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WO2014017342A1 - Indole derivative or pharmacologically acceptable salt thereof - Google Patents

Indole derivative or pharmacologically acceptable salt thereof Download PDF

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Publication number
WO2014017342A1
WO2014017342A1 PCT/JP2013/069347 JP2013069347W WO2014017342A1 WO 2014017342 A1 WO2014017342 A1 WO 2014017342A1 JP 2013069347 W JP2013069347 W JP 2013069347W WO 2014017342 A1 WO2014017342 A1 WO 2014017342A1
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WIPO (PCT)
Prior art keywords
methylcyclopropyl
group
indol
ylmethyl
pyridine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2013/069347
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French (fr)
Japanese (ja)
Inventor
田谷　和也
近藤　敦志
茂樹 瀬戸
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kissei Pharmaceutical Co Ltd
Kyorin Pharmaceutical Co Ltd
Original Assignee
Kissei Pharmaceutical Co Ltd
Kyorin Pharmaceutical Co Ltd
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Filing date
Publication date
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Publication of WO2014017342A1 publication Critical patent/WO2014017342A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • 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
    • 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
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • 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
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • the present invention relates to an indole derivative having an EP 1 receptor antagonistic activity useful as a pharmaceutical product, or a pharmacologically acceptable salt thereof, a pharmaceutical composition containing the same, and a pharmaceutical use thereof.
  • OAB overactive bladder syndrome
  • OABs are also sometimes referred to as overactive bladder (OAB).
  • OAB is a disease defined as “a symptom syndrome requiring urgency of urine, usually accompanied by frequent urination and nocturia. Imminent urinary incontinence is not essential”.
  • 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 describes a compound in which the substituent of R 2 of the above compound is a C 3-6 cycloalkyl group, and the C 3-6 cycloalkyl group is further substituted with a C 1-6 alkyl group. The compound is not described.
  • An object of the present invention is to provide a compound having a novel EP 1 receptor antagonistic action, or a pharmacologically acceptable salt thereof, a pharmaceutical composition containing the compound, and a pharmaceutical use thereof.
  • the present inventors diligently studied to find a compound having an EP 1 receptor antagonistic action. As a result, it was found that the compound (I) of the present invention or a pharmacologically acceptable salt thereof has a strong EP 1 receptor antagonistic activity, and has led to the present invention.
  • A is the following a), b), d) and h):
  • R 1 is a hydrogen atom
  • R 4 is a hydrogen atom
  • [3] The compound according to [2], or a pharmaceutically acceptable salt thereof, wherein Y 2 is a single bond, a C 2-4 alkenylene group or a C 2-4 alkynylene group.
  • R 3 is a hydrogen atom, or a pharmacologically acceptable salt thereof.
  • A is the following b) and h):
  • R 5 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group
  • R 6 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a haloC 1-6 alkyl, hydroxyalkyl C 1-6 alkyl group, C 1-6 alkoxy, halo C 1-6 alkoxy group, C 1-6 alkylsulfanyl group, C 1-6 alkylsulfinyl group, C 1-6 alkylsulfonyl group, A C 3-6 cycloalkyl group, a cyano group, or a C 2-6 alkenyl group, or R 5 and R 6 are bonded to
  • R 5 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group
  • R 6 is a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a haloC A 1-6 alkoxy group, a C 1-6 alkylsulfanyl group, a C 3-6 cycloalkyl group or a C 2-6 alkenyl group, or R 5 and R 6 are bonded to each other to form
  • a pharmaceutical composition comprising the compound according to any one of [1] to [9] or a pharmacologically acceptable salt thereof.
  • the pharmaceutical composition compris
  • An EP 1 receptor antagonist comprising the compound according to any one of [1] to [9], or a pharmacologically acceptable salt thereof.
  • a preventive or therapeutic agent for lower urinary tract symptoms comprising the compound according to any one of [1] to [9], or a pharmacologically acceptable salt thereof.
  • a method for preventing or treating lower urinary tract symptoms comprising administering an effective amount of the compound according to any one of [1] to [9] or a pharmacologically acceptable salt thereof.
  • a compound of any one of [1] to [9] or a pharmaceutically acceptable salt thereof for producing a pharmaceutical composition for preventing or treating lower urinary tract symptoms use.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof exhibited a strong EP 1 receptor antagonism in, for example, an EP 1 receptor antagonism confirmation test. Therefore, the compound (I) of the present invention, or a pharmacologically acceptable salt thereof, treats lower urinary tract symptoms (LUTS), particularly overactive bladder syndrome (OABs), etc., based on EP 1 receptor antagonism. Useful as a drug or prophylactic.
  • LUTS lower urinary tract symptoms
  • OABs overactive bladder syndrome
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferably, they are a fluorine atom or a chlorine atom.
  • C 1-6 alkyl group means an optionally branched alkyl group having 1 to 6 carbon atoms.
  • R 6 is preferably a methyl group, an ethyl group or an isopropyl group. In R 2 , a methyl group is preferable.
  • the “C 1-6 alkoxy group” means an optionally branched alkoxy group having 1 to 6 carbon atoms. Examples include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, hexyloxy group and the like.
  • halo C 1-6 alkyl group means the above C 1-6 alkyl group substituted with 1 to 5 of the same or different halogen atoms.
  • “Hydroxy C 1-6 alkyl group” means the above C 1-6 alkyl group substituted with a hydroxyl group. Examples thereof include a hydroxymethyl group, 1-hydroxyethyl group, 1-hydroxy-1,1-dimethylmethyl group, 2-hydroxyethyl group, 2-hydroxy-2-methylpropyl group, 3-hydroxypropyl group and the like.
  • C 1-6 alkylsulfanyl group means a group represented by (C 1-6 alkyl) -S—. Examples thereof include a methylsulfanyl group, an ethylsulfanyl group, a propylsulfanyl group, a butylsulfanyl group, a pentylsulfanyl group, and a hexylsulfanyl group.
  • C 1-6 alkylsulfinyl group means a group represented by (C 1-6 alkyl) -S ( ⁇ O) —. Examples thereof include a methylsulfinyl group, an ethylsulfinyl group, a propylsulfinyl group, a butylsulfinyl group, a pentylsulfinyl group, and a hexylsulfinyl group.
  • C 1-6 alkylsulfonyl group means a group represented by (C 1-6 alkyl) —SO 2 —. Examples thereof include a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group, a butanesulfonyl group, a pentanesulfonyl group, and a hexanesulfonyl group.
  • the “C 3-6 cycloalkyl group” means a monocyclic saturated alicyclic hydrocarbon group having 3 to 6 carbon atoms. Examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. Preferably, it is a cyclopropyl group.
  • halo C 1-6 alkoxy group means the above C 1-6 alkoxy group substituted with 1 to 5 same or different halogen atoms.
  • C 7-10 aralkyl group means an alkyl group having 1 to 4 carbon atoms substituted with a phenyl group. Examples include benzyl group, phenethyl group, 1-phenylethyl group, 3-phenylpropyl group, 4-phenylbutyl group and the like.
  • the “C 1-6 alkylene group” means a saturated hydrocarbon chain having 1 to 6 carbon atoms which may be branched.
  • C 2-4 alkenylene group examples include —CH ⁇ CH—, —C (CH 3 ) ⁇ CH—, —CH ⁇ C (CH 3 ) —, —CH ⁇ CHCH 2 —, —CH 2 CH ⁇ CH— and the like.
  • C 2-4 alkynylene group examples include ethynylene group, 1-propynylene group, 2-propynylene group and the like.
  • C 2-6 alkenyl group examples include vinyl group, allyl group, 1-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 2-methylallyl group and the like.
  • the compound (I) of the present invention includes stereoisomers such as optical isomers and geometric isomers.
  • the optical isomer of the compound (I) of the present invention has an R configuration or a configuration at each asymmetric carbon atom. Any three-dimensional arrangement of S arrangement may be sufficient.
  • any optical isomer is included in the present invention, and a mixture of these optical isomers is also included.
  • a racemate consisting of an equal amount of each optical isomer in a mixture of optically active substances is also included in the scope of the present invention.
  • the compound (I) of the present invention when the compound (I) of the present invention is a racemic solid or crystal, racemic compounds, racemic mixtures and racemic solid solutions are also included in the scope of the present invention.
  • the present invention when a geometric isomer exists, the present invention includes any of the geometric isomers.
  • the compound (I) of the present invention when a tautomer exists, the present invention includes any of the tautomers.
  • Compound (I) of the present invention can be converted into a pharmacologically acceptable salt thereof according to a conventional method as necessary.
  • salts include acid addition salts and salts with bases.
  • Acid addition salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, Acid addition with organic acids such as p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid Mention may be made of salts.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, Acid addition with
  • salts with bases include salts with inorganic bases such as sodium salts, potassium salts, calcium salts and magnesium salts, and salts with organic bases such as piperidine, morpholine, pyrrolidine, arginine and lysine.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof includes solvates with pharmaceutically acceptable solvents such as hydrates and ethanol.
  • EP 1 receptor antagonism as used in the present invention 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 reduces or suppresses the inflow of calcium into the cell and decreases the intracellular calcium concentration.
  • the EP 1 receptor antagonism exhibits actions such as smooth muscle relaxation and suppression of sensory nerve stimulation.
  • EP 1 receptor antagonists are useful as therapeutic or prophylactic agents for symptoms such as LUTS, especially OABs, by acting on the bladder, urothelium, and the like.
  • EP 1 receptor antagonism can be evaluated by the efficacy of inhibiting the amount of calcium inflow into cells by PGE 2 . 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.
  • (I-1) A is preferably a benzene ring, a pyridine ring, a pyrazine ring, a furan ring, a thiazole ring or an oxazole ring, more preferably a pyridine ring, a pyrazine ring or a thiazole ring, still more preferably a pyridine ring It is a ring.
  • Y 1 is preferably a C 1-6 alkylene group or a sulfur atom, more preferably —CH 2 —, —CH (CH 3 ) —, —C (CH 3 ) 2 — or sulfur. An atom, more preferably —CH 2 — or a sulfur atom.
  • Y 2 is preferably a single bond, a C 2-4 alkenylene group or a C 2-4 alkynylene group, and more preferably a single bond.
  • R 1 is preferably a hydrogen atom.
  • R 2 is preferably a methyl group or an ethyl group, and more preferably a methyl group.
  • R 3 is preferably a hydrogen atom, a methyl group or an ethyl group, more preferably a hydrogen atom.
  • R 4 is preferably a hydrogen atom.
  • R 5 is preferably a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group, more preferably a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, An ethyl group or a methoxy group, more preferably a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group or an ethyl group.
  • R 6 is preferably a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 1-6 alkoxy group, a halo C 1-6 alkoxy group, a C 1-6 alkyl A sulfanyl group, a C 3-6 cycloalkyl group or a C 2-6 alkenyl group, more preferably a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 3-6 cycloalkyl group or C A 2-6 alkenyl group, more preferably a methoxy group, a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group.
  • R 7 is preferably a hydrogen atom.
  • Z is preferably a hydrogen atom or a fluorine atom, more preferably a hydrogen atom.
  • Q is preferably a methylene group or a single bond, more preferably a single bond.
  • a preferred embodiment of the compound (I) of the present invention or a pharmacologically acceptable salt thereof is a compound comprising a combination of substituents described below.
  • A is a benzene ring, pyridine ring, pyrazine ring, furan ring, thiazole ring or oxazole ring;
  • Y 1 is a C 1-6 alkylene group or a sulfur atom;
  • Y 2 is a single bond, a C 2-4 alkenylene group or a C 2-4 alkynylene group;
  • R 1 is a hydrogen atom;
  • R 2 is a methyl group or an ethyl group;
  • R 3 is a hydrogen atom, a methyl group or an ethyl group;
  • R 4 is a hydrogen atom;
  • R 5 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group;
  • R 6 represents a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a halo C 1-6 alkoxy group, a
  • Embodiment 2 In embodiment 1, further: A is a pyridine ring, pyrazine ring or thiazole ring; Y 1 is —CH 2 — or a sulfur atom; Y 2 is a single bond; R 3 is a hydrogen atom; Z is a hydrogen atom.
  • Embodiment 3 In embodiment 2, further: R 2 is a methyl group; Q is a single bond.
  • Embodiment 4 In embodiment 3, further: A is a pyridine ring.
  • Embodiment 5 in embodiment 4, further: R 5 is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group or a methoxy group.
  • Embodiment 6 In embodiment 5, further: R 6 is a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 3-6 cycloalkyl group or a C 2-6 alkenyl group.
  • Embodiment 7 in embodiment 6, further: R 5 is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group or an ethyl group; R 6 is a methoxy group, a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group.
  • Embodiment 8 In any of embodiment 1 to embodiment 4, further R 5 and R 6 are bonded to each other to form — (CH 2 ) 3 —, —O— (CH 2 ) 2 —, — (CH 2 ) 2 —O—, — (CH 2 ) 4 —, —O Selected from the group consisting of — (CH 2 ) 3 —, — (CH 2 ) 3 —O—, —CH 2 —O— (CH 2 ) 2 —, and — (CH 2 ) 2 —O—CH 2 —.
  • Embodiment 9 In embodiment 8, further: R 5 and R 6 are bonded to each other, - (CH 2) 3 - or - (CH 2) 4 - to form a.
  • Specific compounds included in this embodiment include the following compounds. 6- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 57), 6- [6-cyclopropyl-2- (1- Methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 58), 6- [6-chloro-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] Pyridine-2-carboxylic acid (Example 59), 6- [6-Methyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 60), 6 -[6-Ethoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxy
  • Compound (I) of the present invention or a pharmacologically acceptable salt thereof can be produced according to the method shown in the following schemes 1 to 4 or a method analogous thereto. it can.
  • R 8 is a C 1-6 alkyl group or C 7-10 represents an aralkyl group
  • R 9 represents a C 1-6 alkyl group
  • L 1 represents a leaving group such as a chlorine atom, a bromine atom, an iodine atom, or a methanesulfonyloxy group.
  • Step 1-1 Compound (2) can be produced by reacting compound (1) with ditert-butyl dicarbonate in a solvent.
  • the solvent used include tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, a mixed solvent thereof and the like.
  • the reaction temperature is usually room temperature to reflux temperature.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 1 hour to 3 days.
  • This step can also be carried out using a known method for protecting an amino group with a tert-butoxycarbonyl group. As such a method, for example, Theodora W. et al. Greene & Peter G. M.M. Edited by Wuts, “Greene's Protective Groups in Organic Synthesis”, fourth edition, Wiley-Interscience. Nce, 2006 can be exemplified.
  • Step 1-2 Compound (3) can be produced by reacting compound (2) treated with a base with compound (5) in a solvent.
  • the solvent used include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, a mixed solvent thereof and the like.
  • the base used include n-butyllithium, sec-butyllithium, tert-butyllithium and the like, and sec-butyllithium is preferable.
  • the reaction temperature is usually ⁇ 78 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature and the like, but is usually 30 minutes to 1 day.
  • the compound (5) used at this process can use a commercial item, can also be manufactured by the method of literature description, or the method according to them.
  • Step 1-3 Compound (4) can be produced by reacting compound (3) treated with a base with compound (6) in a solvent.
  • the solvent used include N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethylimidazolidin-2-one, tetrahydrofuran, a mixed solvent thereof and the like.
  • the base used include sodium hydride, potassium tert-butoxide, cesium carbonate and the like.
  • the reaction temperature is usually ⁇ 20 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
  • the compound (6) used at this process can use a commercial item, and can also manufacture it by the method of literature description, or the method according to them.
  • Step 1-4 Compound (Ia) can be produced by treating compound (4) with an acid in a solvent.
  • the solvent used include dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, a mixed solvent thereof and the like.
  • the acid used include trifluoroacetic acid, methanesulfonic acid, concentrated hydrochloric acid, concentrated sulfuric acid and the like.
  • the reaction temperature is usually ⁇ 78 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 1-5 Compound (Ib) can be produced by treating compound (Ia) by a general method for converting an ester group to a carboxy group. Such methods are well known to those skilled in the art and are described in, for example, Theodora W. et al. Greene & Peter G. M.M. A description by Wuts, “Green's Protective Groups in Organic Synthesis”, fourth edition, Wiley-Interscience, 2006 can be exemplified.
  • Step 1-6 Compound (Ic) can be produced by reacting compound (Ia) with compound (7) in the presence of a base in a solvent.
  • a solvent used include N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethylimidazolidin-2-one, N-methyl-2-pyrrolidinone, and mixed solvents thereof.
  • the base used include sodium hydride, potassium tert-butoxide, cesium carbonate, potassium carbonate and the like.
  • the reaction temperature is usually ⁇ 20 ° C. to 60 ° C.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
  • the compound (7) used at this process can use a commercial item, can also be manufactured by the method of literature description, or the method according to them.
  • Step 1-7 Compound (Id) can be produced by treating compound (Ic) by a general method for converting an ester group to a carboxy group. This step can be performed according to the above step 1-5.
  • Y 3 is a single bond or C 1. Represents a -5 alkylene group.
  • Step 2-1 Compound (9) can be produced by reacting compound (8) with compound (11) in the absence or presence of a base in the absence or presence of a solvent.
  • a solvent examples include ethanol, 2-ethoxyethanol, ethyl acetate, toluene, xylene, N, N-dimethylformamide, N, N-dimethylacetamide, a mixed solvent thereof and the like.
  • the base used examples include N, N-dimethylaniline and triethylamine.
  • the reaction temperature is usually room temperature to reflux temperature.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
  • the compound (8) and (11) used at this process can use a commercial item, can also be manufactured by the method of literature description, or the method according to them.
  • Step 2-2 Compound (9) can be produced by treating compound (3) with an acid in a solvent.
  • the solvent used include dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, a mixed solvent thereof and the like.
  • the acid used include trifluoroacetic acid, methanesulfonic acid, concentrated hydrochloric acid, concentrated sulfuric acid and the like.
  • the reaction temperature is usually ⁇ 78 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 2-3 Compound (Ia) can be produced by reacting compound (9) with compound (12) in a solvent in the presence of a reducing agent and an acid.
  • a solvent used include dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrahydrofuran, a mixed solvent thereof and the like.
  • An example of the reducing agent used is triethylsilane.
  • the acid used include trifluoroacetic acid, trimethylsilyl trifluoromethanesulfonate, and boron trifluoride diethyl ether complex.
  • the reaction temperature is usually ⁇ 78 ° C. to room temperature.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
  • the compound (12) used at this process can use a commercial item, can also be manufactured by the method of literature description, or the method according to them.
  • Step 2-4 Compound (10) can be produced by reacting compound (9) with compound (12) in the presence of a base in a solvent.
  • a solvent include dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, toluene, methanol, ethanol, a mixed solvent thereof and the like.
  • the base used include 1,8-diazabicyclo [5,4,0] -undec-7-ene, 1,5-diazabicyclo [4,3,0] -non-5-ene, sodium methoxide, sodium ethoxy And the like.
  • the reaction temperature is usually ⁇ 20 ° C. to 50 ° C.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 2-5 Compound (Ia) can be produced by subjecting compound (10) to a reduction reaction.
  • Specific examples of the method include the following methods (a) to (c).
  • the reaction temperature is usually ⁇ 30 ° C. to room temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 10 minutes to 24 hours.
  • (B) Method of reacting compound (10) with a reducing agent in the presence of an acid
  • the reaction is carried out in a solvent such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, a mixed solvent thereof or the like.
  • the acid used include trifluoroacetic acid, trimethylsilyl trifluoromethanesulfonate, and boron trifluoride diethyl ether complex.
  • An example of the reducing agent used is triethylsilane.
  • the reaction temperature is usually ⁇ 78 ° C. to room temperature.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
  • (C) Process for treating compound (10) under catalytic hydrogenation conditions
  • a method well known to those skilled in the art can be used.
  • the reaction is carried out, for example, in a hydrogen atmosphere using a reduction catalyst such as palladium-carbon or platinum oxide in a solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid, or a mixed solvent thereof.
  • the reaction temperature is usually from 0 ° C to 60 ° C.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
  • R 10 is bonded to each other to form a ring.
  • Step 3-1 Compound (13) can be produced by treating compound (Ie) with an acid in a solvent.
  • the solvent used include dichloromethane, chloroform, 1,2-dichloroethane, toluene, acetonitrile, tetrahydrofuran, a mixed solvent thereof and the like.
  • the acid used include boron tribromide.
  • the reaction temperature is usually ⁇ 78 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 3-2 Compound (14) can be produced by reacting compound (13) with a trifluoromethanesulfonylating agent in the presence of a base in a solvent.
  • a solvent include dichloromethane, chloroform, 1,2-dichloroethane, toluene, acetonitrile, pyridine, tetrahydrofuran, 1,4-dioxane, diethyl ether, N, N-dimethylformamide, a mixed solvent thereof and the like.
  • Examples of the base used include triethylamine, N, N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 2,6-lutidine, 2,4,6-trimethylpyridine, sodium carbonate, potassium carbonate, sodium hydride, sodium tert -Butoxide, potassium tert-butoxide, potassium phosphate and the like.
  • Examples of the trifluoromethanesulfonylating agent to be used include trifluoromethanesulfonic anhydride, N-phenylbis (trifluoromethanesulfonimide) and the like.
  • the reaction temperature is usually ⁇ 78 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 3-3 Compound (Ia) can be produced by reacting compound (14) with compound (15) in the presence of a palladium reagent and a base in a solvent.
  • a palladium reagent examples include 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, toluene, N, N-dimethylformamide, ethanol, water and a mixed solvent thereof.
  • Examples of the palladium reagent used include palladium (II) acetate, bis (triphenylphosphine) palladium (II) dichloride, tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0) and the like. It is done.
  • Examples of the base used include sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, potassium phosphate monohydrate, cesium fluoride, sodium tert-butoxide and the like.
  • the reaction temperature is usually room temperature to reflux temperature.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
  • This step can also be performed by adding a ligand such as 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, bis (diphenylphosphino) ferrocene, if necessary.
  • a ligand such as 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, bis (diphenylphosphino) ferrocene, if necessary.
  • the compound (15) 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 3-4 Compound (Ia) can be produced by reacting compound (14) with compound (16) in the presence of a palladium reagent in a solvent.
  • a solvent examples include 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, toluene, N, N-dimethylformamide, ethanol, water and a mixed solvent thereof.
  • Palladium reagents used include palladium (II) acetate, bis (triphenylphosphine) palladium (II) dichloride, tetrakis (triphenylphosphine) palladium (0), bis (dibenzylideneacetone) palladium (0), tris (di Benzylideneacetone) dipalladium (0) and the like.
  • Examples of the base used include sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, potassium phosphate monohydrate, cesium fluoride, sodium tert-butoxide and the like.
  • the reaction temperature is usually room temperature to reflux temperature.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
  • This step can also be performed by adding a ligand such as 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, bis (diphenylphosphino) ferrocene, if necessary.
  • the compound (16) 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 4-1 Compound (If) can be produced by reacting compound (9) with compound (17) in the presence of an oxidizing agent in a solvent.
  • the solvent used include dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol, water, a mixed solvent thereof and the like.
  • the oxidizing agent used include iodine, N-chlorosuccinimide, [bis (trifluoroacetoxy) iodo] benzene, and oxone (registered trademark).
  • the reaction temperature is usually ⁇ 78 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
  • 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 4-2 Compound (Ig) can be produced by treating compound (If) by a general method for converting an ester group to a carboxy group. This step can be performed according to the above step 1-5.
  • Step 4-3 Compound (Ih) can be produced by N-alkylating compound (If). This step can be performed according to the above step 1-6.
  • Step 4-4 Compound (Ii) can be produced by treating compound (Ih) by a general method for converting an ester group to a carboxy group. This step can be performed according to the above step 1-5.
  • a protective group when required depending on the type of functional group, it can be carried out by appropriately combining introduction and desorption operations according to a conventional method.
  • introduction and elimination of the protecting group see, for example, Theodora W. Green & Peter G. M. ⁇ Wuts, edited by “Greene's Protective Groups in Organic Synthesis”, fourth edition, Wiley-Interscience, 2006.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof, and an intermediate used for producing the compound, if necessary, are isolated and purified well known to those skilled in the art. It can be isolated and purified by means such as solvent extraction, crystallization / recrystallization, chromatography, preparative high performance liquid chromatography, and the like.
  • the pharmaceutical composition containing the compound (I) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient may be used in various dosage forms depending on the usage.
  • dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, solutions, ointments, suppositories, patches, sublinguals, etc. It is administered orally or parenterally.
  • compositions are prepared according to known methods depending on the dosage form, using appropriate excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents. It can be prepared by appropriately mixing or diluting / dissolving with pharmaceutical additives such as emulsifiers, dispersants, stabilizers, and solubilizing agents.
  • pharmaceutical additives such as emulsifiers, dispersants, stabilizers, and solubilizing agents.
  • compound (I) or a pharmaceutically acceptable non-salt and EP 1 receptor antagonist agents of the present invention simultaneously or separately each of active ingredients, and the aforementioned It can manufacture by formulating similarly.
  • Compound (I) or a pharmaceutically acceptable salt of the present invention exhibit a strong EP 1 receptor antagonism in the EP 1 receptor antagonistic activity confirmatory test and the like. Therefore, the compound (I) of the present invention can reduce the intracellular calcium concentration. Therefore, the pharmaceutical composition containing the compound (I) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient is used for the treatment of a disease or symptom caused by the activation of EP 1 receptor by PGE 2 stimulating action. It can be used as a medicine or a prophylactic.
  • Examples of diseases that activate the EP 1 receptor by PGE 2 stimulation include lower urinary tract symptoms (LUTS), inflammatory diseases, pain diseases, osteoporosis, cancer, and the like.
  • the pharmaceutical composition containing the compound (I) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient is preferably used as a therapeutic or prophylactic agent for LUTS, inflammatory disease or pain disease. . More preferably, it is LUTS.
  • 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 urine storage symptoms, urination symptoms, post-urination symptoms, and the like.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof is preferably used for the treatment or prevention of urinary retention symptoms.
  • Urine accumulation symptoms include urinary urgency, daytime frequent urination, night frequent urination, urinary incontinence (such as stress urinary incontinence, urge urinary incontinence, mixed urinary incontinence, enuresis, nocturia, persistent urinary incontinence), and Bladder perception (increased bladder perception, decreased bladder perception, lack of bladder perception, nonspecific bladder perception, etc.) is included.
  • Compound (I) of the present invention or a pharmacologically acceptable salt thereof is urinary urgency, daytime frequent urination, nocturia, urge urinary incontinence, mixed urinary incontinence, enuresis, nocturia, increased bladder perception, or It is preferably used for the treatment or prevention of nonspecific bladder perception. More preferred are urinary urgency, daytime frequent urination, nocturia, urge incontinence, or increased bladder perception.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof is particularly preferable for the treatment or prevention of OABs.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof can also be used in appropriate combination with at least one drug other than the EP 1 receptor antagonist.
  • Examples of the drug that can be used in combination with the compound (I) of the present invention or a pharmacologically acceptable salt thereof include overactive bladder (OAB), prostatic hypertrophy (PD) having a mechanism of action different from that of the EP 1 receptor antagonist. BPH), cystitis such as interstitial cystitis, and therapeutic agents for prostatitis and the like.
  • 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, TRPV1 modulators, endothelin antagonists, 5-HT 1A antagonists, ⁇ 1 agonists, opioid agonists, P 2 X antagonists, COX inhibitors, ⁇ agonists, muscarinic agonists, etc.
  • anticholinergic agents ⁇ 1 antagonists, ⁇ agonists, 5 ⁇ -reductase inhibitors, PDE inhibitors, progesterone hormones, antidiuretics, smooth muscle direct acting agents or tricyclic antidepressants. More preferred are anticholinergic agents, ⁇ 1 antagonists, ⁇ agonists, smooth muscle direct acting agents or tricyclic antidepressants. More preferred are anticholinergic agents, ⁇ 1 antagonists or tricyclic antidepressants. Most preferred is an anticholinergic agent.
  • anticholinergic agent examples include oxybutynin, propiverine, solifenacin, tolterodine, imidafenacin, temiverine, darifenacin, fesoterodine, trospium, propantheline and the like.
  • Oxybutynin, propiverine, solifenacin, tolterodine or imidafenacin is preferable. More preferred is solifenacin or imidafenacin.
  • ⁇ 1 antagonist examples include urapidil, naphthopidyl, tamsulosin, silodosin, prazosin, terazosin, alfuzosin, doxazosin, CR-2991, feduxin and the like.
  • ⁇ agonist examples include mirabegron, KUC-7383, KRP-204, SM-350300, TRK-380, amibegron, clenbuterol, SAR-150640, sorabegron and the like.
  • Mirabegron or KUC-7383 is preferred. More preferred is mirabegron.
  • dutasteride examples include dutasteride, TF-505, finasteride, and izonsteride. Preferred is dutasteride or 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. Tadalafil, vardenafil, sildenafil or avanafil is preferred.
  • 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, propiverine, temiverine, PD-299685, alanidipine, azelnidipine, varnidipine, benidipine, bevantolol, clevidipine, CYC-381, diltiazem, efonidipine, fasudil, felodipine, gabamil Rasidipine, lercanidipine, romeridine, manidipine, MEM-1003, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, SB-751689, verapamil, YM-58483, ziconotide and the like.
  • “Smooth muscle direct acting drugs” include flavoxate and the like.
  • tricyclic antidepressants examples include imipramine, clomipramine, amitriptyline and the like. Preferably, imipramine is used.
  • 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 includes acribastine, alcaftadine, bepotastine, bilastine, cetirizine, desloratadine, ebastine, efletirizine, epinastine, fexofenadine, GSK-835726, levocabastine, levocetirizine, loratadine, mequitadine, mizolastine, NBI-7, 43 Examples thereof include ReN-1869, terfenadine, UCB-35440, bapitazine, 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, pagoclone, 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 capsaicin, resiniferatoxin, DE-096, GRC-6221, AMG-8562, JTS-653, SB-705498, A-4256619, A-784168, ABT-102, AMG-628. AZD-1386, JNJ-17203212, NGD-8243, PF-38664086, SAR-115740, SB-784443, and the like.
  • Endothelin antagonists include SB-234551, ACT-064992, ambrisentan, atrasentan, bosentan, clazosentan, darsentan, fundsentan, S-0139, TA-0201, TBC-3711, dibotentan, 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 pharmaceutical composition of the present invention comprises the following 1) to 5): 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, It includes any one administration method selected from 4) administration at different times by the same route of administration as separate formulations, and 5) administration at different times by different routes of administration as separate formulations. Moreover, when administering at different time as a separate formulation like 4) or 5), there is no restriction
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof can be used in combination with one or more of the above drugs as appropriate, thereby providing an additive effect in preventing or treating the above diseases.
  • the above advantageous effects can be obtained.
  • the amount of use can be reduced compared with the case of using it alone, or the side effect of the combined drug can be avoided or reduced.
  • composition of the present invention can be administered systemically or locally, orally or parenterally (nasal, pulmonary, intravenous, rectal, subcutaneous, intramuscular, transdermal, etc.).
  • the dose of the compound (I) of the present invention depends on the age, sex, body weight, disease of the patient. It is appropriately determined depending on the degree of treatment. For example, in the case of oral administration, it can be appropriately administered in one or several divided doses within the range of about 3 to 1000 mg, 6 to 540 mg or 10 to 100 mg per adult day. In the case of an injection, it can be appropriately administered in a single dose or divided into several doses within the range of about 0.1 to 300 mg, 1 to 100 mg, or 3 to 30 mg per day for an adult.
  • the dose of compound (I), which is an active ingredient of the EP 1 receptor antagonist of the present invention, or a pharmacologically acceptable salt thereof depends on the dose of a drug other than the EP 1 receptor antagonist. You can lose weight.
  • Step 1 A solution of 1-methylcyclopropanecarboxylic acid (5.00 g) in dichloromethane (30 mL) was cooled in an ice-saturated saline bath under an argon atmosphere. Thereto, oxalyl chloride (4.71 mL) was added dropwise in 5 portions every 5 minutes, and the mixture was stirred under the same conditions for 2 hours and then at room temperature for 18 hours. The reaction mixture was used in Step 2 below.
  • Step 2 A suspension of N, O-dimethylhydroxylamine hydrochloride (4.87 g) in dichloromethane (50 mL) was cooled in an ice-water bath under an argon atmosphere.
  • Ethyl bromide (5.98 g) was added dropwise thereto. The mixture was stirred at ⁇ 78 ° C. for a further 3 hours and gradually warmed to room temperature. After 14 hours, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain tert-butyl 1-ethylcyclopropanecarboxylate (2.16 g).
  • Step 1 A solution of 1-ethylcyclopropanecarboxylic acid (1.29 g) in dichloromethane (6.8 mL) was cooled in an ice-saturated saline bath under an argon atmosphere. Thereto, oxalyl chloride (1.06 mL) was added dropwise in 3 portions every 5 minutes, and the mixture was stirred under the same conditions for 2 hours and then at room temperature for 16 hours. The reaction mixture was used in Step 2 below.
  • Step 2 A suspension of N, O-dimethylhydroxylamine hydrochloride (1.10 g) in dichloromethane (11.3 mL) was cooled in an ice-water bath under an argon atmosphere.
  • Reference Example 70 5- ⁇ 2- [2- (tert-butoxycarbonylamino) -4-methoxyphenyl] -3- (1-methylcyclopropyl) was prepared in the same manner as in Reference Example 69 using the corresponding starting materials and reactants. Methyl -3-oxopropyl ⁇ -2-fluorobenzoate was synthesized.
  • Step 2 N, N-dimethylformamide (3.2 mL) of tert-butyl ⁇ 5-methoxy-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl ⁇ carbamate (328 mg) under argon atmosphere The solution was cooled in an ice water bath. Sodium hydride (50-72% in oil, 52 mg) was added thereto, and the mixture was stirred for 35 minutes under the same conditions. The solution obtained in Step 1 was added dropwise thereto, and the mixture was stirred for 70 minutes under the same conditions. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Reference Example 84 A mixture of dimethyl 2- (1-methylcyclopropyl) -1H-indole-3,6-dicarboxylate (174 mg), 1 mol / L aqueous sodium hydroxide (6 mL) and methanol (6 mL) was placed in a sealed tube with microwaves. The mixture was stirred at 150 ° C. for 1 hour under irradiation. Another lot of reaction was carried out under the same conditions. The two reaction mixtures were combined and 1 mol / L hydrochloric acid was added thereto. The mixture was concentrated under reduced pressure to remove methanol. The residue was extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate.
  • reaction mixture was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- [6- (acetoxymethyl) -2- (1-methylcyclopropyl) -1H-indole- Methyl 3-ylmethyl] pyridine-2-carboxylate (61.0 mg) was obtained.
  • Reference Example 101 6-Methoxy-2- (1-methylcyclopropyl) -5-propyl-1H-indole was synthesized in the same manner as in Reference Example 79 using the corresponding starting materials and reactants.
  • Methyl iodide (11.3 g) was added dropwise thereto. The mixture was stirred at ⁇ 78 ° C. for 1 hour and gradually warmed to room temperature. After 22 hours, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain tert-butyl 1-methylcyclobutanecarboxylate (2.50 g).
  • Step 1 A solution of 1-methylcyclobutanecarboxylic acid (1.06 g) in dichloromethane (5.6 mL) was cooled in an ice-saturated saline bath under an argon atmosphere. Oxalyl chloride (0.876 mL) was added dropwise thereto, and the mixture was stirred at the same temperature for 1.5 hours and then at room temperature for 20 hours. The reaction mixture was used in Step 2 below.
  • Step 2 A suspension of N, O-dimethylhydroxylamine hydrochloride (906 mg) in dichloromethane (9.3 mL) was cooled in an ice-water bath under an argon atmosphere.
  • Triethylamine (4.5 mL) and then the reaction mixture obtained in Step 1 were added thereto. The mixture was stirred at the same temperature for 1.5 hours and then at room temperature for 24 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was separated and washed with saturated aqueous sodium bicarbonate. Silica gel was added to the organic layer and the mixture was stirred at room temperature for 2 hours. The insoluble material was filtered off and washed with diethyl ether / dichloromethane (1/1). The filtrate was concentrated under reduced pressure to obtain N-methoxy-N, 1-dimethylcyclobutanecarboxamide (1.26 g).
  • Reference Example 140 6-Methoxy-3- (6-methoxycarbonylpyridin-2-ylethynyl) -2- (1-methylcyclopropyl) -1H-indole-1-carboxylate tert-butyl (65.0 mg) in methanol (1.4 mL ) 10% palladium on carbon (water content 56.5 wt%, 22 mg) was added to the solution. Triethylsilane (0.225 mL) was added dropwise thereto, and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. The reaction mixture was filtered through a Celite (registered trademark) pad, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (1.4 mL).
  • Example 5 6- [6-Ethoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 4 using the corresponding starting materials and reagents. Methyl was synthesized.
  • Example 6 [6-Isopropoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid was prepared in the same manner as in Example 4 using the corresponding starting materials and reagents. Methyl acid was synthesized.
  • reaction mixture was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- [6-chloro-5-methoxy-2- (1-methylcyclopropyl) -1H-indole.
  • Methyl -3-ylmethyl] pyridine-2-carboxylate (71.8 mg) was obtained.
  • Example 8 6- [6-Ethyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 4 using the corresponding starting materials and reagents. Methyl was synthesized.
  • reaction mixture is purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) and then silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- [5-chloro-6- Methyl methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (253 mg) was obtained.
  • Example 10 6- [6-Isopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 4 using the corresponding starting materials and reagents. Methyl was synthesized.
  • Example 11 Under an argon atmosphere, 6-methoxy-5-methyl-2- (1-methylcyclopropyl) -1H-indole (586 mg), methyl 6-formylpyridine-2-carboxylate (450 mg) and triethylsilane (1.30 mL) Of dichloromethane in 13.6 mL was cooled in an ice-water bath. Trifluoroacetic acid (0.313 mL) was added thereto, and the mixture was stirred under the same conditions for 30 minutes and then at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine.
  • Example 13 Dichloromethane of methyl 3- ⁇ 2- [2- (tert-butoxycarbonylamino) -4-cyclopropylphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl ⁇ benzoate (260 mg) under argon atmosphere The solution (5.5 mL) was cooled in an ice-water bath. Trifluoroacetic acid (1.1 mL) was added thereto, and the mixture was stirred at room temperature for 14 hours and then at 30 ° C. for 5 hours. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the organic layer was separated.
  • Example 14 5- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] furan-2-carboxylic acid in the same manner as in Example 13 using the corresponding starting materials and reagents. Ethyl acid was synthesized.
  • Example 15 Under ice cooling, methyl 3- ⁇ 2- [2- (tert-butoxycarbonylamino) -4-cyclopropylphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl ⁇ -2-fluorobenzoate ( 142 mg) was added trifluoroacetic acid (1 mL) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was washed successively with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Example 16 Under argon atmosphere, 6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indole (134 mg), ethyl 2-formylthiazole-4-carboxylate (109 mg) and triethylsilane (0.304 mL) in dichloromethane ( (2 mL) The solution was cooled in an ice-water bath. Trifluoroacetic acid (0.071 mL) was added thereto, and the mixture was stirred for 30 minutes under the same conditions and then at room temperature for 13 hours.
  • reaction mixture was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 2- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indole-3- Ethyl [Ilmethyl] thiazole-4-carboxylate (180 mg) was obtained.
  • Example 17 Dichloromethane of methyl 2- ⁇ 2- [2- (tert-butoxycarbonylamino) -4-methoxyphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl ⁇ isonicotinate (191 mg) under argon atmosphere (2.1 mL) The solution was cooled in an ice-water bath. Trifluoroacetic acid (0.7 mL) was added there, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 18 Under an argon atmosphere, 6-methoxy-2- (1-methylcyclopropyl) -1H-indole (140 mg), ethyl 5-formylthiophene-2-carboxylate (128 mg) and triethylsilane (0.333 mL) in dichloromethane (3 .5 mL) The solution was cooled in an ice-water bath. Trifluoroacetic acid (0.080 mL) was added thereto, and the mixture was stirred for 30 minutes under the same conditions and then at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate.
  • Example 20 Trimethyl 3- ⁇ 2- [2- (tert-butoxycarbonylamino) -4-methoxyphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl ⁇ benzoate (215 mg) under argon atmosphere Fluoroacetic acid (1 mL) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 3- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl. ] Methyl benzoate (132 mg) was obtained.
  • Example 21 5- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] furan-2-carboxylic acid in the same manner as in Example 20 using the corresponding starting materials and reagents. Ethyl was synthesized.
  • Example 22 Methyl 2-fluoro-3- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] benzoate in the same manner as in Example 20 using the corresponding starting materials and reactants was synthesized.
  • Example 23 2- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiazole-4-carboxylic acid was prepared in the same manner as in Example 16 using the corresponding starting materials and reactants. Ethyl was synthesized.
  • Example 24 Methyl 6- ⁇ 2- [2- (tert-butoxycarbonylamino) -4,5-dimethylphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl ⁇ pyridine-2-carboxylate under an argon atmosphere A solution of (202 mg) in dichloromethane (2.16 mL) was cooled in an ice-water bath. Trifluoroacetic acid (0.72 mL) was added there, and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate.
  • Example 25 5- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiophene-3-carboxylic acid was prepared in the same manner as in Example 18 using the corresponding starting materials and reactants. Methyl was synthesized.
  • Example 26 5- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiophene-2-carboxylic acid was prepared in the same manner as in Example 18 using the corresponding starting materials and reagents. Ethyl acid was synthesized.
  • Example 27 Under an argon atmosphere, 6-difluoromethoxy- (1-methylcyclopropyl) -1H-indole (170 mg), methyl 6-formylpyridine-2-carboxylate (118 mg) and triethylsilane (0.344 mL) in dichloromethane (3. (0 mL) The solution was cooled in an ice-water bath. Trifluoroacetic acid (0.080 mL) was added thereto, and the mixture was stirred for 30 minutes under the same conditions and then at room temperature for 7 hours.
  • reaction mixture is purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- [6-difluoromethoxy-2- (1-methylcyclopropyl) -1H-indole-3- [Ilmethyl] methyl pyridine-2-carboxylate (160 mg) was obtained.
  • Example 28 Under an argon atmosphere, methyl 2- ⁇ 2- [2- (tert-butoxycarbonylamino) -4-cyclopropylphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl ⁇ oxazole-4-carboxylate ( (137 mg) in dichloromethane (1.5 mL) was cooled in an ice-water bath. Trifluoroacetic acid (0.5 mL) was added thereto, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate.
  • Example 29 5- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiophene-3-carboxylic acid was prepared in the same manner as in Example 18 using the corresponding starting materials and reactants. Methyl acid was synthesized.
  • Example 30 To a solution of methyl 6- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (70.0 mg) in N, N-dimethylformamide (1 mL), Cesium carbonate (163 mg) and methyl iodide (0.025 mL) were added and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 31 5- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] -2-fluorobenzoic acid in the same manner as in Example 20 using the corresponding starting materials and reagents. Methyl acid was synthesized.
  • Example 32 2-Fluoro-5- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] benzoic acid in the same manner as in Example 20 using the corresponding starting materials and reagents. Methyl was synthesized.
  • reaction mixture was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- [5,6-dimethoxy-2- (1-methylcyclopropyl) -1H-indole-3. -Ilmethyl] methyl pyridine-2-carboxylate (265 mg) was obtained.
  • Example 34 Methyl 5- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] nicotinate was synthesized in the same manner as in Example 20 using the corresponding starting materials and reactants. .
  • Example 35 Synthesis of methyl 5- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] nicotinate in the same manner as in Example 15 using the corresponding starting materials and reactants did.
  • Example 36 Under an argon atmosphere, 2- (1-methylcyclopropyl) -1,5,6,7-tetrahydrocyclopenta [f] indole (200 mg), methyl 6-formylpyridine-2-carboxylate (156 mg) and triethylsilane ( 0.454 mL) in dichloromethane (4.0 mL) was cooled in an ice-water bath. Trifluoroacetic acid (0.106 mL) was added thereto, and the mixture was stirred under the same conditions for 30 minutes and then at room temperature for 3.5 hours. The reaction mixture was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane).
  • Example 37 [1-Ethyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-- in the same manner as in Example 30 using the corresponding starting materials and reactants Methyl 2-carboxylate was synthesized.
  • Example 38 Under an argon atmosphere, 5-ethyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indole (37.4 mg), methyl 6-formylpyridine-2-carboxylate (26.9 mg) and triethylsilane (A solution of 0.078 mL) in dichloromethane (1.6 mL) was cooled in an ice-water bath. Trifluoroacetic acid (0.019 mL) was added thereto, and the mixture was stirred under the same conditions for 35 minutes and then at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate.
  • Example 39 [2- (1-Methylcyclopropyl) -6- (methylsulfanyl) -1H-indol-3-ylmethyl] pyridine-2 in the same manner as in Example 18 using the corresponding starting materials and reagents. -Methyl carboxylate was synthesized.
  • Example 40 Dichloromethane of 6-methoxy-2- (1-methylcyclopropyl) -1H-indole (106 mg), methyl 6-acetylpyridine-2-carboxylate (94.4 mg) and triethylsilane (0.253 mL) under argon atmosphere (2.0 mL) The solution was cooled in an ice-water bath. Trifluoroacetic acid (0.059 mL) was added thereto, and the mixture was stirred for 30 minutes under the same conditions and then at room temperature for 48 hours.
  • reaction mixture was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- ⁇ 1- [6-methoxy-2- (1-methylcyclopropyl) -1H-indole- Methyl 3-yl] ethyl ⁇ pyridine-2-carboxylate (149 mg) was obtained.
  • Example 41 [6- (1-Methylcyclopropyl) -5H- [1,3] dioxolo [4,5-f] indole-7 in the same manner as in Example 33, using the corresponding starting materials and reagents. -Methyl] pyridin-2-carboxylate was synthesized.
  • Example 42 A solution of methyl 6- [2- (1-methylcyclopropyl) -6- (methylsulfanyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (100 mg) in dichloromethane (1.36 mL) under an argon atmosphere. Was cooled in an ice-water bath. m-Chloroperbenzoic acid (about 25% water wet product, purity 65%, 174 mg) was added in two portions, and the mixture was stirred under the same conditions for 30 minutes and then at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Example 43 Methyl 2- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] isonicotinate was prepared in the same manner as in Example 4 using the corresponding starting materials and reactants. Synthesized.
  • Example 44 1,1,1,3,3 of methyl 6- [2- (1-methylcyclopropyl) -6- (methylsulfanyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (65.0 mg) , 3-Hexafluoropropan-2-ol (1.8 mL) solution was added 30% aqueous hydrogen peroxide (0.037 mL), and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added 10% aqueous sodium sulfite solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 45 Under an argon atmosphere, methyl 6- ⁇ 2- [2- (tert-butoxycarbonylamino) -4-methoxyphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl ⁇ pyrazine-2-carboxylate (111 mg ) In dichloromethane (1.2 mL) was cooled in an ice-water bath. Trifluoroacetic acid (0.4 mL) was added there, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 46 Under an argon atmosphere, methyl 6- ⁇ 2- [2- (tert-butoxycarbonylamino) -4-cyclopropylphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl ⁇ pyrazine-2-carboxylate ( A solution of 188 mg) in dichloromethane (1.95 mL) was cooled in an ice-water bath. Trifluoroacetic acid (0.65 mL) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate.
  • Example 47 Under argon atmosphere, methyl 6- ⁇ 2- [2- (tert-butoxycarbonylamino) phenyl] -3- (1-methylcyclopropyl) -3-oxopropyl ⁇ pyridine-2-carboxylate (227 mg) in dichloromethane ( (2.7 mL) The solution was cooled in an ice-water bath. Trifluoroacetic acid (0.9 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 48 [5-Cyclopropyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine in the same manner as in Example 38 using the corresponding starting materials and reagents. Methyl -2-carboxylate was synthesized.
  • Example 49 6- [6-Methoxy-2- (1-methylcyclopropyl) -5-propyl-1H-indol-3-ylmethyl] pyridine-- in the same manner as in Example 38 using the corresponding starting materials and reactants Methyl 2-carboxylate was synthesized.
  • Example 50 6- [6-Methoxy-2- (1-methylcyclobutyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 45 using the corresponding starting materials and reagents. Methyl was synthesized.
  • Example 51 [5-Butyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine--in the same manner as in Example 38 using the corresponding starting materials and reactants Methyl 2-carboxylate was synthesized.
  • Example 52 6- [6-Cyclopropyl-2- (1-methylcyclobutyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 45 using the corresponding starting materials and reagents. Methyl acid was synthesized.
  • Example 54 Under an argon atmosphere, 7-fluoro-6-methoxy-2- (1-methylcyclopropyl) -1H-indole (110 mg), methyl 6-formylpyridine-2-carboxylate (82.9 mg) and triethylsilane (0.
  • a solution of 240 mL) in dichloromethane (5 mL) was cooled in an ice-water bath.
  • Trifluoroacetic acid (0.058 mL) was added thereto, and the mixture was stirred under the same conditions for 1 hour and then at room temperature for 3 hours.
  • the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate.
  • Example 56 [6-Cyclopropyl-5-fluoro-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine in the same manner as in Example 19 using the corresponding starting materials and reagents. Methyl -2-carboxylate was synthesized.
  • Example 57 To a solution of methyl 6- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (584 mg) in tetrahydrofuran / methanol (9.92 mL / 4.25 mL). A 2 mol / L aqueous sodium hydroxide solution (2.50 mL) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (5.00 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 30 minutes.
  • Example 58 A solution of methyl 6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (355 mg) in tetrahydrofuran / methanol (5.86 mL / 2.51 mL). Was added 2 mol / L aqueous sodium hydroxide solution (1.48 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (2.96 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 30 minutes.
  • Example 59 To a solution of methyl 6- [6-chloro-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (427 mg) in tetrahydrofuran / methanol (7.16 mL / 3.07 mL). A 2 mol / L aqueous sodium hydroxide solution (1.81 mL) was added, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (3.62 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 1 hour.
  • Example 60 To a solution of methyl 6- [6-methyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (171 mg) in tetrahydrofuran / methanol (3.04 mL / 1.30 mL). 2 mol / L aqueous sodium hydroxide solution (0.768 mL) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (1.54 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 30 minutes.
  • Example 61 [6-Ethoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 60 using the corresponding starting materials and reagents. Was synthesized.
  • Example 62 6- [6-Isopropoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid was prepared in the same manner as in Example 60 using the corresponding starting materials and reactants. An acid was synthesized.
  • Example 63 Methyl 6- [6-chloro-5-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (70 mg) in tetrahydrofuran / methanol (0.9 mL / 0. 9 mol) solution was added 2 mol / L aqueous sodium hydroxide solution (0.27 mL) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 2 mol / L hydrochloric acid (0.27 mL) was added thereto while stirring. The mixture was stirred at room temperature for 30 minutes.
  • Example 64 [6-Ethyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 60 using the corresponding starting materials and reagents. Was synthesized.
  • Example 65 To a solution of methyl 6- [5-chloro-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (250 mg) in tetrahydrofuran / methanol (3 mL / 3 mL) A 2 mol / L aqueous sodium hydroxide solution (0.974 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 2 mol / L hydrochloric acid (0.98 mL) was added thereto while stirring. The mixture was stirred at room temperature for 30 minutes.
  • Example 66 [6-Isopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 60 using the corresponding starting materials and reagents. Was synthesized.
  • Example 69 To a solution of methyl 3- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] benzoate (44 mg) in tetrahydrofuran / methanol (0.6 mL / 0.6 mL), 2 mol / L Aqueous sodium hydroxide solution (0.183 mL) was added and the mixture was stirred at 60 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 2 mol / L hydrochloric acid (0.183 mL) was added thereto while stirring. The mixture was stirred at room temperature for 10 minutes.
  • Example 70 Ethyl 5- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] furan-2-carboxylate (95.7 mg) in tetrahydrofuran / methanol (1.3 mL / 1.3 mL) ) 2 mol / L aqueous sodium hydroxide solution (0.395 mL) was added to the solution, and the mixture was stirred at 60 ° C. for 80 minutes. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 2 mol / L hydrochloric acid (0.4 mL) was added thereto while stirring. The mixture was stirred at room temperature for 10 minutes.
  • Example 71 A solution of methyl 3- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] -2-fluorobenzoate (74 mg) in tetrahydrofuran / methanol (1.0 mL / 1.0 mL) was added 2 mol / L aqueous sodium hydroxide solution (0.295 mL), and the mixture was stirred at 60 ° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 2 mol / L hydrochloric acid (0.295 mL) was added thereto while stirring. The mixture was stirred at room temperature for 10 minutes.
  • Example 72 2- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiazole-4-carboxylate (177 mg) in tetrahydrofuran / methanol (2.3 mL / 2.3 mL) solution was added 2 mol / L aqueous sodium hydroxide solution (0.697 mL), and the mixture was stirred at 50 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 2 mol / L hydrochloric acid (0.7 mL) was added thereto while stirring. The mixture was stirred at room temperature for 30 minutes.
  • Example 73 2- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] isonicotinic acid was synthesized in the same manner as in Example 60 using the corresponding starting materials and reactants. .
  • Example 74 Ethyl 5- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiophene-2-carboxylate (75.2 mg) in tetrahydrofuran / methanol (1.21 mL / 0.519 mL) To the solution was added 2 mol / L aqueous sodium hydroxide solution (0.305 mL). The mixture was stirred at room temperature for 4 hours and then at 50 ° C. for 3 hours. The reaction mixture was allowed to cool and concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (0.710 mL) was added dropwise thereto while stirring.
  • Example 75 6- [2- (1-Ethylcyclopropyl) -6-methoxy-1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 60 using the corresponding starting materials and reagents. Was synthesized.
  • Example 76 3- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] benzoic acid was synthesized in the same manner as in Example 69 using the corresponding starting materials and reagents.
  • Example 77 5- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] furan-2-carboxylic acid in the same manner as in Example 69 using the corresponding starting materials and reagents. Was synthesized.
  • Example 78 2-Fluoro-3- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] benzoic acid in the same manner as in Example 69 using the corresponding starting materials and reactants was synthesized.
  • Example 79 2- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiazole-4-carboxylic acid in the same manner as in Example 72 using the corresponding starting materials and reagents. Was synthesized.
  • Example 81 Ethyl 5- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiophene-3-carboxylate (86.7 mg) in tetrahydrofuran / methanol (1.45 mL / 0.622 mL) To the solution was added 2 mol / L aqueous sodium hydroxide solution (0.366 mL). The mixture was stirred at room temperature for 3.5 hours and then at 60 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (0.732 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 30 minutes.
  • Example 82 A solution of ethyl 5- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiophene-2-carboxylate (334 mg) in tetrahydrofuran / methanol (5.24 mL / 2.24 mL). Was added 2 mol / L aqueous sodium hydroxide solution (1.32 mL), and the mixture was stirred at 60 ° C. for 3 hours. The reaction mixture was allowed to cool and concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (2.64 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 1 hour.
  • Example 83 [6-Difluoromethoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 65 using the corresponding starting materials and reactants An acid was synthesized.
  • Example 84 2- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] oxazole-4-carboxylic acid was prepared in the same manner as in Example 59 using the corresponding starting materials and reactants. An acid was synthesized.
  • Example 85 5- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiophene-3-carboxylic acid was prepared in the same manner as in Example 82 using the corresponding starting materials and reagents. An acid was synthesized.
  • Example 86 [6-Methoxy-1-methyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-- in the same manner as in Example 59 using the corresponding starting materials and reactants 2-carboxylic acid was synthesized.
  • Example 87 5- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] -2-fluorobenzoic acid in the same manner as in Example 70 using the corresponding starting materials and reagents. An acid was synthesized.
  • Example 88 2-Fluoro-5- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] benzoic acid in the same manner as in Example 70 using the corresponding starting materials and reactants was synthesized.
  • Example 90 5- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] nicotinic acid was synthesized in the same manner as in Example 63 using the corresponding starting materials and reactants.
  • Example 91 5- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] nicotinic acid was synthesized in the same manner as in Example 63 using the corresponding starting materials and reactants. .
  • 2 mol / L aqueous sodium hydroxide solution (0.270 mL)
  • the reaction mixture was concentrated under reduced pressure.
  • the residue was dissolved in water, and 2 mol / L hydrochloric acid (0.275 mL) was added thereto while stirring.
  • the mixture was stirred at room temperature for 10 minutes.
  • Example 93 [1-Ethyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-- in the same manner as in Example 59 using the corresponding starting materials and reactants 2-carboxylic acid was synthesized.
  • Example 94 [5-Ethyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate methyl (44.2 mg) in tetrahydrofuran / methanol (0.968 mL / 0.415 mL) solution was added 2 mol / L aqueous sodium hydroxide solution (0.175 mL), and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (0.350 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 1 hour.
  • a -2-carboxylic acid was synthesized.
  • Example 99 2 mol of methyl 2- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] isonicotinate (143 mg) in tetrahydrofuran / methanol (2.36 mL / 1.01 mL) / L aqueous sodium hydroxide solution (0.595 mL) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (1.19 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 1 hour.
  • Example 100 [2- (1-Methylcyclopropyl) -6- (methylsulfinyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (42.0 mg) in tetrahydrofuran / methanol (1.42 mL / 0 .609 mL) solution was added 2 mol / L sodium hydroxide aqueous solution (0.165 mL), and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (0.330 mL) was added dropwise thereto while stirring.
  • Example 101 6- [6- (Acetoxymethyl) -2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate methyl ester (54.5 mg) in tetrahydrofuran / methanol (0.7 mL / 0 To the solution was added 2 mol / L aqueous sodium hydroxide solution (0.28 mL), and the mixture was stirred at 40 ° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 2 mol / L hydrochloric acid (0.28 mL) was added dropwise thereto while stirring. The mixture was diluted with water and extracted with ethyl acetate.
  • Example 104 6- [2- (1-Methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid was synthesized in the same manner as in Example 94 using the corresponding starting materials and reactants.
  • Example 107 6- [6-Methoxy-2- (1-methylcyclobutyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 60 using the corresponding starting materials and reagents. Was synthesized.
  • Example 114 At room temperature, (E) -3- ⁇ 6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridin-2-yl ⁇ ethyl acrylate (75.0 mg) ) In ethanol (1 mL) was added 10% palladium-carbon (15 mg), and the suspension was stirred under a hydrogen gas atmosphere for 3 hours. The suspension was filtered through Celite (registered trademark), and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure.
  • Example 115 Chlorination of 6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indole (85.0 mg) and methyl 3- (6-formylpyridin-2-yl) propiolate (84.0 mg) under ice cooling
  • To a methylene (1.5 mL) solution were added triethylsilane (0.27 mL) and trifluoroacetic acid (0.08 mL). The solution was stirred under the same conditions for 0.5 hour and then at room temperature for 3 hours.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the solution, extracted with methylene chloride, and dried over anhydrous sodium sulfate.
  • Example 116 Methyl 6- [2- (1-methylcyclopropyl) -6- (trifluoromethylsulfonyloxy) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (60.0 mg), cyanide under argon atmosphere Zinc (30.0 mg), bis (dibenzylideneacetone) palladium (0) (7.5 mg), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (11.0 mg) in N, N-dimethylformamide A suspension of water (99: 1 v / v, 1.3 mL) was stirred at 60 ° C. for 6 hours.
  • the mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate.
  • the residue obtained by evaporating the solvent was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate), and 6- [2- (1-methylcyclopropyl) -6- (1-propene-2- Yl) -1H-indol-3-ylmethyl] methyl pyridine-2-carboxylate (42.0 mg).
  • Example 118 A solution of 6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indole (100 mg) and methyl 6-thioxo-1,6-dihydropyridine-2-carboxylate (120 mg) in methanol (5 mL) at room temperature was added with OXONE® (210 mg) and the mixture was stirred under the same conditions for 3 hours. Water was added to the mixture, extracted with methylene chloride, and the organic layer was dried over anhydrous sodium sulfate.
  • Example 119 6- [6- (1-methylcyclopropyl) -3,7-dihydro-2H-furo [3,2-f] indol-5-ylmethyl] pyridine-2-carboxylate methyl ester (50.0 mg) in tetrahydrofuran ( A 2 mol / L aqueous potassium hydroxide solution (0.3 mL) was added to a 0.3 mL) -methanol (0.6 mL) solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure, the resulting residue was diluted with water, and 1 mol / L hydrochloric acid (0.6 mL) was added under ice cooling.
  • Example 120 (E) -3- ⁇ 6- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridin-2-yl ⁇ ethyl acrylate (27.0 mg) in ethanol ( 0.7 mL) solution was added 2 mol / L potassium hydroxide aqueous solution (0.2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure, the resulting residue was diluted with water, and 1 mol / L hydrochloric acid (0.4 mL) was added under ice cooling.
  • Example 121 Ethanol (1.0 mL) of ethyl 3- ⁇ 6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridin-2-yl ⁇ propionate (52.0 mg) To the solution was added 2 mol / L potassium hydroxide aqueous solution (0.3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure, the resulting residue was diluted with water, and 1 mol / L hydrochloric acid (0.6 mL) was added under ice cooling.
  • Example 122 ⁇ 6- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridin-2-yl ⁇ methyl propiolate (60.0 mg) in methanol (0.6 mL) 2 mol / L potassium hydroxide aqueous solution (0.3 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure, the resulting residue was diluted with water, and 1 mol / L hydrochloric acid (0.6 mL) was added under ice cooling.
  • Example 123 6- [6-Cyano-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (11.0 mg) in methanol (0.2 mL) in 2 mol / L water Aqueous potassium oxide (0.1 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure, the resulting residue was diluted with water, and 1 mol / L hydrochloric acid (0.2 mL) was added under ice cooling. The precipitate was collected by filtration to obtain 6- [6-cyano-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (9.8 mg).
  • Example 124 Methyl 6- [2- (1-methylcyclopropyl) -6- (1-propen-2-yl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (37.0 mg) in methanol (0. 6 mL) solution was added 2 mol / L potassium hydroxide aqueous solution (0.3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure, the resulting residue was diluted with water, and 1 mol / L hydrochloric acid (0.6 mL) was added under ice cooling.
  • Example 125 6- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylsulfanyl] methyl pyridine-2-carboxylate (97.0 mg) in tetrahydrofuran (1.0 mL) -methanol (1 0.0 mL) solution was added 2 mol / L potassium hydroxide aqueous solution (0.5 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure, the resulting residue was diluted with water, and 1 mol / L hydrochloric acid (1.0 mL) was added under ice cooling. The precipitate was collected by filtration to obtain 6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylsulfanyl] pyridine-2-carboxylic acid (88.5 mg).
  • Example 128 [5-Isopropyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-- in the same manner as in Example 54 using the corresponding starting materials and reactants Methyl 2-carboxylate was synthesized.
  • Example 130 Of tert-butyl 6-methoxy-3- [2- (6-methoxycarbonylpyridin-2-yl) ethyl] -2- (1-methylcyclopropyl) -1H-indole-1-carboxylate (54.6 mg)
  • the dichloromethane (0.588 mL) solution was cooled in an ice water bath.
  • Trifluoroacetic acid (0.588 mL) was added thereto, and the mixture was stirred at room temperature for 1 hour.
  • the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate.
  • the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Comparative Example 2 6- (2-Cyclobutyl-6-methoxy-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid was synthesized in the same manner as in Comparative Example 1 using the corresponding starting materials and reactants.
  • Test example 1 EP 1 receptor antagonism confirmation test
  • 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 Escherichia coli was cultured on an LB agar medium for 1 day. After the culture, colonies were selected and cultured in an LB liquid medium containing 50 ⁇ g / mL ampicillin. After culture, the vector was purified using QIAprep Spin Miniprep Kit (Qiagen).
  • COS-1 cell culture COS-1 cells (Dainippon Sumitomo Pharma Co., Ltd.) are penicillin-streptomycin solution (Invitrogen Corporation, final concentration: 100 U / mL as benzylpenicillin; 100 ⁇ g / mL as streptomycin) as an antibiotic, D-MEM liquid medium (containing high glucose and L-glutamine) supplemented with MEM non-essential amino acids (Invitrogen Corporation, final concentration: 0.1 mM) and fetal calf serum (Sanko Junyaku Co., Ltd., final concentration: 10%) Invitrogen Corp.) was cultured in an incubator under 5% CO 2 gas conditions at 37 ° C. until confluence.
  • penicillin-streptomycin solution Invitrogen Corporation, final concentration: 100 U / mL as benzylpenicillin; 100 ⁇ g / mL as streptomycin
  • D-MEM liquid medium containing high glucose and L-glutamine
  • 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 with 5% CO 2 gas. When the cells for introduction of the rat EP 1 expression vector were adhered (after about 2 hours after seeding), the rat EP 1 expression vector was introduced by the following procedure.
  • BD BioCoat registered trademark
  • rat EP 1 expression vector For the introduction of rat EP 1 expression vector, using Lipofectamine 2000 (Invitrogen Corporation).
  • the rat EP 1 expression vector was diluted with OPTI-MEM (registered trademark) I Reduced-Serum Medium (Invitrogen Corporation) to 200 ng / 25 ⁇ L / well.
  • Lipofectamine 2000 (Invitrogen Corporation) is diluted with OPTI-MEM (registered trademark) I Reduced-Serum Medium (Invitrogen Corporation) to 0.5 ⁇ L / 25 ⁇ L / well and incubated at room temperature for 5 minutes. did.
  • 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.
  • 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 rat EP 1 expression vector / Lipofectamine 2000 complex was dispensed were cultured at 37 ° C. for 20 hours in an incubator under 5% CO 2 gas conditions. After culturing for 20 hours, the cells were used as rat EP 1 receptor-expressing cells for measurement of intracellular calcium concentration.
  • 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.
  • Fluorescent calcium indicator (Calcium kit II, Fluo4 (Dojindo Laboratories Co., Ltd.): Prepared by the same product protocol, Invitrogen Co., Ltd., containing 2.5 mM probenecid) 100 ⁇ L was added to each well, and 37 ° C. for 60 minutes. Incubated in incubator. Thereafter, the intracellular calcium concentration was measured immediately.
  • the intracellular calcium concentration was measured as a fluorescence signal using FDSS (registered trademark) 7000 (manufactured by Hamamatsu Photonics). 20 seconds after the start of reading the fluorescence signal, 50 ⁇ L of each test compound (final concentration: 1 nM to 10 ⁇ M) 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.
  • IC 50 value 100% of the fluorescence signal obtained when prostaglandin E 2 was added when assay buffer was added instead of the test compound in the above method, and the signal obtained when neither test compound nor prostaglandin E 2 was added was defined as 0%, and the concentration showing 50% inhibition from the concentration-response curve of the test compound was defined as the IC 50 value.
  • IC 50 values of the obtained test compounds are shown in Table 39 below.
  • the compounds of the present invention exhibited potent EP 1 receptor antagonism.
  • Test example 2 Inhibitory effect of compounds on sarprostone-induced bladder contraction
  • a tracheal cannula (Size8, HBIKI) and a femoral vein cannula for administration (PE50 with a 23G needle) were inserted.
  • a bladder cannula (PE50) was inserted from the top of the bladder. The bladder cannula was connected to a three-way stopcock, one connected to a pressure transducer, and the other connected to a syringe filled with saline.
  • the difference between the maximum bladder contraction rate (100%) and the average bladder contraction rate (%) after administration of the test drug was calculated according to the following formula, and was defined as the bladder contraction suppression rate of the test drug.
  • the compound of the present invention Since the compound of the present invention has a strong and long-lasting EP 1 receptor antagonistic action, it is useful as a therapeutic or prophylactic agent for diseases or symptoms caused by the activation of EP 1 receptor by stimulating action of PGE 2. . Among them, it is useful as a therapeutic or prophylactic 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 EP 1 receptor amplified using the primers of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4.

