, the pharmaceutical composition according to the present embodiment is preferably used as a therapeutic or prophylactic agent for LUTS, inflammatory disease or pain disease, and more preferably used as a therapeutic or prophylactic agent for LUTS. preferable.
　下部尿路症状の原因疾患としては、過活動膀胱（ＯＡＢ）、前立腺肥大症（ＢＰＨ）、間質性膀胱炎等の膀胱炎や前立腺炎等が挙げられる。 Examples of the causative diseases of lower urinary tract symptoms include overactive bladder (OAB), prostatic hypertrophy (BPH), cystitis such as interstitial cystitis, prostatitis and the like.
  「下部尿路症状」とは、例えば蓄尿症状、排尿症状、排尿後症状を意味する。本実施形態の化合物（Ｉ）またはその薬理学的に許容される塩は、蓄尿症状の治療または予防のために使用するのが好ましい。 “Lower urinary tract symptoms” means, for example, urine storage symptoms, urination symptoms, and post-urination symptoms. The compound (I) of the present embodiment or a pharmacologically acceptable salt thereof is preferably used for the treatment or prevention of urinary retention symptoms.
  「蓄尿症状」としては、尿意切迫感、昼間頻尿、夜間頻尿、腹圧性尿失禁、切迫性尿失禁、混合性尿失禁、遺尿、夜間遺尿、持続性尿失禁等の尿失禁、および膀胱知覚亢進、膀胱知覚低下、膀胱知覚欠如、非特異的膀胱知覚等の膀胱知覚が含まれる。
　本実施形態の化合物（Ｉ）またはその薬理学的に許容される塩は、尿意切迫感、昼間頻尿、夜間頻尿、切迫性尿失禁、混合性尿失禁、遺尿、夜間遺尿、膀胱知覚亢進もしくは非特異的膀胱知覚の治療または予防のために使用するのが好ましい。より好ましくは、本実施形態の化合物（Ｉ）またはその薬理学的に許容される塩は、尿意切迫感、昼間頻尿、夜間頻尿、切迫性尿失禁または膀胱知覚亢進の治療または予防のために使用される。
　また、本発明の化合物（Ｉ）またはその薬理学的に許容される塩は、ＯＡＢｓの治療または予防には特に好ましい。 Urinary urgency, daytime frequent urination, nighttime frequent urination, stress urinary incontinence, urge urinary incontinence, mixed urinary incontinence, enuresis, nocturia, persistent urinary incontinence, and bladder It includes bladder perception, such as increased perception, decreased bladder perception, lack of bladder perception, and nonspecific bladder perception.
Compound (I) or a pharmacologically acceptable salt thereof according to this embodiment includes urinary urgency, daytime frequent urination, nocturia, urge urinary incontinence, mixed urinary incontinence, enuresis, nocturia, increased bladder perception Alternatively, it is preferably used for treatment or prevention of nonspecific bladder perception. More preferably, the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof is used for the treatment or prevention of urgency, daytime frequent urination, nocturia, urinary urinary incontinence or increased bladder perception. Used for.
In addition, the compound (I) of the present invention or a pharmacologically acceptable salt thereof is particularly preferable for the treatment or prevention of OABs.
本実施形態の化合物（Ｉ）またはその薬理学的に許容される塩の併用、または合剤
　本実施形態の化合物（Ｉ）またはその薬理学的に許容される塩は、ＥＰ１受容体拮抗薬以外の少なくとも１種の薬剤と適宜組み合わせて使用することもできる。 Compound (I) of the present embodiment or a pharmacologically acceptable salt thereof, or a combination thereof Compound (I) of the present embodiment or a pharmaceutically acceptable salt thereof is an EP 1 receptor antagonist It can also be used in combination with at least one kind of drug other than
本実施形態の化合物（Ｉ）またはその薬理学的に許容される塩と組み合わせて使用できる薬剤としては、ＥＰ１受容体桔抗薬とは異なる作用機序の過活動膀胱（ＯＡＢ）、前立腺肥大症（ＢＰＨ）、間質性膀胱炎等の膀胱炎、前立腺炎等の治療薬が挙げられる。このような薬剤としては、抗コリン薬、α１アンタゴニスト、βアゴニスト、5α－リダクターゼ阻害薬、ＰＤＥ阻害薬、アセチルコリンエステラーゼ阻害薬、抗男性ホルモン、プロゲステロン系ホルモン、ＬＨ－ＲＨアナログ、ニューロキニン阻害薬、抗利尿薬、カルシウムチャネルブロッカー、平滑筋直接作用薬、三環系抗うつ薬、カリウムチャネル調節薬、ナトリウムチャネルブロッカー、Ｈ１ブロッカー、セロトニン再取り込み阻害薬、ノルエピネフリン再取り込み阻害薬、ドーパミン再取り込み阻害薬、ＧＡＢＡアゴニスト、ＴＲＰＶ１調節薬、エンドセリン拮抗薬、５－ＨＴ１Ａアンタゴニスト、α１アゴニスト、オピオイドアゴニスト、Ｐ２Ｘアンタゴニスト、ＣＯＸ阻害薬、σアゴニスト、ムスカリンアゴニスト等が挙げられる。好ましくは、抗コリン薬、α１アンタゴニスト、βアゴニスト、5α－リダクターゼ阻害薬、ＰＤＥ阻害薬、プロゲステロン系ホルモン、抗利尿薬、平滑筋直接作用薬または三環系抗うつ薬である。 Examples of the drug that can be used in combination with the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof include overactive bladder (OAB) and prostatic hypertrophy having a mechanism of action different from that of the EP 1 receptor antagonist. And therapeutic agents for cystitis (BPH), cystitis such as interstitial cystitis, prostatitis and the like. Examples of such agents, anticholinergics, alpha 1 antagonists, beta agonists, 5.alpha.-reductase inhibitors, PDE inhibitors, acetylcholinesterase inhibitors, antiandrogens, progesterone-based hormone, LH-RH analogs, neurokinin inhibitors , Antidiuretic, calcium channel blocker, smooth muscle direct acting drug, tricyclic antidepressant, potassium channel modulator, sodium channel blocker, H 1 blocker, serotonin reuptake inhibitor, norepinephrine reuptake inhibitor, dopamine reuptake inhibitors, GABA agonists, TRPVl modulators, endothelin antagonists, 5-HT 1A antagonist, alpha 1 agonists, opioid agonists, P 2 X antagonists, COX inhibitors, sigma agonists, et al include muscarinic agonists such as That. Preferred are anticholinergic agents, α 1 antagonists, β agonists, 5α-reductase inhibitors, PDE inhibitors, progesterone hormones, antidiuretics, smooth muscle direct acting agents or tricyclic antidepressants.
　また、本実施形態の化合物（Ｉ）またはその薬理学的に許容される塩と組み合わせて使用される薬剤については以下の通り具体的に例示する。但し、本発明の内容はこれらに限定されるものではない。また、具体的な化合物においてはそのフリー体、およびその他の薬理学的に許容される塩を含む。 The drug used in combination with the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof is specifically exemplified as follows. However, the contents of the present invention are not limited to these. In addition, specific compounds include free forms thereof and other pharmacologically acceptable salts.
　「抗コリン薬」としては、オキシブチニン、プロピベリン、ソリフェナシン、トルテ口ジン、イミダフェナシン、テミベリン、ダリフェナシン、フェソテロジン、トロスピウム、プロパンテリン等を挙げることができる。 Examples of the “anticholinergic agent” include oxybutynin, propiverine, solifenacin, torte mouth gin, imidafenacin, temiverine, darifenacin, fesoterodine, trospium, propantelin and the like.
　「α１アンタゴニスト」としては、ウラピジル、ナフトピジル、タムスロシン、シロドシン、プラゾシン、テラゾシン、アルフゾシン、ドキサゾシン、ＣＲ－２９９１、フェデュキソシン等を挙げることができる。 Examples of the “α 1 antagonist” include urapidil, naphthopidyl, tamsulosin, silodosin, prazosin, terazosin, alfuzosin, doxazosin, CR-2991, feduxin and the like.
  「βアゴニスト」としては、ミラベグロン、ＫＵＣ－７４８３、ＫＲＰ－２０４、ＳＭ－３５０３００、ＴＲＫ－３８０、アミベグロン、クレンブテロール、ＳＡＲ－１５０６４０、ソラベグロン等を挙げることができる。 Examples of “β agonists” include mirabegron, KUC-7383, KRP-204, SM-350300, TRK-380, amibegron, clenbuterol, SAR-150640, sorabegron and the like.
  「５α－リダクターゼ阻害薬」としては、デュタステリド、ＴＦ－５０５、フィナステリド、イゾンステリド等を挙げることができる。 Examples of “5α-reductase inhibitors” include dutasteride, TF-505, finasteride, and izonsteride.
　「ＰＤＥ阻害薬」とは、ホスホジエステラーゼ阻害薬を意味し、タダラフィル、バルデナフィル、シルデナフィル、アバナフィル、ＵＫ－３６９００３、Ｔ－０１５６、ＡＫＰ－００２、エタゾラート等を挙げることができる。 “PDE inhibitor” means a phosphodiesterase inhibitor, and examples thereof include tadalafil, vardenafil, sildenafil, avanafil, UK-369003, T-0156, AKP-002, etazolate and the like.
　「アセチルコリンエステラーゼ阻害薬」としては、ジスチグミン、ドネペジル、Ｚ－３３８、リバスチグミン、ガンスチグミン、ＢＧＣ－２０－１２５９、ガランタミン、イトプリド、ＮＰ－６１、ＳＰＨ－１２８６、トルセリン、ＺＴ－１等を挙げることができる。 Examples of the “acetylcholinesterase inhibitor” include distigmine, donepezil, Z-338, rivastigmine, ganstigmine, BGC-20-1259, galantamine, itopride, NP-61, SPH-1286, tolserine, ZT-1 and the like. .
　「抗男性ホルモン」としては、ゲストノロン、オキセンドロン、ビカルタミド、ＢＭＳ－６４１９８８、ＣＢ－０３－０１、ＣＨ－４８９２７８９、フルタミド、ＭＤＶ－３１００、ニルタミド、ＴＡＫ－７００、ＹＭ－５８０等を挙げることができる。 Examples of the “anti-androgen” include guestnolone, oxendron, bicalutamide, BMS-641988, CB-03-01, CH-489789, flutamide, MDV-3100, nilutamide, TAK-700, YM-580 and the like.
　「プロゲステロン系ホルモン」としては、クロマジノン、アリルエストレノール等を挙げることができる。 Examples of “progesterone hormones” include chromazinone and allylestrenol.
　「ＬＨ－ＲＨアナログ」とは、性腺刺激ホルモン放出ホルモンアナログを意味する。また、性腺刺激ホルモン放出ホルモンは、黄体形成ホルモン放出ホルモンと称されることもある。例えば、ＡＥＺＳ－１０８、ブセレリン、デスロレリン、ゴセレリン、ヒストレリン、リュープロレリン、ルトロピン、ナファレリン、トリプトレリン、ＡＥＺＳ－０１９、セトロレリクス、デガレリクス、エラゴリクス、ガニリレクス、オザレリクス、ＰＴＤ－６３４、ＴＡＫ－３８５、テベレリクス、ＴＡＫ－４４８、ＴＡＫ－６８３等を挙げることができる。 “LH-RH analog” means a gonadotropin releasing hormone analog. Gonadotropin releasing hormone may also be referred to as luteinizing hormone releasing hormone. For example, AEZS-108, buserelin, deslorelin, goserelin, histrelin, leuprorelin, lutropin, nafarelin, triptorelin, AEZS-019, cetrorelix, degarelix, elagorix, ganilelex, ozarelix, PTD-634, TAK-385, Taverix 448, TAK-683 and the like.
　「ニューロキニン阻害薬」としては、ＫＲＰ－１０３、アプレピタント、ＡＶ－６０８、カソピタント、ＣＰ－１２２７２１、ＤＮＫ－３３３、フォスアプレピタント、ＬＹ－６８６０１７、ネツピタント、オルベピタント、ロラピタント、ＴＡ－５５３８、Ｔ－２３２８、ヴェスチピタント、ＡＺＤ－２６２４、Ｚ－５０１、１１４４８１４、ＭＥＮ－１５５９６、ＭＥＮ－１１４２０、ＳＡＲ－１０２７７９、ＳＡＲ－１０２２７９、サレデュタント、ＳＳＲ－２４１５８６等を挙げることができる。 Examples of the “neurokinin inhibitor” include KRP-103, aprepitant, AV-608, Casopitant, CP-122721, DNK-333, fosprepitant, LY-686017, netpitant, olbepitant, lolapitant, TA-5538, T-2328, Vestipitant, AZD-2624, Z-501, 1144814, MEN-15596, MEN-11420, SAR-102779, SAR-102279, Saleduant, SSR-241586, and the like.
　「抗利尿薬」としては、デスモプレシン、ＶＡ－１０６４８３等を挙げることができる。 Examples of the “antidiuretic” include desmopressin, VA-106483 and the like.
　「カルシウムチャネルブロッカー」としては、アムロジピン、シルニジピン、プ口ピベリン、テミベリン、ＰＤ－２９９６８５、アラニジピン、アゼルニジピン、バルニジピン、ベニジピン、ベバントロール、クレビジピン、ＣＹＣ－３８１、ジルチアゼム、エホニジピン、ファスジル、フェロジピン、ギャバペンチン、ガロパミル、イスラジピン、ラシジピン、レルカニジピン、ロメリジン、マニジピン、ＭＥＭ－１００３、ニカルジピン、ニフェジピン、ニルバジピン、ニモジピン、ニソルジピン、ＳＢ－７５１６８９、ベラパミル、ＹＭ－５８４８３、ジコノタイド等を挙げることができる。 Examples of “calcium channel blockers” include amlodipine, cilnidipine, puffer piverine, temiverine, PD-299685, alanidipine, azelnidipine, balnidipine, benidipine, bevantolol, clevidipine, CYC-381, diltiazem, efonidipine, fasudil, felodipine, gabamil Examples include isradipine, lacidipine, lercanidipine, lomerizine, manidipine, MEM-1003, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, SB-751689, verapamil, YM-58483, and ziconotide.
　「平滑筋直接作用薬」としては、フラボキサート等を挙げることができる。 “Smooth muscle direct acting drugs” include flavoxate and the like.
  「三環系抗うつ薬」としては、イミプラミン、クロミプラミン、アミトリプチリン等を挙げることができる。 “Tricyclic antidepressants” include imipramine, clomipramine, amitriptyline, and the like.
　「カリウムチャネル調節薬」としては、ニコランジル、ＮＩＰ－１４１、ＮＳ－４５９１、ＮＳ－１６４３、アンドラスト、ジアゾキシド、ＩＣＡ－１０５６６５、ミノキシジル、ピナシジル、チリソロール、ＶＲＸ－６９８等を挙げることができる。 Examples of the “potassium channel modulator” include nicorandil, NIP-141, NS-4591, NS-1643, andlast, diazoxide, ICA-105665, minoxidil, pinacidil, tirisolol, VRX-698 and the like.
　「ナトリウムチャネルブロッカー」としては、ベプリジル、ドロネダロン、プロパフェノン、サフィナミド、ＳＵＮ－Ｎ８０７５、ＳＭＰ－９８６、１０１４８０２、５５２－０２、Ａ－８０３４６７、ブリバラセタム、シベンゾリン、エスリカルバゼピン、Ｆ－１５８４５、フレカイニド、ホスフェニトイン、ラコサミド、ラモトリギン、レボブピバカイン、Ｍ－５８３７３、メキシレチン、モラシジン、ネリスピリジン、ＮＷ－３５０９、オクスカルバゼピン、ピルジカイニド、ピルメノール、プロパフェノン、ＮＷ－１０２９、ロピバカイン、バナカラント等を挙げることができる。 Examples of the “sodium channel blocker” include bepridil, dronedarone, propafenone, safinamide, SUN-N8075, SMP-986, 1014802, 552-02, A-803467, brivaracetam, cibenzoline, eslicarbazepine, F-15845, flecainide Phosphenytoin, lacosamide, lamotrigine, levobupivacaine, M-58373, mexiletine, moracidin, nerispyridine, NW-3509, oxcarbazepine, pilsicainide, pirmenol, propafenone, NW-1029, ropivacaine, vanacarant, etc. it can.
　「Ｈ１ブロッカー」としては、アクリバスチン、アルカフタジン、ベポタスチン、ビラスチン、セチリジン、デスロラタジン、エバスチン、エフレチリジン、エピナスチン、フェキソフェナジン、ＧＳＫ－８３５７２６、レボカバスチン、レボセチリジン、ロラタジン、メキタジン、ミゾラスチン、ＮＢＩ－７５０４３、ＲｅＮ－１８６９、テルフェナジン、ＵＣＢ－３５４４０、バピタジン、ＹＭ－３４４４８４、ジフェンヒドラミン、クロルフェニラミン等を挙げることができる。 Examples of the “H 1 blocker” include acribastine, alcaftadine, bepotastine, bilastine, cetirizine, desloratadine, ebastine, efletirizine, epinastine, fexofenadine, GSK-835726, levocabastine, levocetirizine, loratadine, mequitadine, mizolastine, NBI-7, 43 -1869, terfenadine, UCB-35440, vapitadine, YM-344484, diphenhydramine, chlorpheniramine and the like.
　「セロトニン再取り込み阻害剤」としては、ＵＣＢ－４６３３１、４２４８８７、ＡＤ－３３７、ＢＧＣ－２０－１２５９、ＢＭＳ－５０５１３０、シタロプラム、ダポキセチン、デスベンラファキシン、ＤＯＶ－１０２６７７、ＤＯＶ－２１６３０３、ＤＯＶ－２１９４７、デュロキセチン、エスシタロプラム、Ｆ－２６９５、Ｆ－９８２１４－ＴＡ、フルオキセチン、フルボキサミン、ＩＤＮ－５４９１、ミルナシプラン、ミナプリン、ＮＳ－２３５９、ＮＳＤ－６４４、パロキセチン、ＰＦ－１８４２９８、ＳＤ－７２６、ＳＥＰ－２２５２８９、ＳＥＰ－２２７１６２、ＳＥＰ－２２８４２５、ＳＥＰ－２２８４３２、セルトラリン、シブトラミン、テソフェンシン、トラマドール、トラゾドン、ＵＣＢ－４６３３１、ベンラファキシン、ビラゾドン、ＷＡＹ－４２６、ＷＦ－５１６等を挙げることができる。 “Serotonin reuptake inhibitors” include UCB-46331, 424887, AD-337, BGC-20-1259, BMS-505130, citalopram, dapoxetine, desvenlafaxine, DOV-102673, DOV-216303, DOV-21947 , Duloxetine, escitalopram, F-2695, F-98214-TA, fluoxetine, fluvoxamine, IDN-5491, milnacipran, minaprine, NS-2359, NSD-644, paroxetine, PF-184298, SD-726, SEP-225289 , SEP-227162, SEP-228425, SEP-228432, sertraline, sibutramine, tesofensin, tramadol, trazodone, UCB-46331, venlafa Singh, mention may be made Birazodon, the WAY-426, WF-516 and the like.
　「ノルエピネフリン再取り込み阻害剤」としては、ＡＤ－３３７、デスベンラファキシン、ＤＯＶ－１０２６７７、ＤＯＶ－２１６３０３、ＤＯＶ－２１９４７、デュロキセチン、Ｆ－２６９５、Ｆ－９８２１４－ＴＡ、ミルナシプラン、ＮＳ－２３５９、ＮＳＤ－６４４、ＰＦ－１８４２９８、ＳＤ－７２６、ＳＥＰ－２２５２８９、ＳＥＰ－２２７１６２、ＳＥＰ－２２８４２５、ＳＥＰ－２２８４３２、シブトラミン、テソフェンシン、トラマドール、ベンラファキシン、ブプロピオン、ラダファキシン、アトモキセチン、ＤＤＰ－２２５、ＬＹ－２２１６６８４、ネボグラミン、ＮＲＩ－１９３、レボキセチン、タペンタドール、ＷＡＹ－２５６８０５、ＷＡＹ－２６００２２等を挙げることができる。 Examples of “norepinephrine reuptake inhibitors” include AD-337, desvenlafaxine, DOV-102677, DOV-216303, DOV-21947, duloxetine, F-2695, F-98214-TA, milnacipran, NS-2359 , NSD-644, PF-184298, SD-726, SEP-225289, SEP-227162, SEP-228425, SEP-228432, Sibutramine, Tesofensin, Tramadol, Venlafaxine, Bupropion, Radafaxin, Atomoxetine, DDP-225, LY -2216684, nevogramin, NRI-193, reboxetine, tapentadol, WAY-256805, WAY-260022, and the like.
　「ドーパミン再取り込み阻害剤」としては、ＤＯＶ－１０２６７７、ＤＯＶ－２１６３０３、ＤＯＶ－２１９４７、ＩＤＮ－５４９１、ＮＳ－２３５９、ＮＳＤ－６４４、ＳＥＰ－２２５２８９、ＳＥＰ－２２８４２５、ＳＥＰ－２２８４３２、シブトラミン、テソフェンシン、トラマドール、ブラソフェンシン、ブプロピオン、ＮＳ－２７１００、ラダファキシン、サフィナミド等を挙げることができる。 Examples of the “dopamine reuptake inhibitor” include DOV-102777, DOV-216303, DOV-21947, IDN-5491, NS-2359, NSD-644, SEP-225289, SEP-228425, SEP-228432, sibutramine, tesofensin, Examples thereof include tramadol, brasofensin, bupropion, NS-27100, radafaxin, safinamide and the like.
　「ＧＡＢＡアゴニスト」としては、レチガビン、エスゾピクロン、インディプロン、パゴク口ン、ＳＥＰ－２２５４４１、アカンプロセート、バクロフェン、ＡＺＤ－７３２５、ＢＬ－１０２０、ブロチゾラム、ＤＰ－ＶＰＡ、プロガバイド、プロポフォール、トピラマート、ゾピクロン、ＥＶＴ－２０１、ＡＺＤ－３０４３、ガナキソロン、ＮＳ－１１３９４、アルバクロフェン、ＡＺＤ－３３５５、ＧＳ－３９７８３、ＡＤＸ－７１４４１、ＡＤＸ－７１９４３等を挙げることができる。 “GABA agonists” include retigabine, eszopiclone, indipron, pagok mouth, SEP-225441, acamprosate, baclofen, AZD-7325, BL-1020, brotizolam, DP-VPA, progabide, propofol, topiramate, zopiclone EVT-201, AZD-3043, ganaxolone, NS-11394, albaclofen, AZD-3355, GS-39783, ADX-71441, ADX-71943, and the like.
　「ＴＲＰＶ１調節薬」としては、力プサイシン、レジニフェラトキシン、ＤＥ－０９６、ＧＲＣ－６２１１、ＡＭＧ－８５６２、ＪＴＳ－６５３、ＳＢ－７０５４９８、Ａ－４２５６１９、Ａ－７８４１６８、ＡＢＴ－１０２、ＡＭＧ－６２８、ＡＺＤ－１３８６、ＪＮＪ－１７２０３２１２、ＮＧＤ－８２４３、ＰＦ－３８６４０８６、ＳＡＲ－１１５７４０、ＳＢ－７８２４４３等を挙げることができる。 “TRPV1 modulators” include force psaicin, resiniferatoxin, DE-096, GRC-6611, AMG-8562, JTS-653, SB-705498, A-4256619, A-784168, ABT-102, AMG- 628, AZD-1386, JNJ-17203212, NGD-8243, PF-386486, SAR-115740, SB-784243, and the like.
　「エンドセリン拮抗薬」としては、ＳＢ－２３４５５１、ＡＣＴ－０６４９９２、アンブリセンタン、アトラセンタン、ボセンタン、クラゾセンタン、ダルセンタン、ファンドセンタン、Ｓ－０１３９、ＴＡ－０２０１、ＴＢＣ－３７１１、ジボテンタン、ＢＭＳ－５０９７０１、ＰＳ－４３３５４０等を挙げることができる。 “Endothelin antagonists” include SB-234551, ACT-064992, ambrisentan, atrasentan, bosentan, clazosentan, darsentan, fundsentan, S-0139, TA-0201, TBC-3711, dibotentane, BMS-509701, PS -433540 and the like.
　「５－ＨＴ１Ａアンタゴニスト」としては、エスピンドロール、レコゾタン、ルラシドン、Ｅ－２１１０、ＲＥＣ－０２０６、ＳＢ－６４９９１５、ＷＡＹ－４２６、ＷＦ－５１６等を挙げることができる。 Examples of the “5-HT 1A antagonist” include espindolol, lecozotan, lurasidone, E-2110, REC-0206, SB-649915, WAY-426, WF-516 and the like.
　「α１アゴニスト」としては、ＣＭ－２２３６、アルモダフィニル、ミドドリン、モダフィニル等を挙げることができる。 Examples of the “α 1 agonist” include CM-2236, armodafinil, midodrine, modafinil and the like.
　「オピオイドアゴニスト」としては、モルヒネ、ＴＲＫ－１３０、ＤＰＩ－１２５、ＤＰＩ－３２９０、フェンタニル、ＬＩＦ－３０１、ロペラミド、ロペラミドオキサイド、レミフェンタニル、タペンタドール、ＷＹ－１６２２５、オキシコドン、ＰＴＩ－２０２、ＰＴＩ－７２１、ＡＤＬ－５７４７、ＡＤＬ－５８５９、ＤＰＩ－２２１、ＤＰＩ－３５３、ＩＰＰ－１０２１９９、ＳＮ－１１、ＡＤＬ－１０－０１０１、ＡＤＬ－１０－０１１６、アシマドリン、ブプレノルフィン、ＣＲ－６６５、ＣＲ－８４５、エプタゾシン、ナルブフィン、ナルフラフィン、ペンタゾシン、ＸＥＮ－０５４８、Ｗ－２１２３９３、ＺＰ－１２０、ナルメフェン等を挙げることができる。 “Opioid agonists” include morphine, TRK-130, DPI-125, DPI-3290, fentanyl, LIF-301, loperamide, loperamide oxide, remifentanil, tapentadol, WY-16225, oxycodone, PTI-202, PTI-721 ADL-5747, ADL-5589, DPI-221, DPI-353, IPP-102199, SN-11, ADL-10-0101, ADL-10-0116, asimadoline, buprenorphine, CR-665, CR-845, eptazosin Nalbuphine, nalflaphine, pentazocine, XEN-0548, W-212393, ZP-120, nalmefene and the like.
　「Ｐ２Ｘアンタゴニスト」としては、Ａ－７４０００３、ＡＺ－１１６５７３１２、ＡＺＤ－９０５６、ＧＳＫ－１４８２１６０、ＧＳＫ－３１４８１Ａ等を挙げることができる。 Examples of the “P 2 X antagonist” include A-740003, AZ-1157312, AZD-9056, GSK-14482160, GSK-31481A and the like.
　「ＣＯＸ阻害薬」とは、シクロオキシゲナーゼ阻害薬を意味し、アセクロフェナク、ＳＴ－６７９、アスピリン、ブロムフェナク、デキスケトプロフェン、フルルビプロフェン、ＦＹＯ－７５０、イブプロフェン、ケトプロフェン、ケトロラック、リコフェロン、ロルノキシカム、ロキソプロフェン、ＬＴ－ＮＳ００１、ジクロフェナク、モフェゾラク、ナブメトン、ナプロキセン、オキサプロジン、ピロキシカム、プラノプロフェン、スプロフェン、テノキシカム、チアプロフェン酸、トルフェナム酸、ザルトプロフェン、６４４７８４、ＡＢＴ－９６３、アジュレミン酸、アプリコキシブ、セレコキシブ、シミコキシブ、エトリコキシブ、イグラチモド、ルミラコキシブ、メロキシカム、ニメスリド、パレコキシブ、ＲＯ－２６－２１９８、バルデコキシブ等を挙げることができる。 “COX inhibitor” means a cyclooxygenase inhibitor such as aceclofenac, ST-679, aspirin, bromfenac, dexketoprofen, flurbiprofen, FYO-750, ibuprofen, ketoprofen, ketorolac, lycoferon, lornoxicam, loxoprofen, LT -NS001, diclofenac, mofezolac, nabumetone, naproxen, oxaprozin, piroxicam, pranoprofen, suprofen, tenoxicam, thiaprofenic acid, tolfenamic acid, zaltoprofen, 644784, ABT-963, ajulemic acid, apricoxib, celecoxib, citricoxib, citricoxib Lumiracoxib, meloxicam, nimesulide, parecoxib, RO-26-21 8, it can be mentioned valdecoxib and the like.
　「σアゴニスト」としては、ＡＮＡＶＥＸ－２７－１０４１、ＰＲＳ－０１３、ＳＡ－４５０３、ＡＮＡＶＥＸ－２－７３、シラメシン、ＡＮＡＶＥＸ－７－１０３７、ＡＮＡＶＥＸ－１－４１等を挙げることができる。 Examples of the “σ agonist” include ANAVEX-27-1041, PRS-013, SA-4503, ANAVEX-2-73, silamesine, ANAVEX-7-1037, ANAVEX-1-41, and the like.
　「ムスカリンアゴニスト」としては、ＡＣ－２６０５８４、セビメリン、ＭＣＤ－３８６、ＮＧＸ－２６７、ＮＧＸ－２９２、サブコメリン、ピロカルピン、ベタネコール等を挙げることができる。 Examples of “muscarinic agonists” include AC-260584, cevimeline, MCD-386, NGX-267, NGX-292, subcomerin, pilocarpine, bethanechol and the like.
