WO2012020813A1 - Fused-ring pyrrolidine derivative - Google Patents

Fused-ring pyrrolidine derivative Download PDF

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WO2012020813A1
WO2012020813A1 PCT/JP2011/068316 JP2011068316W WO2012020813A1 WO 2012020813 A1 WO2012020813 A1 WO 2012020813A1 JP 2011068316 W JP2011068316 W JP 2011068316W WO 2012020813 A1 WO2012020813 A1 WO 2012020813A1
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group
oxo
piperidin
carboxylate
dihydro
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PCT/JP2011/068316
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French (fr)
Japanese (ja)
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健太郎 ▲高▼井
孝明 住吉
篤志 諏訪
洋子 ▲高▼橋
義治 宇留野
康子 村田
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大日本住友製薬株式会社
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Publication of WO2012020813A1 publication Critical patent/WO2012020813A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention relates to novel fused pyrrolidine derivatives having muscarinic receptor activity and pharmaceutical compositions containing them as active ingredients.
  • the present invention also provides a preventive and / or therapeutic agent for muscarinic receptor-mediated diseases containing them.
  • the neurotransmitter acetylcholine receptor is known to have two types of cholinergic receptors, nicotine receptor and muscarinic receptor.
  • Muscarinic receptors are cell membrane-bound G protein-coupled receptors (GPCRs), and five subtypes (M 1 -M 5 ) are currently known. These M 1 -M 5 muscarinic receptors exert excitatory and inhibitory control on central and peripheral tissues and are involved in many physiological functions including heart rate, arousal, cognition, motor control and the like.
  • Muscarinic receptor agonists have various pharmacological actions such as analgesic action, memory improving action, antipsychotic action, and cognitive impairment improving action, and may be used as therapeutic agents for these (Non-Patent Document 1).
  • conventional muscarinic receptor agonists such as carbachol and pilocarpine have low selectivity for muscarinic receptor subtypes, and as a result, many side effects have been observed, so their clinical application is limited.
  • Patent Document 1 discloses, for example, an oxindole compound represented by the following formula.
  • the compound differs in structure from the compound of the present invention in which the 1-position nitrogen atom of the oxindole ring is bonded to the piperidine ring in that the 3-position carbon atom of the oxindole ring is bonded to the piperidine ring. Also, there is no specific disclosure or suggestion regarding muscarinic M 1 and M 4 receptor agonists and muscarinic receptor selectivity.
  • Patent Document 2 discloses a compound having muscarinic M 4 receptor activity as, for example, the following formula:
  • Patent Document 4 discloses, for example, the following formula:
  • An oxindole compound is disclosed. However, these compounds are structurally different from the compounds of the present invention in that the pyrrolidine ring is bonded to the nitrogen atom of the piperidine ring.
  • the agonist activity of the compound is selective for muscarinic M 1 receptor, and no specific disclosure or suggestion is made regarding an oxindole compound that selectively activates both muscarinic M 1 and M 4 receptors. .
  • the present invention provides a fused-ring pyrrolidine compound that selectively activates muscarinic M 1 and M 4 receptors to express effects and has reduced side effects via other muscarinic receptors or other receptors. This is the issue.
  • the present inventors have found that a compound having a specific condensed pyrrolidine structure selectively activates muscarinic M 1 and M 4 receptors, thereby causing antipsychotic action and cognitive impairment.
  • the present invention was completed by finding that it has an excellent effect of improving central diseases including an improving action and the like and reduces side effects via other muscarinic receptors or other receptors. That is, the present invention [1] The following formula (I)
  • R 5 represents a halogen atom, a C 3-7 cycloalkyl group, a C 6-14 aryl group, a heteroaryl group, a C 6-14 arylalkyl group, a heteroarylalkyl group, a C 2-6 alkenyl group, a C 2-6 Alkynyl group, C 1-6 alkoxy group, cyano group, C 1-6 alkylsulfanyl group, acyl group, sulfamoyl group, hydroxyl group, amino group, nitro group, C 1-6 alkylsulfonyl group, or optionally substituted
  • a C 1-6 alkyl group, R 1 and R 2 are the same or different and each represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, a halogen atom, a hydroxyl group, a C 3-7 cycloalkyl
  • R 1 and R 2 are bonded to each other so that R 1 and R 2 together with the adjacent carbon atom form a C 3-7 cycloalkane or a 3-7 membered heterocyclic ring, or together
  • Form CR 6 R 7
  • R 6 and R 7 are the same or different and are each a hydrogen atom or an optionally substituted C 1-6 alkyl group, or R 6 and R 7 are bonded to each other to form R 6 and R 7.