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Abstract

The present invention provides a compound represented by general formula (I), which has an EP1 receptor antagonist activity, or a pharmacologically acceptable salt thereof. The compound (I) of the present invention can be used as a therapeutic agent or prophylactic agent for LUTS, especially for various symptoms of OABs. (In the formula, A represents a pyridine ring or the like; Y1 represents a C1-6 alkylene group or the like; Y2 represents a single bond or the like; R1 represents a hydrogen atom or the like; R2 represents a C1-6 alkyl group; R3 represents a hydrogen atom or the like; R4 represents a hydrogen atom or the like; R5 represents a hydrogen atom, a halogen atom, a C1-6 alkyl group or the like; R6 represents a C1-6 alkyl group, a C3-6 cycloalkyl group or the like; R7 represents a hydrogen atom or the like; X represents a methylene group; and Q represents a single bond or the like.)

Description

インドール誘導体、またはその薬理学的に許容される塩Indole derivatives or pharmacologically acceptable salts thereof

　本発明は、医薬品として有用なＥＰ１受容体拮抗作用を有するインドール誘導体、またはその薬理学的に許容される塩、それを含有する医薬組成物およびその医薬用途に関する。 The present invention relates to an indole derivative having an EP 1 receptor antagonistic activity useful as a pharmaceutical product, or a pharmacologically acceptable salt thereof, a pharmaceutical composition containing the same, and a pharmaceutical use 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、「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はない。」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、必ずしも全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, it is a disease defined as “a symptom syndrome requiring urgency of urine, usually accompanied by frequent urination and nocturia. Imminent urinary incontinence is not essential”. 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. In LUTS, it has become clear that various chemical mediators are released in urothelial cells and cause a micturition reflex through a receptor of the bladder sensory nerve ending. Among them, prostaglandin E 2 (PGE 2 ), one of chemical transmitters, binds to prostaglandin E receptor 1 (EP 1 receptor) of afferent nerves (particularly C fibers) in the 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.

　さて、ＥＰ１受容体拮抗作用を有するインドール誘導体としては、下記一般式（ＩＡ）で表される化合物が開示されている（例えば、特許文献１参照）。 As an indole derivative having an EP 1 receptor antagonistic action, a compound represented by the following general formula (IA) is disclosed (for example, see Patent Document 1).

Figure JPOXMLDOC01-appb-C000005
〔式（ＩＡ）中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、ＲN、ＡおよびＹは、特許文献１と同義である。〕
　特許文献１には、上記化合物のＲ２の置換基がＣ３－６シクロアルキル基である化合物の記載があるが、Ｃ３－６シクロアルキル基に、さらにＣ１－６アルキル基が置換した化合物については記載されていない。
Figure JPOXMLDOC01-appb-C000005
 [In formula (IA), R 1 , R 2 , R 3 , R 4 , R 5 , R N , A and Y have the same meanings as in Patent Document 1. ]
Patent Document 1 describes a compound in which the substituent of R 2 of the above compound is a C 3-6 cycloalkyl group, and the C 3-6 cycloalkyl group is further substituted with a C 1-6 alkyl group. The compound is not described.

国際公開第２０１１／０１３６２３号パンフレットInternational Publication No. 2011-013623 Pamphlet

関成人, 「日本薬理学雑誌」, 2007年, 129巻, p. 368-373Seki adults, “The Journal of Japanese Pharmacology”, 2007, 129, p. 368-373 Xiaojun Wang, et al., 「Biomedical Research」, 2008年, 29巻, p. 105-111Xiaojun Wang, et al., `` Biomedical Research '', 2008, 」29, p. 105-111 Masahito Kawatani, 「PAIN RESEARCH」, 2004年, 19巻, p. 185-190Masahito Kawatani, “PAIN RESEARCH”, E2004, 19, p. 185-190 前川正信, 「日本排尿機能学会誌」, 2008年, 19巻, p. 169Masanobu Maekawa, Journal of the Japan Urinary Function Society, 2008, 19, p. 169

　本発明は、新規なＥＰ１受容体拮抗作用を有する化合物、またはその薬理学的に許容される塩、それを含有する医薬組成物およびその医薬用途を提供することを課題とする。 An object of the present invention is to provide a compound having a novel EP 1 receptor antagonistic action, or a pharmacologically acceptable salt thereof, a pharmaceutical composition containing the compound, and a pharmaceutical use thereof.

　本発明者らは、ＥＰ１受容体拮抗作用を有する化合物を見出すべく鋭意検討した。その結果、本発明の化合物（Ｉ）またはその薬理学的に許容される塩に強力なＥＰ１受容体拮抗作用があることを見出し、本発明をなすに至った。 The present inventors diligently studied to find a compound having an EP 1 receptor antagonistic action. As a result, it was found that the compound (I) of the present invention or a pharmacologically acceptable salt thereof has a strong EP 1 receptor antagonistic activity, and has led to the present invention.

　即ち、前記課題を解決する為の手段は下記の通りである。
〔１〕一般式（Ｉ）で表される化合物、またはその薬理学的に許容される塩 That is, the means for solving the above problems are as follows.
[1] A compound represented by the general formula (I) or a pharmacologically acceptable salt thereof

Figure JPOXMLDOC01-appb-C000006
〔式中、Ａは、以下のａ）～ｈ）：
Figure JPOXMLDOC01-appb-C000006
 [Wherein A represents the following a) to h):

Figure JPOXMLDOC01-appb-C000007
からなる群から選択される基であり；
Ｗ１およびＷ２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；
Ｗ３は、酸素原子または硫黄原子であり；
Ｗ４は、＝ＣＨ－または窒素原子であり； 
Ｚは、水素原子またはハロゲン原子であり；
Ｙ１は、Ｃ１－６アルキレン基または硫黄原子であり； 
Ｙ２は、単結合、Ｃ１－６アルキレン基、Ｃ２－４アルケニレン基またはＣ２－４アルキニレン基であり；
Ｒ１は、水素原子またはＣ１－６アルキル基であり；
Ｒ２は、Ｃ１－６アルキル基であり；
Ｒ３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；
Ｒ４は、水素原子、ハロゲン原子、Ｃ１－６アルキル基またはＣ１－６アルコキシ基であり；
Ｒ５は、水素原子、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基またはＣ３－６シクロアルキル基であり、Ｒ６は、水素原子、ハロゲン原子、Ｃ１－６アルキル基、ハロＣ１－６アルキル基、ヒドロキシＣ１－６アルキル基、Ｃ１－６アルコキシ基、ハロＣ１－６アルコキシ基、Ｃ１－６アルキルスルファニル基、Ｃ１－６アルキルスルフィニル基、Ｃ１－６アルキルスルホニル基、Ｃ３－６シクロアルキル基、シアノ基またはＣ２－６アルケニル基であるか、または、Ｒ５とＲ６が、互いに結合して、－（ＣＨ２）３－、－Ｏ－（ＣＨ２）２－、－（ＣＨ２）２－Ｏ－、－Ｏ－ＣＨ２－Ｏ－、－（ＣＨ２）４－、－Ｏ－（ＣＨ２）３－、－（ＣＨ２）３－Ｏ－、－Ｏ－（ＣＨ２）２－Ｏ－、－ＣＨ２－Ｏ－（ＣＨ２）２－、および－（ＣＨ２）２－Ｏ－ＣＨ２－からなる群から選択される基を形成し；
Ｒ７は、水素原子、ハロゲン原子、Ｃ１－６アルキル基またはＣ１－６アルコキシ基であり；
Ｘは、メチレン基であり；
Ｑは、メチレン基または単結合である。（ただし、（＊）を付された結合はＹ１と結合し、（＊＊）を付された結合はＹ２と結合することを表す。）。〕。
Figure JPOXMLDOC01-appb-C000007
 A group selected from the group consisting of:
One of W 1 and W 2 is a nitrogen atom and the other is ═CH— or a nitrogen atom;
W 3 is an oxygen atom or a sulfur atom;
W 4 is ═CH— or a nitrogen atom;
Z is a hydrogen atom or a halogen atom;
Y 1 is a C 1-6 alkylene group or a sulfur atom;
Y 2 is a single bond, a C 1-6 alkylene group, a C 2-4 alkenylene group or a C 2-4 alkynylene group;
R 1 is a hydrogen atom or a C 1-6 alkyl group;
R 2 is a C 1-6 alkyl group;
R 3 is a hydrogen atom, a C 1-6 alkyl group or a C 7-10 aralkyl group;
R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group;
R 5 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group or a C 3-6 cycloalkyl group, and R 6 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group Halo C 1-6 alkyl group, hydroxy C 1-6 alkyl group, C 1-6 alkoxy group, halo C 1-6 alkoxy group, C 1-6 alkylsulfanyl group, C 1-6 alkylsulfinyl group, C 1 A -6 alkylsulfonyl group, a C 3-6 cycloalkyl group, a cyano group or a C 2-6 alkenyl group, or R 5 and R 6 are bonded to each other to form — (CH 2 ) 3 —, — O— (CH 2 ) 2 —, — (CH 2 ) 2 —O—, —O—CH 2 —O—, — (CH 2 ) 4 —, —O— (CH 2 ) 3 —, — (CH 2 ) 3 -O -, - O- ( CH 2) 2 -O- -CH 2 -O- (CH 2) 2 -, and - to form a group selected from the group consisting of - (CH 2) 2 -O- CH 2;
R 7 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group;
X is a methylene group;
Q is a methylene group or a single bond. (However, the bond marked with (*) is linked to Y 1 and the bond marked with (**) is linked to Y 2 ). ].

〔２〕Ａが、以下のａ）、ｂ）、ｄ）およびｈ）： [2] A is the following a), b), d) and h):

Figure JPOXMLDOC01-appb-C000008
からなる群から選択される基であり； 
Ｒ１が水素原子であり；
Ｒ４が、水素原子であり；
Ｒ７が、水素原子である、〔１〕記載の化合物、またはその薬理学的に許容される塩（ただし、（＊）を付された結合はＹ１と結合し、（＊＊）を付された結合はＹ２と結合する
ことを表す。）。〕。
〔３〕Ｙ２が、単結合、Ｃ２－４アルケニレン基またはＣ２－４アルキニレン基である、〔２〕記載の化合物、またはその薬理学的に許容される塩。
〔４〕Ｒ３が水素原子である、〔３〕記載の化合物、またはその薬理学的に許容される塩。
〔５〕Ａが、以下のｂ）およびｈ）：
Figure JPOXMLDOC01-appb-C000008
 A group selected from the group consisting of:
R 1 is a hydrogen atom;
R 4 is a hydrogen atom;
The compound according to [1], wherein R 7 is a hydrogen atom, or a pharmacologically acceptable salt thereof (provided that a bond marked with (*) is linked to Y 1 and (**) is attached). Represents a bond to Y 2 ). ].
[3] The compound according to [2], or a pharmaceutically acceptable salt thereof, wherein Y 2 is a single bond, a C 2-4 alkenylene group or a C 2-4 alkynylene group.
[4] The compound according to [3], wherein R 3 is a hydrogen atom, or a pharmacologically acceptable salt thereof.
[5] A is the following b) and h):

Figure JPOXMLDOC01-appb-C000009
からなる群から選択される基である、〔４〕記載の化合物、またはその薬理学的に許容される塩。
〔６〕Ｑが単結合である、〔５〕記載の化合物、またはその薬理学的に許容される塩。
〔７〕Ｒ５が水素原子、ハロゲン原子、Ｃ１－６アルキル基またはＣ１－６アルコキシ基であり、Ｒ６が、水素原子、ハロゲン原子、Ｃ１－６アルキル基、ハロＣ１－６アルキル基、ヒドロキシＣ１－６アルキル基、Ｃ１－６アルコキシ基、ハロＣ１－６アルコキシ基、Ｃ１－６アルキルスルファニル基、Ｃ１－６アルキルスルフィニル基、Ｃ１－６アルキルスルホニル基、Ｃ３－６シクロアルキル基、シアノ基またはＣ２－６アルケニル基であるか、または、Ｒ５とＲ６が、互いに結合して、－（ＣＨ２）３－、－Ｏ－（ＣＨ２）２－、－（ＣＨ２）２－Ｏ－、－（ＣＨ２）４－、－Ｏ－（ＣＨ２）３－、－（ＣＨ２）３－Ｏ－、－ＣＨ２－Ｏ－（ＣＨ２）２－、および－（ＣＨ２）２－Ｏ－ＣＨ２－からなる群から選択される基を形成する、〔６〕記載の化合物、またはその薬理学的に許容される塩。
〔８〕Ｒ５が水素原子、ハロゲン原子、Ｃ１－６アルキル基またはＣ１－６アルコキシ基であり、Ｒ６がハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基、ハロＣ１－６アルコキシ基、Ｃ１－６アルキルスルファニル基、Ｃ３－６シクロアルキル基またはＣ２－６アルケニル基であるか、または、Ｒ５とＲ６が、互いに結合して、－（ＣＨ２）３－または－（ＣＨ２）４－を形成する、〔７〕記載の化合物、またはその薬理学的に許容される塩。
〔９〕下記の群から選択される〔１〕記載の化合物またはその薬理学的に許容される塩：６－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－クロロ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－メチル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－エトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－クロロ－５－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－エチル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［５－クロロ－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－イソプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－メトキシ－５－メチル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［５－フルオロ－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
３－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］－２－フルオロ安息香酸、
２－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］チアゾール－４－カルボン酸、
６－［２－（１－エチルシクロプロピル）－６－メトキシ－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
３－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］安息香酸、
２－フルオロ－３－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］安息香酸、
６－［５，６－ジメチル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－ジフルオロメトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［２－（１－メチルシクロプロピル）－１，５，６，７－テトラヒドロシクロペンタ［ｆ］インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［５－エチル－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［２－（１－メチルシクロプロピル）－６－（メチルスルファニル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピラジン－２－カルボン酸、
６－［５－シクロプロピル－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－メトキシ－２－（１－メチルシクロプロピル）－５－プロピル－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－メトキシ－２－（１－メチルシクロブチル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［５－ブチル－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－シクロプロピル－２－（１－メチルシクロブチル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［５－クロロ－６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－シクロプロピル－５－フルオロ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
（Ｅ）－３－｛６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－イル｝アクリル酸、
｛６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－イル｝プロピオール酸、
６－［２－（１－メチルシクロプロピル）－６－（１－プロペン－２－イル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルスルファニル］ピリジン－２－カルボン酸、および
６－［５－イソプロピル－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸。
Figure JPOXMLDOC01-appb-C000009
 The compound of [4], which is a group selected from the group consisting of: or a pharmacologically acceptable salt thereof.
[6] The compound according to [5] or a pharmacologically acceptable salt thereof, wherein Q is a single bond.
[7] R 5 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group, and R 6 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a haloC 1-6 alkyl, hydroxyalkyl C 1-6 alkyl group, C 1-6 alkoxy, halo C 1-6 alkoxy group, C 1-6 alkylsulfanyl group, C 1-6 alkylsulfinyl group, C 1-6 alkylsulfonyl group, A C 3-6 cycloalkyl group, a cyano group, or a C 2-6 alkenyl group, or R 5 and R 6 are bonded to each other to form — (CH 2 ) 3 —, —O— (CH 2 ). 2 —, — (CH 2 ) 2 —O—, — (CH 2 ) 4 —, —O— (CH 2 ) 3 —, — (CH 2 ) 3 —O—, —CH 2 —O— (CH 2 ) 2- , and-(CH 2 ) 2 -O-CH 2- The compound according to [6], or a pharmacologically acceptable salt thereof, which forms a group selected from the group consisting of:
[8] R 5 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group, and R 6 is a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a haloC A 1-6 alkoxy group, a C 1-6 alkylsulfanyl group, a C 3-6 cycloalkyl group or a C 2-6 alkenyl group, or R 5 and R 6 are bonded to each other to form — (CH 2 ) 3 - or - (CH 2) 4 - to form a [7] the compound according or a pharmacologically acceptable salt thereof.
[9] The compound of [1] selected from the following group or a pharmacologically acceptable salt thereof: 6- [6-methoxy-2- (1-methylcyclopropyl) -1H-indole-3- Ylmethyl] pyridine-2-carboxylic acid,
6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-chloro-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-methyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-Ethoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-chloro-5-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-ethyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [5-chloro-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-Isopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-methoxy-5-methyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [5-fluoro-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
3- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] -2-fluorobenzoic acid,
2- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiazole-4-carboxylic acid,
6- [2- (1-ethylcyclopropyl) -6-methoxy-1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
3- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] benzoic acid,
2-fluoro-3- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] benzoic acid,
6- [5,6-dimethyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-difluoromethoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [2- (1-methylcyclopropyl) -1,5,6,7-tetrahydrocyclopenta [f] indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [5-ethyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [2- (1-methylcyclopropyl) -6- (methylsulfanyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyrazine-2-carboxylic acid,
6- [5-cyclopropyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-methoxy-2- (1-methylcyclopropyl) -5-propyl-1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-methoxy-2- (1-methylcyclobutyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [5-butyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-cyclopropyl-2- (1-methylcyclobutyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [5-chloro-6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-cyclopropyl-5-fluoro-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
(E) -3- {6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridin-2-yl} acrylic acid,
{6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridin-2-yl} propiolic acid,
6- [2- (1-methylcyclopropyl) -6- (1-propen-2-yl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylsulfanyl] pyridine-2-carboxylic acid, and 6- [5-isopropyl-6-methoxy-2- (1 -Methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid.

〔１０〕〔１〕～〔９〕の何れか一項に記載の化合物、またはその薬理学的に許容される塩を含有する、医薬組成物。
〔１１〕以下からなる群：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から選択される少なくとも１種の薬剤を含む、〔１０〕記載の医薬組成物。
〔１２〕〔１〕～〔９〕の何れか一項に記載の化合物、またはその薬理学的に許容される塩を含有する、ＥＰ１受容体拮抗剤。
〔１３〕〔１〕～〔９〕の何れか一項に記載の化合物、またはその薬理学的に許容される塩を含有する、下部尿路症状の予防または治療剤。
〔１４〕〔１〕～〔９〕の何れか一項に記載の化合物、またはその薬理学的に許容される塩を有効量投与することからなる、下部尿路症状の予防または治療方法。
〔１５〕下部尿路症状の予防または治療用の医薬組成物を製造するための、〔１〕～〔９〕の何れか一項に記載の化合物、またはその薬理学的に許容される塩の使用。 [10] A pharmaceutical composition comprising the compound according to any one of [1] to [9] or a pharmacologically acceptable salt thereof.
[11] the group consisting of: anticholinergics, alpha 1 antagonists, beta agonists, 5.alpha.-reductase inhibitors, PDE inhibitors, acetylcholinesterase inhibitors, antiandrogens, progesterone-based hormone, LH-RH analogs, neurokinin inhibitory drugs, anti-diuretics, calcium channel blockers, smooth muscle direct action, tricyclic antidepressants, potassium channel modulators, sodium channel blockers, H 1 blockers, serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, dopamine re Uptake inhibitor, GABA agonist, TRPV1 modulator, endothelin antagonist, 5-HT 1A antagonist, α 1 agonist, opioid agonist, P 2 X antagonist, COX inhibitor, σ agonist, muscarinic agonist [10] The pharmaceutical composition according to [10], which comprises at least one drug.
[12] An EP 1 receptor antagonist comprising the compound according to any one of [1] to [9], or a pharmacologically acceptable salt thereof.
[13] A preventive or therapeutic agent for lower urinary tract symptoms, comprising the compound according to any one of [1] to [9], or a pharmacologically acceptable salt thereof.
[14] A method for preventing or treating lower urinary tract symptoms, comprising administering an effective amount of the compound according to any one of [1] to [9] or a pharmacologically acceptable salt thereof.
[15] A compound of any one of [1] to [9] or a pharmaceutically acceptable salt thereof for producing a pharmaceutical composition for preventing or treating lower urinary tract symptoms use.

　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、例えば、ＥＰ１受容体拮抗作用確認試験において、強力なＥＰ１受容体拮抗作用を示した。よって、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、ＥＰ１受容体拮抗作用に基づき、下部尿路症状（ＬＵＴＳ）、特に過活動膀胱症候群（ＯＡＢｓ）等の治療薬または予防薬として有用である。 The compound (I) of the present invention or a pharmacologically acceptable salt thereof exhibited a strong EP 1 receptor antagonism in, for example, an EP 1 receptor antagonism confirmation test. Therefore, the compound (I) of the present invention, or a pharmacologically acceptable salt thereof, treats lower urinary tract symptoms (LUTS), particularly overactive bladder syndrome (OABs), etc., based on EP 1 receptor antagonism. Useful as a drug or prophylactic.

　本明細書における用語について説明する。 The terms used in this specification will be explained.

　「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子またはヨウ素原子を意味する。好ましくは、フッ素原子または塩素原子である。 “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferably, they are a fluorine atom or a chlorine atom.

　「Ｃ１－６アルキル基」とは、炭素数１～６の分枝していても良いアルキル基を意味する。例えば、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基、ｎ－ペンチル基、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、ｎ－ヘキシル基、イソヘキシル基等が挙げられる。Ｒ６においては、メチル基、エチル基またはイソプロピル基が好ましい。Ｒ2においては、メチル基が好ましい。 “C 1-6 alkyl group” means an optionally branched alkyl group having 1 to 6 carbon atoms. For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, tert-pentyl group, Examples thereof include 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, n-hexyl group, isohexyl group and the like. R 6 is preferably a methyl group, an ethyl group or an isopropyl group. In R 2 , a methyl group is preferable.

　「Ｃ１－６アルコキシ基」とは、炭素数１～６の分枝していても良いアルコキシ基を意味する。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、ブトキシ基、イソブトキシ基、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。 The “C 1-6 alkoxy group” means an optionally branched alkoxy group having 1 to 6 carbon atoms. Examples include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, hexyloxy 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上記ハロゲン原子で置換された上記Ｃ１－６アルキル基を意味する。例えば、モノフルオロメチル基、ジフルオロメチル基、トリフルオロメチル基、２－クロロエチル基、２－フルオロエチル基、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、１－フルオロブチル基、１－フルオロペンチル基または１－フルオロヘキシル基等が挙げられる。好ましくは、モノフルオロメチル基、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、２，２－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または２，２，２－トリフルオロエチル基である。より好ましくは、モノフルオロメチル基、トリフルオロメチル基、２－フルオロエチル基、１，１－ジフルオロエチル基、１，２－ジフルオロエチル基または２，２，２－トリフルオロエチル基である。さらに好ましくは、モノフルオロメチル基またはトリフルオロメチル基である。 The “halo C 1-6 alkyl group” means the above C 1-6 alkyl group substituted with 1 to 5 of the same or different halogen atoms. For example, monofluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-chloroethyl group, 2-fluoroethyl group, 2,2-difluoroethyl group, 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, -Fluoropropyl group, 3,3-difluoropropyl group, 2,2-difluoropropyl group, 1,1-difluoropropyl group, 1-fluorobutyl group, 1-fluoropentyl group or 1-fluorohexyl group . Preferably, monofluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2,2-difluoroethyl group, 1,1-difluoroethyl group, 1,2-difluoroethyl group or 2,2 , 2-trifluoroethyl group. More preferred are a monofluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 1,1-difluoroethyl group, a 1,2-difluoroethyl group, or a 2,2,2-trifluoroethyl group. More preferably, it is a monofluoromethyl group or a trifluoromethyl group.

　「ヒドロキシＣ１－６アルキル基」とは、水酸基で置換された上記Ｃ１－６アルキル基を意味する。例えば、ヒドロキシメチル基、１－ヒドロキシエチル基、１－ヒドロキシ－１，１－ジメチルメチル基、２－ヒドロキシエチル基、２－ヒドロキシ－２－メチルプロピル基、３－ヒドロキシプロピル基等が挙げられる。 “Hydroxy C 1-6 alkyl group” means the above C 1-6 alkyl group substituted with a hydroxyl group. Examples thereof include a hydroxymethyl group, 1-hydroxyethyl group, 1-hydroxy-1,1-dimethylmethyl group, 2-hydroxyethyl group, 2-hydroxy-2-methylpropyl group, 3-hydroxypropyl 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。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、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 thereof include a methylsulfanyl group, an ethylsulfanyl group, a propylsulfanyl group, a butylsulfanyl group, a pentylsulfanyl group, and a hexylsulfanyl group.

　「Ｃ１－６アルキルスルフィニル基」とは、（Ｃ１－６アルキル）－Ｓ（＝Ｏ）－で表される基を意味する。例えば、メチルスルフィニル基、エチルスルフィニル基、プロピルスルフィニル基、ブチルスルフィニル基、ペンチルスルフィニル基、ヘキシルスルフィニル基等が挙げられる。 The “C 1-6 alkylsulfinyl group” means a group represented by (C 1-6 alkyl) -S (═O) —. Examples thereof include a methylsulfinyl group, an ethylsulfinyl group, a propylsulfinyl group, a butylsulfinyl group, a pentylsulfinyl group, and a hexylsulfinyl group.

　「Ｃ１－６アルキルスルホニル基」とは、（Ｃ１－６アルキル）－ＳＯ２－で表される基を意味する。例えば、メタンスルホニル基、エタンスルホニル基、プロパンスルホニル基、ブタンスルホニル基、ペンタンスルホニル基、ヘキサンスルホニル基等が挙げられる。 The “C 1-6 alkylsulfonyl group” means a group represented by (C 1-6 alkyl) —SO 2 —. Examples thereof include a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group, a butanesulfonyl group, a pentanesulfonyl group, and a hexanesulfonyl group.

　「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。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。好ましくは、シクロプロピル基である。 The “C 3-6 cycloalkyl group” means a monocyclic saturated alicyclic hydrocarbon group having 3 to 6 carbon atoms. Examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. Preferably, it is a cyclopropyl group.

　「ハロＣ１－６アルコキシ基」とは、１～５個の同種または異種の上記ハロゲン原子で置換された上記Ｃ１－６アルコキシ基を意味する。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－クロロエトキシ基、２－フルオロエトキシ基、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、２－フルオロエトキシ基、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または２，２，２－トリフルオロエトキシ基である。より好ましくは、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、２－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または２，２，２－トリフルオロエトキシ基である。さらに好ましくは、ジフルオロメトキシ基またはトリフルオロメトキシ基である。 The “halo C 1-6 alkoxy group” means the above C 1-6 alkoxy group substituted with 1 to 5 same or different halogen atoms. For example, monofluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, 2-chloroethoxy group, 2-fluoroethoxy group, 2,2-difluoroethoxy group, 1,1-difluoroethoxy group, 1,2-difluoroethoxy Group, 2,2,2-trifluoroethoxy group, 1,1,2,2,2-pentafluoroethoxy group, 2,2,2-trichloroethoxy group, 3-fluoropropoxy 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, etc. Is mentioned. Preferably, monofluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, 2-fluoroethoxy group, 2,2-difluoroethoxy group, 1,1-difluoroethoxy group, 1,2-difluoroethoxy group or 2,2 , 2-trifluoroethoxy group. More preferably, a monofluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a 2-fluoroethoxy group, a 1,1-difluoroethoxy group, a 1,2-difluoroethoxy group, or a 2,2,2-trifluoroethoxy group It is. More preferred is a difluoromethoxy group or a trifluoromethoxy group.

　「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。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 include benzyl group, phenethyl group, 1-phenylethyl group, 3-phenylpropyl group, 4-phenylbutyl group and the like.

　「Ｃ１－６アルキレン基」とは、炭素数１～６の２価の分枝していても良い飽和炭化水素鎖を意味する。例えば、－ＣＨ２－、－ＣＨ２ＣＨ２－、－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）２（ＣＨ２）２－、－（ＣＨ２）６－、－Ｃ（ＣＨ３）２（ＣＨ２）３－等が挙げられる。
　なお、本明細書中、－ＣＨ２－をメチレン基と称する場合がある。 The “C 1-6 alkylene group” means a saturated hydrocarbon chain having 1 to 6 carbon atoms which may be branched. For example, -CH 2 -, - CH 2 CH 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 ) 2 —, — (CH 2 ) 6 —, — C (CH 3 ) 2 (CH 2 ) 3 — and the like can be mentioned.
In the present specification, —CH 2 — may be referred to as a methylene group.

　「Ｃ２－４アルケニレン基」としては、例えば、－ＣＨ＝ＣＨ－、－Ｃ（ＣＨ３）＝ＣＨ－、－ＣＨ＝Ｃ（ＣＨ３）－、－ＣＨ＝ＣＨＣＨ２－、－ＣＨ２ＣＨ＝ＣＨ－等が挙げられる。 Examples of the “C 2-4 alkenylene group” include —CH═CH—, —C (CH 3 ) ═CH—, —CH═C (CH 3 ) —, —CH═CHCH 2 —, —CH 2 CH ═CH— and the like.

　「Ｃ２－４アルキニレン基」としては、例えば、エチニレン基、１－プロピニレン基、２－プロピニレン基等が挙げられる。 Examples of the “C 2-4 alkynylene group” include ethynylene group, 1-propynylene group, 2-propynylene group and the like.

　「Ｃ２－６アルケニル基」としては、例えば、ビニル基、アリル基、１－プロペニル基、イソプロペニル基、１－ブテニル基、２－ブテニル基、２－メチルアリル基等が挙げられる。 Examples of the “C 2-6 alkenyl group” include vinyl group, allyl group, 1-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 2-methylallyl group and the like.

　以下、本発明をより詳細に説明する。 Hereinafter, the present invention will be described in more detail.

　本発明の化合物（Ｉ）には、光学異性体、幾何異性体等のような立体異性体も含まれる。
　本発明の化合物（Ｉ）が１つ以上の不斉炭素原子を有する光学異性体である場合、本発明の化合物（Ｉ）の光学異性体は、各不斉炭素原子における立体配置がＲ配置またはＳ配置のいずれの立体配置であってもよい。また、いずれの光学異性体も本発明に含まれ、それらの光学異性体の混合物も含まれる。さらに、光学活性体の混合物において、等量の各光学異性体からなるラセミ体も本発明の範囲に含まれる。本発明の化合物（Ｉ）がラセミ体の固体または結晶である場合、ラセミ化合物、ラセミ混合物およびラセミ固溶体も本発明の範囲に含まれる。
　本発明の化合物（Ｉ）において、幾何異性体が存在する場合、本発明はその幾何異性体のいずれも包含する。
　また、本発明の化合物（Ｉ）において、互変異性体が存在する場合、本発明はその互変異性体のいずれも包含する。 The compound (I) of the present invention includes stereoisomers such as optical isomers and geometric isomers.
When the compound (I) of the present invention is an optical isomer having one or more asymmetric carbon atoms, the optical isomer of the compound (I) of the present invention has an R configuration or a configuration at each asymmetric carbon atom. Any three-dimensional arrangement of S arrangement may be sufficient. In addition, any optical isomer is included in the present invention, and a mixture of these optical isomers is also included. Furthermore, a racemate consisting of an equal amount of each optical isomer in a mixture of optically active substances is also included in the scope of the present invention. When the compound (I) of the present invention is a racemic solid or crystal, racemic compounds, racemic mixtures and racemic solid solutions are also included in the scope of the present invention.
In the compound (I) of the present invention, when a geometric isomer exists, the present invention includes any of the geometric isomers.
In the compound (I) of the present invention, when a tautomer exists, the present invention includes any of the tautomers.

　本発明の化合物（Ｉ）は、必要に応じて常法に従い、その薬理学的に許容される塩とすることができる。このような塩としては、酸付加塩または塩基との塩を挙げることができる。 Compound (I) of the present invention can be converted into a pharmacologically acceptable salt thereof according to a conventional method as necessary. Examples of such salts include acid addition salts and salts with bases.

　酸付加塩としては、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸等の鉱酸との酸付加塩、ギ酸、酢酸、トリフルオロ酢酸、メタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、プロピオン酸、クエン酸、コハク酸、酒石酸、フマル酸、酪酸、シュウ酸、マロン酸、マレイン酸、乳酸、リンゴ酸、炭酸、グルタミン酸、アスパラギン酸等の有機酸との酸付加塩を挙げることができる。 Acid addition salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, Acid addition with organic acids such as p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid Mention may be made of salts.

　塩基との塩としては、ナトリウム塩、カリウム塩、カルシウム塩、マグネシウム塩等の無機塩基との塩、ピペリジン、モルホリン、ピロリジン、アルギニン、リジン等の有機塩基との塩を挙げることができる。 Examples of salts with bases include salts with inorganic bases such as sodium salts, potassium salts, calcium salts and magnesium salts, and salts with organic bases such as piperidine, morpholine, pyrrolidine, arginine and lysine.

　さらに本発明の化合物（Ｉ）またはその薬理学的に許容される塩には、水和物、エタノール等の医薬品として許容される溶媒との溶媒和物も含まれる。 Furthermore, the compound (I) of the present invention or a pharmacologically acceptable salt thereof includes solvates with pharmaceutically acceptable solvents such as hydrates and ethanol.

　本発明でいう「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。
　ＥＰ１受容体拮抗作用は、細胞内へのカルシウムの流入量を減少または抑制させ、細胞内カルシウム濃度を低下させる。この結果、ＥＰ１受容体拮抗作用は平滑筋弛緩および知覚神経刺激抑制等の作用を示す。特に、ＥＰ１受容体拮抗薬は、膀胱、尿路上皮等において作用することにより、ＬＵＴＳ、中でもＯＡＢｓ等の症状の治療薬または予防薬として有用である。
　また、ＥＰ１受容体拮抗作用は、ＰＧＥ２による細胞内へのカルシウム流入量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。 The “EP 1 receptor antagonism” as used in the present invention 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 reduces or suppresses the inflow of calcium into the cell and decreases the intracellular calcium concentration. As a result, the EP 1 receptor antagonism exhibits actions such as smooth muscle relaxation and suppression of sensory nerve stimulation. In particular, EP 1 receptor antagonists are useful as therapeutic or prophylactic agents for symptoms such as LUTS, especially OABs, by acting on the bladder, urothelium, and the like.
Moreover, EP 1 receptor antagonism can be evaluated by the efficacy of inhibiting the amount of calcium inflow into cells by PGE 2 . 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.

　本発明の化合物（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 invention or a pharmacologically acceptable salt thereof, preferred substituents are as follows.

（Ｉ－１）Ａは、好ましくは、ベンゼン環、ピリジン環、ピラジン環、フラン環、チアゾール環またはオキサゾール環であり、より好ましくは、ピリジン環、ピラジン環またはチアゾール環であり、さらに好ましくはピリジン環である。
（Ｉ－２）Ｙ１は、好ましくはＣ１－６アルキレン基または硫黄原子であり、より好ましくは、－ＣＨ２－、－ＣＨ（ＣＨ３）－、－Ｃ（ＣＨ３）２－または硫黄原子であり、さらに好ましくは－ＣＨ２－または硫黄原子である。
（Ｉ－３）Ｙ２は、好ましくは、単結合、Ｃ２－４アルケニレン基またはＣ２－４アルキニレン基であり、より好ましくは、単結合である。
（Ｉ－４）Ｒ１は、好ましくは、水素原子である。
（Ｉ－５）Ｒ２は、好ましくはメチル基またはエチル基であり、より好ましくはメチル基である。
（Ｉ－６）Ｒ３は、好ましくは、水素原子、メチル基またはエチル基であり、より好ましくは、水素原子である。
（Ｉ－７）Ｒ４は、好ましくは、水素原子である。
（Ｉ－８）Ｒ５は、好ましくは、水素原子、ハロゲン原子、Ｃ１－６アルキル基またはＣ１－６アルコキシ基であり、より好ましくは、水素原子、フッ素原子、塩素原子、メチル基、エチル基またはメトキシ基であり、さらに好ましくは、水素原子、フッ素原子、塩素原子、メチル基またはエチル基である。
（Ｉ－９）Ｒ６は、好ましくは、ハロゲン原子、Ｃ１－６アルキル基、ハロＣ１－６アルキル基、Ｃ１－６アルコキシ基、ハロＣ１－６アルコキシ基、Ｃ１－６アルキルスルファニル基、Ｃ３－６シクロアルキル基またはＣ２－６アルケニル基であり、より好ましくは、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基、Ｃ３－６シクロアルキル基またはＣ２－６アルケニル基であり、さらに好ましくは、メトキシ基、メチル基、エチル基、イソプロピル基またはシクロプロピル基である。
（Ｉ－１０）Ｒ７は、好ましくは、水素原子である。
（Ｉ－１１）Ｚは、好ましくは、水素原子またはフッ素原子であり、より好ましくは水素原子である。
（Ｉ－１２）Ｑは、好ましくは、メチレン基または単結合であり、より好ましくは単結合である。  (I-1) A is preferably a benzene ring, a pyridine ring, a pyrazine ring, a furan ring, a thiazole ring or an oxazole ring, more preferably a pyridine ring, a pyrazine ring or a thiazole ring, still more preferably a pyridine ring It is a ring.
(I-2) Y 1 is preferably a C 1-6 alkylene group or a sulfur atom, more preferably —CH 2 —, —CH (CH 3 ) —, —C (CH 3 ) 2 — or sulfur. An atom, more preferably —CH 2 — or a sulfur atom.
(I-3) Y 2 is preferably a single bond, a C 2-4 alkenylene group or a C 2-4 alkynylene group, and more preferably a single bond.
(I-4) R 1 is preferably a hydrogen atom.
(I-5) R 2 is preferably a methyl group or an ethyl group, and more preferably a methyl group.
(I-6) R 3 is preferably a hydrogen atom, a methyl group or an ethyl group, more preferably a hydrogen atom.
(I-7) R 4 is preferably a hydrogen atom.
(I-8) R 5 is preferably a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group, more preferably a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, An ethyl group or a methoxy group, more preferably a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group or an ethyl group.
(I-9) R 6 is preferably a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 1-6 alkoxy group, a halo C 1-6 alkoxy group, a C 1-6 alkyl A sulfanyl group, a C 3-6 cycloalkyl group or a C 2-6 alkenyl group, more preferably a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 3-6 cycloalkyl group or C A 2-6 alkenyl group, more preferably a methoxy group, a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group.
(I-10) R 7 is preferably a hydrogen atom.
(I-11) Z is preferably a hydrogen atom or a fluorine atom, more preferably a hydrogen atom.
(I-12) Q is preferably a methylene group or a single bond, more preferably a single bond.

　本発明の化合物（Ｉ）、またはその薬理学的に許容される塩の好ましい態様としては、以下に記載の置換基の組み合わせからなる化合物である。 A preferred embodiment of the compound (I) of the present invention or a pharmacologically acceptable salt thereof is a compound comprising a combination of substituents described below.

実施態様１
　本発明の好ましい実施態様としては、Ａが、ベンゼン環、ピリジン環、ピラジン環，フラン環、チアゾール環またはオキサゾール環であり；
Ｙ１が、Ｃ１－６アルキレン基または硫黄原子であり；
Ｙ２が、単結合、Ｃ２－４アルケニレン基またはＣ２－４アルキニレン基であり；
Ｒ１が、水素原子であり；
Ｒ２が、メチル基またはエチル基であり；
Ｒ３が、水素原子、メチル基またはエチル基であり；
Ｒ４が、水素原子であり；
Ｒ５が、水素原子、ハロゲン原子、Ｃ１－６アルキル基またはＣ１－６アルコキシ基であり；
Ｒ６が、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基、ハロＣ１－６アルコキシ基、Ｃ１－６アルキルスルファニル基、Ｃ３－６シクロアルキル基またはＣ２－６アルケニル基であり；
Ｒ７が、水素原子であり；
Ｚが水素原子またはフッ素原子であり；
Ｑがメチレン基または単結合である。 Embodiment 1
In a preferred embodiment of the present invention, A is a benzene ring, pyridine ring, pyrazine ring, furan ring, thiazole ring or oxazole ring;
Y 1 is a C 1-6 alkylene group or a sulfur atom;
Y 2 is a single bond, a C 2-4 alkenylene group or a C 2-4 alkynylene group;
R 1 is a hydrogen atom;
R 2 is a methyl group or an ethyl group;
R 3 is a hydrogen atom, a methyl group or an ethyl group;
R 4 is a hydrogen atom;
R 5 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group;
R 6 represents a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a halo C 1-6 alkoxy group, a C 1-6 alkylsulfanyl group, a C 3-6 cycloalkyl group, or a C 2-6 alkenyl. A group;
R 7 is a hydrogen atom;
Z is a hydrogen atom or a fluorine atom;
Q is a methylene group or a single bond.

実施態様２
実施態様１において、さらに、
Ａが、ピリジン環、ピラジン環またはチアゾール環であり；
Ｙ１が、－ＣＨ２－または硫黄原子であり； 
Ｙ２が、単結合であり；
Ｒ３が、水素原子であり；
Ｚが水素原子である。 Embodiment 2
In embodiment 1, further:
A is a pyridine ring, pyrazine ring or thiazole ring;
Y 1 is —CH 2 — or a sulfur atom;
Y 2 is a single bond;
R 3 is a hydrogen atom;
Z is a hydrogen atom.

実施態様３
実施態様２において、さらに、
Ｒ２が、メチル基であり；
Ｑが単結合である。 Embodiment 3
In embodiment 2, further:
R 2 is a methyl group;
Q is a single bond.