　本実施形態の化合物（Ｉ）またはその薬理学的に許容される塩と上記薬剤の１種類またはそれ以上とを組み合わせて使用する場合、本発明は、以下の１）～５）から選択される何れか１つの投与方法を含む。
１）配合剤による同時投与、
２）別個の製剤として、同一投与経路による同時投与、
３）別個の製剤として、異なる投与経路による同時投与、
４）別個の製剤として、同一投与経路による異なる時間での投与、または
５）別個の製剤として、異なる投与経路による異なる時間での投与
　また、４）または５）のような別個の製剤として異なる時間に投与する場合、本発明の化合物（Ｉ）と上記の薬剤との投与順序については特に制限されない。 When the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof and one or more of the above drugs are used in combination, the present invention is selected from the following 1) to 5) Any one method of administration is included.
1) Simultaneous administration with combination drug,
2) As separate formulations, co-administration by the same route of administration,
3) As separate formulations, co-administration by different routes of administration,
4) Administration at different times by the same route of administration as separate formulations, or 5) Administration at different times by different routes of administration as separate formulations Also at different times as separate formulations as in 4) or 5) The administration order of the compound (I) of the present invention and the above drug is not particularly limited.
　また、本実施形態の化合物（Ｉ）またはその薬理学的に許容される塩は、１種類またはそれ以上の上記薬剤を適宜組み合わせて使用することにより、上記疾患の予防または治療上における相加効果以上の有利な効果を得ることができる。または、同様に、単独に使用する場合と比較してその使用量を減少させたり、もしくは併用する薬剤の副作用を減少させたり、もしくは併用する薬剤の副作用を回避または軽減させることができる。 In addition, the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof can be used as an additive effect in preventing or treating the above diseases by using one or more of the above drugs in appropriate combination. The above advantageous effects can be obtained. Similarly, it is possible to reduce the amount of use compared to the case of using it alone, or to reduce the side effects of the drugs used in combination, or to avoid or reduce the side effects of the drugs used in combination.
本実施形態の化合物（Ｉ）の用法・用量
　本実施形態に係る医薬は、全身的または局所的に、経口または非経口（経鼻、経肺、静脈内、直腸内、皮下、筋肉内、経皮等）により、投与することができる。 Usage / Dosage of Compound (I) of this Embodiment The medicament according to this embodiment can be used systemically or locally, orally or parenterally (nasal, pulmonary, intravenous, rectal, subcutaneous, intramuscular, transdermal). Can be administered via the skin).
　本実施形態に係る医薬組成生物を実際の治療に用いる場合、その有効成分である本実施形態の化合物（Ｉ）またはその薬理学的に許容される塩の投与量は、患者の年齢、性別、体重、疾患および治療の程度等により適宜決定される。例えば、経口投与の場合、成人（体重６０ｋｇとする）１日当たり概ね３～１０００ｍｇ／体の範囲で、一回または数回に分けて適宜投与することができる。経口剤としての１日当たりの投与量は、６～５４０ｍｇ／体が好ましく、１８～１８０ｍｇ／体がより好ましい。非経口投与の場合、成人１日当たり概ね０．０１～３００ｍｇの範囲で、一回または数回に分けて適宜投与することができる。非経口剤としての１日当たりの投与量は、１～１００ｍｇ／体が好ましく、６～６０ｍｇ／体がより好ましい。また、本実施形態の化合物（Ｉ）またはその薬理学的に許容される塩の投与量は、ＥＰ１受容体拮抗薬以外の薬剤の投与量に応じて減量することができる。 When the pharmaceutical composition organism according to the present embodiment is used for actual treatment, the dose of compound (I) of the present embodiment, which is an active ingredient thereof, or a pharmacologically acceptable salt thereof is determined by the patient's age, sex, It is determined as appropriate according to body weight, disease, degree of treatment, and the like. For example, in the case of oral administration, an adult (with a body weight of 60 kg) can be appropriately administered once or in several divided doses within a range of about 3 to 1000 mg / body per day. The daily dose as an oral preparation is preferably 6 to 540 mg / body, more preferably 18 to 180 mg / body. In the case of parenteral administration, it can be appropriately administered once or in several divided doses in the range of about 0.01 to 300 mg per day for an adult. The daily dose as a parenteral preparation is preferably 1 to 100 mg / body, more preferably 6 to 60 mg / body. In addition, the dose of the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof can be reduced according to the dose of a drug other than the EP 1 receptor antagonist.
　以下、試験例、実施例および参考例に基づいて本発明をより詳細に説明する。また、化合物（Ｉ）の製造に用いる原料化合物の中にも新規化合物が含まれているので、原料化合物の製造例についても参考例として説明する。本発明は、下記実施例に記載の化合物に限定されるものではなく、本発明の範囲を逸脱しない範囲で変化させても良い。 Hereinafter, the present invention will be described in more detail based on test examples, examples, and reference examples. Moreover, since the new compound is contained also in the raw material compound used for manufacture of compound (I), the manufacture example of a raw material compound is demonstrated as a reference example. The present invention is not limited to the compounds described in the following examples, and may be changed without departing from the scope of the present invention.
＜参考例１－１＞ <Reference Example 1-1>
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
３－アミノ－２，５－ジクロロ安息香酸メチル
　アルゴン雰囲気下、３－アミノ－２，５－ジクロロ安息香酸（５．００ ｇ）のメタノール（２５０ ｍＬ）溶液に、０℃で塩化チオニル（３５．５ｍＬ）を１時間かけて滴下し、反応液とした。反応液を８０℃で３時間加熱攪拌した。反応液を減圧濃縮した後、残渣を酢酸エチルで希釈した。希釈液を飽和炭酸水素ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、黄色オイルとして表題化合物を得た（５．８６ｇ）。
1H-NMR (400 MHz, CDCl3)δ 3.92 (3H, s), 4.33 (2H, brs), 6.87 (1H, d, J = 2.4 Hz), 7.14 (1H, d, J = 2.4 Hz). Methyl 3-amino-2,5-dichlorobenzoate Under argon atmosphere, a solution of 3-amino-2,5-dichlorobenzoic acid (5.00 g) in methanol (250 mL) at 0 ° C. at thionyl chloride (35. 5 mL) was added dropwise over 1 hour to prepare a reaction solution. The reaction solution was heated and stirred at 80 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with a saturated aqueous sodium hydrogen carbonate solution and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound as a yellow oil (5.86 g).
1 H-NMR (400 MHz, CDCl 3 ) δ 3.92 (3H, s), 4.33 (2H, brs), 6.87 (1H, d, J = 2.4 Hz), 7.14 (1H, d, J = 2.4 Hz).
 ＜参考例２－１＞ <Reference Example 2-1>
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
３－（ベンゾイルアミノ）－２，５－ジクロロ安息香酸メチル
　アルゴン雰囲気下、３－アミノ－２，５－ジクロロ安息香酸メチル（２．２０ ｇ）のトルエン（３８ ｍＬ）溶液に、室温で炭酸カリウム（１．３９ ｇ）と塩化ベンゾイル（１．１６ ｍＬ）を加え、反応液とした。反応液を８０℃で５時間攪拌した。反応液を酢酸エチルで希釈して、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去した後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝５：１）を用いて精製し、無色固体として表題化合物を得た（３．０３ｇ）。
1H-NMR (400 MHz, CDCl3) δ 3.69 (3H, s), 7.52-7.58 (2H, m), 7.60 (1H, d, J = 2.4 Hz), 7.60-7.65 (1H, m), 7.90-7.95 (2H, m), 8.69 (1H, brs), 8.88 (1H, d, J = 2.4 Hz). Methyl 3- (benzoylamino) -2,5-dichlorobenzoate To a solution of methyl 3-amino-2,5-dichlorobenzoate (2.20 g) in toluene (38 mL) under an argon atmosphere at room temperature (1.39 g) and benzoyl chloride (1.16 mL) were added to obtain a reaction solution. The reaction was stirred at 80 ° C. for 5 hours. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the title compound as a colorless solid (3.03 g).
1 H-NMR (400 MHz, CDCl 3 ) δ 3.69 (3H, s), 7.52-7.58 (2H, m), 7.60 (1H, d, J = 2.4 Hz), 7.60-7.65 (1H, m), 7.90 -7.95 (2H, m), 8.69 (1H, brs), 8.88 (1H, d, J = 2.4 Hz).
＜参考例２－２＞ <Reference Example 2-2>
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
５－クロロ－２－［（１－メチルシクロプロピルカルボニル）アミノ］安息香酸メチル
　アルゴン雰囲気下、２－アミノ－５－クロロ安息香酸メチル（２．５０ ｇ）のジクロロメタン（２０ ｍＬ）溶液に、０℃でトリエチルアミン（８．５ｍＬ）と１－メチルシクロプロパンカルボン酸クロリド（２．３７ ｇ）を加え、反応液とした。反応液を０℃で５時間攪拌した。反応液を酢酸エチルで希釈して、飽和炭酸水素ナトリウム水溶液、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝３：１）を用いて精製し、淡褐色固体として表題化合物を得た（２．３５ｇ）。
1H-NMR (400 MHz, CDCl3) δ 0.72 (2H, dd, J = 6.7, 4.2 Hz), 1.31 (2H, dd, J = 6.7, 4.2 Hz), 1.54 (3H, s), 3.95 (3H, s), 7.47 (1H, dd, J = 9.1, 2.4 Hz), 8.01 (1H, d, J = 2.4 Hz), 8.73 (1H, d, J = 9.1 Hz), 11.34 (1H, brs). Methyl 5-chloro-2-[(1-methylcyclopropylcarbonyl) amino] benzoate To a solution of methyl 2-amino-5-chlorobenzoate (2.50 g) in dichloromethane (20 mL) under an argon atmosphere, 0 Triethylamine (8.5 mL) and 1-methylcyclopropanecarboxylic acid chloride (2.37 g) were added at 0 ° C. to prepare a reaction solution. The reaction was stirred at 0 ° C. for 5 hours. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the title compound as a light brown solid (2.35 g).
1 H-NMR (400 MHz, CDCl 3 ) δ 0.72 (2H, dd, J = 6.7, 4.2 Hz), 1.31 (2H, dd, J = 6.7, 4.2 Hz), 1.54 (3H, s), 3.95 (3H , s), 7.47 (1H, dd, J = 9.1, 2.4 Hz), 8.01 (1H, d, J = 2.4 Hz), 8.73 (1H, d, J = 9.1 Hz), 11.34 (1H, brs).
 ＜参考例３－１＞ <Reference Example 3-1>
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
２，５－ジクロロ－３－（チオベンゾイルアミノ）安息香酸メチル
　アルゴン雰囲気下、３－（ベンゾイルアミノ）－２，５－ジクロロ安息香酸メチル（３．００ｇ）、ローソン試薬（３．７５ ｇ）、トルエン（２４ ｍＬ）の混合物を、１時間加熱還流した。反応液を酢酸エチルで希釈して、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝５：１）で精製し、無色固体として表題化合物を得た（２．２４ｇ）。
1H-NMR (400 MHz, CDCl3) δ 3.96 (3H, s), 7.47 (2H, t, J = 7.9 Hz), 7.56 (1H, t, J = 7.9 Hz), 7.74 (1H, d, J = 2.4 Hz), 7.88 (2H, d, J = 7.9 Hz), 9.08 (1H, brs), 9.44 (1H, brs). Methyl 2,5-dichloro-3- (thiobenzoylamino) benzoate Under argon atmosphere, methyl 3- (benzoylamino) -2,5-dichlorobenzoate (3.00 g), Lawesson's reagent (3.75 g), A mixture of toluene (24 mL) was heated to reflux for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the title compound as a colorless solid (2.24 g).
1 H-NMR (400 MHz, CDCl 3 ) δ 3.96 (3H, s), 7.47 (2H, t, J = 7.9 Hz), 7.56 (1H, t, J = 7.9 Hz), 7.74 (1H, d, J = 2.4 Hz), 7.88 (2H, d, J = 7.9 Hz), 9.08 (1H, brs), 9.44 (1H, brs).
 ＜参考例３－２＞ <Reference Example 3-2>
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
５－クロロ－２－［（１－メチルシクロプロピルチオカルボニル）アミノ］安息香酸メチル
　アルゴン雰囲気下、反応液としての５－クロロ－２－［（１－メチルシクロプロピルカルボニル）アミノ］安息香酸メチル（２．２７ｇ）、ローソン試薬（３．５０ ｇ）、トルエン（４０ ｍＬ）の混合物を、２時間加熱還流した。反応液を酢酸エチルで希釈して、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去した後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝５：１）を用いて精製し、黄色固体として表題化合物を得た（１．５５ｇ）。
1H-NMR (400 MHz, CDCl3) δ 0.93 (2H, dd, J = 6.7, 3.6 Hz), 1.63 (2H, dd, J = 6.7, 3.6 Hz), 1.65 (3H, s), 3.97 (3H, s), 7.52 (1H, dd, J = 9.1, 2.4 Hz), 8.03 (1H, d, J = 2.4 Hz), 9.39 (1H, d, J = 9.1 Hz), 12.11 (1H, brs). Methyl 5-chloro-2-[(1-methylcyclopropylthiocarbonyl) amino] benzoate under argon atmosphere, methyl 5-chloro-2-[(1-methylcyclopropylcarbonyl) amino] benzoate ( 2.27 g), Lawesson's reagent (3.50 g), and toluene (40 mL) were heated to reflux for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the title compound as a yellow solid (1.55 g).
1 H-NMR (400 MHz, CDCl 3 ) δ 0.93 (2H, dd, J = 6.7, 3.6 Hz), 1.63 (2H, dd, J = 6.7, 3.6 Hz), 1.65 (3H, s), 3.97 (3H , s), 7.52 (1H, dd, J = 9.1, 2.4 Hz), 8.03 (1H, d, J = 2.4 Hz), 9.39 (1H, d, J = 9.1 Hz), 12.11 (1H, brs).
 ＜参考例４－１＞ <Reference Example 4-1>
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
５－クロロ－２－フェニルベンゾ［ｄ］チアゾール－７－カルボン酸メチル
　アルゴン雰囲気下、２，５－ジクロロ－３－（チオベンゾイルアミノ）安息香酸メチル（２．１２ｇ）のＮ，Ｎ－ジメチルホルムアミド（３１ ｍＬ）溶液に、室温で１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（ＤＢＵ）（１．２０ｍＬ）を加え、反応液とした。反応液を室温で３時間、続いて５０℃で１時間攪拌した。反応液に水を加え、酢酸エチルで抽出し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝５：１）を用いて精製し、無色結晶として表題化合物を得た（１．８１ｇ）。
1H-NMR (400 MHz, CDCl3) δ 4.05 (3H, s), 7.50-7.55 (3H, m), 8.09 (1H, d, J = 2.4 Hz), 8.12-8.18 (2H, m), 8.23 (1H, d, J = 2.4 Hz). Methyl 5-chloro-2-phenylbenzo [d] thiazole-7-carboxylate N, N-dimethylformamide of methyl 2,5-dichloro-3- (thiobenzoylamino) benzoate (2.12 g) under argon atmosphere To the (31 mL) solution, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) (1.20 mL) was added at room temperature to obtain a reaction solution. The reaction was stirred at room temperature for 3 hours, then at 50 ° C. for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the title compound as colorless crystals (1.81 g).
1 H-NMR (400 MHz, CDCl 3 ) δ 4.05 (3H, s), 7.50-7.55 (3H, m), 8.09 (1H, d, J = 2.4 Hz), 8.12-8.18 (2H, m), 8.23 (1H, d, J = 2.4 Hz).
 ＜参考例４－２＞ <Reference Example 4-2>
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
６－クロロ－２－（１－メチルシクロプロピル）ベンゾ［ｄ］チアゾール－４－カルボン酸メチル
　Ｋ３［Ｆｅ（ＣＮ）６］（７．１０ｇ）の水（５．５ｍＬ）溶液に、８５℃で５－クロロ－２－［（１－メチルシクロプロピルチオカルボニル）アミノ］安息香酸メチル（１．５３ｇ）のエタノール（２．７ ｍＬ）溶液、３０％水酸化ナトリウム水溶液（４．５２ ｍＬ）を加え、反応液とした。反応液を８５℃で２時間攪拌した。反応液を室温まで冷却後、１ｍｏｌ／Ｌ塩酸（３０ｍＬ）中に注いだ。酢酸エチルで抽出し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去後、得られた残渣をメタノール（５ｍＬ）とジエチルエーテル（１０ｍＬ）の混合溶媒に溶解し、トリメチルシリルジアゾメタン（５ｍＬ、２ｍｏｌ／Ｌジエチルエーテル溶液）を加えた。溶媒を減圧留去後、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１０：１）を用いて精製し、無色オイルとして表題化合物が得た（２０９ｍｇ）。
1H-NMR (400 MHz, CDCl3) δ 1.09 (2H, dd, J = 7.3, 4.2 Hz), 1.49 (2H, dd, J = 7.3, 4.2 Hz), 1.67 (3H, s), 4.00 (3H, s), 7.94 (1H, d, J = 2.4 Hz), 7.97 (1H, d, J = 2.4 Hz). To a solution of methyl 6-chloro-2- (1-methylcyclopropyl) benzo [d] thiazole-4-carboxylate K 3 [Fe (CN) 6 ] (7.10 g) in water (5.5 mL) at 85 ° C. A solution of methyl 5-chloro-2-[(1-methylcyclopropylthiocarbonyl) amino] benzoate (1.53 g) in ethanol (2.7 mL) and 30% aqueous sodium hydroxide (4.52 mL) was added. In addition, a reaction solution was obtained. The reaction was stirred at 85 ° C. for 2 hours. The reaction solution was cooled to room temperature and then poured into 1 mol / L hydrochloric acid (30 mL). The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was dissolved in a mixed solvent of methanol (5 mL) and diethyl ether (10 mL), and trimethylsilyldiazomethane (5 mL, 2 mol / L diethyl ether solution) was added. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain the title compound as a colorless oil (209 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ 1.09 (2H, dd, J = 7.3, 4.2 Hz), 1.49 (2H, dd, J = 7.3, 4.2 Hz), 1.67 (3H, s), 4.00 (3H , s), 7.94 (1H, d, J = 2.4 Hz), 7.97 (1H, d, J = 2.4 Hz).
 ＜参考例５－１＞ <Reference Example 5-1>
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
２－アミノ－３－ブロモ－５－クロロフェノール
　アルゴン雰囲気下、２－アミノ－５－クロロフェノール（１２．５ ｇ）のジクロロメタン（３５０ ｍＬ）溶液に、０℃で臭素（４．９０ ｍＬ）を０．５時間かけて滴下し、反応液とした。反応液を室温で３時間攪拌した。反応液を減圧濃縮した後、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝５：１）を用いて精製し、茶色固体として表題化合物を得た（２、６４ｇ）。
1H-NMR (400 MHz, CDCl3) δ 4.03 (2H, brs), 5.30 (1H, brs), 6.71 (1H, d, J = 2.4 Hz), 7.05 (1H, d, J = 2.4 Hz). 2-Amino-3-bromo-5-chlorophenol Bromine (4.90 mL) was added to a solution of 2-amino-5-chlorophenol (12.5 g) in dichloromethane (350 mL) at 0 ° C. under an argon atmosphere. The reaction solution was added dropwise over 0.5 hour. The reaction was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and then purified using silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound as a brown solid (2, 64 g).
1 H-NMR (400 MHz, CDCl 3 ) δ 4.03 (2H, brs), 5.30 (1H, brs), 6.71 (1H, d, J = 2.4 Hz), 7.05 (1H, d, J = 2.4 Hz).
 ＜参考例６－１＞ <Reference Example 6-1>
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
２－アミノ－４－ブロモ－６－クロロベンゾ［ｄ］オキサゾール
　アルゴン雰囲気下、反応液としての２－アミノ－３－ブロモ－５－クロロフェノール（９．００ｇ）と臭化シアン（４．７２ ｇ）とのエタノール（４００ ｍＬ）懸濁液を、室温で３日間攪拌した。反応液を減圧留去して、得られた残渣を、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：１）を用いて精製し、黄色固体として表題化合物を得た（６．３４ｇ）。
1H-NMR (400 MHz, DMSO-d6) δ 7.39 (1H, d, J = 1.8 Hz), 7.55 (1H, d, J = 1.8 Hz), 7.86 (2H, brs). 2-Amino-4-bromo-6-chlorobenzo [d] oxazole Under an argon atmosphere, 2-amino-3-bromo-5-chlorophenol (9.00 g) and cyanogen bromide (4.72 g) as a reaction solution And an ethanol (400 mL) suspension with was stirred at room temperature for 3 days. The reaction solution was evaporated under reduced pressure, and the obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound as a yellow solid (6.34 g).
1 H-NMR (400 MHz, DMSO-d 6 ) δ 7.39 (1H, d, J = 1.8 Hz), 7.55 (1H, d, J = 1.8 Hz), 7.86 (2H, brs).
 ＜参考例７－１＞ <Reference Example 7-1>
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
４－ブロモ－６－クロロ－２－フェニルベンゾ［ｄ］オキサゾール
　アルゴン雰囲気下、２－アミノ－３－ブロモ－５－クロロフェノール（２．６０ ｇ）とピリジン（１．０ ｍＬ）とのキシレン（８０ ｍＬ）溶液に、０℃で塩化ベンゾイル（１．５０ ｍＬ）を加え、反応液とした。反応液を０℃で１時間攪拌した後、ｐ－トルエンスルホン酸１水和物（１１．１ｇ）を加えて、１４０℃で５時間加熱攪拌した。反応液を室温まで冷却した後、飽和炭酸水素ナトリウムを加えて反応液のｐＨを１１とした。酢酸エチルで抽出し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１０：１）を用いて精製し、黄色固体として表題化合物を得た（１．８７ｇ）
1H-NMR (400 MHz, CDCl3) δ 7.50-7.60 (5H, m), 8.25-8.30 (2H, m). 4-Bromo-6-chloro-2-phenylbenzo [d] oxazole xylene of 2-amino-3-bromo-5-chlorophenol (2.60 g) and pyridine (1.0 mL) under argon atmosphere 80 mL) solution was added benzoyl chloride (1.50 mL) at 0 ° C. to prepare a reaction solution. The reaction mixture was stirred at 0 ° C. for 1 hour, p-toluenesulfonic acid monohydrate (11.1 g) was added, and the mixture was stirred with heating at 140 ° C. for 5 hours. After the reaction solution was cooled to room temperature, saturated sodium hydrogen carbonate was added to adjust the pH of the reaction solution to 11. Extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give the title compound as a yellow solid (1.87 g).
1 H-NMR (400 MHz, CDCl 3 ) δ 7.50-7.60 (5H, m), 8.25-8.30 (2H, m).
 ＜参考例８－１＞ <Reference Example 8-1>
Figure JPOXMLDOC01-appb-C000044
   　 
Figure JPOXMLDOC01-appb-C000044
   　 
５－クロロ－４－メチル－２－フェニルベンゾ［ｄ］チアゾール
　アルゴン雰囲気下、Ｎ－ベンゾイル－３－クロロ－２－メチルアニリン（５００ ｍｇ）のトルエン（５．１ｍＬ）懸濁液に、ローソン試薬（８２３ mg） を加えた後に、１時間加熱還流した。室温まで放冷後、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１０：１ ～ ４：１）を用いて精製し、黄色液体を得た。次に、得られた黄色液体のトリフルオロ酢酸（４．６ ｍＬ）溶液に［ビス（トリフルオロアセトキシ）ヨ－ド］ベンゼン（８７７ｍｇ）を加えて室温で３０分間攪拌した。反応溶液を濃縮後、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２０：１～４：１）を用いて精製し、淡黄色固体として表題化合物を得た（５００ ｍｇ）。
1H-NMR (400 MHz, CDCl3) δ 2.86 (3H, s), 7.47-7.50 (3H, m), 7.65 (1H, d, J = 9.1 Hz), 7.71 (1H, d, J = 9.1 Hz), 8.09-8.12 (2H, m). 5-Chloro-4-methyl-2-phenylbenzo [d] thiazole Lawson reagent in a suspension of N-benzoyl-3-chloro-2-methylaniline (500 mg) in toluene (5.1 mL) under an argon atmosphere After adding (823 mg), the mixture was heated to reflux for 1 hour. After cooling to room temperature, the mixture was purified using silica gel column chromatography (hexane: ethyl acetate = 10: 1 to 4: 1) to obtain a yellow liquid. Next, [bis (trifluoroacetoxy) iodo] benzene (877 mg) was added to a solution of the obtained yellow liquid in trifluoroacetic acid (4.6 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated and purified using silica gel column chromatography (hexane: ethyl acetate = 20: 1 to 4: 1) to give the title compound as a pale yellow solid (500 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ 2.86 (3H, s), 7.47-7.50 (3H, m), 7.65 (1H, d, J = 9.1 Hz), 7.71 (1H, d, J = 9.1 Hz ), 8.09-8.12 (2H, m).
＜参考例８－２および８－３＞
　対応するアニリンを用い、参考例８－１と同様にして、以下の参考例８－２および８－３の化合物を得た。これらの構造およびスペクトルデータを表１に示した。 <Reference Examples 8-2 and 8-3>
The corresponding compounds of Reference Examples 8-2 and 8-3 were obtained in the same manner as in Reference Example 8-1, using the corresponding aniline. These structures and spectral data are shown in Table 1.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
＜参考例９－１＞ <Reference Example 9-1>
Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045
２－アミノ－４－ブロモ－６－クロロベンゾ［ｄ］チアゾール
　アルゴン雰囲気下、２－ブロモ－４－クロロアニリン（１５．５ ｇ）とチオシアン酸アンモニウム（２３．０ｇ）の酢酸（１００ ｍＬ）懸濁液に、０℃で臭素（７．８ ｍＬ）の酢酸（２０ ｍＬ）溶液を1時間かけて滴下し、反応液とした。反応液を室温で３時間攪拌した。濾取して得られた黄色固体を水に懸濁した後、炭酸カリウムを当該懸濁液に加えて反応液のｐＨを１１とした。析出した固体を濾取し、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝３：１）を用いて精製し、黄色固体として表題化合物を得た（１４．２ｇ）。
1H-NMR (400 MHz, CDCl3) δ 7.49 (1H, d, J = 1.8 Hz), 7.81 (1H, d, J = 1.8 Hz), 7.96 (2H, brs). 2-Amino-4-bromo-6-chlorobenzo [d] thiazole Suspension of acetic acid (100 mL) of 2-bromo-4-chloroaniline (15.5 g) and ammonium thiocyanate (23.0 g) under an argon atmosphere To the solution, a solution of bromine (7.8 mL) in acetic acid (20 mL) was added dropwise at 0 ° C. over 1 hour to prepare a reaction solution. The reaction was stirred at room temperature for 3 hours. The yellow solid obtained by filtration was suspended in water, and potassium carbonate was added to the suspension to adjust the pH of the reaction solution to 11. The precipitated solid was collected by filtration and purified using silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound as a yellow solid (14.2 g).
1 H-NMR (400 MHz, CDCl 3 ) δ 7.49 (1H, d, J = 1.8 Hz), 7.81 (1H, d, J = 1.8 Hz), 7.96 (2H, brs).
＜参考例９－２～９－５＞
　対応するアニリンを用い、参考例９－１と同様にして、以下の参考例９－２～９－５の化合物を得た。これらの構造およびスペクトルデータを表２に示した。 <Reference Examples 9-2 to 9-5>
The corresponding compounds of Reference Examples 9-2 to 9-5 were obtained in the same manner as in Reference Example 9-1 using the corresponding aniline. These structures and spectral data are shown in Table 2.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
＜参考例１０－１＞ <Reference Example 10-1>
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046
４－ブロモ－２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－６－クロロベンゾ［ｄ］チアゾール
　アルゴン雰囲気下、２－アミノ－４－ブロモ－６－クロロベンゾ［ｄ］チアゾール（１４．１ｇ）をジクロロメタン（３００ ｍＬ）及びテトラヒドロフラン（２００ｍL）に懸濁した。懸濁液に０℃でＢｏｃ２Ｏ（１３．０ ｇ）、トリエチルアミン（１５．０ ｍＬ）、４－ジメチルアミノピリジン（６５０ｍｇ）を加え、反応液とした。反応液を０℃で２時間攪拌した。反応液に水を加え、酢酸エチルで抽出し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝５：１）を用いて精製し、無色固体として表題化合物を得た（１５．８ｇ）。
1H-NMR (400 MHz, CDCl3) δ 1.55 (9H, s), 7.59 (1H, d, J = 1.8 Hz), 7.69 (1H, d, J = 1.8 Hz), 8.47 (1H, brs). 4-Bromo-2- (tert-butoxycarbonylamino) -6-chlorobenzo [d] thiazole Under an argon atmosphere, 2-amino-4-bromo-6-chlorobenzo [d] thiazole (14.1 g) was added to dichloromethane (300 mL). ) And tetrahydrofuran (200 mL). Boc 2 O (13.0 g), triethylamine (15.0 mL) and 4-dimethylaminopyridine (650 mg) were added to the suspension at 0 ° C. to prepare a reaction solution. The reaction was stirred at 0 ° C. for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound as a colorless solid (15.8 g).