  • R 3 and R 4 together form ⁇ O or ⁇ S;
  • X is a single bond or methylene,
  • Y and Z are the same or different and each represents an oxygen atom or a sulfur atom,
  • R is an optionally substituted C 1-6 alkyl group, a C 2-6 alkynyl group or a C 2-6 alkenyl group,
  • Ring A is a 6- to 7-membered nitrogen-containing group optionally substituted with 1 to 2 substituents selected from the group consisting of a hydroxyl group, a halogen atom, a C 1-6 alkyl group and a C 1-6 alkoxy group Heterocycle.
  • Ring A is represented by the following formula (2a)
  • Ring A is represented by the following formula (2)
  • R 8 represents a hydrogen atom, a hydroxyl group, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group.
  • the compound according to [7] The above [1], [2a], [2], [3], [4a], [4], [5]
  • the compound of the present invention exhibits an excellent effect of improving central diseases including an antipsychotic effect, a cognitive impairment improving effect, and the like, and thus is useful as a novel preventive and / or therapeutic agent for central diseases.
  • muscle receptor without a prefix identifying a receptor subtype means one or more of the five receptor subtypes M 1 -M 5 .
  • agonists or agonists Compounds that bind to muscarinic receptors and enhance muscarinic activity are called agonists or agonists.
  • antagonists or antagonists Compounds that reduce the activity of muscarinic receptors are called antagonists or antagonists.
  • Agonists interact with muscarinic receptors to increase their ability to transduce intracellular signals in response to endogenous ligand binding.
  • Antagonists interact with the muscarinic receptor and compete for binding site (s) on the receptor with endogenous ligand (s) or substrate (s) and the receptor responds to endogenous ligand binding Reducing the ability to transmit intracellular signals.
  • C 1-6 alkyl group means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group and n-hexyl group, and structural isomers thereof, Among these, a C 1-4 alkyl group is preferable, a methyl group, an ethyl group, an n-propyl group, and an isopropyl group are more preferable, and a methyl group and an ethyl group are particularly preferable.
  • C 2-6 alkenyl group means a linear or branched unsaturated aliphatic hydrocarbon having 2 to 6 carbon atoms having one or more double bonds.
  • Group includes, for example, ethenyl group, propenyl group, crotyl group, butenyl group, pentenyl group and hexenyl group, and structural isomers and geometric isomers thereof.
  • the position of the double bond may be any position on the carbon chain. Of these, a C2-4 alkenyl group is preferable.
  • C 2-6 alkynyl group means a linear or branched unsaturated aliphatic hydrocarbon group having 2 to 6 carbon atoms and having one or more triple bonds. And includes, for example, ethynyl group, propynyl group, butynyl group, pentynyl group and hexynyl group, and structural isomers thereof.
  • the position of the triple bond may be any position on the carbon chain. Of these, a C 2-4 alkynyl group is preferable.
  • C 3-7 cycloalkyl group means a 3- to 7-membered saturated or unsaturated aliphatic carbocyclic group constituting a ring only with carbon atoms.
  • Specific examples of the “C 3-7 cycloalkyl group” include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclopentenyl group, cyclopentadienyl group, cyclohexyl group, cyclohexenyl group, 1,3-cyclohexadienyl.
  • C 3-6 cycloalkyl group is preferable.
  • the “C 3-7 cycloalkyl group” may optionally have one or more unsaturated bonds as long as an aromatic ⁇ -electron system does not occur, and is condensed with a C 6-14 arene. You may do it.
  • heterocyclic group means 3 to 7-membered saturated or unsaturated containing one or more heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen atoms as ring-constituting atoms.
  • the “heterocyclic group” may optionally have one or more unsaturated bonds as long as an aromatic ⁇ -electron system does not occur, and C 6-14 It may be condensed with an arene or a heterocyclic ring.
  • the ring-constituting member may contain one or more carbonyl or thiocarbonyl.
  • a cyclic group such as lactam, lactone, cyclic imide, cyclic thioimide, and cyclic carbamate is also included in the heterocyclic group. It is. Binding position of the "heterocyclic group” may even on the carbon atoms also on hetero atoms, in the case of condensate of C 6-14 arene or heterocyclic ring, on a ring of C 6-14 arene or heterocyclic There may be.