実施態様４ 
実施態様３において、さらに、
Ａが、ピリジン環である。 Embodiment 4
In embodiment 3, further:
A is a pyridine ring.

実施態様５
実施態様４において、さらに、
Ｒ５が、水素原子、フッ素原子、塩素原子、メチル基、エチル基またはメトキシ基である。 Embodiment 5
In embodiment 4, further:
R 5 is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group or a methoxy group.

実施態様６ 
実施態様５において、さらに、
Ｒ６が、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基、Ｃ３－６シクロアルキル基またはＣ２－６アルケニル基である。 Embodiment 6
In embodiment 5, further:
R 6 is a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 3-6 cycloalkyl group or a C 2-6 alkenyl group.

実施態様７ 
実施態様６において、さらに、
Ｒ５が、水素原子、フッ素原子、塩素原子、メチル基またはエチル基であり；
Ｒ６が、メトキシ基、メチル基、エチル基、イソプロピル基またはシクロプロピル基である。 Embodiment 7
In embodiment 6, further:
R 5 is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group or an ethyl group;
R 6 is a methoxy group, a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group.

実施態様８
実施態様１から実施態様４のいずれかにおいて、さらに、
Ｒ５とＲ６が、互いに結合して、－（ＣＨ２）３－、－Ｏ－（ＣＨ２）２－、－（ＣＨ２）２－Ｏ－、－（ＣＨ２）４－、－Ｏ－（ＣＨ２）３－、－（ＣＨ２）３－Ｏ－、－ＣＨ２－Ｏ－（ＣＨ２）２－、および－（ＣＨ２）２－Ｏ－ＣＨ２－からなる群から選択される基を形成する。 Embodiment 8
In any of embodiment 1 to embodiment 4, further
R 5 and R 6 are bonded to each other to form — (CH 2 ) 3 —, —O— (CH 2 ) 2 —, — (CH 2 ) 2 —O—, — (CH 2 ) 4 —, —O Selected from the group consisting of — (CH 2 ) 3 —, — (CH 2 ) 3 —O—, —CH 2 —O— (CH 2 ) 2 —, and — (CH 2 ) 2 —O—CH 2 —. Form a group.

実施態様９
実施態様８において、さらに、
Ｒ５とＲ６が、互いに結合して、－（ＣＨ２）３－または－（ＣＨ２）４－を形成する。 Embodiment 9
In embodiment 8, further:
R 5 and R 6 are bonded to each other, - (CH 2) 3 - or - (CH 2) 4 - to form a.

　本実施態様に包含される具体的化合物としては、以下の化合物が挙げられる。
６－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（実施例５７）、６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（実施例５８）、６－［６－クロロ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（実施例５９）、６－［６－メチル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（実施例６０）、６－［６－エトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（実施例６１）、６－［６－クロロ－５－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（実施例６３）、６－［６－エチル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（実施例６４）、６－［５－クロロ－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（実施例６５）、６－［６－イソプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（実施例６６）、６－［６－メトキシ－５－メチル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（実施例６７）、６－［５－フルオロ－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（実施例６８）、３－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］－２－フルオロ安息香酸（実施例７１）、２－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］チアゾール－４－カルボン酸（実施例７２）、６－［２－（１－エチルシクロプロピル）－６－メトキシ－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（実施例７５）、３－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］安息香酸（実施例７６）、２－フルオロ－３－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］安息香酸（実施例７８）、６－［５，６－ジメチル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（実施例８０）、６－［６－ジフルオロメトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（実施例８３）、６－［２－（１－メチルシクロプロピル）－１，５，６，７－テトラヒドロシクロペンタ［ｆ］インドール－３－イルメチル］ピリジン－２－カルボン酸（実施例９２）、６－［５－エチル－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（実施例９４）、６－［２－（１－メチルシクロプロピル）－６－（メチルスルファニル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（実施例９５）、６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピラジン－２－カルボン酸（実施例１０３）、６－［５－シクロプロピル－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（実施例１０５）、６－［６－メトキシ－２－（１－メチルシクロプロピル）－５－プロピル－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（実施例１０６）、６－［６－メトキシ－２－（１－メチルシクロブチル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（実施例１０７）、６－［５－ブチル－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（実施例１０８）、６－［６－シクロプロピル－２－（１－メチルシクロブチル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（実施例１０９）、６－［５－クロロ－６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（実施例１１０）、６－［６－シクロプロピル－５－フルオロ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（実施例１１３）、（Ｅ）－３－｛６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－イル｝アクリル酸（実施例１２０）、｛６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－イル｝プロピオール酸（実施例１２２）、６－［２－（１－メチルシクロプロピル）－６－（１－プロペン－２－イル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（実施例１２４）、６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルスルファニル］ピリジン－２－カルボン酸（実施例１２５）、６－［５－イソプロピル－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（実施例１２９）。 Specific compounds included in this embodiment include the following compounds.
6- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 57), 6- [6-cyclopropyl-2- (1- Methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 58), 6- [6-chloro-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] Pyridine-2-carboxylic acid (Example 59), 6- [6-Methyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 60), 6 -[6-Ethoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 61), 6- [6-Chloro-5-methyl Xyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 63), 6- [6-ethyl-2- (1-methylcyclopropyl) -1H -Indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 64), 6- [5-Chloro-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine- 2-carboxylic acid (Example 65), 6- [6-isopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 66), 6- [ 6-Methoxy-5-methyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 67), 6- [5-F Oro-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 68), 3- [6-cyclopropyl-2- (1-methyl) Cyclopropyl) -1H-indol-3-ylmethyl] -2-fluorobenzoic acid (Example 71), 2- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] Thiazole-4-carboxylic acid (Example 72), 6- [2- (1-ethylcyclopropyl) -6-methoxy-1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 75), 3 -[6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] benzoic acid (Example 76), 2-fluoro-3- [6-methoxy Ci-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] benzoic acid (Example 78), 6- [5,6-dimethyl-2- (1-methylcyclopropyl) -1H-indole -3-ylmethyl] pyridine-2-carboxylic acid (Example 80), 6- [6-difluoromethoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid ( Example 83), 6- [2- (1-methylcyclopropyl) -1,5,6,7-tetrahydrocyclopenta [f] indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 92), 6- [5-Ethyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 94), 6- [ -(1-methylcyclopropyl) -6- (methylsulfanyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 95), 6- [6-cyclopropyl-2- (1-methyl) Cyclopropyl) -1H-indol-3-ylmethyl] pyrazine-2-carboxylic acid (Example 103), 6- [5-cyclopropyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indole- 3-ylmethyl] pyridine-2-carboxylic acid (Example 105), 6- [6-methoxy-2- (1-methylcyclopropyl) -5-propyl-1H-indol-3-ylmethyl] pyridine-2-carboxylic acid Acid (Example 106), 6- [6-Methoxy-2- (1-methylcyclobutyl) -1H-indol-3-ylmethyl] pyridine-2- Rubonic acid (Example 107), 6- [5-butyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 108), 6 -[6-Cyclopropyl-2- (1-methylcyclobutyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 109), 6- [5-Chloro-6-cyclopropyl-2 -(1-Methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 110), 6- [6-cyclopropyl-5-fluoro-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 113), (E) -3- {6- [6-cyclopropyl-2- (1-methylcyclopropyl) Pyll) -1H-indol-3-ylmethyl] pyridin-2-yl} acrylic acid (Example 120), {6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indole-3- Ylmethyl] pyridin-2-yl} propiolic acid (Example 122), 6- [2- (1-methylcyclopropyl) -6- (1-propen-2-yl) -1H-indol-3-ylmethyl] pyridine -2-carboxylic acid (Example 124), 6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylsulfanyl] pyridine-2-carboxylic acid (Example 125), 6- [5-Isopropyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Examples) 29).

本発明の化合物（Ｉ）の製造方法
　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、以下のスキーム１～４に示した方法もしくはそれに準じた方法等に従って製造することができる。 Production Method of Compound (I) of the Present Invention Compound (I) of the present invention or a pharmacologically acceptable salt thereof can be produced according to the method shown in the following schemes 1 to 4 or a method analogous thereto. it can.

Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010

（式中、Ａ、Ｑ、Ｒ２、Ｒ４、Ｒ５、Ｒ６、Ｒ７、Ｘ、Ｙ１およびＹ２は、前記と同義である。Ｒ８は、Ｃ１－６アルキル基又はＣ７－１０アラルキル基を表し、Ｒ９は、Ｃ１－６アルキル基を表し、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の脱離基を表す。） Wherein A, Q, R 2 , R 4 , R 5 , R 6 , R 7 , X, Y 1 and Y 2 are as defined above. R 8 is a C 1-6 alkyl group or C 7-10 represents an aralkyl group, R 9 represents a C 1-6 alkyl group, and L 1 represents a leaving group such as a chlorine atom, a bromine atom, an iodine atom, or a methanesulfonyloxy group.

工程１－１
　化合物（２）は、溶媒中、化合物（１）を二炭酸ジｔｅｒｔ－ブチル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、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が挙げられる。反応温度は、通常、室温～還流温度である。反応時間は、用いる原料物質、溶媒、反応温度などにより異なるが、通常１時間～３日間である。本工程は、アミノ基をｔｅｒｔ－ブトキシカルボニル基で保護する公知の方法を用いて実施することもできる。そのような方法として、例えば、Ｔｈｅｏｄｏｒａ Ｗ．Ｇｒｅｅｎｅ & Ｐｅｔｅｒ Ｇ． Ｍ． Ｗｕｔｓ著編，「Ｇｒｅｅｎｅ’ｓ　Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ」，ｆｏｕｒｔｈ　ｅｄｉｔｉｏｎ，Ｗｉｌｅｙ－Ｉｎｔｅｒｓｃｉｅ
ｎｃｅ，２００６年の記載を例示することができる。 Step 1-1
Compound (2) can be produced by reacting compound (1) with ditert-butyl dicarbonate in a solvent. Examples of the solvent used include tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, a mixed solvent thereof and the like. The reaction temperature is usually room temperature to reflux temperature. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 1 hour to 3 days. This step can also be carried out using a known method for protecting an amino group with a tert-butoxycarbonyl group. As such a method, for example, Theodora W. et al. Greene & Peter G. M.M. Edited by Wuts, “Greene's Protective Groups in Organic Synthesis”, fourth edition, Wiley-Interscience.
Nce, 2006 can be exemplified.

工程１－２
　化合物（３）は、溶媒中、塩基で処理した化合物（２）を化合物（５）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、それらの混合溶媒等が挙げられる。用いられる塩基としては、例えば、ｎ－ブチルリチウム、ｓｅｃ－ブチルリチウム、ｔｅｒｔ－ブチルリチウム等が挙げられ、ｓｅｃ－ブチルリチウムが好ましい。反応温度は、通常－７８℃～還流温度である。反応時間は、用いる原料物質、溶媒、反応温度などにより異なるが、通常３０分間～１日間である。なお、本工程で用いられる化合物（５）は、市販品を用いることができるほか、文献記載の方法又はそれらに準じた方法で製造することもできる。 Step 1-2
Compound (3) can be produced by reacting compound (2) treated with a base with compound (5) in a solvent. Examples of the solvent used include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, a mixed solvent thereof and the like. Examples of the base used include n-butyllithium, sec-butyllithium, tert-butyllithium and the like, and sec-butyllithium is preferable. The reaction temperature is usually −78 ° C. to reflux temperature. The reaction time varies depending on the raw material used, solvent, reaction temperature and the like, but is usually 30 minutes to 1 day. In addition, the compound (5) used at this process can use a commercial item, can also be manufactured by the method of literature description, or the method according to them.

工程１－３
　化合物（４）は、溶媒中、塩基で処理した化合物（３）を化合物（６）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、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、１，３－ジメチルイミダゾリジン－２－オン、テトラヒドロフラン、それらの混合溶媒等が挙げられる。用いられる塩基としては、水素化ナトリウム、カリウムｔｅｒｔ－ブトキシド、炭酸セシウム等が挙げられる。反応温度は通常－２０℃～還流温度である。反応時間は、用いる原料物質、溶媒、反応温度などにより異なるが、通常３０分間～３日間である。なお、本工程で用いられる化合物（６）は、市販品を用いることができるほか、文献記載の方法又はそれらに準じた方法で製造することもできる。 Step 1-3
Compound (4) can be produced by reacting compound (3) treated with a base with compound (6) in a solvent. Examples of the solvent used include N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethylimidazolidin-2-one, tetrahydrofuran, a mixed solvent thereof and the like. Examples of the base used include sodium hydride, potassium tert-butoxide, cesium carbonate and the like. The reaction temperature is usually −20 ° C. to reflux temperature. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days. In addition, the compound (6) used at this process can use a commercial item, and can also manufacture it by the method of literature description, or the method according to them.

工程１－４
　化合物（Ｉａ）は、溶媒中、化合物（４）を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、ジクロロメタン、クロロホルム、１，２－ジクロロエタン、メタノール、エタノール、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が挙げられる。用いられる酸としては、トリフルオロ酢酸、メタンスルホン酸、濃塩酸、濃硫酸等が挙げられる。反応温度は通常－７８℃～還流温度である。反応時間は、用いる原料物質、溶媒、反応温度などにより異なるが、通常３０分間～３日間である。 Step 1-4
Compound (Ia) can be produced by treating compound (4) with an acid in a solvent. Examples of the solvent used include dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, a mixed solvent thereof and the like. Examples of the acid used include trifluoroacetic acid, methanesulfonic acid, concentrated hydrochloric acid, concentrated sulfuric acid and the like. The reaction temperature is usually −78 ° C. to reflux temperature. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.

工程１－５
　化合物（Ｉｂ）は、一般的なエステル基のカルボキシ基への変換方法で化合物（Ｉａ）を処理することにより製造することができる。そのような方法は、当業者には周知であり、例えば、Ｔｈｅｏｄｏｒａ Ｗ．Ｇｒｅｅｎｅ & Ｐｅｔｅｒ Ｇ． Ｍ． Ｗｕｔｓ著編，「Ｇｒｅｅｎｅ’ｓ　Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ」，ｆｏｕｒｔｈ　ｅｄｉｔｉｏｎ，Ｗｉｌｅｙ－Ｉｎｔｅｒｓｃｉｅｎｃｅ，２００６年の記載を例示することができる。 Step 1-5
Compound (Ib) can be produced by treating compound (Ia) by a general method for converting an ester group to a carboxy group. Such methods are well known to those skilled in the art and are described in, for example, Theodora W. et al. Greene & Peter G. M.M. A description by Wuts, “Green's Protective Groups in Organic Synthesis”, fourth edition, Wiley-Interscience, 2006 can be exemplified.

工程１－６
　化合物（Ｉｃ）は、溶媒中、塩基の存在下、化合物（Ｉａ）を化合物（７）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、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、１，３－ジメチルイミダゾリジン－２－オン、Ｎ－メチル－２－ピロリジノン、それらの混合溶媒等が挙げられる。用いられる塩基としては、水素化ナトリウム、カリウムｔｅｒｔ－ブトキシド、炭酸セシウム、炭酸カリウム等が挙げられる。反応温度は、通常－２０℃～６０℃である。反応時間は、用いる原料物質、溶媒、反応温度などにより異なるが、通常３０分間～３日間である。なお、本工程で用いられる化合物（７）は、市販品を用いることができるほか、文献記載の方法又はそれ
らに準じた方法で製造することもできる。 Step 1-6
Compound (Ic) can be produced by reacting compound (Ia) with compound (7) in the presence of a base in a solvent. Examples of the solvent used include N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethylimidazolidin-2-one, N-methyl-2-pyrrolidinone, and mixed solvents thereof. Examples of the base used include sodium hydride, potassium tert-butoxide, cesium carbonate, potassium carbonate and the like. The reaction temperature is usually −20 ° C. to 60 ° C. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days. In addition, the compound (7) used at this process can use a commercial item, can also be manufactured by the method of literature description, or the method according to them.

工程１－７
　化合物（Ｉｄ）は、一般的なエステル基のカルボキシ基への変換方法で化合物（Ｉｃ）を処理することにより製造することができる。本工程は、前記工程１－５に準じて実施することができる。 Step 1-7
Compound (Id) can be produced by treating compound (Ic) by a general method for converting an ester group to a carboxy group. This step can be performed according to the above step 1-5.

Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011

（式中、Ａ、Ｑ、Ｒ２、Ｒ４、Ｒ５、Ｒ６、Ｒ７、Ｒ８、Ｘ、Ｙ１およびＹ２は、前記と同義である。Ｙ３は、単結合またはＣ１－５アルキレン基を表す。） (In the formula, A, Q, R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , X, Y 1 and Y 2 are as defined above. Y 3 is a single bond or C 1. Represents a -5 alkylene group.)

工程２－１
　化合物（９）は、無溶媒又は溶媒中、塩基の存在下又は非存在下、化合物（８）を化合物（１１）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、エタノール、２－エトキシエタノール、酢酸エチル、トルエン、キシレン、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、それらの混合溶媒等が挙げられる。用いられる塩基としては、Ｎ，Ｎ－ジメチルアニリン、トリエチルアミン等が挙げられる。反応温度は、通常室温～還流温度である。反応時間は、用いる原料物質、溶媒、反応温度などにより異なるが、通常３０分間～３日間である。なお、本工程で用いられる化合物（８）及び（１１）は、市販品を用いることができるほか、文献記載の方法又はそれらに準じた方法で製造することもできる。 Step 2-1
Compound (9) can be produced by reacting compound (8) with compound (11) in the absence or presence of a base in the absence or presence of a solvent. Examples of the solvent used include ethanol, 2-ethoxyethanol, ethyl acetate, toluene, xylene, N, N-dimethylformamide, N, N-dimethylacetamide, a mixed solvent thereof and the like. Examples of the base used include N, N-dimethylaniline and triethylamine. The reaction temperature is usually room temperature to reflux temperature. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days. In addition, the compound (8) and (11) used at this process can use a commercial item, can also be manufactured by the method of literature description, or the method according to them.

工程２－２
　化合物（９）は、溶媒中、化合物（３）を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、ジクロロメタン、クロロホルム、１，２－ジクロロエタン、メタノール、エタノール、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が挙げられる。用いられる酸としては、トリフルオロ酢酸、メタンスルホン酸、濃塩酸、濃硫酸等が挙げられる。反応温度は通常－７８℃～還流温度である。反応時間は、用いる原料物質、溶媒、反応温度などにより異なるが、通常３０分間～３日間である。 Step 2-2
Compound (9) can be produced by treating compound (3) with an acid in a solvent. Examples of the solvent used include dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, a mixed solvent thereof and the like. Examples of the acid used include trifluoroacetic acid, methanesulfonic acid, concentrated hydrochloric acid, concentrated sulfuric acid and the like. The reaction temperature is usually −78 ° C. to reflux temperature. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.

工程２－３
　化合物（Ｉａ）は、溶媒中、還元剤及び酸の存在下、化合物（９）を化合物（１２）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、ジクロロメタン、クロロホルム、四塩化炭素、１，２－ジクロロエタン、テトラヒドロフラン、それらの混合溶媒等が挙げられる。用いられる還元剤としては、例えば、トリエチルシランが挙げられる。用いられる酸としては、トリフルオロ酢酸、トリフルオロメタンスルホン酸トリメチルシリル、三フッ化ホウ素ジエチルエーテル錯体等が挙げられる。反応温度は、通常－７８℃～室温である。反応時間は、用いる原料物質、溶媒、反応温度などにより異なるが、通常３０分間～３日間である。なお、本工程で用いられる化合物（１２）は、市販品を用いることができるほか、文献記載の方法又はそれらに準じた方法で製造することもできる。 Step 2-3
Compound (Ia) can be produced by reacting compound (9) with compound (12) in a solvent in the presence of a reducing agent and an acid. Examples of the solvent used include dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrahydrofuran, a mixed solvent thereof and the like. An example of the reducing agent used is triethylsilane. Examples of the acid used include trifluoroacetic acid, trimethylsilyl trifluoromethanesulfonate, and boron trifluoride diethyl ether complex. The reaction temperature is usually −78 ° C. to room temperature. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days. In addition, the compound (12) used at this process can use a commercial item, can also be manufactured by the method of literature description, or the method according to them.

工程２－４
　化合物（１０）は、溶媒中、塩基の存在下、化合物（９）を化合物（１２）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、ジクロロメタン、クロロホルム、１，２－ジクロロエタン、テトラヒドロフラン、トルエン、メタノール、エタノール、それらの混合溶媒等が挙げられる。用いられる塩基としては、１，８－ジアザビシクロ［５，４，０］－ウンデカ－７－エン、１，５－ジアザビシクロ［４，３，０］－ノナ－５－エン、ナトリウムメトキシド、ナトリウムエトキシド等が挙げられる。反応温度は、通常－２０℃～５０℃である。反応時間は、用いる原料物質、溶媒、反応温度などにより異なるが、通常３０分間～３日間である。 Step 2-4
Compound (10) can be produced by reacting compound (9) with compound (12) in the presence of a base in a solvent. Examples of the solvent used include dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, toluene, methanol, ethanol, a mixed solvent thereof and the like. Examples of the base used include 1,8-diazabicyclo [5,4,0] -undec-7-ene, 1,5-diazabicyclo [4,3,0] -non-5-ene, sodium methoxide, sodium ethoxy And the like. The reaction temperature is usually −20 ° C. to 50 ° C. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.

工程２－５
　化合物（Ｉａ）は、化合物（１０）を還元反応に付すことにより製造することができる。具体的な方法としては、例えば、下記の方法（ａ）～（ｃ）が例示できる。
（ａ）化合物（１０）を溶媒中、ヨウ化ナトリウム及びクロロトリメチルシランより調製した試薬と反応させる方法　
　該反応は、アセトニトリル等の溶媒中で実施される。その反応温度は、通常－３０℃～室温である。反応時間は、用いる原料物質、溶媒、反応温度などにより異なるが、通常１０分間～２４時間である。
（ｂ）酸の存在下、化合物（１０）を還元剤と反応させる方法　
　該反応は、ジクロロメタン、クロロホルム、１，２－ジクロロエタン、テトラヒドロフラン、それらの混合溶媒等の溶媒中で実施される。用いられる酸としては、トリフルオロ酢酸、トリフルオロメタンスルホン酸トリメチルシリル、三フッ化ホウ素ジエチルエーテル錯体等が挙げられる。用いられる還元剤としては、例えば、トリエチルシランが挙げられる。反応温度は、通常－７８℃～室温である。反応時間は、用いる原料物質、溶媒、反応温度などにより異なるが、通常３０分間～３日間である。
（ｃ）化合物（１０）を接触水素化条件下に処理する方法　
　該接触水素化は、当業者に周知の方法を用いることができる。該反応は、例えば、水素雰囲気下、メタノール、エタノール、酢酸エチル、テトラヒドロフラン、酢酸、それらの混合溶媒等の溶媒中、パラジウム－炭素や酸化白金等の還元触媒を用いて実施される。反応温度は、通常０℃～６０℃である。反応時間は、用いる原料物質、溶媒、反応温度などにより異なるが、通常３０分間～３日間である。 Step 2-5
Compound (Ia) can be produced by subjecting compound (10) to a reduction reaction. Specific examples of the method include the following methods (a) to (c).
(A) Method of reacting compound (10) with a reagent prepared from sodium iodide and chlorotrimethylsilane in a solvent
The reaction is carried out in a solvent such as acetonitrile. The reaction temperature is usually −30 ° C. to room temperature. The reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 10 minutes to 24 hours.
(B) Method of reacting compound (10) with a reducing agent in the presence of an acid
The reaction is carried out in a solvent such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, a mixed solvent thereof or the like. Examples of the acid used include trifluoroacetic acid, trimethylsilyl trifluoromethanesulfonate, and boron trifluoride diethyl ether complex. An example of the reducing agent used is triethylsilane. The reaction temperature is usually −78 ° C. to room temperature. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
(C) Process for treating compound (10) under catalytic hydrogenation conditions
For the catalytic hydrogenation, a method well known to those skilled in the art can be used. The reaction is carried out, for example, in a hydrogen atmosphere using a reduction catalyst such as palladium-carbon or platinum oxide in a solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid, or a mixed solvent thereof. The reaction temperature is usually from 0 ° C to 60 ° C. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.

Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012

（式中、Ａ、Ｑ、Ｒ２、Ｒ４、Ｒ５、Ｒ６、Ｒ７、Ｒ８、Ｘ、Ｙ１およびＹ２は、前記と同義である。Ｒ１０は、互いに結合して環を形成してもよいＣ１－６アルキル基等を表す。） (In the formula, A, Q, R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , X, Y 1 and Y 2 are as defined above. R 10 is bonded to each other to form a ring. Represents a C 1-6 alkyl group or the like which may form

工程３－１
　化合物（１３）は、溶媒中、化合物（Ｉｅ）を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、ジクロロメタン、クロロホルム、１，２－ジクロロエタン、トルエン、アセトニトリル、テトラヒドロフラン、それらの混合溶媒等が挙げられる。用いられる酸としては、例えば、三臭化ホウ素が挙げられる。反応温度は、通常－７８℃～還流温度である。反応時間は、用いる原料物質、溶媒、反応温度などにより異なるが、通常３０分間～３日間である。 Step 3-1
Compound (13) can be produced by treating compound (Ie) with an acid in a solvent. Examples of the solvent used include dichloromethane, chloroform, 1,2-dichloroethane, toluene, acetonitrile, tetrahydrofuran, a mixed solvent thereof and the like. Examples of the acid used include boron tribromide. The reaction temperature is usually −78 ° C. to reflux temperature. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.

工程３－２
　化合物（１４）は、溶媒中、塩基の存在下、化合物（１３）をトリフルオロメタンスルホニル化剤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、ジクロロメタン、クロロホルム、１，２－ジクロロエタン、トルエン、アセトニトリル、ピリジン、テトラヒドロフラン、１，４－ジオキサン、ジエチルエーテル、Ｎ，Ｎ－ジメチルホルムアミド、それらの混合溶媒等が挙げられる。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、４－ジメチルアミノピリジン、２，６－ルチジン、２，４，６－トリメチルピリジン、炭酸ナトリウム、炭酸カリウム、水素化ナトリウム、ナトリウムｔｅｒｔ－ブトキシド、カリウムｔｅｒｔ－ブトキシド、リン酸カリウム等が挙げられる。用いられるトリフルオロメタンスルホニル化剤としては、トリフルオロメタンスルホン酸無水物、Ｎ－フェニルビス（トリフルオロメタンスルホンイミド）等が挙げられる。反応温度は、通常－７８℃～還流温度である。反応時間は、用いる原料物質、溶媒、反応温度などにより異なるが、通常３０分間～３日間である。 Step 3-2
Compound (14) can be produced by reacting compound (13) with a trifluoromethanesulfonylating agent in the presence of a base in a solvent. Examples of the solvent used include dichloromethane, chloroform, 1,2-dichloroethane, toluene, acetonitrile, pyridine, tetrahydrofuran, 1,4-dioxane, diethyl ether, N, N-dimethylformamide, a mixed solvent thereof and the like. Examples of the base used include triethylamine, N, N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 2,6-lutidine, 2,4,6-trimethylpyridine, sodium carbonate, potassium carbonate, sodium hydride, sodium tert -Butoxide, potassium tert-butoxide, potassium phosphate and the like. Examples of the trifluoromethanesulfonylating agent to be used include trifluoromethanesulfonic anhydride, N-phenylbis (trifluoromethanesulfonimide) and the like. The reaction temperature is usually −78 ° C. to reflux temperature. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.

工程３－３
　化合物（Ｉａ）は、溶媒中、パラジウム試薬および塩基の存在下、化合物（１４）を化合物（１５）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、１，２－ジメトキシエタン、テトラヒドロフラン、１，４－ジオキサン、トルエン、Ｎ，Ｎ－ジメチルホルムアミド、エタノール、水それらの混合溶媒等が挙げられる。用いられるパラジウム試薬としては、酢酸パラジウム（ＩＩ）、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）ジクロリド、テトラキス（トリフェニルホスフィン）パラジウム（０）、トリス（ジベンジリデンアセトン）ジパラジウム（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、炭酸セシウム、リン酸カリウム、リン酸カリウム・一水和物、フッ化セシウム、ナトリウムｔｅｒｔ－ブトキシド等が挙げられる。反応温度は通常室温～還流温度である。反応時間は、用いる原料物質、溶媒、反応温度などにより異なるが、通常３０分間～３日間である。なお、本工程は、必要に応じて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、ビス（ジフェニルホスフィノ）フェロセンなどの配位子を添加して行うこともできる。また、本工程で用いられる化合物（１５）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 3-3
Compound (Ia) can be produced by reacting compound (14) with compound (15) in the presence of a palladium reagent and a base in a solvent. Examples of the solvent used include 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, toluene, N, N-dimethylformamide, ethanol, water and a mixed solvent thereof. Examples of the palladium reagent used include palladium (II) acetate, bis (triphenylphosphine) palladium (II) dichloride, tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0) and the like. It is done. Examples of the base used include sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, potassium phosphate monohydrate, cesium fluoride, sodium tert-butoxide and the like. The reaction temperature is usually room temperature to reflux temperature. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days. This step can also be performed by adding a ligand such as 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, bis (diphenylphosphino) ferrocene, if necessary. Moreover, the compound (15) 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３－４
　化合物（Ｉａ）は、溶媒中、パラジウム試薬の存在下、化合物（１４）を化合物（１６）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、１，２－ジメトキシエタン、テトラヒドロフラン、１，４－ジオキサン、トルエン、Ｎ，Ｎ－ジメチルホルムアミド、エタノール、水それらの混合溶媒等が挙げられる。用いられるパラジウム試薬としては、酢酸パラジウム（ＩＩ）、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）ジクロリド、テトラキス（トリフェニルホスフィン）パラジウム（０）、ビス（ジベンジリデンアセトン）パラジウム（０）、トリス（ジベンジリデンアセトン）ジパラジウム（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、炭酸セシウム、リン酸カリウム、リン酸カリウム・一水和物、フッ化セシウム、ナトリウムｔｅｒｔ－ブトキシド等が挙げられる。反応温度は通常室温～還流温度である。反応時間は、用いる原料物質、溶媒、反応温度などにより異なるが、通常３０分間～３日間である。なお、本工程は、必要に応じて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、ビス（ジフェニルホスフィノ）フェロセンなどの配位子を添加して行うこともできる。また、本工程で用いられる化合物（１６）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 3-4
Compound (Ia) can be produced by reacting compound (14) with compound (16) in the presence of a palladium reagent in a solvent. Examples of the solvent used include 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, toluene, N, N-dimethylformamide, ethanol, water and a mixed solvent thereof. Palladium reagents used include palladium (II) acetate, bis (triphenylphosphine) palladium (II) dichloride, tetrakis (triphenylphosphine) palladium (0), bis (dibenzylideneacetone) palladium (0), tris (di Benzylideneacetone) dipalladium (0) and the like. Examples of the base used include sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, potassium phosphate monohydrate, cesium fluoride, sodium tert-butoxide and the like. The reaction temperature is usually room temperature to reflux temperature. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days. This step can also be performed by adding a ligand such as 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, bis (diphenylphosphino) ferrocene, if necessary. Moreover, the compound (16) 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.

Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013

（式中、Ａ、Ｑ、Ｒ２、Ｒ４、Ｒ５、Ｒ６、Ｒ７、Ｒ８、Ｒ９、Ｘ、Ｌ１およびＹ２は、前記と同義である。） (In the formula, A, Q, R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , X, L 1 and Y 2 are as defined above.)

工程４－１
　化合物（Ｉｆ）は、溶媒中、酸化剤の存在下、化合物（９）を化合物（１７）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、ジクロロメタン、クロロホルム、１，２－ジクロロエタン、メタノール、エタノール、水、それらの混合溶媒等が挙げられる。用いられる酸化剤としては、ヨウ素、Ｎ－クロロコハク酸イミド、［ビス（トリフルオロアセトキシ）ヨード］ベンゼン、オキソン（登録商標）等が挙げられる。反応温度は、通常－７８℃～還流温度である。反応時間は、用いる原料物質、溶媒、反応温度などにより異なるが、通常３０分間～３日間である。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 4-1
Compound (If) can be produced by reacting compound (9) with compound (17) in the presence of an oxidizing agent in a solvent. Examples of the solvent used include dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol, water, a mixed solvent thereof and the like. Examples of the oxidizing agent used include iodine, N-chlorosuccinimide, [bis (trifluoroacetoxy) iodo] benzene, and oxone (registered trademark). The reaction temperature is usually −78 ° C. to reflux temperature. The reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days. 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４－２
　化合物（Ｉｇ）は、一般的なエステル基のカルボキシ基への変換方法で化合物（Ｉｆ）を処理することにより製造することができる。本工程は、前記工程１－５に準じて実施することができる。 Step 4-2
Compound (Ig) can be produced by treating compound (If) by a general method for converting an ester group to a carboxy group. This step can be performed according to the above step 1-5.

工程４－３
　化合物（Ｉｈ）は、化合物（Ｉｆ）をＮ－アルキル化することにより製造することができる。本工程は、前記工程１－６に準じて実施することができる。 Step 4-3
Compound (Ih) can be produced by N-alkylating compound (If). This step can be performed according to the above step 1-6.

工程４－４
　化合物（Ｉｉ）は、一般的なエステル基のカルボキシ基への変換方法で化合物（Ｉｈ）を処理することにより製造することができる。本工程は、前記工程１－５に準じて実施することができる。 Step 4-4
Compound (Ii) can be produced by treating compound (Ih) by a general method for converting an ester group to a carboxy group. This step can be performed according to the above step 1-5.

上記に示したスキームは、本発明の化合物（Ｉ）またはその製造中間体を製造する為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 illustration of a method for producing the compound (I) of the present invention 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、常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 introduction and desorption operations according to a conventional method. Regarding the type, introduction and elimination of the protecting group, see, for example, Theodora W. Green & Peter G. M.方法 Wuts, edited by “Greene's Protective Groups in Organic Synthesis”, fourth edition, Wiley-Interscience, 2006.

　本発明の化合物（Ｉ）またはその薬理学的に許容される塩、および当該化合物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 compound (I) of the present invention or a pharmacologically acceptable salt thereof, and an intermediate used for producing the compound, if necessary, are isolated and purified well known to those skilled in the art. It can be isolated and purified by means such as solvent extraction, crystallization / recrystallization, chromatography, preparative high performance liquid chromatography, and the like.

　本発明の化合物（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、用法に応じ種々の剤形のものが使用される。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。 The pharmaceutical composition containing the compound (I) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient may be used in various dosage forms depending on the usage. 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.

　これらの医薬組成物は、その剤形に応じて公知の手法により、適切な賦形剤、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、溶解補助剤等の医薬品添加物と適宜混合または希釈・溶解することにより調剤することができる。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とＥＰ１受容体拮抗薬以外の薬剤とを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。 These pharmaceutical compositions are prepared according to known methods depending on the dosage form, using appropriate excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents. It can be prepared by appropriately mixing or diluting / dissolving with pharmaceutical additives such as emulsifiers, dispersants, stabilizers, and solubilizing agents. In the case of combined use of compound (I) or a pharmaceutically acceptable non-salt and EP 1 receptor antagonist agents of the present invention, simultaneously or separately each of active ingredients, and the aforementioned It can manufacture by formulating similarly.

　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、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、本発明の化合物（Ｉ）は、細胞内カルシウム濃度を低下させることができる。したがって、本発明の化合物（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。 Compound (I) or a pharmaceutically acceptable salt of the present invention exhibit a strong EP 1 receptor antagonism in the EP 1 receptor antagonistic activity confirmatory test and the like. Therefore, the compound (I) of the present invention can reduce the intracellular calcium concentration. Therefore, the pharmaceutical composition containing the compound (I) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient is used for the treatment of a disease or symptom caused by the activation of EP 1 receptor by PGE 2 stimulating action. It can be used as a medicine or a prophylactic.

　また、ＰＧＥ２刺激作用によるＥＰ１受容体を活性化させる疾患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。本発明の化合物（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、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い。より好ましくは、ＬＵＴＳである。 Examples of diseases that activate the EP 1 receptor by PGE 2 stimulation include lower urinary tract symptoms (LUTS), inflammatory diseases, pain diseases, osteoporosis, cancer, and the like. The pharmaceutical composition containing the compound (I) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient is preferably used as a therapeutic or prophylactic agent for LUTS, inflammatory disease or pain disease. . More preferably, it is LUTS.

　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、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、蓄尿症状、排尿症状、排尿後症状等を意味する。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、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 urine storage symptoms, urination symptoms, post-urination symptoms, and the like. The compound (I) of the present invention 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、尿失禁（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）、および膀胱知覚（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）が含まれる。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、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、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である。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。 "Urine accumulation symptoms" include urinary urgency, daytime frequent urination, night frequent urination, urinary incontinence (such as stress urinary incontinence, urge urinary incontinence, mixed urinary incontinence, enuresis, nocturia, persistent urinary incontinence), and Bladder perception (increased bladder perception, decreased bladder perception, lack of bladder perception, nonspecific bladder perception, etc.) is included. Compound (I) of the present invention or a pharmacologically acceptable salt thereof is urinary urgency, daytime frequent urination, nocturia, urge urinary incontinence, mixed urinary incontinence, enuresis, nocturia, increased bladder perception, or It is preferably used for the treatment or prevention of nonspecific bladder perception. More preferred are urinary urgency, daytime frequent urination, nocturia, urge incontinence, or increased bladder perception. 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.

　本発明の化合物（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。 The compound (I) of the present invention or a pharmacologically acceptable salt thereof can also be used in appropriate combination with at least one drug other than the EP 1 receptor antagonist.

　本発明の化合物（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受容体拮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。より好ましくは、抗コリン薬、α１アンタゴニスト、βアゴニスト、平滑筋直接作用薬または三環系抗うつ薬である。さらに好ましくは、抗コリン薬、α１アンタゴニストまたは三環系抗うつ薬である。最も好ましくは、抗コリン薬である。 Examples of the drug that can be used in combination with the compound (I) of the present invention or a pharmacologically acceptable salt thereof include overactive bladder (OAB), prostatic hypertrophy (PD) having a mechanism of action different from that of the EP 1 receptor antagonist. BPH), cystitis such as interstitial cystitis, and therapeutic agents for prostatitis and the like. 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, TRPV1 modulators, endothelin antagonists, 5-HT 1A antagonists, α 1 agonists, opioid agonists, P 2 X antagonists, COX inhibitors, σ agonists, muscarinic agonists, etc. It is. 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. More preferred are anticholinergic agents, α 1 antagonists, β agonists, smooth muscle direct acting agents or tricyclic antidepressants. More preferred are anticholinergic agents, α 1 antagonists or tricyclic antidepressants. Most preferred is an anticholinergic agent.

　また、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が、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。 Moreover, although the chemical | medical agent used in combination is illustrated concretely as follows, the content of this invention is 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、トルテロジン、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。好ましくは、オキシブチニン、プロピベリン、ソリフェナシン、トルテロジンまたはイミダフェナシンである。より好ましくは、ソリフェナシンまたはイミダフェナシンである。 Examples of the “anticholinergic agent” include oxybutynin, propiverine, solifenacin, tolterodine, imidafenacin, temiverine, darifenacin, fesoterodine, trospium, propantheline and the like. Oxybutynin, propiverine, solifenacin, tolterodine or imidafenacin is preferable. More preferred is solifenacin or imidafenacin.

　「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。好ましくは、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、テラゾシンまたはフェデュキソシンである。より好ましくは、タムスロシン、シロドシンまたはプラゾシンである。さらに好ましくはタムスロシンまたはシロドシンである。最も好ましくは、シロドシンである。 Examples of the “α 1 antagonist” include urapidil, naphthopidyl, tamsulosin, silodosin, prazosin, terazosin, alfuzosin, doxazosin, CR-2991, feduxin and the like. Preferably, urapidil, naphthopidyl, tamsulosin, silodosin, prazosin, terazosin or feduxin. More preferred is tamsulosin, silodosin or prazosin. More preferred is tamsulosin or silodosin. Most preferred is silodosin.

　「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。好ましくは、ミラベグロンまたはＫＵＣ－７４８３である。より好ましくは、ミラベグロンである。 Examples of the “β agonist” include mirabegron, KUC-7383, KRP-204, SM-350300, TRK-380, amibegron, clenbuterol, SAR-150640, sorabegron and the like. Mirabegron or KUC-7383 is preferred. More preferred is mirabegron.

　「５α－リダクターゼ阻害剤」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。好ましくは、デュタステリドまたはイゾンステリドである。 Examples of the “5α-reductase inhibitor” include dutasteride, TF-505, finasteride, and izonsteride. Preferred is dutasteride or 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。好ましくは、タダラフィル、バルデナフィル、シルデナフィルまたはアバナフィルである。 “PDE inhibitor” means a phosphodiesterase inhibitor, and examples thereof include tadalafil, vardenafil, sildenafil, avanafil, UK-369003, T-0156, AKP-002, etazolate and the like. Tadalafil, vardenafil, sildenafil or avanafil is preferred.

　「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、プロピベリン、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, propiverine, temiverine, PD-299685, alanidipine, azelnidipine, varnidipine, benidipine, bevantolol, clevidipine, CYC-381, diltiazem, efonidipine, fasudil, felodipine, gabamil Rasidipine, lercanidipine, romeridine, manidipine, MEM-1003, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, SB-751689, verapamil, YM-58483, ziconotide and the like.

　「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。好ましくは、イミプラミンである。 Examples of “tricyclic antidepressants” include imipramine, clomipramine, amitriptyline and the like. Preferably, imipramine is used.

　「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－」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。 “H 1 blocker” includes acribastine, alcaftadine, bepotastine, bilastine, cetirizine, desloratadine, ebastine, efletirizine, epinastine, fexofenadine, GSK-835726, levocabastine, levocetirizine, loratadine, mequitadine, mizolastine, NBI-7, 43 Examples thereof include ReN-1869, terfenadine, UCB-35440, bapitazine, 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、パゴクロン、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, pagoclone, 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、カプサイシン、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 capsaicin, resiniferatoxin, DE-096, GRC-6221, AMG-8562, JTS-653, SB-705498, A-4256619, A-784168, ABT-102, AMG-628. AZD-1386, JNJ-17203212, NGD-8243, PF-38664086, SAR-115740, SB-784443, 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, dibotentan, 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.

　本発明の化合物（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、本発明の医薬組成物は、以下の１）～５）：
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、および
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
から選択される何れか１つの投与方法を含む。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 invention or a pharmacologically acceptable salt thereof and one or more of the above drugs are used in combination, the pharmaceutical composition of the present invention comprises the following 1) to 5):
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,
It includes any one administration method selected from 4) administration at different times by the same route of administration as separate formulations, and 5) administration at different times by different routes of administration as separate formulations. Moreover, when administering at different time as a separate formulation like 4) or 5), there is no restriction | limiting in particular about the administration order of the compound (I) of this invention, and said agent.

　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、１種類またはそれ以上の上記薬剤と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回避または軽減させることができる。 In addition, the compound (I) of the present invention or a pharmacologically acceptable salt thereof can be used in combination with one or more of the above drugs as appropriate, thereby providing an additive effect in preventing or treating the above diseases. The above advantageous effects can be obtained. Or similarly, the amount of use can be reduced compared with the case of using it alone, or the side effect of the combined drug can be avoided or reduced.

　本発明の医薬組成物は、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。 The pharmaceutical composition of the present invention can be administered systemically or locally, orally or parenterally (nasal, pulmonary, intravenous, rectal, subcutaneous, intramuscular, transdermal, etc.).

　本発明の医薬組成物を実際の治療に用いる場合、その有効成分である本発明の化合物（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１日当たり概ね３～１０００ｍｇ、６～５４０ｍｇまたは１０～１００ｍｇ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。注射剤の場合、成人１日当たり概ね０．１～３００ｍｇ、１～１００ｍｇまたは３～３０ｍｇ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。また、本発明のＥＰ１受容体拮抗薬の有効成分である化合物（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 of the present invention is used for actual treatment, the dose of the compound (I) of the present invention, which is an active ingredient thereof, or a pharmacologically acceptable salt thereof depends on the age, sex, body weight, disease of the patient. It is appropriately determined depending on the degree of treatment. For example, in the case of oral administration, it can be appropriately administered in one or several divided doses within the range of about 3 to 1000 mg, 6 to 540 mg or 10 to 100 mg per adult day. In the case of an injection, it can be appropriately administered in a single dose or divided into several doses within the range of about 0.1 to 300 mg, 1 to 100 mg, or 3 to 30 mg per day for an adult. The dose of compound (I), which is an active ingredient of the EP 1 receptor antagonist of the present invention, or a pharmacologically acceptable salt thereof depends on the dose of a drug other than the EP 1 receptor antagonist. You can lose weight.

　以下、本発明を実施例、参考例および試験例にて更に詳細に説明するが、本発明の範囲はこれらに限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, and Test Examples, but the scope of the present invention is not limited thereto.

　各参考例、各実施例、各表中で用いている記号のうち、Ｒｅｆ．Ｎｏ．は参考例番号、Ｅｘ．Ｎｏ．は実施例番号、Ｓｔｒ．は構造式、Ｐ．Ｄ．は物性値、１Ｈ－ＮＭＲは水素核核磁気共鳴スペクトルを意味し、ＣＤＣｌ３はクロロホルム－ｄ、ＤＭＳＯ－ｄ６はジメチルスルホキシド－ｄ６を意味する。また、ＥＳＩ－ＭＳはエレクトロスプレーイオン化法により測定した質量分析スペクトルデータを意味する。 Of the symbols used in each reference example, each example, and each table, Ref. No. Are reference example numbers, Ex. No. Is an example number, Str. Is the structural formula, P.I. D. Physical property values, 1 H-NMR means hydrogen jittery magnetic resonance spectrum, CDCl 3 chloroform -d, DMSO-d 6 means dimethylsulfoxide -d 6. ESI-MS means mass spectral data measured by electrospray ionization.

参考例１
　Step１：アルゴン雰囲気下、１－メチルシクロプロパンカルボン酸（５．００ｇ）のジクロロメタン（３０ｍＬ）溶液を氷－飽和食塩水浴中で冷却した。そこへ塩化オキサリル（４．７１ｍＬ）を８回に分けて５分おきに滴下し、その混合物を同条件下２時間、次いで室温にて１８時間攪拌した。反応混合物を下記Step２で使用した。
　Step２：アルゴン雰囲気下、Ｎ，Ｏ－ジメチルヒドロキシルアミン塩酸塩（４．８７ｇ）のジクロロメタン（５０ｍＬ）懸濁液を氷水浴中で冷却した。そこへトリエチルアミン（２４．４ｍＬ）、次いでStep１で得た反応混合物を加えた。その混合物を室温にて２４時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。有機層を分離し、飽和炭酸水素ナトリウム水溶液で洗浄した。有機層にシリカゲルを加え、その混合物を室温にて２時間攪拌した。不溶物を濾別し、ジエチルエーテル／ジクロロメタン（１／１）で洗浄した。濾液を減圧下濃縮することにより、Ｎ－メトキシ－Ｎ，１－ジメチルシクロプロパンカルボキサミド（６．８１ｇ）を得た。 Reference example 1
Step 1: A solution of 1-methylcyclopropanecarboxylic acid (5.00 g) in dichloromethane (30 mL) was cooled in an ice-saturated saline bath under an argon atmosphere. Thereto, oxalyl chloride (4.71 mL) was added dropwise in 5 portions every 5 minutes, and the mixture was stirred under the same conditions for 2 hours and then at room temperature for 18 hours. The reaction mixture was used in Step 2 below.
Step 2: A suspension of N, O-dimethylhydroxylamine hydrochloride (4.87 g) in dichloromethane (50 mL) was cooled in an ice-water bath under an argon atmosphere. Thereto was added triethylamine (24.4 mL), and then the reaction mixture obtained in Step 1. The mixture was stirred at room temperature for 24 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was separated and washed with saturated aqueous sodium bicarbonate. Silica gel was added to the organic layer and the mixture was stirred at room temperature for 2 hours. The insoluble material was filtered off and washed with diethyl ether / dichloromethane (1/1). The filtrate was concentrated under reduced pressure to obtain N-methoxy-N, 1-dimethylcyclopropanecarboxamide (6.81 g).

参考例２
　アルゴン雰囲気下、（５－メトキシ－２－メチルフェニル）カルバミン酸ｔｅｒｔ－ブチル（２．００ｇ）のテトラヒドロフラン（４２ｍＬ）溶液に、ｓｅｃ－ブチルリチウム（１．０８ｍｏｌ／Ｌヘキサン－シクロヘキサン溶液、２２ｍＬ）を－４５℃にてゆっくり滴下し、その混合物を同条件下４５分間攪拌した。そこへＮ－メトキシ－Ｎ，１－ジメチルシクロプロパンカルボキサミド（１．３３ｇ）のテトラヒドロフラン（４．２ｍＬ）溶液を滴下し、その混合物を－４５℃にて４５分間、次いで室温にて３時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、｛５－メトキシ－２－［２－（１－メチルシクロプロピル）－２－オキソエチル］フェニル｝カルバミン酸ｔｅｒｔ－ブチル（１．７７ｇ）を得た。　　　 Reference example 2
Under an argon atmosphere, sec-butyllithium (1.08 mol / L hexane-cyclohexane solution, 22 mL) was added to a tetrahydrofuran (42 mL) solution of tert-butyl (5-methoxy-2-methylphenyl) carbamate (2.00 g). The solution was slowly added dropwise at −45 ° C., and the mixture was stirred for 45 minutes under the same conditions. Thereto was added dropwise a solution of N-methoxy-N, 1-dimethylcyclopropanecarboxamide (1.33 g) in tetrahydrofuran (4.2 mL), and the mixture was stirred at −45 ° C. for 45 minutes and then at room temperature for 3 hours. . A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give {5-methoxy-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamic acid tert -Butyl (1.77 g) was obtained.

参考例３
　アルゴン雰囲気下、　{５－メトキシ－２－[２－（１－メチルシクロプロピル）－２－オキソエチル]フェニル}カルバミン酸ｔｅｒｔ－ブチル（１．００ｇ）のＮ，Ｎ－ジメチルホルムアミド（１５．７ｍＬ）溶液を氷水浴中で冷却した。そこへ水素化ナトリウム（５０－７２％　ｉｎ　ｏｉｌ，１５８ｍｇ）を２回に分けて加え、その混合物を同条件下１時間攪拌した。そこへ６－（クロロメチル）ピリジン－２－カルボン酸メチル（５８２ｍｇ）を３回に分けて加え、その混合物を室温にて１４時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、酢酸エチルで抽出した。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－メトキシフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝ピリジン－２－カルボン酸メチル（９５９ｍｇ）を得た。　　　 Reference example 3
N, N-dimethylformamide (15.7 mL) of tert-butyl {5-methoxy-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamate (1.00 g) under argon atmosphere The solution was cooled in an ice water bath. Thereto was added sodium hydride (50-72% in oil, 158 mg) in two portions, and the mixture was stirred for 1 hour under the same conditions. Thereto was added methyl 6- (chloromethyl) pyridine-2-carboxylate (582 mg) in three portions, and the mixture was stirred at room temperature for 14 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- {2- [2- (tert-butoxycarbonylamino) -4-methoxyphenyl] -3- (1- Methylcyclopropyl) -3-oxopropyl} pyridine-2-carboxylate methyl (959 mg) was obtained.

参考例４
　５－ブロモ－２－メチルアニリン（３．５１ｇ）、シクロプロピルボロン酸一水和物（２．５５ｇ）、トリシクロヘキシルホスフィン（約０．６ｍｏｌ／Ｌトルエン溶液、３．１４ｍＬ）、リン酸三カリウム一水和物（１５．２ｇ）、トルエン（５２．４ｍＬ）及び水（５．２４ｍＬ）の混合物に、酢酸パラジウム（ＩＩ）（２１２ｍｇ）を加え、その混合物を１００℃にて１３時間攪拌した。反応混合物を放冷し、セライト（登録商標）パッドを通じ濾過した。そのパッドを酢酸エチル（１００ｍＬ）で洗浄した。濾液を水／飽和食塩水（１／１）で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、５－シクロプロピル－２－メチルアニリン（２．２５ｇ）を得た。　 Reference example 4
5-Bromo-2-methylaniline (3.51 g), cyclopropylboronic acid monohydrate (2.55 g), tricyclohexylphosphine (approximately 0.6 mol / L toluene solution, 3.14 mL), tripotassium phosphate To a mixture of monohydrate (15.2 g), toluene (52.4 mL) and water (5.24 mL) was added palladium (II) acetate (212 mg) and the mixture was stirred at 100 ° C. for 13 hours. The reaction mixture was allowed to cool and filtered through a Celite® pad. The pad was washed with ethyl acetate (100 mL). The filtrate was washed with water / saturated brine (1/1). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane) to give 5-cyclopropyl-2-methylaniline (2.25 g).

参考例５　
　５－シクロプロピル－２－メチルアニリン（２．２５ｇ）及び二炭酸ジｔｅrt－ブチル（３．６７ｇ）のテトラヒドロフラン（３０．６ｍＬ）溶液を、還流下２８時間攪拌した。反応混合物を放冷し、減圧下濃縮した。残渣をアミノプロピル化シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、（５－シクロプロピル－２－メチルフェニル）カルバミン酸ｔｅｒｔ－ブチル（３．６７ｇ）を得た。 Reference Example 5
A solution of 5-cyclopropyl-2-methylaniline (2.25 g) and ditert-butyl dicarbonate (3.67 g) in tetrahydrofuran (30.6 mL) was stirred under reflux for 28 hours. The reaction mixture was allowed to cool and concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to obtain tert-butyl (5-cyclopropyl-2-methylphenyl) carbamate (3.67 g).