1 H-NMR (400 MHz, CDCl 3 ) δ 1.55 (9H, s), 7.59 (1H, d, J = 1.8 Hz), 7.69 (1H, d, J = 1.8 Hz), 8.47 (1H, brs).
＜参考例１０－２～１０－４＞
　対応するアミンを用い、参考例１０－１と同様にして、以下の参考例１０－２から１０－４の化合物を得た。これらの構造およびスペクトルデータを表３に示した。 <Reference Examples 10-2 to 10-4>
The following compounds of Reference Examples 10-2 to 10-4 were obtained in the same manner as in Reference Example 10-1, using the corresponding amine. These structures and spectral data are shown in Table 3.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
＜参考例１１－１＞ <Reference Example 11-1>
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047
６－［［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－６－クロロベンゾ［ｄ］チアゾール－４－イル］（ヒドロキシ）メチル］ピリジン－２－カルボン酸メチル
　アルゴン雰囲気下、４－ブロモ－２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－６－クロロベンゾ［ｄ］チアゾール（７．００ｇ）のテトラヒドロフラン溶液（１５０ｍＬ）に、－１０℃でイソプロピルマグネシウムクロリド　リチウムクロリド錯体（３６．０ ｍＬ, １．３ ｍｏｌ/Ｌ　テトラヒドロフラン溶液）を加え、室温で２時間攪拌した。得られた混合物に６－ホルミルピリジン－２－カルボン酸メチル（３．８１ｇ） のテトラヒドロフラン溶液 （４０ ｍＬ）を－４０℃で０．５時間かけて加え、反応液とした。反応液をその後室温まで徐々に昇温した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝３：１）を用いて精製し、黄色固体として表題化合物を得た（７．１０ｇ）。
1H-NMR (400 MHz, CDCl3) δ 1.58 (9H, s), 4.02 (3H, s), 5.78 (1H, d, J = 5.5 Hz), 6.57 (1H, d, J = 5.5 Hz), 7.37 (1H, d, J = 1.8 Hz), 7.56 (1H, d, J = 7.9 Hz), 7.65 (1H, d, J = 1.8 Hz), 7.72 (1H, t, J = 7.9 Hz), 8.01 (1H, d, J = 7.9 Hz), 8.27 (1H, brs). Methyl 6-[[2- (tert-butoxycarbonylamino) -6-chlorobenzo [d] thiazol-4-yl] (hydroxy) methyl] pyridine-2-carboxylate 4-bromo-2- (tert -Butoxycarbonylamino) -6-chlorobenzo [d] thiazole (7.00 g) in tetrahydrofuran solution (150 mL) at −10 ° C. with isopropylmagnesium chloride lithium chloride complex (36.0 mL, 1.3 mol / L tetrahydrofuran solution) ) And stirred at room temperature for 2 hours. To the obtained mixture, a solution of methyl 6-formylpyridine-2-carboxylate (3.81 g) in tetrahydrofuran (40 mL) was added at −40 ° C. over 0.5 hours to prepare a reaction solution. The reaction was then gradually warmed to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound as a yellow solid (7.10 g).
1 H-NMR (400 MHz, CDCl 3 ) δ 1.58 (9H, s), 4.02 (3H, s), 5.78 (1H, d, J = 5.5 Hz), 6.57 (1H, d, J = 5.5 Hz), 7.37 (1H, d, J = 1.8 Hz), 7.56 (1H, d, J = 7.9 Hz), 7.65 (1H, d, J = 1.8 Hz), 7.72 (1H, t, J = 7.9 Hz), 8.01 ( 1H, d, J = 7.9 Hz), 8.27 (1H, brs).
＜参考例１１－２～１１－４＞
　対応するブロモ体を用い、参考例１１－１と同様にして、以下の参考例１１－２～１１－４の化合物を得た。これらの構造およびスペクトルデータを表４に示した。 <Reference Examples 11-2 to 11-4>
The corresponding compounds of Reference Examples 11-2 to 11-4 were obtained in the same manner as in Reference Example 11-1, using the corresponding bromo compound. These structures and spectral data are shown in Table 4.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
＜参考例１２－１＞ <Reference Example 12-1>
Figure JPOXMLDOC01-appb-C000048
  　 
Figure JPOXMLDOC01-appb-C000048
  　 
２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－６－クロロベンゾ［ｄ］オキサゾール－４－カルボキシアルデヒド
　アルゴン雰囲気下、４－ブロモ－２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－６－クロロベンゾ［ｄ］オキサゾール（４．００ｇ）のテトラヒドロフラン溶液（１２０ｍＬ）に、－１０℃でイソプロピルマグネシウムクロリド　リチウムクロリド錯体（２１．５ ｍＬ, １．３ ｍｏｌ/Ｌ　テトラヒドロフラン溶液）を加え、室温で２時間攪拌した。得られた混合物にＮ，Ｎ－ジメチルホルムアミド（１０ｍＬ）を－７８℃で０．５時間かけて加え、反応液とした。反応液をその後０℃まで徐々に昇温した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水にて洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：１）を用いて精製し、淡黄色固体として表題化合物を得た（２．８０ｇ）。
1H-NMR (400 MHz, CDCl3) δ 1.57 (9H, s), 7.67 (1H, s), 7.80 (1H, s), 8.06 (1H, brs), 10.52 (1H, brs). 2- (tert-Butoxycarbonylamino) -6-chlorobenzo [d] oxazole-4-carboxaldehyde 4-Bromo-2- (tert-butoxycarbonylamino) -6-chlorobenzo [d] oxazole (4. 00 g) in tetrahydrofuran (120 mL) was added isopropylmagnesium chloride lithium chloride complex (21.5 mL, 1.3 mol / L in tetrahydrofuran) at −10 ° C. and stirred at room temperature for 2 hours. N, N-dimethylformamide (10 mL) was added to the obtained mixture at −78 ° C. over 0.5 hour to obtain a reaction solution. The reaction solution was then gradually warmed to 0 ° C. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound as a pale yellow solid (2.80 g).
1 H-NMR (400 MHz, CDCl 3 ) δ 1.57 (9H, s), 7.67 (1H, s), 7.80 (1H, s), 8.06 (1H, brs), 10.52 (1H, brs).
＜参考例１２－２～１２－５＞
　対応するブロモ体を用い、参考例１２－１と同様にして、以下の参考例１２－２～１２－５の化合物を得た。これらの構造およびスペクトルデータを表５に示した。 <Reference Examples 12-2 to 12-5>
The corresponding compounds of Reference Examples 12-2 to 12-5 were obtained in the same manner as in Reference Example 12-1, using the corresponding bromo compound. These structures and spectral data are shown in Table 5.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
＜参考例１３－１＞ <Reference Example 13-1>
Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049
２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－６－クロロベンゾ［ｄ］チアゾール－４－ボロン酸
　アルゴン雰囲気下、４－ブロモ－２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－６－クロロベンゾ［ｄ］チアゾール（５．００ｇ）のテトラヒドロフラン溶液（１１０ｍＬ）に、－１０℃でイソプロピルマグネシウムクロリド　リチウムクロリド錯体（２６．０ ｍＬ, １．３ ｍｏｌ/Ｌ　テトラヒドロフラン溶液）を加え、室温で２時間攪拌した。得られた混合物にトリメトキシボラン（８．５ｍＬ）を－７８℃で０．５時間かけて加え、反応液とした。反応液をその後０℃まで徐々に昇温した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。溶媒を留去し、淡黄色固体として表題化合物を得た（４．５０ｇ）。
1H-NMR (400 MHz, CDCl3) δ 1.51 (9H, s), 7.71 (1H, d, J = 1.8 Hz), 8.15 (1H, d, J = 1.8 Hz), 8.65 (2H, brs), 12.06 (1H, brs). 2- (tert-Butoxycarbonylamino) -6-chlorobenzo [d] thiazole-4-boronic acid Under an argon atmosphere, 4-bromo-2- (tert-butoxycarbonylamino) -6-chlorobenzo [d] thiazole (5. 00 g) in tetrahydrofuran (110 mL) was added isopropylmagnesium chloride lithium chloride complex (26.0 mL, 1.3 mol / L tetrahydrofuran solution) at −10 ° C., and the mixture was stirred at room temperature for 2 hours. Trimethoxyborane (8.5 mL) was added to the obtained mixture at −78 ° C. over 0.5 hour to obtain a reaction solution. The reaction solution was then gradually warmed to 0 ° C. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off to give the title compound as a pale yellow solid (4.50 g).
1 H-NMR (400 MHz, CDCl 3 ) δ 1.51 (9H, s), 7.71 (1H, d, J = 1.8 Hz), 8.15 (1H, d, J = 1.8 Hz), 8.65 (2H, brs), 12.06 (1H, brs).
＜参考例１４－１＞ <Reference Example 14-1>
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050
６－［（２－アミノ－６－クロロベンゾ［ｄ］チアゾール－４－イル）メチル］ピリジン－２－カルボン酸メチル
　アルゴン雰囲気下、６－［［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－６－クロロベンゾ［ｄ］チアゾール－４－イル］（ヒドロキシ）メチル］ピリジン－２－カルボン酸メチル（３．００ｇ）のクロロホルム（６５ｍＬ）懸濁液に、室温で三臭化リン（１．９０ ｍＬ）を加え、反応液とした。反応液を室温で０．５時間、続いて８０℃で３時間攪拌した。反応液を０℃に冷却し、水、飽和炭酸水素ナトリウム水溶液を加え、反応液のｐＨを１１とした後、酢酸エチルで抽出した。溶媒を留去して得られた残渣をジクロロメタン（３０ｍＬ）に溶解し、室温でトリフルオロ酢酸（５．０ ｍＬ）を加え、第２の反応液とした。第２の反応液を室温で２４時間攪拌した。第２の反応液を１ｍｏｌ／Ｌ 炭酸カリウム水溶液（１００ ｍＬ）に注ぎ、析出した固体を濾取し、無色結晶として表題化合物を得た（１．３７ ｇ）。
1H-NMR (400 MHz, CDCl3) δ 3.87 (3H, s), 4.37 (2H, s), 7.03 (1H, d, J = 1.8 Hz), 7.35 (1H, dd, J = 6.7, 1.8 Hz), 7.65-7.72 (3H, m), 7.83-7.90 (2H, m). 6-[(2-Amino-6-chlorobenzo [d] thiazol-4-yl) methyl] pyridine-2-carboxylate 6-[[2- (tert-butoxycarbonylamino) -6-chlorobenzoate under argon atmosphere To a suspension of [d] methyl thiazol-4-yl] (hydroxy) methyl] pyridine-2-carboxylate (3.00 g) in chloroform (65 mL) was added phosphorus tribromide (1.90 mL) at room temperature. The reaction solution was used. The reaction was stirred at room temperature for 0.5 hour followed by 3 hours at 80 ° C. The reaction solution was cooled to 0 ° C., water and a saturated aqueous sodium hydrogen carbonate solution were added to adjust the pH of the reaction solution to 11, and the mixture was extracted with ethyl acetate. The residue obtained by distilling off the solvent was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (5.0 mL) was added at room temperature to obtain a second reaction solution. The second reaction was stirred at room temperature for 24 hours. The second reaction solution was poured into a 1 mol / L aqueous potassium carbonate solution (100 mL), and the precipitated solid was collected by filtration to give the title compound as colorless crystals (1.37 g).
1 H-NMR (400 MHz, CDCl 3 ) δ 3.87 (3H, s), 4.37 (2H, s), 7.03 (1H, d, J = 1.8 Hz), 7.35 (1H, dd, J = 6.7, 1.8 Hz ), 7.65-7.72 (3H, m), 7.83-7.90 (2H, m).
＜参考例１４－２～１４－４＞
　対応するヒドロキシメチル体を用い、参考例１４－１と同様にして、以下の参考例１４－２～１４－４の化合物を得た。これらの構造およびスペクトルデータを表６に示した。 <Reference Examples 14-2 to 14-4>
Using the corresponding hydroxymethyl compound, the following compounds of Reference Examples 14-2 to 14-4 were obtained in the same manner as Reference Example 14-1. These structures and spectral data are shown in Table 6.
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
＜参考例１５－１＞ <Reference Example 15-1>
Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000051
２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－６－クロロ－４－（ヒドロキシメチル）ベンゾ［ｄ］オキサゾール
　アルゴン雰囲気下、２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－６－クロロベンゾ［ｄ］オキサゾール－４－カルボキシアルデヒド（２．８０ｇ）のメタノール（５０ ｍＬ）溶液に、０℃で水素化ホウ素ナトリウム（４００ ｍｇ）を加え、反応液とした。反応液を０℃で３時間攪拌した。反応液を０℃に冷却後、水を加え、ジクロロメタンで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：１）を用いて精製し、無色固体として表題化合物を得た（２．９３ｇ）。
1H-NMR (400 MHz, CDCl3) δ 1.57 (9H, s), 3.52 (1H, brs), 4.93 (2H, brs), 7.29 (1H, d, J = 1.8 Hz), 7.39 (1H, d, J = 1.8 Hz), 8.64 (1H, brs). 2- (tert-Butoxycarbonylamino) -6-chloro-4- (hydroxymethyl) benzo [d] oxazole Under argon atmosphere, 2- (tert-butoxycarbonylamino) -6-chlorobenzo [d] oxazole-4-carboxyl Sodium borohydride (400 mg) was added to a solution of aldehyde (2.80 g) in methanol (50 mL) at 0 ° C. to prepare a reaction solution. The reaction was stirred at 0 ° C. for 3 hours. The reaction mixture was cooled to 0 ° C., water was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound as a colorless solid (2.93 g).
1 H-NMR (400 MHz, CDCl 3 ) δ 1.57 (9H, s), 3.52 (1H, brs), 4.93 (2H, brs), 7.29 (1H, d, J = 1.8 Hz), 7.39 (1H, d , J = 1.8 Hz), 8.64 (1H, brs).
＜参考例１５－２～１５－７＞
　対応するアルデヒド体を用い、参考例１５－１と同様にして、以下の参考例１５－２～１５－７の化合物を得た。これらの構造およびスペクトルデータを表７および８に示した。 <Reference Examples 15-2 to 15-7>
The corresponding compounds of Reference Examples 15-2 to 15-7 were obtained in the same manner as in Reference Example 15-1, using the corresponding aldehyde compounds. Their structures and spectral data are shown in Tables 7 and 8.
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
＜参考例１６－１＞ <Reference Example 16-1>
Figure JPOXMLDOC01-appb-C000052
Figure JPOXMLDOC01-appb-C000052
６－［（６－クロロ－２－ヨードベンゾ［ｄ］チアゾール－４－イル）メチル］ピリジン－２－カルボン酸メチル
　アルゴン雰囲気下、６－［（２－アミノ－６－クロロベンゾ［ｄ］チアゾール－４－イル）メチル］ピリジン－２－カルボン酸メチル（３．３７ｇ）のアセトニトリル（４５ｍＬ）懸濁液に、１０℃でｐ－トルエンスルホン酸１水和物（５．７７ ｇ）を加え、１０℃で０．５時間攪拌した。次に、当該懸濁液に亜硝酸ナトリウム（１．４１ ｇ）の水（３ ｍＬ）溶液、ヨウ化カリウム（４．２０ ｇ）の水（３．５ ｍＬ）溶液を順次加え、反応液とした。反応液を１０℃で０．５時間、室温で２４時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、反応液のｐＨを１１とした後、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥した後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝３：１）を用いて精製し、黄色固体として表題化合物を得た。（３．２０ｇ）。
1H-NMR (400 MHz, CDCl3) δ 4.03 (3H, s), 4.76 (2H, s), 7.29 (1H, d, J = 2.4 Hz), 7.36 (1H, d, J = 7.8 Hz), 7.70 (1H, d, J = 2.4 Hz), 7.72 (1H, t, J = 7.8 Hz), 8.00 (1H, d, J = 7.8 Hz). 6-[(6-Chloro-2-iodobenzo [d] thiazol-4-yl) methyl] pyridine-2-carboxylate 6-[(2-Amino-6-chlorobenzo [d] thiazole-4 under argon atmosphere P-Toluenesulfonic acid monohydrate (5.77 g) was added to a suspension of methyl (-yl) methyl] pyridine-2-carboxylate (3.37 g) in acetonitrile (45 mL) at 10 ° C. For 0.5 hour. Next, a solution of sodium nitrite (1.41 g) in water (3 mL) and a solution of potassium iodide (4.20 g) in water (3.5 mL) were sequentially added to the suspension. did. The reaction was stirred at 10 ° C. for 0.5 hour and at room temperature for 24 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution to adjust the pH of the reaction solution to 11, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound as a yellow solid. (3.20 g).
1 H-NMR (400 MHz, CDCl 3 ) δ 4.03 (3H, s), 4.76 (2H, s), 7.29 (1H, d, J = 2.4 Hz), 7.36 (1H, d, J = 7.8 Hz), 7.70 (1H, d, J = 2.4 Hz), 7.72 (1H, t, J = 7.8 Hz), 8.00 (1H, d, J = 7.8 Hz).
＜参考例１６－２～１６－１４＞
対応するアミノ体を用い、参考例１６－１と同様にして、以下の参考例１６－２～１６－１４の化合物を得た。これらの構造およびスペクトルデータを表９～１１に示した。 <Reference Examples 16-2 to 16-14>
The corresponding compounds of Reference Examples 16-2 to 16-14 were obtained in the same manner as in Reference Example 16-1, using the corresponding amino form. Their structures and spectral data are shown in Tables 9-11.
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000011
 ＜参考例１７－１＞ <Reference Example 17-1>
Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000053
２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－６－フルオロ－４－（ヒドロキシメチル）ベンゾ［ｄ］チアゾール
　アルゴン雰囲気下、４－ブロモ－２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－６－フルオロベンゾ［ｄ］チアゾール（６．３２ｇ）のテトラヒドロフラン溶液（１８０ ｍＬ）に、－１０℃でイソプロピルマグネシウムクロリド　リチウムクロリド錯体（３４．０ｍＬ, １．３ ｍｏｌ/Ｌ　テトラヒドロフラン溶液）を加え、室温で２時間攪拌した。得られた混合物にパラホルムアルデヒド（５．００ｇ）を－４０℃で加え反応液とした。反応液を、その後室温まで徐々に昇温した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝３：１）を用いて精製し、黄色固体として表題化合物を得た（２．８８ｇ）。
1H-NMR (400 MHz, DMSO-d6) δ 1.49 (9H, s), 4.84 (2H, d, J = 5.5 Hz), 5.34 (1H, t, J = 5.5 Hz), 7.23 (1H, dd, J = 10.3, 2.4 Hz), 7.69 (1H, dd, J = 8.5, 2.4 Hz), 11.83 (1H, s). 2- (tert-Butoxycarbonylamino) -6-fluoro-4- (hydroxymethyl) benzo [d] thiazole 4-bromo-2- (tert-butoxycarbonylamino) -6-fluorobenzo [d] under argon atmosphere To a tetrahydrofuran solution (180 mL) of thiazole (6.32 g) was added isopropylmagnesium chloride lithium chloride complex (34.0 mL, 1.3 mol / L tetrahydrofuran solution) at −10 ° C., and the mixture was stirred at room temperature for 2 hours. Paraformaldehyde (5.00 g) was added to the obtained mixture at −40 ° C. to obtain a reaction solution. The reaction was then gradually warmed to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound as a yellow solid (2.88 g).
1 H-NMR (400 MHz, DMSO-d 6 ) δ 1.49 (9H, s), 4.84 (2H, d, J = 5.5 Hz), 5.34 (1H, t, J = 5.5 Hz), 7.23 (1H, dd , J = 10.3, 2.4 Hz), 7.69 (1H, dd, J = 8.5, 2.4 Hz), 11.83 (1H, s).
 ＜参考例１８－１＞ <Reference Example 18-1>
Figure JPOXMLDOC01-appb-C000054
Figure JPOXMLDOC01-appb-C000054
２－アミノ－６－フルオロ－４－（ヒドロキシメチル）ベンゾ［ｄ］チアゾール
　アルゴン雰囲気下、２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－６－フルオロ－４－（ヒドロキシメチル）ベンゾ［ｄ］チアゾール（２．８５ｇ）のジクロロメタン（５０ ｍＬ）溶液に、室温でトリフルオロ酢酸（７．１ ｍＬ）を加え、反応液とした。反応液を室温で２４時間攪拌した。反応液を１ ｍｏｌ／Ｌ炭酸カリウム水溶液（１５０ ｍＬ）に注いだ後、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：１）を用いて精製し、黄色固体として表題化合物を得た（１．２１ｇ）。
1H-NMR (400 MHz, DMSO-d6) δ 4.71 (2H, s), 7.06 (1H, dd, J = 10.3, 2.4 Hz), 7.43 (1H, dd, J = 10.3, 2.4 Hz), 7.53 (2H, brs). 2-Amino-6-fluoro-4- (hydroxymethyl) benzo [d] thiazole Under argon atmosphere, 2- (tert-butoxycarbonylamino) -6-fluoro-4- (hydroxymethyl) benzo [d] thiazole (2 .85 g) in dichloromethane (50 mL) was added trifluoroacetic acid (7.1 mL) at room temperature to prepare a reaction solution. The reaction was stirred at room temperature for 24 hours. The reaction mixture was poured into 1 mol / L aqueous potassium carbonate solution (150 mL), and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound as a yellow solid (1.21 g).
1 H-NMR (400 MHz, DMSO-d 6 ) δ 4.71 (2H, s), 7.06 (1H, dd, J = 10.3, 2.4 Hz), 7.43 (1H, dd, J = 10.3, 2.4 Hz), 7.53 (2H, brs).
 ＜参考例１９－１＞ <Reference Example 19-1>
Figure JPOXMLDOC01-appb-C000055
Figure JPOXMLDOC01-appb-C000055
２－クロロ－４－（クロロメチル）－６－フルオロベンゾ［ｄ］チアゾール
　アルゴン雰囲気下、６－フルオロ－４－（ヒドロキシメチル）－２－ヨードベンゾ［ｄ］チアゾール（１．０４ｇ）のジクロロメタン（１７ ｍＬ）溶液に、室温で塩化チオニル（１．３ｍＬ）を加え、反応液とした。反応液を室温で１時間攪拌した後、Ｎ，Ｎ－ジメチルホルムアミド（３滴）を加え、室温で１０時間攪拌した。反応液を０℃に冷却しながら、飽和炭酸水素ナトリウム水溶液を加え、反応液のｐＨを１１とした後、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝５：１）を用いて精製し、黄色オイルとして表題化合物を得た（７９２ｍｇ）。
1H-NMR (400 MHz, CDCl3) δ 5.04 (2H, s), 7.36 (1H, dd, J = 9.8, 2.4 Hz), 7.44 (1H, dd, J = 7.8, 2.4 Hz). 2-Chloro-4- (chloromethyl) -6-fluorobenzo [d] thiazole Under argon atmosphere, 6-fluoro-4- (hydroxymethyl) -2-iodobenzo [d] thiazole (1.04 g) in dichloromethane (17 To the solution, thionyl chloride (1.3 mL) was added at room temperature to obtain a reaction solution. The reaction mixture was stirred at room temperature for 1 hour, N, N-dimethylformamide (3 drops) was added, and the mixture was stirred at room temperature for 10 hours. While cooling the reaction solution to 0 ° C., a saturated aqueous sodium hydrogen carbonate solution was added to adjust the pH of the reaction solution to 11, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound as a yellow oil (792 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ 5.04 (2H, s), 7.36 (1H, dd, J = 9.8, 2.4 Hz), 7.44 (1H, dd, J = 7.8, 2.4 Hz).
＜参考例１９－２～１９－５＞
　対応するヒドロキシメチル体を用い、参考例１９－１と同様にして、以下の参考例１９－２～１９－５の化合物を得た。これらの構造およびスペクトルデータを表１２に示した。 <Reference Examples 19-2 to 19-5>
Using the corresponding hydroxymethyl compound, the following Reference Examples 19-2 to 19-5 were obtained in the same manner as Reference Example 19-1. Their structures and spectral data are shown in Table 12.
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000012
 ＜参考例２０－１＞ <Reference Example 20-1>
Figure JPOXMLDOC01-appb-C000056
Figure JPOXMLDOC01-appb-C000056
７－（ブロモメチル）－５－クロロ－２－フェニルベンゾ［ｄ］オキサゾール
　アルゴン雰囲気下、５－クロロ－７－（ヒドロキシメチル）－２－フェニルベンゾ［ｄ］オキサゾール（１．００ｇ）のジクロロメタン（２６ ｍＬ）懸濁液に、イミダゾール（３４１ ｍｇ）、及び四臭化炭素（１．５３ ｇ） を加え、反応液とした。次に、トリフェニルホスフィン（１．１１ｇ）を加えたところ、反応液が溶液となった。溶液である反応液を室温で30分間攪拌した後に、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝４：１～１：１）を用いて精製し、無色固体として表題化合物を得た（８５３ ｍｇ）。
1H-NMR (400 MHz, CDCl3) δ 4.74 (2H, s), 7.37 (1H, d, J = 1.8 Hz), 7.50-7.61 (3H, m), 7.70 (1H, d, J = 2.4 Hz), 8.26 (1H, d, J = 1.8 Hz), 8.29 (1H, d, J = 1.2 Hz). 7- (Bromomethyl) -5-chloro-2-phenylbenzo [d] oxazole Under argon atmosphere, 5-chloro-7- (hydroxymethyl) -2-phenylbenzo [d] oxazole (1.00 g) in dichloromethane (26 mL) To the suspension, imidazole (341 mg) and carbon tetrabromide (1.53 g) were added to obtain a reaction solution. Next, when triphenylphosphine (1.11 g) was added, the reaction solution became a solution. The reaction solution, which was a solution, was stirred at room temperature for 30 minutes and then purified using silica gel column chromatography (hexane: ethyl acetate = 4: 1 to 1: 1) to give the title compound as a colorless solid (853 mg). .
1 H-NMR (400 MHz, CDCl 3 ) δ 4.74 (2H, s), 7.37 (1H, d, J = 1.8 Hz), 7.50-7.61 (3H, m), 7.70 (1H, d, J = 2.4 Hz ), 8.26 (1H, d, J = 1.8 Hz), 8.29 (1H, d, J = 1.2 Hz).
＜参考例２０－１＞
　対応するヒドロキシメチル体を用い、参考例２０－１と同様にして、以下の参考例２０－２～２０－４の化合物を得た。これらの構造およびスペクトルデータを表１３に示した。 <Reference Example 20-1>
Using the corresponding hydroxymethyl compound, the following Reference Examples 20-2 to 20-4 were obtained in the same manner as Reference Example 20-1. Their structures and spectral data are shown in Table 13.
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000013
 ＜参考例２１－１＞ <Reference Example 21-1>
Figure JPOXMLDOC01-appb-C000057
Figure JPOXMLDOC01-appb-C000057
１－［（５－クロロ－２－ヒドロキシ－３－ニトロフェニル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル
　５－クロロ－２－ヒドロキシ－３－ニトロベンズアルデヒド（２３．０ ｇ）のジクロロメタン（５７０ ｍＬ）溶液にｔｅｒｔ-ブチルカルバゼート（１５．１ ｇ）、酢酸（６．５１ ｍＬ）を加え、第１の反応液とした。第１の反応液を室温で１時間攪拌した。続いて第１の反応液にトリアセトキシ水素化ホウ素ナトリウム（３４．０ｇ）を加えて室温で１９時間攪拌した。第１の反応液を氷冷して、塩化水素水溶液（１．０ ｍｏｌ/Ｌ， ３００ ｍＬ）を加えて抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去後、残渣にジクロロメタン（４５０ ｍＬ）、及びトリフルオロ酢酸（２００ ｍＬ）を加え、第２の反応液とした。第２の反応液を室温で２時間攪拌した。溶媒を減圧留去後、残渣に酢酸（２００ ｍＬ）、２，４－ジオキソヘプタン酸エチル（１６．０ｍＬ）を加え、第３の反応液とした。第３の反応液を１時間攪拌した。溶媒を減圧留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：０～２：１）を用いて精製し、淡黄色固体として表題化合物を得た（３３．４ ｇ）。
1H-NMR (400 MHz, CDCl3) δ 1.40 (3H, t, J = 7.3 Hz), 2.29 (3H, s), 4.41 (2H, q, J = 7.3 Hz), 5.44 (2H, s), 6.64 (1H, s), 6.67 (1H, s), 7.00 (1H, d, J = 3.0 Hz), 8.06 (1H, d, J = 3.0 Hz). 1-[(5-Chloro-2-hydroxy-3-nitrophenyl) methyl] -5-methyl-1H-pyrazole-3-carboxylate 5-chloro-2-hydroxy-3-nitrobenzaldehyde (23.0 g ) In dichloromethane (570 mL) was added tert-butylcarbazate (15.1 g) and acetic acid (6.51 mL) to give a first reaction solution. The first reaction was stirred at room temperature for 1 hour. Subsequently, sodium triacetoxyborohydride (34.0 g) was added to the first reaction solution, and the mixture was stirred at room temperature for 19 hours. The first reaction solution was ice-cooled, and an aqueous hydrogen chloride solution (1.0 mol / L, 300 mL) was added for extraction. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, dichloromethane (450 mL) and trifluoroacetic acid (200 mL) were added to the residue to obtain a second reaction solution. The second reaction solution was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, acetic acid (200 mL) and ethyl 2,4-dioxoheptanoate (16.0 mL) were added to the residue to obtain a third reaction solution. The third reaction was stirred for 1 hour. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0-2: 1) to give the title compound as a pale yellow solid (33.4 g).