  • heterocyclic group examples include, for example, a tetrahydrothiopyranyl group, 4H-pyranyl group, tetrahydropyranyl group, piperidyl group, 1-ethoxycarbonylpiperidyl group, 1-ethoxycarbonylpiperidinylidenyl group, 1,3-dioxinyl group, 1,3-dioxanyl group, 1,4-dioxinyl group, 1,4-dioxanyl group, piperazinyl group, 1,3-oxathianyl group, 1,4-oxathiinyl group, 1,4-oxathianyl group Group, tetrahydro-1,4-thiazinyl group, 2H-1,2-oxazinyl group, maleimide group, succinimide group, dioxopiperazinyl group, hydantoin group, dihydrouracil group, morpholino group, hexahydro-1,3,
  • C 6-14 aryl group means an aromatic carbocyclic group having 6 to 14 carbon atoms.
  • the “C 6-14 aryl group” may be condensed with at least one C 6-14 arene or C 3-7 cycloalkane.
  • Specific examples of the “C 6-14 aryl group” include a phenyl group, a naphthyl group, a phenanthryl group, an anthryl group, a fluorenyl group, a tetrahydronaphthyl group, an indenyl group and an indanyl group, and among them, a phenyl group and a naphthyl group.
  • a phenyl group is particularly preferable.
  • the “C 6-14 aryl group” is a halogen atom, a hydroxyl group, an amino group, a cyano group, a nitro group, a C 1-6 alkyl-carbamoyl group, an acyl group, a C 1-6 alkoxy group or an optionally substituted group.
  • C 1-6 alkyl group a mono- or di-C 1-6 alkylamino group, C 1-6 alkylsulfanyl group, C 1-6 alkylsulfinyl group, C 1-6 alkylsulfonyl group, a sulfamoyl group and a trifluoromethyl group It may have one or more arbitrary substituents selected from the group consisting of, preferably a phenyl group having the same or different one or two substituents.
  • C 6-14 aryl group examples include a phenyl group, a phenyl group substituted with a halogen atom (for example, a phenyl group substituted with a halogen atom at the 3-position or 4-position), a 3-hydroxyphenyl group, 4-hydroxy Phenyl group, 3-aminophenyl group, 4-aminophenyl group, 3-methylphenyl group, 4-methylphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 3-cyanophenyl group, 4-cyanophenyl group 3,4-dimethylphenyl group, naphthyl group, 1-hydroxynaphthyl group, 4- (hydroxymethyl) phenyl group and 4- (trifluoromethyl) phenyl group, but are not limited thereto.
  • C 6-14 arylalkyl group means a C 1-6 alkyl group substituted with a C 6-14 aryl group.
  • heteroaryl group means a 5- to 10-membered aromatic ring group containing one or more heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom as ring-constituting atoms. Means.
  • heteroaryl group examples include, for example, furyl group, benzofuranyl group, thienyl group, benzothiophenyl group, pyrrolyl group, pyridyl group, indolyl group, oxazolyl group, benzoxazolyl group, isoxazolyl group, benzoiso Oxazolyl group, thiazolyl group, benzothiazolyl group, isothiazolyl group, imidazolyl group, benzoimidazolyl group, pyrazolyl group, indazolyl group, tetrazolyl group, furazanyl group, 1,2,3-oxadiazolyl group, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, benzotriazolyl group, quinolinyl group, isoquinolinyl group, pyridazinyl group, pyrroly
  • the “heteroaryl group” is a halogen atom, a hydroxyl group, an amino group, a cyano group, a nitro group, a C 1-6 alkyl-carbamoyl group, an acyl group, a C 1-6 alkoxy group, an optionally substituted C 1 1- 6 alkyl group, a mono- or di-C 1-6 alkylamino group, C 1-6 alkylsulfanyl group, C 1-6 alkylsulfinyl group, C 1-6 alkylsulfonyl group, from a sulfamoyl group and a group consisting of a trifluoromethyl group It may have one or more selected substituents, and may preferably have one or two of the same or different substituents. The most typical substituents are a halogen atom, a hydroxyl group, a cyano group, a C 1-6 alkoxy group, and an optionally substituted C 1-6 alkyl group
  • heteroarylalkyl group means a C 1-6 alkyl group substituted with a heteroaryl group.
  • C 1-6 alkoxy group means —O— to which a C 1-6 alkyl group is bonded, specifically, a methoxy group, an ethoxy group, an n-propoxy group, an iso Examples include propoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, and hexyloxy group, and among them, C 1-3 alkoxy group Are preferred, and methoxy and ethoxy groups are particularly preferred.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Among these, a fluorine atom, a bromine atom and a chlorine atom are preferable.