参考例６
　アルゴン雰囲気下、（５－シクロプロピル－２－メチルフェニル）カルバミン酸ｔｅｒｔ－ブチル（１．００ｇ）のテトラヒドロフラン（２０．２ｍＬ）溶液に、ｓｅｃ－ブチルリチウム（１．０８ｍｏｌ／Ｌヘキサン－シクロヘキサン溶液、１０．５ｍＬ）を－４５℃にてゆっくり滴下し、その混合物を同条件下４５分間攪拌した。そこへＮ－メトキシ－Ｎ，１－ジメチルシクロプロパンカルボキサミド（６３７ｍｇ）のテトラヒドロフラン（２．０２ｍＬ）溶液を滴下し、その混合物を－４５℃にて４０分間、次いで室温にて３．５時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、｛５－シクロプロピル－２－[２－（１－メチルシクロプロピル）－２－オキソエチル]フェニル｝カルバミン酸ｔｅｒｔ－ブチル（８７６ｍｇ）を得た。　　　 Reference Example 6
Under an argon atmosphere, sec-butyllithium (1.08 mol / L hexane-cyclohexane solution) was added to a solution of tert-butyl (5-cyclopropyl-2-methylphenyl) carbamate (1.00 g) in tetrahydrofuran (20.2 mL). 10.5 mL) was slowly added dropwise at −45 ° C., and the mixture was stirred for 45 minutes under the same conditions. Thereto was added dropwise a solution of N-methoxy-N, 1-dimethylcyclopropanecarboxamide (637 mg) in tetrahydrofuran (2.02 mL), and the mixture was stirred at −45 ° C. for 40 minutes and then at room temperature for 3.5 hours. . A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give {5-cyclopropyl-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamic acid. Tert-butyl (876 mg) was obtained.

参考例７　
　アルゴン雰囲気下、｛５－シクロプロピル－２－[２－（１－メチルシクロプロピル）－２－オキソエチル]フェニル｝カルバミン酸ｔｅｒｔ－ブチル（５１５ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５．２ｍＬ）溶液を氷水浴中で冷却した。そこへ水素化ナトリウム（５０－７２％　ｉｎ　ｏｉｌ，８３ｍｇ）を加えた。その混合物を室温にて１時間攪拌した後、再び氷水浴中で冷却した。そこへ６－（クロロメチル）ピリジン－２－カルボン酸メチル（３２０ｍｇ）を２回に分けて加え、その混合物を室温にて７時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－シクロプロピルフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝ピリジン－２－カルボン酸メチル（５５１ｍｇ）を得た。　　　 Reference Example 7
A solution of tert-butyl {5-cyclopropyl-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamate (515 mg) in N, N-dimethylformamide (5.2 mL) under an argon atmosphere Was cooled in an ice-water bath. Thereto was added sodium hydride (50-72% in oil, 83 mg). The mixture was stirred at room temperature for 1 hour and then cooled again in an ice-water bath. Thereto was added methyl 6- (chloromethyl) pyridine-2-carboxylate (320 mg) in two portions, and the mixture was stirred at room temperature for 7 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- {2- [2- (tert-butoxycarbonylamino) -4-cyclopropylphenyl] -3- (1 -Methylcyclopropyl) -3-oxopropyl} pyridine-2-carboxylate methyl ester (551 mg) was obtained.

参考例８
　アルゴン雰囲気下、（５－クロロ－２－メチルフェニル）カルバミン酸ｔｅｒｔ－ブチル（１．００ｇ）のテトラヒドロフラン（２０．７ｍＬ）溶液に、ｓｅｃ－ブチルリチウム（１．０８ｍｏｌ／Ｌヘキサン－シクロヘキサン溶液、１０．７ｍＬ）を－４５℃にてゆっくり滴下し、その混合物を同条件下４５分間攪拌した。そこへＮ－メトキシ－Ｎ，１－ジメチルシクロプロパンカルボキサミド（６５２ｍｇ）のテトラヒドロフラン（２．０７ｍＬ）溶液を滴下し、その混合物を－４５℃にて５０分間、次いで室温にて３時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、｛５－クロロ－２－[２－（１－メチルシクロプロピル）－２－オキソエチル]フェニル｝カルバミン酸ｔｅｒｔ－ブチル（１．０６ｇ）を得た。 Reference Example 8
Under an argon atmosphere, sec-butyl lithium (1.08 mol / L hexane-cyclohexane solution) was added to a tetrahydrofuran (20.7 mL) solution of tert-butyl (5-chloro-2-methylphenyl) carbamate (1.00 g). 7 mL) was slowly added dropwise at −45 ° C., and the mixture was stirred for 45 minutes under the same conditions. Thereto was added dropwise a solution of N-methoxy-N, 1-dimethylcyclopropanecarboxamide (652 mg) in tetrahydrofuran (2.07 mL), and the mixture was stirred at −45 ° C. for 50 minutes and then at room temperature for 3 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give {5-chloro-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamic acid tert -Butyl (1.06 g) was obtained.

参考例９
　アルゴン雰囲気下、｛５－クロロ－２－[２－（１－メチルシクロプロピル）－２－オキソエチル]フェニル｝カルバミン酸ｔｅｒｔ－ブチル（７５２ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（７．７ｍＬ）溶液を氷水浴中で冷却した。そこへ水素化ナトリウム（５０－７２％　ｉｎ　ｏｉｌ，１２３ｍｇ）を加えた。その混合物を室温にて１時間攪拌した後、再び氷水浴中で冷却した。そこへ６－（クロロメチル）ピリジン－２－カルボン酸メチル（４７４ｍｇ）を４回に分けて加え、その混合物を室温にて３時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－クロロフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝ピリジン－２－カルボン酸メチル（７８８ｍｇ）を得た。 Reference Example 9
Under an argon atmosphere, a solution of tert-butyl {5-chloro-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamate (752 mg) in N, N-dimethylformamide (7.7 mL) was added. Cooled in an ice-water bath. To this was added sodium hydride (50-72% in oil, 123 mg). The mixture was stirred at room temperature for 1 hour and then cooled again in an ice-water bath. Thereto was added methyl 6- (chloromethyl) pyridine-2-carboxylate (474 mg) in four portions, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- {2- [2- (tert-butoxycarbonylamino) -4-chlorophenyl] -3- (1-methyl Cyclopropyl) -3-oxopropyl} pyridine-2-carboxylate methyl ester (788 mg) was obtained.

参考例１０
　アルゴン雰囲気下、（２，５－ジメチルフェニル）カルバミン酸ｔｅｒｔ－ブチル（８７７ｍｇ）のテトラヒドロフラン（１９．８ｍＬ）溶液に、ｓｅｃ－ブチルリチウム（１．０８ｍｏｌ／Ｌヘキサン－シクロヘキサン溶液、１０．３ｍＬ）を－４５℃にてゆっくり滴下し、その混合物を同条件下３５分間攪拌した。そこへＮ－メトキシ－Ｎ，１－ジメチルシクロプロパンカルボキサミド（６２４ｍｇ）のテトラヒドロフラン（１．９８ｍＬ）溶液を滴下し、その混合物を－４５℃にて３０分間、次いで室温にて２時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、｛５－メチル－２－[２－（１－メチルシクロプロピル）－２－オキソエチル]フェニル｝カルバミン酸ｔｅｒｔ－ブチル（７２４ｍｇ）を得た。 Reference Example 10
Under an argon atmosphere, sec-butyllithium (1.08 mol / L hexane-cyclohexane solution, 10.3 mL) was added to a solution of tert-butyl (2,5-dimethylphenyl) carbamate (877 mg) in tetrahydrofuran (19.8 mL). The solution was slowly added dropwise at −45 ° C., and the mixture was stirred for 35 minutes under the same conditions. Thereto was added dropwise a solution of N-methoxy-N, 1-dimethylcyclopropanecarboxamide (624 mg) in tetrahydrofuran (1.98 mL), and the mixture was stirred at −45 ° C. for 30 minutes and then at room temperature for 2 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give {5-methyl-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamic acid tert -Butyl (724 mg) was obtained.

参考例１１
　アルゴン雰囲気下、｛５－メチル－２－[２－（１－メチルシクロプロピル）－２－オキソエチル]フェニル｝カルバミン酸ｔｅｒｔ－ブチル（４１７ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（４．６ｍＬ）溶液を氷水浴中で冷却した。そこへ水素化ナトリウム（５０－７２％　ｉｎ　ｏｉｌ，７３ｍｇ）を加えた。その混合物を室温にて１時間攪拌した後、再び氷水浴中で冷却した。そこへ６－（クロロメチル）ピリジン－２－カルボン酸メチル（２８１ｍｇ）を２回に分けて加え、その混合物を室温にて３．５時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、酢酸エチルで抽出した。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－メチルフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝ピリジン－２－カルボン酸メチル（４３５ｍｇ）を得た。 Reference Example 11
Under an argon atmosphere, a solution of tert-butyl {5-methyl-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamate (417 mg) in N, N-dimethylformamide (4.6 mL) was added. Cooled in an ice-water bath. Thereto was added sodium hydride (50-72% in oil, 73 mg). The mixture was stirred at room temperature for 1 hour and then cooled again in an ice-water bath. Thereto was added methyl 6- (chloromethyl) pyridine-2-carboxylate (281 mg) in two portions, and the mixture was stirred at room temperature for 3.5 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- {2- [2- (tert-butoxycarbonylamino) -4-methylphenyl] -3- (1- Methyl cyclopropyl) -3-oxopropyl} pyridine-2-carboxylate (435 mg) was obtained.

参考例１２
　４－メチル－３－ニトロフェノール（２．００ｇ）のＮ，Ｎ－ジメチルホルムアミド（２０ｍＬ）溶液に、炭酸カリウム（３．６１ｇ）及びヨウ化エチル（３．０６ｇ）のＮ，Ｎ－ジメチルホルムアミド（６．１ｍＬ）溶液を加え、その混合物を室温にて４時間攪拌した。反応混合物を水で希釈し、次いで酢酸エチルで抽出した。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮することにより、４－エトキシ－１－メチル－２－ニトロベンゼン（２．３６ｇ）を得た。 Reference Example 12
To a solution of 4-methyl-3-nitrophenol (2.00 g) in N, N-dimethylformamide (20 mL) was added potassium carbonate (3.61 g) and ethyl iodide (3.06 g) in N, N-dimethylformamide ( 6.1 mL) solution was added and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 4-ethoxy-1-methyl-2-nitrobenzene (2.36 g).

参考例１３
　４－エトキシ－１－メチル－２－ニトロベンゼン（２．３６ｇ）の酢酸エチル（６５．３ｍＬ）溶液に、１０％パラジウム炭素（含水率５６．５ｗｔ％，５４３ｍｇ）を加え、その混合物を水素雰囲気下、室温にて４時間攪拌した。反応混合物をセライト（登録商標）パッドを通じ濾過した。濾液を減圧下濃縮することにより、５－エトキシ－２－メチルアニリン（１．８７ｇ）を得た。 Reference Example 13
To a solution of 4-ethoxy-1-methyl-2-nitrobenzene (2.36 g) in ethyl acetate (65.3 mL) was added 10% palladium carbon (water content 56.5 wt%, 543 mg), and the mixture was placed under a hydrogen atmosphere. And stirred at room temperature for 4 hours. The reaction mixture was filtered through a Celite® pad. The filtrate was concentrated under reduced pressure to give 5-ethoxy-2-methylaniline (1.87 g).

参考例１４
　対応する出発物質及び反応剤を用い、参考例５と同様の方法で、（５－エトキシ－２－メチルフェニル）カルバミン酸ｔｅｒｔ－ブチルを合成した。 Reference Example 14
Tert-butyl (5-ethoxy-2-methylphenyl) carbamate was synthesized in the same manner as in Reference Example 5 using the corresponding starting materials and reactants.

参考例１５
　対応する出発物質及び反応剤を用い、参考例２と同様の方法で、｛５－エトキシ－２－［２－（１－メチルシクロプロピル）－２－オキソエチル］フェニル｝カルバミン酸ｔｅｒｔ－ブチルを合成した。 Reference Example 15
Synthesis of tert-butyl {5-ethoxy-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamate using the corresponding starting materials and reagents in the same manner as in Reference Example 2 did.

参考例１６　
　対応する出発物質及び反応剤を用い、参考例３と同様の方法で、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－エトキシフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝ピリジン－２－カルボン酸メチルを合成した。 Reference Example 16
6- {2- [2- (tert-Butoxycarbonylamino) -4-ethoxyphenyl] -3- (1-methylcyclopropyl) was prepared in the same manner as in Reference Example 3 using the corresponding starting materials and reactants. Methyl -3-oxopropyl} pyridine-2-carboxylate was synthesized.

参考例１７
　４－メチル－３－ニトロフェノール（２．００ｇ）のＮ，Ｎ－ジメチルホルムアミド（２０ｍＬ）溶液に、炭酸カリウム（３．６１ｇ）及びヨウ化イソプロピル（３．３３ｇ）のＮ，Ｎ－ジメチルホルムアミド（６．１ｍＬ）溶液を加え、その混合物を室温にて１５時間攪拌した。反応混合物を水で希釈し、次いで酢酸エチルで抽出した。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮することにより、４－イソプロポキシ－１－メチル－２－ニトロベンゼン（２．５１ｇ）を得た。 Reference Example 17
To a solution of 4-methyl-3-nitrophenol (2.00 g) in N, N-dimethylformamide (20 mL) was added potassium carbonate (3.61 g) and isopropyl iodide (3.33 g) in N, N-dimethylformamide ( 6.1 mL) solution was added and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4-isopropoxy-1-methyl-2-nitrobenzene (2.51 g).

参考例１８
　４－イソプロポキシ－１－メチル－２－ニトロベンゼン（２．５１ｇ）の酢酸エチル（６５．３ｍＬ）溶液に、１０％パラジウム炭素（含水率５６．５ｗｔ％，５７７ｍｇ）を加え、その混合物を水素雰囲気下、室温にて７時間攪拌した。反応混合物をセライト（登録商標）パッドを通じ濾過した。濾液を減圧下濃縮することにより、５－イソプロポキシ－２－メチルアニリン（２．１１ｇ）を得た。 Reference Example 18
To a solution of 4-isopropoxy-1-methyl-2-nitrobenzene (2.51 g) in ethyl acetate (65.3 mL) was added 10% palladium on carbon (water content 56.5 wt%, 577 mg), and the mixture was added to a hydrogen atmosphere. The mixture was stirred at room temperature for 7 hours. The reaction mixture was filtered through a Celite® pad. The filtrate was concentrated under reduced pressure to give 5-isopropoxy-2-methylaniline (2.11 g).

参考例１９
　対応する出発物質及び反応剤を用い、参考例５と同様の方法で、（５－イソプロポキシ－２－メチルフェニル）カルバミン酸ｔｅｒｔ－ブチルを合成した。 Reference Example 19
Tert-butyl (5-isopropoxy-2-methylphenyl) carbamate was synthesized in the same manner as in Reference Example 5 using the corresponding starting materials and reactants.

参考例２０
　対応する出発物質及び反応剤を用い、参考例２と同様の方法で、｛５－イソプロポキシ－２－［２－（１－メチルシクロプロピル）－２－オキソエチル］フェニル｝カルバミン酸ｔｅｒｔ－ブチルを合成した。 Reference Example 20
Using corresponding starting materials and reagents, tert-butyl {5-isopropoxy-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamate was prepared in the same manner as in Reference Example 2. Synthesized.

参考例２１　
　対応する出発物質及び反応剤を用い、参考例３と同様の方法で、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－イソプロポキシフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝ピリジン－２－カルボン酸メチルを合成した。 Reference Example 21
6- {2- [2- (tert-Butoxycarbonylamino) -4-isopropoxyphenyl] -3- (1-methylcyclopropyl) was prepared in the same manner as in Reference Example 3 using the corresponding starting materials and reactants. ) -3-oxopropyl} pyridine-2-carboxylate methyl ester was synthesized.

参考例２２
　２－クロロ－５－メチル－４－ニトロアニソール（２ｇ）の酢酸エチル（５０ｍＬ）溶液に、氷冷下、５％白金炭素（４００ｍｇ）を加え、その混合物を水素雰囲気下、室温にて６時間攪拌した。反応混合物をセライト（登録商標）パッドを通じ濾過した。濾液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、５－クロロ－４－メトキシ－２－メチルアニリン（１．４６ｇ）を得た。 Reference Example 22
To a solution of 2-chloro-5-methyl-4-nitroanisole (2 g) in ethyl acetate (50 mL) was added 5% platinum carbon (400 mg) under ice cooling, and the mixture was allowed to stand at room temperature for 6 hours under a hydrogen atmosphere. Stir. The reaction mixture was filtered through a Celite® pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane) to give 5-chloro-4-methoxy-2-methylaniline (1.46 g).

参考例２３
　５－クロロ－４－メトキシ－２－メチルアニリン（１．４６ｇ）及び二炭酸ジｔｅｒｔ－ブチル（２．０４ｇ）のテトラヒドロフラン（１５ｍＬ）溶液を、還流下４．５時間攪拌した。反応混合物を放冷し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、（５－クロロ－４－メトキシ－２－メチルフェニル）カルバミン酸ｔｅｒｔ－ブチル（２．１７ｇ）を得た。 Reference Example 23
A solution of 5-chloro-4-methoxy-2-methylaniline (1.46 g) and ditert-butyl dicarbonate (2.04 g) in tetrahydrofuran (15 mL) was stirred under reflux for 4.5 hours. The reaction mixture was allowed to cool and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to obtain tert-butyl (5-chloro-4-methoxy-2-methylphenyl) carbamate (2.17 g).

参考例２４
　アルゴン雰囲気下、（５－クロロ－４－メトキシ－２－メチルフェニル）カルバミン酸ｔｅｒｔ－ブチル（２．１７ｇ）のテトラヒドロフラン（４０ｍＬ）溶液に、ｓｅｃ－ブチルリチウム（１．０２ｍｏｌ／Ｌヘキサン－シクロヘキサン溶液、１９．７ｍＬ）を－４０℃にてゆっくり滴下し、その混合物を同条件下１５分間攪拌した。そこへＮ－メトキシ－Ｎ，１－ジメチルシクロプロパンカルボキサミド（１．２６ｇ）のテトラヒドロフラン（４ｍＬ）溶液を滴下し、その混合物を－４０℃にて１５分間、次いで室温にて１時間攪拌した。反応混合物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し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、｛５－クロロ－４－メトキシ－２－[２－（１－メチルシクロプロピル）－２－オキソエチル]フェニル｝カルバミン酸ｔｅｒｔ－ブチル（２．４６ｇ）を得た。 Reference Example 24
Under an argon atmosphere, sec-butyllithium (1.02 mol / L hexane-cyclohexane solution) was added to a tetrahydrofuran (40 mL) solution of tert-butyl (5-chloro-4-methoxy-2-methylphenyl) carbamate (2.17 g). , 19.7 mL) was slowly added dropwise at −40 ° C., and the mixture was stirred for 15 minutes under the same conditions. Thereto was added dropwise a solution of N-methoxy-N, 1-dimethylcyclopropanecarboxamide (1.26 g) in tetrahydrofuran (4 mL), and the mixture was stirred at −40 ° C. for 15 minutes and then at room temperature for 1 hour. 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, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give {5-chloro-4-methoxy-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl. } Tert-Butyl carbamate (2.46 g) was obtained.

参考例２５　
　アルゴン雰囲気下、｛５－クロロ－４－メトキシ－２－[２－（１－メチルシクロプロピル）－２－オキソエチル]フェニル｝カルバミン酸ｔｅｒｔ－ブチル（０．２ｇ）のＮ，Ｎ－ジメチルホルムアミド（２ｍＬ）溶液を氷水浴中で冷却した。そこへ水素化ナトリウム（５０－７２％　ｉｎ　ｏｉｌ，２９ｍｇ）を加えた。その混合物を同条件下３０分間攪拌した。そこへ６－（クロロメチル）ピリジン－２－カルボン酸メチル（１０５ｍｇ）を加え、その混合物を同条件下１時間攪拌した。反応混合物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。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－クロロ－５－メトキシフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝ピリジン－２－カルボン酸メチル（１９２ｍｇ）を得た。　　　 Reference Example 25
Under an argon atmosphere, tert-butyl {5-chloro-4-methoxy-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamate (0.2 g) in N, N-dimethylformamide ( (2 mL) The solution was cooled in an ice-water bath. To this was added sodium hydride (50-72% in oil, 29 mg). The mixture was stirred for 30 minutes under the same conditions. Thereto was added methyl 6- (chloromethyl) pyridine-2-carboxylate (105 mg), and the mixture was stirred for 1 hour under the same conditions. 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 successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- {2- [2- (tert-butoxycarbonylamino) -4-chloro-5-methoxyphenyl] -3. There was obtained methyl-(1-methylcyclopropyl) -3-oxopropyl} pyridine-2-carboxylate (192 mg).

参考例２６
　１－（４－メチル－３－ニトロフェニル）エタノン（２．００ｇ）のエタノール／テトラヒドロフラン（１５ｍＬ／７．５ｍＬ）溶液に、水素化ほう素ナトリウム（２１１ｍｇ）を加え、その混合物を室温にて１０分間攪拌した。反応混合物に０．５ｍｏｌ／Ｌ塩酸、次いで水を加え、その混合物を酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮することにより、１－（４－メチル－３－ニトロフェニル）エタノール（１．９６ｇ）を得た。 Reference Example 26
To a solution of 1- (4-methyl-3-nitrophenyl) ethanone (2.00 g) in ethanol / tetrahydrofuran (15 mL / 7.5 mL) was added sodium borohydride (211 mg), and the mixture was stirred at room temperature for 10 minutes. Stir for minutes. 0.5 mol / L hydrochloric acid and then water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 1- (4-methyl-3-nitrophenyl) ethanol (1.96 g). It was.

参考例２７
　１－（４－メチル－３－ニトロフェニル）エタノール（１．９６ｇ）の酢酸エチル（５５ｍＬ）溶液に、１０％パラジウム炭素（含水率５６．５ｗｔ％，９０１ｍｇ）を加え、その混合物を水素雰囲気下、室温にて７時間攪拌した。反応混合物をセライト（登録商標）パッドを通じ濾過した。濾液を減圧下濃縮することにより、５－（１－ヒドロキシエチル）－２－メチルアニリン（１．６０ｇ）を得た。 Reference Example 27
To a solution of 1- (4-methyl-3-nitrophenyl) ethanol (1.96 g) in ethyl acetate (55 mL) was added 10% palladium carbon (water content 56.5 wt%, 901 mg), and the mixture was placed under a hydrogen atmosphere. And stirred at room temperature for 7 hours. The reaction mixture was filtered through a Celite® pad. The filtrate was concentrated under reduced pressure to obtain 5- (1-hydroxyethyl) -2-methylaniline (1.60 g).

参考例２８
　５－（１－ヒドロキシエチル）－２－メチルアニリン（１．６０ｇ）及び二炭酸ジｔｅrt－ブチル（２．５３ｇ）のテトラヒドロフラン（２１．２ｍＬ）溶液を、還流下２６時間攪拌した。反応混合物を放冷し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、［５－（１－ヒドロキシエチル）－２－メチルフェニル］カルバミン酸ｔｅｒｔ－ブチル（２．４０ｇ）を得た。 Reference Example 28
A solution of 5- (1-hydroxyethyl) -2-methylaniline (1.60 g) and ditert-butyl dicarbonate (2.53 g) in tetrahydrofuran (21.2 mL) was stirred under reflux for 26 hours. The reaction mixture was allowed to cool and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give tert-butyl [5- (1-hydroxyethyl) -2-methylphenyl] carbamate (2.40 g). .

参考例２９
　［５－（１－ヒドロキシエチル）－２－メチルフェニル］カルバミン酸ｔｅｒｔ－ブチル（２．３９ｇ）の酢酸エチル（４７．５ｍＬ）溶液に、１０％パラジウム炭素（含水率５６．５ｗｔ％，１．１０ｇ）を加え、その混合物を水素雰囲気下、室温にて６時間攪拌した。反応混合物をセライト（登録商標）パッドを通じ濾過した。濾液を減圧下濃縮することにより、（５－エチル－２－メチルフェニル）カルバミン酸ｔｅｒｔ－ブチル（２．２３ｇ）を得た。 Reference Example 29
To a solution of tert-butyl [5- (1-hydroxyethyl) -2-methylphenyl] carbamate (2.39 g) in ethyl acetate (47.5 mL) was added 10% palladium on carbon (water content 56.5 wt%, 1. 10 g) was added and the mixture was stirred for 6 hours at room temperature under hydrogen atmosphere. The reaction mixture was filtered through a Celite® pad. The filtrate was concentrated under reduced pressure to obtain tert-butyl (5-ethyl-2-methylphenyl) carbamate (2.23 g).

参考例３０
　対応する出発物質及び反応剤を用い、参考例２と同様の方法で、｛５－エチル－２－[２－（１－メチルシクロプロピル）－２－オキソエチル]フェニル｝カルバミン酸ｔｅｒｔ－ブチルを合成した。 Reference Example 30
Synthesis of tert-butyl {5-ethyl-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamate using the corresponding starting materials and reactants in the same manner as in Reference Example 2 did.

参考例３１
　対応する出発物質及び反応剤を用い、参考例３と同様の方法で、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－エチルフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝ピリジン－２－カルボン酸メチルを合成した。 Reference Example 31
6- {2- [2- (tert-Butoxycarbonylamino) -4-ethylphenyl] -3- (1-methylcyclopropyl) was prepared in the same manner as in Reference Example 3 using the corresponding starting materials and reactants. Methyl -3-oxopropyl} pyridine-2-carboxylate was synthesized.

参考例３２
　１－（１－メチルシクロプロピル）エタノン（１．１０ｇ）のメタノール（１０ｍL）溶液を氷水浴中で冷却した。そこへ臭素（０．６０９ｍL）を滴下し、その混合物を室温にて７０分間攪拌した。反応混合物に水を加え、その混合物を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、減圧下濃縮することにより、２－ブロモ－１－（１－メチルシクロプロピル）エタノン（１．９８ｇ）を得た。 Reference Example 32
A solution of 1- (1-methylcyclopropyl) ethanone (1.10 g) in methanol (10 mL) was cooled in an ice-water bath. Bromine (0.609 mL) was added dropwise thereto, and the mixture was stirred at room temperature for 70 minutes. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 2-bromo-1- (1-methylcyclopropyl) ethanone (1.98 g).

参考例３３
　４－クロロ－３－メトキシアニリン（２．１２ｇ）のエタノール（２．２ｍＬ）溶液を還流下で攪拌した。そこへ２－ブロモ－１－（１－メチルシクロプロピル）エタノン（７２２ｍｇ）のエタノール（２．２ｍＬ）溶液を滴下し、その混合物を還流下５時間攪拌した。反応混合物を放冷した。反応混合物に２ｍｏｌ／Ｌ塩酸を加え、その混合物を酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、水及び飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、５－クロロ－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール（４４９ｍｇ）を得た。　　　 Reference Example 33
A solution of 4-chloro-3-methoxyaniline (2.12 g) in ethanol (2.2 mL) was stirred under reflux. Thereto was added dropwise a solution of 2-bromo-1- (1-methylcyclopropyl) ethanone (722 mg) in ethanol (2.2 mL), and the mixture was stirred under reflux for 5 hours. The reaction mixture was allowed to cool. 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane) to give 5-chloro-6-methoxy-2- (1-methylcyclopropyl) -1H-indole (449 mg).

参考例３４
　２－ニトロ－ｐ－シメン（２．００ｇ）の酢酸エチル（５５．８ｍＬ）溶液に、１０％パラジウム炭素（含水率５６．５ｗｔ％，９２０ｍｇ）を加え、その混合物を水素雰囲気下、室温にて２．５時間攪拌した。反応混合物をセライト（登録商標）パッドを通じ濾過した。濾液を減圧下濃縮することにより、５－イソプロピル－２－メチルアニリン（１．７６ｇ）を得た。 Reference Example 34
To a solution of 2-nitro-p-cymene (2.00 g) in ethyl acetate (55.8 mL) was added 10% palladium carbon (moisture content 56.5 wt%, 920 mg), and the mixture was allowed to stand at room temperature under a hydrogen atmosphere. Stir for 2.5 hours. The reaction mixture was filtered through a Celite® pad. The filtrate was concentrated under reduced pressure to give 5-isopropyl-2-methylaniline (1.76 g).

参考例３５
　対応する出発物質及び反応剤を用い、参考例２３と同様の方法で、（５－イソプロピル－２－メチルフェニル）カルバミン酸ｔｅｒｔ－ブチルを合成した。 Reference Example 35
Using corresponding starting materials and reactants, tert-butyl (5-isopropyl-2-methylphenyl) carbamate was synthesized in the same manner as in Reference Example 23.

参考例３６
　対応する出発物質及び反応剤を用い、参考例２と同様の方法で、｛５－イソプロピル－２－[２－（１－メチルシクロプロピル）－２－オキソエチル]フェニル｝カルバミン酸ｔｅｒｔ－ブチルを合成した。 Reference Example 36
Synthesis of tert-butyl {5-isopropyl-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamate in the same manner as in Reference Example 2 using corresponding starting materials and reactants did.

参考例３７
　対応する出発物質及び反応剤を用い、参考例３と同様の方法で、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－イソプロピルフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝ピリジン－２－カルボン酸メチルを合成した。 Reference Example 37
6- {2- [2- (tert-Butoxycarbonylamino) -4-isopropylphenyl] -3- (1-methylcyclopropyl) was prepared in the same manner as in Reference Example 3 using the corresponding starting materials and reactants. Methyl -3-oxopropyl} pyridine-2-carboxylate was synthesized.

参考例３８
　３－メトキシ－４－メチルアニリン（２．２６ｇ）のエタノール（７ｍＬ）溶液を、還流下、攪拌した。そこへ２－ブロモ－１－（１－メチルシクロプロピル）エタノン（８８５ｍｇ）のエタノール（３ｍＬ）溶液を滴下し、その混合物を還流下３時間攪拌した。反応混合物を放冷した。反応混合物に１ｍｏｌ／Ｌ塩酸を加え、その混合物を酢酸エチルで抽出した。有機層を１ｍｏｌ／Ｌ塩酸、飽和炭酸水素ナトリウム水溶液及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、６－メトキシ－５－メチル－２－（１－メチルシクロプロピル）－１Ｈ－インドール（５８８ｍｇ）を得た。 Reference Example 38
A solution of 3-methoxy-4-methylaniline (2.26 g) in ethanol (7 mL) was stirred under reflux. Thereto was added dropwise a solution of 2-bromo-1- (1-methylcyclopropyl) ethanone (885 mg) in ethanol (3 mL), and the mixture was stirred under reflux for 3 hours. The reaction mixture was allowed to cool. 1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1 mol / L hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane) to give 6-methoxy-5-methyl-2- (1-methylcyclopropyl) -1H-indole (588 mg).

参考例３９
　対応する出発物質及び反応剤を用い、参考例３８と同様の方法で、５－フルオロ－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドールを合成した。 Reference Example 39
5-Fluoro-6-methoxy-2- (1-methylcyclopropyl) -1H-indole was synthesized in the same manner as in Reference Example 38 using the corresponding starting materials and reactants.

参考例４０
　アルゴン雰囲気下、{５－シクロプロピル－２－[２－（１－メチルシクロプロピル）－２－オキソエチル]フェニル}カルバミン酸ｔｅｒｔ－ブチル（２５０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（２．５ｍＬ）溶液を氷水浴中で冷却した。そこへ水素化ナトリウム（５０－７２％　ｉｎ　ｏｉｌ，３８ｍｇ）を加え、その混合物を同条件下３５分間攪拌した。そこへ３－（ブロモメチル）安息香酸メチル（１９１ｍｇ）を加え、その混合物を同条件下８０分間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、酢酸エチルで抽出した。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、３－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－シクロプロピルフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝安息香酸メチル（２６０ｍｇ）を得た。 Reference Example 40
A solution of tert-butyl {5-cyclopropyl-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamate (250 mg) in N, N-dimethylformamide (2.5 mL) under an argon atmosphere Was cooled in an ice-water bath. Sodium hydride (50-72% in oil, 38 mg) was added thereto, and the mixture was stirred for 35 minutes under the same conditions. Thereto was added methyl 3- (bromomethyl) benzoate (191 mg), and the mixture was stirred for 80 minutes under the same conditions. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 3- {2- [2- (tert-butoxycarbonylamino) -4-cyclopropylphenyl] -3- (1 -Methylcyclopropyl) -3-oxopropyl} methyl benzoate (260 mg) was obtained.

参考例４１
　アルゴン雰囲気下、{５－シクロプロピル－２－[２－（１－メチルシクロプロピル）－２－オキソエチル]フェニル}カルバミン酸ｔｅｒｔ－ブチル（２５０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（２．５ｍＬ）溶液を氷水浴中で冷却した。そこへ水素化ナトリウム（５０－７２％　ｉｎ　ｏｉｌ，３８ｍｇ）を加え、その混合物を同条件下３５分間攪拌した。そこへ５－（クロロメチル）フラン－２－カルボン酸エチル（０．１２７ｍL）を加え、その混合物を同条件下８０分間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、その混合物を酢酸エチルで抽出した。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、５－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－シクロプロピルフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝フラン－２－カルボン酸エチル（２９０ｍｇ）を得た。 Reference Example 41
A solution of tert-butyl {5-cyclopropyl-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamate (250 mg) in N, N-dimethylformamide (2.5 mL) under an argon atmosphere Was cooled in an ice-water bath. Sodium hydride (50-72% in oil, 38 mg) was added thereto, and the mixture was stirred for 35 minutes under the same conditions. Thereto was added ethyl 5- (chloromethyl) furan-2-carboxylate (0.127 mL), and the mixture was stirred for 80 minutes under the same conditions. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 5- {2- [2- (tert-butoxycarbonylamino) -4-cyclopropylphenyl] -3- (1 -Methylcyclopropyl) -3-oxopropyl} furan-2-carboxylate (290 mg) was obtained.

参考例４２
　２－フルオロ－３－メチル安息香酸（５００ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（７ｍＬ）溶液に、炭酸カリウム（５３８ｍｇ）及びヨウ化メチル（０．２４２ｍＬ）を順次加え、その混合物を室温にて６１時間攪拌した。反応混合物に水を加え、その混合物を酢酸エチルで抽出した。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮することにより、２－フルオロ－３－メチル安息香酸メチル（４９８ｍｇ）を得た。 Reference Example 42
To a solution of 2-fluoro-3-methylbenzoic acid (500 mg) in N, N-dimethylformamide (7 mL), potassium carbonate (538 mg) and methyl iodide (0.242 mL) were sequentially added, and the mixture was added at room temperature. Stir for hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give methyl 2-fluoro-3-methylbenzoate (498 mg).

参考例４３
　２－フルオロ－３－メチル安息香酸メチル（４９５ｍｇ）の四塩化炭素（１５ｍＬ）溶液に、Ｎ－ブロモこはく酸イミド（５５０ｍｇ）及び過酸化ジベンゾイル（約２５％水湿潤品，４８ｍｇ）を加え、その混合物を還流下１５時間攪拌した。反応混合物を放冷し、濾過した。濾液を減圧下濃縮した。残渣をシリカゲルカラムクロマトフラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、３－（ブロモメチル）－２－フルオロ安息香酸メチル（４１１ｍｇ）を得た。 Reference Example 43
To a solution of methyl 2-fluoro-3-methylbenzoate (495 mg) in carbon tetrachloride (15 mL) was added N-bromosuccinimide (550 mg) and dibenzoyl peroxide (about 25% water-wet product, 48 mg). The mixture was stirred at reflux for 15 hours. The reaction mixture was allowed to cool and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to obtain methyl 3- (bromomethyl) -2-fluorobenzoate (411 mg).

参考例４４
　アルゴン雰囲気下、{５－シクロプロピル－２－[２－（１－メチルシクロプロピル）－２－オキソエチル]フェニル}カルバミン酸ｔｅｒｔ－ブチル（２５０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（２．５ｍＬ）溶液を氷水浴中で冷却した。そこへ水素化ナトリウム（５０－７２％　ｉｎ　ｏｉｌ，３８ｍｇ）を加え、その混合物を同条件下４０分間攪拌した。そこへ３－（ブロモメチル）－２－フルオロ安息香酸メチル（２０６ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１ｍＬ）溶液を加え、その混合物を同条件下８０分間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、その混合物を酢酸エチルで抽出した。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、３－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－シクロプロピルフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝－２－フルオロ安息香酸メチル（３１９ｍｇ）を得た。 Reference Example 44
A solution of tert-butyl {5-cyclopropyl-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamate (250 mg) in N, N-dimethylformamide (2.5 mL) under an argon atmosphere Was cooled in an ice-water bath. Thereto was added sodium hydride (50-72% in oil, 38 mg), and the mixture was stirred for 40 minutes under the same conditions. Thereto was added a solution of methyl 3- (bromomethyl) -2-fluorobenzoate (206 mg) in N, N-dimethylformamide (1 mL), and the mixture was stirred for 80 minutes under the same conditions. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 3- {2- [2- (tert-butoxycarbonylamino) -4-cyclopropylphenyl] -3- (1 -Methylcyclopropyl) -3-oxopropyl} -2-fluorobenzoic acid methyl ester (319 mg) was obtained.

参考例４５
　アルゴン雰囲気下、トリフルオロ酢酸（２．５ｍＬ）に、｛５－シクロプロピル－２－[２－（１－メチルシクロプロピル）－２－オキソエチル]フェニル｝カルバミン酸ｔｅｒｔ－ブチル（２５０ｍｇ）を加え、その混合物を室温にて１時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液及び飽和食塩水で順次洗浄した。有機層を無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をアミノプロピル化シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール（１３５ｍｇ）を得た。 Reference Example 45
Under an argon atmosphere, tert-butyl {5-cyclopropyl-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamate (250 mg) was added to trifluoroacetic acid (2.5 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (eluent: ethyl acetate-hexane) to give 6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indole (135 mg).

参考例４６　
　ピリジン－２，４－ジカルボン酸水和物（２．００ｇ）のメタノール（５４ｍＬ）懸濁液を室温にて攪拌した。そこへ塩化チオニル（１．９７ｍＬ）をゆっくり滴下した。その混合物を還流下１６時間攪拌した。反応混合物を放冷し、減圧下濃縮した。残渣に飽和炭酸水素ナトリウム水溶液を注意深く加え、酢酸エチルで抽出した。有機層を水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮することにより、ピリジン－２，４－ジカルボン酸ジメチル（１．６４ｇ）を得た。 Reference Example 46
A suspension of pyridine-2,4-dicarboxylic acid hydrate (2.00 g) in methanol (54 mL) was stirred at room temperature. Thionyl chloride (1.97 mL) was slowly added dropwise thereto. The mixture was stirred at reflux for 16 hours. The reaction mixture was allowed to cool and concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was carefully added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain dimethyl pyridine-2,4-dicarboxylate (1.64 g).

参考例４７
　ピリジン－２，４－ジカルボン酸ジメチル（１．６４ｇ）のメタノール／ジクロロメタン（１４ｍＬ／７ｍＬ）溶液を氷水浴中で冷却した。そこへ水素化ほう素ナトリウム（３５０ｍｇ）を５回に分けて加えた。その混合物を同条件下２時間、次いで室温にて１２時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加えた。その混合物を室温にて１時間攪拌し、次いでジクロロメタンで抽出した。水層をジクロロメタンで抽出した。水層に飽和食塩水を加え、その混合物をジクロロメタンで抽出した。有機層を合一し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：メタノール－酢酸エチル）にて精製することにより、２－（ヒドロキシメチル）イソニコチン酸メチル（４７５ｍｇ）を得た。 Reference Example 47
A solution of dimethyl pyridine-2,4-dicarboxylate (1.64 g) in methanol / dichloromethane (14 mL / 7 mL) was cooled in an ice-water bath. Thereto was added sodium borohydride (350 mg) in 5 portions. The mixture was stirred under the same conditions for 2 hours and then at room temperature for 12 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture. The mixture was stirred at room temperature for 1 hour and then extracted with dichloromethane. The aqueous layer was extracted with dichloromethane. Saturated brine was added to the aqueous layer, and the mixture was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol-ethyl acetate) to give methyl 2- (hydroxymethyl) isonicotinate (475 mg).

参考例４８
　アルゴン雰囲気下、２－（ヒドロキシメチル）イソニコチン酸メチル（２８３ｍｇ）の酢酸エチル（３．４ｍＬ）溶液を氷水浴中で冷却した。そこへトリエチルアミン（０．２８３ｍＬ）、次いで塩化メタンスルホニル（０．１４４ｍＬ）を加え、その混合物を同条件下２時間攪拌した。反応混合物をセライト（登録商標）パッドを通じ濾過した。濾液に臭化リチウム一水和物（５３３ｍｇ）を加え、その混合物を５０℃にて２．５時間攪拌した。反応混合物を放冷した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、２－（ブロモメチル）イソニコチン酸メチル（３７０ｍｇ）を得た。 Reference Example 48
Under an argon atmosphere, a solution of methyl 2- (hydroxymethyl) isonicotinate (283 mg) in ethyl acetate (3.4 mL) was cooled in an ice-water bath. Triethylamine (0.283 mL) and then methanesulfonyl chloride (0.144 mL) were added thereto, and the mixture was stirred for 2 hours under the same conditions. The reaction mixture was filtered through a Celite® pad. Lithium bromide monohydrate (533 mg) was added to the filtrate, and the mixture was stirred at 50 ° C. for 2.5 hours. The reaction mixture was allowed to cool. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane) to give methyl 2- (bromomethyl) isonicotinate (370 mg).

参考例４９
　アルゴン雰囲気下、　{５－メトキシ－２－[２－（１－メチルシクロプロピル）－２－オキソエチル]フェニル}カルバミン酸ｔｅｒｔ－ブチル（２００ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３．１ｍＬ）溶液を氷水浴中で冷却した。そこへ水素化ナトリウム（５０－７２％　ｉｎ　ｏｉｌ，３２ｍｇ）を加え、その混合物を同条件下７５分間攪拌した。そこへ２－（ブロモメチル）イソニコチン酸メチル（１４４ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１．１ｍＬ）溶液を滴下し、その混合物を同条件下３０分間、次いで室温にて３時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、酢酸エチルで抽出した。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、２－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－メトキシフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝イソニコチン酸メチル（１９２ｍｇ）を得た。 Reference Example 49
Under an argon atmosphere, a solution of tert-butyl {5-methoxy-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamate (200 mg) in N, N-dimethylformamide (3.1 mL) was added. Cooled in an ice-water bath. Sodium hydride (50-72% in oil, 32 mg) was added thereto, and the mixture was stirred for 75 minutes under the same conditions. Thereto was added dropwise a solution of methyl 2- (bromomethyl) isonicotinate (144 mg) in N, N-dimethylformamide (1.1 mL), and the mixture was stirred under the same conditions for 30 minutes and then at room temperature for 3 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 2- {2- [2- (tert-butoxycarbonylamino) -4-methoxyphenyl] -3- (1- Methylcyclopropyl) -3-oxopropyl} isonicotinic acid methyl ester (192 mg) was obtained.

参考例５０
　５－ホルミルチオフェン－２－カルボン酸（１．００ｇ）のＮ，Ｎ－ジメチルホルムアミド（１５ｍＬ）溶液に、炭酸ナトリウム（３．３３ｇ）及びヨウ化エチル（１ｍＬ）を加え、その混合物を３０℃にて１３時間攪拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を水及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮することにより、５－ホルミルチオフェン－２－カルボン酸エチル（９６９ｍｇ）を得た。 Reference Example 50
To a solution of 5-formylthiophene-2-carboxylic acid (1.00 g) in N, N-dimethylformamide (15 mL) was added sodium carbonate (3.33 g) and ethyl iodide (1 mL), and the mixture was brought to 30 ° C. And stirred for 13 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give ethyl 5-formylthiophene-2-carboxylate (969 mg).

参考例５１
　アルゴン雰囲気下、｛５－メトキシ－２－[２－（１－メチルシクロプロピル）－２－オキソエチル]フェニル｝カルバミン酸ｔｅｒｔ－ブチル（３００ｍｇ）のジクロロメタン（４．８ｍＬ）溶液を氷水浴中で冷却した。そこへトリフルオロ酢酸（１．６ｍＬ）を加え、その混合物を室温にて４．５時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液及び飽和食塩水で順次洗浄した。有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をアミノプロピル化シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール（１４２ｍｇ）を得た。 Reference Example 51
A solution of tert-butyl {5-methoxy-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamate (300 mg) in dichloromethane (4.8 mL) was cooled in an ice-water bath under an argon atmosphere. did. Trifluoroacetic acid (1.6 mL) was added there, and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6-methoxy-2- (1-methylcyclopropyl) -1H-indole (142 mg).

参考例５２
　アルゴン雰囲気下、カリウムｔｅｒｔ－ブトキシド（５．３７ｇ）のテトラヒドロフラン（４８ｍＬ）懸濁液に、塩化シクロプロパンカルボニル（４．３５ｍＬ）のテトラヒドロフラン（７．２ｍＬ）溶液を滴下し、その混合物を室温にて２８時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、ジエチルエーテルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮することにより、シクロプロパンカルボン酸ｔｅｒｔ－ブチル（３．１２ｇ）を得た。 Reference Example 52
Under a argon atmosphere, a solution of cyclopropanecarbonyl chloride (4.35 mL) in tetrahydrofuran (7.2 mL) was added dropwise to a suspension of potassium tert-butoxide (5.37 g) in tetrahydrofuran (48 mL), and the mixture was added at room temperature. Stir for 28 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain tert-butyl cyclopropanecarboxylate (3.12 g).

参考例５３
　アルゴン雰囲気下、ジイソプロピルアミン（２．６６ｇ）のテトラヒドロフラン（２００ｍＬ）溶液に、ｎ－ブチルリチウム（２．６９ｍｏｌ／Ｌヘキサン溶液、９．７９ｍＬ）を－７８℃にて滴下し、その混合物を－７８℃にて３０分間攪拌した。そこへシクロプロパンカルボン酸ｔｅｒｔ－ブチル（３．１２ｇ）のテトラヒドロフラン（２０ｍＬ）溶液を滴下し、その混合物を－７８℃にて２時間攪拌した。そこへ臭化エチル（５．９８ｇ）を滴下した。その混合物を－７８℃にてさらに３時間攪拌し、徐々に室温まで昇温した。１４時間後、反応混合物に飽和塩化アンモニウム水溶液を加え、ジエチルエーテルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧下濃縮することにより、１－エチルシクロプロパンカルボン酸ｔｅｒｔ－ブチル（２．１６ｇ）を得た。 Reference Example 53
Under an argon atmosphere, n-butyllithium (2.69 mol / L hexane solution, 9.79 mL) was added dropwise to a solution of diisopropylamine (2.66 g) in tetrahydrofuran (200 mL) at −78 ° C., and the mixture was added to −78 ° C. Stir at 30 ° C. for 30 minutes. Thereto was added dropwise a solution of tert-butyl cyclopropanecarboxylate (3.12 g) in tetrahydrofuran (20 mL), and the mixture was stirred at −78 ° C. for 2 hours. Ethyl bromide (5.98 g) was added dropwise thereto. The mixture was stirred at −78 ° C. for a further 3 hours and gradually warmed to room temperature. After 14 hours, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain tert-butyl 1-ethylcyclopropanecarboxylate (2.16 g).

参考例５４
　１－エチルシクロプロパンカルボン酸ｔｅｒｔ－ブチル（２．１６ｇ）にトリフルオロ酢酸（１．６８ｍＬ）を室温にて加え、その混合物を還流下５時間攪拌した。反応混合物を放冷した。反応混合物に２ｍｏｌ／Ｌ水酸化ナトリウム水溶液を加えて塩基性とし、ジエチルエーテルで抽出した。水層に１ｍｏｌ／Ｌ塩酸を加えて酸性とし、ジエチルエーテルで抽出した。有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮することにより、１－エチルシクロプロパンカルボン酸（１．３０ｇ）を得た。 Reference Example 54
To tert-butyl 1-ethylcyclopropanecarboxylate (2.16 g) was added trifluoroacetic acid (1.68 mL) at room temperature, and the mixture was stirred under reflux for 5 hours. The reaction mixture was allowed to cool. The reaction mixture was basified with 2 mol / L aqueous sodium hydroxide solution and extracted with diethyl ether. The aqueous layer was acidified with 1 mol / L hydrochloric acid and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1-ethylcyclopropanecarboxylic acid (1.30 g).

参考例５５
　Step１：アルゴン雰囲気下、１－エチルシクロプロパンカルボン酸（１．２９ｇ）のジクロロメタン（６．８ｍＬ）溶液を氷－飽和食塩水浴中で冷却した。そこへ塩化オキサリル（１．０６ｍＬ）を３回に分けて５分おきに滴下し、その混合物を同条件下２時間、次いで室温にて１６時間攪拌した。反応混合物を下記Step２で使用した。
　Step２：アルゴン雰囲気下、Ｎ，Ｏ－ジメチルヒドロキシルアミン塩酸塩（１．１０ｇ）のジクロロメタン（１１．３ｍＬ）懸濁液を氷水浴中で冷却した。そこへトリエチルアミン（５．５２ｍＬ）、次いでStep１で得た反応混合物を加えた。その混合物を同条件下１．５時間、次いで室温にて２５時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。有機層を分離し、飽和炭酸水素ナトリウム水溶液で洗浄した。有機層にシリカゲルを加え、その混合物を室温にて４５分間攪拌した。不溶物を濾別し、ジエチルエーテル／ジクロロメタン（１／１）で洗浄した。濾液を減圧下濃縮することにより、１－エチル－Ｎ－メトキシ－Ｎ－メチルシクロプロパンカルボキサミド（１．１４ｇ）を得た。 Reference Example 55
Step 1: A solution of 1-ethylcyclopropanecarboxylic acid (1.29 g) in dichloromethane (6.8 mL) was cooled in an ice-saturated saline bath under an argon atmosphere. Thereto, oxalyl chloride (1.06 mL) was added dropwise in 3 portions every 5 minutes, and the mixture was stirred under the same conditions for 2 hours and then at room temperature for 16 hours. The reaction mixture was used in Step 2 below.
Step 2: A suspension of N, O-dimethylhydroxylamine hydrochloride (1.10 g) in dichloromethane (11.3 mL) was cooled in an ice-water bath under an argon atmosphere. Thereto was added triethylamine (5.52 mL), and then the reaction mixture obtained in Step 1. The mixture was stirred under the same conditions for 1.5 hours and then at room temperature for 25 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was separated and washed with saturated aqueous sodium bicarbonate. Silica gel was added to the organic layer and the mixture was stirred at room temperature for 45 minutes. The insoluble material was filtered off and washed with diethyl ether / dichloromethane (1/1). The filtrate was concentrated under reduced pressure to obtain 1-ethyl-N-methoxy-N-methylcyclopropanecarboxamide (1.14 g).

参考例５６
　アルゴン雰囲気下、（５－メトキシ－２－メチルフェニル）カルバミン酸ｔｅｒｔ－ブチル（７１１ｍｇ）のテトラヒドロフラン（１５ｍＬ）溶液に、ｓｅｃ－ブチルリチウム（１．０８ｍｏｌ／Ｌヘキサン－シクロヘキサン溶液、７．８ｍＬ）を－４５℃にてゆっくり滴下し、その混合物を同条件下３０分間攪拌した。そこへ１－エチル－Ｎ－メトキシ－Ｎ－メチルシクロプロパンカルボキサミド（４７２ｍｇ）のテトラヒドロフラン（１．５ｍＬ）溶液を滴下し、その混合物を－４５℃にて３０分間、次いで室温にて２時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、｛２－［２－（１－エチルシクロプロピル）－２－オキソエチル］－５－メトキシフェニル｝カルバミン酸ｔｅｒｔ－ブチル（４９７ｍｇ）を得た。 Reference Example 56
Under an argon atmosphere, sec-butyllithium (1.08 mol / L hexane-cyclohexane solution, 7.8 mL) was added to a tetrahydrofuran (15 mL) solution of tert-butyl (5-methoxy-2-methylphenyl) carbamate (711 mg). The solution was slowly added dropwise at −45 ° C., and the mixture was stirred for 30 minutes under the same conditions. Thereto was added dropwise a solution of 1-ethyl-N-methoxy-N-methylcyclopropanecarboxamide (472 mg) in tetrahydrofuran (1.5 mL), and the mixture was stirred at −45 ° C. for 30 minutes and then at room temperature for 2 hours. . A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give {2- [2- (1-ethylcyclopropyl) -2-oxoethyl] -5-methoxyphenyl} carbamic acid tert -Butyl (497 mg) was obtained.

参考例５７
　アルゴン雰囲気下、{２－[２－（１－エチルシクロプロピル）－２－オキソエチル]－５－メトキシフェニル}カルバミン酸ｔｅｒｔ－ブチル（２７５ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（４．１ｍＬ）溶液を氷水浴中で冷却した。そこへ水素化ナトリウム（５０－７２％　ｉｎ　ｏｉｌ，４２ｍｇ）を加え、その混合物を同条件下７０分間攪拌した。そこへ６－（クロロメチル）ピリジン－２－カルボン酸メチル（１５３ｍｇ）を２回に分けて加え、その混合物を同条件下３０分間、次いで室温にて３時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、酢酸エチルで抽出した。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－メトキシフェニル］－３－（１－エチルシクロプロピル）－３－オキソプロピル｝ピリジン－２－カルボン酸メチル（２５０ｍｇ）を得た。 Reference Example 57
Under an argon atmosphere, a solution of tert-butyl {2- [2- (1-ethylcyclopropyl) -2-oxoethyl] -5-methoxyphenyl} carbamate (275 mg) in N, N-dimethylformamide (4.1 mL) was added. Cooled in an ice-water bath. Sodium hydride (50-72% in oil, 42 mg) was added thereto, and the mixture was stirred for 70 minutes under the same conditions. Thereto was added methyl 6- (chloromethyl) pyridine-2-carboxylate (153 mg) in two portions, and the mixture was stirred under the same conditions for 30 minutes and then at room temperature for 3 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- {2- [2- (tert-butoxycarbonylamino) -4-methoxyphenyl] -3- (1- Ethylcyclopropyl) -3-oxopropyl} pyridine-2-carboxylate methyl ester (250 mg) was obtained.

参考例５８
　対応する出発物質及び反応剤を用い、参考例４０と同様の方法で、３－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－メトキシフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝安息香酸メチルを合成した。 Reference Example 58
3- {2- [2- (tert-butoxycarbonylamino) -4-methoxyphenyl] -3- (1-methylcyclopropyl) was prepared in the same manner as in Reference Example 40 using the corresponding starting materials and reactants. Methyl -3-oxopropyl} benzoate was synthesized.

参考例５９
　対応する出発物質及び反応剤を用い、参考例４１と同様の方法で、５－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－メトキシフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝フラン－２－カルボン酸エチルを合成した。 Reference Example 59
5- {2- [2- (tert-butoxycarbonylamino) -4-methoxyphenyl] -3- (1-methylcyclopropyl) was prepared in the same manner as in Reference Example 41 using the corresponding starting materials and reagents. Ethyl -3-oxopropyl} furan-2-carboxylate was synthesized.