1 H-NMR (400 MHz, CDCl 3 ) δ 1.40 (3H, t, J = 7.3 Hz), 2.29 (3H, s), 4.41 (2H, q, J = 7.3 Hz), 5.44 (2H, s), 6.64 (1H, s), 6.67 (1H, s), 7.00 (1H, d, J = 3.0 Hz), 8.06 (1H, d, J = 3.0 Hz).
＜参考例２１－２＞ <Reference Example 21-2>
Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000058
１－［（３－アミノ－５－クロロ－２－ヒドロキシフェニル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル
　１－［（５－クロロ－２－ヒドロキシ－３－ニトロフェニル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル（２０．０ ｇ）の酢酸（３０ｍＬ）及びメタノール（２５８ｍＬ）溶液に、アルゴン雰囲気下、鉄（１４．５ｇ）を加え、反応液とした。反応液を４０分間加熱還流した。飽和重曹水で反応液のｐＨを９とした後に、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：０～１：１）を用いて精製し、黄色固体として表題化合物を得た（１４．０ ｇ）。
1H-NMR (400 MHz, CDCl3) δ 1.38 (3H, t, J = 7.1 Hz), 2.40 (3H, s), 4.00 (2H, s), 4.36 (2H, q, J = 7.1 Hz), 5.11 (2H, s), 6.54 (1H, d, J = 1.8 Hz), 6.67 (2H, td, J = 2.4 Hz), 9.72 (1H, s). 1-[(3-Amino-5-chloro-2-hydroxyphenyl) methyl] -5-methyl-1H-pyrazole-3-carboxylate 1-[(5-Chloro-2-hydroxy-3-nitrophenyl) To a solution of ethyl [methyl] -5-methyl-1H-pyrazole-3-carboxylate (20.0 g) in acetic acid (30 mL) and methanol (258 mL) was added iron (14.5 g) under an argon atmosphere. It was. The reaction was heated to reflux for 40 minutes. The reaction mixture was adjusted to pH 9 with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 0 to 1: 1) to obtain the title compound as a yellow solid (14.0 g).
1 H-NMR (400 MHz, CDCl 3 ) δ 1.38 (3H, t, J = 7.1 Hz), 2.40 (3H, s), 4.00 (2H, s), 4.36 (2H, q, J = 7.1 Hz), 5.11 (2H, s), 6.54 (1H, d, J = 1.8 Hz), 6.67 (2H, td, J = 2.4 Hz), 9.72 (1H, s).
＜参考例２２－１＞ <Reference Example 22-1>
Figure JPOXMLDOC01-appb-C000059
   　 
Figure JPOXMLDOC01-appb-C000059
   　 
１－［（２－クロロ－６－フルオロベンゾ［ｄ］チアゾール－４－イル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル
　アルゴン雰囲気下、５-メチル-1H-ピラゾール-３-カルボン酸エチル（４２０ ｍｇ）のＮ，Ｎ－ジメチルホルムアミド溶液（５ ｍＬ）に、氷冷下で水素化ナトリウム（１２０ ｍｇ,　６０％オイル懸濁）を加え、室温で０．５時間撹拌した。得られた混合物に２－クロロ－４－（クロロメチル）－６－フルオロベンゾ［ｄ］チアゾール（８１０ ｍｇ）のＮ，Ｎ－ジメチルホルムアミド溶液（５ ｍＬ）を－７８℃で滴下し、反応液とした。反応液を、その後氷冷下で1時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝４：１）を用いて精製し、無色粉体として表題化合物を得た（５７０ｍｇ）。
1H-NMR (400 MHz, CDCl3) δ 1.41 (3H, t, J = 7.3 Hz), 2.24 (3H, s), 4.42 (2H, q, J = 7.3 Hz), 5.83 (2H, s), 6.66 (1H, s), 6.68 (1H, dd, J = 9.7, 2.4 Hz), 7.40 (1H, dd, J = 7.3, 2.4 Hz). Ethyl 1-[(2-chloro-6-fluorobenzo [d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate 5-methyl-1H-pyrazole-3 under argon atmosphere -Sodium hydride (120 mg, 60% oil suspension) was added to a solution of ethyl carboxylate (420 mg) in N, N-dimethylformamide (5 mL) under ice cooling, and the mixture was stirred at room temperature for 0.5 hour. . To the resulting mixture was added dropwise a solution of 2-chloro-4- (chloromethyl) -6-fluorobenzo [d] thiazole (810 mg) in N, N-dimethylformamide (5 mL) at −78 ° C. It was. The reaction solution was then stirred for 1 hour under ice cooling. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound as a colorless powder (570 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ 1.41 (3H, t, J = 7.3 Hz), 2.24 (3H, s), 4.42 (2H, q, J = 7.3 Hz), 5.83 (2H, s), 6.66 (1H, s), 6.68 (1H, dd, J = 9.7, 2.4 Hz), 7.40 (1H, dd, J = 7.3, 2.4 Hz).
＜参考例２２－２および２２－３＞
　対応するクロロメチル体を用い、参考例２２－１と同様にして、以下の参考例２２－２および２２－３の化合物を得た。これらの構造およびスペクトルデータを表１４に示した。 <Reference Examples 22-2 and 22-3>
The corresponding compounds of Reference Examples 22-2 and 22-3 were obtained in the same manner as in Reference Example 22-1 using the corresponding chloromethyl compound. Their structure and spectral data are shown in Table 14.
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000014
＜参考例２３－１＞ <Reference Example 23-1>
Figure JPOXMLDOC01-appb-C000060
   　 
Figure JPOXMLDOC01-appb-C000060
   　 
１－［（２－ヨードベンゾ［ｄ］チアゾール－４－イル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル
　アルゴン雰囲気下、２－ヨード－４－メチルベンゾ［ｄ］チアゾール（２０ ｇ）の四塩化炭素溶液（１４５ ｍＬ）に、室温でＮ－ブロモスクシンイミド（１５．５ ｇ）、過酸化ベンゾイル（１．１ ｇ）を加え、第１の反応液とした。第１の反応液を９０℃で４時間撹拌した。反応液に飽和チオ硫酸ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を留去し、黄色固体として４－（ブロモメチル）－２－ヨードベンゾ［ｄ］チアゾールを得た（２６．０ｇ）。
　アルゴン雰囲気下、５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル（１３．４ｇ）のＮ，Ｎ－ジメチルホルムアミド溶液（１８２ ｍＬ）に、氷冷下で水素化ナトリウム（３．２ｇ， ６０％ オイル懸濁）を加え、室温で１０分撹拌した。得られた混合物に４－（ブロモメチル）－２－ヨードベンゾ［ｄ］チアゾール（２６．０ｇ）のＮ，Ｎ－ジメチルホルムアミド溶液（１８２ ｍＬ）を滴下し、第２の反応液とした。第２の反応液をその後氷冷下で１時間撹拌した。第２の反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：１）を用いて精製し、無色粉体として表題化合物を得た（１７．６ｇ）。
1H-NMR (400 MHz, CDCl3) δ 1.40 (3H, t, J = 7.3 Hz), 2.22 (3H, s), 4.41 (2H, q, J = 7.3 Hz), 5.91 (2H, s), 6.64 (1H, s), 6.89 (1H, dd, J = 7.9, 1.2 Hz), 7.30 (1H, t, J = 7.9 Hz), 7.76 (1H, dd, J = 7.9, 1.2 Hz). 1-[(2-Iodobenzo [d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate 2-iodo-4-methylbenzo [d] thiazole (20 g ) To a carbon tetrachloride solution (145 mL) was added N-bromosuccinimide (15.5 g) and benzoyl peroxide (1.1 g) at room temperature to obtain a first reaction solution. The first reaction was stirred at 90 ° C. for 4 hours. A saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off to give 4- (bromomethyl) -2-iodobenzo [d] thiazole as a yellow solid (26.0 g).
To an N, N-dimethylformamide solution (182 mL) of ethyl 5-methyl-1H-pyrazole-3-carboxylate (13.4 g) under an argon atmosphere, sodium hydride (3.2 g, 60%) was cooled with ice. Oil suspension) was added and stirred at room temperature for 10 minutes. To the resulting mixture was added dropwise N, N-dimethylformamide solution (182 mL) of 4- (bromomethyl) -2-iodobenzo [d] thiazole (26.0 g) to give a second reaction solution. The second reaction solution was then stirred for 1 hour under ice cooling. A saturated aqueous ammonium chloride solution was added to the second reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound as a colorless powder (17.6 g).
1 H-NMR (400 MHz, CDCl 3 ) δ 1.40 (3H, t, J = 7.3 Hz), 2.22 (3H, s), 4.41 (2H, q, J = 7.3 Hz), 5.91 (2H, s), 6.64 (1H, s), 6.89 (1H, dd, J = 7.9, 1.2 Hz), 7.30 (1H, t, J = 7.9 Hz), 7.76 (1H, dd, J = 7.9, 1.2 Hz).
＜参考例２３－２～２３－５＞
　対応するメチル体を用い、参考例２３－１と同様にして、以下の参考例２３－２～２３－５の化合物を得た。これらの構造およびスペクトルデータを表１５に示した。 <Reference Examples 23-2 to 23-5>
The following compounds of Reference Examples 23-2 to 23-5 were obtained in the same manner as in Reference Example 23-1, using the corresponding methyl form. Their structures and spectral data are shown in Table 15.
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000015
 ＜参考例２４－１＞ <Reference Example 24-1>
Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-C000061
６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－４－（ヒドロキシメチル）ベンゾ［ｄ］オキサゾール
　アルゴン雰囲気下、６－クロロ－４－（ヒドロキシメチル）－２－ヨードベンゾ［ｄ］オキサゾール（８０．０ｍｇ）のテトラヒドロフラン溶液（１ ｍＬ）に、室温で１，２，３，６－テトラヒドロピリジン（０．１ ｍＬ）を加え、反応液とした。反応液を室温で１時間攪拌した。溶媒を減圧留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：１）を用いて精製し、無色固体として表題化合物を得た（２７．０ｍｇ）。
1H-NMR (400 MHz, CDCl3) δ 2.26-2.34 (2H, m), 3.27-3.37 (1H, m), 3.79 (2H, t, J = 5.5 Hz), 4.12-4.18 (2H, m), 4.88 (2H, d, J = 2.4 Hz), 5.75-5.82 (1H, m), 5.90-5.97 (1H, m), 7.07 (1H, d, J = 1.8 Hz), 7.18 (1H, d, J = 1.8 Hz). 6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) -4- (hydroxymethyl) benzo [d] oxazole 6-chloro-4- (hydroxymethyl) -2-iodobenzo under argon atmosphere [D] To a tetrahydrofuran solution (1 mL) of oxazole (80.0 mg), 1,2,3,6-tetrahydropyridine (0.1 mL) was added at room temperature to prepare a reaction solution. The reaction was stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the title compound as a colorless solid (27.0 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ 2.26-2.34 (2H, m), 3.27-3.37 (1H, m), 3.79 (2H, t, J = 5.5 Hz), 4.12-4.18 (2H, m) , 4.88 (2H, d, J = 2.4 Hz), 5.75-5.82 (1H, m), 5.90-5.97 (1H, m), 7.07 (1H, d, J = 1.8 Hz), 7.18 (1H, d, J = 1.8 Hz).
＜参考例２４－２および２４－３＞
　対応するヨウ素体を用い、参考例２４－１と同様にして、以下の参考例２４－２および２４－３の化合物を得た。これらの構造およびスペクトルデータを表１６に示した。 <Reference Examples 24-2 and 24-3>
Using the corresponding iodine form, the following compounds of Reference Examples 24-2 and 24-3 were obtained in the same manner as Reference Example 24-1. Their structures and spectral data are shown in Table 16.
Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-T000016
＜参考例２５－１＞ <Reference Example 25-1>
Figure JPOXMLDOC01-appb-C000062
Figure JPOXMLDOC01-appb-C000062
１－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボニトリル
　アルゴン雰囲気下、１－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボキシアミド（４００ｍｇ）のＮ，Ｎ－ジメチルホルムアミド溶液（１０ ｍＬ）に、室温で塩化チオニル（０．２ｍＬ）を加え、反応液とした。反応液を室温で２時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：１）を用いて精製し、黄色粉体として表題化合物を得た（３１２ｍｇ）。
1H-NMR (400 MHz, CDCl3) δ 2.31 (3H, s), 2.32-2.36 (2H, m), 3.75 (2H, t, J = 5.8 Hz), 4.09 (2H, t, J = 2.7 Hz), 5.60 (2H, s), 5.80 (1H, d, J = 10.3 Hz), 5.93-5.99 (1H, m), 6.44 (1H, s), 6.92 (1H, d, J = 1.8 Hz), 7.53 (1H, d, J = 1.8 Hz). 1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carbonitrile Argon 1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3- Thionyl chloride (0.2 mL) was added to a solution of carboxamide (400 mg) in N, N-dimethylformamide (10 mL) at room temperature to prepare a reaction solution. The reaction was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound as a yellow powder (312 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ 2.31 (3H, s), 2.32-2.36 (2H, m), 3.75 (2H, t, J = 5.8 Hz), 4.09 (2H, t, J = 2.7 Hz ), 5.60 (2H, s), 5.80 (1H, d, J = 10.3 Hz), 5.93-5.99 (1H, m), 6.44 (1H, s), 6.92 (1H, d, J = 1.8 Hz), 7.53 (1H, d, J = 1.8 Hz).
＜参考例２６－１＞ <Reference Example 26-1>
Figure JPOXMLDOC01-appb-C000063
Figure JPOXMLDOC01-appb-C000063
６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－４－ヒドロキシベンゾ［ｄ］チアゾール
　アルゴン雰囲気下、６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－ボロン酸（５３０ｍｇ）のテトラヒドロフラン（１．２ ｍＬ）溶液に、水酸化ナトリウム水溶液（１．０ ｍｏｌ ／ Ｌ, ７．２ ｍＬ）、及び過酸化水素水溶液（４．５ ｍＬ）を加え、反応液とした。反応液を室温で２時間攪拌した後に、塩化水素水溶液を加えて反応液のｐＨを１とした。次に、反応液にジエチルエーテルを加えた。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン:酢酸エチル＝１０：１～１：１）を用いて精製し、無色固体として表題化合物を得た（４３４ ｍｇ）。
1H-NMR (400 MHz, CDCl3) δ 2.27-2.32 (2H, m), 3.69 (2H, t, J = 5.8 Hz), 4.01-4.04 (2H, m), 5.73-5.78 (1H, m), 5.89-5.95 (1H, m), 6.84 (1H, d, J = 1.8 Hz), 6.87 (1H, bs), 7.11 (1H, d, J = 1.8 Hz). 6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) -4-hydroxybenzo [d] thiazole 6-chloro-2- (3,6-dihydropyridine-1 (2H) under argon atmosphere -Yl) A solution of benzo [d] thiazole-4-boronic acid (530 mg) in tetrahydrofuran (1.2 mL), aqueous sodium hydroxide (1.0 mol / L, 7.2 mL), and aqueous hydrogen peroxide (4.5 mL) was added to prepare a reaction solution. After stirring the reaction solution at room temperature for 2 hours, an aqueous hydrogen chloride solution was added to adjust the pH of the reaction solution to 1. Next, diethyl ether was added to the reaction solution. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 10: 1 to 1: 1) to give the title compound as a colorless solid (434 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ 2.27-2.32 (2H, m), 3.69 (2H, t, J = 5.8 Hz), 4.01-4.04 (2H, m), 5.73-5.78 (1H, m) , 5.89-5.95 (1H, m), 6.84 (1H, d, J = 1.8 Hz), 6.87 (1H, bs), 7.11 (1H, d, J = 1.8 Hz).
＜参考例２７－１＞ <Reference Example 27-1>
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000064
３－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］チオ］プロピオン酸　２－エチルヘキシル
　アルゴン雰囲気下、反応容器内の４－ブロモ－６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール（２００ｍｇ）の１，４－ジオキサン（３．０ ｍＬ）溶液に、３－メルカプトプロピオン酸 ２－エチルヘキシル（５５．０ ｍｇ）、キサントホス（３２．４ ｍｇ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（０．２０６ ｍＬ）、及びトリス(ジベンジリデンアセトン)ジパラジウム（０）（２３．２ｍｇ） を加えた。反応容器をマイクロウェーブ（ＣＥＭ）で３０分間加熱（１５０Ｗ, １３０℃）した。その後、室温まで放冷し、次いで溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２０：１～４：１）を用いて精製し、淡黄色油状物として表題化合物を得た（２２８ ｍｇ）。
1H-NMR (400 MHz, CDCl3) δ 0.89 (6H, t, J = 7.9 Hz), 1.23-1.41 (8H, m), 1.52-1.62 (1H, m), 2.28-2.35 (2H, m), 2.68 (2H, t, J = 7.6 Hz), 3.36 (2H, t, J = 7.6 Hz), 3.75 (2H, t, J = 6.1 Hz), 4.01 (2H, dd, J = 6.1, 2.4 Hz), 4.07-4.09 (2H, m), 5.73-5.80 (1H, m), 5.89-5.96 (1H, m), 7.19 (1H, d, J = 1.8 Hz), 7.42 (1H, d, J = 1.8 Hz). 3-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] thio] propionic acid 2-ethylhexyl 4 in a reaction vessel under argon atmosphere To a solution of -bromo-6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazole (200 mg) in 1,4-dioxane (3.0 mL), 3-mercaptopropion 2-ethylhexyl acid (55.0 mg), xanthophos (32.4 mg), N, N-diisopropylethylamine (0.206 mL), and tris (dibenzylideneacetone) dipalladium (0) (23.2 mg) added. The reaction vessel was heated with microwave (CEM) for 30 minutes (150 W, 130 ° C.). Thereafter, the mixture was allowed to cool to room temperature, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1-4: 1) to give the title compound as a pale yellow oil (228 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ 0.89 (6H, t, J = 7.9 Hz), 1.23-1.41 (8H, m), 1.52-1.62 (1H, m), 2.28-2.35 (2H, m) , 2.68 (2H, t, J = 7.6 Hz), 3.36 (2H, t, J = 7.6 Hz), 3.75 (2H, t, J = 6.1 Hz), 4.01 (2H, dd, J = 6.1, 2.4 Hz) , 4.07-4.09 (2H, m), 5.73-5.80 (1H, m), 5.89-5.96 (1H, m), 7.19 (1H, d, J = 1.8 Hz), 7.42 (1H, d, J = 1.8 Hz ).
＜参考例２８－１＞ <Reference Example 28-1>
Figure JPOXMLDOC01-appb-C000065
Figure JPOXMLDOC01-appb-C000065
（Ｚ）－１－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－Ｎ‘－ヒドロキシ－５－メチル－１Ｈ－ピラゾール－３－カルボキシイミダミド
　アルゴン雰囲気下、１－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボニトリル（１００ｍｇ）のＮ，Ｎ－ジメチルホルムアミド-エタノール混合溶液（２．８ ｍＬ， １：１）に、室温でヒドロキシルアミン塩酸塩（３８ｍｇ）、トリエチルアミン（０．０７５ ｍＬ）を加え、反応液とした。反応液を８０℃で１時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を留去し、薄黄色粉体として表題化合物を得た（１０９ｍｇ）。
1H-NMR (400 MHz, CDCl3) δ 2.26 (3H, s), 2.32-2.36 (2H, m), 3.76 (2H, t, J = 5.8 Hz), 4.10 (2H, t, J = 2.4 Hz), 5.18 (2H, brs), 5.56 (2H, s), 5.80 (1H, d, J = 10.3 Hz), 5.92-5.98 (1H, m), 6.35 (1H, s), 6.76 (1H, d, J = 1.8 Hz), 7.48 (1H, d, J = 1.8 Hz). (Z) -1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -N′-hydroxy-5-methyl- 1H-pyrazol-3-carboxyimidamide 1-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl]-under argon atmosphere To a mixed solution of 5-methyl-1H-pyrazole-3-carbonitrile (100 mg) in N, N-dimethylformamide-ethanol (2.8 mL, 1: 1), hydroxylamine hydrochloride (38 mg), triethylamine ( 0.075 mL) was added to give a reaction solution. The reaction was stirred at 80 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off to give the title compound as a pale yellow powder (109 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ 2.26 (3H, s), 2.32-2.36 (2H, m), 3.76 (2H, t, J = 5.8 Hz), 4.10 (2H, t, J = 2.4 Hz ), 5.18 (2H, brs), 5.56 (2H, s), 5.80 (1H, d, J = 10.3 Hz), 5.92-5.98 (1H, m), 6.35 (1H, s), 6.76 (1H, d, J = 1.8 Hz), 7.48 (1H, d, J = 1.8 Hz).
＜参考例２９－１＞ <Reference Example 29-1>
Figure JPOXMLDOC01-appb-C000066
   　 
Figure JPOXMLDOC01-appb-C000066
   　 
１－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボキシアミド
　アルゴン雰囲気下、１－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸（４８０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド溶液（６．２ ｍＬ）に、室温で塩化アンモニウム（６６ｍｇ）、２－（１Ｈ－７－アザベンゾトリアゾール－１－イル）－１，１，３，３－テトラメチルウロニウム　ヘキサフルオロホスフェート　メタナミニウム（ＨＡＴＵ）（５６３ｍｇ）、ジイソプロピルエチルアミン（０．７ ｍＬ）を加え、反応液とした。反応液を室温で３時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：１）を用いて精製し、黄色粉体として表題化合物を得た（４１２ ｍｇ）。
1H-NMR (400 MHz, CDCl3) δ 2.30 (3H, s), 2.32-2.37 (2H, m), 3.76 (2H, t, J = 5.8 Hz), 4.08-4.11 (2H, m), 5.56 (2H, s), 5.80 (1H, d, J = 10.3 Hz), 5.96 (1H, d, J = 10.3 Hz), 6.61 (1H, s), 6.79 (1H, d, J = 1.8 Hz), 7.50 (1H, d, J = 1.8 Hz). 1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxamide Argon 1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3- To a solution of carboxylic acid (480 mg) in N, N-dimethylformamide (6.2 mL) at room temperature, ammonium chloride (66 mg), 2- (1H-7-azabenzotriazol-1-yl) -1,1,3 , 3-tetramethyluronium hexafluorophosphate metanaminium (HATU) (563 mg) and diisopropylethylamine (0.7 mL) were added to give a reaction solution. The reaction was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound as a yellow powder (412 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ 2.30 (3H, s), 2.32-2.37 (2H, m), 3.76 (2H, t, J = 5.8 Hz), 4.08-4.11 (2H, m), 5.56 (2H, s), 5.80 (1H, d, J = 10.3 Hz), 5.96 (1H, d, J = 10.3 Hz), 6.61 (1H, s), 6.79 (1H, d, J = 1.8 Hz), 7.50 (1H, d, J = 1.8 Hz).
＜実施例１－１＞ <Example 1-1>
Figure JPOXMLDOC01-appb-C000067
Figure JPOXMLDOC01-appb-C000067
１－［（６－クロロ－２－フェニルベンゾ［ｄ］オキサゾール－４－イル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸
　１－［（６－クロロ－２－フェニルベンゾ［ｄ］オキサゾール－４－イル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル（１１１ｍｇ）のエタノール（１．４ｍＬ）及びテトラヒドロフラン（１．４ｍＬ）溶液に、水酸化カリウム水溶液（２ｍｏｌ／Ｌ、０．７ｍＬ）を加え、反応液とした。反応液を室温で３時間攪拌した。反応液に塩酸（２ｍｏｌ／Ｌ、０．８ｍＬ）を加えて反応液のｐＨを１とした。析出した結晶をろ取し、無色結晶として表題化合物を得た（８０．８ｍｇ）。
1H-NMR (400 MHz, DMSO-d6) δ 2.40 (3H, s), 5.76 (2H, s), 6.59 (1H, s), 7.52-7.68 (4H, m), 7.80 (1H, d, J = 8.5 Hz), 8.04 (1H, d, J = 1.2 Hz), 8.07 (1H, s), 12.58 (1H, brs). 1-[(6-Chloro-2-phenylbenzo [d] oxazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid 1-[(6-Chloro-2-phenylbenzo [d ] To a solution of ethyl oxazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate (111 mg) in ethanol (1.4 mL) and tetrahydrofuran (1.4 mL), an aqueous potassium hydroxide solution (2 mol / L, 0.7 mL) was added to give a reaction solution. The reaction was stirred at room temperature for 3 hours. Hydrochloric acid (2 mol / L, 0.8 mL) was added to the reaction solution to adjust the pH of the reaction solution to 1. The precipitated crystals were collected by filtration to give the title compound as colorless crystals (80.8 mg).
1 H-NMR (400 MHz, DMSO-d 6 ) δ 2.40 (3H, s), 5.76 (2H, s), 6.59 (1H, s), 7.52-7.68 (4H, m), 7.80 (1H, d, J = 8.5 Hz), 8.04 (1H, d, J = 1.2 Hz), 8.07 (1H, s), 12.58 (1H, brs).
＜実施例１－２～１－１８２＞
　対応するエステルを用い、実施例１－１と同様にして、以下の実施例１－２から１－１８２を得た。これらの構造およびスペクトルデータを表１７～６３に示した。 <Examples 1-2 to 1-182>
The following Examples 1-2 to 1-182 were obtained in the same manner as in Example 1-1 using the corresponding esters. Their structures and spectral data are shown in Tables 17-63.
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000048
Figure JPOXMLDOC01-appb-T000048
Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000050
Figure JPOXMLDOC01-appb-T000050
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000056
Figure JPOXMLDOC01-appb-T000056
Figure JPOXMLDOC01-appb-T000057
Figure JPOXMLDOC01-appb-T000057
Figure JPOXMLDOC01-appb-T000058
Figure JPOXMLDOC01-appb-T000058
Figure JPOXMLDOC01-appb-T000059
Figure JPOXMLDOC01-appb-T000059
Figure JPOXMLDOC01-appb-T000060
Figure JPOXMLDOC01-appb-T000060
Figure JPOXMLDOC01-appb-T000061
Figure JPOXMLDOC01-appb-T000061
Figure JPOXMLDOC01-appb-T000062
Figure JPOXMLDOC01-appb-T000062
Figure JPOXMLDOC01-appb-T000063
Figure JPOXMLDOC01-appb-T000063
＜実施例２－１＞ <Example 2-1>
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000068
１－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］オキサゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸
　アルゴン雰囲気下、６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－４－（ヒドロキシメチル）ベンゾ［ｄ］オキサゾール（１．０４ｇ）のジクロロメタン（１ｍＬ）溶液に、室温で塩化チオニル（０．０５ｍＬ）を加え、第１の反応液とした。第１の反応液を室温で２４時間攪拌した。第１の反応液を０℃に冷却しながら、飽和炭酸水素ナトリウム水溶液を加え、第１の反応液のｐＨを１１とした後、ジクロロメタンで抽出した。有機層を無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、黄色オイルとして６－クロロ－４－（クロロメチル）－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］オキサゾールを得た（２８．０ｍｇ）。
　アルゴン雰囲気下、５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル（１９．０ ｍｇ）のＮ，Ｎ－ジメチルホルムアミド溶液（０．５ｍＬ）に、氷冷下で水素化ナトリウム（１２０ ｍｇ，６０％オイル懸濁）を加え、室温で０．５時間撹拌した。得られた混合物に６－クロロ－４－（クロロメチル）－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］オキサゾール（２８．０ ｍｇ）のＮ，Ｎ－ジメチルホルムアミド溶液（０．５ ｍＬ）を－７８℃で滴下し、第２の反応液とした。第２の反応液をその後氷冷下で３時間撹拌した。第２の反応液をエタノール（１ｍＬ）で希釈し、水酸化ナトリウム水溶液（２ｍｏｌ／Ｌ、１．０ｍＬ）を加えた後、室温で２時間攪拌した。第２の反応液に塩酸（２ｍｏｌ／Ｌ、０．６ｍＬ）を加えて第２の反応液のｐＨを４とした後、酢酸エチルで抽出し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去後、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝５：１）を用いて精製し、無色固体として表題化合物を得た（１１．５ ｍｇ）。
1H-NMR (400 MHz, DMSO-d6) δ 2.19-2.29 (2H, m), 2.37 (3H, s), 3.72 (2H, t, J = 5.5 Hz), 4.07-4.13 (2H, m), 5.43 (2H, s), 5.77-5.85 (1H, m), 5.87-5.94 (1H, m), 6.49 (1H, s), 6.78 (1H, d, J = 1.8 Hz), 7.54 (1H, d, J = 1.8 Hz), 12.56 (1H, brs). 1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] oxazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid Argon Under atmosphere, add 6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) -4- (hydroxymethyl) benzo [d] oxazole (1.04 g) in dichloromethane (1 mL) at room temperature. Thionyl chloride (0.05 mL) was added to give a first reaction solution. The first reaction was stirred at room temperature for 24 hours. While cooling the first reaction liquid to 0 ° C., a saturated aqueous sodium hydrogen carbonate solution was added to adjust the pH of the first reaction liquid to 11, and then extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 6-chloro-4- (chloromethyl) -2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] oxazole as a yellow oil (28.0 mg). .