  • C 1-6 alkylsulfanyl group means —S— to which a C 1-6 alkyl group is bonded.
  • Groups pentylsulfanyl (ie, amylsulfanyl), hexylsulfanyl, isopropylsulfanyl, isobutylsulfanyl, secondary butylsulfanyl, tertiary butylsulfanyl, isopentylsulfanyl, neopentylsulfanyl and tertiary
  • a primary pentylsulfanyl group is exemplified, among which a C 1-3 alkylsulfanyl group is preferable, and a methylsulfanyl group and an ethylsulfanyl group are particularly preferable.
  • acyl group means “C 1-6 alkyl-carbonyl group” (—CO— to which a C 1-6 alkyl group is bonded, such as acetyl group, propionyl group, butyryl group, isobutyryl group).
  • Valeryl group pivaloyl group, hexanoyl group and heptanoyl group
  • C 6-14 aryl-carbonyl group (—CO— to which a C 6-14 aryl group is bonded, such as benzoyl group and naphthoyl group)
  • C 6 -14 arylalkyl-carbonyl group (-CO- to which a C 6-14 arylalkyl group is bonded, such as benzylcarbonyl group, 2-phenylethylcarbonyl group and 3-phenylpropylcarbonyl group), among which acetyl Groups, propionyl groups and benzoyl groups are preferred.
  • the benzene ring and naphthalene ring in the “acyl group” are 1 to 5 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group, a nitro group, a cyano group, a hydroxyl group, and a C 1-6 alkoxy group. It may have a group, and the substitution position is not particularly limited.
  • amino group refers to a secondary or tertiary amino group having an amino group and a C 1-6 alkyl group, such as an amino group and mono- or di-C 1-6.
  • alkylamino groups methylamino group, dimethylamino group, ethylamino group, diethylamino group, propylamino group, dipropylamino group, butylamino group, dibutylamino group, etc.
  • a —C 1-3 alkylamino group is preferred, and an amino group, a methylamino group and a dimethylamino group are particularly preferred.
  • C 1-6 alkylsulfonyl group means —SO 2 — to which a C 1-6 alkyl group is bonded, and examples thereof include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, and And a isopropylsulfonyl group.
  • a C 1-3 alkylsulfonyl group is preferable, and a methylsulfonyl group and an ethylsulfonyl group are particularly preferable.
  • C 1-6 alkylsulfinyl group means —SO— to which a C 1-6 alkyl group is bonded, and examples thereof include a methylsulfinyl group, an ethylsulfinyl group, a propylsulfinyl group, and an isopropylsulfinyl group. Among them, a C 1-3 alkylsulfinyl group is preferable.
  • sulfamoyl group means a sulfamoyl group (—SO 2 NH 2 ) and a group in which one or two hydrogen atoms on the nitrogen atom of the sulfamoyl group are substituted with a C 1-6 alkyl group.
  • sulfamoyl group means, for example, a sulfamoyl group, and mono- or di -C 1-6 alkylsulfamoyl group (e.g., methylsulfamoyl group, dimethylsulfamoyl group, ethylsulfamoyl group, diethylsulfamoyl group, Propylsulfamoyl group, dipropylsulfamoyl group, butylsulfamoyl group and dibutylsulfamoyl group), among which sulfamoyl group and mono- or di-C 1-3 alkylsulfamoyl group are preferred, amino Particularly preferred are groups, methylsulfamoyl and dimethylsulfamoyl groups.
  • nitrogen-containing heterocycle means a 6- to 7-membered saturated aliphatic ring containing at least one nitrogen atom as a ring-constituting atom, and further oxygen atom and It may contain one or more heteroatoms selected from sulfur atoms and may be fused with at least one C 6-14 arene, C 3-7 cycloalkane or 3-7 membered heterocycle .
  • Specific examples of the “nitrogen-containing heterocycle” include piperidine, piperazine, azepan, diazepan, oxazepan, thiazepan, morpholine and thiomorpholine.
  • C 1-6 alkyl group means a hydroxyl group, C 1-6 alkylsulfanyl group, halogen atom, amino group, formyl group, carbamoyl group at a substitutable position.
  • cyano group, nitro group, C 1-6 alkoxy, C 3-7 cycloalkyl and heterocycle may be substituted with 1 to 4 atoms or substituents selected from the group consisting of group C 1 -6 means an alkyl group.