参考例６０
　対応する出発物質及び反応剤を用い、参考例４４と同様の方法で、３－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－メトキシフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝－２－フルオロ安息香酸メチルを合成した。 Reference Example 60
3- {2- [2- (tert-butoxycarbonylamino) -4-methoxyphenyl] -3- (1-methylcyclopropyl) was prepared in the same manner as in Reference Example 44 using the corresponding starting materials and reactants. Methyl -3-oxopropyl} -2-fluorobenzoate was synthesized.

参考例６１
　１，２，４－トリメチル－５－ニトロベンゼン（２．００ｇ）の酢酸エチル（６０．５ｍＬ）溶液に、１０％パラジウム炭素（含水率５６．５ｗｔ％，９２０ｍｇ）を加え、その混合物を水素雰囲気下、３５℃にて２時間攪拌した。反応混合物をセライト（登録商標）パッドを通じ濾過した。濾液を減圧下濃縮することにより、２，４，５－トリメチルアニリン（１．６２ｇ）を得た。 Reference Example 61
To a solution of 1,2,4-trimethyl-5-nitrobenzene (2.00 g) in ethyl acetate (60.5 mL) was added 10% palladium carbon (water content 56.5 wt%, 920 mg), and the mixture was placed under a hydrogen atmosphere. And stirred at 35 ° C. for 2 hours. The reaction mixture was filtered through a Celite® pad. The filtrate was concentrated under reduced pressure to obtain 2,4,5-trimethylaniline (1.62 g).

参考例６２
　対応する出発物質及び反応剤を用い、参考例５と同様の方法で、（２，４，５－トリメチルフェニル）カルバミン酸ｔｅｒｔ－ブチルを合成した。 Reference Example 62
Tert-butyl (2,4,5-trimethylphenyl) carbamate was synthesized in the same manner as in Reference Example 5 using the corresponding starting materials and reactants.

参考例６３
　アルゴン雰囲気下、（２，４，５－トリメチルフェニル）カルバミン酸ｔｅｒｔ－ブチル（７００ｍｇ）のテトラヒドロフラン（１４．９ｍＬ）溶液に、ｓｅｃ－ブチルリチウム（１．０８ｍｏｌ／Ｌヘキサン－シクロヘキサン溶液、７．７ｍＬ）を－４５℃にてゆっくり滴下し、その混合物を同条件下３０分間攪拌した。そこへＮ－メトキシ－Ｎ，１－ジメチルシクロプロパンカルボキサミド（４６９ｍｇ）のテトラヒドロフラン（１．４９ｍＬ）溶液を滴下し、その混合物を－４５℃にて１時間、次いで室温にて２．５時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、｛４，５－ジメチル－２－［２－（１－メチルシクロプロピル）－２－オキソエチル］フェニル｝カルバミン酸ｔｅｒｔ－ブチル（７２４ｍｇ）を得た。 Reference Example 63
Under argon atmosphere, sec-butyllithium (1.08 mol / L hexane-cyclohexane solution, 7.7 mL) was added to a solution of tert-butyl (2,4,5-trimethylphenyl) carbamate (700 mg) in tetrahydrofuran (14.9 mL). ) Was slowly added dropwise at −45 ° C., and the mixture was stirred for 30 minutes under the same conditions. Thereto was added dropwise a solution of N-methoxy-N, 1-dimethylcyclopropanecarboxamide (469 mg) in tetrahydrofuran (1.49 mL), and the mixture was stirred at −45 ° C. for 1 hour and then at room temperature for 2.5 hours. . A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give {4,5-dimethyl-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamine. Tert-butyl acid (724 mg) was obtained.

参考例６４
　アルゴン雰囲気下、{４，５－ジメチル－２－[２－（１－メチルシクロプロピル）－２－オキソエチル]フェニル}カルバミン酸ｔｅｒｔ－ブチル（２００ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３．２ｍＬ）溶液を氷水浴中で冷却した。そこへ水素化ナトリウム（５０－７２％　ｉｎ　ｏｉｌ，３２ｍｇ）を加え、その混合物を同条件下１時間攪拌した。そこへ６－（クロロメチル）ピリジン－２－カルボン酸メチル（１１７ｍｇ）を２回に分けて加え、その混合物を同条件下３０分間、次いで室温にて２時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、酢酸エチルで抽出した。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４，５－ジメチルフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝ピリジン－２－カルボン酸メチル（２０４ｍｇ）を得た。 Reference Example 64
N, N-dimethylformamide (3.2 mL) of tert-butyl {4,5-dimethyl-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamate (200 mg) under argon atmosphere The solution was cooled in an ice water bath. Sodium hydride (50-72% in oil, 32 mg) was added thereto, and the mixture was stirred for 1 hour under the same conditions. Thereto was added methyl 6- (chloromethyl) pyridine-2-carboxylate (117 mg) in two portions, and the mixture was stirred under the same conditions for 30 minutes and then at room temperature for 2 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- {2- [2- (tert-butoxycarbonylamino) -4,5-dimethylphenyl] -3- ( Methyl 1-methylcyclopropyl) -3-oxopropyl} pyridine-2-carboxylate (204 mg) was obtained.

参考例６５
　３－ジフルオロメトキシアニリン（２．００ｇ）のエタノール（２．０ｍＬ）溶液を、還流下、攪拌した。そこへ２－ブロモ－１－（１－メチルシクロプロピル）エタノン（６７５ｍｇ）のエタノール（２．０ｍＬ）溶液を滴下し、その混合物を還流下１４時間攪拌した。反応混合物を放冷した。反応混合物に２ｍｏｌ／Ｌ塩酸を加え、その混合物を酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液及び飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、６－ジフルオロメトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール（１７４ｍｇ）を得た。 Reference Example 65
A solution of 3-difluoromethoxyaniline (2.00 g) in ethanol (2.0 mL) was stirred under reflux. A solution of 2-bromo-1- (1-methylcyclopropyl) ethanone (675 mg) in ethanol (2.0 mL) was added dropwise thereto, and the mixture was stirred under reflux for 14 hours. The reaction mixture was allowed to cool. 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane) to give 6-difluoromethoxy-2- (1-methylcyclopropyl) -1H-indole (174 mg).

参考例６６
　対応する出発物質及び反応剤を用い、参考例５７と同様の方法で、２－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－シクロプロピルフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝オキサゾール－４－カルボン酸メチルを合成した。 Reference Example 66
2- {2- [2- (tert-butoxycarbonylamino) -4-cyclopropylphenyl] -3- (1-methylcyclopropyl) was prepared in the same manner as in Reference Example 57 using the corresponding starting materials and reactants. ) Methyl 3-oxopropyl} oxazole-4-carboxylate was synthesized.

参考例６７
　２－フルオロ－５－メチル安息香酸（５００ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（７ｍＬ）溶液に、炭酸カリウム（５３８ｍｇ）及びヨウ化メチル（０．２４２ｍＬ）を加え、その混合物を室温にて１６時間攪拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮することにより、２－フルオロ－５－メチル安息香酸メチル（４６２ｍｇ）を得た。 Reference Example 67
To a solution of 2-fluoro-5-methylbenzoic acid (500 mg) in N, N-dimethylformamide (7 mL) was added potassium carbonate (538 mg) and methyl iodide (0.242 mL), and the mixture was stirred at room temperature for 16 hours. Stir. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give methyl 2-fluoro-5-methylbenzoate (462 mg).

参考例６８
　２－フルオロ－５－メチル安息香酸メチル（４６０ｍｇ）の四塩化炭素（１５ｍＬ）溶液に、Ｎ－ブロモこはく酸イミド（５１１ｍｇ）及び過酸化ジベンゾイル（約２５％水湿潤品、４４ｍｇ）を加え、その混合物を還流下１３時間攪拌した。反応混合物を放冷し、濾過した。濾液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、５－（ブロモメチル）－２－フルオロ安息香酸メチル（４２７ｍｇ）を得た。 Reference Example 68
To a solution of methyl 2-fluoro-5-methylbenzoate (460 mg) in carbon tetrachloride (15 mL) was added N-bromosuccinimide (511 mg) and dibenzoyl peroxide (approx. 25% water-wet product, 44 mg). The mixture was stirred at reflux for 13 hours. The reaction mixture was allowed to cool and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane) to give methyl 5- (bromomethyl) -2-fluorobenzoate (427 mg).

参考例６９
　アルゴン雰囲気下、{５－シクロプロピル－２－[２－（１－メチルシクロプロピル）－２－オキソエチル]フェニル}カルバミン酸ｔｅｒｔ－ブチル（１５０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１．５ｍＬ）溶液を氷水浴中で冷却した。そこへ水素化ナトリウム（５０－７２％　ｉｎ　ｏｉｌ，２３ｍｇ）を加え、その混合物を同条件下３５分間攪拌した。そこへ５－（ブロモメチル）－２－フルオロ安息香酸メチル（１２４ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１ｍＬ）溶液を加え、その混合物を同条件下、さらに１時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、その混合物を酢酸エチルで抽出した。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、５－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－シクロプロピルフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝－２－フルオロ安息香酸メチル（１５７ｍｇ）を得た。 Reference Example 69
A solution of tert-butyl {5-cyclopropyl-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamate (150 mg) in N, N-dimethylformamide (1.5 mL) under an argon atmosphere Was cooled in an ice-water bath. Thereto was added sodium hydride (50-72% in oil, 23 mg), and the mixture was stirred for 35 minutes under the same conditions. Thereto was added a solution of methyl 5- (bromomethyl) -2-fluorobenzoate (124 mg) in N, N-dimethylformamide (1 mL), and the mixture was further stirred for 1 hour under the same conditions. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 5- {2- [2- (tert-butoxycarbonylamino) -4-cyclopropylphenyl] -3- (1 -Methylcyclopropyl) -3-oxopropyl} -2-fluorobenzoic acid methyl ester (157 mg) was obtained.

参考例７０
　対応する出発物質及び反応剤を用い、参考例６９と同様の方法で、５－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－メトキシフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝－２－フルオロ安息香酸メチルを合成した。 Reference Example 70
5- {2- [2- (tert-butoxycarbonylamino) -4-methoxyphenyl] -3- (1-methylcyclopropyl) was prepared in the same manner as in Reference Example 69 using the corresponding starting materials and reactants. Methyl -3-oxopropyl} -2-fluorobenzoate was synthesized.

参考例７１
　対応する出発物質及び反応剤を用い、参考例６５と同様の方法で、５，６－ジメトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドールを合成した。 Reference Example 71
5,6-Dimethoxy-2- (1-methylcyclopropyl) -1H-indole was synthesized in the same manner as in Reference Example 65 using the corresponding starting materials and reactants.

参考例７２
　Step1：５－メチルニコチン酸メチル（２０２ｍｇ）の四塩化炭素（４．０ｍＬ）溶液に、Ｎ－ブロモこはく酸イミド（２３８ｍｇ）及び過酸化ジベンゾイル（約２５％水湿潤品、６４ｍｇ）を加え、その混合物を還流下３時間攪拌した。反応混合物を放冷し、濾過した。濾液にＮ，Ｎ－ジメチルホルムアミド（１．０ｍＬ）を加え、減圧下濃縮して四塩化炭素を除去した。得られた溶液をそのまま下記Step2で使用した。
　Step2：アルゴン雰囲気下、{５－メトキシ－２－[２－（１－メチルシクロプロピル）－２－オキソエチル]フェニル}カルバミン酸ｔｅｒｔ－ブチル（３２８ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３．２ｍＬ）溶液を氷水浴中で冷却した。そこへ水素化ナトリウム（５０－７２％　ｉｎ　ｏｉｌ，５２ｍｇ）を加え、その混合物を同条件下３５分間攪拌した。そこへStep1で得た溶液を滴下し、その混合物を同条件下７０分間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、酢酸エチルで抽出した。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、５－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－メトキシフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝ニコチン酸メチル（１５５ｍｇ）を得た。 Reference Example 72
Step1: To a solution of methyl 5-methylnicotinate (202 mg) in carbon tetrachloride (4.0 mL), N-bromosuccinimide (238 mg) and dibenzoyl peroxide (about 25% water-wet product, 64 mg) were added. The mixture was stirred at reflux for 3 hours. The reaction mixture was allowed to cool and filtered. N, N-dimethylformamide (1.0 mL) was added to the filtrate and concentrated under reduced pressure to remove carbon tetrachloride. The obtained solution was directly used in Step 2 below.
Step 2: N, N-dimethylformamide (3.2 mL) of tert-butyl {5-methoxy-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamate (328 mg) under argon atmosphere The solution was cooled in an ice water bath. Sodium hydride (50-72% in oil, 52 mg) was added thereto, and the mixture was stirred for 35 minutes under the same conditions. The solution obtained in Step 1 was added dropwise thereto, and the mixture was stirred for 70 minutes under the same conditions. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 5- {2- [2- (tert-butoxycarbonylamino) -4-methoxyphenyl] -3- (1- Methylcyclopropyl) -3-oxopropyl} methyl nicotinate (155 mg) was obtained.

参考例７３
　対応する出発物質及び反応剤を用い、参考例７２と同様の方法で、５－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－シクロプロピルフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝ニコチン酸メチルを合成した。 Reference Example 73
5- {2- [2- (tert-butoxycarbonylamino) -4-cyclopropylphenyl] -3- (1-methylcyclopropyl) was prepared in the same manner as in Reference Example 72 using the corresponding starting materials and reactants. ) -3-oxopropyl} methyl nicotinate was synthesized.

参考例７４
　対応する出発物質及び反応剤を用い、参考例６５と同様の方法で、２－（１－メチルシクロプロピル）－１，５，６，７－テトラヒドロシクロペンタ［ｆ］インドールを合成した。 Reference Example 74
2- (1-Methylcyclopropyl) -1,5,6,7-tetrahydrocyclopenta [f] indole was synthesized in the same manner as in Reference Example 65 using the corresponding starting materials and reactants.

参考例７５
　アルゴン雰囲気下、２－ブロモ－５－ニトロアニソール（１．００ｇ）及びトリブチルビニルすず（１．３８ｍＬ）の１，４－ジオキサン（８．６ｍＬ）溶液に、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）ジクロリド（１５１ｍｇ）を加え、その混合物を還流下１８時間攪拌した。反応混合物を放冷し、減圧下濃縮した。残渣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。水層を酢酸エチルで抽出した。有機層を合一し、そこへフッ化カリウム（１．１１ｇ）の水（１６．６ｍＬ）溶液を加えた。その混合物を室温にて１．５時間攪拌した後、セライト（登録商標）パッドを通じ濾過した。濾液を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、５－ニトロ－２－ビニルアニソール（４１８ｍｇ）を得た。 Reference Example 75
Under a argon atmosphere, bis (triphenylphosphine) palladium (II) was added to a solution of 2-bromo-5-nitroanisole (1.00 g) and tributylvinyltin (1.38 mL) in 1,4-dioxane (8.6 mL). Dichloride (151 mg) was added and the mixture was stirred at reflux for 18 hours. The reaction mixture was allowed to cool and concentrated under reduced pressure. A saturated aqueous ammonium chloride solution was added to the residue, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, and a solution of potassium fluoride (1.11 g) in water (16.6 mL) was added thereto. The mixture was stirred at room temperature for 1.5 hours and then filtered through a Celite® pad. The filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane) to give 5-nitro-2-vinylanisole (418 mg).

参考例７６
　５－ニトロ－２－ビニルアニソール（４１７ｍｇ）のテトラヒドロフラン（１１．６ｍＬ）溶液に、１０％パラジウム炭素（含水率５６．５ｗｔ％，１９２ｍｇ）を加え、その混合物を水素雰囲気下、３５℃にて３時間攪拌した。反応混合物をセライト（登録商標）パッドを通じ濾過した。濾液を減圧下濃縮することにより、４－エチル－３－メトキシアニリン（２５０ｍｇ）を得た。 Reference Example 76
To a solution of 5-nitro-2-vinylanisole (417 mg) in tetrahydrofuran (11.6 mL) was added 10% palladium carbon (water content 56.5 wt%, 192 mg), and the mixture was added at 35 ° C. under a hydrogen atmosphere at 35 ° C. Stir for hours. The reaction mixture was filtered through a Celite® pad. The filtrate was concentrated under reduced pressure to obtain 4-ethyl-3-methoxyaniline (250 mg).

参考例７７
　対応する出発物質及び反応剤を用い、参考例３８と同様の方法で、５－エチル－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドールを合成した。 Reference Example 77
5-ethyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indole was synthesized in the same manner as in Reference Example 38 using the corresponding starting materials and reactants.

参考例７８
　３－（メチルスルファニル）アニリン（１．３０ｇ）のエタノール（４．０ｍＬ）溶液を還流下、攪拌した。そこへ２－ブロモ－１－（１－メチルシクロプロピル）エタノン（５００ｍｇ）のエタノール（１．６５ｍＬ）溶液を滴下し、その混合物を還流下２４時間攪拌した。反応混合物を放冷した。反応混合物に１ｍｏｌ／Ｌ塩酸を加え、その混合物を酢酸エチルで抽出した。有機層を１ｍｏｌ／Ｌ塩酸、飽和炭酸水素ナトリウム水溶液及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、２－（１－メチルシクロプロピル）－６－（メチルスルファニル）－１Ｈ－インドール（３２７ｍｇ）を得た。 Reference Example 78
A solution of 3- (methylsulfanyl) aniline (1.30 g) in ethanol (4.0 mL) was stirred under reflux. A solution of 2-bromo-1- (1-methylcyclopropyl) ethanone (500 mg) in ethanol (1.65 mL) was added dropwise thereto, and the mixture was stirred under reflux for 24 hours. The reaction mixture was allowed to cool. 1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 1 mol / L hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 2- (1-methylcyclopropyl) -6- (methylsulfanyl) -1H-indole (327 mg).

参考例７９
　ベンゾ［１，３］ジオキソール－５－イルアミン（２．０５ｇ）のエタノール（２．０ｍＬ）溶液を還流下、攪拌した。そこへ２－ブロモ－１－（１－メチルシクロプロピル）エタノン（８００ｍｇ）のエタノール（２．０ｍＬ）溶液を滴下し、その混合物を還流下８時間攪拌した。反応混合物を放冷した。反応混合物に２ｍｏｌ／Ｌ塩酸を加え、その混合物を酢酸エチルで抽出した。水層を酢酸エチルで抽出した。合一した有機層を飽和炭酸水素ナトリウム水溶液、水及び飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、６－（１－メチルシクロプロピル）－５Ｈ－［１，３］ジオキソロ［４，５－ｆ］インドール（４３０ｍｇ）を得た。 Reference Example 79
A solution of benzo [1,3] dioxol-5-ylamine (2.05 g) in ethanol (2.0 mL) was stirred under reflux. A solution of 2-bromo-1- (1-methylcyclopropyl) ethanone (800 mg) in ethanol (2.0 mL) was added dropwise thereto, and the mixture was stirred under reflux for 8 hours. The reaction mixture was allowed to cool. 2 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- (1-methylcyclopropyl) -5H- [1,3] dioxolo [4,5-f] indole (430 mg). )

参考例８０
　アルゴン雰囲気下、{５－シクロプロピル－２－[２－（１－メチルシクロプロピル）－２－オキソエチル]フェニル}カルバミン酸ｔｅｒｔ－ブチル（２１９ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３．３ｍＬ）溶液を氷水浴中で冷却した。そこへ水素化ナトリウム（５０－７２％　ｉｎ　ｏｉｌ，３４ｍｇ）を加え、その混合物を同条件下７０分間攪拌した。そこへ２－（ブロモメチル）イソニコチン酸メチル（１５３ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３．３ｍＬ）溶液を滴下し、その混合物を同条件下１時間、次いで室温にて１７時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、酢酸エチルで抽出した。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、２－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－シクロプロピルフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝イソニコチン酸メチル（２２５ｍｇ）を得た。 Reference Example 80
A solution of tert-butyl {5-cyclopropyl-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamate (219 mg) in N, N-dimethylformamide (3.3 mL) under an argon atmosphere Was cooled in an ice-water bath. Sodium hydride (50-72% in oil, 34 mg) was added thereto, and the mixture was stirred for 70 minutes under the same conditions. A solution of methyl 2- (bromomethyl) isonicotinate (153 mg) in N, N-dimethylformamide (3.3 mL) was added dropwise thereto, and the mixture was stirred for 1 hour under the same conditions and then at room temperature for 17 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 2- {2- [2- (tert-butoxycarbonylamino) -4-cyclopropylphenyl] -3- (1 -Methylcyclopropyl) -3-oxopropyl} isonicotinic acid methyl ester (225 mg) was obtained.

参考例８１
　アルゴン雰囲気下、３－アミノ－４－ヨード安息香酸メチル（１．００ｇ）のジクロロメタン（５ｍＬ）縣濁液を氷水浴中で冷却した。そこへトリフルオロ酢酸無水物（０．７５ｍＬ）を加え、その混合物を室温にて７．５時間攪拌した。反応混合物を減圧下濃縮した。残渣を酢酸エチル及び飽和炭酸水素ナトリウム水溶液間で分配した。有機層を分離した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮することにより、４－ヨード－３－（２，２，２－トリフルオロアセチルアミノ）安息香酸メチル（１．３０ｇ）を得た。 Reference Example 81
Under an argon atmosphere, a suspension of methyl 3-amino-4-iodobenzoate (1.00 g) in dichloromethane (5 mL) was cooled in an ice-water bath. Trifluoroacetic anhydride (0.75 mL) was added thereto, and the mixture was stirred at room temperature for 7.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give methyl 4-iodo-3- (2,2,2-trifluoroacetylamino) benzoate (1.30 g). Got.

参考例８２
　アルゴン雰囲気下、１－（１－メチルシクロプロピル）エタノン（１．５ｇ）のテトラヒドロフラン（４０ｍＬ）溶液に、リチウムビス（トリメチルシリル）アミド（１．０Ｍテトラヒドロフラン溶液、３３．６ｍＬ）を－７８℃にて加え、その混合物を室温にて５０分間攪拌した。そこへ炭酸ジメチル（１．４５ｇ）を加え、その混合物を室温にて２０時間攪拌した。揮発物を減圧下留去した。残渣に酢酸エチル（５０ｍＬ）及び水（１００ｍＬ）を加えた。その混合物に攪拌しながら酢酸（２．２ｍＬ）を加えた。有機層を分離した。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、３－（１－メチルシクロプロピル）－３－オキソプロピオン酸メチル（１．５９ｇ）を得た。 Reference Example 82
Under an argon atmosphere, lithium bis (trimethylsilyl) amide (1.0M tetrahydrofuran solution, 33.6 mL) was added to a solution of 1- (1-methylcyclopropyl) ethanone (1.5 g) in tetrahydrofuran (40 mL) at −78 ° C. In addition, the mixture was stirred at room temperature for 50 minutes. Dimethyl carbonate (1.45 g) was added thereto, and the mixture was stirred at room temperature for 20 hours. Volatiles were removed under reduced pressure. To the residue was added ethyl acetate (50 mL) and water (100 mL). Acetic acid (2.2 mL) was added to the mixture with stirring. The organic layer was separated. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane) to give methyl 3- (1-methylcyclopropyl) -3-oxopropionate (1.59 g).

参考例８３
　アルゴン雰囲気下、４－ヨード－３－（２，２，２－トリフルオロアセチルアミノ）安息香酸メチル（７４６ｍｇ）、Ｌ－プロリン（４６．１ｍｇ）、ヨウ化銅（Ｉ）（３８．１ｍｇ）、炭酸セシウム（２．６１ｇ）及びジメチルスルホキシド（３．０ｍＬ）の混合物に、３－（１－メチルシクロプロピル）－３－オキソプロピオン酸メチル（６８９ｍｇ）のジメチルスルホキシド（１．０ｍＬ）溶液を加え、その混合物を４０℃にて２．５時間攪拌した。反応混合物にメタノール（８．０ｍＬ）、次いで濃塩酸（８．０ｍＬ）をゆっくり加えた。その混合物を６０℃にて１時間攪拌した後、放冷した。反応混合物に水を加え、酢酸エチルで抽出した。水層を酢酸エチルで抽出した。合一した有機層を飽和炭酸水素ナトリウム水溶液、水及び飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、２－（１－メチルシクロプロピル）－１Ｈ－インドール－３，６－ジカルボン酸ジメチル（３４９ｍｇ）を得た。 Reference Example 83
Under an argon atmosphere, methyl 4-iodo-3- (2,2,2-trifluoroacetylamino) benzoate (746 mg), L-proline (46.1 mg), copper (I) iodide (38.1 mg), To a mixture of cesium carbonate (2.61 g) and dimethyl sulfoxide (3.0 mL) was added a solution of methyl 3- (1-methylcyclopropyl) -3-oxopropionate (689 mg) in dimethyl sulfoxide (1.0 mL), The mixture was stirred at 40 ° C. for 2.5 hours. Methanol (8.0 mL) was added slowly to the reaction mixture, followed by concentrated hydrochloric acid (8.0 mL). The mixture was stirred at 60 ° C. for 1 hour and then allowed to cool. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to obtain dimethyl 2- (1-methylcyclopropyl) -1H-indole-3,6-dicarboxylate (349 mg).

参考例８４
　２－（１－メチルシクロプロピル）－１Ｈ－インドール－３，６－ジカルボン酸ジメチル（１７４ｍｇ）、１ｍｏｌ／Ｌ水酸化ナトリウム水溶液（６ｍＬ）及びメタノール（６ｍＬ）の混合物を、封管中、マイクロ波照射下、１５０℃にて１時間攪拌した。同条件下、反応をもう１ロット実施した。２つの反応混合物を合一し、そこへ１ｍｏｌ／Ｌ塩酸を加えた。その混合物を減圧下濃縮してメタノールを除去した。残渣を酢酸エチルで抽出した。水層を酢酸エチルで抽出した。合一した有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、２－（１－メチルシクロプロピル）－１Ｈ－インドール－６－カルボン酸（１７９ｍｇ）を得た。 Reference Example 84
A mixture of dimethyl 2- (1-methylcyclopropyl) -1H-indole-3,6-dicarboxylate (174 mg), 1 mol / L aqueous sodium hydroxide (6 mL) and methanol (6 mL) was placed in a sealed tube with microwaves. The mixture was stirred at 150 ° C. for 1 hour under irradiation. Another lot of reaction was carried out under the same conditions. The two reaction mixtures were combined and 1 mol / L hydrochloric acid was added thereto. The mixture was concentrated under reduced pressure to remove methanol. The residue was extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane) to give 2- (1-methylcyclopropyl) -1H-indole-6-carboxylic acid (179 mg).

参考例８５
　アルゴン雰囲気下、２－（１－メチルシクロプロピル）－１Ｈ－インドール－６－カルボン酸（１４８ｍｇ）のテトラヒドロフラン（３．５ｍＬ）溶液を氷水浴中で冷却した。そこへ水素化アルミニウムリチウム（５２．３ｍｇ）を加え、その混合物を５０℃にて１５時間、次いで室温にて６時間攪拌した。反応混合物を氷水浴中で冷却し、そこへ水（０．０７４ｍＬ）をゆっくり加えた。その混合物を１ｍｏｌ／Ｌ塩酸に注ぎ、酢酸エチルで抽出した。水層を酢酸エチルで抽出した。合一した有機層を飽和炭酸水素ナトリウム水溶液及び飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣をアミノプロピル化シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、６－ヒドロキシメチル－２－（１－メチルシクロプロピル）－１Ｈ－インドール（７３．７ｍｇ）を得た。 Reference Example 85
Under an argon atmosphere, a solution of 2- (1-methylcyclopropyl) -1H-indole-6-carboxylic acid (148 mg) in tetrahydrofuran (3.5 mL) was cooled in an ice-water bath. Thereto was added lithium aluminum hydride (52.3 mg), and the mixture was stirred at 50 ° C. for 15 hours and then at room temperature for 6 hours. The reaction mixture was cooled in an ice-water bath, and water (0.074 mL) was slowly added thereto. The mixture was poured into 1 mol / L hydrochloric acid and extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6-hydroxymethyl-2- (1-methylcyclopropyl) -1H-indole (73.7 mg). It was.

参考例８６
　アルゴン雰囲気下、６－ヒドロキシメチル－２－（１－メチルシクロプロピル）－１Ｈ－インドール（７３．０ｍｇ）のジクロロメタン（２．０ｍＬ）溶液に、ピリジン（０．２３５ｍＬ）、次いで無水酢酸（０．１３７ｍＬ）を加え、その混合物を室温にて２時間攪拌した。反応混合物に酢酸エチル及び０．５ｍｏｌ／Ｌ塩酸を加え、有機層を分離した。有機層を飽和炭酸水素ナトリウム水溶液及び飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、酢酸［２－（１－メチルシクロプロピル）－１Ｈ－インドール－６－イル］メチル（６４．０ｍｇ）を得た。 Reference Example 86
Under a argon atmosphere, 6-hydroxymethyl-2- (1-methylcyclopropyl) -1H-indole (73.0 mg) in dichloromethane (2.0 mL) was added to pyridine (0.235 mL) and then acetic anhydride (0. 137 mL) was added and the mixture was stirred at room temperature for 2 hours. Ethyl acetate and 0.5 mol / L hydrochloric acid were added to the reaction mixture, and the organic layer was separated. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to obtain [2- (1-methylcyclopropyl) -1H-indol-6-yl] methyl acetate (64.0 mg). It was.

参考例８７
　アルゴン雰囲気下、酢酸［２－（１－メチルシクロプロピル）－１Ｈ－インドール－６－イル］メチル（６３．０ｍｇ）、６－ホルミルピリジン－２－カルボン酸メチル（４７．１ｍｇ）及びトリエチルシラン（０．１２４ｍＬ）のジクロロメタン（１．３ｍＬ）溶液を氷水浴中で冷却した。そこへトリフルオロ酢酸（０．０２９ｍＬ）を加え、その混合物を同条件下３０分間、次いで室温にて３時間攪拌した。反応混合物をアミノプロピル化シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、６－［６－（アセトキシメチル）－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（６１．０ｍｇ）を得た。 Reference Example 87
Under an argon atmosphere, [2- (1-methylcyclopropyl) -1H-indol-6-yl] methyl acetate (63.0 mg), methyl 6-formylpyridine-2-carboxylate (47.1 mg) and triethylsilane ( A solution of 0.124 mL) in dichloromethane (1.3 mL) was cooled in an ice-water bath. Trifluoroacetic acid (0.029 mL) was added thereto, and the mixture was stirred under the same conditions for 30 minutes and then at room temperature for 3 hours. The reaction mixture was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- [6- (acetoxymethyl) -2- (1-methylcyclopropyl) -1H-indole- Methyl 3-ylmethyl] pyridine-2-carboxylate (61.0 mg) was obtained.

参考例８８
　６－メチルピラジン－２－カルボン酸（５００ｍｇ）のメタノール（１８．１ｍＬ）懸濁液を室温にて攪拌した。そこへ塩化チオニル（０．３３０ｍＬ）をゆっくり滴下した。その混合物を還流下２４時間攪拌した。反応混合物を放冷し、減圧下濃縮した。残渣に飽和炭酸水素ナトリウム水溶液をゆっくり加え、その混合物を酢酸エチルで抽出した。水層を酢酸エチルで２回抽出した。合一した有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をアミノプロピル化シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、６－メチルピラジン－２－カルボン酸メチル（４２３ｍｇ）を得た。 Reference Example 88
A suspension of 6-methylpyrazine-2-carboxylic acid (500 mg) in methanol (18.1 mL) was stirred at room temperature. Thionyl chloride (0.330 mL) was slowly added dropwise thereto. The mixture was stirred under reflux for 24 hours. The reaction mixture was allowed to cool and concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was slowly added to the residue, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (eluent: ethyl acetate-hexane) to give methyl 6-methylpyrazine-2-carboxylate (423 mg).

参考例８９
　６－メチルピラジン－２－カルボン酸メチル（２５０ｍｇ）の四塩化炭素（５．５ｍＬ）溶液に、Ｎ－ブロモこはく酸イミド（４３９ｍｇ）及びアゾビスイソブチロニトリル（１３５ｍｇ）を加え、その混合物を還流下２４時間攪拌した。反応混合物を放冷し、そこへ飽和炭酸水素ナトリウム水溶液を加えた。その混合物をジクロロメタンで抽出した。有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をジクロロメタンに溶かし、シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、６－（ブロモメチル）ピラジン－２－カルボン酸メチル（１１１ｍｇ）を得た。 Reference Example 89
To a solution of methyl 6-methylpyrazine-2-carboxylate (250 mg) in carbon tetrachloride (5.5 mL) was added N-bromosuccinimide (439 mg) and azobisisobutyronitrile (135 mg), and the mixture was The mixture was stirred for 24 hours under reflux. The reaction mixture was allowed to cool, and a saturated aqueous sodium hydrogen carbonate solution was added thereto. The mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in dichloromethane and purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give methyl 6- (bromomethyl) pyrazine-2-carboxylate (111 mg).

参考例９０
　アルゴン雰囲気下、　{５－メトキシ－２－[２－（１－メチルシクロプロピル）－２－オキソエチル]フェニル}カルバミン酸ｔｅｒｔ－ブチル（１３７ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（２．１ｍＬ）溶液を氷水浴中で冷却した。そこへ水素化ナトリウム（５０－７２％　ｉｎ　ｏｉｌ，２２ｍｇ）を加え、その混合物を同条件下１時間攪拌した。そこへ６－（ブロモメチル）ピラジン－２－カルボン酸メチル（１０９ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（０．７６ｍＬ）溶液を滴下し、その混合物を同条件下３０分間、次いで室温にて一晩攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、酢酸エチルで抽出した。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－メトキシフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝ピラジン－２－カルボン酸メチル（１１２ｍｇ）を得た。　　　　　　 Reference Example 90
Under an argon atmosphere, a solution of tert-butyl {5-methoxy-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamate (137 mg) in N, N-dimethylformamide (2.1 mL) was added. Cooled in an ice-water bath. Thereto was added sodium hydride (50-72% in oil, 22 mg), and the mixture was stirred for 1 hour under the same conditions. Thereto was added dropwise a solution of methyl 6- (bromomethyl) pyrazine-2-carboxylate (109 mg) in N, N-dimethylformamide (0.76 mL), and the mixture was stirred under the same conditions for 30 minutes and then at room temperature overnight. did. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- {2- [2- (tert-butoxycarbonylamino) -4-methoxyphenyl] -3- (1- Methyl cyclopropyl) -3-oxopropyl} pyrazine-2-carboxylate (112 mg) was obtained.

参考例９１
　アルゴン雰囲気下、　{５－シクロプロピル－２－[２－（１－メチルシクロプロピル）－２－オキソエチル]フェニル}カルバミン酸ｔｅｒｔ－ブチル（２０７ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３．１ｍＬ）溶液を氷水浴中で冷却した。そこへ水素化ナトリウム（５０－７２％　ｉｎ　ｏｉｌ，３２ｍｇ）を加え、その混合物を同条件下１時間攪拌した。そこへ６－（ブロモメチル）ピラジン－２－カルボン酸メチル（１６０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１．１ｍＬ）溶液を滴下し、その混合物を同条件下３０分間、次いで室温にて１５時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、酢酸エチルで抽出した。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－シクロプロピルフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝ピラジン－２－カルボン酸メチル（１９０ｍｇ）を得た。　　　 Reference Example 91
A solution of tert-butyl {5-cyclopropyl-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamate (207 mg) in N, N-dimethylformamide (3.1 mL) under an argon atmosphere Was cooled in an ice-water bath. Sodium hydride (50-72% in oil, 32 mg) was added thereto, and the mixture was stirred for 1 hour under the same conditions. A solution of methyl 6- (bromomethyl) pyrazine-2-carboxylate (160 mg) in N, N-dimethylformamide (1.1 mL) was added dropwise thereto, and the mixture was stirred for 30 minutes under the same conditions and then at room temperature for 15 hours. did. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- {2- [2- (tert-butoxycarbonylamino) -4-cyclopropylphenyl] -3- (1 -Methylcyclopropyl) -3-oxopropyl} pyrazine-2-carboxylate methyl ester (190 mg) was obtained.

参考例９２
　対応する出発物質及び反応剤を用い、参考例５と同様の方法で、（２－メチルフェニル）カルバミン酸ｔｅｒｔ－ブチルを合成した。 Reference Example 92
Using corresponding starting materials and reactants, tert-butyl (2-methylphenyl) carbamate was synthesized in the same manner as in Reference Example 5.

参考例９３
　対応する出発物質及び反応剤を用い、参考例２と同様の方法で、｛２－［２－（１－メチルシクロプロピル）－２－オキソエチル］フェニル｝カルバミン酸ｔｅｒｔ－ブチルを合成した。 Reference Example 93
Using corresponding starting materials and reactants, tert-butyl {2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamate was synthesized in the same manner as in Reference Example 2.

参考例９４
　対応する出発物質及び反応剤を用い、参考例５７と同様の方法で、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）フェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝ピリジン－２－カルボン酸メチルを合成した。 Reference Example 94
6- {2- [2- (tert-Butoxycarbonylamino) phenyl] -3- (1-methylcyclopropyl) -3-oxo was prepared in the same manner as in Reference Example 57 using the corresponding starting materials and reactants. Methyl propyl} pyridine-2-carboxylate was synthesized.

参考例９５
　４－ブロモ－３－メトキシアニリン（１．５０ｇ）、シクロプロピルボロン酸一水和物（１．００ｇ）、トリシクロヘキシルホスフィン（約０．６ｍｏｌ／Ｌトルエン溶液、１．２４ｍＬ）、リン酸三カリウム一水和物（５．９８ｇ）、トルエン（２０．６ｍＬ）及び水（２．０６ｍＬ）の混合物に、酢酸パラジウム（ＩＩ）（８３．５ｍｇ）を加え、この混合物を１００℃にて２４時間攪拌した。反応混合物を放冷し、セライト（登録商標）パッドを通じ濾過した。そのパッドを酢酸エチルで洗浄した。濾液を水／飽和食塩水（１／１）で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をアミノプロピル化シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、４－シクロプロピル－３－メトキシアニリン（５８６ｍｇ）を得た。 Reference Example 95
4-bromo-3-methoxyaniline (1.50 g), cyclopropylboronic acid monohydrate (1.00 g), tricyclohexylphosphine (approximately 0.6 mol / L toluene solution, 1.24 mL), tripotassium phosphate To a mixture of monohydrate (5.98 g), toluene (20.6 mL) and water (2.06 mL) was added palladium (II) acetate (83.5 mg) and the mixture was stirred at 100 ° C. for 24 hours. did. The reaction mixture was allowed to cool and filtered through a Celite® pad. The pad was washed with ethyl acetate. The filtrate was washed with water / saturated brine (1/1). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (eluent: ethyl acetate-hexane) to give 4-cyclopropyl-3-methoxyaniline (586 mg).

参考例９６
　対応する出発物質及び反応剤を用い、参考例６５と同様の方法で、５－シクロプロピル－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドールを合成した。 Reference Example 96
5-Cyclopropyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indole was synthesized in the same manner as in Reference Example 65 using the corresponding starting materials and reactants.

参考例９７
　対応する出発物質及び反応剤を用い、参考例５と同様の方法で、（４－ブロモ－３－メトキシフェニル）カルバミン酸ｔｅｒｔ－ブチルを合成した。 Reference Example 97
Using corresponding starting materials and reactants, tert-butyl (4-bromo-3-methoxyphenyl) carbamate was synthesized in the same manner as in Reference Example 5.

参考例９８
　アルゴン雰囲気下、（４－ブロモ－３－メトキシフェニル）カルバミン酸ｔｅｒｔ－ブチル（１．８０ｇ）のテトラヒドロフラン（２７ｍＬ）溶液に、ｎ－ブチルリチウム（２．６９ｍｏｌ／Ｌヘキサン溶液、４．４３ｍＬ）を－７８℃にて滴下し、その混合物を－７８℃にて３０分間攪拌した。そこへプロピオンアルデヒド（０．５２０ｍＬ）のテトラヒドロフラン（３ｍＬ）溶液を滴下した。その混合物を－７８℃にて３０分間攪拌し、次いで２時間で室温までゆっくり昇温した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、［４－（１－ヒドロキシプロピル）－３－メトキシフェニル］カルバミン酸ｔｅｒｔ－ブチル（８１５ｍｇ）を得た。 Reference Example 98
Under an argon atmosphere, n-butyllithium (2.69 mol / L hexane solution, 4.43 mL) was added to a tetrahydrofuran (27 mL) solution of tert-butyl (4-bromo-3-methoxyphenyl) carbamate (1.80 g). The mixture was added dropwise at −78 ° C., and the mixture was stirred at −78 ° C. for 30 minutes. A solution of propionaldehyde (0.520 mL) in tetrahydrofuran (3 mL) was added dropwise thereto. The mixture was stirred at −78 ° C. for 30 minutes and then slowly warmed to room temperature over 2 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to obtain tert-butyl [4- (1-hydroxypropyl) -3-methoxyphenyl] carbamate (815 mg).

参考例９９
　［４－（１－ヒドロキシプロピル）－３－メトキシフェニル］カルバミン酸ｔｅｒｔ－ブチル（８１４ｍｇ）のエタノール（１４．５ｍＬ）溶液に、１０％パラジウム炭素（含水率５６．５ｗｔ％，３７４ｍｇ）を加え、その混合物を水素雰囲気下、室温にて５時間攪拌した。反応混合物をセライト（登録商標）パッドを通じ濾過した。濾液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、（３－メトキシ－４－プロピルフェニル）カルバミン酸ｔｅｒｔ－ブチル（６２３ｍｇ）を得た。 Reference Example 99
To a solution of tert-butyl [4- (1-hydroxypropyl) -3-methoxyphenyl] carbamate (814 mg) in ethanol (14.5 mL) was added 10% palladium carbon (water content 56.5 wt%, 374 mg), The mixture was stirred at room temperature for 5 hours under hydrogen atmosphere. The reaction mixture was filtered through a Celite® pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to obtain tert-butyl (3-methoxy-4-propylphenyl) carbamate (623 mg).

参考例１００
　アルゴン雰囲気下、（３－メトキシ－４－プロピルフェニル）カルバミン酸ｔｅｒｔ－ブチル（６２２ｍｇ）のジクロロメタン（１１．７ｍＬ）溶液を氷冷した。トリフルオロ酢酸（３．９ｍＬ）を加え、その混合物を室温にて２時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮することにより、３－メトキシ－４－プロピルアニリン（４１１ｍｇ）を得た。 Reference Example 100
Under an argon atmosphere, a solution of tert-butyl (3-methoxy-4-propylphenyl) carbamate (622 mg) in dichloromethane (11.7 mL) was ice-cooled. Trifluoroacetic acid (3.9 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 3-methoxy-4-propylaniline (411 mg).

参考例１０１
　対応する出発物質及び反応剤を用い、参考例７９と同様の方法で、６－メトキシ－２－（１－メチルシクロプロピル）－５－プロピル－１Ｈ－インドールを合成した。 Reference Example 101
6-Methoxy-2- (1-methylcyclopropyl) -5-propyl-1H-indole was synthesized in the same manner as in Reference Example 79 using the corresponding starting materials and reactants.

参考例１０２
　アルゴン雰囲気下、カリウムｔｅｒｔ－ブトキシド（５．６８ｇ）のテトラヒドロフラン（５１ｍＬ）懸濁液に、塩化シクロブタンカルボニル（５．７７ｍＬ）のテトラヒドロフラン（７．６ｍＬ）溶液を滴下し、その混合物を室温にて２５時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、ジエチルエーテルで抽出した。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮することにより、シクロブタンカルボン酸ｔｅｒｔ－ブチル（４．９６ｇ）を得た。 Reference Example 102
Under an argon atmosphere, a solution of cyclobutanecarbonyl chloride (5.77 mL) in tetrahydrofuran (7.6 mL) was added dropwise to a suspension of potassium tert-butoxide (5.68 g) in tetrahydrofuran (51 mL). Stir for hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give tert-butyl cyclobutanecarboxylate (4.96 g).

参考例１０３
　アルゴン雰囲気下、ジイソプロピルアミン（５．３５ｍＬ）のテトラヒドロフラン（２６０ｍＬ）溶液に、ｎ－ブチルリチウム（２．６９ｍｏｌ／Ｌヘキサン溶液、１４．２ｍＬ）を－７８℃にて滴下し、その混合物を－７８℃にて４５分間攪拌した。そこへシクロブタンカルボン酸ｔｅｒｔ－ブチル（４．９６ｇ）のテトラヒドロフラン（５７ｍＬ）溶液を滴下し、その混合物を－７８℃にて２時間攪拌した。そこへよう化メチル（１１．３ｇ）を滴下した。その混合物を－７８℃にて１時間攪拌し、徐々に室温まで昇温した。２２時間後、反応混合物に飽和塩化アンモニウム水溶液を加え、ジエチルエーテルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧下濃縮することにより、１－メチルシクロブタンカルボン酸ｔｅｒｔ－ブチル（２．５０ｇ）を得た。 Reference Example 103
Under an argon atmosphere, n-butyllithium (2.69 mol / L hexane solution, 14.2 mL) was added dropwise to a solution of diisopropylamine (5.35 mL) in tetrahydrofuran (260 mL) at −78 ° C., and the mixture was added to −78 ° C. Stir at 45 ° C. for 45 minutes. A solution of tert-butyl cyclobutanecarboxylate (4.96 g) in tetrahydrofuran (57 mL) was added dropwise thereto, and the mixture was stirred at −78 ° C. for 2 hours. Methyl iodide (11.3 g) was added dropwise thereto. The mixture was stirred at −78 ° C. for 1 hour and gradually warmed to room temperature. After 22 hours, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain tert-butyl 1-methylcyclobutanecarboxylate (2.50 g).

参考例１０４
　１－メチルシクロブタンカルボン酸ｔｅｒｔ－ブチル（２．５０ｇ）にトリフルオロ酢酸（２．４３ｍＬ）を室温にて加え、その混合物を還流下５時間攪拌した。反応混合物を放冷した。反応混合物に２ｍｏｌ／Ｌ水酸化ナトリウム水溶液を加えて塩基性とし、ジエチルエーテルで抽出した。水層に１ｍｏｌ／Ｌ塩酸を加えて酸性とし、ジエチルエーテルで抽出した。水層をジエチルエーテルで抽出した。合一した有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮することにより、１－メチルシクロブタンカルボン酸（１．０６ｇ）を得た。 Reference Example 104
Trifluoroacetic acid (2.43 mL) was added to tert-butyl 1-methylcyclobutanecarboxylate (2.50 g) at room temperature, and the mixture was stirred under reflux for 5 hours. The reaction mixture was allowed to cool. The reaction mixture was basified with 2 mol / L aqueous sodium hydroxide solution and extracted with diethyl ether. The aqueous layer was acidified with 1 mol / L hydrochloric acid and extracted with diethyl ether. The aqueous layer was extracted with diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1-methylcyclobutanecarboxylic acid (1.06 g).

参考例１０５
　Step１：アルゴン雰囲気下、１－メチルシクロブタンカルボン酸（１．０６ｇ）のジクロロメタン（５．６ｍＬ）溶液を氷－飽和食塩水浴中で冷却した。そこへ塩化オキサリル（０．８７６ｍＬ）を滴下し、その混合物を同温にて１．５時間、次いで室温にて２０時間攪拌した。反応混合物を下記Step２で使用した。
　Step２：アルゴン雰囲気下、Ｎ，Ｏ－ジメチルヒドロキシルアミン塩酸塩（９０６ｍｇ）のジクロロメタン（９．３ｍＬ）懸濁液を氷水浴中で冷却した。そこへトリエチルアミン（４．５ｍＬ）、次いでStep１で得た反応混合物を加えた。その混合物を同温にて１．５時間、次いで室温にて２４時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。有機層を分離し、飽和炭酸水素ナトリウム水溶液で洗浄した。有機層にシリカゲルを加え、その混合物を室温にて２時間攪拌した。不溶物を濾別し、ジエチルエーテル／ジクロロメタン（１／１）で洗浄した。濾液を減圧下濃縮することにより、Ｎ－メトキシ－Ｎ，１－ジメチルシクロブタンカルボキサミド（１．２６ｇ）を得た。 Reference Example 105
Step 1: A solution of 1-methylcyclobutanecarboxylic acid (1.06 g) in dichloromethane (5.6 mL) was cooled in an ice-saturated saline bath under an argon atmosphere. Oxalyl chloride (0.876 mL) was added dropwise thereto, and the mixture was stirred at the same temperature for 1.5 hours and then at room temperature for 20 hours. The reaction mixture was used in Step 2 below.
Step 2: A suspension of N, O-dimethylhydroxylamine hydrochloride (906 mg) in dichloromethane (9.3 mL) was cooled in an ice-water bath under an argon atmosphere. Triethylamine (4.5 mL) and then the reaction mixture obtained in Step 1 were added thereto. The mixture was stirred at the same temperature for 1.5 hours and then at room temperature for 24 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was separated and washed with saturated aqueous sodium bicarbonate. Silica gel was added to the organic layer and the mixture was stirred at room temperature for 2 hours. The insoluble material was filtered off and washed with diethyl ether / dichloromethane (1/1). The filtrate was concentrated under reduced pressure to obtain N-methoxy-N, 1-dimethylcyclobutanecarboxamide (1.26 g).

参考例１０６
　アルゴン雰囲気下、（５－メトキシ－２－メチルフェニル）カルバミン酸ｔｅｒｔ－ブチル（７００ｍｇ）のテトラヒドロフラン（１４．７ｍＬ）溶液に、ｓｅｃ－ブチルリチウム（１．０８ｍｏｌ／Ｌヘキサン－シクロヘキサン溶液、７．６５ｍＬ）を－４５℃にてゆっくり滴下し、その混合物を同条件下３０分間攪拌した。そこへＮ－メトキシ－Ｎ，１－ジメチルシクロブタンカルボキサミド（５１０ｍｇ）のテトラヒドロフラン（１．４７ｍＬ）溶液を滴下し、その混合物を－４５℃にて３０分間、次いで室温にて２．５時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、｛５－メトキシ－２－［２－（１－メチルシクロブチル）－２－オキソエチル］フェニル｝カルバミン酸ｔｅｒｔ－ブチル（６２０ｍｇ）を得た。 Reference Example 106
Under an argon atmosphere, sec-butyllithium (1.08 mol / L hexane-cyclohexane solution, 7.65 mL) was added to a solution of tert-butyl (5-methoxy-2-methylphenyl) carbamate (700 mg) in tetrahydrofuran (14.7 mL). ) Was slowly added dropwise at −45 ° C., and the mixture was stirred for 30 minutes under the same conditions. A solution of N-methoxy-N, 1-dimethylcyclobutanecarboxamide (510 mg) in tetrahydrofuran (1.47 mL) was added dropwise thereto, and the mixture was stirred at −45 ° C. for 30 minutes and then at room temperature for 2.5 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give {5-methoxy-2- [2- (1-methylcyclobutyl) -2-oxoethyl] phenyl} carbamic acid tert -Butyl (620 mg) was obtained.

参考例１０７
　アルゴン雰囲気下、｛５－メトキシ－２－[２－（１－メチルシクロブチル）－２－オキソエチル]フェニル｝カルバミン酸ｔｅｒｔ－ブチル（３００ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（４．５ｍＬ）溶液を氷水浴中で冷却した。そこへ水素化ナトリウム（５０－７２％　ｉｎ　ｏｉｌ，４６ｍｇ）を加え、その混合物を同条件下６５分間攪拌した。そこへ６－（クロロメチル）ピリジン－２－カルボン酸メチル（１６７ｍｇ）を加え、その混合物を同条件下で３０分間、次いで室温にて３．５時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、酢酸エチルで抽出した。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－メトキシフェニル］－３－（１－メチルシクロブチル）－３－オキソプロピル｝ピリジン－２－カルボン酸メチル（２１６ｍｇ）を得た。　　　 Reference Example 107
Under an argon atmosphere, a solution of tert-butyl {5-methoxy-2- [2- (1-methylcyclobutyl) -2-oxoethyl] phenyl} carbamate (300 mg) in N, N-dimethylformamide (4.5 mL) was added. Cooled in an ice-water bath. Sodium hydride (50-72% in oil, 46 mg) was added thereto, and the mixture was stirred for 65 minutes under the same conditions. Thereto was added methyl 6- (chloromethyl) pyridine-2-carboxylate (167 mg), and the mixture was stirred under the same conditions for 30 minutes and then at room temperature for 3.5 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- {2- [2- (tert-butoxycarbonylamino) -4-methoxyphenyl] -3- (1- Methyl cyclobutyl) -3-oxopropyl} pyridine-2-carboxylate (216 mg) was obtained.

参考例１０８
　アルゴン雰囲気下、（４－ブロモ－３－メトキシフェニル）カルバミン酸ｔｅｒｔ－ブチル（２．９５ｇ）のテトラヒドロフラン（４４ｍＬ）溶液に、ｎ－ブチルリチウム（２．６９ｍｏｌ／Ｌヘキサン溶液、７．２６ｍＬ）を－７８℃にて滴下し、その混合物を－７８℃にて３０分間攪拌した。そこへブチルアルデヒド（１．７４ｍＬ）のテトラヒドロフラン（４．８ｍＬ）溶液を滴下し、その混合物を－７８℃にて３０分間、０℃（氷水浴）にて１．５時間、次いで室温にて１時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、［４－（１－ヒドロキシブチル）－３－メトキシフェニル］カルバミン酸ｔｅｒｔ－ブチル（１．１４ｇ）を得た。 Reference Example 108
Under an argon atmosphere, n-butyllithium (2.69 mol / L hexane solution, 7.26 mL) was added to a tetrahydrofuran (44 mL) solution of tert-butyl (4-bromo-3-methoxyphenyl) carbamate (2.95 g). The mixture was added dropwise at −78 ° C., and the mixture was stirred at −78 ° C. for 30 minutes. A solution of butyraldehyde (1.74 mL) in tetrahydrofuran (4.8 mL) was added dropwise thereto, and the mixture was added at −78 ° C. for 30 minutes, at 0 ° C. (ice water bath) for 1.5 hours, and then at room temperature for 1 hour. Stir for hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give tert-butyl [4- (1-hydroxybutyl) -3-methoxyphenyl] carbamate (1.14 g). .