Under an argon atmosphere, ethyl 5-methyl-1H-pyrazole-3-carboxylate (19.0 mg) in N, N-dimethylformamide (0.5 mL) was added to sodium hydride (120 mg, 60 mg) under ice-cooling. % Oil suspension) and stirred at room temperature for 0.5 hour. To the resulting mixture was added 6-chloro-4- (chloromethyl) -2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] oxazole (28.0 mg) in N, N-dimethylformamide. The solution (0.5 mL) was added dropwise at −78 ° C. to obtain a second reaction solution. The second reaction solution was then stirred for 3 hours under ice cooling. The 2nd reaction liquid was diluted with ethanol (1 mL), and after adding sodium hydroxide aqueous solution (2 mol / L, 1.0 mL), it stirred at room temperature for 2 hours. Hydrochloric acid (2 mol / L, 0.6 mL) was added to the second reaction solution to adjust the pH of the second reaction solution to 4, followed by extraction with ethyl acetate and drying over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: methanol = 5: 1) to obtain the title compound as a colorless solid (11.5 mg).
1 H-NMR (400 MHz, DMSO-d 6 ) δ 2.19-2.29 (2H, m), 2.37 (3H, s), 3.72 (2H, t, J = 5.5 Hz), 4.07-4.13 (2H, m) , 5.43 (2H, s), 5.77-5.85 (1H, m), 5.87-5.94 (1H, m), 6.49 (1H, s), 6.78 (1H, d, J = 1.8 Hz), 7.54 (1H, d , J = 1.8 Hz), 12.56 (1H, brs).
＜実施例３－１＞ <Example 3-1>
Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000069
６－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］アミノ］ピリジン－２－カルボン酸メチル
　アルゴン雰囲気下、反応容器中の４－ブロモ－６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール（１００ｍｇ）の１，４－ジオキサン（２．５ ｍＬ）溶液に、６－アミノピリジン－２－カルボン酸メチル（３８．４ｍｇ）、キサントホス（８．１ ｍｇ）、炭酸セシウム（２４７ ｍｇ）、及びトリス(ジベンジリデンアセトン)ジパラジウム（０）（５．８ ｍｇ）を加えた。反応容器をマイクロウェーブ（ＣＥＭ）で４５分間加熱（１５０Ｗ, １４０℃）した。室温まで放冷し、次いで溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１０：１～２：１）を用いて精製し、淡黄色固体として表題化合物を得た（４７．０ ｍｇ）。
1H-NMR (400 MHz, CDCl3) δ 2.31-2.38 (2H, m), 3.76 (2H, t, J = 5.8 Hz), 4.03 (3H, s), 4.07-4.10 (2H, m), 5.77-5.83 (1H, m), 5.92-5.98 (1H, m), 7.15 (1H, dd, J = 7.9, 1.2 Hz), 7.21 (1H, d, J = 1.8 Hz), 7.63-7.71 (2H, m), 7.85 (1H, s), 8.36 (1H, d, J = 1.8 Hz). Methyl 6-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] amino] pyridine-2-carboxylate in a reaction vessel under argon atmosphere Of 4-bromo-6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazole (100 mg) in 1,4-dioxane (2.5 mL) Methyl aminopyridine-2-carboxylate (38.4 mg), xanthophos (8.1 mg), cesium carbonate (247 mg), and tris (dibenzylideneacetone) dipalladium (0) (5.8 mg) were added. . The reaction vessel was heated (150 W, 140 ° C.) for 45 minutes with microwave (CEM). The mixture was allowed to cool to room temperature, and then the solvent was distilled off under reduced pressure. The residue was purified using silica gel column chromatography (hexane: ethyl acetate = 10: 1 to 2: 1) to give the title compound as a pale yellow solid (47.0 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ 2.31-2.38 (2H, m), 3.76 (2H, t, J = 5.8 Hz), 4.03 (3H, s), 4.07-4.10 (2H, m), 5.77 -5.83 (1H, m), 5.92-5.98 (1H, m), 7.15 (1H, dd, J = 7.9, 1.2 Hz), 7.21 (1H, d, J = 1.8 Hz), 7.63-7.71 (2H, m ), 7.85 (1H, s), 8.36 (1H, d, J = 1.8 Hz).
＜実施例３－２＞ <Example 3-2>
Figure JPOXMLDOC01-appb-C000070
Figure JPOXMLDOC01-appb-C000070
５－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］アミノ］フラン－２－カルボン酸メチル
　アルゴン雰囲気下、反応容器中の４－ブロモ－６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール（１００ｍｇ）の１，４－ジオキサン（２．５ ｍＬ）溶液に、５－アミノフラン－２－カルボン酸メチル（６４．０ｍｇ）、キサントホス（１６．２ ｍｇ）、炭酸セシウム（２４７ ｍｇ）、及びトリス(ジベンジリデンアセトン)ジパラジウム（０）（１１．６ ｍｇ）を加えた。反応容器をマイクロウェーブ（ＣＥＭ）で３０分間加熱（１５０Ｗ, １４０℃）した。室温まで放冷し、次いで溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２０：１～４：１）を用いて精製し、淡黄色固体として表題化合物を得た（６０．０ ｍｇ）。
1H-NMR (400 MHz, CDCl3) δ 2.31-2.38 (2H, m), 3.75 (2H, t, J = 5.8 Hz), 3.89 (3H, s), 4.06-4.09 (2H, m), 5.76-5.84 (1H, m), 5.90-5.99 (2H, m), 7.13 (1H, d, J = 1.8 Hz), 7.16 (1H, d, J = 1.8 Hz), 7.25 (1H, s), 7.78 (1H, s). 5-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] amino] furan-2-carboxylate in an argon atmosphere in a reaction vessel Of 4-bromo-6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazole (100 mg) in 1,4-dioxane (2.5 mL) Methyl aminofuran-2-carboxylate (64.0 mg), xanthophos (16.2 mg), cesium carbonate (247 mg), and tris (dibenzylideneacetone) dipalladium (0) (11.6 mg) were added. . The reaction vessel was heated with microwave (CEM) for 30 minutes (150 W, 140 ° C.). The mixture was allowed to cool to room temperature, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1-4: 1) to give the title compound as a pale yellow solid (60.0 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ 2.31-2.38 (2H, m), 3.75 (2H, t, J = 5.8 Hz), 3.89 (3H, s), 4.06-4.09 (2H, m), 5.76 -5.84 (1H, m), 5.90-5.99 (2H, m), 7.13 (1H, d, J = 1.8 Hz), 7.16 (1H, d, J = 1.8 Hz), 7.25 (1H, s), 7.78 ( 1H, s).
＜実施例４－１＞ <Example 4-1>
Figure JPOXMLDOC01-appb-C000071
Figure JPOXMLDOC01-appb-C000071
６－クロロ－４－［［５－メチル－３－（１Ｈ－テトラゾール－５－イル）－１Ｈ－ピラゾール－１－イル］メチル］－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール
　アルゴン雰囲気下、１－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボニトリル（２０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド-水混合溶液（１．３ ｍＬ， ３：１）に、室温でアジ化ナトリウム（６ｍｇ）、臭化亜鉛（１３ ｍｇ）を加え、反応液とした。反応液を８０℃で２時間撹拌し、その後１５０℃で３時間攪拌した。反応液に１ｍｏｌ／Ｌ 塩酸を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）を用いて精製し、黄色液体として表題化合物を得た（１８ｍｇ）。
1H-NMR (400 MHz, DMSO-d6) δ 2.22-2.29 (2H, m), 2.72 (3H, s), 3.72 (2H, t, J = 5.4 Hz), 4.05-4.08 (2H, m), 5.55 (2H, s), 5.82 (1H, d, J = 10.3 Hz), 5.92 (1H, d, J = 10.3 Hz), 6.56 (1H, s), 6.86 (1H, s), 7.85 (1H, s), 7.94 (1H, s). 6-Chloro-4-[[5-methyl-3- (1H-tetrazol-5-yl) -1H-pyrazol-1-yl] methyl] -2- (3,6-dihydropyridin-1 (2H) -yl ) Benzo [d] thiazole 1-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl under argon atmosphere To a mixed solution of 1H-pyrazole-3-carbonitrile (20 mg) in N, N-dimethylformamide-water (1.3 mL, 3: 1) at room temperature, sodium azide (6 mg), zinc bromide (13 mg) ) Was added to obtain a reaction solution. The reaction solution was stirred at 80 ° C. for 2 hours, and then stirred at 150 ° C. for 3 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified using silica gel column chromatography (ethyl acetate) to obtain the title compound as a yellow liquid (18 mg).
1 H-NMR (400 MHz, DMSO-d 6 ) δ 2.22-2.29 (2H, m), 2.72 (3H, s), 3.72 (2H, t, J = 5.4 Hz), 4.05-4.08 (2H, m) , 5.55 (2H, s), 5.82 (1H, d, J = 10.3 Hz), 5.92 (1H, d, J = 10.3 Hz), 6.56 (1H, s), 6.86 (1H, s), 7.85 (1H, s), 7.94 (1H, s).
＜実施例５－１＞ <Example 5-1>
Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000072
５－［（ｔｅｒｔ－ブトキシカルボニル）［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］アミノ］フラン－２－カルボン酸メチル
　５－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］アミノ］フラン－２－カルボン酸メチル（３５．０ｍｇ）のジクロロメタン（１．０ ｍＬ）溶液に、ジ－ｔｅｒｔ－ブチルジカルボネート（３９．０ ｍｇ）、及び４－ジメチルアミノピリジン（触媒量）を加え、反応液とした。反応液を室温で２時間攪拌した。反応液をシリカゲルカラムクロマトグラフィー（ＮＨ、ヘキサン：酢酸エチル＝１０：１～４：１）を用いて精製し、無色油状物として表題化合物を得た（１８．３ ｍｇ）。
1H-NMR (400 MHz, CDCl3) δ 1.43 (9H, s), 2.25-2.32 (2H, m), 3.71 (2H, t, J = 5.8 Hz), 3.83 (3H, s), 4.00-4.05 (2H, m), 5.71-5.78 (1H, m), 5.88-5.95 (1H, m), 6.30 (1H, d, J = 3.6 Hz), 7.14 (1H, d, J = 3.6 Hz), 7.27 (1H, d, J = 1.8 Hz), 7.50 (1H, d, J = 1.8 Hz). 5-[(tert-Butoxycarbonyl) [6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] amino] furan-2-carboxylate methyl 5 -[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] amino] furan-2-carboxylate methyl (35.0 mg) in dichloromethane ( To the 1.0 mL solution, di-tert-butyl dicarbonate (39.0 mg) and 4-dimethylaminopyridine (catalytic amount) were added to obtain a reaction solution. The reaction was stirred at room temperature for 2 hours. The reaction mixture was purified using silica gel column chromatography (NH, hexane: ethyl acetate = 10: 1 to 4: 1) to give the title compound as a colorless oil (18.3 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ 1.43 (9H, s), 2.25-2.32 (2H, m), 3.71 (2H, t, J = 5.8 Hz), 3.83 (3H, s), 4.00-4.05 (2H, m), 5.71-5.78 (1H, m), 5.88-5.95 (1H, m), 6.30 (1H, d, J = 3.6 Hz), 7.14 (1H, d, J = 3.6 Hz), 7.27 ( 1H, d, J = 1.8 Hz), 7.50 (1H, d, J = 1.8 Hz).
＜実施例６－１＞ <Example 6-1>
Figure JPOXMLDOC01-appb-C000073
Figure JPOXMLDOC01-appb-C000073
３－［１－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－イル］－１，２，４－オキサジアゾール－５（４Ｈ）－チオン
　アルゴン雰囲気下、（Ｚ）－１－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－Ｎ‘－ヒドロキシ－５－メチル－１Ｈ－ピラゾール－３－カルボキシイミダミド（２０ｍｇ）のアセトニトリル溶液（１ ｍＬ）に、室温で１，８－ジアザビシクロ［５．４．０］ウンデセン（０．０３ｍＬ）、チオカルボニルジイミダゾール（１３ ｍｇ）を加え、反応液とした。反応液を室温で２時間撹拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：１）を用いて精製し、無色粉体として表題化合物を得た（２１ｍｇ）。
1H-NMR (400 MHz, CDCl3) δ 2.32-2.37 (2H, m), 2.38 (3H, s), 3.76 (2H, t, J = 5.4 Hz), 4.07-4.11 (2H, m), 5.60 (2H, s), 5.80 (1H, d, J = 10.3 Hz), 5.96 (1H, d, J = 10.3 Hz), 6.67 (1H, s), 6.87 (1H, d, J = 1.8 Hz), 7.51 (1H, d, J = 1.8 Hz), 11.48 (1H, brs). 3- [1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3- Yl] -1,2,4-oxadiazole-5 (4H) -thione under an argon atmosphere, (Z) -1-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl] ) Benzo [d] thiazol-4-yl] methyl] -N′-hydroxy-5-methyl-1H-pyrazole-3-carboxyimidamide (20 mg) in acetonitrile (1 mL) at room temperature Diazabicyclo [5.4.0] undecene (0.03 mL) and thiocarbonyldiimidazole (13 mg) were added to prepare a reaction solution. The reaction was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound as a colorless powder (21 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ 2.32-2.37 (2H, m), 2.38 (3H, s), 3.76 (2H, t, J = 5.4 Hz), 4.07-4.11 (2H, m), 5.60 (2H, s), 5.80 (1H, d, J = 10.3 Hz), 5.96 (1H, d, J = 10.3 Hz), 6.67 (1H, s), 6.87 (1H, d, J = 1.8 Hz), 7.51 (1H, d, J = 1.8 Hz), 11.48 (1H, brs).
＜実施例６－２＞ <Example 6-2>
Figure JPOXMLDOC01-appb-C000074
Figure JPOXMLDOC01-appb-C000074
４－［１－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－イル］－３Ｈ－１，２，３，５－オキサチアジアゾール－２－オキシド
　アルゴン雰囲気下、（Ｚ）－１－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－Ｎ‘－ヒドロキシ－５－メチル－１Ｈ－ピラゾール－３－カルボキシイミダミド（２０ｍｇ）のテトラヒドロフラン溶液（１ ｍＬ）に、氷冷下でピリジン（０．００８ ｍＬ）、塩化チオニル（０．００４ ｍＬ）を加え、反応液とした。反応液を氷冷下で１時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝４：１）を用いて精製し、無色液体として表題化合物を得た（１５ｍｇ）。
1H-NMR (400 MHz, CDCl3) δ 2.31-2.35 (2H, m), 2.36 (3H, s), 3.75 (2H, t, J = 5.8 Hz), 4.08 (2H, t, J = 2.4 Hz), 5.56 (2H, s), 5.79 (1H, d, J = 10.3 Hz), 5.93-5.98 (1H, m), 6.62 (1H, s), 6.85 (1H, d, J = 2.4 Hz), 7.51 (1H, d, J = 2.4 Hz). 4- [1-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3- Yl] -3H-1,2,3,5-oxathiadiazole-2-oxide (Z) -1-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl] under argon atmosphere ) Benzo [d] thiazol-4-yl] methyl] -N′-hydroxy-5-methyl-1H-pyrazole-3-carboxyimidamide (20 mg) in tetrahydrofuran (1 mL) was added pyridine ( 0.008 mL) and thionyl chloride (0.004 mL) were added to prepare a reaction solution. The reaction solution was stirred for 1 hour under ice cooling. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound as a colorless liquid (15 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ 2.31-2.35 (2H, m), 2.36 (3H, s), 3.75 (2H, t, J = 5.8 Hz), 4.08 (2H, t, J = 2.4 Hz ), 5.56 (2H, s), 5.79 (1H, d, J = 10.3 Hz), 5.93-5.98 (1H, m), 6.62 (1H, s), 6.85 (1H, d, J = 2.4 Hz), 7.51 (1H, d, J = 2.4 Hz).
＜実施例７－１＞ <Example 7-1>
Figure JPOXMLDOC01-appb-C000075
Figure JPOXMLDOC01-appb-C000075
１－［（６－クロロ－２－フェニルベンゾ［ｄ］オキサゾール－４－イル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル
　アルゴン雰囲気下、５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル（９８．５ ｍｇ）のN,N-ジメチルホルムアミド溶液（１ｍＬ）に、氷冷下で水素化ナトリウム（２５．５ ｍｇ，６０％オイル懸濁）を加え、室温で０．５時間撹拌した。得られた混合物に６－クロロ－４－（クロロメチル）－２－フェニルベンゾ［ｄ］オキサゾール（１４６ ｍｇ）のＮ，Ｎ－ジメチルホルムアミド溶液（２ ｍＬ）を－７８℃で滴下し、反応液とした。反応液をその後氷冷下で２時間撹拌した。反応液に水を加え、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝３：１）を用いて精製し、無色結晶として表題化合物を得た（１３２ｍｇ）。
1H-NMR (400 MHz, CDCl3) δ 1.39 (3H, t, J = 7.3 Hz), 2.25 (3H, s), 4.42 (2H, q, J = 7.3 Hz), 5.80 (2H, s), 6.69 (1H, s), 7.41 (1H, d, J = 8.5 Hz), 7.43-7.55 (3H, m), 7.64 (1H, d, J = 8.5 Hz), 8.01 (1H, d, J = 1.2 Hz), 8.04 (1H, s). 1-[(6-Chloro-2-phenylbenzo [d] oxazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate 5-methyl-1H-pyrazole-3 under argon atmosphere -Sodium hydride (25.5 mg, 60% oil suspension) was added to a solution of ethyl carboxylate (98.5 mg) in N, N-dimethylformamide (1 mL) under ice cooling, and 0.5% at room temperature. Stir for hours. To the resulting mixture, 6-chloro-4- (chloromethyl) -2-phenylbenzo [d] oxazole (146 mg) in N, N-dimethylformamide (2 mL) was added dropwise at −78 ° C. It was. The reaction solution was then stirred for 2 hours under ice cooling. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound as colorless crystals (132 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ 1.39 (3H, t, J = 7.3 Hz), 2.25 (3H, s), 4.42 (2H, q, J = 7.3 Hz), 5.80 (2H, s), 6.69 (1H, s), 7.41 (1H, d, J = 8.5 Hz), 7.43-7.55 (3H, m), 7.64 (1H, d, J = 8.5 Hz), 8.01 (1H, d, J = 1.2 Hz ), 8.04 (1H, s).
＜実施例７－２～７－９＞
　対応するクロロメチル体を用い、実施例７－１と同様にして、以下の実施例７－２～７－９の化合物を得た。これらの構造およびスペクトルデータを表６４～６６に示した。 <Examples 7-2 to 7-9>
The following compounds of Examples 7-2 to 7-9 were obtained in the same manner as in Example 7-1 using the corresponding chloromethyl compounds. Their structures and spectral data are shown in Tables 64-66.
Figure JPOXMLDOC01-appb-T000064
Figure JPOXMLDOC01-appb-T000064
Figure JPOXMLDOC01-appb-T000065
Figure JPOXMLDOC01-appb-T000065
Figure JPOXMLDOC01-appb-T000066
Figure JPOXMLDOC01-appb-T000066
＜実施例８－１＞ <Example 8-1>
Figure JPOXMLDOC01-appb-C000076
Figure JPOXMLDOC01-appb-C000076
１－［（６－クロロ－２－フェニルベンゾ［ｄ］チアゾール－４－イル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル
　アルゴン雰囲気下、６－クロロ－４－メチル－２－フェニルベンゾ［ｄ］チアゾール（３００ｍｇ）の四塩化炭素（７．５ｍＬ）溶液に、Ｎ－ブロモスクシンイミド（２４６ ｍｇ）を加えた後に、アゾイソブチロニトリル（１９ｍｇ）を加え、反応液とした。反応液を８時間加熱還流した。反応液を半分程度濃縮後、ジエチルエーテルを加えた。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン）を用いて精製し、無色固体を得た（２２０ ｍｇ）。
　次に、アルゴン雰囲気下、５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル（８２．１ ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（０．９ ｍＬ）溶液を氷冷して、水素化ナトリウム（３８．０ｍｇ）を加えた。室温まで昇温して１０分間攪拌した後に再び氷冷した。次に、当該溶液に前記無色固体（２２０ ｍｇ）をゆっくり加えて反応液とした。反応液を３０分間攪拌した後に、反応液に酢酸エチルと飽和塩化アンモニウム水溶液を加えた。続いて、有機層にヘキサンを加えた。飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２０：１～２：１）を用いて精製し、無色固体として表題化合物を得た（５３．０ ｍｇ）。
1H NMR (CDCl3, 400 MHz) δ1.41 (3H, t, J = 7.1 Hz), 2.29 (3H, s), 4.43 (2H, q, J = 7.1 Hz), 5.96 (2H, s), 6.66 (1H, s), 6.97 (1H, d, J = 1.8 Hz), 7.51-7.53 (3H, m), 7.81 (1H, d, J = 1.8 Hz), 8.07-8.12 (2H, m). 1-[(6-Chloro-2-phenylbenzo [d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate 6-chloro-4-methyl-2 under argon atmosphere -N-bromosuccinimide (246 mg) was added to a solution of phenylbenzo [d] thiazole (300 mg) in carbon tetrachloride (7.5 mL), followed by addition of azoisobutyronitrile (19 mg) to obtain a reaction solution. . The reaction was heated to reflux for 8 hours. After the reaction solution was concentrated about half, diethyl ether was added. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified using silica gel column chromatography (hexane) to obtain a colorless solid (220 mg).
Next, under argon atmosphere, a solution of ethyl 5-methyl-1H-pyrazole-3-carboxylate (82.1 mg) in N, N-dimethylformamide (0.9 mL) was ice-cooled, and sodium hydride ( 38.0 mg) was added. The mixture was warmed to room temperature, stirred for 10 minutes, and then ice-cooled again. Next, the colorless solid (220 mg) was slowly added to the solution to prepare a reaction solution. After stirring the reaction solution for 30 minutes, ethyl acetate and a saturated aqueous ammonium chloride solution were added to the reaction solution. Subsequently, hexane was added to the organic layer. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 20: 1 to 2: 1) to give the title compound as a colorless solid (53.0 mg).
1 H NMR (CDCl 3, 400 MHz) δ1.41 (3H, t, J = 7.1 Hz), 2.29 (3H, s), 4.43 (2H, q, J = 7.1 Hz), 5.96 (2H, s), 6.66 (1H, s), 6.97 (1H, d, J = 1.8 Hz), 7.51-7.53 (3H, m), 7.81 (1H, d, J = 1.8 Hz), 8.07-8.12 (2H, m).
＜実施例８－２～８－４＞
　対応するメチル体を用い、実施例８－１と同様にして、以下の実施例８－２～８－４の化合物を得た。これらの構造およびスペクトルデータを表６７に示した。 <Examples 8-2 to 8-4>
The following compounds of Examples 8-2 to 8-4 were obtained in the same manner as in Example 8-1, using the corresponding methyl compound. Their structures and spectral data are shown in Table 67.
Figure JPOXMLDOC01-appb-T000067
Figure JPOXMLDOC01-appb-T000067
＜実施例９－１＞ <Example 9-1>
Figure JPOXMLDOC01-appb-C000077
Figure JPOXMLDOC01-appb-C000077
５－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］フラン－２－カルボン酸エチル
　アルゴン雰囲気下、４－（ブロモメチル）－６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール（２０ｍｇ）のテトラヒドロフラン溶液（０．６ ｍＬ）に、室温でテトラキス（トリフェニルホスフィン）パラジウム（０）（７ｍｇ）、５－（エトキシカルボニル）－２－フラニル臭化亜鉛（０．２ ｍＬ，０．５ ｍｏｌ／Ｌ テトラヒドロフラン溶液）を加え、反応液とした。反応液を５０℃で１時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン:酢酸エチル＝９：１）を用いて精製し、黄色粉体として表題化合物を得た（１７ ｍｇ）。
1H-NMR (400 MHz, CDCl3) δ 1.37 (3H, t, J = 7.3 Hz), 2.29-2.35 (2H, m), 3.73 (2H, t, J = 5.8 Hz), 4.06 (2H, t, J = 2.4 Hz), 4.35 (2H, q, J = 7.3 Hz), 4.36 (2H, s), 5.78 (1H, d, J = 10.3 Hz), 5.89-5.96 (1H, m), 6.13 (1H, d, J = 3.6 Hz), 7.08 (1H, d, J = 3.6 Hz), 7.10 (1H, d, J = 1.8 Hz), 7.46 (1H, d, J = 1.8 Hz). Ethyl 5-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] furan-2-carboxylate Under argon atmosphere, 4- ( Bromomethyl) -6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazole (20 mg) in tetrahydrofuran (0.6 mL) at room temperature with tetrakis (triphenylphosphine) Palladium (0) (7 mg) and 5- (ethoxycarbonyl) -2-furanyl zinc bromide (0.2 mL, 0.5 mol / L tetrahydrofuran solution) were added to prepare a reaction solution. The reaction was stirred at 50 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 9: 1) to give the title compound as a yellow powder (17 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ 1.37 (3H, t, J = 7.3 Hz), 2.29-2.35 (2H, m), 3.73 (2H, t, J = 5.8 Hz), 4.06 (2H, t , J = 2.4 Hz), 4.35 (2H, q, J = 7.3 Hz), 4.36 (2H, s), 5.78 (1H, d, J = 10.3 Hz), 5.89-5.96 (1H, m), 6.13 (1H , d, J = 3.6 Hz), 7.08 (1H, d, J = 3.6 Hz), 7.10 (1H, d, J = 1.8 Hz), 7.46 (1H, d, J = 1.8 Hz).
＜実施例９－２および９－３＞
　対応するブロモメチル体を用い、実施例９－１と同様にして、以下の実施例９－２および９－３の化合物を得た。これらの構造およびスペクトルデータを表６８に示した。 <Examples 9-2 and 9-3>
The corresponding compounds of Examples 9-2 and 9-3 were obtained in the same manner as Example 9-1 using the corresponding bromomethyl compounds. Their structure and spectral data are shown in Table 68.
Figure JPOXMLDOC01-appb-T000068
Figure JPOXMLDOC01-appb-T000068
＜実施例１０－１＞ <Example 10-1>
Figure JPOXMLDOC01-appb-C000078
Figure JPOXMLDOC01-appb-C000078
１－［（５－クロロ－２－（３－クロロフェニル）ベンゾ［ｄ］オキサゾール－７－イル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル
　１－［（３－アミノ－５－クロロ－２－ヒドロキシフェニル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル（２５０ ｍｇ）のキシレン（４．０ ｍＬ）溶液にピリジン（０．０６５ ｍＬ）、３－クロロベンゾイルクロリド（０．１２０ ｍＬ）を加え、反応液とした。反応液を室温で０．５時間攪拌した後に、p-トルエンスルホン酸１水和物（４６０ ｍｇ）を加えて室温で５分間攪拌した。反応液をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２０：１～２：１）を用いて精製し、無色固体として表題化合物を得た（２７７ ｍｇ）。
1H NMR (400 MHz, CDCl3) δ 1.41 (3H, t, J = 7.3 Hz), 2.29 (3H, s), 4.42 (2H, q, J = 7.3 Hz), 5.69 (2H, s), 6.69 (1H, s), 6.98 (1H, d, J = 1.8 Hz), 7.48 (1H, t, J = 7.9 Hz), 7.54-7.56 (1H, m), 7.68 (1H, d, J = 2.4 Hz), 8.08 (1H, dd, J = 9.1, 1.2 Hz), 8.17 (1H, t, J = 1.8 Hz). 1-[(5-Chloro-2- (3-chlorophenyl) benzo [d] oxazol-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate 1-[(3-amino-5 -Chloro-2-hydroxyphenyl) methyl] -5-methyl-1H-pyrazole-3-carboxylate (250 mg) in xylene (4.0 mL) solution with pyridine (0.065 mL), 3-chlorobenzoyl Chloride (0.120 mL) was added to prepare a reaction solution. The reaction solution was stirred at room temperature for 0.5 hour, p-toluenesulfonic acid monohydrate (460 mg) was added, and the mixture was stirred at room temperature for 5 minutes. The reaction solution was purified using silica gel column chromatography (hexane: ethyl acetate = 20: 1-2: 1) to give the title compound as a colorless solid (277 mg).
1 H NMR (400 MHz, CDCl 3 ) δ 1.41 (3H, t, J = 7.3 Hz), 2.29 (3H, s), 4.42 (2H, q, J = 7.3 Hz), 5.69 (2H, s), 6.69 (1H, s), 6.98 (1H, d, J = 1.8 Hz), 7.48 (1H, t, J = 7.9 Hz), 7.54-7.56 (1H, m), 7.68 (1H, d, J = 2.4 Hz) , 8.08 (1H, dd, J = 9.1, 1.2 Hz), 8.17 (1H, t, J = 1.8 Hz).