  • substituted C 1-6 alkyl group examples include a trifluoromethyl group, a fluoromethyl group, a 2-fluoroethyl group, a methoxyethyl group, a hydroxymethyl group, a cyclopropylmethyl group, a furylmethyl group, an oxa group.
  • substituted C 1-6 alkyl group examples include a trifluoromethyl group, a fluoromethyl group, a 2-fluoroethyl group, a methoxyethyl group, a hydroxymethyl group, a cyclopropylmethyl group, a furylmethyl group, an oxa group.
  • C 6-14 arene means a ring corresponding to “C 6-14 aryl group”.
  • heterocycle means a ring corresponding to “heterocyclic group”.
  • C 3-7 cycloalkane means a ring corresponding to the "C 3-7 cycloalkyl group”.
  • salt refers to the basic form of a functional group such as an amine and a suitable acid, such as an inorganic acid [eg, hydrohalic acid (eg, hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid).
  • a suitable acid such as an inorganic acid [eg, hydrohalic acid (eg, hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid).
  • organic acids eg acetic acid, propionic acid, hydroacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, ethanedioic acid, propanedioic acid, Butanedioic acid, (Z) -2-butenedioic acid, (E) -butenedioic acid, 2-hydroxybutanedioic acid, 2,3-dihydroxybutanedioic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid Acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, It can be obtained by treatment with another organic acid] known to beauty those skilled in the art, to mean a pharmaceutically acceptable acid addition
  • the compound of the general formula (1) of the present invention may have stereoisomers such as optical isomers, diastereoisomers and geometric isomers depending on the mode of the substituent.
  • the compound of 1) also includes all these stereoisomers and mixtures thereof.
  • a, b, c and d are the same or different and are each CH or CR 5 , preferably a and d are both CH, and b and c are same or different, CH or CR 5.
  • c is CR 5
  • the selectivity of muscarinic M 1 and M 4 receptors is improved and the pharmacokinetics tends to be improved.
  • a and d are both CH, and either of b and c is CH, the other is CR 5.
  • R 5 represents a halogen atom, a C 3-7 cycloalkyl group, a C 6-14 aryl group, a heteroaryl group, a C 6-14 arylalkyl group, a heteroarylalkyl group, a C 2- 6 alkenyl group, C 2-6 alkynyl group, C 1-6 alkoxy group, cyano group, C 1-6 alkylsulfanyl group, acyl group, sulfamoyl group, hydroxyl group, amino group, nitro group, C 1-6 alkylsulfonyl group Or an optionally substituted C 1-6 alkyl group.
  • R 5 is preferably a halogen atom, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 1-6 alkoxy group, a cyano group, a C 1-6 alkylsulfanyl group, an acyl group, a sulfamoyl group, a hydroxyl group, An amino group, a nitro group, a C 1-6 alkylsulfonyl group, or an optionally substituted C 1-6 alkyl group (preferably a hydroxyl group, a C 1-6 alkylsulfanyl group, a halogen atom, a cyano group, a nitro group, and And optionally substituted with 1 to 4 substituents selected from the group consisting of methoxy groups), More preferably, a halogen atom, a C 1-6 alkoxy group, a cyano group, a C 1-6 alkylsulfanyl group, a hydroxyl group, an
  • a halogen atom, a methyl group, an ethyl group, a propyl group, a cyano group, a hydroxyl group, a methoxy group or a trifluoromethyl group Particularly preferably, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a propyl group, a methoxy group or a trifluoromethyl group, Most preferably, they are a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a propyl group, or a methoxy group.
  • R 1 and R 2 are the same or different and each is a hydrogen atom, an optionally substituted C 1-6 alkyl group, a halogen atom, a hydroxyl group, a C 3-7 cycloalkyl group or A 3- to 7-membered heterocyclic group, or R 1 and R 2 are bonded to each other, and R 1 and R 2 together with an adjacent carbon atom form a C 3-7 cycloalkane or a 3- to 7-membered heterocyclic ring. Or together form ⁇ CR 6 R 7 .
  • R 6 and R 7 are the same or different and are each a hydrogen atom or an optionally substituted C 1-6 alkyl group, or R 6 and R 7 are bonded to each other, and R 6 And R 7 together with the adjacent carbon atom form a C 3-7 cycloalkane or a 3-7 membered heterocycle.
  • R 1 and R 2 are preferably the same or different and each is a hydrogen atom, an optionally substituted C 1-6 alkyl group, a halogen atom, a hydroxyl group, a C 3-7 cycloalkyl group, or a 3-7 member.