参考例１０９
　［４－（１－ヒドロキシブチル）－３－メトキシフェニル］カルバミン酸ｔｅｒｔ－ブチル（１．１４ｇ）のエタノール（１９．３ｍＬ）溶液に、１０％パラジウム炭素（含水率５６．５ｗｔ％，５２４ｍｇ）を加え、その混合物を水素雰囲気下、室温にて３時間攪拌した。反応混合物をセライト（登録商標）パッドを通じ濾過した。濾液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、（４－ブチル－３－メトキシフェニル）カルバミン酸ｔｅｒｔ－ブチル（９９９ｍｇ）を得た。 Reference Example 109
To a solution of tert-butyl [4- (1-hydroxybutyl) -3-methoxyphenyl] carbamate (1.14 g) in ethanol (19.3 mL) was added 10% palladium carbon (water content 56.5 wt%, 524 mg). In addition, the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction mixture was filtered through a Celite® pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to obtain tert-butyl (4-butyl-3-methoxyphenyl) carbamate (999 mg).

参考例１１０
　アルゴン雰囲気下、（４－ブチル－３－メトキシフェニル）カルバミン酸ｔｅｒｔ－ブチル（９９７ｍｇ）のジクロロメタン（１７．７ｍＬ）溶液を氷水浴中で冷却した。そこへトリフルオロ酢酸（５．９ｍＬ）を加え、その混合物を室温にて６時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮することにより、４－ブチル－３－メトキシアニリン（７６０ｍｇ）を得た。 Reference Example 110
Under an argon atmosphere, a solution of tert-butyl (4-butyl-3-methoxyphenyl) carbamate (997 mg) in dichloromethane (17.7 mL) was cooled in an ice-water bath. Trifluoroacetic acid (5.9 mL) was added thereto, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 4-butyl-3-methoxyaniline (760 mg).

参考例１１１
　対応する出発物質及び反応剤を用い、参考例７９と同様の方法で、５－ブチル－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドールを合成した。 Reference Example 111
5-butyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indole was synthesized in the same manner as in Reference Example 79 using the corresponding starting materials and reactants.

参考例１１２
　アルゴン雰囲気下、（５－シクロプロピル－２－メチルフェニル）カルバミン酸ｔｅｒｔ－ブチル（７００ｍｇ）のテトラヒドロフラン（１４．２ｍＬ）溶液に、ｓｅｃ－ブチルリチウム（１．０８ｍｏｌ／Ｌヘキサン－シクロヘキサン溶液、７．３４ｍＬ）を－４５℃にてゆっくり滴下し、その混合物を同条件下３０分間攪拌した。そこへＮ－メトキシ－Ｎ，１－ジメチルシクロブタンカルボキサミド（４９０ｍｇ）のテトラヒドロフラン（１．４２ｍＬ）溶液を滴下し、その混合物を－４５℃にて４０分間、次いで室温にて３時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、｛５－シクロプロピル－２－［２－（１－メチルシクロブチル）－２－オキソエチル］フェニル｝カルバミン酸ｔｅｒｔ－ブチル（５８１ｍｇ）を得た。 Reference Example 112
Under an argon atmosphere, sec-butyl lithium (1.08 mol / L hexane-cyclohexane solution, 7%) was added to a solution of tert-butyl (5-cyclopropyl-2-methylphenyl) carbamate (700 mg) in tetrahydrofuran (14.2 mL). 34 mL) was slowly added dropwise at −45 ° C., and the mixture was stirred for 30 minutes under the same conditions. Thereto was added dropwise a solution of N-methoxy-N, 1-dimethylcyclobutanecarboxamide (490 mg) in tetrahydrofuran (1.42 mL), and the mixture was stirred at −45 ° C. for 40 minutes and then at room temperature for 3 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give {5-cyclopropyl-2- [2- (1-methylcyclobutyl) -2-oxoethyl] phenyl} carbamic acid. Tert-butyl (581 mg) was obtained.

参考例１１３
　アルゴン雰囲気下、｛５－シクロプロピル－２－[２－（１－メチルシクロブチル）－２－オキソエチル]フェニル｝カルバミン酸ｔｅｒｔ－ブチル（３００ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（４．４ｍＬ）溶液を氷水浴中で冷却した。そこへ水素化ナトリウム（５０－７２％　ｉｎ　ｏｉｌ，４４ｍｇ）を加え、その混合物を同条件下４０分間攪拌した。そこへ６－（クロロメチル）ピリジン－２－カルボン酸メチル（１６２ｍｇ）を加え、その混合物を同条件下３０分間、次いで室温にて１．５時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、酢酸エチルで抽出した。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－シクロプロピルフェニル］－３－（１－メチルシクロブチル）－３－オキソプロピル｝ピリジン－２－カルボン酸メチル（２４１ｍｇ）を得た。　　　 Reference Example 113
A solution of tert-butyl {5-cyclopropyl-2- [2- (1-methylcyclobutyl) -2-oxoethyl] phenyl} carbamate (300 mg) in N, N-dimethylformamide (4.4 mL) under an argon atmosphere Was cooled in an ice-water bath. Thereto was added sodium hydride (50-72% in oil, 44 mg), and the mixture was stirred for 40 minutes under the same conditions. Thereto was added methyl 6- (chloromethyl) pyridine-2-carboxylate (162 mg), and the mixture was stirred under the same conditions for 30 minutes and then at room temperature for 1.5 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- {2- [2- (tert-butoxycarbonylamino) -4-cyclopropylphenyl] -3- (1 -Methylcyclobutyl) -3-oxopropyl} pyridine-2-carboxylate methyl ester (241 mg) was obtained.

参考例１１４
　アルゴン雰囲気下、５－ブロモ－２－メチルアニリン（２．００ｇ）のアセトニトリル（４３ｍＬ）溶液に、Ｎ－クロロこはく酸イミド（１．５１ｇ）を加え、その混合物を還流下２１．５時間攪拌した。反応混合物を放冷し、減圧下濃縮した。残渣に水を加え、その混合物を酢酸エチルで抽出した。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、５－ブロモ－４－クロロ－２－メチルアニリン（１．０４ｇ）を得た。 Reference Example 114
Under an argon atmosphere, N-chlorosuccinimide (1.51 g) was added to a solution of 5-bromo-2-methylaniline (2.00 g) in acetonitrile (43 mL), and the mixture was stirred under reflux for 21.5 hours. . The reaction mixture was allowed to cool and concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane) to give 5-bromo-4-chloro-2-methylaniline (1.04 g).

参考例１１５
　５－ブロモ－４－クロロ－２－メチルアニリン（１．０４ｇ）、シクロプロピルボロン酸一水和物（６３７ｍｇ）、トリシクロヘキシルホスフィン（約０．６ｍｏｌ／Ｌトルエン溶液、０．７８６ｍＬ）、リン酸三カリウム一水和物（３．８０ｇ）、トルエン（１３．１ｍＬ）及び水（１．３１ｍＬ）の混合物に、酢酸パラジウム（ＩＩ）（５３．０ｍｇ）を加え、この混合物を１００℃にて２４時間攪拌した。反応混合物を放冷し、セライト（登録商標）パッドを通じ濾過した。そのパッドを酢酸エチルで洗浄した。濾液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、４－クロロ－５－シクロプロピル－２－メチルアニリン（４３５ｍｇ）を得た。　　　 Reference Example 115
5-bromo-4-chloro-2-methylaniline (1.04 g), cyclopropylboronic acid monohydrate (637 mg), tricyclohexylphosphine (approximately 0.6 mol / L toluene solution, 0.786 mL), phosphoric acid To a mixture of tripotassium monohydrate (3.80 g), toluene (13.1 mL) and water (1.31 mL) was added palladium (II) acetate (53.0 mg) and the mixture was added at 100 ° C. at 24 ° C. Stir for hours. The reaction mixture was allowed to cool and filtered through a Celite® pad. The pad was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane) to give 4-chloro-5-cyclopropyl-2-methylaniline (435 mg).

参考例１１６
　対応する出発物質及び反応剤を用い、参考例５と同様の方法で、（４－クロロ－５－シクロプロピル－２－メチルフェニル）カルバミン酸ｔｅｒｔ－ブチルを合成した。 Reference Example 116
Tert-butyl (4-chloro-5-cyclopropyl-2-methylphenyl) carbamate was synthesized in the same manner as in Reference Example 5 using the corresponding starting materials and reactants.

参考例１１７
　アルゴン雰囲気下、（４－クロロ－５－シクロプロピル－２－メチルフェニル）カルバミン酸ｔｅｒｔ－ブチル（４００ｍｇ）のテトラヒドロフラン（７．１ｍＬ）溶液に、ｓｅｃ－ブチルリチウム（１．０８ｍｏｌ／Ｌヘキサン－シクロヘキサン溶液、３．６８ｍＬ）を－４５℃にてゆっくり滴下し、その混合物を同条件下２０分間攪拌した。そこへＮ－メトキシ－Ｎ，１－ジメチルシクロプロパンカルボキサミド（２２４ｍｇ）のテトラヒドロフラン（０．７１０ｍＬ）溶液を滴下し、その混合物を－４５℃にて４０分間、次いで室温にて８０分間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、｛４－クロロ－５－シクロプロピル－２－［２－（１－メチルシクロプロピル）－２－オキソエチル］フェニル｝カルバミン酸ｔｅｒｔ－ブチル（３４９ｍｇ）を得た。 Reference Example 117
Under an argon atmosphere, sec-butyllithium (1.08 mol / L hexane-cyclohexane) was added to a solution of tert-butyl (4-chloro-5-cyclopropyl-2-methylphenyl) carbamate (400 mg) in tetrahydrofuran (7.1 mL). Solution, 3.68 mL) was slowly added dropwise at −45 ° C., and the mixture was stirred for 20 minutes under the same conditions. Thereto was added dropwise a solution of N-methoxy-N, 1-dimethylcyclopropanecarboxamide (224 mg) in tetrahydrofuran (0.710 mL), and the mixture was stirred at −45 ° C. for 40 minutes and then at room temperature for 80 minutes. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give {4-chloro-5-cyclopropyl-2- [2- (1-methylcyclopropyl) -2-oxoethyl] Phenyl} carbamate tert-butyl (349 mg) was obtained.

参考例１１８
　アルゴン雰囲気下、｛４－クロロ－５－シクロプロピル－２－[２－（１－メチルシクロプロピル）－２－オキソエチル]フェニル｝カルバミン酸ｔｅｒｔ－ブチル（３４８ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（４．８ｍＬ）溶液を氷水浴中で冷却した。そこへ水素化ナトリウム（５０－７２％　ｉｎ　ｏｉｌ，４８ｍｇ）を加え、その混合物を同条件下１時間攪拌した。そこへ６－（クロロメチル）ピリジン－２－カルボン酸メチル（１９５ｍｇ）を加え、その混合物を同条件下１．５時間、次いで室温にて１．５時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－５－クロロ－４－シクロプロピルフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝ピリジン－２－カルボン酸メチル（３４５ｍｇ）を得た。 Reference Example 118
Under argon atmosphere, tert-butyl {4-chloro-5-cyclopropyl-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamate (348 mg) in N, N-dimethylformamide (4 .8 mL) The solution was cooled in an ice-water bath. Thereto was added sodium hydride (50-72% in oil, 48 mg), and the mixture was stirred for 1 hour under the same conditions. Thereto was added methyl 6- (chloromethyl) pyridine-2-carboxylate (195 mg), and the mixture was stirred under the same conditions for 1.5 hours and then at room temperature for 1.5 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- {2- [2- (tert-butoxycarbonylamino) -5-chloro-4-cyclopropylphenyl]- Methyl 3- (1-methylcyclopropyl) -3-oxopropyl} pyridine-2-carboxylate (345 mg) was obtained.

参考例１１９
　対応する出発物質及び反応剤を用い、参考例７８と同様の方法で、７－フルオロ－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドールを合成した。 Reference Example 119
7-Fluoro-6-methoxy-2- (1-methylcyclopropyl) -1H-indole was synthesized in the same manner as in Reference Example 78 using the corresponding starting materials and reactants.

参考例１２０
　室温にて、６－オキソ－１，６－ジヒドロピリジン－２－カルボン酸メチル（１．５４ｇ）のテトラヒドロフラン（５０ｍＬ）溶液にローソン試薬（１．０１ｇ）を加え、その混合物を６０℃で３時間攪拌した。溶媒を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－（溶出溶媒：ヘキサン－酢酸エチル）で精製し、６－チオキソ－１，６－ジヒドロピリジン－２－カルボン酸メチル（１．１０ｇ）を得た。 Reference Example 120
At room temperature, Lawesson's reagent (1.01 g) was added to a solution of methyl 6-oxo-1,6-dihydropyridine-2-carboxylate (1.54 g) in tetrahydrofuran (50 mL), and the mixture was stirred at 60 ° C. for 3 hours. did. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate) to obtain methyl 6-thioxo-1,6-dihydropyridine-2-carboxylate (1.10 g). It was.

参考例１２１
　５－ブロモ－４－フルオロ－２－メチルアニリン（１．００ｇ）、シクロプロピルボロン酸一水和物（６６２ｍｇ）、トリシクロヘキシルホスフィン（約０．６ｍｏｌ／Ｌトルエン溶液、０．８１７ｍＬ）、リン酸三カリウム一水和物（３．９５ｇ）、トルエン（１３．６ｍＬ）及び水（１．３６ｍＬ）の混合物に、酢酸パラジウム（ＩＩ）（５５．１ｍｇ）を加え、この混合物を１００℃にて２４時間攪拌した。反応混合物を放冷し、セライト（登録商標）パッドを通じ濾過した。そのパッドを酢酸エチルで洗浄した。濾液を水／飽和食塩水（１／１）で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をアミノプロピル化シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、５－シクロプロピル－４－フルオロ－２－メチルアニリン（６２２ｍｇ）を得た。　　　 Reference Example 121
5-Bromo-4-fluoro-2-methylaniline (1.00 g), cyclopropylboronic acid monohydrate (662 mg), tricyclohexylphosphine (approximately 0.6 mol / L toluene solution, 0.817 mL), phosphoric acid To a mixture of tripotassium monohydrate (3.95 g), toluene (13.6 mL) and water (1.36 mL) was added palladium (II) acetate (55.1 mg) and the mixture was added at 100 ° C. Stir for hours. The reaction mixture was allowed to cool and filtered through a Celite® pad. The pad was washed with ethyl acetate. The filtrate was washed with water / saturated brine (1/1). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 5-cyclopropyl-4-fluoro-2-methylaniline (622 mg).

参考例１２２
　対応する出発物質及び反応剤を用い、参考例５と同様の方法で、（５－シクロプロピル－４－フルオロ－２－メチルフェニル）カルバミン酸ｔｅｒｔ－ブチルを合成した。 Reference Example 122
Tert-butyl (5-cyclopropyl-4-fluoro-2-methylphenyl) carbamate was synthesized in the same manner as in Reference Example 5 using the corresponding starting materials and reactants.

参考例１２３
　アルゴン雰囲気下、（５－シクロプロピル－４－フルオロ－２－メチルフェニル）カルバミン酸ｔｅｒｔ－ブチル（１．０７ｇ）のテトラヒドロフラン（１８．８ｍＬ）溶液に、ｓｅｃ－ブチルリチウム（１．０８ｍｏｌ／Ｌヘキサン－シクロヘキサン溶液、７．６６ｍＬ）を－４５℃にてゆっくり滴下し、その混合物を同条件下２５分間攪拌した。そこへＮ－メトキシ－Ｎ，１－ジメチルシクロプロパンカルボキサミド（５９２ｍｇ）のテトラヒドロフラン（１．８８ｍＬ）溶液を滴下し、その混合物を－４５℃にて２５分間、次いで室温にて２．５時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、｛５－シクロプロピル－４－フルオロ－２－［２－（１－メチルシクロプロピル）－２－オキソエチル］フェニル｝カルバミン酸ｔｅｒｔ－ブチル（５５９ｍｇ）を得た。　　　 Reference Example 123
Under an argon atmosphere, sec-butyllithium (1.08 mol / L hexane) was added to a solution of tert-butyl (5-cyclopropyl-4-fluoro-2-methylphenyl) carbamate (1.07 g) in tetrahydrofuran (18.8 mL). -Cyclohexane solution (7.66 mL) was slowly added dropwise at -45 ° C, and the mixture was stirred for 25 minutes under the same conditions. Thereto was added dropwise a solution of N-methoxy-N, 1-dimethylcyclopropanecarboxamide (592 mg) in tetrahydrofuran (1.88 mL), and the mixture was stirred at −45 ° C. for 25 minutes and then at room temperature for 2.5 hours. . A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give {5-cyclopropyl-4-fluoro-2- [2- (1-methylcyclopropyl) -2-oxoethyl] Phenyl} carbamate tert-butyl (559 mg) was obtained.

参考例１２４
　アルゴン雰囲気下、｛５－シクロプロピル－４－フルオロ－２－[２－（１－メチルシクロプロピル）－２－オキソエチル]フェニル｝カルバミン酸ｔｅｒｔ－ブチル（３００ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（４．３ｍＬ）溶液を氷水浴中で冷却した。そこへ水素化ナトリウム（５０－７２％　ｉｎ　ｏｉｌ，４４ｍｇ）を加え、その混合物を同条件下７５分間攪拌した。そこへ６－（クロロメチル）ピリジン－２－カルボン酸メチル（１７６ｍｇ）を加え、その混合物を同条件下１時間、次いで室温にて２時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液及び水を加え、酢酸エチルで抽出した。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－シクロプロピル－５－フルオロフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝ピリジン－２－カルボン酸メチル（２６９ｍｇ）を得た。 Reference Example 124
Under an argon atmosphere, tert-butyl {5-cyclopropyl-4-fluoro-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl} carbamate (300 mg) with N, N-dimethylformamide (4 .3 mL) The solution was cooled in an ice-water bath. Thereto was added sodium hydride (50-72% in oil, 44 mg), and the mixture was stirred for 75 minutes under the same conditions. Thereto was added methyl 6- (chloromethyl) pyridine-2-carboxylate (176 mg), and the mixture was stirred under the same conditions for 1 hour and then at room temperature for 2 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- {2- [2- (tert-butoxycarbonylamino) -4-cyclopropyl-5-fluorophenyl]- Methyl 3- (1-methylcyclopropyl) -3-oxopropyl} pyridine-2-carboxylate (269 mg) was obtained.

参考例１２５
　加熱還流した２，３－ジヒドロベンゾフラン－６－アミン（３５４ｍｇ）のエタノール（１ｍＬ）溶液に、２－ブロモ－１－（１－メチルシクロプロピル）エタノン（８２２ｍｇ）のエタノール（１．０ｍＬ）溶液を１０分間かけて滴下した。その溶液を５時間加熱還流した。その溶液を室温まで冷却し、１ｍｏｌ／Ｌ塩酸を加え、次いで水を加えた。その溶液を酢酸エチルで希釈して、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を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－（溶出溶媒：ヘキサン－酢酸エチル）で精製し、６－（１－メチルシクロプロピル）－３，７－ジヒドロ－２Ｈ－フロ［３，２－ｆ］インドール（１９７ｍｇ）を得た。 Reference Example 125
A solution of 2-bromo-1- (1-methylcyclopropyl) ethanone (822 mg) in ethanol (1.0 mL) was added to a solution of 2,3-dihydrobenzofuran-6-amine (354 mg) in ethanol (1 mL) heated to reflux. It was added dropwise over 10 minutes. The solution was heated to reflux for 5 hours. The solution was cooled to room temperature, 1 mol / L hydrochloric acid was added, and then water was added. The solution was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate) to give 6- (1-methylcyclopropyl) -3,7-dihydro-2H-furo [3, 2-f] indole (197 mg) was obtained.

参考例１２６
　室温にて、６－（１－メチルシクロプロピル）－３，７－ジヒドロ－２Ｈ－フロ［３，２－ｆ］インドール（６７．０ｍｇ）と６－ホルミルピリジン－２－カルボン酸メチル（５７．５ｍｇ）の塩化メチレン溶液（１ｍＬ）に、１，８－ジアザビシクロ［５，４，０］ウンデカ－７－エン（５μＬ）を加え、その溶液をアルゴン雰囲気下１２時間攪拌した。減圧下、その溶液を濃縮した。残渣をシリカゲルカラムクロマトグラフィ－（溶出溶媒：ヘキサン－酢酸エチル）で精製し、６－｛ヒドロキシ［６－（１－メチルシクロプロピル）－３，７－ジヒドロ－２Ｈ－フロ［３，２－ｆ］インドール－５－イル］メチル｝ピリジン－２－カルボン酸メチル（８４．０ｍｇ）を得た。 Reference Example 126
At room temperature, 6- (1-methylcyclopropyl) -3,7-dihydro-2H-furo [3,2-f] indole (67.0 mg) and methyl 6-formylpyridine-2-carboxylate (57. 5 mg) in methylene chloride (1 mL) was added 1,8-diazabicyclo [5,4,0] undec-7-ene (5 μL) and the solution was stirred under an argon atmosphere for 12 hours. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate), and 6- {hydroxy [6- (1-methylcyclopropyl) -3,7-dihydro-2H-furo [3,2-f] Indol-5-yl] methyl} methyl-2-pyridine-2-carboxylate (84.0 mg) was obtained.

参考例１２７
　アルゴン雰囲気下、２－ブロモ－６－ホルミルピリジン（１．００ｇ）、１，４－ジアザビシクロ［２，２，２］オクタン（２５．０ｍｇ）、炭酸カリウム（７３４ｍｇ）、テトラブチルアンモニウムブロミド（１．７３ｇ）、酢酸パラジウム（２５．０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１０ｍL）懸濁液に、アクリル酸エチル（１．７ｍＬ）を加えて、１００℃で３時間攪拌した。その混合物を室温まで冷却後、酢酸エチルで希釈して、水、飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を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－（溶出溶媒：ヘキサン－酢酸エチル）で精製し、（Ｅ）－３－（６－ホルミルピリジン－２－イル）アクリル酸エチル（３５０ｍｇ）を得た。 Reference Example 127
Under an argon atmosphere, 2-bromo-6-formylpyridine (1.00 g), 1,4-diazabicyclo [2,2,2] octane (25.0 mg), potassium carbonate (734 mg), tetrabutylammonium bromide (1. 73 g) and ethyl acetate (1.7 mL) were added to a suspension of palladium acetate (25.0 mg) in N, N-dimethylformamide (10 mL), and the mixture was stirred at 100 ° C. for 3 hours. The mixture was cooled to room temperature, diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate), and ethyl (E) -3- (6-formylpyridin-2-yl) acrylate (350 mg) Got.

参考例１２８
　室温にて、６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール（２１２ｍｇ）と（Ｅ）－３－（６－ホルミルピリジン－２－イル）アクリル酸エチル（２２５ｍｇ）の塩化メチレン溶液（４ｍＬ）に、１，８－ジアザビシクロ［５，４，０］ウンデカ－７－エン（２０μＬ）を加え、その溶液をアルゴン雰囲気下２４時間攪拌した。減圧下、その溶液を濃縮した。残渣をシリカゲルカラムクロマトグラフィ－（溶出溶媒：ヘキサン－酢酸エチル）で精製し、（Ｅ）－３－（６－｛［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イル］（ヒドロキシ）メチル｝ピリジン－２－イル）アクリル酸エチル（３１３ｍｇ）を得た。 Reference Example 128
Chlorination of 6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indole (212 mg) and ethyl (E) -3- (6-formylpyridin-2-yl) acrylate (225 mg) at room temperature To the methylene solution (4 mL) was added 1,8-diazabicyclo [5,4,0] undec-7-ene (20 μL), and the solution was stirred under an argon atmosphere for 24 hours. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate), and (E) -3- (6-{[6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indole-3 -Il] (hydroxy) methyl} pyridin-2-yl) ethyl acrylate (313 mg) was obtained.

参考例１２９
　室温にて、６－エチニルピリジン－２－カルボキサルデヒド（３９４ｍｇ）、炭酸カリウム（８３２ｍｇ）、トリフェニルホスフィン（１５７ｍｇ）、塩化パラジウム（ＩＩ）（５８．２ｍｇ）、１，４－ジクロロ－２－ブテン（０．６３ｍＬ）のテトラヒドロフラン（１５ｍＬ）－メタノール（９ｍＬ）懸濁液を一酸化炭素雰囲気下、６時間攪拌した。溶媒を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－（溶出溶媒：ヘキサン－酢酸エチル）で精製し、３－（６－ホルミルピリジン－２－イル）プロピオール酸メチル（２２０ｍｇ）を得た。 Reference Example 129
At room temperature, 6-ethynylpyridine-2-carboxaldehyde (394 mg), potassium carbonate (832 mg), triphenylphosphine (157 mg), palladium (II) chloride (58.2 mg), 1,4-dichloro-2- A suspension of butene (0.63 mL) in tetrahydrofuran (15 mL) -methanol (9 mL) was stirred under a carbon monoxide atmosphere for 6 hours. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain methyl 3- (6-formylpyridin-2-yl) propiolate (220 mg).

参考例１３０
　氷冷下、６－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（４５５ｍｇ）の塩化メチレン（１３ｍＬ）溶液に三臭化ホウ素（１．０ｍｏｌ／Ｌ　塩化メチレン溶液、２．６ｍＬ）を加えて、同条件下、２時間攪拌した。その溶液にメタノール（１ｍＬ）、飽和炭酸水素ナトリウム水溶液を順次加えて、酢酸エチルにて抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を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－（溶出溶媒：ヘキサン－酢酸エチル）で精製し、６－［６－ヒドロキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（２３７ｍｇ）を得た。 Reference Example 130
Tribromide to a solution of methyl 6- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (455 mg) in methylene chloride (13 mL) under ice cooling Boron (1.0 mol / L methylene chloride solution, 2.6 mL) was added and stirred for 2 hours under the same conditions. Methanol (1 mL) and saturated aqueous sodium hydrogen carbonate solution were sequentially added to the solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate) to give 6- [6-hydroxy-2- (1-methylcyclopropyl) -1H-indole-3. -Ilmethyl] methyl pyridine-2-carboxylate (237 mg) was obtained.

参考例１３１
　氷冷下、６－［６－ヒドロキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（２５７ｍｇ）テトラヒドロフラン（４ｍＬ）溶液にピリジン（０．２０ｍＬ）とトリフルオロメタンスルホン酸無水物（０．１５ｍＬ）を順次加えた。その混合物を氷冷下で３０分間、室温で１時間攪拌した。その混合物を酢酸エチルで希釈し、飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥した。溶媒を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－（溶出溶媒：ヘキサン－酢酸エチル）で精製し、６－［２－（１－メチルシクロプロピル）－６－（トリフルオロメチルスルホニルオキシ）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（２９０ｍｇ）を得た。 Reference Example 131
Under ice-cooling, methyl 6- [6-hydroxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (257 mg) in tetrahydrofuran (4 mL) was dissolved in pyridine (0.20 mL). ) And trifluoromethanesulfonic anhydride (0.15 mL) were sequentially added. The mixture was stirred for 30 minutes under ice cooling and 1 hour at room temperature. The mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate) to give 6- [2- (1-methylcyclopropyl) -6- (trifluoromethylsulfonyloxy). -1H-Indol-3-ylmethyl] pyridine-2-carboxylate methyl ester (290 mg) was obtained.

参考例１３２
　アルゴン雰囲気下、Ｎ，Ｎ－ジメチルホルムアミド（０．６５６ｍＬ）を氷水浴中で冷却した。そこへ塩化ホスホリル（０．５８９ｍＬ）を滴下し、その混合物を室温まで昇温した。そこへフラン－３－カルボン酸エチル（０．６３１ｍＬ）を滴下した。その混合物を徐々に１００℃まで加熱し、１．５時間攪拌した。反応混合物を放冷し、次いで氷水に加えた。その混合物をジエチルエーテルで抽出した。水層をジエチルエーテルで抽出した。合一した有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、５－ホルミルフラン－３－カルボン酸エチル（２９４ｍｇ）を得た。 Reference Example 132
N, N-dimethylformamide (0.656 mL) was cooled in an ice-water bath under an argon atmosphere. Phosphoryl chloride (0.589 mL) was added dropwise thereto, and the mixture was warmed to room temperature. Thereto, ethyl furan-3-carboxylate (0.631 mL) was added dropwise. The mixture was gradually heated to 100 ° C. and stirred for 1.5 hours. The reaction mixture was allowed to cool and then added to ice water. The mixture was extracted with diethyl ether. The aqueous layer was extracted with diethyl ether. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane) to give ethyl 5-formylfuran-3-carboxylate (294 mg).

参考例１３３
　アルゴン雰囲気下、２－メトキシ－４－ニトロフェノール（１．００ｇ）のジクロロメタン（２９．６ｍＬ）懸濁液に、ピリジン（１．４４ｍＬ）を加えた。そこへトリフルオロメタンスルホン酸無水物（１．４６ｍＬ）を滴下し、その混合物を室温にて４時間攪拌した。反応混合物にクラッシュアイスを加え、その混合物をさらに２０分間攪拌した。その混合物に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、トリフルオロメタンスルホン酸２－メトキシ－４－ニトロフェニル（１．７７ｇ）を得た。 Reference Example 133
Pyridine (1.44 mL) was added to a suspension of 2-methoxy-4-nitrophenol (1.00 g) in dichloromethane (29.6 mL) under an argon atmosphere. Trifluoromethanesulfonic anhydride (1.46 mL) was added dropwise thereto, and the mixture was stirred at room temperature for 4 hours. Crush ice was added to the reaction mixture and the mixture was stirred for an additional 20 minutes. Saturated aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 2-methoxy-4-nitrophenyl trifluoromethanesulfonate (1.77 g).

参考例１３４
　トリフルオロメタンスルホン酸２－メトキシ－４－ニトロフェニル（８７０ｍｇ）、イソプロペニルボロン酸ピナコールエステル（０．５１４ｍＬ）、２ｍｏｌ／Ｌ炭酸ナトリウム水溶液（２．８９ｍＬ）及び１，２－ジメトキシエタン（１４．４ｍＬ）の混合物に、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）ジクロリド（１５２ｍｇ）を加え、その混合物をマイクロ波照射下１００℃にて１時間攪拌した。反応混合物を放冷した。反応混合物に水／飽和食塩水（１／１）を加え、その混合物を酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、２－イソプロペニル－５－ニトロアニソール（４２２ｍｇ）を得た。 Reference Example 134
2-methoxy-4-nitrophenyl trifluoromethanesulfonate (870 mg), isopropenylboronic acid pinacol ester (0.514 mL), 2 mol / L aqueous sodium carbonate solution (2.89 mL) and 1,2-dimethoxyethane (14.4 mL) ) Was added bis (triphenylphosphine) palladium (II) dichloride (152 mg), and the mixture was stirred at 100 ° C. for 1 hour under microwave irradiation. The reaction mixture was allowed to cool. Water / saturated brine (1/1) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane) to give 2-isopropenyl-5-nitroanisole (422 mg).

参考例１３５
　２－イソプロペニル－５－ニトロアニソール（８７５ｍｇ）の酢酸エチル（２２．６ｍＬ）溶液に、１０％パラジウム炭素（含水率５６．５ｗｔ％，２０２ｍｇ）を加え、その混合物を水素雰囲気下、室温にて一晩攪拌した。反応混合物をセライト（登録商標）パッドを通じ濾過した。濾液を減圧下濃縮することにより、４－イソプロピル－３－メトキシアニリン（７７７ｍｇ）を得た。 Reference Example 135
To a solution of 2-isopropenyl-5-nitroanisole (875 mg) in ethyl acetate (22.6 mL) was added 10% palladium carbon (moisture content 56.5 wt%, 202 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere. Stir overnight. The reaction mixture was filtered through a Celite® pad. The filtrate was concentrated under reduced pressure to give 4-isopropyl-3-methoxyaniline (777 mg).

参考例１３６
　対応する出発物質及び反応剤を用い、参考例３８と同様の方法で、５－イソプロピル－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドールを合成した。 Reference Example 136
5-isopropyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indole was synthesized in the same manner as in Reference Example 38 using the corresponding starting materials and reactants.

参考例１３７
　６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール（３１４ｍｇ）及び４－ジメチルアミノピリジン（９．５ｍｇ）のアセトニトリル（１１ｍＬ）溶液に、二炭酸ジｔｅｒｔ－ブチル（５１１ｍｇ）のアセトニトリル（４．６ｍＬ）溶液を滴下し、その混合物を室温にて４時間攪拌した。そこへ二炭酸ジｔｅｒｔ－ブチル（３４１ｍｇ）のアセトニトリル（２．３ｍＬ）溶液を滴下し、その混合物を室温にてさらに２日間攪拌した。反応混合物を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－１－カルボン酸ｔｅｒｔ－ブチル（４１４ｍｇ）を得た。 Reference Example 137
To a solution of 6-methoxy-2- (1-methylcyclopropyl) -1H-indole (314 mg) and 4-dimethylaminopyridine (9.5 mg) in acetonitrile (11 mL), ditert-butyl dicarbonate (511 mg) in acetonitrile. (4.6 mL) solution was added dropwise and the mixture was stirred at room temperature for 4 hours. A solution of di-tert-butyl dicarbonate (341 mg) in acetonitrile (2.3 mL) was added dropwise thereto, and the mixture was further stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give tert-butyl 6-methoxy-2- (1-methylcyclopropyl) -1H-indole-1-carboxylate (414 mg). )

参考例１３８
　６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－１－カルボン酸ｔｅｒｔ－ブチル（３１３ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３．８ｍＬ）溶液に、Ｎ－ヨードコハク酸イミド（２５７ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（２．４ｍＬ）溶液を滴下し、その混合物を室温にて２４時間攪拌した。反応混合物を酢酸エチルで希釈し、水で洗浄した。有機層を水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮することにより、３－ヨード－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－１－カルボン酸ｔｅｒｔ－ブチル（４８０ｍｇ）を得た。 Reference Example 138
To a solution of tert-butyl 6-methoxy-2- (1-methylcyclopropyl) -1H-indole-1-carboxylate (313 mg) in N, N-dimethylformamide (3.8 mL) was added N-iodosuccinimide (257 mg). ) In N, N-dimethylformamide (2.4 mL) was added dropwise, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 3-iodo-6-methoxy-2- (1-methylcyclopropyl) -1H-indole-1-carboxylic acid tert- Butyl (480 mg) was obtained.

参考例１３９
　３－ヨード－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－１－カルボン酸ｔｅｒｔ－ブチル（４４４ｍｇ）、６－エチニルピリジン－２－カルボン酸メチル（２５１ｍｇ）、よう化銅（Ｉ）（１９．８ｍｇ）、トリエチルアミン（０．４３４ｍＬ）及びアセトニトリル（２．６ｍＬ）の混合物に、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）ジクロリド（３６．４ｍｇ）を加え、その混合物をマイクロ波照射下１２０℃にて２時間攪拌した。反応混合物を放冷した。反応混合物に飽和食塩水を加え、酢酸エチルで抽出した。水層を酢酸エチルで抽出した。合一した有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、６－メトキシ－３－（６－メトキシカルボニルピリジン－２－イルエチニル）－２－（１－メチルシクロプロピル）－１Ｈ－インドール－１－カルボン酸ｔｅｒｔ－ブチル（６６．２ｍｇ）を得た。 Reference Example 139
3-iodo-6-methoxy-2- (1-methylcyclopropyl) -1H-indole-1-carboxylate tert-butyl (444 mg), methyl 6-ethynylpyridine-2-carboxylate (251 mg), copper iodide To a mixture of (I) (19.8 mg), triethylamine (0.434 mL) and acetonitrile (2.6 mL) was added bis (triphenylphosphine) palladium (II) dichloride (36.4 mg) and the mixture was microwaved. The mixture was stirred at 120 ° C. for 2 hours under irradiation. The reaction mixture was allowed to cool. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6-methoxy-3- (6-methoxycarbonylpyridin-2-ylethynyl) -2- (1-methylcyclopropyl) Tert-Butyl-1H-indole-1-carboxylate (66.2 mg) was obtained.

参考例１４０
　６－メトキシ－３－（６－メトキシカルボニルピリジン－２－イルエチニル）－２－（１－メチルシクロプロピル）－１Ｈ－インドール－１－カルボン酸ｔｅｒｔ－ブチル（６５．０ｍｇ）のメタノール（１．４ｍＬ）溶液に、１０％パラジウム炭素（含水率５６．５ｗｔ％，２２ｍｇ）を加えた。そこへトリエチルシラン（０．２２５ｍＬ）を滴下し、その混合物を水素雰囲気下、室温にて３時間攪拌した。反応混合物をセライト（登録商標）パッドを通じ濾過し、濾液を減圧下濃縮した。残渣をメタノール（１．４ｍＬ）に溶解した。そこへ１０％パラジウム炭素（含水率５６．５ｗｔ％，２２ｍｇ）及びトリエチルシランを順次加え、その混合物を水素雰囲気下、室温にて９時間攪拌した。反応混合物をセライト（登録商標）パッドを通じ濾過し、濾液を減圧下濃縮した。残渣をアミノプロピル化シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、６－メトキシ－３－［２－（６－メトキシカルボニルピリジン－２－イル）エチル］－２－（１－メチルシクロプロピル）－１Ｈ－インドール－１－カルボン酸ｔｅｒｔ－ブチル（５４．６ｍｇ）を得た。 Reference Example 140
6-Methoxy-3- (6-methoxycarbonylpyridin-2-ylethynyl) -2- (1-methylcyclopropyl) -1H-indole-1-carboxylate tert-butyl (65.0 mg) in methanol (1.4 mL ) 10% palladium on carbon (water content 56.5 wt%, 22 mg) was added to the solution. Triethylsilane (0.225 mL) was added dropwise thereto, and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. The reaction mixture was filtered through a Celite (registered trademark) pad, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (1.4 mL). 10% palladium carbon (water content 56.5 wt%, 22 mg) and triethylsilane were sequentially added thereto, and the mixture was stirred at room temperature for 9 hours in a hydrogen atmosphere. The reaction mixture was filtered through a Celite (registered trademark) pad, and the filtrate was concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6-methoxy-3- [2- (6-methoxycarbonylpyridin-2-yl) ethyl] -2- There was obtained tert-butyl (54.6 mg) (1-methylcyclopropyl) -1H-indole-1-carboxylate.

なお、参考例１～１４０の構造式および物性値を表１～１７に示した。  The structural formulas and physical property values of Reference Examples 1 to 140 are shown in Tables 1 to 17.

Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000014

Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000015

Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-T000016

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

実施例１
　アルゴン雰囲気下、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－メトキシフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝ピリジン－２－カルボン酸メチル（９５７ｍｇ）のジクロロメタン／アセトニトリル（６．８ｍL／６．８ｍL）溶液を氷水浴中で冷却した。そこへトリフルオロ酢酸（６．８ｍＬ）を加え、その混合物を室温にて４０時間攪拌した。反応混合物を減圧下濃縮した。残渣を酢酸エチルに溶かし、飽和炭酸水素ナトリウム水溶液で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、６－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（５８６ｍｇ）を得た。 Example 1
Under an argon atmosphere, methyl 6- {2- [2- (tert-butoxycarbonylamino) -4-methoxyphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl} pyridine-2-carboxylate (957 mg) ) In dichloromethane / acetonitrile (6.8 mL / 6.8 mL) was cooled in an ice-water bath. Trifluoroacetic acid (6.8 mL) was added thereto, and the mixture was stirred at room temperature for 40 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine- Methyl 2-carboxylate (586 mg) was obtained.

実施例２
　アルゴン雰囲気下、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－シクロプロピルフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝ピリジン－２－カルボン酸メチル（５５０ｍｇ）のジクロロメタン／アセトニトリル（３．８ｍL／３．８ｍL）溶液を氷水浴中で冷却した。そこへトリフルオロ酢酸（３．８ｍＬ）を加え、その混合物を室温にて４６時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液で洗浄した。有機層を無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－へキサン）にて精製することにより、６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（３５６ｍｇ）を得た。 Example 2
Under an argon atmosphere, methyl 6- {2- [2- (tert-butoxycarbonylamino) -4-cyclopropylphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl} pyridine-2-carboxylate ( 550 mg) in dichloromethane / acetonitrile (3.8 mL / 3.8 mL) was cooled in an ice-water bath. Trifluoroacetic acid (3.8 mL) was added there, and the mixture was stirred at room temperature for 46 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine. Methyl -2-carboxylate (356 mg) was obtained.

実施例３
　アルゴン雰囲気下、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－クロロフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝ピリジン－２－カルボン酸メチル（７８６ｍｇ）のジクロロメタン（８．４ｍL）溶液を氷水浴中で冷却した。そこへトリフルオロ酢酸（２．８ｍＬ）を加え、その混合物を室温にて２４時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液及び飽和炭酸水素ナトリウム水溶液／飽和食塩水（１／１）で順次洗浄した。有機層を無水硫酸マグネシウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ジクロロメタン）にて精製することにより、６－［６－クロロ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（５２３ｍｇ）を得た。 Example 3
Methyl 6- {2- [2- (tert-butoxycarbonylamino) -4-chlorophenyl] -3- (1-methylcyclopropyl) -3-oxopropyl} pyridine-2-carboxylate (786 mg) under argon atmosphere Of dichloromethane (8.4 mL) was cooled in an ice-water bath. Trifluoroacetic acid (2.8 mL) was added thereto, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium hydrogen carbonate solution / saturated brine (1/1). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-dichloromethane) to give 6- [6-chloro-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2. -Methyl carboxylate (523 mg) was obtained.

実施例４
　アルゴン雰囲気下、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－メチルフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝ピリジン－２－カルボン酸メチル（４３３ｍｇ）のジクロロメタン（４．８ｍL）溶液を氷水浴中で冷却した。そこへトリフルオロ酢酸（１．６ｍＬ）を加え、その混合物を室温にて２４時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、６－［６－メチル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（１７２ｍｇ）を得た。 Example 4
Under an argon atmosphere, methyl 6- {2- [2- (tert-butoxycarbonylamino) -4-methylphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl} pyridine-2-carboxylate (433 mg) ) In dichloromethane (4.8 mL) was cooled in an ice-water bath. Trifluoroacetic acid (1.6 mL) was added there, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- [6-methyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2. -Methyl carboxylate (172 mg) was obtained.

実施例５
　対応する出発物質及び反応剤を用い、実施例４と同様の方法で、６－［６－エトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチルを合成した。 Example 5
6- [6-Ethoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 4 using the corresponding starting materials and reagents. Methyl was synthesized.

実施例６
　対応する出発物質及び反応剤を用い、実施例４と同様の方法で、６－［６－イソプロポキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチルを合成した。 Example 6
6- [6-Isopropoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid was prepared in the same manner as in Example 4 using the corresponding starting materials and reagents. Methyl acid was synthesized.

実施例７
　アルゴン雰囲気下、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－クロロ－５－メトキシフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝ピリジン－２－カルボン酸メチル（１０２ｍｇ）のジクロロメタン（２ｍL）溶液に、トリフルオロ酢酸（０．４ｍＬ）を加え、その混合物を室温にて１７時間攪拌した。反応混合物をアミノプロピル化シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、６－［６－クロロ－５－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（７１．８ｍｇ）を得た。 Example 7
Under an argon atmosphere, 6- {2- [2- (tert-butoxycarbonylamino) -4-chloro-5-methoxyphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl} pyridine-2-carvone To a solution of methyl acid (102 mg) in dichloromethane (2 mL) was added trifluoroacetic acid (0.4 mL), and the mixture was stirred at room temperature for 17 hours. The reaction mixture was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- [6-chloro-5-methoxy-2- (1-methylcyclopropyl) -1H-indole. Methyl -3-ylmethyl] pyridine-2-carboxylate (71.8 mg) was obtained.

実施例８
　対応する出発物質及び反応剤を用い、実施例４と同様の方法で、６－［６－エチル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチルを合成した。 Example 8
6- [6-Ethyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 4 using the corresponding starting materials and reagents. Methyl was synthesized.

実施例９
　アルゴン雰囲気下、５－クロロ－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール（２００ｍｇ）、６－ホルミルピリジン－２－カルボン酸メチル（１４０ｍｇ）及びトリエチルシラン（０．４０７ｍＬ）のジクロロメタン（２ｍＬ）溶液を氷水浴中で冷却した。そこへトリフルオロ酢酸（０．０９５ｍＬ）を加え、その混合物を同条件下３０分間、次いで室温にて１２時間攪拌した。反応混合物をアミノプロピル化シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）、次いでシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、６－［５－クロロ－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（２５３ｍｇ）を得た。 Example 9
Under an argon atmosphere, 5-chloro-6-methoxy-2- (1-methylcyclopropyl) -1H-indole (200 mg), methyl 6-formylpyridine-2-carboxylate (140 mg) and triethylsilane (0.407 mL) Of dichloromethane (2 mL) was cooled in an ice-water bath. Trifluoroacetic acid (0.095 mL) was added thereto, and the mixture was stirred under the same conditions for 30 minutes and then at room temperature for 12 hours. The reaction mixture is purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) and then silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- [5-chloro-6- Methyl methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (253 mg) was obtained.

実施例１０
　対応する出発物質及び反応剤を用い、実施例４と同様の方法で、６－［６－イソプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチルを合成した。 Example 10
6- [6-Isopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 4 using the corresponding starting materials and reagents. Methyl was synthesized.

実施例１１
　アルゴン雰囲気下、６－メトキシ－５－メチル－２－（１－メチルシクロプロピル）－１Ｈ－インドール（５８６ｍｇ）、６－ホルミルピリジン－２－カルボン酸メチル（４５０ｍｇ）及びトリエチルシラン（１．３０ｍＬ）のジクロロメタン（１３．６ｍＬ）溶液を氷水浴中で冷却した。そこへトリフルオロ酢酸（０．３１３ｍＬ）を加え、その混合物を同条件下３０分間、次いで室温にて３時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液及び飽和食塩水で順次洗浄した。有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮した。残渣をメタノールに懸濁した。析出物を濾取し、メタノールで洗浄後、減圧下乾燥することにより、６－［６－メトキシ－５－メチル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（６８８ｍｇ）を得た。 Example 11
Under an argon atmosphere, 6-methoxy-5-methyl-2- (1-methylcyclopropyl) -1H-indole (586 mg), methyl 6-formylpyridine-2-carboxylate (450 mg) and triethylsilane (1.30 mL) Of dichloromethane in 13.6 mL was cooled in an ice-water bath. Trifluoroacetic acid (0.313 mL) was added thereto, and the mixture was stirred under the same conditions for 30 minutes and then at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was suspended in methanol. The precipitate is collected by filtration, washed with methanol, and dried under reduced pressure to give 6- [6-methoxy-5-methyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine- Methyl 2-carboxylate (688 mg) was obtained.

実施例１２
　アルゴン雰囲気下、５－フルオロ－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール（７３３ｍｇ）、６－ホルミルピリジン－２－カルボン酸メチル（５５２ｍｇ）及びトリエチルシラン（１．６０ｍＬ）のジクロロメタン（１６．７ｍＬ）溶液を氷水浴中で冷却した。そこへトリフルオロ酢酸（０．３８４ｍＬ）を加え、その混合物を同条件下３０分間、次いで室温にて７時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液で洗浄した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をヘキサン／ジクロロメタンに懸濁した。析出物を濾取し、ヘキサン／ジクロロメタンで洗浄後、減圧下乾燥した。得られた固体をアセトニトリルに懸濁させた。その懸濁液を還流下攪拌し、得られた溶液を放冷した。析出物を濾去した。濾液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、６－［５－フルオロ－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（３８９ｍｇ）を得た。 Example 12
Under an argon atmosphere, 5-fluoro-6-methoxy-2- (1-methylcyclopropyl) -1H-indole (733 mg), methyl 6-formylpyridine-2-carboxylate (552 mg) and triethylsilane (1.60 mL) Of dichloromethane (16.7 mL) was cooled in an ice-water bath. Trifluoroacetic acid (0.384 mL) was added thereto, and the mixture was stirred under the same conditions for 30 minutes and then at room temperature for 7 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was suspended in hexane / dichloromethane. The precipitate was collected by filtration, washed with hexane / dichloromethane, and dried under reduced pressure. The resulting solid was suspended in acetonitrile. The suspension was stirred under reflux and the resulting solution was allowed to cool. The precipitate was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- [5-fluoro-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl. ] Methyl pyridine-2-carboxylate (389 mg) was obtained.

実施例１３
　アルゴン雰囲気下、３－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－シクロプロピルフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝安息香酸メチル（２６０ｍｇ）のジクロロメタン（５．５ｍＬ）溶液を氷水浴中で冷却した。そこへトリフルオロ酢酸（１．１ｍＬ）を加え、その混合物を室温にて１４時間、次いで３０℃にて５時間攪拌した。反応混合物に酢酸エチル及び飽和炭酸水素ナトリウム水溶液を加え、有機層を分離した。その有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、３－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］安息香酸メチル（４５．２ｍｇ）を得た。 Example 13
Dichloromethane of methyl 3- {2- [2- (tert-butoxycarbonylamino) -4-cyclopropylphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl} benzoate (260 mg) under argon atmosphere The solution (5.5 mL) was cooled in an ice-water bath. Trifluoroacetic acid (1.1 mL) was added thereto, and the mixture was stirred at room temperature for 14 hours and then at 30 ° C. for 5 hours. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 3- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] benzoic acid. Methyl (45.2 mg) was obtained.

実施例１４
　対応する出発物質及び反応剤を用い、実施例１３と同様の方法で、５－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］フラン－２－カルボン酸エチルを合成した。 Example 14
5- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] furan-2-carboxylic acid in the same manner as in Example 13 using the corresponding starting materials and reagents. Ethyl acid was synthesized.

実施例１５
　氷冷下、３－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－シクロプロピルフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝－２－フルオロ安息香酸メチル（１４２ｍｇ）に、トリフルオロ酢酸（１ｍＬ）を加え、その混合物を室温にて３０分間攪拌した。反応混合物を酢酸エチルで希釈し，飽和炭酸水素ナトリウム水溶液で洗浄した。その有機層を飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、３－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］－２－フルオロ安息香酸メチル（７５．２ｍｇ）を得た。 Example 15
Under ice cooling, methyl 3- {2- [2- (tert-butoxycarbonylamino) -4-cyclopropylphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl} -2-fluorobenzoate ( 142 mg) was added trifluoroacetic acid (1 mL) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was washed successively with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 3- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] -2 -Methyl fluorobenzoate (75.2 mg) was obtained.

実施例１６
　アルゴン雰囲気下、６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール（１３４ｍｇ）、２－ホルミルチアゾール－４－カルボン酸エチル（１０９ｍｇ）及びトリエチルシラン（０．３０４ｍＬ）のジクロロメタン（２ｍＬ）溶液を氷水浴中で冷却した。そこへトリフルオロ酢酸（０．０７１ｍＬ）を加え、その混合物を同条件下３０分間、次いで室温にて１３時間攪拌した。反応混合物をアミノプロピル化シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、２－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］チアゾール－４－カルボン酸エチル（１８０ｍｇ）を得た。 Example 16
Under argon atmosphere, 6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indole (134 mg), ethyl 2-formylthiazole-4-carboxylate (109 mg) and triethylsilane (0.304 mL) in dichloromethane ( (2 mL) The solution was cooled in an ice-water bath. Trifluoroacetic acid (0.071 mL) was added thereto, and the mixture was stirred for 30 minutes under the same conditions and then at room temperature for 13 hours. The reaction mixture was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 2- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indole-3- Ethyl [Ilmethyl] thiazole-4-carboxylate (180 mg) was obtained.

実施例１７
　アルゴン雰囲気下、２－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－メトキシフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝イソニコチン酸メチル（１９１ｍｇ）のジクロロメタン（２．１ｍＬ）溶液を氷水浴中で冷却した。そこへトリフルオロ酢酸（０．７ｍＬ）を加え、その混合物を室温にて５時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液で洗浄した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をアミノプロピル化シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、２－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］イソニコチン酸メチル（１２３ｍｇ）を得た。 Example 17
Dichloromethane of methyl 2- {2- [2- (tert-butoxycarbonylamino) -4-methoxyphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl} isonicotinate (191 mg) under argon atmosphere (2.1 mL) The solution was cooled in an ice-water bath. Trifluoroacetic acid (0.7 mL) was added there, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 2- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl]. Methyl isonicotinate (123 mg) was obtained.

実施例１８
　アルゴン雰囲気下、６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール（１４０ｍｇ）、５－ホルミルチオフェン－２－カルボン酸エチル（１２８ｍｇ）及びトリエチルシラン（０．３３３ｍＬ）のジクロロメタン（３．５ｍＬ）溶液を氷水浴中で冷却した。そこへトリフルオロ酢酸（０．０８０ｍＬ）を加え、その混合物を同条件下３０分間、次いで室温にて２時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液で洗浄した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をアミノプロピル化シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、５－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］チオフェン－２－カルボン酸エチル（７６．３ｍｇ）を得た。 Example 18
Under an argon atmosphere, 6-methoxy-2- (1-methylcyclopropyl) -1H-indole (140 mg), ethyl 5-formylthiophene-2-carboxylate (128 mg) and triethylsilane (0.333 mL) in dichloromethane (3 .5 mL) The solution was cooled in an ice-water bath. Trifluoroacetic acid (0.080 mL) was added thereto, and the mixture was stirred for 30 minutes under the same conditions and then at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 5- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl]. Ethyl thiophene-2-carboxylate (76.3 mg) was obtained.

実施例１９
　アルゴン雰囲気下、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－メトキシフェニル］－３－（１－エチルシクロプロピル）－３－オキソプロピル｝ピリジン－２－カルボン酸メチル（２４８ｍｇ）のジクロロメタン（２．６ｍＬ）溶液を氷水浴中で冷却した。そこへトリフルオロ酢酸（０．８７ｍＬ）を加え、その混合物を室温にて１０時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液で洗浄した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ジクロロメタン）にて精製することにより、６－［２－（１－エチルシクロプロピル）－６－メトキシ－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（１６７ｍｇ）を得た。 Example 19
Under an argon atmosphere, methyl 6- {2- [2- (tert-butoxycarbonylamino) -4-methoxyphenyl] -3- (1-ethylcyclopropyl) -3-oxopropyl} pyridine-2-carboxylate (248 mg) ) In dichloromethane (2.6 mL) was cooled in an ice-water bath. Trifluoroacetic acid (0.87 mL) was added there, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-dichloromethane) to give 6- [2- (1-ethylcyclopropyl) -6-methoxy-1H-indol-3-ylmethyl] pyridine-2. -Methyl carboxylate (167 mg) was obtained.