＜実施例１０－２＞ <Example 10-2>
Figure JPOXMLDOC01-appb-C000079
Figure JPOXMLDOC01-appb-C000079
１－［（５－クロロ－２－（２－クロロフェニル）ベンゾ［ｄ］オキサゾール－７－イル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル
　１－［（３－アミノ－５－クロロ－２－ヒドロキシフェニル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル（５００ ｍｇ）のキシレン（８．０ ｍＬ） 溶液にピリジン（０．１３０ ｍＬ）、２－クロロベンゾイルクロリド（０．２４６ ｍＬ）を加え、反応液とした。反応液を室温で０．５時間攪拌した後に、p-トルエンスルホン酸１水和物（２３０ ｍｇ）を加えて５時間加熱還流した。反応液をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２０：１～２：１）を用いて精製し、無色固体として表題化合物を得た（１９０ ｍｇ）。
1H NMR (400 MHz, CDCl3) δ 1.40 (3H, t, J = 7.1 Hz), 2.29 (3H, s), 4.42 (2H, q, J = 7.1 Hz), 5.67 (2H, s), 6.66 (1H, s), 7.03 (1H, s), 7.42-7.59 (2H, m), 7.59 (1H, dd, J = 7.9, 1.2 Hz), 7.75 (1H, d, J = 1.8 Hz), 8.11 (1H, dd, J = 7.9, 1.8 Hz). 1-[(5-Chloro-2- (2-chlorophenyl) benzo [d] oxazol-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate ethyl 1-[(3-amino-5 -Chloro-2-hydroxyphenyl) methyl] -5-methyl-1H-pyrazole-3-carboxylate (500 mg) in xylene (8.0 mL) solution in pyridine (0.130 mL), 2-chlorobenzoyl Chloride (0.246 mL) was added to give a reaction solution. The reaction mixture was stirred at room temperature for 0.5 hour, p-toluenesulfonic acid monohydrate (230 mg) was added, and the mixture was heated to reflux for 5 hours. The reaction solution was purified using silica gel column chromatography (hexane: ethyl acetate = 20: 1 to 2: 1) to give the title compound as a colorless solid (190 mg).
1 H NMR (400 MHz, CDCl 3 ) δ 1.40 (3H, t, J = 7.1 Hz), 2.29 (3H, s), 4.42 (2H, q, J = 7.1 Hz), 5.67 (2H, s), 6.66 (1H, s), 7.03 (1H, s), 7.42-7.59 (2H, m), 7.59 (1H, dd, J = 7.9, 1.2 Hz), 7.75 (1H, d, J = 1.8 Hz), 8.11 ( (1H, dd, J = 7.9, 1.8 Hz).
＜実施例１１－１＞ <Example 11-1>
Figure JPOXMLDOC01-appb-C000080
Figure JPOXMLDOC01-appb-C000080
１－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－フルオロベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル
　アルゴン雰囲気下、１－［［２－クロロ－６－フルオロベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル（７８．０ｍｇ）及び１，２，３，６－テトラヒドロピリジン（１８．０ ｍｇ）をＮ，Ｎ－ジメチルホルムアミド（０．５ｍＬ）に溶解し、反応液とした。反応液に室温で炭酸カリウム（３０．０ ｍｇ）を加え、室温で２４時間撹拌した。反応液を酢酸エチルで希釈して、水及び飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝３：１）を用いて精製し、薄黄色粉体として表題化合物を得た（８３．０ｍｇ）。
1H-NMR (400 MHz, CDCl3) δ 1.40 (3H, t, J = 7.3 Hz), 2.23 (3H, s), 2.30-2.38 (2H, m), 3.75 (2H, t, J = 5.5 Hz), 4.06-4.13 (2H, m), 4.41 (2H, q, J = 7.3 Hz), 5.70 (2H, s), 5.77-5.84 (1H, m), 5.92-6.00 (1H, m), 6.55 (1H, dd, J = 9.7, 2.4 Hz), 6.62 (1H, s), 7.22 (1H, dd, J = 7.8, 2.4 Hz). 1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6-fluorobenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate Under an argon atmosphere, ethyl 1-[[2-chloro-6-fluorobenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate (78.0 mg) and 1,2 , 3,6-tetrahydropyridine (18.0 mg) was dissolved in N, N-dimethylformamide (0.5 mL) to give a reaction solution. To the reaction solution was added potassium carbonate (30.0 mg) at room temperature, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound as a pale yellow powder (83.0 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ 1.40 (3H, t, J = 7.3 Hz), 2.23 (3H, s), 2.30-2.38 (2H, m), 3.75 (2H, t, J = 5.5 Hz ), 4.06-4.13 (2H, m), 4.41 (2H, q, J = 7.3 Hz), 5.70 (2H, s), 5.77-5.84 (1H, m), 5.92-6.00 (1H, m), 6.55 ( 1H, dd, J = 9.7, 2.4 Hz), 6.62 (1H, s), 7.22 (1H, dd, J = 7.8, 2.4 Hz).
＜実施例１１－２～１１－９３＞
　対応するハロゲン体を用い、実施例１１－１と同様にして、以下の実施例１１－２～１１－９３の化合物を得た。これらの構造およびスペクトルデータを表６９～９３に示した。 <Examples 11-2 to 11-93>
The following compounds of Examples 11-2 to 11-93 were obtained in the same manner as Example 11-1 using the corresponding halogen compounds. Their structures and spectral data are shown in Tables 69-93.
Figure JPOXMLDOC01-appb-T000069
Figure JPOXMLDOC01-appb-T000069
Figure JPOXMLDOC01-appb-T000070
Figure JPOXMLDOC01-appb-T000070
Figure JPOXMLDOC01-appb-T000071
Figure JPOXMLDOC01-appb-T000071
Figure JPOXMLDOC01-appb-T000072
Figure JPOXMLDOC01-appb-T000072
Figure JPOXMLDOC01-appb-T000073
Figure JPOXMLDOC01-appb-T000073
Figure JPOXMLDOC01-appb-T000074
Figure JPOXMLDOC01-appb-T000074
Figure JPOXMLDOC01-appb-T000075
Figure JPOXMLDOC01-appb-T000075
Figure JPOXMLDOC01-appb-T000076
Figure JPOXMLDOC01-appb-T000076
Figure JPOXMLDOC01-appb-T000077
Figure JPOXMLDOC01-appb-T000077
Figure JPOXMLDOC01-appb-T000078
Figure JPOXMLDOC01-appb-T000078
Figure JPOXMLDOC01-appb-T000079
Figure JPOXMLDOC01-appb-T000079
Figure JPOXMLDOC01-appb-T000080
Figure JPOXMLDOC01-appb-T000080
Figure JPOXMLDOC01-appb-T000081
Figure JPOXMLDOC01-appb-T000081
Figure JPOXMLDOC01-appb-T000082
Figure JPOXMLDOC01-appb-T000082
Figure JPOXMLDOC01-appb-T000083
Figure JPOXMLDOC01-appb-T000083
Figure JPOXMLDOC01-appb-T000084
Figure JPOXMLDOC01-appb-T000084
Figure JPOXMLDOC01-appb-T000085
Figure JPOXMLDOC01-appb-T000085
Figure JPOXMLDOC01-appb-T000086
Figure JPOXMLDOC01-appb-T000086
Figure JPOXMLDOC01-appb-T000087
Figure JPOXMLDOC01-appb-T000087
Figure JPOXMLDOC01-appb-T000088
Figure JPOXMLDOC01-appb-T000088
Figure JPOXMLDOC01-appb-T000089
Figure JPOXMLDOC01-appb-T000089
Figure JPOXMLDOC01-appb-T000090
Figure JPOXMLDOC01-appb-T000090
Figure JPOXMLDOC01-appb-T000091
Figure JPOXMLDOC01-appb-T000091
Figure JPOXMLDOC01-appb-T000092
Figure JPOXMLDOC01-appb-T000092
Figure JPOXMLDOC01-appb-T000093
Figure JPOXMLDOC01-appb-T000093
＜実施例１２－１＞ <Example 12-1>
Figure JPOXMLDOC01-appb-C000081
Figure JPOXMLDOC01-appb-C000081
１－［［２－（１－プロペン－２－イル）－６－（トリフルオロメトキシ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル
　１－［［２－ヨード－６－（トリフルオロメトキシ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル（４１．２ｍｇ） の１，２－ジメトキシエタン（０．３ｍＬ）溶液に、４,４,５,５－テトラメチル－２－ （１－プロペン－２－イル）－１,３,２－ジオキサボロラン（２０．０ ｍｇ）、飽和炭酸ナトリウム水溶液（０．１２ｍＬ）、ジクロロビス（トリフェニルホスフィン）パラジウム（ＩＩ）（５．６ｍｇ）を加え、反応液とした。反応液を、マイクロウェーブ(CEM, 150W)を用いた９０℃で１時間の反応に供した。反応液をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１０：１～１：１）を用いて精製し、淡茶色液体として表題化合物を得た（２７．３ ｍｇ）。
1H NMR (CDCl3, 400 MHz) δ1.40 (3H, t, J = 7.3 Hz), 2.27 (3H, s), 2.32 (3H, s), 4.41 (2H, q, J = 7.3 Hz), 5.58 (1H, d, J = 1.2 Hz), 5.90 (2H, s), 5.98 (1H, s), 6.64 (1H, s), 6.87 (1H, s), 7.63 (1H, s). Ethyl 1-[[2- (1-propen-2-yl) -6- (trifluoromethoxy) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate 1 1,2-[[2-Iodo-6- (trifluoromethoxy) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate (41.2 mg) To a solution of dimethoxyethane (0.3 mL), 4,4,5,5-tetramethyl-2- (1-propen-2-yl) -1,3,2-dioxaborolane (20.0 mg), saturated sodium carbonate An aqueous solution (0.12 mL) and dichlorobis (triphenylphosphine) palladium (II) (5.6 mg) were added to obtain a reaction solution. The reaction solution was subjected to a reaction at 90 ° C. for 1 hour using a microwave (CEM, 150 W). The reaction solution was purified using silica gel column chromatography (hexane: ethyl acetate = 10: 1 to 1: 1) to give the title compound as a light brown liquid (27.3 mg).
1 H NMR (CDCl 3, 400 MHz) δ1.40 (3H, t, J = 7.3 Hz), 2.27 (3H, s), 2.32 (3H, s), 4.41 (2H, q, J = 7.3 Hz), 5.58 (1H, d, J = 1.2 Hz), 5.90 (2H, s), 5.98 (1H, s), 6.64 (1H, s), 6.87 (1H, s), 7.63 (1H, s).
＜実施例１２－２～１２－３３＞
　対応するハロゲン体を用い、実施例１２－１と同様にして、以下の実施例１２－２～１２－３３の化合物を得た。これらの構造およびスペクトルデータを表９４～１０１に示した。 <Examples 12-2 to 12-33>
Using the corresponding halogen compounds, the following compounds of Examples 12-2 to 12-33 were obtained in the same manner as in Example 12-1. Their structures and spectral data are shown in Tables 94-101.
Figure JPOXMLDOC01-appb-T000094
Figure JPOXMLDOC01-appb-T000094
Figure JPOXMLDOC01-appb-T000095
Figure JPOXMLDOC01-appb-T000095
Figure JPOXMLDOC01-appb-T000096
Figure JPOXMLDOC01-appb-T000096
Figure JPOXMLDOC01-appb-T000097
Figure JPOXMLDOC01-appb-T000097
Figure JPOXMLDOC01-appb-T000098
Figure JPOXMLDOC01-appb-T000098
Figure JPOXMLDOC01-appb-T000099
Figure JPOXMLDOC01-appb-T000099
Figure JPOXMLDOC01-appb-T000100
Figure JPOXMLDOC01-appb-T000100
Figure JPOXMLDOC01-appb-T000101
Figure JPOXMLDOC01-appb-T000101
＜実施例１３－１＞ <Example 13-1>
Figure JPOXMLDOC01-appb-C000082
   　 
Figure JPOXMLDOC01-appb-C000082
   　 
５－メチル－１－［［２－（モルホリン－４－イル）－６－フェニルベンゾ［ｄ］チアゾール－４－イル］メチル］－１Ｈ－ピラゾール－３－カルボン酸エチル
　アルゴン雰囲気下、１－［［６－クロロ－２－（モルホリン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル（５０ｍｇ）の１，４－ジオキサン溶液（１．２ ｍＬ）に、室温でフェニルボロン酸（１７ｍｇ）、２ ｍｏｌ／Ｌ炭酸ナトリウム水溶液（０．２ ｍＬ）、テトラキス（トリフェニルホスフィン）パラジウム（０）（１４ ｍｇ）、2-ジシクロヘキシルホスフィノ－２’－ジメチルアミノビフェニル（９ｍｇ）を加え、反応液とした。反応液を６０℃で５時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝４：１）を用いて精製し、薄黄色粉体として表題化合物を得た（４８ｍｇ）。
1H-NMR (400 MHz, CDCl3) δ 1.39 (3H, t, J = 7.3 Hz), 2.24 (3H, s), 3.65-3.69 (4H, m), 3.84-3.88 (4H, m), 4.40 (2H, q, J = 7.3 Hz), 5.77 (2H, s), 6.61 (1H, s), 7.11 (1H, d, J = 1.8 Hz), 7.30 (1H, dt, J = 7.3, 1.2 Hz), 7.38 (2H, t, J = 7.3 Hz), 7.47 (1H, d, J = 1.2 Hz), 7.48-7.50 (1H, m), 7.75 (1H, d, J = 1.8 Hz). Ethyl 5-methyl-1-[[2- (morpholin-4-yl) -6-phenylbenzo [d] thiazol-4-yl] methyl] -1H-pyrazole-3-carboxylate 1- [ 1,6-Dioxane solution of [6-chloro-2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate (50 mg) (1.2 mL) at room temperature with phenylboronic acid (17 mg), 2 mol / L aqueous sodium carbonate solution (0.2 mL), tetrakis (triphenylphosphine) palladium (0) (14 mg), 2-dicyclohexylphosphine Fino-2'-dimethylaminobiphenyl (9 mg) was added to give a reaction solution. The reaction was stirred at 60 ° C. for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the title compound as a pale yellow powder (48 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ 1.39 (3H, t, J = 7.3 Hz), 2.24 (3H, s), 3.65-3.69 (4H, m), 3.84-3.88 (4H, m), 4.40 (2H, q, J = 7.3 Hz), 5.77 (2H, s), 6.61 (1H, s), 7.11 (1H, d, J = 1.8 Hz), 7.30 (1H, dt, J = 7.3, 1.2 Hz) , 7.38 (2H, t, J = 7.3 Hz), 7.47 (1H, d, J = 1.2 Hz), 7.48-7.50 (1H, m), 7.75 (1H, d, J = 1.8 Hz).
＜実施例１３－２～１３－２３＞
　対応するハロゲン体を用い、実施例１３－１と同様にして、以下の実施例１３－２～１３－２３の化合物を得た。これらの構造およびスペクトルデータを表１０２～１０９に示した。 <Examples 13-2 to 13-23>
The following compounds of Examples 13-2 to 13-23 were obtained in the same manner as in Example 13-1, using the corresponding halogen compounds. Their structures and spectral data are shown in Tables 102-109.
Figure JPOXMLDOC01-appb-T000102
Figure JPOXMLDOC01-appb-T000102
Figure JPOXMLDOC01-appb-T000103
Figure JPOXMLDOC01-appb-T000103
Figure JPOXMLDOC01-appb-T000104
Figure JPOXMLDOC01-appb-T000104
Figure JPOXMLDOC01-appb-T000105
Figure JPOXMLDOC01-appb-T000105
Figure JPOXMLDOC01-appb-T000106
Figure JPOXMLDOC01-appb-T000106
Figure JPOXMLDOC01-appb-T000107
Figure JPOXMLDOC01-appb-T000107
Figure JPOXMLDOC01-appb-T000108
Figure JPOXMLDOC01-appb-T000108
Figure JPOXMLDOC01-appb-T000109
Figure JPOXMLDOC01-appb-T000109
＜実施例１４－１＞ <Example 14-1>
Figure JPOXMLDOC01-appb-C000083
Figure JPOXMLDOC01-appb-C000083
１－［［６－アミノ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル
　アルゴン雰囲気下、１－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－ニトロベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル（６０ｍｇ）のエタノール-酢酸混合溶液（１．５ｍＬ， １０：９）に、室温で鉄粉（８ ｍｇ）を加え、反応液とした。反応液を８０℃で１時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：１）を用いて精製し、黄色アモルファスとして表題化合物を得た（４１ｍｇ）。
1H-NMR (400 MHz, CDCl3) δ 1.38 (3H, t, J = 7.3 Hz), 2.22 (3H, s), 2.29-2.36 (2H, m), 3.71 (2H, t, J = 5.4 Hz), 4.06 (2H, t, J = 2.7 Hz), 4.42 (2H, q, J = 7.3 Hz), 5.66 (2H, s), 5.79 (1H, d, J = 10.3 Hz), 5.93 (1H, d, J = 10.3 Hz), 6.26 (1H, d, J = 2.4 Hz), 6.59 (1H, s), 6.86 (1H, d, J = 2.4 Hz). 1-[[6-Amino-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate 1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6-nitrobenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3- under argon atmosphere Iron powder (8 mg) was added to an ethanol-acetic acid mixed solution (1.5 mL, 10: 9) of ethyl carboxylate (60 mg) at room temperature to prepare a reaction solution. The reaction was stirred at 80 ° C. for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound as a yellow amorphous (41 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ 1.38 (3H, t, J = 7.3 Hz), 2.22 (3H, s), 2.29-2.36 (2H, m), 3.71 (2H, t, J = 5.4 Hz ), 4.06 (2H, t, J = 2.7 Hz), 4.42 (2H, q, J = 7.3 Hz), 5.66 (2H, s), 5.79 (1H, d, J = 10.3 Hz), 5.93 (1H, d , J = 10.3 Hz), 6.26 (1H, d, J = 2.4 Hz), 6.59 (1H, s), 6.86 (1H, d, J = 2.4 Hz).
＜実施例１５－１＞ <Example 15-1>
Figure JPOXMLDOC01-appb-C000084
１－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－（メチルアミノ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル
１－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－（ジメチルアミノ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル
　アルゴン雰囲気下、１－［［６－アミノ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル（４２ｍｇ）のアセトン溶液（０．６ ｍＬ）に、室温でヨードメタン（０．０３ ｍＬ）、炭酸カリウム（１４６ ｍｇ）を加え、反応液とした。反応液を室温で２時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：４）を用いて精製し、それぞれ無色液体として表題化合物を得た（メチルアミノ体（１６ ｍｇ）、ジメチルアミノ体（１９ｍｇ））。
メチルアミノ体
1H-NMR (400 MHz, CDCl3)　δ 1.38 (3H, t, J = 7.3 Hz), 2.22 (3H, s), 2.29-2.35 (2H, m), 2.76 (3H, s), 3.66-3.74 (2H, m), 4.02-4.08 (2H, m), 4.40 (2H, q, J = 7.3 Hz), 5.67 (2H, s), 5.79 (1H, d, J = 10.4 Hz), 5.93 (1H, d, J = 10.4 Hz), 6.23 (1H, s), 6.58 (1H, s), 6.77 (1H, s).
ジメチルアミノ体
1H-NMR (400 MHz, CDCl3) δ 1.39 (3H, t, J = 7.3 Hz), 2.23 (3H, s), 2.29-2.35 (2H, m), 2.83 (6H, s), 3.68-3.73 (2H, m), 4.02-4.08 (2H, m), 4.40 (2H, q, J = 7.3 Hz), 5.70 (2H, s), 5.79 (1H, d, J = 10.4 Hz), 5.93 (1H, d, J = 10.4 Hz), 6.44 (1H, s), 6.57 (1H, s), 6.92 (1H, s).
Figure JPOXMLDOC01-appb-C000084
1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6- (methylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3- Ethyl carboxylate 1-[[2- (3,6-dihydropyridin-1 (2H) -yl) -6- (dimethylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole Ethyl-3-carboxylate 1-[[6-Amino-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl under argon atmosphere To an acetone solution (0.6 mL) of ethyl -1H-pyrazole-3-carboxylate (42 mg), iodomethane (0.03 mL) and potassium carbonate (146 mg) were added at room temperature to prepare a reaction solution. The reaction was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 1: 4) to give the title compound as a colorless liquid, respectively (methylamino compound (16 mg), dimethylamino compound (19 mg). )).
Methylamino form
1 H-NMR (400 MHz, CDCl 3 ) δ 1.38 (3H, t, J = 7.3 Hz), 2.22 (3H, s), 2.29-2.35 (2H, m), 2.76 (3H, s), 3.66-3.74 (2H, m), 4.02-4.08 (2H, m), 4.40 (2H, q, J = 7.3 Hz), 5.67 (2H, s), 5.79 (1H, d, J = 10.4 Hz), 5.93 (1H, d, J = 10.4 Hz), 6.23 (1H, s), 6.58 (1H, s), 6.77 (1H, s).
Dimethylamino form
1 H-NMR (400 MHz, CDCl 3 ) δ 1.39 (3H, t, J = 7.3 Hz), 2.23 (3H, s), 2.29-2.35 (2H, m), 2.83 (6H, s), 3.68-3.73 (2H, m), 4.02-4.08 (2H, m), 4.40 (2H, q, J = 7.3 Hz), 5.70 (2H, s), 5.79 (1H, d, J = 10.4 Hz), 5.93 (1H, d, J = 10.4 Hz), 6.44 (1H, s), 6.57 (1H, s), 6.92 (1H, s).
＜実施例１５－２＞ <Example 15-2>
Figure JPOXMLDOC01-appb-C000085
   　 
Figure JPOXMLDOC01-appb-C000085
   　 
１－［［６－クロロ－２－［［（フラン－２－イル）メチル］（メチル）アミノ］ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル
１－［［６－クロロ－２－［［（フラン－２－イル）メチル］アミノ］ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル（４０．８ ｍｇ）のアセトン（２．０ ｍＬ）溶液に、炭酸カリウム（６４．０ ｍｇ）、及びヨウ化メチル（０．０１７ｍＬ）を加え、反応液とした。反応液をマイクロウェーブ
 （ＣＥＭ， １５０Ｗ）を用いた８０℃で４０分間の反応に供した。反応溶液をシリカゲルカラムクロマトグラフィー（ＮＨ，ヘキサン：酢酸エチル ＝１０：１～３：１）を用いて精製し、無色固体として表題化合物を得た（２７．９ ｍｇ）。
1H-NMR (400 MHz, CDCl3) δ 1.40 (3H, t, J = 7.3 Hz), 2.23 (3H, s), 3.17 (3H, s), 4.41 (2H, q, J = 7.3 Hz), 4.75 (2H, s), 5.69 (2H, s), 6.32-6.36 (2H, m), 6.61 (1H, s), 6.81 (1H, d, J = 1.8 Hz), 7.39 (1H, d, J = 1.8 Hz), 7.48 (1H, d, J = 1.8 Hz). 1-[[6-Chloro-2-[[(furan-2-yl) methyl] (methyl) amino] benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carvone Ethyl 1-[[6-chloro-2-[[(furan-2-yl) methyl] amino] benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid To a solution of ethyl (40.8 mg) in acetone (2.0 mL), potassium carbonate (64.0 mg) and methyl iodide (0.017 mL) were added to obtain a reaction solution. The reaction solution was subjected to a reaction for 40 minutes at 80 ° C. using a microwave (CEM, 150 W). The reaction solution was purified using silica gel column chromatography (NH, hexane: ethyl acetate = 10: 1 to 3: 1) to obtain the title compound as a colorless solid (27.9 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ 1.40 (3H, t, J = 7.3 Hz), 2.23 (3H, s), 3.17 (3H, s), 4.41 (2H, q, J = 7.3 Hz), 4.75 (2H, s), 5.69 (2H, s), 6.32-6.36 (2H, m), 6.61 (1H, s), 6.81 (1H, d, J = 1.8 Hz), 7.39 (1H, d, J = 1.8 Hz), 7.48 (1H, d, J = 1.8 Hz).
＜実施例１６－１＞ <Example 16-1>
Figure JPOXMLDOC01-appb-C000086
Figure JPOXMLDOC01-appb-C000086
１－［［６－クロロ－２－（プロパン－２－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル
　１－［［６－クロロ－２－（１－プロペン－２－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル（２０．０ｍｇ）の酢酸エチル（１．０　ｍＬ）溶液に、酸化白金（５．０ ｍｇ）を加え、反応液とした。反応液を含む反応容器を水素置換した後に、室温で３時間、激しく攪拌した。不溶物をセライトで除去し、濾液を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１０：１～１：１）を用いて精製し、無色油状物として表題化合物を得た（１５．１ ｍｇ）。
1H-NMR (400 MHz, CDCl3) δ 1.40 (3H, t, J = 7.3 Hz), 1.48 (6H, d, J = 7.3 Hz), 2.26 (3H, s), 3.36-3.46 (1H, m), 4.41 (2H, q, J = 7.3 Hz), 5.86 (2H, s), 6.64 (1H, s), 6.93 (1H, d, J = 2.4 Hz), 7.74 (1H, d, J = 2.4 Hz). 1-[[6-Chloro-2- (propan-2-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate 1-[[6-Chloro -2- (1-propen-2-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate (20.0 mg) in ethyl acetate (1.0 mL) solution was added platinum oxide (5.0 mg) to prepare a reaction solution. The reaction vessel containing the reaction solution was purged with hydrogen and then stirred vigorously at room temperature for 3 hours. Insolubles were removed with Celite, and the filtrate was distilled off under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate = 10: 1 to 1: 1) to give the title compound as a colorless oil (15.1 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ 1.40 (3H, t, J = 7.3 Hz), 1.48 (6H, d, J = 7.3 Hz), 2.26 (3H, s), 3.36-3.46 (1H, m ), 4.41 (2H, q, J = 7.3 Hz), 5.86 (2H, s), 6.64 (1H, s), 6.93 (1H, d, J = 2.4 Hz), 7.74 (1H, d, J = 2.4 Hz ).
＜実施例１６－２＞ <Example 16-2>
Figure JPOXMLDOC01-appb-C000087
Figure JPOXMLDOC01-appb-C000087
１－［（６－クロロ－２－シクロヘキシルベンゾ［ｄ］チアゾール－４－イル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル
　１－［［６－クロロ－２－（１－シクロヘキセン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル（３０．０ｍｇ）の酢酸エチル（１．０　ｍＬ）溶液に、酸化白金（１５．０ ｍｇ）を加え、反応液とした。反応液を含む反応容器を水素置換した後に、室温で３０時間、激しく攪拌した。不溶物をセライトで除去し、濾液を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１０：１～１：１）を用いて精製し、無色油状物として表題化合物を得た（１３．８ ｍｇ）。
1H-NMR (400 MHz, CDCl3) δ 1.26-1.52 (6H, m), 1.63 (2H, dq, J = 12.7, 3.6 Hz), 1.73-1.83 (1H, m), 1.90 (2H, dt, J = 12.7, 3.6 Hz), 2.16-2.24 (2H, m), 2.25 (3H, s), 3.10 (1H, tt, J = 11.5, 3.6 Hz), 4.42 (2H, q, J = 7.1 Hz), 5.86 (2H, s), 6.64 (1H, s), 6.90 (1H, d, J = 1.8 Hz), 7.74 (1H, d, J = 1.8 Hz). 1-[(6-Chloro-2-cyclohexylbenzo [d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate 1-[[6-Chloro-2- (1- Cyclohexen-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylate (30.0 mg) in ethyl acetate (1.0 mL) was oxidized to Platinum (15.0 mg) was added to prepare a reaction solution. The reaction vessel containing the reaction solution was purged with hydrogen and then stirred vigorously at room temperature for 30 hours. Insolubles were removed with Celite, and the filtrate was distilled off under reduced pressure. The obtained residue was purified using silica gel column chromatography (hexane: ethyl acetate = 10: 1 to 1: 1) to give the title compound as a colorless oil (13.8 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ 1.26-1.52 (6H, m), 1.63 (2H, dq, J = 12.7, 3.6 Hz), 1.73-1.83 (1H, m), 1.90 (2H, dt, J = 12.7, 3.6 Hz), 2.16-2.24 (2H, m), 2.25 (3H, s), 3.10 (1H, tt, J = 11.5, 3.6 Hz), 4.42 (2H, q, J = 7.1 Hz), 5.86 (2H, s), 6.64 (1H, s), 6.90 (1H, d, J = 1.8 Hz), 7.74 (1H, d, J = 1.8 Hz).