  • R 1 and R 2 are bonded to each other, or R 1 and R 2 form a heterocyclic ring of C 3-7 cycloalkane or 3-7 membered together with the carbon atom adjacent, Or R 1 and R 2 together form ⁇ CR 6 R 7 , More preferably, they are the same or different and each represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, a halogen atom, a hydroxyl group, or a C 3-7 cycloalkyl group, or R 1 and R 2 are Bonded to each other, R 1 and R 2 together with adjacent carbon atoms form a C 3-7 cycloalkane or a 3-7 membered heterocyclic ring; More preferably, they are the same or different and each is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, or an optionally substituted C 1-6 alkyl group, or R 1 and R 2
  • R 1 and R 2 are bonded together to form a 3- to 7-membered heterocycle with R 1 and R 2 together with adjacent carbon atoms; Particularly preferably, they are the same or different and each is a hydrogen atom, a fluorine atom, a hydroxyl group, or an optionally substituted C 1-6 alkyl group (particularly a C 1-3 alkyl group optionally substituted with a hydroxyl group).
  • R 1 and R 2 are bonded together to form a tetrahydropyran ring with R 1 and R 2 together with adjacent carbon atoms; Most preferably, they are the same or different and each is a hydrogen atom, a fluorine atom, a hydroxyl group, or a C 1-3 alkyl group (particularly hydroxymethyl) optionally substituted with a hydroxyl group, or R 1 and R 2 are Together, R 1 and R 2 together with the adjacent carbon atoms form a tetrahydropyran ring.
  • R 1 and R 2 are the same or different, (1) hydrogen atom, (2) (a) a hydroxyl group, (b) a C 1-6 alkoxy group (eg, methoxy), (c) a 3- to 7-membered heterocyclic group (eg, furyl, oxazolyl, tetrahydrofuryl), and (d) a C 3-7 cycloalkyl group (eg, cyclopropyl) A C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-ethylpropyl, 1-propyl) which may be substituted with 1 to 4 substituents selected from the group consisting of Butyl), (3) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (4) hydroxyl group, (5) a C 3-7 cycloalkyl group (eg, cyclobutyl, cyclopentyl group
  • R 1 and R 2 are preferably the same or different, (1) hydrogen atom, (2) (a) a hydroxyl group, (b) a C 1-6 alkoxy group (eg, methoxy), (c) a 3- to 7-membered heterocyclic group (eg, furyl, oxazolyl, tetrahydrofuryl), and (d) a C 3-7 cycloalkyl group (eg, cyclopropyl) A C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-ethylpropyl, 1-propyl) which may be substituted with 1 to 4 substituents selected from the group consisting of Butyl), (3) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (4) hydroxyl group, (5) a C 3-7 cycloalkyl group (eg, cyclobutyl, cyclopenty
  • R 1 and R 2 are more preferably the same or different, (1) hydrogen atom, (2) (a) a hydroxyl group, (b) a C 1-6 alkoxy group (eg, methoxy), (c) a 3- to 7-membered heterocyclic group (eg, furyl, oxazolyl, tetrahydrofuryl), and (d) a C 3-7 cycloalkyl group (eg, cyclopropyl) A C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-ethylpropyl, 1-propyl) which may be substituted with 1 to 4 substituents selected from the group consisting of Butyl), (3) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (4) hydroxyl group, or (5) C 3-7 cycloalkyl group (eg, cyclobutyl, cyclopenty
  • R 1 and R 2 are more preferably the same or different, (1) hydrogen atom, (2) (a) a hydroxyl group, (b) a C 1-6 alkoxy group (eg, methoxy), (c) a 3- to 7-membered heterocyclic group (eg, furyl, oxazolyl, tetrahydrofuryl), and (d) a C 3-7 cycloalkyl group (eg, cyclopropyl) A C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-ethylpropyl, 1-propyl) which may be substituted with 1 to 4 substituents selected from the group consisting of Butyl), (3) fluorine atom, chlorine atom or bromine atom, or (4) is a hydroxyl group, or R 1 and R 2 are bonded to each other, and R 1 and R 2 together with adjacent carbon atoms (1) C 3-7 cyclo
  • R 1 and R 2 are particularly preferably the same or different, (1) hydrogen atom, (2) (a) a hydroxyl group, (b) a C 1-6 alkoxy group (eg, methoxy), (c) a 3- to 7-membered heterocyclic group (eg, furyl, oxazolyl, tetrahydrofuryl), and (d) a C 3-7 cycloalkyl group (eg, cyclopropyl)