実施例２０
　アルゴン雰囲気下、３－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－メトキシフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝安息香酸メチル（２１５ｍｇ）に、トリフルオロ酢酸（１ｍＬ）を加え、その混合物を室温にて１時間攪拌した。反応混合物をアミノプロピル化シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、３－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］安息香酸メチル（１３２ｍｇ）を得た。 Example 20
Trimethyl 3- {2- [2- (tert-butoxycarbonylamino) -4-methoxyphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl} benzoate (215 mg) under argon atmosphere Fluoroacetic acid (1 mL) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 3- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl. ] Methyl benzoate (132 mg) was obtained.

実施例２１
　対応する出発物質及び反応剤を用い、実施例２０と同様の方法で、５－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］フラン－２－カルボン酸エチルを合成した。 Example 21
5- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] furan-2-carboxylic acid in the same manner as in Example 20 using the corresponding starting materials and reagents. Ethyl was synthesized.

実施例２２
　対応する出発物質及び反応剤を用い、実施例２０と同様の方法で２－フルオロ－３－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］安息香酸メチルを合成した。 Example 22
Methyl 2-fluoro-3- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] benzoate in the same manner as in Example 20 using the corresponding starting materials and reactants Was synthesized.

実施例２３
　対応する出発物質及び反応剤を用い、実施例１６と同様の方法で、２－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］チアゾール－４－カルボン酸エチルを合成した。 Example 23
2- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiazole-4-carboxylic acid was prepared in the same manner as in Example 16 using the corresponding starting materials and reactants. Ethyl was synthesized.

実施例２４
　アルゴン雰囲気下、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４，５－ジメチルフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝ピリジン－２－カルボン酸メチル（２０２ｍｇ）のジクロロメタン（２．１６ｍＬ）溶液を氷水浴中で冷却した。そこへトリフルオロ酢酸（０．７２ｍＬ）を加え、その混合物を室温にて４．５時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液で洗浄した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ジクロロメタン）にて精製することにより、６－［５，６－ジメチル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（１２９ｍｇ）を得た。 Example 24
Methyl 6- {2- [2- (tert-butoxycarbonylamino) -4,5-dimethylphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl} pyridine-2-carboxylate under an argon atmosphere A solution of (202 mg) in dichloromethane (2.16 mL) was cooled in an ice-water bath. Trifluoroacetic acid (0.72 mL) was added there, and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-dichloromethane) to give 6- [5,6-dimethyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine. Methyl -2-carboxylate (129 mg) was obtained.

実施例２５
　対応する出発物質及び反応剤を用い、実施例１８と同様の方法で、５－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］チオフェン－３－カルボン酸メチルを合成した。 Example 25
5- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiophene-3-carboxylic acid was prepared in the same manner as in Example 18 using the corresponding starting materials and reactants. Methyl was synthesized.

実施例２６
　対応する出発物質及び反応剤を用い、実施例１８と同様の方法で、５－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］チオフェン－２－カルボン酸エチルを合成した。 Example 26
5- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiophene-2-carboxylic acid was prepared in the same manner as in Example 18 using the corresponding starting materials and reagents. Ethyl acid was synthesized.

実施例２７
　アルゴン雰囲気下、６－ジフルオロメトキシ－（１－メチルシクロプロピル）－１Ｈ－インドール（１７０ｍｇ）、６－ホルミルピリジン－２－カルボン酸メチル（１１８ｍｇ）及びトリエチルシラン（０．３４４ｍＬ）のジクロロメタン（３．０ｍＬ）溶液を氷水浴中で冷却した。そこへトリフルオロ酢酸（０．０８０ｍＬ）を加え、その混合物を同条件下３０分間、次いで室温にて７時間攪拌した。反応混合物をアミノプロピル化シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、６－［６－ジフルオロメトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（１６０ｍｇ）を得た。 Example 27
Under an argon atmosphere, 6-difluoromethoxy- (1-methylcyclopropyl) -1H-indole (170 mg), methyl 6-formylpyridine-2-carboxylate (118 mg) and triethylsilane (0.344 mL) in dichloromethane (3. (0 mL) The solution was cooled in an ice-water bath. Trifluoroacetic acid (0.080 mL) was added thereto, and the mixture was stirred for 30 minutes under the same conditions and then at room temperature for 7 hours. The reaction mixture is purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- [6-difluoromethoxy-2- (1-methylcyclopropyl) -1H-indole-3- [Ilmethyl] methyl pyridine-2-carboxylate (160 mg) was obtained.

実施例２８
　アルゴン雰囲気下、２－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－シクロプロピルフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝オキサゾール－４－カルボン酸メチル（１３７ｍｇ）のジクロロメタン（１．５ｍＬ）溶液を氷水浴中で冷却した。そこへトリフルオロ酢酸（０．５ｍＬ）を加え、その混合物を室温にて５時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液で洗浄した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、２－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］オキサゾール－４－カルボン酸メチル（８６．３ｍｇ）を得た。 Example 28
Under an argon atmosphere, methyl 2- {2- [2- (tert-butoxycarbonylamino) -4-cyclopropylphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl} oxazole-4-carboxylate ( (137 mg) in dichloromethane (1.5 mL) was cooled in an ice-water bath. Trifluoroacetic acid (0.5 mL) was added thereto, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 2- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] oxazole- Methyl 4-carboxylate (86.3 mg) was obtained.

実施例２９
　対応する出発物質及び反応剤を用い、実施例１８と同様の方法で、５－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］チオフェン－３－カルボン酸メチルを合成した。 Example 29
5- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiophene-3-carboxylic acid was prepared in the same manner as in Example 18 using the corresponding starting materials and reactants. Methyl acid was synthesized.

実施例３０
　６－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（７０．０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（１ｍＬ）溶液に、炭酸セシウム（１６３ｍｇ）及びヨウ化メチル（０．０２５ｍＬ）を加え、その混合物を室温にて６時間攪拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、６－［６－メトキシ－１－メチル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（６４．５ｍｇ）を得た。 Example 30
To a solution of methyl 6- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (70.0 mg) in N, N-dimethylformamide (1 mL), Cesium carbonate (163 mg) and methyl iodide (0.025 mL) were added and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- [6-methoxy-1-methyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl. ] Methyl pyridine-2-carboxylate (64.5 mg) was obtained.

実施例３１
　対応する出発物質及び反応剤を用い、実施例２０と同様の方法で、５－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］－２－フルオロ安息香酸メチルを合成した。 Example 31
5- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] -2-fluorobenzoic acid in the same manner as in Example 20 using the corresponding starting materials and reagents. Methyl acid was synthesized.

実施例３２
　対応する出発物質及び反応剤を用い、実施例２０と同様の方法で、２－フルオロ－５－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］安息香酸メチルを合成した。 Example 32
2-Fluoro-5- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] benzoic acid in the same manner as in Example 20 using the corresponding starting materials and reagents. Methyl was synthesized.

実施例３３
　アルゴン雰囲気下、５，６－ジメトキシ－（１－メチルシクロプロピル）－１Ｈ－インドール（１８３ｍｇ）、６－ホルミルピリジン－２－カルボン酸メチル（１３１ｍｇ）及びトリエチルシラン（０．３７９ｍＬ）のジクロロメタン（３．０ｍＬ）溶液を氷水浴中で冷却した。そこへトリフルオロ酢酸（０．０８９ｍＬ）を加え、その混合物を同条件下３０分間、次いで室温にて３．５時間攪拌した。反応混合物をアミノプロピル化シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、６－［５，６－ジメトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（２６５ｍｇ）を得た。 Example 33
Under an argon atmosphere, 5,6-dimethoxy- (1-methylcyclopropyl) -1H-indole (183 mg), methyl 6-formylpyridine-2-carboxylate (131 mg) and triethylsilane (0.379 mL) in dichloromethane (3 0.0 mL) solution was cooled in an ice-water bath. Trifluoroacetic acid (0.089 mL) was added thereto, and the mixture was stirred for 30 minutes under the same conditions and then at room temperature for 3.5 hours. The reaction mixture was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- [5,6-dimethoxy-2- (1-methylcyclopropyl) -1H-indole-3. -Ilmethyl] methyl pyridine-2-carboxylate (265 mg) was obtained.

実施例３４
　対応する出発物質及び反応剤を用い、実施例２０と同様の方法で、５－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ニコチン酸メチルを合成した。 Example 34
Methyl 5- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] nicotinate was synthesized in the same manner as in Example 20 using the corresponding starting materials and reactants. .

実施例３５
　対応する出発物質及び反応剤を用い、実施例１５と同様の方法で、５－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ニコチン酸メチルを合成した。 Example 35
Synthesis of methyl 5- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] nicotinate in the same manner as in Example 15 using the corresponding starting materials and reactants did.

実施例３６
　アルゴン雰囲気下、２－（１－メチルシクロプロピル）－１，５，６，７－テトラヒドロシクロペンタ［ｆ］インドール（２００ｍｇ）、６－ホルミルピリジン－２－カルボン酸メチル（１５６ｍｇ）及びトリエチルシラン（０．４５４ｍＬ）のジクロロメタン（４．０ｍＬ）溶液を氷水浴中で冷却した。そこへトリフルオロ酢酸（０．１０６ｍＬ）を加え、その混合物を同条件下３０分間、次いで室温にて３．５時間攪拌した。反応混合物をアミノプロピル化シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製した。得られた固体を酢酸エチル－ヘキサンから２度再結晶することにより、６－［２－（１－メチルシクロプロピル）－１，５，６，７－テトラヒドロシクロペンタ［ｆ］インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（６６．０ｍｇ）を得た。 Example 36
Under an argon atmosphere, 2- (1-methylcyclopropyl) -1,5,6,7-tetrahydrocyclopenta [f] indole (200 mg), methyl 6-formylpyridine-2-carboxylate (156 mg) and triethylsilane ( 0.454 mL) in dichloromethane (4.0 mL) was cooled in an ice-water bath. Trifluoroacetic acid (0.106 mL) was added thereto, and the mixture was stirred under the same conditions for 30 minutes and then at room temperature for 3.5 hours. The reaction mixture was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane). The obtained solid was recrystallized twice from ethyl acetate-hexane to give 6- [2- (1-methylcyclopropyl) -1,5,6,7-tetrahydrocyclopenta [f] indol-3-ylmethyl. ] Methyl pyridine-2-carboxylate (66.0 mg) was obtained.

実施例３７
　対応する出発物質及び反応剤を用い、実施例３０と同様の方法で、６－［１－エチル－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチルを合成した。 Example 37
6- [1-Ethyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-- in the same manner as in Example 30 using the corresponding starting materials and reactants Methyl 2-carboxylate was synthesized.

実施例３８
　アルゴン雰囲気下、５－エチル－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール（３７．４ｍｇ）、６－ホルミルピリジン－２－カルボン酸メチル（２６．９ｍｇ）及びトリエチルシラン（０．０７８ｍＬ）のジクロロメタン（１．６ｍＬ）溶液を氷水浴中で冷却した。そこへトリフルオロ酢酸（０．０１９ｍＬ）を加え、その混合物を同条件下３５分間、次いで室温にて２時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液で洗浄した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、６－［５－エチル－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（４５．７ｍｇ）を得た。 Example 38
Under an argon atmosphere, 5-ethyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indole (37.4 mg), methyl 6-formylpyridine-2-carboxylate (26.9 mg) and triethylsilane ( A solution of 0.078 mL) in dichloromethane (1.6 mL) was cooled in an ice-water bath. Trifluoroacetic acid (0.019 mL) was added thereto, and the mixture was stirred under the same conditions for 35 minutes and then at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- [5-ethyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl. ] Methyl pyridine-2-carboxylate (45.7 mg) was obtained.

実施例３９
　対応する出発物質及び反応剤を用い、実施例１８と同様の方法で、６－［２－（１－メチルシクロプロピル）－６－（メチルスルファニル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチルを合成した。 Example 39
6- [2- (1-Methylcyclopropyl) -6- (methylsulfanyl) -1H-indol-3-ylmethyl] pyridine-2 in the same manner as in Example 18 using the corresponding starting materials and reagents. -Methyl carboxylate was synthesized.

実施例４０
　アルゴン雰囲気下、６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール（１０６ｍｇ）、６－アセチルピリジン－２－カルボン酸メチル（９４．４ｍｇ）及びトリエチルシラン（０．２５３ｍＬ）のジクロロメタン（２．０ｍＬ）溶液を氷水浴中で冷却した。そこへトリフルオロ酢酸（０．０５９ｍＬ）を加え、その混合物を同条件下３０分間、次いで室温にて４８時間攪拌した。反応混合物をアミノプロピル化シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、６－｛１－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イル］エチル｝ピリジン－２－カルボン酸メチル（１４９ｍｇ）を得た。 Example 40
Dichloromethane of 6-methoxy-2- (1-methylcyclopropyl) -1H-indole (106 mg), methyl 6-acetylpyridine-2-carboxylate (94.4 mg) and triethylsilane (0.253 mL) under argon atmosphere (2.0 mL) The solution was cooled in an ice-water bath. Trifluoroacetic acid (0.059 mL) was added thereto, and the mixture was stirred for 30 minutes under the same conditions and then at room temperature for 48 hours. The reaction mixture was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- {1- [6-methoxy-2- (1-methylcyclopropyl) -1H-indole- Methyl 3-yl] ethyl} pyridine-2-carboxylate (149 mg) was obtained.

実施例４１
　対応する出発物質及び反応剤を用い、実施例３３と同様の方法で、６－［６－（１－メチルシクロプロピル）－５Ｈ－［１，３］ジオキソロ［４，５－ｆ］インドール－７－イルメチル］ピリジン－２－カルボン酸メチルを合成した。 Example 41
6- [6- (1-Methylcyclopropyl) -5H- [1,3] dioxolo [4,5-f] indole-7 in the same manner as in Example 33, using the corresponding starting materials and reagents. -Methyl] pyridin-2-carboxylate was synthesized.

実施例４２
　アルゴン雰囲気下、６－［２－（１－メチルシクロプロピル）－６－（メチルスルファニル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（１００ｍｇ）のジクロロメタン（１．３６ｍＬ）溶液を氷水浴中で冷却した。ｍ－クロロ過安息香酸（約２５％水湿潤品、純度６５％、１７４ｍｇ）を２回に分けて加え、その混合物を同条件下３０分間、次いで室温にて１時間攪拌した。反応混合物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。有機層を飽和炭酸水素ナトリウム水溶液及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をアミノプロピル化シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ジクロロメタン）にて精製することにより、６－［２－（１－メチルシクロプロピル）－６－メチルスルホニル－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（６７．８ｍｇ）を得た。 Example 42
A solution of methyl 6- [2- (1-methylcyclopropyl) -6- (methylsulfanyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (100 mg) in dichloromethane (1.36 mL) under an argon atmosphere. Was cooled in an ice-water bath. m-Chloroperbenzoic acid (about 25% water wet product, purity 65%, 174 mg) was added in two portions, and the mixture was stirred under the same conditions for 30 minutes and then at room temperature 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 successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-dichloromethane) to give 6- [2- (1-methylcyclopropyl) -6-methylsulfonyl-1H-indol-3-ylmethyl. ] Methyl pyridine-2-carboxylate (67.8 mg) was obtained.

実施例４３
　対応する出発物質及び反応剤を用い、実施例４と同様の方法で、２－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］イソニコチン酸メチルを合成した。 Example 43
Methyl 2- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] isonicotinate was prepared in the same manner as in Example 4 using the corresponding starting materials and reactants. Synthesized.

実施例４４
　６－［２－（１－メチルシクロプロピル）－６－（メチルスルファニル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（６５．０ｍｇ）の１，１，１，３，３，３－ヘキサフルオロプロパン－２－オール（１．８ｍＬ）溶液に、３０％過酸化水素水（０．０３７ｍＬ）を加え、その混合物を室温にて１．５時間攪拌した。反応混合物に１０％亜硫酸ナトリウム水溶液を加え、その混合物を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をアミノプロピル化シリカゲルカラムクロマトグラフィー（溶出溶媒：メタノール－酢酸エチル）にて精製することにより、６－［２－（１－メチルシクロプロピル）－６－（メチルスルフィニル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（４３．３ｍｇ）を得た。 Example 44
1,1,1,3,3 of methyl 6- [2- (1-methylcyclopropyl) -6- (methylsulfanyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (65.0 mg) , 3-Hexafluoropropan-2-ol (1.8 mL) solution was added 30% aqueous hydrogen peroxide (0.037 mL), and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added 10% aqueous sodium sulfite solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (elution solvent: methanol-ethyl acetate) to give 6- [2- (1-methylcyclopropyl) -6- (methylsulfinyl) -1H-indole-3. There was obtained methyl -ylmethyl] pyridine-2-carboxylate (43.3 mg).

実施例４５
　アルゴン雰囲気下、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－メトキシフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝ピラジン－２－カルボン酸メチル（１１１ｍｇ）のジクロロメタン（１．２ｍＬ）溶液を氷水浴中で冷却した。そこへトリフルオロ酢酸（０．４ｍＬ）を加え、その混合物を室温にて２．５時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液で洗浄した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をアミノプロピル化シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、６－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピラジン－２－カルボン酸メチル（６６．５ｍｇ）を得た。 Example 45
Under an argon atmosphere, methyl 6- {2- [2- (tert-butoxycarbonylamino) -4-methoxyphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl} pyrazine-2-carboxylate (111 mg ) In dichloromethane (1.2 mL) was cooled in an ice-water bath. Trifluoroacetic acid (0.4 mL) was added there, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl]. Methyl pyrazine-2-carboxylate (66.5 mg) was obtained.

実施例４６
　アルゴン雰囲気下、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－シクロプロピルフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝ピラジン－２－カルボン酸メチル（１８８ｍｇ）のジクロロメタン（１．９５ｍＬ）溶液を氷水浴中で冷却した。トリフルオロ酢酸（０．６５ｍＬ）を加え、その混合物を室温にて３時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液で洗浄した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をアミノプロピル化シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）、次いでシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）、にて精製することにより、６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピラジン－２－カルボン酸メチル（８９．７ｍｇ）を得た。 Example 46
Under an argon atmosphere, methyl 6- {2- [2- (tert-butoxycarbonylamino) -4-cyclopropylphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl} pyrazine-2-carboxylate ( A solution of 188 mg) in dichloromethane (1.95 mL) was cooled in an ice-water bath. Trifluoroacetic acid (0.65 mL) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) and then silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- [6-cyclopropyl-2 There was obtained methyl-(1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyrazine-2-carboxylate (89.7 mg).

実施例４７
　アルゴン雰囲気下、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）フェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝ピリジン－２－カルボン酸メチル（２２７ｍｇ）のジクロロメタン（２．７ｍＬ）溶液を氷水浴中で冷却した。トリフルオロ酢酸（０．９ｍＬ）を加え、その混合物を室温にて２時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液で洗浄した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、６－［２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（１５９ｍｇ）を得た。 Example 47
Under argon atmosphere, methyl 6- {2- [2- (tert-butoxycarbonylamino) phenyl] -3- (1-methylcyclopropyl) -3-oxopropyl} pyridine-2-carboxylate (227 mg) in dichloromethane ( (2.7 mL) The solution was cooled in an ice-water bath. Trifluoroacetic acid (0.9 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give methyl 6- [2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (159 mg) was obtained.

実施例４８
　対応する出発物質及び反応剤を用い、実施例３８と同様の方法で、６－［５－シクロプロピル－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチルを合成した。 Example 48
6- [5-Cyclopropyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine in the same manner as in Example 38 using the corresponding starting materials and reagents. Methyl -2-carboxylate was synthesized.

実施例４９
　対応する出発物質及び反応剤を用い、実施例３８と同様の方法で、６－［６－メトキシ－２－（１－メチルシクロプロピル）－５－プロピル－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチルを合成した。 Example 49
6- [6-Methoxy-2- (1-methylcyclopropyl) -5-propyl-1H-indol-3-ylmethyl] pyridine-- in the same manner as in Example 38 using the corresponding starting materials and reactants Methyl 2-carboxylate was synthesized.

実施例５０
　対応する出発物質及び反応剤を用い、実施例４５と同様の方法で、６－［６－メトキシ－２－（１－メチルシクロブチル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチルを合成した。 Example 50
6- [6-Methoxy-2- (1-methylcyclobutyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 45 using the corresponding starting materials and reagents. Methyl was synthesized.

実施例５１
　対応する出発物質及び反応剤を用い、実施例３８と同様の方法で、６－［５－ブチル－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチルを合成した。 Example 51
6- [5-Butyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine--in the same manner as in Example 38 using the corresponding starting materials and reactants Methyl 2-carboxylate was synthesized.

実施例５２
　対応する出発物質及び反応剤を用い、実施例４５と同様の方法で、６－［６－シクロプロピル－２－（１－メチルシクロブチル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチルを合成した。 Example 52
6- [6-Cyclopropyl-2- (1-methylcyclobutyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 45 using the corresponding starting materials and reagents. Methyl acid was synthesized.

実施例５３
　アルゴン雰囲気下、６－｛２－［２－（ｔｅｒｔ－ブトキシカルボニルアミノ）－５－クロロ－４－シクロプロピルフェニル］－３－（１－メチルシクロプロピル）－３－オキソプロピル｝ピリジン－２－カルボン酸メチル（３４４ｍｇ）のジクロロメタン（３．３ｍＬ）溶液を氷水浴中で冷却した。そこへトリフルオロ酢酸（１．１ｍＬ）を加え、その混合物を室温にて６時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液で洗浄した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をメタノール中に懸濁した。析出物を濾取し、メタノールで洗浄後、減圧下６０℃にて乾燥することにより、６－［５－クロロ－６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（１８９ｍｇ）を得た。 Example 53
Under an argon atmosphere, 6- {2- [2- (tert-butoxycarbonylamino) -5-chloro-4-cyclopropylphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl} pyridine-2- A solution of methyl carboxylate (344 mg) in dichloromethane (3.3 mL) was cooled in an ice-water bath. Trifluoroacetic acid (1.1 mL) was added thereto, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was suspended in methanol. The precipitate is collected by filtration, washed with methanol, and dried at 60 ° C. under reduced pressure to give 6- [5-chloro-6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indole-3. -Ilmethyl] methyl pyridine-2-carboxylate (189 mg) was obtained.

実施例５４
　アルゴン雰囲気下、７－フルオロ－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール（１１０ｍｇ）、６－ホルミルピリジン－２－カルボン酸メチル（８２．９ｍｇ）及びトリエチルシラン（０．２４０ｍＬ）のジクロロメタン（５ｍＬ）溶液を氷水浴中で冷却した。そこへトリフルオロ酢酸（０．０５８ｍＬ）を加え、その混合物を同条件下１時間、次いで室温にて３時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液で洗浄した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した、残渣をアミノプロピル化シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、６－［７－フルオロ－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（８６．９ｍｇ）を得た。 Example 54
Under an argon atmosphere, 7-fluoro-6-methoxy-2- (1-methylcyclopropyl) -1H-indole (110 mg), methyl 6-formylpyridine-2-carboxylate (82.9 mg) and triethylsilane (0. A solution of 240 mL) in dichloromethane (5 mL) was cooled in an ice-water bath. Trifluoroacetic acid (0.058 mL) was added thereto, and the mixture was stirred under the same conditions for 1 hour and then at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- [ Methyl 7-fluoro-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (86.9 mg) was obtained.

実施例５５
　氷冷下、６－｛ヒドロキシ［６－（１－メチルシクロプロピル）－３，７－ジヒドロ－２Ｈ－フロ［３，２－ｆ］インドール－５－イル］メチル｝ピリジン－２－カルボン酸メチル（９２．９ｍｇ）の塩化メチレン（１ｍＬ）溶液に、トリエチルシラン（０．２０ｍＬ）とトリフルオロ酢酸（０．１６ｍＬ）を加えた。その溶液を同条件下０．５時間攪拌し、次いで室温にて１２時間攪拌した。その溶液に飽和炭酸水素ナトリウム水溶液を加えて、塩化メチレンにて抽出し、無水硫酸ナトリウムで乾燥した。溶媒を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－（溶出溶媒：ヘキサン－酢酸エチル）で精製し、６－［６－（１－メチルシクロプロピル）－３，７－ジヒドロ－２Ｈ－フロ［３，２－ｆ］インドール－５－イルメチル］ピリジン－２－カルボン酸メチル（７６．５ｍｇ）を得た。 Example 55
Under ice cooling, methyl 6- {hydroxy [6- (1-methylcyclopropyl) -3,7-dihydro-2H-furo [3,2-f] indol-5-yl] methyl} pyridine-2-carboxylate Triethylsilane (0.20 mL) and trifluoroacetic acid (0.16 mL) were added to a solution of (92.9 mg) in methylene chloride (1 mL). The solution was stirred under the same conditions for 0.5 hour and then at room temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the solution, extracted with methylene chloride, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate) and purified by 6- [6- (1-methylcyclopropyl) -3,7-dihydro-2H-fluoro. Methyl [3,2-f] indol-5-ylmethyl] pyridine-2-carboxylate (76.5 mg) was obtained.

実施例５６
　対応する出発物質及び反応剤を用い、実施例１９と同様の方法で、６－［６－シクロプロピル－５－フルオロ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチルを合成した。 Example 56
6- [6-Cyclopropyl-5-fluoro-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine in the same manner as in Example 19 using the corresponding starting materials and reagents. Methyl -2-carboxylate was synthesized.

実施例５７
　６－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（５８４ｍｇ）のテトラヒドロフラン／メタノール（９．９２ｍL／４．２５ｍL）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（２．５０ｍＬ）を加え、その混合物を室温にて５時間攪拌した。反応混合物を減圧下濃縮した。残渣を水に溶かし、そこへ攪拌しながら１ｍｏｌ／Ｌ塩酸（５．００ｍＬ）を滴下した。その混合物を室温にて３０分間攪拌した。析出物を濾取し、水で洗浄後、風乾することにより、６－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（４７０ｍｇ）を得た。 Example 57
To a solution of methyl 6- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (584 mg) in tetrahydrofuran / methanol (9.92 mL / 4.25 mL). A 2 mol / L aqueous sodium hydroxide solution (2.50 mL) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (5.00 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with water, and air-dried to give 6- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (470 mg). )

実施例５８
　６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（３５５ｍｇ）のテトラヒドロフラン／メタノール（５．８６ｍL／２．５１ｍL）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（１．４８ｍＬ）を加え、その混合物を室温にて２時間攪拌した。反応混合物を減圧下濃縮した。残渣を水に溶かし、そこへ攪拌しながら１ｍｏｌ／Ｌ塩酸（２．９６ｍＬ）を滴下した。その混合物を室温にて３０分間攪拌した。析出物を濾取し、水で洗浄後、風乾することにより、６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（３３９ｍｇ）を得た。 Example 58
A solution of methyl 6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (355 mg) in tetrahydrofuran / methanol (5.86 mL / 2.51 mL). Was added 2 mol / L aqueous sodium hydroxide solution (1.48 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (2.96 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with water, and then air-dried to give 6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid ( 339 mg) was obtained.

実施例５９
　６－［６－クロロ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（４２７ｍｇ）のテトラヒドロフラン／メタノール（７．１６ｍL／３．０７ｍL）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（１．８１ｍＬ）を加え、その混合物を室温にて３．５時間攪拌した。反応混合物を減圧下濃縮した。残渣を水に溶かし、そこへ攪拌しながら１ｍｏｌ／Ｌ塩酸（３．６２ｍＬ）を滴下した。その混合物を室温にて１時間攪拌した。析出物を濾取し、水で洗浄後、減圧下８０℃にて乾燥することにより、６－［６－クロロ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（３８０ｍｇ）を得た。 Example 59
To a solution of methyl 6- [6-chloro-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (427 mg) in tetrahydrofuran / methanol (7.16 mL / 3.07 mL). A 2 mol / L aqueous sodium hydroxide solution (1.81 mL) was added, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (3.62 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 1 hour. The precipitate is collected by filtration, washed with water, and dried at 80 ° C. under reduced pressure to give 6- [6-chloro-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine- 2-carboxylic acid (380 mg) was obtained.

実施例６０
　６－［６－メチル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（１７１ｍｇ）のテトラヒドロフラン／メタノール（３．０４ｍL／１．３０ｍL）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０．７６８ｍＬ）を加え、その混合物を室温にて３時間攪拌した。反応混合物を減圧下濃縮した。残渣を水に溶かし、そこへ攪拌しながら１ｍｏｌ／Ｌ塩酸（１．５４ｍＬ）を滴下した。その混合物を室温にて３０分間攪拌した。析出物を濾取し、水で洗浄後、減圧下８０℃にて乾燥することにより、６－［６－メチル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（１３５ｍｇ）を得た。 Example 60
To a solution of methyl 6- [6-methyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (171 mg) in tetrahydrofuran / methanol (3.04 mL / 1.30 mL). 2 mol / L aqueous sodium hydroxide solution (0.768 mL) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (1.54 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 30 minutes. The precipitate is collected by filtration, washed with water, and dried at 80 ° C. under reduced pressure to give 6- [6-methyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine- 2-carboxylic acid (135 mg) was obtained.

実施例６１
　対応する出発物質及び反応剤を用い、実施例６０と同様の方法で、６－［６－エトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸を合成した。 Example 61
6- [6-Ethoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 60 using the corresponding starting materials and reagents. Was synthesized.

実施例６２
　対応する出発物質及び反応剤を用い、実施例６０と同様の方法で、６－［６－イソプロポキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸を合成した。 Example 62
6- [6-Isopropoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid was prepared in the same manner as in Example 60 using the corresponding starting materials and reactants. An acid was synthesized.

実施例６３
　６－［６－クロロ－５－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（７０ｍｇ）のテトラヒドロフラン／メタノール（０．９ｍL／０．９ｍL）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０．２７ｍＬ）を加え、その混合物を室温にて２時間攪拌した。反応混合物を減圧下濃縮した。残渣を水に溶かし、そこへ攪拌しながら２ｍｏｌ／Ｌ塩酸（０．２７ｍＬ）を加えた。その混合物を室温にて３０分間攪拌した。析出物を濾取し、水で洗浄後、減圧下乾燥することにより、６－［６－クロロ－５－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（５６．９ｍｇ）を得た。 Example 63
Methyl 6- [6-chloro-5-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (70 mg) in tetrahydrofuran / methanol (0.9 mL / 0. 9 mol) solution was added 2 mol / L aqueous sodium hydroxide solution (0.27 mL) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 2 mol / L hydrochloric acid (0.27 mL) was added thereto while stirring. The mixture was stirred at room temperature for 30 minutes. The precipitate is collected by filtration, washed with water, and dried under reduced pressure to give 6- [6-chloro-5-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine- 2-carboxylic acid (56.9 mg) was obtained.

実施例６４
　対応する出発物質及び反応剤を用い、実施例６０と同様の方法で、６－［６－エチル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸を合成した。 Example 64
6- [6-Ethyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 60 using the corresponding starting materials and reagents. Was synthesized.

実施例６５
　６－［５－クロロ－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（２５０ｍｇ）のテトラヒドロフラン／メタノール（３ｍL／３ｍL）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０．９７４ｍＬ）を加え、その混合物を室温にて３時間攪拌した。反応混合物を減圧下濃縮した。残渣を水に溶かし、そこへ攪拌しながら２ｍｏｌ／Ｌ塩酸（０．９８ｍＬ）を加えた。その混合物を室温にて３０分間攪拌した。析出物を濾取し、水で洗浄後、減圧下乾燥することにより、６－［５－クロロ－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（２２１ｍｇ）を得た。 Example 65
To a solution of methyl 6- [5-chloro-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (250 mg) in tetrahydrofuran / methanol (3 mL / 3 mL) A 2 mol / L aqueous sodium hydroxide solution (0.974 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 2 mol / L hydrochloric acid (0.98 mL) was added thereto while stirring. The mixture was stirred at room temperature for 30 minutes. The precipitate is collected by filtration, washed with water, and dried under reduced pressure to give 6- [5-chloro-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine- 2-carboxylic acid (221 mg) was obtained.

実施例６６
　対応する出発物質及び反応剤を用い、実施例６０と同様の方法で、６－［６－イソプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸を合成した。 Example 66
6- [6-Isopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 60 using the corresponding starting materials and reagents. Was synthesized.

実施例６７
　対応する出発物質及び反応剤を用い、実施例６０と同様の方法で、６－［６－メトキシ－５－メチル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸を合成した。 Example 67
6- [6-Methoxy-5-methyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-- in the same manner as in Example 60 using the corresponding starting materials and reactants 2-carboxylic acid was synthesized.

実施例６８
　対応する出発物質及び反応剤を用い、実施例６０と同様の方法で、６－［５－フルオロ－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸を合成した。 Example 68
6- [5-Fluoro-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-- in the same manner as in Example 60 using the corresponding starting materials and reactants 2-carboxylic acid was synthesized.

実施例６９
　３－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］安息香酸メチル（４４ｍｇ）のテトラヒドロフラン／メタノール（０．６ｍL／０．６ｍL）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０．１８３ｍＬ）を加え、その混合物を６０℃にて２時間攪拌した。反応混合物を減圧下濃縮した。残渣を水に溶かし、そこへ攪拌しながら２ｍｏｌ／Ｌ塩酸（０．１８３ｍＬ）を加えた。その混合物を室温にて１０分間攪拌した。析出物を濾取し、水で洗浄後、減圧下乾燥することにより、３－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］安息香酸（３４．６ｍｇ）を得た。 Example 69
To a solution of methyl 3- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] benzoate (44 mg) in tetrahydrofuran / methanol (0.6 mL / 0.6 mL), 2 mol / L Aqueous sodium hydroxide solution (0.183 mL) was added and the mixture was stirred at 60 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 2 mol / L hydrochloric acid (0.183 mL) was added thereto while stirring. The mixture was stirred at room temperature for 10 minutes. The precipitate was collected by filtration, washed with water, and dried under reduced pressure to give 3- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] benzoic acid (34. 6 mg) was obtained.

実施例７０
　５－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］フラン－２－カルボン酸エチル（９５．７ｍｇ）のテトラヒドロフラン／メタノール（１．３ｍL／１．３ｍL）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０．３９５ｍＬ）を加え、その混合物を６０℃にて８０分間攪拌した。反応混合物を減圧下濃縮した。残渣を水に溶かし、そこへ攪拌しながら２ｍｏｌ／Ｌ塩酸（０．４ｍＬ）を加えた。その混合物を室温にて１０分間攪拌した。析出物を濾取し、水で洗浄後、減圧下乾燥することにより、５－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］フラン－２－カルボン酸（６８．０ｍｇ）を得た。 Example 70
Ethyl 5- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] furan-2-carboxylate (95.7 mg) in tetrahydrofuran / methanol (1.3 mL / 1.3 mL) ) 2 mol / L aqueous sodium hydroxide solution (0.395 mL) was added to the solution, and the mixture was stirred at 60 ° C. for 80 minutes. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 2 mol / L hydrochloric acid (0.4 mL) was added thereto while stirring. The mixture was stirred at room temperature for 10 minutes. The precipitate is collected by filtration, washed with water, and dried under reduced pressure to give 5- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] furan-2-carbon. The acid (68.0 mg) was obtained.

実施例７１
　３－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］－２－フルオロ安息香酸メチル（７４ｍｇ）のテトラヒドロフラン／メタノール（１．０ｍL／１．０ｍL）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０．２９５ｍＬ）を加え、その混合物を６０℃にて２．５時間攪拌した。反応混合物を減圧下濃縮した。残渣を水に溶かし、そこへ攪拌しながら２ｍｏｌ／Ｌ塩酸（０．２９５ｍＬ）を加えた。その混合物を室温にて１０分間攪拌した。析出物を濾取し、水で洗浄し、減圧下乾燥後、シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、３－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］－２－フルオロ安息香酸（３８．１ｍｇ）を得た。 Example 71
A solution of methyl 3- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] -2-fluorobenzoate (74 mg) in tetrahydrofuran / methanol (1.0 mL / 1.0 mL) Was added 2 mol / L aqueous sodium hydroxide solution (0.295 mL), and the mixture was stirred at 60 ° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 2 mol / L hydrochloric acid (0.295 mL) was added thereto while stirring. The mixture was stirred at room temperature for 10 minutes. The precipitate was collected by filtration, washed with water, dried under reduced pressure, and purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 3- [6-cyclopropyl-2- (1- Methylcyclopropyl) -1H-indol-3-ylmethyl] -2-fluorobenzoic acid (38.1 mg) was obtained.

実施例７２
　２－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］チアゾール－４－カルボン酸エチル（１７７ｍｇ）のテトラヒドロフラン／メタノール（２．３ｍL／２．３ｍL）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０．６９７ｍＬ）を加え、その混合物を５０℃にて２時間攪拌した。反応混合物を減圧下濃縮した。残渣を水に溶かし、そこへ攪拌しながら２ｍｏｌ／Ｌ塩酸（０．７ｍＬ）を加えた。その混合物を室温にて３０分間攪拌した。析出物を濾取し、水で洗浄後、減圧下乾燥することにより、２－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］チアゾール－４－カルボン酸（１３６ｍｇ）を得た。 Example 72
2- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiazole-4-carboxylate (177 mg) in tetrahydrofuran / methanol (2.3 mL / 2.3 mL) solution Was added 2 mol / L aqueous sodium hydroxide solution (0.697 mL), and the mixture was stirred at 50 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 2 mol / L hydrochloric acid (0.7 mL) was added thereto while stirring. The mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration, washed with water, and dried under reduced pressure to give 2- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiazole-4-carboxylic acid. The acid (136 mg) was obtained.

実施例７３
　対応する出発物質及び反応剤を用い、実施例６０と同様の方法で、２－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］イソニコチン酸を合成した。 Example 73
2- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] isonicotinic acid was synthesized in the same manner as in Example 60 using the corresponding starting materials and reactants. .

実施例７４
　５－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］チオフェン－２－カルボン酸エチル（７５．２ｍｇ）のテトラヒドロフラン／メタノール（１．２１ｍL／０．５１９ｍL）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０．３０５ｍＬ）を加えた。その混合物を室温にて４時間、次いで５０℃にて３時間攪拌した。反応混合物を放冷し、減圧下濃縮した。残渣を水に溶かし、そこへ攪拌しながら１ｍｏｌ／Ｌ塩酸（０．７１０ｍＬ）を滴下した。その混合物を室温にて３０分間攪拌した。析出物を濾取し、水で洗浄後、減圧下８０℃にて乾燥することにより、５－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］チオフェン－２－カルボン酸（６７．０ｍｇ）を得た。 Example 74
Ethyl 5- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiophene-2-carboxylate (75.2 mg) in tetrahydrofuran / methanol (1.21 mL / 0.519 mL) To the solution was added 2 mol / L aqueous sodium hydroxide solution (0.305 mL). The mixture was stirred at room temperature for 4 hours and then at 50 ° C. for 3 hours. The reaction mixture was allowed to cool and concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (0.710 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 30 minutes. The precipitate is collected by filtration, washed with water, and dried at 80 ° C. under reduced pressure to give 5- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiophene- 2-carboxylic acid (67.0 mg) was obtained.

実施例７５
　対応する出発物質及び反応剤を用い、実施例６０と同様の方法で、６－［２－（１－エチルシクロプロピル）－６－メトキシ－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸を合成した。 Example 75
6- [2- (1-Ethylcyclopropyl) -6-methoxy-1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 60 using the corresponding starting materials and reagents. Was synthesized.

実施例７６
　対応する出発物質及び反応剤を用い、実施例６９と同様の方法で、３－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］安息香酸を合成した。 Example 76
3- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] benzoic acid was synthesized in the same manner as in Example 69 using the corresponding starting materials and reagents.

実施例７７
　対応する出発物質及び反応剤を用い、実施例６９と同様の方法で、５－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］フラン－２－カルボン酸を合成した。 Example 77
5- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] furan-2-carboxylic acid in the same manner as in Example 69 using the corresponding starting materials and reagents. Was synthesized.

実施例７８
　対応する出発物質及び反応剤を用い、実施例６９と同様の方法で、２－フルオロ－３－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］安息香酸を合成した。 Example 78
2-Fluoro-3- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] benzoic acid in the same manner as in Example 69 using the corresponding starting materials and reactants Was synthesized.

実施例７９
　対応する出発物質及び反応剤を用い、実施例７２と同様の方法で、２－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］チアゾール－４－カルボン酸を合成した。 Example 79
2- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiazole-4-carboxylic acid in the same manner as in Example 72 using the corresponding starting materials and reagents. Was synthesized.

実施例８０
　６－［５，６－ジメチル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（１１９ｍｇ）のテトラヒドロフラン／メタノール（２．０３ｍL／０．８６８ｍL）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０．５１０ｍＬ）を加え、その混合物を室温にて３時間攪拌した。反応混合物を減圧下濃縮した。残渣を水に溶かし、そこへ攪拌しながら１ｍｏｌ／Ｌ塩酸（１．０２ｍＬ）を滴下した。その混合物を室温にて４０分間攪拌した。析出物を濾取し、水で洗浄後、減圧下８０℃にて乾燥することにより、６－［５，６－ジメチル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（８８．０ｍｇ）を得た。 Example 80
6- [5,6-Dimethyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (119 mg) in tetrahydrofuran / methanol (2.03 mL / 0.868 mL) To the solution was added 2 mol / L aqueous sodium hydroxide solution (0.510 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (1.02 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 40 minutes. The precipitate is collected by filtration, washed with water, and dried at 80 ° C. under reduced pressure to give 6- [5,6-dimethyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl]. Pyridine-2-carboxylic acid (88.0 mg) was obtained.

実施例８１
　５－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］チオフェン－３－カルボン酸エチル（８６．７ｍｇ）のテトラヒドロフラン／メタノール（１．４５ｍL／０．６２２ｍL）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０．３６６ｍＬ）を加えた。その混合物を室温にて３．５時間、次いで６０℃にて２時間攪拌した。反応混合物を減圧下濃縮した。残渣を水に溶かし、そこへ攪拌しながら１ｍｏｌ／Ｌ塩酸（０．７３２ｍＬ）を滴下した。その混合物を室温にて３０分間攪拌した。析出物を濾取し、水で洗浄後、減圧下８０℃にて乾燥することにより、５－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］チオフェン－３－カルボン酸（８１．６ｍｇ）を得た。 Example 81
Ethyl 5- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiophene-3-carboxylate (86.7 mg) in tetrahydrofuran / methanol (1.45 mL / 0.622 mL) To the solution was added 2 mol / L aqueous sodium hydroxide solution (0.366 mL). The mixture was stirred at room temperature for 3.5 hours and then at 60 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (0.732 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 30 minutes. The precipitate is collected by filtration, washed with water, and dried at 80 ° C. under reduced pressure to give 5- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiophene- 3-carboxylic acid (81.6 mg) was obtained.

実施例８２
　５－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］チオフェン－２－カルボン酸エチル（３３４ｍｇ）のテトラヒドロフラン／メタノール（５．２４ｍL／２．２４ｍL）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（１．３２ｍＬ）を加え、その混合物を６０℃にて３時間攪拌した。反応混合物を放冷し、減圧下濃縮した。残渣を水に溶かし、そこへ攪拌しながら１ｍｏｌ／Ｌ塩酸（２．６４ｍＬ）を滴下した。その混合物を室温にて１時間攪拌した。析出物を濾取し、水で洗浄後、減圧下８０℃にて乾燥することにより、５－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］チオフェン－２－カルボン酸（２９９ｍｇ）を得た。 Example 82
A solution of ethyl 5- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiophene-2-carboxylate (334 mg) in tetrahydrofuran / methanol (5.24 mL / 2.24 mL). Was added 2 mol / L aqueous sodium hydroxide solution (1.32 mL), and the mixture was stirred at 60 ° C. for 3 hours. The reaction mixture was allowed to cool and concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (2.64 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 1 hour. The precipitate is collected by filtration, washed with water, and dried at 80 ° C. under reduced pressure to give 5- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiophene. -2-carboxylic acid (299 mg) was obtained.

実施例８３
　対応する出発物質及び反応剤を用い、実施例６５と同様の方法で、６－［６－ジフルオロメトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸を合成した。 Example 83
6- [6-Difluoromethoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 65 using the corresponding starting materials and reactants An acid was synthesized.

実施例８４
　対応する出発物質及び反応剤を用い、実施例５９と同様の方法で、２－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］オキサゾール－４－カルボン酸を合成した。 Example 84
2- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] oxazole-4-carboxylic acid was prepared in the same manner as in Example 59 using the corresponding starting materials and reactants. An acid was synthesized.

実施例８５
　対応する出発物質及び反応剤を用い、実施例８２と同様の方法で、５－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］チオフェン－３－カルボン酸を合成した。 Example 85
5- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiophene-3-carboxylic acid was prepared in the same manner as in Example 82 using the corresponding starting materials and reagents. An acid was synthesized.

実施例８６
　対応する出発物質及び反応剤を用い、実施例５９と同様の方法で、６－［６－メトキシ－１－メチル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸を合成した。 Example 86
6- [6-Methoxy-1-methyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-- in the same manner as in Example 59 using the corresponding starting materials and reactants 2-carboxylic acid was synthesized.

実施例８７
　対応する出発物質及び反応剤を用い、実施例７０と同様の方法で、５－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］－２－フルオロ安息香酸を合成した。 Example 87
5- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] -2-fluorobenzoic acid in the same manner as in Example 70 using the corresponding starting materials and reagents. An acid was synthesized.

実施例８８
　対応する出発物質及び反応剤を用い、実施例７０と同様の方法で、２－フルオロ－５－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］安息香酸を合成した。 Example 88
2-Fluoro-5- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] benzoic acid in the same manner as in Example 70 using the corresponding starting materials and reactants Was synthesized.

実施例８９
　対応する出発物質及び反応剤を用い、実施例６３と同様の方法で、６－［５，６－ジメトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸を合成した。 Example 89
6- [5,6-Dimethoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridin-2-in the same manner as in Example 63 using the corresponding starting materials and reagents. Carboxylic acid was synthesized.

実施例９０
　対応する出発物質及び反応剤を用い、実施例６３と同様の方法で、５－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ニコチン酸を合成した。 Example 90
5- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] nicotinic acid was synthesized in the same manner as in Example 63 using the corresponding starting materials and reactants.

実施例９１
　対応する出発物質及び反応剤を用い、実施例６３と同様の方法で、５－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ニコチン酸を合成した。 Example 91
5- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] nicotinic acid was synthesized in the same manner as in Example 63 using the corresponding starting materials and reactants. .

実施例９２
　６－［２－（１－メチルシクロプロピル）－１，５，６，７－テトラヒドロシクロペンタ［ｆ］インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（６５．０ｍｇ）のテトラヒドロフラン／メタノール（０．９ｍL／０．９ｍL）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０．２７０ｍＬ）を加え、その混合物を室温にて１．５時間攪拌した。反応混合物を減圧下濃縮した。残渣を水に溶かし、そこへ攪拌しながら２ｍｏｌ／Ｌ塩酸（０．２７５ｍＬ）を加えた。その混合物を室温にて１０分間攪拌した。析出物を濾取し、水で洗浄後、減圧下乾燥することにより、６－［２－（１－メチルシクロプロピル）－１，５，６，７－テトラヒドロシクロペンタ［ｆ］インドール－３－イルメチル］ピリジン－２－カルボン酸（５７．９ｍｇ）を得た。 Example 92
6- [2- (1-Methylcyclopropyl) -1,5,6,7-tetrahydrocyclopenta [f] indol-3-ylmethyl] pyridine-2-carboxylate methyl (65.0 mg) in tetrahydrofuran / methanol (65.0 mg) To the 0.9 mL / 0.9 mL) solution was added 2 mol / L aqueous sodium hydroxide solution (0.270 mL), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 2 mol / L hydrochloric acid (0.275 mL) was added thereto while stirring. The mixture was stirred at room temperature for 10 minutes. The precipitate is collected by filtration, washed with water, and dried under reduced pressure to give 6- [2- (1-methylcyclopropyl) -1,5,6,7-tetrahydrocyclopenta [f] indole-3- [Ilmethyl] pyridine-2-carboxylic acid (57.9 mg) was obtained.

実施例９３
　対応する出発物質及び反応剤を用い、実施例５９と同様の方法で、６－［１－エチル－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸を合成した。 Example 93
6- [1-Ethyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-- in the same manner as in Example 59 using the corresponding starting materials and reactants 2-carboxylic acid was synthesized.

実施例９４
　６－［５－エチル－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（４４．２ｍｇ）のテトラヒドロフラン／メタノール（０．９６８ｍL／０．４１５ｍL）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０．１７５ｍＬ）を加え、その混合物を室温にて４．５時間攪拌した。反応混合物を減圧下濃縮した。残渣を水に溶かし、そこへ攪拌しながら１ｍｏｌ／Ｌ塩酸（０．３５０ｍＬ）を滴下した。その混合物を室温にて１時間攪拌した。析出物を濾取し、水で洗浄し、風乾後、減圧下７５℃にて乾燥することにより、６－［５－エチル－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（３３．９ｍｇ）を得た。 Example 94
6- [5-Ethyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate methyl (44.2 mg) in tetrahydrofuran / methanol (0.968 mL / 0.415 mL) solution was added 2 mol / L aqueous sodium hydroxide solution (0.175 mL), and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (0.350 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 1 hour. The precipitate is collected by filtration, washed with water, air-dried and then dried at 75 ° C. under reduced pressure to give 6- [5-ethyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indole. -3-ylmethyl] pyridine-2-carboxylic acid (33.9 mg) was obtained.

実施例９５
　６－［２－（１－メチルシクロプロピル）－６－（メチルスルファニル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（６０．０ｍｇ）のテトラヒドロフラン／メタノール（０．９７４ｍL／０．４１８ｍL）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０．２４５ｍＬ）を加え、その混合物を室温にて３時間攪拌した。反応混合物に１ｍｏｌ／Ｌ塩酸を加え、その混合物を酢酸エチルで抽出した。有機層を水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮することにより、６－［２－（１－メチルシクロプロピル）－６－（メチルスルファニル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（５６．０ｍｇ）を得た。 Example 95
Methyl 6- [2- (1-methylcyclopropyl) -6- (methylsulfanyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (60.0 mg) in tetrahydrofuran / methanol (0.974 mL / 0 .418 mL) solution was added 2 mol / L aqueous sodium hydroxide solution (0.245 mL) and the mixture was stirred at room temperature for 3 hours. 1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 6- [2- (1-methylcyclopropyl) -6- (methylsulfanyl) -1H-indol-3-ylmethyl] Pyridine-2-carboxylic acid (56.0 mg) was obtained.

実施例９６
　対応する出発物質及び反応剤を用い、実施例９２と同様の方法で、６－｛１－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イル］エチル｝ピリジン－２－カルボン酸を合成した。 Example 96
6- {1- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-yl] ethyl} pyridine in the same manner as in Example 92 using the corresponding starting materials and reagents. A -2-carboxylic acid was synthesized.

実施例９７
　対応する出発物質及び反応剤を用い、実施例６３と同様の方法で、６－［６－（１－メチルシクロプロピル）－５Ｈ－［１，３］ジオキソロ［４，５－ｆ］インドール－７－イルメチル］ピリジン－２－カルボン酸を合成した。 Example 97
6- [6- (1-Methylcyclopropyl) -5H- [1,3] dioxolo [4,5-f] indole-7 in the same manner as in Example 63, using the corresponding starting materials and reagents. -Ilmethyl] pyridine-2-carboxylic acid was synthesized.

実施例９８
　６－［２－（１－メチルシクロプロピル）－６－（メチルスルホニル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（６５．８ｍｇ）のテトラヒドロフラン／メタノール（０．９８２ｍL／０．４２１ｍL）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０．２４８ｍＬ）を加え、その混合物を室温にて３時間攪拌した。反応混合物を減圧下濃縮した。残渣を水に溶かし、そこへ攪拌しながら１ｍｏｌ／Ｌ塩酸（０．４９６ｍＬ）を滴下した。その混合物を酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮することにより、６－［２－（１－メチルシクロプロピル）－６－（メチルスルホニル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（５９．０ｍｇ）を得た。 Example 98
Methyl 6- [2- (1-methylcyclopropyl) -6- (methylsulfonyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (65.8 mg) in tetrahydrofuran / methanol (0.982 mL / 0 .421 mL) solution was added 2 mol / L aqueous sodium hydroxide (0.248 mL) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (0.496 mL) was added dropwise thereto while stirring. The mixture was extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 6- [2- (1-methylcyclopropyl) -6- (methylsulfonyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid. The acid (59.0 mg) was obtained.

実施例９９
　２－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］イソニコチン酸メチル（１４３ｍｇ）のテトラヒドロフラン／メタノール（２．３６ｍL／１．０１ｍL）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０．５９５ｍＬ）を加え、その混合物を室温にて３時間攪拌した。反応混合物を減圧下濃縮した。残渣を水に溶かし、そこへ攪拌しながら１ｍｏｌ／Ｌ塩酸（１．１９ｍＬ）を滴下した。その混合物を室温にて１時間攪拌した。析出物を濾取し、水で洗浄後、減圧下６０℃にて乾燥することにより、２－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］イソニコチン酸（１３０ｍｇ）を得た。 Example 99
2 mol of methyl 2- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] isonicotinate (143 mg) in tetrahydrofuran / methanol (2.36 mL / 1.01 mL) / L aqueous sodium hydroxide solution (0.595 mL) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (1.19 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 1 hour. The precipitate is collected by filtration, washed with water, and dried at 60 ° C. under reduced pressure to give 2- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] iso Nicotinic acid (130 mg) was obtained.

実施例１００
　６－［２－（１－メチルシクロプロピル）－６－（メチルスルフィニル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（４２．０ｍｇ）のテトラヒドロフラン／メタノール（１．４２ｍL／０．６０９ｍL）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０．１６５ｍＬ）を加え、その混合物を室温にて３．５時間攪拌した。反応混合物を減圧下濃縮した。残渣を水に溶かし、そこへ攪拌しながら１ｍｏｌ／Ｌ塩酸（０．３３０ｍＬ）を滴下した。その混合物を飽和食塩水で希釈し、酢酸エチルで抽出した。水層を酢酸エチルで抽出した。合一した有機層を無水硫酸ナトリウムで乾燥し、減圧下濃縮することにより、６－［２－（１－メチルシクロプロピル）－６－（メチルスルフィニル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（３７．６ｍｇ）を得た。 Example 100
6- [2- (1-Methylcyclopropyl) -6- (methylsulfinyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (42.0 mg) in tetrahydrofuran / methanol (1.42 mL / 0 .609 mL) solution was added 2 mol / L sodium hydroxide aqueous solution (0.165 mL), and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (0.330 mL) was added dropwise thereto while stirring. The mixture was diluted with saturated brine and extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers are dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 6- [2- (1-methylcyclopropyl) -6- (methylsulfinyl) -1H-indol-3-ylmethyl] pyridine- 2-carboxylic acid (37.6 mg) was obtained.