＜実施例１７－１＞ <Example 17-1>
Figure JPOXMLDOC01-appb-C000088
Figure JPOXMLDOC01-appb-C000088
１－［（６－クロロ－２－シクロプロピルベンゾ［ｄ］チアゾール－４－イル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル
　１－［（６－クロロ－２－ヨードベンゾ［ｄ］チアゾール－４－イル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸エチル（１００ｍｇ）のテトラヒドロフラン（１．０　ｍＬ）溶液に、シクロプロピルジンク（II）ブロミド、テトラキス（トリフェニルホスフィン）パラジウム（０）（８．０ ｍｇ）を加え、反応液とした。反応液を室温で１時間攪拌した。なお、シクロプロピルジンク（II）ブロミドは、ブロモシクロプロパン（５２．５ ｍｇ）のテトラヒドロフラン（１．０ ｍＬ）溶液にリーケ亜鉛（１．１３ ｍＬ， ０．７６４ ｍｏｌ／Ｌテトラヒドロフラン溶液）を加えて室温で２時間攪拌することにより調製した。反応液をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１０：１～３：１）を用いて精製し、無色固体として表題化合物を得た（２５．０ ｍｇ）。
1H-NMR (400 MHz, CDCl3) δ 1.18-1.31 (4H, m), 1.40 (3H, t, J = 7.3 Hz), 2.23 (3H, s), 2.35-2.41 (1H, m), 4.41 (2H, q, J = 7.3 Hz), 5.80 (2H, s), 6.63 (1H, s), 6.88 (1H, d, J = 1.8 Hz), 7.67 (1H, d, J = 1.8 Hz). 1-[(6-Chloro-2-cyclopropylbenzo [d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate 1-[(6-Chloro-2-iodobenzo [ d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylate (100 mg) in tetrahydrofuran (1.0 mL) was added to cyclopropylzinc (II) bromide, tetrakis (triphenyl Phosphine) palladium (0) (8.0 mg) was added to give a reaction solution. The reaction was stirred at room temperature for 1 hour. Cyclopropylzinc (II) bromide was prepared by adding Likezinc (1.13 mL, 0.764 mol / L tetrahydrofuran solution) to a tetrahydrofuran (1.0 mL) solution of bromocyclopropane (52.5 mg). Prepared by stirring at room temperature for 2 hours. The reaction mixture was purified using silica gel column chromatography (hexane: ethyl acetate = 10: 1-3: 1) to give the title compound as a colorless solid (25.0 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ 1.18-1.31 (4H, m), 1.40 (3H, t, J = 7.3 Hz), 2.23 (3H, s), 2.35-2.41 (1H, m), 4.41 (2H, q, J = 7.3 Hz), 5.80 (2H, s), 6.63 (1H, s), 6.88 (1H, d, J = 1.8 Hz), 7.67 (1H, d, J = 1.8 Hz).
＜実施例１８－１＞ <Example 18-1>
Figure JPOXMLDOC01-appb-C000089
Figure JPOXMLDOC01-appb-C000089
６－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］オキシ］ピリジン－２－カルボン酸メチル
　アルゴン雰囲気下、６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－４－ヒドロキシベンゾ［ｄ］チアゾール（２６．６ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１．０ ｍＬ）溶液に、６－フルオロピリジン－２－カルボン酸メチル（１５．５ｍｇ）、炭酸カリウム （２７．６ ｍｇ）を加え、反応液とした。反応液を１００℃で２時間攪拌した。室温まで放冷後、水、酢酸エチル、及びヘキサン (酢酸エチル ／ヘキサン＝１／１)を加えて分層した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去後、残渣をシリカゲルカラムクロマトグラフィー（NH,ヘキサン：酢酸エチル＝２０：１～１：１）を用いて精製し、無色固体として表題化合物を得た（１５．１ ｍｇ）。
1H-NMR (400 MHz, CDCl3) δ 2.19-2.26 (2H, m), 3.60 (2H, t, J = 5.8 Hz), 3.92 (2H, t, J = 2.7 Hz), 3.94 (3H, s), 5.66-5.73 (1H, m), 5.84-5.91 (1H, m), 6.99 (1H, d, J = 7.3 Hz), 7.18 (1H, d, J = 1.8 Hz), 7.44 (1H, d, J = 1.8 Hz), 7.78 (1H, t, J = 7.3 Hz), 7.86 (1H, d, J = 7.3 Hz). Methyl 6-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] oxy] pyridine-2-carboxylate 6-chloro under argon atmosphere To a solution of -2- (3,6-dihydropyridin-1 (2H) -yl) -4-hydroxybenzo [d] thiazole (26.6 mg) in N, N-dimethylformamide (1.0 mL) was added 6-fluoro. Methyl pyridine-2-carboxylate (15.5 mg) and potassium carbonate (27.6 mg) were added to give a reaction solution. The reaction was stirred at 100 ° C. for 2 hours. After cooling to room temperature, water, ethyl acetate, and hexane (ethyl acetate / hexane = 1/1) were added and the layers were separated. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (NH, hexane: ethyl acetate = 20: 1 to 1: 1) to obtain the title compound as a colorless solid (15.1 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ 2.19-2.26 (2H, m), 3.60 (2H, t, J = 5.8 Hz), 3.92 (2H, t, J = 2.7 Hz), 3.94 (3H, s ), 5.66-5.73 (1H, m), 5.84-5.91 (1H, m), 6.99 (1H, d, J = 7.3 Hz), 7.18 (1H, d, J = 1.8 Hz), 7.44 (1H, d, J = 1.8 Hz), 7.78 (1H, t, J = 7.3 Hz), 7.86 (1H, d, J = 7.3 Hz).
＜実施例１８－２～１８－４＞
　対応するハロゲン体を用い、実施例１８－１と同様にして、以下の実施例１８－２～１８－４の化合物を得た。これらの構造およびスペクトルデータを表１１０に示した。 <Examples 18-2 to 18-4>
The following compounds of Examples 18-2 to 18-4 were obtained in the same manner as in Example 18-1, using the corresponding halogen compound. Their structure and spectral data are shown in Table 110.
Figure JPOXMLDOC01-appb-T000110
Figure JPOXMLDOC01-appb-T000110
＜実施例１９－１＞ <Example 19-1>
Figure JPOXMLDOC01-appb-C000090
Figure JPOXMLDOC01-appb-C000090
３－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］安息香酸メチル
　アルゴン雰囲気下、６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－ボロン酸（４７．０ｍｇ）、３－（ブロモメチル）安息香酸メチル（４４．０ｍｇ）、リン酸カリウム（８５．０ｍｇ）、ジクロロビス（トリフェニルホスフィン）パラジウム（ＩＩ）（１２．０ｍｇ）、Ｎ，Ｎ－ジメチルホルムアミド（１ｍＬ）、水（０．２ｍＬ）を混合し、反応液とした。反応液を８０℃で１時間撹拌した。反応液を酢酸エチルで希釈して、水、飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥した。溶媒留去後、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝５：１）を用いて精製し、黄色粉体として表題化合物を得た（４１．４ｍｇ）。
1H-NMR (400 MHz, CDCl3) δ 2.28-2.37 (2H, m), 3.76 (2H, t, J = 5.5 Hz), 3.90 (3H, s), 4.07-4.13 (2H, m), 4.29 (2H, s), 5.76-5.83 (1H, m), 5.90-5.98 (1H, m), 7.01 (1H, d, J = 2.4 Hz), 7.33 (1H, d, J = 7.8 Hz), 7.42 (1H, d, J = 2.4 Hz), 7.52 (1H, d, J = 7.8 Hz), 7.86 (1H, d, J = 7.8 Hz), 8.08 (1H, s). Methyl 3-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] benzoate 6-chloro-2- ( 3,6-Dihydropyridin-1 (2H) -yl) benzo [d] thiazole-4-boronic acid (47.0 mg), methyl 3- (bromomethyl) benzoate (44.0 mg), potassium phosphate (85.0 mg) ), Dichlorobis (triphenylphosphine) palladium (II) (12.0 mg), N, N-dimethylformamide (1 mL), and water (0.2 mL) were mixed to obtain a reaction solution. The reaction was stirred at 80 ° C. for 1 hour. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified using silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound as a yellow powder (41.4 mg).
1 H-NMR (400 MHz, CDCl 3 ) δ 2.28-2.37 (2H, m), 3.76 (2H, t, J = 5.5 Hz), 3.90 (3H, s), 4.07-4.13 (2H, m), 4.29 (2H, s), 5.76-5.83 (1H, m), 5.90-5.98 (1H, m), 7.01 (1H, d, J = 2.4 Hz), 7.33 (1H, d, J = 7.8 Hz), 7.42 ( 1H, d, J = 2.4 Hz), 7.52 (1H, d, J = 7.8 Hz), 7.86 (1H, d, J = 7.8 Hz), 8.08 (1H, s).
　次に、実施例の化合物を用いた試験例を示すことにより、本発明の有用性の一端を説明する。 Next, the usefulness of the present invention will be explained by showing test examples using the compounds of the examples.
＜試験例１＞
ＥＰ１受容体拮抗作用確認試験
 (1) ラットＥＰ１発現ベクターの調製
　Rat Kidney BD Marathon-Ready cDNA　(日本ベクトン・ディッキンソン株式会社)を鋳型として、配列番号1に示したフォワードプライマーおよび配列番号2に示したリバースプライマーを使用し、KOD-Plus-Ver2. 0 (東洋紡績株式会社)を用いて1回目のPCRを行った。さらに、この増幅産物を鋳型とし、配列番号3に示したフォワードプライマーおよび配列番号4に示したリバースプライマーを使用し、さらに同様に2回目のPCRを行った。2回目のPCRで得られた増幅産物をベクター(pcDNA3.1 D/V5-His-TOPO (登録商標)、インビトロジェン株式会社)に組み込んだ。常法により、この増幅産物を組み込んだベクターを大腸菌(ワンショットTOP10コンピテントセル、インビトロジェン株式会社)に導入し形質転換した。この形質転換した大腸菌をLB寒天培地で1日培養した。培養後、コロニーを選択し、50 μg/mLのアンピシリンを含むLB液体培地で培養した。培養後、QIAprep Spin Miniprep Kit (株式会社キアゲン)を用いてベクターを精製した。このベクターの挿入部位の塩基配列(配列番号5) を公知のデータベース(NCBI)のアクセッション番号NM_013100で登録されているラットＥＰ１の塩基配列(Ptger1) と比較したところ、1塩基以外全て一致していた。また、この塩基配列によって翻訳されたアミノ酸配列は、NCBIのアクセッション番号NP_037232で登録されているラットＥＰ１受容体のアミノ酸配列と完全に一致した。したがって、クローニングした遺伝子配列はラットＥＰ１受容体の塩基配列であり、得られたアミノ酸配列はラットＥＰ１受容体であることが確認された。配列番号5に示した核酸が挿入されたpcDNA3.1 D/V5-His-TOPO (登録商標)をラットＥＰ１発現ベクターとした。 <Test Example 1>
EP 1 receptor antagonism confirmation test (1) Preparation of rat EP 1 expression vector Using Rat Kidney BD Marathon-Ready cDNA (Nippon Becton Dickinson Co., Ltd.) as a template, forward primer and SEQ ID NO: 2 The first PCR was performed using KOD-Plus-Ver2.0 (Toyobo Co., Ltd.) using the indicated reverse primer. Furthermore, using this amplification product as a template, the forward primer shown in SEQ ID NO: 3 and the reverse primer shown in SEQ ID NO: 4 were used, and a second PCR was performed in the same manner. The amplification product obtained by the second PCR was incorporated into a vector (pcDNA3.1 D / V5-His-TOPO (registered trademark), Invitrogen Corporation). By a conventional method, the vector incorporating this amplification product was introduced into E. coli (One-shot TOP10 competent cell, Invitrogen) and transformed. The transformed E. coli was cultured on LB agar medium for 1 day. After culture, colonies were selected and cultured in LB liquid medium containing 50 μg / mL ampicillin. After culture, the vector was purified using QIAprep Spin Miniprep Kit (Qiagen). When the base sequence (SEQ ID NO: 5) of the insertion site of this vector was compared with the base sequence (Ptger1) of rat EP 1 registered under the accession number NM_013100 of the publicly known database (NCBI), all but one base was identical. It was. The amino acid sequence translated by this base sequence completely matched the amino acid sequence of the rat EP 1 receptor registered under NCBI accession number NP_037232. Therefore, it was confirmed that the cloned gene sequence was the base sequence of rat EP 1 receptor, and the obtained amino acid sequence was rat EP 1 receptor. PcDNA3.1 D / V5-His-TOPO (registered trademark) into which the nucleic acid shown in SEQ ID NO: 5 was inserted was used as a rat EP 1 expression vector.
 (2) ラットＥＰ１受容体発現細胞の調製
 (2-1) C0S-1細胞培養
　COS-1細胞(大日本住友製薬)は抗生物質としてペニシリン－ストレプトマイシン溶液(インビトロジェン株式会社、最終濃度:ベンジルペニシリンとして100U/mL;ストレプトマイシンとして100μg/mL)、MEM非必須アミノ酸(インビトロジェン株式会社、最終濃度0.1 mM) および牛胎児血清(MoregateBiotech社、最終濃度：10%) を添加したD-MEM液体培地(高グルコースおよびL-グルタミン含有、インビトロジェン株式会社)を用いて、5%CO２ガス条件のインキュベーター内で37℃にてコンフルエントに達するまで培養した。 (2) Preparation of rat EP 1 receptor-expressing cells (2-1) C0S-1 cell culture COS-1 cells (Dainippon Sumitomo Pharma) are penicillin-streptomycin solution (Invitrogen Corporation, final concentration: benzylpenicillin) as an antibiotic. 100 U / mL; 100 μg / mL as streptomycin), D-MEM liquid medium (high concentration, MEM non-essential amino acid (Invitrogen Corporation, final concentration 0.1 mM)) and fetal bovine serum (MoregateBiotech, final concentration: 10%) Using glucose and L-glutamine, Invitrogen Corporation), the cells were cultured in an incubator under 5% CO 2 gas conditions at 37 ° C. until they reached confluence.
 (2-2) COS-1細胞の継代
　コンフルエントに達した細胞を0.05%トリプシン/0.53mM EDTA・4Na (インビトロジェン株式会社)にて剥がし、上記液体培地にて再懸濁した。再懸濁した細胞を上記液体培地にてスプレットレシオが1：4から1：8になるように希釈し、培養した。 (2-2) Passage of COS-1 cells Cells that reached confluence were detached with 0.05% trypsin / 0.53 mM EDTA · 4Na (Invitrogen Corporation) and resuspended in the liquid medium. The resuspended cells were diluted with the above liquid medium so that the spread ratio was 1: 4 to 1: 8 and cultured.
 (2-3) ラットＥＰ１発現ベクター導入用細胞の準備
　コンフルエントに達した細胞を0.05%トリプシン/0.53mM EDTA・4Naにて剥がし、MEM非必須アミノ酸(最終濃度：0.1 mM)及び牛胎児血清(最終濃度：10%) を添加したD-MEM液体培地(高グルコース及びL-グルタミン含有、インビトロジェン株式会社)にて再懸濁した。この再懸濁した細胞懸濁液をポリD-リジンコートした96ウェルマイクロプレート(BD BioCoat (登録商標)、日本ベクトン・ディッキンソン株式会社)の各ウェルに細胞数５×１０4個／液体培地１００μＬ／ウェルになるように液体培地にて調製し、この細胞調製液を１００μＬずつ各ウェルに分注し、播種した。播種後、その細胞を5%CO２ガス条件のインキュベーター内で37℃にて培養した。このラットＥＰ１発現ベクターの導入用細胞が接着した時点(播種後約2時間後)に下記に示す手順でラットＥＰ１発現ベクターの導入を行った。 (2-3) Preparation of cells for introducing rat EP 1 expression vector Cells that have reached confluence are removed with 0.05% trypsin / 0.53 mM EDTA · 4Na, MEM non-essential amino acids (final concentration: 0.1 mM) and fetal bovine serum ( It was resuspended in a D-MEM liquid medium (containing high glucose and L-glutamine, Invitrogen Corporation) supplemented with a final concentration of 10%. This resuspended cell suspension was poly D-lysine coated 96 well microplate (BD BioCoat (registered trademark), Nippon Becton Dickinson Co., Ltd.) in each well 5 × 10 4 cells / liquid medium 100 μL / Well in a liquid medium so that it becomes a well, 100 μL of this cell preparation was dispensed into each well and seeded. After seeding, the cells were cultured at 37 ° C. in an incubator under 5% CO 2 gas conditions. When the cells for introduction of the rat EP 1 expression vector were adhered (about 2 hours after seeding), the rat EP 1 expression vector was introduced by the following procedure.
 (2-4) ラットＥＰ１発現ベクター導入
　ラットＥＰ１発現ベクターの導入のために、リポフェクタミン2000 (インビトロジェン株式会社)を使用した。ラットＥＰ１発現ベクターを200ng/25μL/ウェルになるようにOPTI-MEM(登録商標) I Reduced-Serum Medium (インビトロジェン株式会社)で希釈した。同時に、リポフェクタミン2000 (インビトロジェン株式会社)を0.5μL/25μL/ウェルになるように、OPTI-MEM (登録商標) I Reduced-Serum Medium(インビトロジェン株式会社)にて希釈し、室温にて5分間インキュベートした。5分間のインキュベート後、ラットＥＰ１発現ベクター/リポフェクタミン2000の複合体形成のために、希釈したラットＥＰ１発現ベクターと希釈したリポフェクタミン2000とを混合し、室温で30分間インキュベートした。30分間のインキュベート後、ラットＥＰ１発現ベクター/リポフェクタミン2000の複合体を上記ラットＥＰ１発現ベクター導入用細胞に50μL/ウェルずつ分注した。このラットＥＰ１発現ベクター/リポフェクタミン2000の複合体が分注された細胞を5%CO２ガス条件のインキュベーター内で37℃で24時間培養した。24時間の培養後、この細胞をラットＥＰ１受容体発現細胞として、細胞内カルシウム濃度の測定に使用した。 (2-4) for the introduction of rat EP 1 expression vector introduced rat EP 1 expression vector, using Lipofectamine 2000 (Invitrogen Corporation). Rats EP 1 expression vector was diluted with 200 ng / 25 [mu] L / to be well OPTI-MEM (R) I Reduced-Serum Medium (Invitrogen Corporation). At the same time, Lipofectamine 2000 (Invitrogen Corp.) was diluted with OPTI-MEM (registered trademark) I Reduced-Serum Medium (Invitrogen Corp.) to 0.5 μL / 25 μL / well and incubated at room temperature for 5 minutes. . After incubation for 5 minutes, diluted rat EP 1 expression vector and diluted Lipofectamine 2000 were mixed and incubated at room temperature for 30 minutes for complex formation of rat EP 1 expression vector / Lipofectamine 2000. After incubation for 30 minutes, the rat EP 1 expression vector / Lipofectamine 2000 complex was dispensed into the rat EP 1 expression vector introduction cells at 50 μL / well. The cells into which the complex of rat EP 1 expression vector / Lipofectamine 2000 was dispensed were cultured at 37 ° C. for 24 hours in an incubator under 5% CO 2 gas conditions. After culturing for 24 hours, this cell was used as a rat EP 1 receptor-expressing cell to measure intracellular calcium concentration.
 (3)細胞内カルシウム濃度上昇抑制作用の検討
　ラットＥＰ１受容体発現細胞を用いて、プロスタグランジンＥ２誘発細胞内カルシウム濃度の上昇に対する各試験化合物の抑制効果を以下に示した方法により検討した。
方法:
　各試験化合物の10mMジメチルスルホキシド溶液をアッセイバッファー(20mM HEPES/Hank's Balanced Salt Solution (HBSS)、pH7.2)で希釈した。
　ラットＥＰ１受容体発現細胞をアッセイバッファーで洗浄した。蛍光カルシウム指示薬(Fluo 4-AM(株式会社同仁化学研究所))にPluronic F-127(インビトロジェン株式会社)を最終濃度0.0004%となるよう混合した後、アッセイバッファーを加え、4μmol/LのFluo 4-AM溶液を調製した。この溶液100μLを各ウェルに添加し、37℃で90分間、インキュベーター内でインキュベートした。その後、細胞上清を全て吸引し、2.5mMプロベネシドを含むアッセイバッファー100μLを各ウェルに添加した。15分間インキュベーター内でインキュベートした後、細胞内カルシウム濃度を測定した。細胞内カルシウム濃度は、FlexStation (登録商標) (モレキュラーデバイス社製)を用いて蛍光シグナルとして測定した。蛍光シグナル読み込み開始から20秒後にアッセイバッファーで希釈した上記各試験化合物50μL　(最終濃度：0.1 nM～10 μM) を各ウェルに添加し、60秒間蛍光シグナルを測定した。その後、50μLプロスタグランジンＥ２バッファー溶液を各ウェルに添加し(最終濃度10 nM)、60秒間蛍光シグナルを測定した。上記に示した方法において、試験化合物の代わりにアッセイバッファーを添加したときのプロスタグランジンＥ２添加時に得られた蛍光シグナルを100%、試験化合物およびプロスタグランジンＥ２のいずれも添加しない時に得られたシグナルを0%とした。また、試験化合物の用量－反応曲線から50%の阻害を示す濃度をIC50値とした。得られた各試験化合物のIC50値を以下の表Iに示した。 (3) with considering the rat EP 1 receptor-expressing cells in the intracellular calcium concentration elevation inhibitory action, examined by the method shown the inhibitory effect of each test compound is shown below for the increase in prostaglandin E 2 induced intracellular calcium concentration did.
Method:
A 10 mM dimethyl sulfoxide solution of each test compound was diluted with an assay buffer (20 mM HEPES / Hank's Balanced Salt Solution (HBSS), pH 7.2).
Rat EP 1 receptor-expressing cells were washed with assay buffer. Pluronic F-127 (Invitrogen Corporation) was mixed with a fluorescent calcium indicator (Fluo 4-AM (Dojindo Laboratories)) to a final concentration of 0.0004%, then assay buffer was added, and 4 μmol / L Fluo 4 -An AM solution was prepared. 100 μL of this solution was added to each well and incubated in an incubator at 37 ° C. for 90 minutes. Thereafter, all the cell supernatant was aspirated, and 100 μL of assay buffer containing 2.5 mM probenecid was added to each well. After incubation in the incubator for 15 minutes, the intracellular calcium concentration was measured. The intracellular calcium concentration was measured as a fluorescence signal using FlexStation (registered trademark) (manufactured by Molecular Devices). Twenty seconds after the start of reading the fluorescence signal, 50 μL of each test compound (final concentration: 0.1 nM to 10 μM) diluted with the assay buffer was added to each well, and the fluorescence signal was measured for 60 seconds. Then added 50μL prostaglandin E 2 buffer solution to each well (final concentration 10 nM), was measured for 60 seconds the fluorescence signal. In the method shown above, the fluorescence signal obtained when prostaglandin E 2 was added when assay buffer was added instead of the test compound was obtained when 100% of the test signal and prostaglandin E 2 were not added. The signal obtained was 0%. The concentration showing 50% inhibition from the dose-response curve of the test compound was taken as the IC 50 value. The IC 50 values of the obtained test compounds are shown in Table I below.
Figure JPOXMLDOC01-appb-T000111
 ＜試験例２＞
17-phenyl trinor Prostaglandin E2 (17-PTP)誘発膀胱収縮に対する抑制作用
 (1)実験動物の作成
　Wistar系雄性ラットに10w/v%ウレタン溶液を1.5 g/kg の用量で皮下投与 (s. c. )することで麻酔を導入した。ウレタン投与約40分後、ラットが完全に麻酔にかかったのを確認し、背部、両側大腿部、腹部および頚部の毛を刈り、腹位に固定した。背部皮膚を正中切開後、脊椎に沿って両側の胸背部の筋肉を切開し開創器で筋肉層を開き胸部脊椎を露出させた。第9胸椎を頭側に引っ張るようにしながら骨鉗子で小穴を開けそこから半田ごてを用いて脊髄を切断した。この時、出血がひどい場合には切断箇所に止血用のゼラチンスポンジを詰めた。胸背部切開層を外科用接着剤を用いて閉じた後、ラットを背位に固定した。左大腿部の皮膚を切開し、大腿動脈を露出させ剥離後、200ヘパリン単位/mLのヘパリンを満たした動脈カテーテルを15 mm挿入した。左大腿部切開層を外科用接着剤を用いて閉じた。右大腿部の皮膚を切開し、大腿動脈を露出させ剥離後結紮した。薬物を静脈内投与する場合には右側の大腿静脈を露出させ剥離後、静脈カテーテルを挿入した。右大腿部切開層を外科用接着剤を用いて閉じた。腹部を正中切開し両側の輸尿管を露出し結紮後、腎臓側を切断した。膀胱頂部に2本のミッヘル止血鉗子を約3 mmの間隔で掛け、その間を切開しそこから膀胱カテーテルを5 mm挿入し巾着縫合した。腹部切開層を縫合した後、ペニスを露出させ結紮した。頚部を正中切開し、気管を露出させて切開を加え末梢側を結紮した後、エッペンドルフチップの先端を気管の下に置き気管を少し持ち上げることで気道を確保した。
Figure JPOXMLDOC01-appb-T000111
 <Test Example 2>
Inhibitory effect on 17-phenyl trinor Prostaglandin E2 (17-PTP) -induced bladder contraction (1) Preparation of experimental animals Wistar male rats should be subcutaneously administered (sc) with a 10 w / v% urethane solution at a dose of 1.5 g / kg. Anesthesia was introduced at About 40 minutes after urethane administration, it was confirmed that the rat was completely anesthetized, and the hair on the back, both sides of the thigh, the abdomen and the neck was shaved and fixed in the abdominal position. After midline incision of the back skin, the muscles on both sides of the back of the chest were incised along the spine, and the muscle layer was opened with a retractor to expose the thorax spine. While pulling the ninth thoracic vertebra to the head side, a small hole was made with bone forceps, and the spinal cord was cut from there using a soldering iron. At this time, if bleeding was severe, a gelatin sponge for hemostasis was packed in the cut portion. After closing the chest back incision layer with surgical adhesive, the rat was fixed in the dorsal position. The skin of the left thigh was incised, the femoral artery was exposed and peeled, and an arterial catheter filled with 200 heparin units / mL heparin was inserted 15 mm. The left femoral incision layer was closed with surgical adhesive. The skin of the right thigh was incised to expose the femoral artery and ligated after peeling. When the drug was administered intravenously, the right femoral vein was exposed and peeled, and a venous catheter was inserted. The right femoral incision layer was closed with surgical adhesive. A midline incision was made in the abdomen to expose the ureters on both sides, and after ligation, the kidney side was cut. Two Michel hemostatic forceps were applied to the top of the bladder at an interval of about 3 mm, an incision was made between them, a bladder catheter was inserted 5 mm therefrom, and a purse-string suture was performed. After the abdominal incision layer was sutured, the penis was exposed and ligated. A midline incision was made in the neck, the trachea was exposed, the incision was made, and the distal side was ligated. The tip of the Eppendorf tip was placed under the trachea, and the trachea was slightly lifted to secure the airway.
 (2）実験方法
　ラットを小動物用ヒーティングパッドの上に背位に置き、直腸温プローブを肛門より挿入し体温を37.5℃に維持した。体温が37.5℃になったのを確認後、膀胱内に0.1 mLの生理食塩液を注入し膀胱内圧を測定した。約30分後、膀胱内圧が安定したのを確認し、動脈カテーテルより17-PTPを5秒で投与した。17-PTPを30分間隔で動脈内投与（i. a.）し膀胱収縮が安定して得られたと判断した個体について、被検化合物を17-PTP投与の5分前に、静脈カテーテルを介して静脈内投与（i. v.）(1 mg/kg) した。被検化合物投与後、17-PTPのi. a.を9回 (被検化合物投与後、5分, 35分, 65分, 95分, 125分, 155分, 185分, 215分, 245分後）行い、膀胱収縮圧の変化を観察した。なお、17-PTPのi. a. の回数は被検化合物の効果の強さと持続により適宜変更した。 (2) Experimental method The rat was placed on a small animal on a heating pad, and a rectal temperature probe was inserted through the anus to maintain the body temperature at 37.5 ° C. After confirming that the body temperature reached 37.5 ° C., 0.1 mL of physiological saline was injected into the bladder and the intravesical pressure was measured. About 30 minutes later, it was confirmed that the intravesical pressure was stable, and 17-PTP was administered from an arterial catheter in 5 seconds. For individuals judged to have stable bladder contraction after intra-arterial administration (ia) of 17-PTP at 30-minute intervals, the test compound was administered intravenously via a venous catheter 5 minutes prior to 17-PTP administration. Administration (iv) (1 mg / kg) was performed. After administration of test compound, perform 17-PTP ia 9 times (5 min, 35 min, 65 min, 95 min, 125 min, 155 min, 185 min, 215 min, 245 min after test compound administration) The change in bladder contraction pressure was observed. The number of i-a. Of 17-PTP was appropriately changed depending on the strength and duration of the test compound.
 (3)解析
　17-PTP投与後最大膀胱収縮圧付近の30秒間の平均膀胱内圧から17-PTP投与直前の30秒間の平均膀胱内圧を差し引いた値を、17-PTPによる膀胱内圧の変化量 (ΔmmHg) とした。被検化合物投与前2回の17-PTPによる膀胱内圧変化量の平均値に対する被検化合物投与後の膀胱内圧変化量を%で示した。被検化合物投与後95分までで最も減少した膀胱内圧変化量を被検化合物の効果とした。得られた試験化合物の膀胱内圧変化量を以下の表ＩＩに示した。 (3) Analysis The value obtained by subtracting the average intravesical pressure for 30 seconds immediately before 17-PTP administration from the average intravesical pressure for 30 seconds near the maximum bladder contraction pressure after 17-PTP administration, and the change in intravesical pressure by 17-PTP ( ΔmmHg). The amount of change in the bladder pressure after administration of the test compound relative to the average value of the change in bladder pressure by 17-PTP twice before administration of the test compound was shown in%. The effect of the test compound was the amount of change in the intravesical pressure that decreased most up to 95 minutes after administration of the test compound. The amount of change in the intravesical pressure of the obtained test compound is shown in Table II below.
Figure JPOXMLDOC01-appb-T000112
Figure JPOXMLDOC01-appb-T000112
　表ＩＩより、化合物（Ｉ）又はその塩は、膀胱収縮に対する優れた抑制作用を示すことが分かる。 From Table II, it can be seen that Compound (I) or a salt thereof exhibits an excellent inhibitory action on bladder contraction.