  • a C 1-6 alkyl group eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-ethylpropyl, 1-propyl
  • substituents selected from the group consisting of butyl, preferably a C 1-3 alkyl group
  • fluorine atom or chlorine atom or (4) It is a hydroxyl group, or R
  • R 1 and R 2 are particularly preferably the same or different, (1) hydrogen atom, (2) (a) a hydroxyl group, (b) a C 1-6 alkoxy group (eg, methoxy), (c) a 3- to 7-membered heterocyclic group (eg, furyl, oxazolyl, tetrahydrofuryl), and (d) a C 3-7 cycloalkyl group (eg, cyclopropyl)
  • a C 1-6 alkyl group eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-ethylpropyl, 1-propyl
  • substituents selected from the group consisting of butyl, preferably a C 1-3 alkyl group
  • fluorine atom or (4) It is a hydroxyl group, or R 1 and R 2
  • R 1 and R 2 are most preferably the same or different, (1) hydrogen atom, (2) a C 1-3 alkyl group optionally substituted with a hydroxyl group (eg, methyl, ethyl, propyl, isopropyl, preferably methyl) (particularly preferably hydroxymethyl), (3) fluorine atom, or (4) It is a hydroxyl group, or R 1 and R 2 are bonded to each other, and R 1 and R 2 together with the adjacent carbon atom form a tetrahydropyran ring.
  • a hydroxyl group eg, methyl, ethyl, propyl, isopropyl, preferably methyl
  • fluorine atom or (4) It is a hydroxyl group, or R 1 and R 2 are bonded to each other, and R 1 and R 2 together with the adjacent carbon atom form a tetrahydropyran ring.
  • ring A may be substituted with 1 to 2 substituents selected from the group consisting of a hydroxyl group, a halogen atom, a C 1-6 alkyl group and a C 1-6 alkoxy group.
  • Ring A is preferably a 6- to 7-membered nitrogen-containing heterocyclic ring optionally substituted with 1 to 2 C 1-6 alkyl groups (the two C 1-6 alkyl groups are bonded to form a bicyclo A ring may be formed) More preferably, the following formula (2)
  • R 8 is a hydrogen atom, a hydroxyl group, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group.
  • R 8 is preferably a hydrogen atom, a hydroxyl group, a fluorine atom, a methyl group, an ethyl group, a propyl group, a methoxy group or an ethoxy group, more preferably a hydrogen atom, a hydroxyl group, a fluorine atom, a methyl group, an ethyl group, A methoxy group, more preferably a hydrogen atom or a methyl group.
  • Ring A is particularly preferably
  • R 3 and R 4 together form ⁇ O or ⁇ S.
  • R 3 and R 4 are preferably taken together to form ⁇ O.
  • X is a single bond or methylene.
  • Y and Z are the same or different and each represents an oxygen atom or a sulfur atom.
  • Y is preferably an oxygen atom.
  • Z is preferably an oxygen atom.
  • R represents an optionally substituted C 1-6 alkyl group, a C 2-6 alkynyl group, or a C 2-6 alkenyl group.
  • R is preferably an optionally substituted C 1-6 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group).
  • a C 2-6 alkynyl group or a C 2-6 alkenyl group More preferably, it may be substituted with an optionally substituted C 1-6 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group).
  • it may be a linear C 1-6 alkyl group which may be substituted (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group). May be) Even more preferably, an optionally substituted straight chain C 1-3 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group). May be) Even more preferably, it is a straight chain C 1-3 alkyl group, Particularly preferred is a methyl group or an ethyl group.
  • examples of preferable compounds include the following compounds.
  • X is a single bond, Y is an oxygen atom or a sulfur atom, Z is an oxygen atom or a sulfur atom, R is an optionally substituted C 1-6 alkyl group (preferably optionally substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and
  • a is CH, b is CH or CR 5 (R 5 is as defined above); c is CR 5 (R 5 is a halogen atom, a C 1-6 alkoxy group, a cyano group, a C 1-6 alkylsulfanyl group, a hydroxyl group, an amino group, a nitro group, or an optionally substituted C 1-6 alkyl A group (preferably substituted with 1 to 4 substituents selected from the group consisting of a hydroxyl group, a C 1-6 alkylsulfanyl group, a halogen atom, a cyano group, a nitro group and a methoxy group).