実施例１０１
　６－［６－（アセトキシメチル）－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（５４．５ｍｇ）のテトラヒドロフラン／メタノール（０．７ｍL／０．７ｍL）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０．２８ｍＬ）を加え、その混合物を４０℃にて１．５時間攪拌した。反応混合物を減圧下濃縮した。残渣を水に溶かし、そこへ攪拌しながら２ｍｏｌ／Ｌ塩酸（０．２８ｍＬ）を滴下した。その混合物を水で希釈し、酢酸エチルで抽出した。水層を酢酸エチルで抽出した。合一した有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下濃縮することにより、６－［６－（ヒドロキシメチル）－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（４２．９ｍｇ）を得た。 Example 101
6- [6- (Acetoxymethyl) -2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate methyl ester (54.5 mg) in tetrahydrofuran / methanol (0.7 mL / 0 To the solution was added 2 mol / L aqueous sodium hydroxide solution (0.28 mL), and the mixture was stirred at 40 ° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 2 mol / L hydrochloric acid (0.28 mL) was added dropwise thereto while stirring. The mixture was diluted with water and extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 6- [6- (hydroxymethyl) -2- (1-methylcyclopropyl) -1H-indole. -3-ylmethyl] pyridine-2-carboxylic acid (42.9 mg) was obtained.

実施例１０２
　６－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピラジン－２－カルボン酸メチル（６５．５ｍｇ）のテトラヒドロフラン／メタノール（１．１１ｍL／０．４７５ｍL）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０．２８０ｍＬ）を加え、その混合物を室温にて４．５時間攪拌した。反応混合物を減圧下濃縮した。残渣を水に溶かし、そこへ攪拌しながら１ｍｏｌ／Ｌ塩酸（０．５６０ｍＬ）を滴下した。その混合物を室温にて１時間攪拌した。析出物を濾取し、水で洗浄し、風乾後、減圧下乾燥することにより、６－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピラジン－２－カルボン酸（６５．０ｍｇ）を得た。 Example 102
6- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyrazine-2-carboxylate (65.5 mg) in tetrahydrofuran / methanol (1.11 mL / 0.475 mL) To the solution was added 2 mol / L aqueous sodium hydroxide solution (0.280 mL), and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (0.560 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 1 hour. The precipitate is collected by filtration, washed with water, air-dried and then dried under reduced pressure to give 6- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyrazine-2. -Carboxylic acid (65.0 mg) was obtained.

実施例１０３
　６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピラジン－２－カルボン酸メチル（８８．７ｍｇ）のテトラヒドロフラン／メタノール（１．４６ｍL／０．６２６ｍL）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０．３６８ｍＬ）を加え、その混合物を室温にて４時間攪拌した。反応混合物を減圧下濃縮した。残渣を水に溶かし、そこへ攪拌しながら１ｍｏｌ／Ｌ塩酸（０．７３６ｍＬ）を滴下した。その混合物を室温にて１時間攪拌した。析出物を濾取し、水で洗浄し、風乾後、減圧下乾燥することにより、６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピラジン－２－カルボン酸（８３．１ｍｇ）を得た。 Example 103
6- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyrazine-2-carboxylate (88.7 mg) in tetrahydrofuran / methanol (1.46 mL / 0.626 mL) ) 2 mol / L aqueous sodium hydroxide solution (0.368 mL) was added to the solution, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (0.736 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 1 hour. The precipitate is collected by filtration, washed with water, air-dried and then dried under reduced pressure to give 6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyrazine- 2-carboxylic acid (83.1 mg) was obtained.

実施例１０４
　対応する出発物質及び反応剤を用い、実施例９４と同様の方法で、６－［２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸を合成した。 Example 104
6- [2- (1-Methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid was synthesized in the same manner as in Example 94 using the corresponding starting materials and reactants.

実施例１０５
　対応する出発物質及び反応剤を用い、実施例９４と同様の方法で、６－［５－シクロプロピル－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸を合成した。 Example 105
6- [5-Cyclopropyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine in the same manner as in Example 94 using the corresponding starting materials and reagents. A -2-carboxylic acid was synthesized.

実施例１０６
　対応する出発物質及び反応剤を用い、実施例９９と同様の方法で、６－［６－メトキシ－２－（１－メチルシクロプロピル）－５－プロピル－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸を合成した。 Example 106
6- [6-Methoxy-2- (1-methylcyclopropyl) -5-propyl-1H-indol-3-ylmethyl] pyridine-- in the same manner as in Example 99 using the corresponding starting materials and reactants 2-carboxylic acid was synthesized.

実施例１０７
　対応する出発物質及び反応剤を用い、実施例６０と同様の方法で、６－［６－メトキシ－２－（１－メチルシクロブチル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸を合成した。 Example 107
6- [6-Methoxy-2- (1-methylcyclobutyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 60 using the corresponding starting materials and reagents. Was synthesized.

実施例１０８
　対応する出発物質及び反応剤を用い、実施例６０と同様の方法で、６－［５－ブチル－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸を合成した。 Example 108
6- [5-Butyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-- in the same manner as in Example 60 using the corresponding starting materials and reactants 2-carboxylic acid was synthesized.

実施例１０９
　対応する出発物質及び反応剤を用い、実施例６０と同様の方法で、６－［６－シクロプロピル－２－（１－メチルシクロブチル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸を合成した。 Example 109
6- [6-Cyclopropyl-2- (1-methylcyclobutyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 60 using the corresponding starting materials and reagents. An acid was synthesized.

実施例１１０
　６－［５－クロロ－６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（１８２ｍｇ）のテトラヒドロフラン／メタノール（２．７４ｍL／１．１８ｍL）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０．６９１ｍＬ）を加え、その混合物を室温にて３時間攪拌した。反応混合物を減圧下濃縮した。残渣を水に溶かし、そこへ攪拌しながら１ｍｏｌ／Ｌ塩酸（１．３８２ｍＬ）を滴下した。その混合物を室温にて１．５時間攪拌した。析出物を濾取し、水で洗浄し、風乾後、減圧下６０℃にて乾燥することにより、６－［５－クロロ－６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（１７０ｍｇ）を得た。 Example 110
6- [5-Chloro-6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate methyl (182 mg) in tetrahydrofuran / methanol (2.74 mL / 1 .18 mL) solution was added 2 mol / L sodium hydroxide aqueous solution (0.691 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (1.382 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 1.5 hours. The precipitate is collected by filtration, washed with water, air-dried and then dried at 60 ° C. under reduced pressure to give 6- [5-chloro-6-cyclopropyl-2- (1-methylcyclopropyl) -1H— Indol-3-ylmethyl] pyridine-2-carboxylic acid (170 mg) was obtained.

実施例１１１
　対応する出発物質及び反応剤を用い、実施例８０と同様の方法で、６－［７－フルオロ－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸を合成した。 Example 111
6- [7-Fluoro-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine--in the same manner as in Example 80 using the corresponding starting materials and reactants 2-carboxylic acid was synthesized.

実施例１１２
　氷冷下、（Ｅ）－３－（６－｛［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イル］（ヒドロキシ）メチル｝ピリジン－２－イル）アクリル酸エチル（３０２ｍｇ）の塩化メチレン（１．５ｍＬ）溶液に、トリエチルシラン（０．４０ｍＬ）とトリフルオロ酢酸（０．３ｍＬ）を加えた。その溶液を同条件下０．５時間攪拌し、次いで室温にて１２時間攪拌した。その溶液に飽和炭酸水素ナトリウム水溶液を加えて、塩化メチレンにて抽出し、無水硫酸ナトリウムで乾燥した。溶媒を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－（溶出溶媒：ヘキサン－酢酸エチル）で精製し、（Ｅ）－３－｛６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－イル｝アクリル酸エチル（１０７ｍｇ）を得た。 Example 112
Under ice cooling, (E) -3- (6-{[6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-yl] (hydroxy) methyl} pyridin-2-yl) acrylic Triethylsilane (0.40 mL) and trifluoroacetic acid (0.3 mL) were added to a solution of ethyl acid (302 mg) in methylene chloride (1.5 mL). The solution was stirred under the same conditions for 0.5 hour and then at room temperature for 12 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the solution, extracted with methylene chloride, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate) to give (E) -3- {6- [6-cyclopropyl-2- (1-methylcyclohexane). Propyl) -1H-indol-3-ylmethyl] pyridin-2-yl} ethyl acrylate (107 mg) was obtained.

実施例１１３
　対応する出発物質及び反応剤を用い、実施例５９と同様の方法で、６－［５－フルオロ－６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸を合成した。 Example 113
6- [5-Fluoro-6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine in the same manner as in Example 59 using the corresponding starting materials and reagents. A -2-carboxylic acid was synthesized.

実施例１１４
　室温にて、（Ｅ）－３－｛６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－イル｝アクリル酸エチル（７５．０ｍｇ）のエタノール（１ｍＬ）溶液に１０％パラジウム－炭素（１５ｍｇ）を加えて、その懸濁液を水素ガス雰囲気下３時間攪拌した。その懸濁液をセライト（登録商標）ろ過し、不溶物をろ去した。ろ液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィ－（溶出溶媒：ヘキサン－酢酸エチル）で精製し、３－｛６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－イル｝プロピオン酸エチル（６０．０ｍｇ）を得た。 Example 114
At room temperature, (E) -3- {6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridin-2-yl} ethyl acrylate (75.0 mg) ) In ethanol (1 mL) was added 10% palladium-carbon (15 mg), and the suspension was stirred under a hydrogen gas atmosphere for 3 hours. The suspension was filtered through Celite (registered trademark), and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate) to give 3- {6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl. ] Pyridin-2-yl} ethyl propionate (60.0 mg) was obtained.

実施例１１５
　氷冷下、６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール（８５．０ｍｇ）と３－（６－ホルミルピリジン－２－イル）プロピオール酸メチル（８４．０ｍｇ）の塩化メチレン（１．５ｍＬ）溶液に、トリエチルシラン（０．２７ｍＬ）とトリフルオロ酢酸（０．０８ｍＬ）を加えた。その溶液を同条件下０．５時間攪拌し、次いで室温にて３時間攪拌した。その溶液に飽和炭酸水素ナトリウム水溶液を加えて、塩化メチレンにて抽出し、無水硫酸ナトリウムで乾燥した。溶媒を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－（溶出溶媒：ヘキサン－酢酸エチル）で精製し、｛６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－イル｝プロピオール酸メチル（１２８ｍｇ）を得た。 Example 115
Chlorination of 6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indole (85.0 mg) and methyl 3- (6-formylpyridin-2-yl) propiolate (84.0 mg) under ice cooling To a methylene (1.5 mL) solution were added triethylsilane (0.27 mL) and trifluoroacetic acid (0.08 mL). The solution was stirred under the same conditions for 0.5 hour and then at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the solution, extracted with methylene chloride, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate) to obtain {6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indole. Methyl -3-ylmethyl] pyridin-2-yl} propiolate (128 mg) was obtained.

実施例１１６
　アルゴン雰囲気下、６－［２－（１－メチルシクロプロピル）－６－（トリフルオロメチルスルホニルオキシ）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（６０．０ｍｇ）、シアン化亜鉛（３０．０ｍｇ）、ビス（ジベンジリデンアセトン）パラジウム（０）（７．５ｍｇ）、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（１１．０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド－水（９９：１　ｖ／ｖ，１．３ｍＬ）懸濁液を６０℃で６時間攪拌した。その混合物を酢酸エチルで希釈し、水、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥した。溶媒を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－（溶出溶媒：ヘキサン－酢酸エチル）で精製し、６－［６－シアノ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（１４．０ｍｇ）を得た。 Example 116
Methyl 6- [2- (1-methylcyclopropyl) -6- (trifluoromethylsulfonyloxy) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (60.0 mg), cyanide under argon atmosphere Zinc (30.0 mg), bis (dibenzylideneacetone) palladium (0) (7.5 mg), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (11.0 mg) in N, N-dimethylformamide A suspension of water (99: 1 v / v, 1.3 mL) was stirred at 60 ° C. for 6 hours. The mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate) to give 6- [6-cyano-2- (1-methylcyclopropyl) -1H-indole-3. There was obtained methyl -ylmethyl] pyridine-2-carboxylate (14.0 mg).

実施例１１７
　アルゴン雰囲気下、６－［２－（１－メチルシクロプロピル）－６－（トリフルオロメチルスルホニルオキシ）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（８０．０ｍｇ）、２－プロペニルボロン酸ピナコールエステル（４３．０ｍｇ）、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）の１，２－ジメトキシエタン（１．７ｍＬ）懸濁液に２ｍｏｌ／Ｌ炭酸水素ナトリウム水溶液（０．６ｍＬ）を加えて、６０℃で２時間攪拌した。その混合物を酢酸エチルで希釈し、水、飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥した。溶媒を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－（溶出溶媒：ヘキサン－酢酸エチル）で精製し、６－［２－（１－メチルシクロプロピル）－６－（１－プロペン－２－イル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（４２．０ｍｇ）を得た。 Example 117
Under an argon atmosphere, methyl 6- [2- (1-methylcyclopropyl) -6- (trifluoromethylsulfonyloxy) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (80.0 mg), 2- To a suspension of propenylboronic acid pinacol ester (43.0 mg), dichlorobis (triphenylphosphine) palladium (II) (12.0 mg) in 1,2-dimethoxyethane (1.7 mL), a 2 mol / L aqueous sodium hydrogen carbonate solution 0.6 mL) was added and stirred at 60 ° C. for 2 hours. The mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate), and 6- [2- (1-methylcyclopropyl) -6- (1-propene-2- Yl) -1H-indol-3-ylmethyl] methyl pyridine-2-carboxylate (42.0 mg).

実施例１１８
　室温にて、６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール（１００ｍｇ）と６－チオキソ－１，６－ジヒドロピリジン－２－カルボン酸メチル（１２０ｍｇ）のメタノール（５ｍＬ）溶液にＯＸＯＮＥ（登録商標）（２１０ｍｇ）を加え、その混合物を同条件下で３時間攪拌した。その混合物に水を加え、塩化メチレンで抽出し、有機層を無水硫酸ナトリウムで乾燥した。溶媒を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－（溶出溶媒：ヘキサン－酢酸エチル）で精製し、６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルスルファニル］ピリジン－２－カルボン酸メチル（１１６ｍｇ）を得た。 Example 118
A solution of 6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indole (100 mg) and methyl 6-thioxo-1,6-dihydropyridine-2-carboxylate (120 mg) in methanol (5 mL) at room temperature Was added with OXONE® (210 mg) and the mixture was stirred under the same conditions for 3 hours. Water was added to the mixture, extracted with methylene chloride, and the organic layer was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate) to give 6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indole- Methyl 3-ylsulfanyl] pyridine-2-carboxylate (116 mg) was obtained.

実施例１１９
　６－［６－（１－メチルシクロプロピル）－３，７－ジヒドロ－２Ｈ－フロ［３，２－ｆ］インドール－５－イルメチル］ピリジン－２－カルボン酸メチル（５０．０ｍｇ）のテトラヒドロフラン（０．３ｍＬ）－メタノール（０．６ｍＬ）溶液に２ｍｏｌ／Ｌ水酸化カリウム水溶液（０．３ｍＬ）を加え、その混合物を室温にて２時間攪拌した。その反応混合物を減圧留去し、得られた残渣を水で希釈した後、氷冷下、１ｍｏｌ／Ｌ塩酸（０．６ｍＬ）を加えた。析出物をろ取し、６－［６－（１－メチルシクロプロピル）－３，７－ジヒドロ－２Ｈ－フロ［３，２－ｆ］インドール－５－イルメチル］ピリジン－２－カルボン酸（３０．０ｍｇ）を得た。 Example 119
6- [6- (1-methylcyclopropyl) -3,7-dihydro-2H-furo [3,2-f] indol-5-ylmethyl] pyridine-2-carboxylate methyl ester (50.0 mg) in tetrahydrofuran ( A 2 mol / L aqueous potassium hydroxide solution (0.3 mL) was added to a 0.3 mL) -methanol (0.6 mL) solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure, the resulting residue was diluted with water, and 1 mol / L hydrochloric acid (0.6 mL) was added under ice cooling. The precipitate was collected by filtration, and 6- [6- (1-methylcyclopropyl) -3,7-dihydro-2H-furo [3,2-f] indol-5-ylmethyl] pyridine-2-carboxylic acid (30 0.0 mg) was obtained.

実施例１２０
　（Ｅ）－３－｛６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－イル｝アクリル酸エチル（２７．０ｍｇ）のエタノール（０．７ｍＬ）溶液に２ｍｏｌ／Ｌ水酸化カリウム水溶液（０．２ｍＬ）を加え、その混合物を室温にて２時間攪拌した。その反応混合物を減圧留去し、得られた残渣を水で希釈した後、氷冷下、１ｍｏｌ／Ｌ塩酸（０．４ｍＬ）を加えた。析出物をろ取し、（Ｅ）－３－｛６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－イル｝アクリル酸（２４．０ｍｇ）を得た。 Example 120
(E) -3- {6- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridin-2-yl} ethyl acrylate (27.0 mg) in ethanol ( 0.7 mL) solution was added 2 mol / L potassium hydroxide aqueous solution (0.2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure, the resulting residue was diluted with water, and 1 mol / L hydrochloric acid (0.4 mL) was added under ice cooling. The precipitate was collected by filtration, and (E) -3- {6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridin-2-yl} acrylic acid (24 0.0 mg) was obtained.

実施例１２１
　３－｛６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－イル｝プロピオン酸エチル（５２．０ｍｇ）のエタノール（１．０ｍＬ）溶液に２ｍｏｌ／Ｌ水酸化カリウム水溶液（０．３ｍＬ）を加え、その混合物を室温にて２時間攪拌した。その反応混合物を減圧留去し、得られた残渣を水で希釈した後、氷冷下、１ｍｏｌ／Ｌ塩酸（０．６ｍＬ）を加えた。析出物をろ取し、３－｛６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－イル｝プロピオン酸（４７．２ｍｇ）を得た。 Example 121
Ethanol (1.0 mL) of ethyl 3- {6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridin-2-yl} propionate (52.0 mg) To the solution was added 2 mol / L potassium hydroxide aqueous solution (0.3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure, the resulting residue was diluted with water, and 1 mol / L hydrochloric acid (0.6 mL) was added under ice cooling. The precipitate was collected by filtration, and 3- {6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridin-2-yl} propionic acid (47.2 mg) was added. Obtained.

実施例１２２
　｛６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－イル｝プロピオール酸メチル（６０．０ｍｇ）のメタノール（０．６ｍＬ）溶液に２ｍｏｌ／Ｌ水酸化カリウム水溶液（０．３ｍＬ）を加え、その混合物を室温にて２時間攪拌した。その反応混合物を減圧留去し、得られた残渣を水で希釈した後、氷冷下、１ｍｏｌ／Ｌ塩酸（０．６ｍＬ）を加えた。析出物をろ取し、｛６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－イル｝プロピオール酸（５２．０ｍｇ）を得た。 Example 122
{6- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridin-2-yl} methyl propiolate (60.0 mg) in methanol (0.6 mL) 2 mol / L potassium hydroxide aqueous solution (0.3 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure, the resulting residue was diluted with water, and 1 mol / L hydrochloric acid (0.6 mL) was added under ice cooling. The precipitate was collected by filtration to obtain {6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridin-2-yl} propiolic acid (52.0 mg). .

実施例１２３
　６－［６－シアノ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（１１．０ｍｇ）のメタノール（０．２ｍＬ）溶液に２ｍｏｌ／Ｌ水酸化カリウム水溶液（０．１ｍＬ）を加え、その混合物を室温にて２時間攪拌した。その反応混合物を減圧留去し、得られた残渣を水で希釈した後、氷冷下、１ｍｏｌ／Ｌ塩酸（０．２ｍＬ）を加えた。析出物をろ取し、６－［６－シアノ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（９．８ｍｇ）を得た。 Example 123
6- [6-Cyano-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (11.0 mg) in methanol (0.2 mL) in 2 mol / L water Aqueous potassium oxide (0.1 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure, the resulting residue was diluted with water, and 1 mol / L hydrochloric acid (0.2 mL) was added under ice cooling. The precipitate was collected by filtration to obtain 6- [6-cyano-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (9.8 mg).

実施例１２４
　６－［２－（１－メチルシクロプロピル）－６－（１－プロペン－２－イル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチル（３７．０ｍｇ）のメタノール（０．６ｍＬ）溶液に２ｍｏｌ／Ｌ水酸化カリウム水溶液（０．３ｍＬ）を加え、その混合物を室温にて２時間攪拌した。その反応混合物を減圧留去し、得られた残渣を水で希釈した後、氷冷下、１ｍｏｌ／Ｌ塩酸（０．６ｍＬ）を加えた。析出物をろ取し、６－［２－（１－メチルシクロプロピル）－６－（１－プロペン－２－イル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸（３１．０ｍｇ）を得た。 Example 124
Methyl 6- [2- (1-methylcyclopropyl) -6- (1-propen-2-yl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (37.0 mg) in methanol (0. 6 mL) solution was added 2 mol / L potassium hydroxide aqueous solution (0.3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure, the resulting residue was diluted with water, and 1 mol / L hydrochloric acid (0.6 mL) was added under ice cooling. The precipitate was collected by filtration, and 6- [2- (1-methylcyclopropyl) -6- (1-propen-2-yl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (31.0 mg) )

実施例１２５
　６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルスルファニル］ピリジン－２－カルボン酸メチル（９７．０ｍｇ）のテトラヒドロフラン（１．０ｍＬ）－メタノール（１．０ｍＬ）溶液に２ｍｏｌ／Ｌ水酸化カリウム水溶液（０．５ｍＬ）を加え、その混合物を室温にて２時間攪拌した。その反応混合物を減圧留去し、得られた残渣を水で希釈した後、氷冷下、１ｍｏｌ／Ｌ塩酸（１．０ｍＬ）を加えた。析出物をろ取し、６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルスルファニル］ピリジン－２－カルボン酸（８８．５ｍｇ）を得た。 Example 125
6- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylsulfanyl] methyl pyridine-2-carboxylate (97.0 mg) in tetrahydrofuran (1.0 mL) -methanol (1 0.0 mL) solution was added 2 mol / L potassium hydroxide aqueous solution (0.5 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure, the resulting residue was diluted with water, and 1 mol / L hydrochloric acid (1.0 mL) was added under ice cooling. The precipitate was collected by filtration to obtain 6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylsulfanyl] pyridine-2-carboxylic acid (88.5 mg).

実施例１２６
　アルゴン雰囲気下、６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール（１５８ｍｇ）、５－ホルミルフラン－３－カルボン酸エチル（１２６ｍｇ）及びトリエチルシラン（０．３５８ｍＬ）のジクロロメタン（７．５ｍＬ）溶液を氷水浴中で冷却した。そこへトリフルオロ酢酸（０．０８６ｍＬ）を加え、その混合物を同条件下３５分間、次いで室温にて２．５時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液で洗浄した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をアミノプロピル化シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、５－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］フラン－３－カルボン酸エチル（１２３ｍｇ）を得た。 Example 126
Under argon atmosphere, 6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indole (158 mg), ethyl 5-formylfuran-3-carboxylate (126 mg) and triethylsilane (0.358 mL) in dichloromethane ( (7.5 mL) The solution was cooled in an ice-water bath. Trifluoroacetic acid (0.086 mL) was added thereto, and the mixture was stirred under the same conditions for 35 minutes and then at room temperature for 2.5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 5- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl. There was obtained ethyl furan-3-carboxylate (123 mg).

実施例１２７
　５－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］フラン－３－カルボン酸エチル（１２１ｍｇ）のテトラヒドロフラン／メタノール（１．９８ｍL／０．８４９ｍL）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０．４９９ｍＬ）を加え、その混合物を６０℃にて１６時間攪拌した。反応混合物を放冷した。反応混合物に１ｍｏｌ／Ｌ塩酸を加え、その混合物を酢酸エチルで抽出した。有機層を水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：メタノール－酢酸エチル）にて精製することにより、５－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］フラン－３－カルボン酸（３６．３ｍｇ）を得た。 Example 127
5- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] furan-3-carboxylate (121 mg) in tetrahydrofuran / methanol (1.98 mL / 0.849 mL) Was added 2 mol / L aqueous sodium hydroxide solution (0.499 mL), and the mixture was stirred at 60 ° C. for 16 hours. The reaction mixture was allowed to cool. 1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: methanol-ethyl acetate) to give 5- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] furan- 3-carboxylic acid (36.3 mg) was obtained.

実施例１２８
　対応する出発物質及び反応剤を用い、実施例５４と同様の方法で、６－［５－イソプロピル－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸メチルを合成した。 Example 128
6- [5-Isopropyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-- in the same manner as in Example 54 using the corresponding starting materials and reactants Methyl 2-carboxylate was synthesized.

実施例１２９
　対応する出発物質及び反応剤を用い、実施例５９と同様の方法で、６－［５－イソプロピル－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸を合成した。 Example 129
6- [5-Isopropyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-- in the same manner as in Example 59 using the corresponding starting materials and reactants 2-carboxylic acid was synthesized.

実施例１３０
　６－メトキシ－３－［２－（６－メトキシカルボニルピリジン－２－イル）エチル］－２－（１－メチルシクロプロピル）－１Ｈ－インドール－１－カルボン酸ｔｅｒｔ－ブチル（５４．６ｍｇ）のジクロロメタン（０．５８８ｍＬ）溶液を氷水浴中で冷却した。そこへトリフルオロ酢酸（０．５８８ｍＬ）を加え、その混合物を室温にて１時間攪拌した。反応混合物を酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液で洗浄した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル－ヘキサン）にて精製することにより、６－｛２－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イル］エチル｝ピリジン－２－カルボン酸メチル（２６．０ｍｇ）を得た。 Example 130
Of tert-butyl 6-methoxy-3- [2- (6-methoxycarbonylpyridin-2-yl) ethyl] -2- (1-methylcyclopropyl) -1H-indole-1-carboxylate (54.6 mg) The dichloromethane (0.588 mL) solution was cooled in an ice water bath. Trifluoroacetic acid (0.588 mL) was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- {2- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-yl]. Ethyl} methyl pyridine-2-carboxylate (26.0 mg) was obtained.

実施例１３１
　６－｛２－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イル］エチル｝ピリジン－２－カルボン酸メチル（２６．０ｍｇ）のテトラヒドロフラン／メタノール（０．９２３ｍＬ／０．３９６ｍＬ）溶液に、２ｍｏｌ／Ｌ水酸化ナトリウム水溶液（０．１０７ｍＬ）を加え、その混合物を室温にて３時間攪拌した。反応混合物に１ｍｏｌ／Ｌ塩酸を加え、その混合物を酢酸エチルで抽出した。有機層を水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮することにより、６－｛２－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イル］エチル｝ピリジン－２－カルボン酸（２３．８ｍｇ）を得た。 Example 131
6- {2- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-yl] ethyl} methyl 2-pyridine-2-carboxylate (26.0 mg) in tetrahydrofuran / methanol (0.923 mL) 2 mol / L aqueous sodium hydroxide solution (0.107 mL) was added to the solution, and the mixture was stirred at room temperature for 3 hours. 1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 6- {2- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-yl]. Ethyl} pyridine-2-carboxylic acid (23.8 mg) was obtained.

なお、実施例１～１３１の構造式および物性値を表１８～３８に示した。 The structural formulas and physical property values of Examples 1 to 131 are shown in Tables 18 to 38.

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

比較例１
　特許文献１に記載の方法で、６－（２－シクロプロピル－６－メトキシ－１Ｈ－インドール－３－イルメチル）ピリジン－２－カルボン酸を合成した。 Comparative Example 1
6- (2-Cyclopropyl-6-methoxy-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid was synthesized by the method described in Patent Document 1.

比較例２
　対応する出発物質及び反応剤を用い、比較例１と同様の方法で、６－（２－シクロブチル－６－メトキシ－１Ｈ－インドール－３－イルメチル）ピリジン－２－カルボン酸を合成した。 Comparative Example 2
6- (2-Cyclobutyl-6-methoxy-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid was synthesized in the same manner as in Comparative Example 1 using the corresponding starting materials and reactants.

試験例１
ＥＰ１受容体拮抗作用確認試験 Test example 1
EP 1 receptor antagonism confirmation test

（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寒天培地にて１日培養した。培養後、コロニーを選択し、５０μｇ／ｍＬのアンピシリンを含むＬＢ液体培地にて培養した。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。 (1) Preparation of rat EP 1 expression vector Using Rat Kidney BD Marathon-Ready cDNA (Nippon Becton Dickinson Co., Ltd.) as a template, the forward primer shown in SEQ ID NO: 1 and the reverse primer shown in SEQ ID NO: 2 were used. The first PCR was performed using KOD-Plus-Ver2.0 (Toyobo Co., Ltd.). Further, using this amplification product as a template, a forward primer shown in SEQ ID NO: 3 and a 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 Escherichia coli was cultured on an LB agar medium for 1 day. After the culture, colonies were selected and cultured in an 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 (Ptger 1 ) of rat EP 1 registered under the accession number NM — 013100 of a known database (NCBI), all except one base were identical. It was. Further, 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) Preparation of rat EP 1 receptor-expressing cells

（２－１）ＣＯＳ－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：０．１ｍＭ）および胎児牛血清（三光純薬株式会社、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。 (2-1) COS-1 cell culture COS-1 cells (Dainippon Sumitomo Pharma Co., Ltd.) are penicillin-streptomycin solution (Invitrogen Corporation, final concentration: 100 U / mL as benzylpenicillin; 100 μg / mL as streptomycin) as an antibiotic, D-MEM liquid medium (containing high glucose and L-glutamine) supplemented with MEM non-essential amino acids (Invitrogen Corporation, final concentration: 0.1 mM) and fetal calf serum (Sanko Junyaku Co., Ltd., final concentration: 10%) Invitrogen Corp.) was cultured in an incubator under 5% CO 2 gas conditions at 37 ° C. until 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ドレシオが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：０．１ｍＭ）及び胎児牛血清（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 introduction of rat EP 1 expression vector Cells that have reached confluence are detached with 0.05% trypsin / 0.53 mM EDTA · 4Na, MEM non-essential amino acids (final concentration: 0.1 mM) and Resuspended in D-MEM liquid medium (containing high glucose and L-glutamine, Invitrogen Corporation) supplemented with fetal calf serum (final concentration: 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 with 5% CO 2 gas. When the cells for introduction of the rat EP 1 expression vector were adhered (after 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 (2-4) Introduction of rat EP 1 expression vector

　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）にて希釈した。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、室温にて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℃にて２０時間培養した。２０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。 For the introduction of rat EP 1 expression vector, using Lipofectamine 2000 (Invitrogen Corporation). The rat EP 1 expression vector was diluted with OPTI-MEM (registered trademark) I Reduced-Serum Medium (Invitrogen Corporation) to 200 ng / 25 μL / well. At the same time, Lipofectamine 2000 (Invitrogen Corporation) is diluted with OPTI-MEM (registered trademark) I Reduced-Serum Medium (Invitrogen Corporation) to 0.5 μL / 25 μL / well and incubated at room temperature for 5 minutes. did. 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 rat EP 1 expression vector / Lipofectamine 2000 complex was dispensed were cultured at 37 ° C. for 20 hours in an incubator under 5% CO 2 gas conditions. After culturing for 20 hours, the cells were used as rat EP 1 receptor-expressing cells for measurement of intracellular calcium concentration.

（３）細胞内カルシウム濃度上昇抑制作用の検討 (3) Examination of the inhibitory effect on the increase in intracellular calcium concentration

　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て検討した。 Using the rat EP 1 receptor-expressing cells, the inhibitory effect of each test compound on the increase in intracellular calcium concentration induced by prostaglandin E 2 was examined by the method described below.

　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（２０ｍＭＨＥＰＥＳ／Ｈａｎｋ’ｓ　Ｂａｌａｎｃｅｄ　Ｓａｌｔ　Ｓｏｌｕｔｉｏｎ（ＨＢＳＳ）、ｐＨ７．２）にて希釈した。ラットＥＰ１受容体発現細胞をアッセイバッファーにて洗浄した。蛍光カルシウム指示薬（Ｃａｌｃｉｕｍ　ｋｉｔ　ＩＩ，Ｆｌｕｏ４（株式会社　同仁化学研究所）：同製品プロトコールで調製、インビトロジェン株式会社、２．５ｍＭプロベネシドを含む）１００μＬを各ウェルに添加し、３７℃にて６０分間、インキュベーター内にてインキュベートした。その後、速やかに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、ＦＤＳＳ（登録商標）７０００（浜松ホトニクス社製）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秒後に各試験化合物５０μＬ（最終濃度：１ｎＭ～１０μＭ）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１０ｎＭ）、６０秒間蛍光シグナルを測定した。 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. Fluorescent calcium indicator (Calcium kit II, Fluo4 (Dojindo Laboratories Co., Ltd.): Prepared by the same product protocol, Invitrogen Co., Ltd., containing 2.5 mM probenecid) 100 μL was added to each well, and 37 ° C. for 60 minutes. Incubated in incubator. Thereafter, the intracellular calcium concentration was measured immediately. The intracellular calcium concentration was measured as a fluorescence signal using FDSS (registered trademark) 7000 (manufactured by Hamamatsu Photonics). 20 seconds after the start of reading the fluorescence signal, 50 μL of each test compound (final concentration: 1 nM to 10 μM) 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.

　上記方法において、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、試験化合物の濃度－反応曲線から５０％の阻害を示す濃度をＩＣ５０値とした。ＥＰ１受容体拮抗作用の値として、得られた各試験化合物のＩＣ５０値を以下の表３９に示した。 100% of the fluorescence signal obtained when prostaglandin E 2 was added when assay buffer was added instead of the test compound in the above method, and the signal obtained when neither test compound nor prostaglandin E 2 was added Was defined as 0%, and the concentration showing 50% inhibition from the concentration-response curve of the test compound was defined as the IC 50 value. As values of EP 1 receptor antagonistic activity, IC 50 values of the obtained test compounds are shown in Table 39 below.

Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000052

　表３９に示したように、本発明の化合物は強力なＥＰ１受容体拮抗作用を示した。 As shown in Table 39, the compounds of the present invention exhibited potent EP 1 receptor antagonism.

　また、実施例５７および１０７と比較例１および２のＩＣ５０値の比較を以下の表４０に示した。 

Figure JPOXMLDOC01-appb-T000053
　表４０に示したように、比較例１および比較例２のＣ３－６シクロアルキル基に、さらにＣ１－６アルキル基が置換した本願化合物は、比較例１および比較例２の化合物に対し、優れたＥＰ１受容体拮抗作用を示した。 The comparison of IC 50 values between Examples 57 and 107 and Comparative Examples 1 and 2 is shown in Table 40 below.
Figure JPOXMLDOC01-appb-T000053
 As shown in Table 40, the compounds of the present invention in which the C 3-6 cycloalkyl group of Comparative Example 1 and Comparative Example 2 was further substituted with a C 1-6 alkyl group were compared with the compounds of Comparative Example 1 and Comparative Example 2. Excellent EP 1 receptor antagonism was exhibited.

試験例２
サルプロストン誘発膀胱収縮に対する化合物の抑制効果 Test example 2
Inhibitory effect of compounds on sarprostone-induced bladder contraction

　雌性ＳＤラットを用いた。ウレタン麻酔下（１．２５ｇ／ｋｇ、皮下投与）に気管カニューレ（Ｓｉｚｅ８、ＨＩＢＩＫＩ）、投薬用大腿静脈カニューレ（２３Ｇ針付きＰＥ５０）を挿入した。膀胱頂部から膀胱カニューレ（ＰＥ５０）を挿入した。膀胱カニューレを三方活栓に接続し、一方を圧トランスデューサーに接続し、他方を生理食塩水にて満たしたシリンジに接続した。生理食塩水を膀胱に注入速度３．６ｍＬ／時で注入し、注入時の膀胱収縮圧を記録計（RECTI－HORITZ－８K、日本電気株式会社）にて記録した。排尿時の膀胱収縮圧が安定してから１０分後に、サルプロストンを皮下投与（０．３ｍｇ／ｋｇ）した。その後、膀胱収縮圧が一定になった時点で被験薬（１．０ｍｇ／ｋｇ）を静脈内投与した。サルプロストン投与前１０分間の平均膀胱収縮圧を基準値（０％）とした。また、被験薬投与直前１０分間の平均膀胱収縮圧を最高膀胱収縮圧（１００％）とした。被験薬投与後１５分および６０分における前後５分間の平均膀胱収縮圧を測定した。最高膀胱収縮圧に対してのこの測定値の比を次式により算出し、被験薬投与後の平均膀胱収縮率 とした。 Female SD rats were used. Under urethane anesthesia (1.25 g / kg, subcutaneous administration), a tracheal cannula (Size8, HBIKI) and a femoral vein cannula for administration (PE50 with a 23G needle) were inserted. A bladder cannula (PE50) was inserted from the top of the bladder. The bladder cannula was connected to a three-way stopcock, one connected to a pressure transducer, and the other connected to a syringe filled with saline. Saline was infused into the bladder at an infusion rate of 3.6 mL / hour, and the bladder contraction pressure at the time of infusion was recorded with a recorder (RECTI-HORITZ-8K, NEC Corporation). Ten minutes after stabilization of the bladder contraction pressure during urination, sarprostone was administered subcutaneously (0.3 mg / kg). Thereafter, when the bladder contraction pressure became constant, the test drug (1.0 mg / kg) was intravenously administered. The average bladder contraction pressure for 10 minutes before administration of salprostone was used as a reference value (0%). The average bladder contraction pressure for 10 minutes immediately before administration of the test drug was defined as the maximum bladder contraction pressure (100%). Average bladder contraction pressure was measured for 5 minutes before and after 15 minutes and 60 minutes after administration of the test drug. The ratio of this measured value with respect to the maximum bladder contraction pressure was calculated by the following equation, and the average bladder contraction rate after administration of the test drug was taken as the mean bladder contraction rate.

（被験薬投与後の平均膀胱収縮率（％））＝［（被験薬投与後の平均膀胱収縮圧）／（最高膀胱収縮圧）］×１００ (Average bladder contraction rate after test drug administration (%)) = [(Average bladder contraction pressure after test drug administration) / (Maximum bladder contraction pressure)] × 100

さらに、最高膀胱収縮率（１００％）と被験薬投与後の平均膀胱収縮率（％）との差分を次式により算出し、被験薬の膀胱収縮抑制率とした。 Furthermore, the difference between the maximum bladder contraction rate (100%) and the average bladder contraction rate (%) after administration of the test drug was calculated according to the following formula, and was defined as the bladder contraction suppression rate of the test drug.

（膀胱収縮抑制率）＝１００％－（被験薬投与後の平均膀胱収縮率（％）） (Bladder contraction inhibition rate) = 100% − (Average bladder contraction rate after test drug administration (%))

この結果を表４１に示した。 The results are shown in Table 41.

Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000054

　以上の結果、本願化合物は、生体内に投与された場合において、比較例１と比較して、膀胱収縮抑制が強力かつ持続的であることが判明した。 As a result of the above, it was found that the compound of the present application had a strong and sustained suppression of bladder contraction when compared with Comparative Example 1 when administered in vivo.

　本発明の化合物は、強力かつ持続的な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）の治療薬または予防薬として有用である。 Since the compound of the present invention has a strong and long-lasting EP 1 receptor antagonistic action, it is useful as a therapeutic or prophylactic agent for diseases or symptoms caused by the activation of EP 1 receptor by stimulating action of PGE 2. . Among them, it is useful as a therapeutic or prophylactic 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 EP 1 receptor amplified using the primers of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4.

Claims (15)

一般式（Ｉ）で表される化合物、またはその薬理学的に許容される塩
Figure JPOXMLDOC01-appb-C000001
 〔式中、Ａは、以下のａ）～ｈ）：
Figure JPOXMLDOC01-appb-C000002
 からなる群から選択される基であり；
Ｗ１およびＷ２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；
Ｗ３は、酸素原子または硫黄原子であり；
Ｗ４は、＝ＣＨ－または窒素原子であり； 
Ｚは、水素原子またはハロゲン原子であり；
Ｙ１は、Ｃ１－６アルキレン基または硫黄原子であり； 
Ｙ２は、単結合、Ｃ１－６アルキレン基、Ｃ２－４アルケニレン基またはＣ２－４アルキニレン基であり；
Ｒ１は、水素原子またはＣ１－６アルキル基であり；
Ｒ２は、Ｃ１－６アルキル基であり；
Ｒ３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；
Ｒ４は、水素原子、ハロゲン原子、Ｃ１－６アルキル基またはＣ１－６アルコキシ基であり；
Ｒ５は、水素原子、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基またはＣ３－６シクロアルキル基であり、Ｒ６は、水素原子、ハロゲン原子、Ｃ１－６アルキル基、ハロＣ１－６アルキル基、ヒドロキシＣ１－６アルキル基、Ｃ１－６アルコキシ基、ハロＣ１－６アルコキシ基、Ｃ１－６アルキルスルファニル基、Ｃ１－６アルキルスルフィニル基、Ｃ１－６アルキルスルホニル基、Ｃ３－６シクロアルキル基、シアノ基またはＣ２－６アルケニル基であるか、または、Ｒ５とＲ６が、互いに結合して、－（ＣＨ２）３－、－Ｏ－（ＣＨ２）２－、－（ＣＨ２）２－Ｏ－、－Ｏ－ＣＨ２－Ｏ－、－（ＣＨ２）４－、－Ｏ－（ＣＨ２）３－、－（ＣＨ２）３－Ｏ－、－Ｏ－（ＣＨ２）２－Ｏ－、－ＣＨ２－Ｏ－（ＣＨ２）２－、および－（ＣＨ２）２－Ｏ－ＣＨ２－からなる群から選択される基を形成し；
Ｒ７は、水素原子、ハロゲン原子、Ｃ１－６アルキル基またはＣ１－６アルコキシ基であり；
Ｘは、メチレン基であり；
Ｑは、メチレン基または単結合である。（ただし、（＊）を付された結合はＹ１と結合し、（＊＊）を付された結合はＹ２と結合することを表す。）。〕。 Compound represented by general formula (I) or a pharmacologically acceptable salt thereof
Figure JPOXMLDOC01-appb-C000001
 [Wherein A represents the following a) to h):
Figure JPOXMLDOC01-appb-C000002
 A group selected from the group consisting of:
One of W 1 and W 2 is a nitrogen atom and the other is ═CH— or a nitrogen atom;
W 3 is an oxygen atom or a sulfur atom;
W 4 is ═CH— or a nitrogen atom;
Z is a hydrogen atom or a halogen atom;
Y 1 is a C 1-6 alkylene group or a sulfur atom;
Y 2 is a single bond, a C 1-6 alkylene group, a C 2-4 alkenylene group or a C 2-4 alkynylene group;
R 1 is a hydrogen atom or a C 1-6 alkyl group;
R 2 is a C 1-6 alkyl group;
R 3 is a hydrogen atom, a C 1-6 alkyl group or a C 7-10 aralkyl group;
R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group;
R 5 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group or a C 3-6 cycloalkyl group, and R 6 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group Halo C 1-6 alkyl group, hydroxy C 1-6 alkyl group, C 1-6 alkoxy group, halo C 1-6 alkoxy group, C 1-6 alkylsulfanyl group, C 1-6 alkylsulfinyl group, C 1 A -6 alkylsulfonyl group, a C 3-6 cycloalkyl group, a cyano group or a C 2-6 alkenyl group, or R 5 and R 6 are bonded to each other to form — (CH 2 ) 3 —, — O— (CH 2 ) 2 —, — (CH 2 ) 2 —O—, —O—CH 2 —O—, — (CH 2 ) 4 —, —O— (CH 2 ) 3 —, — (CH 2 ) 3 -O -, - O- ( CH 2) 2 -O- -CH 2 -O- (CH 2) 2 -, and - to form a group selected from the group consisting of - (CH 2) 2 -O- CH 2;
R 7 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group;
X is a methylene group;
Q is a methylene group or a single bond. (However, the bond marked with (*) is linked to Y 1 and the bond marked with (**) is linked to Y 2 ). ]. Ａが、以下のａ）、ｂ）、ｄ）およびｈ）：
Figure JPOXMLDOC01-appb-C000003
 からなる群から選択される基であり； 
Ｒ１が水素原子であり；
Ｒ４が、水素原子であり；
Ｒ７が、水素原子である、請求項１記載の化合物、またはその薬理学的に許容される塩（ただし、（＊）を付された結合はＹ１と結合し、（＊＊）を付された結合はＹ２と結合することを表す。）。〕。 A is the following a), b), d) and h):
Figure JPOXMLDOC01-appb-C000003
 A group selected from the group consisting of:
R 1 is a hydrogen atom;
R 4 is a hydrogen atom;
The compound according to claim 1, wherein R 7 is a hydrogen atom, or a pharmacologically acceptable salt thereof (provided that a bond marked with (*) binds to Y 1, and (**) Represents a bond to Y 2 ). ]. Ｙ２が、単結合、Ｃ２－４アルケニレン基またはＣ２－４アルキニレン基である、請求項２記載の化合物、またはその薬理学的に許容される塩。 The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein Y 2 is a single bond, a C 2-4 alkenylene group or a C 2-4 alkynylene group. Ｒ３が水素原子である、請求項３記載の化合物、またはその薬理学的に許容される塩。 The compound according to claim 3, wherein R 3 is a hydrogen atom, or a pharmaceutically acceptable salt thereof. Ａが、以下のｂ）およびｈ）：
Figure JPOXMLDOC01-appb-C000004
 からなる群から選択される基である、請求項４記載の化合物、またはその薬理学的に許容される塩。 A is the following b) and h):
Figure JPOXMLDOC01-appb-C000004
 The compound according to claim 4, which is a group selected from the group consisting of: or a pharmaceutically acceptable salt thereof. Ｑが単結合である、請求項５記載の化合物、またはその薬理学的に許容される塩。 The compound according to claim 5, wherein Q is a single bond, or a pharmaceutically acceptable salt thereof. Ｒ５が水素原子、ハロゲン原子、Ｃ１－６アルキル基またはＣ１－６アルコキシ基であり、Ｒ６が、水素原子、ハロゲン原子、Ｃ１－６アルキル基、ハロＣ１－６アルキル基、ヒドロキシＣ１－６アルキル基、Ｃ１－６アルコキシ基、ハロＣ１－６アルコキシ基、Ｃ１－６アルキルスルファニル基、Ｃ１－６アルキルスルフィニル基、Ｃ１－６アルキルスルホニル基、Ｃ３－６シクロアルキル基、シアノ基またはＣ２－６アルケニル基であるか、または、Ｒ５とＲ６が、互いに結合して、－（ＣＨ２）３－、－Ｏ－（ＣＨ２）２－、－（ＣＨ２）２－Ｏ－、－（ＣＨ２）４－、－Ｏ－（ＣＨ２）３－、－（ＣＨ２）３－Ｏ－、－ＣＨ２－Ｏ－（ＣＨ２）２－、および－（ＣＨ２）２－Ｏ－ＣＨ２－からなる群から選択される基を形成する、請求項６記載の化合物、またはその薬理学的に許容される塩。 R 5 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group, and R 6 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, hydroxy C 1-6 alkyl group, C 1-6 alkoxy, halo C 1-6 alkoxy group, C 1-6 alkylsulfanyl group, C 1-6 alkylsulfinyl group, C 1-6 alkylsulfonyl group, C 3- 6 cycloalkyl group, cyano group or C 2-6 alkenyl group, or R 5 and R 6 are bonded to each other to form — (CH 2 ) 3 —, —O— (CH 2 ) 2 —, — (CH 2 ) 2 —O—, — (CH 2 ) 4 —, —O— (CH 2 ) 3 —, — (CH 2 ) 3 —O—, —CH 2 —O— (CH 2 ) 2 — And — (CH 2 ) 2 —O—CH 2 — The compound of Claim 6 which forms group selected from this group, or its pharmacologically acceptable salt. Ｒ５が水素原子、ハロゲン原子、Ｃ１－６アルキル基またはＣ１－６アルコキシ基であり、Ｒ６がハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基、ハロＣ１－６アルコキシ基、Ｃ１－６アルキルスルファニル基、Ｃ３－６シクロアルキル基またはＣ２－６アルケニル基であるか、または、Ｒ５とＲ６が、互いに結合して、－（ＣＨ２）３－または－（ＣＨ２）４－を形成する、請求項７記載の化合物、またはその薬理学的に許容される塩。 R 5 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group, and R 6 is a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a halo C 1-6 An alkoxy group, a C 1-6 alkylsulfanyl group, a C 3-6 cycloalkyl group or a C 2-6 alkenyl group, or R 5 and R 6 are bonded to each other to form — (CH 2 ) 3 — or - (CH 2) 4 - to form a compound of claim 7, wherein or a pharmaceutically acceptable salt thereof. 下記の群から選択される請求項１記載の化合物またはその薬理学的に許容される塩：
６－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－クロロ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－メチル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－エトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－クロロ－５－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－エチル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［５－クロロ－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－イソプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－メトキシ－５－メチル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［５－フルオロ－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
３－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］－２－フルオロ安息香酸、
２－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］チアゾール－４－カルボン酸、
６－［２－（１－エチルシクロプロピル）－６－メトキシ－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
３－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］安息香酸、
２－フルオロ－３－［６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］安息香酸、
６－［５，６－ジメチル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－ジフルオロメトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［２－（１－メチルシクロプロピル）－１，５，６，７－テトラヒドロシクロペンタ［ｆ］インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［５－エチル－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［２－（１－メチルシクロプロピル）－６－（メチルスルファニル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピラジン－２－カルボン酸、
６－［５－シクロプロピル－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－メトキシ－２－（１－メチルシクロプロピル）－５－プロピル－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－メトキシ－２－（１－メチルシクロブチル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［５－ブチル－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－シクロプロピル－２－（１－メチルシクロブチル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［５－クロロ－６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－シクロプロピル－５－フルオロ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
（Ｅ）－３－｛６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－イル｝アクリル酸、
｛６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－イル｝プロピオール酸、
６－［２－（１－メチルシクロプロピル）－６－（１－プロペン－２－イル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸、
６－［６－シクロプロピル－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルスルファニル］ピリジン－２－カルボン酸、および
６－［５－イソプロピル－６－メトキシ－２－（１－メチルシクロプロピル）－１Ｈ－インドール－３－イルメチル］ピリジン－２－カルボン酸。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the following group:
6- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-chloro-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-methyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-Ethoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-chloro-5-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-ethyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [5-chloro-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-Isopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-methoxy-5-methyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [5-fluoro-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
3- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] -2-fluorobenzoic acid,
2- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiazole-4-carboxylic acid,
6- [2- (1-ethylcyclopropyl) -6-methoxy-1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
3- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] benzoic acid,
2-fluoro-3- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] benzoic acid,
6- [5,6-dimethyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-difluoromethoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [2- (1-methylcyclopropyl) -1,5,6,7-tetrahydrocyclopenta [f] indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [5-ethyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [2- (1-methylcyclopropyl) -6- (methylsulfanyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyrazine-2-carboxylic acid,
6- [5-cyclopropyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-methoxy-2- (1-methylcyclopropyl) -5-propyl-1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-methoxy-2- (1-methylcyclobutyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [5-butyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-cyclopropyl-2- (1-methylcyclobutyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [5-chloro-6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-cyclopropyl-5-fluoro-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
(E) -3- {6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridin-2-yl} acrylic acid,
{6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridin-2-yl} propiolic acid,
6- [2- (1-methylcyclopropyl) -6- (1-propen-2-yl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid,
6- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylsulfanyl] pyridine-2-carboxylic acid, and 6- [5-isopropyl-6-methoxy-2- (1 -Methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid. 請求項１～９の何れか一項に記載の化合物、またはその薬理学的に許容される塩を含有する、医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof. 以下からなる群：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から選択される少なくとも１種の薬剤を含む、請求項１０記載の医薬組成物。 Group consisting of: anticholinergics, alpha 1 antagonists, beta agonists, 5.alpha.-reductase inhibitors, PDE inhibitors, acetylcholinesterase inhibitors, antiandrogens, progesterone-based hormone, LH-RH analogs, neurokinin inhibitors, anti diuretics, calcium channel blockers, smooth muscle direct action, tricyclic antidepressants, potassium channel modulators, sodium channel blockers, H 1 blockers, serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, dopamine reuptake inhibitors , GABA agonist, TRPV1 modulator, endothelin antagonist, 5-HT 1A antagonist, α 1 agonist, opioid agonist, P 2 X antagonist, COX inhibitor, σ agonist, muscarinic agonist 11. A pharmaceutical composition according to claim 10, comprising at least one drug. 請求項１～９の何れか一項に記載の化合物、またはその薬理学的に許容される塩を含有する、ＥＰ１受容体拮抗剤。 An EP 1 receptor antagonist comprising the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof. 請求項１～９の何れか一項に記載の化合物、またはその薬理学的に許容される塩を含有する、下部尿路症状の予防または治療剤。 A preventive or therapeutic agent for lower urinary tract symptoms, comprising the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof. 請求項１～９の何れか一項に記載の化合物、またはその薬理学的に許容される塩を有効量投与することからなる、下部尿路症状の予防または治療方法。 A method for preventing or treating lower urinary tract symptoms, comprising administering an effective amount of the compound according to any one of claims 1 to 9, or a pharmacologically acceptable salt thereof. 下部尿路症状の予防または治療用の医薬組成物を製造するための、請求項１～９の何れか一項に記載の化合物、またはその薬理学的に許容される塩の使用。 Use of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for preventing or treating lower urinary tract symptoms.
PCT/JP2013/069347 2012-07-24 2013-07-17 Indole derivative or pharmacologically acceptable salt thereof Ceased WO2014017342A1 (en)

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