　本発明の化合物は、強力なＥＰ１受容体拮抗作用を有するので、ＰＧＥ２の刺激作用によるＥＰ１受容体の活性化に起因する疾患または症状の治療薬または予防薬として有用である。中でも、下部尿路症状（ＬＵＴＳ）、特に過活動膀胱症候群（ＯＡＢｓ）等の治療薬またはその予防薬として有用である。 Since the compound of the present invention has a strong EP 1 receptor antagonism, it is useful as a therapeutic or prophylactic agent for diseases or symptoms caused by the activation of EP 1 receptor by the stimulating action of PGE 2 . Among them, it is useful as a therapeutic agent or preventive agent for lower urinary tract symptoms (LUTS), particularly overactive bladder syndrome (OABs).
＜配列表１＞
　配列番号１は、配列番号５のＤＮＡを増幅するために使用されたフォワードプライマー（５’プライマー）の配列である。
＜配列表２＞
　配列番号２は、配列番号５のＤＮＡを増幅するために使用されたリバースプライマー（３’プライマー）の配列である。
＜配列表３＞
　配列番号３は、配列番号５のＤＮＡを増幅するために使用されたフォワードプライマー（５’プライマー）の配列である。
＜配列番号４＞
　配列番号４は、配列番号５のＤＮＡを増幅するために使用されたリバースプライマー（３’プライマー）の配列である。
＜配列番号５＞
　配列番号５は、配列番号１、配列番号２、配列番号３および配列番号４のプライマーを用いて増幅された、ラットＥＰ1受容体を発現するためのＤＮＡ配列である。 <Sequence Listing 1>
SEQ ID NO: 1 is the sequence of the forward primer (5 ′ primer) used to amplify the DNA of SEQ ID NO: 5.
<Sequence Listing 2>
SEQ ID NO: 2 is the sequence of the reverse primer (3 ′ primer) used to amplify the DNA of SEQ ID NO: 5.
<Sequence Listing 3>
SEQ ID NO: 3 is the sequence of the forward primer (5 ′ primer) used to amplify the DNA of SEQ ID NO: 5.
<SEQ ID NO: 4>
SEQ ID NO: 4 is the sequence of the reverse primer (3 ′ primer) used to amplify the DNA of SEQ ID NO: 5.
<SEQ ID NO: 5>
SEQ ID NO: 5 is a DNA sequence for expressing the rat EP1 receptor amplified using the primers of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4.

Claims (21)

  1. 　下記一般式（Ｉ）で表されるベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。
    Figure JPOXMLDOC01-appb-C000091
    式（Ｉ）中、Ｙ１およびＹ２を含み、Ｒ２、Ｒ３、Ｒ４、Ｒ５およびＹ３が結合するベンゼン環縮合含窒素５員複素環は、以下のａ）～d）からなる群から選択される環であり；
    Figure JPOXMLDOC01-appb-C000092
    Ａは、以下のｅ）～ｉ）からなる群から選択される基であり；
    Figure JPOXMLDOC01-appb-C000093
    　Ｒａは、水素原子、ハロゲン原子またはＣ１－６アルキル基であり；
    　Ｗ１は、ＣＨまたは窒素原子であり；
    　Ｗ２は、酸素原子または硫黄原子であり；
    　Ｗ３およびＷ４は、一方が窒素原子であり、他方がＣＨまたは窒素原子であり；
    　Ｙ３は、Ｃ１－６アルキレン、－Ｏ－、－Ｓ－または－ＮＲｂ－であり；
    　Ｒｂは、水素原子、Ｃ１－６アルキル基または（Ｃ１－６アルコキシ）カルボニル基であり；
    　Ｒ１は、以下のｊ）～ｏ）からなる群から選択される基であり；
    ｊ）－Ｃ（＝Ｏ）－ＯＺ１
    ｋ）－Ｃ（＝Ｏ）－ＮＨＳＯ２Ｚ２
    ｌ）－Ｃ（＝Ｏ）－ＮＨＯＨ
    ｍ）－Ｃ（＝Ｏ）－ＮＨＣＮ
    ｎ）－ＮＨ－Ｃ（＝Ｏ）－Ｚ３
    ｏ）酸性５員ヘテロ環基
    　Ｚ１は、水素原子、Ｃ１－６アルキル基またはＣ７－１０アラルキル基であり；
    　Ｚ２およびＺ３は、以下のｐ）～ｔ）からなる群から選択される基であり；
    ｐ）Ｃ１－６アルキル基
    ｑ）ハロＣ１－６アルキル基
    ｒ）Ｃ３－６シクロアルキル基
    ｓ）非置換またはハロゲン原子、Ｃ１－６アルキル基、ハロＣ１－６アルキル基およびＣ１－６アルコキシ基からなる群から独立して選択される１～５個の基で環が置換されるアリール基
    ｔ）複素環基
    Ｒ２は、以下のａａ）～ｌｌ）からなる群から選択される基であり；
    ａａ）Ｃ１－６アルキル基またはＣ１－６アルコキシＣ１－６アルキル基
    ｂｂ）非置換または１つのＣ１－６アルキル基で環が置換されるＣ３－６シクロアルキル基
    ｃｃ）Ｃ２－６アルケニル基
    ｄｄ）Ｃ５－８シクロアルケニル基
    ｅｅ）非置換またはハロゲン原子、Ｃ１－６アルコキシ基およびＣ７－１０アラルキルオキシ基からなる群から独立して選択される１～５個の基で環が置換されるフェニル基
    ｆｆ）複素環基
    ｇｇ）非置換またはＣ１－６アルキル基、Ｃ２－６アルケニル基、Ｃ１－６アルコキシＣ１－６アルキル基、Ｃ４－６ヘテロシクロアルキル基およびＣ４－１０ヘテロアラルキル基からなる群から選択される１個または２個の基で置換されるアミノ基
    ｈｈ）非置換またはＣ１－６アルキル基、およびＣ１－６アルキレンジオキシ基からなる群から独立して選択される１～３個の基で環が置換される４～７員の環状アミノ基
    ｉｉ）Ｃ１－６アルコキシ基
    ｊｊ）Ｃ７－１０アラルキル基
    ｋｋ）Ｃ１－６アルキルスルファニル基
    ｌｌ）６員の脂肪族環状アミノ基で置換されるＣ１－６アルキル基
    　Ｒ３は、以下のＡ）～Ｎ）からなる群から選択される基であり；
    Ａ）水素原子
    Ｂ）ハロゲン原子
    Ｃ）シアノ基
    Ｄ）ニトロ基
    Ｅ）Ｃ３－６シクロアルキル基またはＣ５－８シクロアルケニル基
    Ｆ）Ｃ２－８アルケニル基
    Ｇ）Ｃ１－７アルカノイル基
    Ｈ）非置換または独立した１もしくは２個のＣ１－６アルキル基で置換されるアミノ基
    Ｉ）Ｃ１－６アルキル基
    Ｊ）Ｃ１－６アルコキシ基
    Ｋ）ハロＣ１－６アルコキシ基
    Ｌ）非置換またはハロゲン原子、Ｃ１－６アルキル基およびＣ１－６アルコキシ基からなる群から独立して選択される１～５個の基で環が置換されるフェニル基
    Ｍ）５員環の芳香族複素環基
    Ｎ）カルボキシル基
    　Ｒ4およびＲ５は、それぞれ独立して、水素原子またはハロゲン原子を表す。（＊）を付された結合はＹ３と結合し、（＊＊）を付された結合はＲ１と結合することを表す。     A benzene ring condensed nitrogen-containing 5-membered heterocyclic compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof.
    Figure JPOXMLDOC01-appb-C000091
    The benzene ring condensed nitrogen-containing 5-membered heterocyclic ring containing Y 1 and Y 2 and having R 2 , R 3 , R 4 , R 5 and Y 3 bonded thereto is represented by the following a) to d): A ring selected from the group consisting of;
    Figure JPOXMLDOC01-appb-C000092
    A is a group selected from the group consisting of e) to i) below:
    Figure JPOXMLDOC01-appb-C000093
    R a is a hydrogen atom, a halogen atom or a C 1-6 alkyl group;
    W 1 is CH or a nitrogen atom;
    W 2 is an oxygen atom or a sulfur atom;
    One of W 3 and W 4 is a nitrogen atom, and the other is CH or a nitrogen atom;
    Y 3 is C 1-6 alkylene, —O—, —S— or —NR b —;
    R b is a hydrogen atom, a C 1-6 alkyl group or a (C 1-6 alkoxy) carbonyl group;
    R 1 is a group selected from the group consisting of j) to o) below:
    j) -C (= O) -OZ 1
    k) —C (═O) —NHSO 2 Z 2
    l) —C (═O) —NHOH
    m) —C (═O) —NHCN
    n) —NH—C (═O) —Z 3
    o) an acidic 5-membered heterocyclic group Z 1 is a hydrogen atom, a C 1-6 alkyl group or a C 7-10 aralkyl group;
    Z 2 and Z 3 are groups selected from the group consisting of p) to t) below;
    p) C 1-6 alkyl group q) halo C 1-6 alkyl group r) C 3-6 cycloalkyl group s) unsubstituted or halogen atom, C 1-6 alkyl group, halo C 1-6 alkyl group and C Aryl group wherein the ring is substituted with 1 to 5 groups independently selected from the group consisting of 1-6 alkoxy groups t) heterocyclic group R 2 is selected from the group consisting of aa) to ll) below A group to be
    aa) a C 1-6 alkyl group or a C 1-6 alkoxy C 1-6 alkyl group bb) a C 3-6 cycloalkyl group cc) C 2 which is unsubstituted or substituted with one C 1-6 alkyl group -6 alkenyl group dd) C 5-8 cycloalkenyl group ee) 1-5 independently selected from the group consisting of unsubstituted or halogen atom, C 1-6 alkoxy group and C 7-10 aralkyloxy group Phenyl group in which the ring is substituted ff) heterocyclic group gg) unsubstituted or C 1-6 alkyl group, C 2-6 alkenyl group, C 1-6 alkoxy C 1-6 alkyl group, C 4-6 hetero one or amino groups hh is substituted with two groups) unsubstituted or C 1-6 alkyl groups are selected from the group consisting of cycloalkyl group and C 4-10 heteroaralkyl groups, and C 1-6 a Are independently selected from the group consisting of Kirenjiokishi group 1-3 cyclic amino group ii) the ring group is a 4-7 membered substituted C 1-6 alkoxy group jj) C 7-10 aralkyl group kk) A C 1-6 alkylsulfanyl group ll) a C 1-6 alkyl group R 3 substituted with a 6-membered aliphatic cyclic amino group is a group selected from the group consisting of A) to N) below;
    A) hydrogen atom B) halogen atom C) cyano group D) nitro group E) C 3-6 cycloalkyl group or C 5-8 cycloalkenyl group F) C 2-8 alkenyl group G) C 1-7 alkanoyl group H ) Amino group which is unsubstituted or substituted by 1 or 2 independent C 1-6 alkyl groups I) C 1-6 alkyl group J) C 1-6 alkoxy group K) Halo C 1-6 alkoxy group L) Unsubstituted or phenyl group in which the ring is substituted with 1 to 5 groups independently selected from the group consisting of halogen atoms, C 1-6 alkyl groups and C 1-6 alkoxy groups M) 5-membered aromatic Group heterocyclic group N) carboxyl group R 4 and R 5 each independently represents a hydrogen atom or a halogen atom. The bond marked with (*) bonded to Y 3, represents a bond with (**) attached to bond R 1.
  2. 　前記一般式（Ｉ）中、Ａが、以下のｅ）、ｆ）、ｈ）およびｉ）からなる群から選択される基である、請求項１に記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。
    Figure JPOXMLDOC01-appb-C000094
    Ｒａ、Ｗ１、Ｗ２、Ｗ３、Ｗ４は前述と同義である。（＊）を付された結合はＹ３と結合し、（＊＊）を付された結合はＲ１と結合することを表す。     The benzene ring condensed nitrogen-containing 5-membered heterocycle according to claim 1, wherein A in the general formula (I) is a group selected from the group consisting of e), f), h) and i) below. Formula compound or pharmacologically acceptable salt thereof.
    Figure JPOXMLDOC01-appb-C000094
    R a , W 1 , W 2 , W 3 , and W 4 are as defined above. The bond marked with (*) bonded to Y 3, represents a bond with (**) attached to bond R 1.
  3. 　前記一般式（Ｉ）中、Ａが、以下のｅ１）、ｆ１）、ｈ）およびｉ１）からなる群から選択される基である、請求項１または２に記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。
    Figure JPOXMLDOC01-appb-C000095
    Ｒａは前述と同義である。（＊）を付された結合はＹ３と結合し、（＊＊）を付された結合はＲ１と結合することを表す。     In the general formula (I), A is a group selected from the group consisting of the following e1), f1), h) and i1). A heterocyclic compound or a pharmacologically acceptable salt thereof.
    Figure JPOXMLDOC01-appb-C000095
    R a has the same meaning as described above. The bond marked with (*) bonded to Y 3, represents a bond with (**) attached to bond R 1.
  4. 　前記一般式（Ｉ）中、Ｒａが水素原子またはＣ１－６アルキル基である、請求項１から３のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。 The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or the drug thereof according to any one of claims 1 to 3, wherein R a in the general formula (I) is a hydrogen atom or a C 1-6 alkyl group. Physically acceptable salt.
  5. 　前記一般式（Ｉ）中、Ｙ３がメチレン、酸素原子または硫黄原子である、請求項１から４のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。 In the general formula (I), Y 3 is a methylene, oxygen or sulfur atom, a benzene-fused nitrogen-containing 5-membered heterocyclic compound as claimed in any one of claims 1 to 4, or a pharmaceutically Acceptable salt.
  6. 　前記一般式（Ｉ）中、Ｒ１が－Ｃ（＝Ｏ）－ＯＺ１である場合にＺ１が水素原子またはＣ１－６アルキル基であり、Ｒ１が－Ｃ（＝Ｏ）－ＮＨＳＯ２Ｚ２である場合にＺ２がＣ１－６アルキル基である、請求項１から５のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。 In the general formula (I), when R 1 is —C (═O) —OZ 1 , Z 1 is a hydrogen atom or a C 1-6 alkyl group, and R 1 is —C (═O) —NHSO. Z 2 when it is 2 Z 2 is a C 1-6 alkyl group, a benzene-fused nitrogen-containing 5-membered heterocyclic compound as claimed in any one of claims 1 to 5, or a pharmaceutically acceptable Salt.
  7. 　前記一般式（Ｉ）中、Ｒ３が、以下のＡ）、Ｂ）、Ｃ）、Ｆ）、Ｇ）、H）、Ｊ）、Ｋ）およびＭ）からなる群から選択される基である、請求項１から６のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。
    Ａ）水素原子
    Ｂ）ハロゲン原子
    Ｃ）シアノ基
    Ｆ）Ｃ２－８アルケニル基
    Ｇ）Ｃ１－７アルカノイル基
    Ｈ）非置換または独立した１もしくは２個のＣ１－６アルキル基で置換されるアミノ基
    Ｊ）Ｃ１－６アルコキシ基
    Ｋ）ハロＣ１－６アルコキシ基
    Ｍ）５員環の芳香族複素環基     In the general formula (I), R 3 is a group selected from the group consisting of A), B), C), F), G), H), J), K) and M) below. The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 6.
    A) hydrogen atom B) halogen atom C) cyano group F) C 2-8 alkenyl group G) C 1-7 alkanoyl group H) unsubstituted or substituted with 1 or 2 independent C 1-6 alkyl groups Amino group J) C 1-6 alkoxy group K) Halo C 1-6 alkoxy group M) 5-membered aromatic heterocyclic group
  8. 　前記一般式（Ｉ）中、Ｒ２が、以下のａａ１）、ｂｂ）、ｃｃ）、ｄｄ）、ｅｅ１）、ｆｆ１）、ｇｇ１）およびｈｈ１）からなる群から選択される基である、請求項１～７のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。
    ａａ１）Ｃ１－６アルキル基
    ｂｂ）非置換または１つのＣ１－６アルキル基で環が置換されるＣ３－６シクロアルキル基
    ｃｃ）Ｃ２－６アルケニル基
    ｄｄ）Ｃ５－８シクロアルケニル基
    ｅｅ１）非置換または独立した１～５個のハロゲン原子で環が置換されるフェニル基
    ｆｆ１）６員環の芳香族複素環基
    ｇｇ１）Ｃ１－６アルキル基およびＣ２－６アルケニル基からなる群から独立して選択される１個または２個の基で置換されるアミノ基
    ｈｈ１）非置換または独立した１～３個のＣ１－６アルキル基で環が置換される４～７員の環状アミノ基     In the general formula (I), R 2 is a group selected from the group consisting of the following aa1), bb), cc), dd), ee1), ff1), gg1) and hh1). The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of 1 to 7.
    aa1) C 1-6 alkyl group bb) C 3-6 cycloalkyl group cc) C 2-6 alkenyl group dd) C 5-8 cycloalkenyl which is unsubstituted or substituted with one C 1-6 alkyl group The group ee1) a phenyl group which is unsubstituted or independently substituted with 1 to 5 halogen atoms ff1) a 6-membered aromatic heterocyclic group gg1) from a C 1-6 alkyl group and a C 2-6 alkenyl group An amino group hh1 substituted with one or two groups independently selected from the group consisting of 4 to 7 members whose ring is substituted by unsubstituted or independent 1 to 3 C 1-6 alkyl groups Cyclic amino group of
  9. 　前記一般式（Ｉ）中、Ａが、以下のｅ１）またはｆ１）として表される基である、請求項１～８のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。
    Figure JPOXMLDOC01-appb-C000096
    Ｒａは前述と同義である。（＊）を付された結合はＹ３と結合し、（＊＊）を付された結合はＲ１と結合することを表す。     The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound according to any one of claims 1 to 8, wherein in the general formula (I), A is a group represented by the following e1) or f1): Or a pharmacologically acceptable salt thereof.
    Figure JPOXMLDOC01-appb-C000096
    R a has the same meaning as described above. The bond marked with (*) bonded to Y 3, represents a bond with (**) attached to bond R 1.
  10. 　前記一般式（Ｉ）中、Ｙ３がメチレンである、請求項１から９のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。 The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein Y 3 in the general formula (I) is methylene.
  11. 　前記一般式（Ｉ）中、Ｒ３が、水素原子、ハロゲン原子、Ｃ２－８アルケニル基、Ｃ１－７アルカノイル基、独立した２個のＣ１－６アルキル基で置換されるアミノ基、Ｃ１－６アルコキシ基、またはハロＣ１－６アルコキシ基である、請求項１から１０のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。 In the general formula (I), R 3 is a hydrogen atom, a halogen atom, a C 2-8 alkenyl group, a C 1-7 alkanoyl group, an amino group substituted with two independent C 1-6 alkyl groups, a C 1-6 alkoxy group or a halo C 1-6 alkoxy group, are claimed benzene-fused nitrogen-containing 5-membered heterocyclic compound as claimed in any one of claim 1 to 10 or a pharmaceutically acceptable Salt.
  12. 　前記一般式（Ｉ）中、Ｒ２が、以下のｂｂ１）、ｃｃ）、ｄｄ）、ｇｇ２）およびｈｈ２）からなる群から選択される基である、請求項１から１１のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。
    ｂｂ１）１つのＣ１－６アルキル基で環が置換されるＣ３－６シクロアルキル基
    ｃｃ）Ｃ２－６アルケニル基
    ｄｄ）Ｃ５－８シクロアルケニル基
    ｇｇ２）独立した２個のＣ１－６アルキル基で置換されるアミノ基
    ｈｈ２）４～７員の環状アミノ基     In the general formula (I), R 2 is a group selected from the group consisting of the following bb1), cc), dd), gg2) and hh2). The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof.
    bb1) C 3-6 cycloalkyl group whose ring is substituted with one C 1-6 alkyl group cc) C 2-6 alkenyl group dd) C 5-8 cycloalkenyl group gg2) two independent C 1 1- Amino groups substituted with 6 alkyl groups hh2) 4-7 membered cyclic amino groups
  13. 　前記一般式（Ｉ）中、前記ベンゼン環縮合含窒素５員複素環が、以下のａ）、ｂ）およびｄ）からなる群から選択される環である、請求項１から１２のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。
    Figure JPOXMLDOC01-appb-C000097
    Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｙ３は前述と同義である。     The general formula (I), wherein the benzene ring condensed nitrogen-containing 5-membered heterocyclic ring is a ring selected from the group consisting of the following a), b) and d): Or a pharmacologically acceptable salt thereof.
    Figure JPOXMLDOC01-appb-C000097
    R 2 , R 3 , R 4 , R 5 and Y 3 are as defined above.
  14. 　前記一般式（Ｉ）中、前記ベンゼン環縮合含窒素５員複素環が、以下のａ）として表される環である、請求項１３記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。
    Figure JPOXMLDOC01-appb-C000098
    Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｙ３は前述と同義である。     The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound according to claim 13, wherein the benzene ring condensed nitrogen-containing 5-membered heterocyclic ring in the general formula (I) is a ring represented by the following a): Pharmacologically acceptable salt.
    Figure JPOXMLDOC01-appb-C000098
    R 2 , R 3 , R 4 , R 5 and Y 3 are as defined above.
  15. 　前記一般式（Ｉ）で表される化合物が、
    １－［［６－ブロモ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
    １－［［６－クロロ－２－（ジエチルアミノ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
    １－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
    １－［［６－クロロ－２－（５－メチル－３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
    １－［［６－クロロ－２－（１－プロペン－２－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
    １－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－ビニルベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
    ６－クロロ－４－［［５－メチル－３－（１Ｈ－テトラゾール－５－イル）－１Ｈ－ピラゾール－１－イル］メチル］－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール、
    １－［（５－クロロ－２－（１－メチルシクロプロピル）ベンゾ［ｄ］チアゾール－４－イル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
    １－［（６－クロロ－２－フェニルベンゾ［ｄ］チアゾール－４－イル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
    １－［（５－クロロ－２－（３－クロロフェニル）ベンゾ［ｄ］オキサゾール－７－イル）メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
    １－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－フルオロベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
    １－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－（トリフルオロメトキシ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
    １－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
    １－［［６－クロロ－２－（ピペリジン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
    １－［［６－クロロ－２－（モルホリン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
    １－［［６－クロロ－２－（ピロリジン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
    １－［［６－クロロ－２－（ジメチルアミノ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
    １－［［６－クロロ－２－（チオモルホリン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
    １－［［６－クロロ－２－（ｃｉｓ－２，６－ジメチルモルホリン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
    １－［［６－クロロ－２－（４－メチル－３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
    １－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－メトキシベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
    １－［［６－クロロ－２－（ピリジン－４－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
    １－［［６－クロロ－２－（２－メチル－１－プロペン－１－イル）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
    １－［［２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）－６－（ジメチルアミノ）ベンゾ［ｄ］チアゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸、
    ５－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］オキシ］フラン－２－カルボン酸、
    ５－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］チアゾール－４－イル］チオ］フラン－２－カルボン酸、または
    １－［［６－クロロ－２－（３，６－ジヒドロピリジン－１（２Ｈ）－イル）ベンゾ［ｄ］オキサゾール－４－イル］メチル］－５－メチル－１Ｈ－ピラゾール－３－カルボン酸である、請求項１記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。     The compound represented by the general formula (I) is:
    1-[[6-bromo-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
    1-[[6-chloro-2- (diethylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
    1-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
    1-[[6-Chloro-2- (5-methyl-3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3 -carboxylic acid,
    1-[[6-chloro-2- (1-propen-2-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
    1-[[2- (3,6-dihydropyridin-1 (2H) -yl) -6-vinylbenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
    6-Chloro-4-[[5-methyl-3- (1H-tetrazol-5-yl) -1H-pyrazol-1-yl] methyl] -2- (3,6-dihydropyridin-1 (2H) -yl ) Benzo [d] thiazole,
    1-[(5-chloro-2- (1-methylcyclopropyl) benzo [d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
    1-[(6-chloro-2-phenylbenzo [d] thiazol-4-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
    1-[(5-chloro-2- (3-chlorophenyl) benzo [d] oxazol-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
    1-[[2- (3,6-dihydropyridin-1 (2H) -yl) -6-fluorobenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
    1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6- (trifluoromethoxy) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3 -carboxylic acid,
    1-[[2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
    1-[[6-chloro-2- (piperidin-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
    1-[[6-chloro-2- (morpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
    1-[[6-chloro-2- (pyrrolidin-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
    1-[[6-chloro-2- (dimethylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
    1-[[6-chloro-2- (thiomorpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
    1-[[6-chloro-2- (cis-2,6-dimethylmorpholin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
    1-[[6-Chloro-2- (4-methyl-3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3 -carboxylic acid,
    1-[[2- (3,6-dihydropyridin-1 (2H) -yl) -6-methoxybenzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
    1-[[6-chloro-2- (pyridin-4-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
    1-[[6-chloro-2- (2-methyl-1-propen-1-yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid,
    1-[[2- (3,6-Dihydropyridin-1 (2H) -yl) -6- (dimethylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3- carboxylic acid,
    5-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] oxy] furan-2-carboxylic acid,
    5-[[6-Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] thio] furan-2-carboxylic acid, or 1-[[6- 2. Chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] oxazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid A nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof.
  16. 　請求項１～１５のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩を含有する医薬。 A medicament comprising the benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 15.
  17. 　請求項１～１５のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩を含有するＥＰ１受容体拮抗薬。 An EP 1 receptor antagonist comprising the benzene ring-fused nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 15.
  18. 　請求項１～１５のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩を含有する下部尿路症状の治療または予防薬。 A therapeutic or prophylactic agent for lower urinary tract symptoms comprising the benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 15.
  19. 　請求項１～１５のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩を患者に投与することを含む下部尿路症状の治療または予防方法。 Treatment or prevention of lower urinary tract symptoms comprising administering to a patient the benzene ring-fused nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 15. Method.
  20. 　下部尿路症状の予防または治療用の医薬を製造するための、請求項１～１５のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩の使用。 The benzene ring-fused nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable product thereof according to any one of claims 1 to 15, for producing a medicament for preventing or treating lower urinary tract symptoms Use of salt.
  21. 　下部尿路症状の予防または治療に使用するための、請求項１～１５のいずれか１つに記載のベンゼン環縮合含窒素５員複素環式化合物またはその薬理学的に許容される塩。 The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 15, for use in the prevention or treatment of lower urinary tract symptoms.
PCT/JP2013/004520 2012-07-25 2013-07-24 Benzene ring-fused, nitrogen-containing 5-membered heterocyclic compound or pharmacologically acceptable salt thereof WO2014017093A1 (en)

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US9782408B2 (en) 2014-10-06 2017-10-10 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US10570115B2 (en) 2016-09-30 2020-02-25 Vertex Pharmaceuticals Incorporated Modulator of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US10654829B2 (en) 2017-10-19 2020-05-19 Vertex Pharmaceuticals Incorporated Crystalline forms and compositions of CFTR modulators
US10738030B2 (en) 2016-03-31 2020-08-11 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US10793547B2 (en) 2016-12-09 2020-10-06 Vertex Pharmaceuticals Incorporated Modulator of the cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US11179367B2 (en) 2018-02-05 2021-11-23 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for treating cystic fibrosis
US11253509B2 (en) 2017-06-08 2022-02-22 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
US11414439B2 (en) 2018-04-13 2022-08-16 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US11434201B2 (en) 2017-08-02 2022-09-06 Vertex Pharmaceuticals Incorporated Processes for preparing pyrrolidine compounds
US11465985B2 (en) 2017-12-08 2022-10-11 Vertex Pharmaceuticals Incorporated Processes for making modulators of cystic fibrosis transmembrane conductance regulator
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US9782408B2 (en) 2014-10-06 2017-10-10 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US10258624B2 (en) 2014-10-06 2019-04-16 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US11426407B2 (en) 2014-10-06 2022-08-30 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US10758534B2 (en) 2014-10-06 2020-09-01 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
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US10738030B2 (en) 2016-03-31 2020-08-11 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US11186566B2 (en) 2016-09-30 2021-11-30 Vertex Pharmaceuticals Incorporated Modulator of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US10570115B2 (en) 2016-09-30 2020-02-25 Vertex Pharmaceuticals Incorporated Modulator of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US10793547B2 (en) 2016-12-09 2020-10-06 Vertex Pharmaceuticals Incorporated Modulator of the cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US11453655B2 (en) 2016-12-09 2022-09-27 Vertex Pharmaceuticals Incorporated Modulator of the cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US11253509B2 (en) 2017-06-08 2022-02-22 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
US11517564B2 (en) 2017-07-17 2022-12-06 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
US11434201B2 (en) 2017-08-02 2022-09-06 Vertex Pharmaceuticals Incorporated Processes for preparing pyrrolidine compounds
US11155533B2 (en) 2017-10-19 2021-10-26 Vertex Pharmaceuticals Incorporated Crystalline forms and compositions of CFTR modulators
US10654829B2 (en) 2017-10-19 2020-05-19 Vertex Pharmaceuticals Incorporated Crystalline forms and compositions of CFTR modulators
US11465985B2 (en) 2017-12-08 2022-10-11 Vertex Pharmaceuticals Incorporated Processes for making modulators of cystic fibrosis transmembrane conductance regulator
US11179367B2 (en) 2018-02-05 2021-11-23 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for treating cystic fibrosis
US11414439B2 (en) 2018-04-13 2022-08-16 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator

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