  • Is) d is CH, R 1 and R 2 are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group; R 3 and R 4 together form ⁇ O, X is a single bond, Y is an oxygen atom, Z is an oxygen atom, R is an optionally substituted linear C 1-6 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group).
  • ring A is represented by the following formula (2a):
  • a nitrogen-containing heterocyclic ring represented by A compound or a pharmaceutically acceptable salt thereof represented by A compound or a pharmaceutically acceptable salt thereof.
  • [Compound C] a is CH, b is CH, c is CR 5 (R 5 is a fluorine atom, chlorine atom, bromine atom, methyl group, methoxy group or trifluoromethyl group, preferably a fluorine atom, chlorine atom, bromine atom, methyl group or methoxy group; Yes.)
  • d is CH, R 1 and R 2 are the same or different and each is a hydrogen atom or a C 1-6 alkyl group (preferably a C 1-3 alkyl group); R 3 and R 4 together form ⁇ O, X is a single bond, Y is an oxygen atom, Z is an oxygen atom, R is an optionally substituted linear C 1-3 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group). (Preferably a straight-chain C 1-3 alkyl group) and ring A is represented by the following formula (2a):
  • a nitrogen-containing heterocyclic ring represented by A compound or a pharmaceutically acceptable salt thereof represented by A compound or a pharmaceutically acceptable salt thereof.
  • Compound D a is CH, b and c are the same or different and are CH or CR 5 (fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, propyl group, methoxy group or trifluoromethyl group); d is CH, R 1 and R 2 are the same or different and are each a hydrogen atom, an optionally substituted C 1-6 alkyl group, a halogen atom or a C 3-7 cycloalkyl group, or R 1 and R 2 are Bonded together, R 1 and R 2 together with adjacent carbon atoms form a C 3-7 cycloalkane or a 3-7 membered heterocycle; R 3 and R 4 together form ⁇ O or ⁇ S; X is a single bond or methylene, Y is an oxygen atom or a sulfur atom, Z is an oxygen atom or a sulfur atom, R is an optionally substituted C 1-6 alkyl group (preferably optionally substituted with 1 to 4 substitu
  • Compound E a is CH, b and c are the same or different and are CH or CR 5 (fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, propyl group, methoxy group or trifluoromethyl group); d is CH, R 1 and R 2 are the same or different and each represents a hydrogen atom, a fluorine atom, a hydroxyl group, or an optionally substituted C 1-6 alkyl group (particularly a C 1-3 alkyl group optionally substituted with a hydroxyl group).
  • R 1 and R 2 are bonded together to form a tetrahydropyran ring with R 1 and R 2 together with adjacent carbon atoms; R 3 and R 4 together form ⁇ O, X is a single bond, Y is an oxygen atom, Z is an oxygen atom, R is an optionally substituted linear C 1-6 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group).
  • ring A is represented by the following formula (2):
  • a nitrogen-containing heterocycle represented by R 8 is a hydrogen atom, a hydroxyl group, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group, A compound or a pharmaceutically acceptable salt thereof.
  • Compound F a is CH, b is CH, c is CR 5 (fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, propyl group, methoxy group or trifluoromethyl group); d is CH, R 1 and R 2 are the same or different and each represents a hydrogen atom, a fluorine atom, a hydroxyl group, or an optionally substituted C 1-6 alkyl group (particularly a C 1-3 alkyl group optionally substituted with a hydroxyl group).
  • R 1 and R 2 are bonded together to form a tetrahydropyran ring with R 1 and R 2 together with adjacent carbon atoms; R 3 and R 4 together form ⁇ O, X is a single bond, Y is an oxygen atom, Z is an oxygen atom, R is an optionally substituted linear C 1-3 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group). (Preferably a straight-chain C 1-3 alkyl group), and ring A is represented by the following formula (2):
  • a nitrogen-containing heterocycle represented by R 8 is a hydrogen atom, a hydroxyl group, a fluorine atom, a methyl group, an ethyl group, or a methoxy group, A compound or a pharmaceutically acceptable salt thereof.
  • Compound G a is CH, b is CR 5 (fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, propyl group, methoxy group, or trifluoromethyl group); c is CH, d is CH, R 1 and R 2 are the same or different and each represents a hydrogen atom, a fluorine atom, a hydroxyl group, or an optionally substituted C 1-6 alkyl group (particularly a C 1-3 alkyl group optionally substituted with a hydroxyl group).
  • R 1 and R 2 are bonded together to form a tetrahydropyran ring with R 1 and R 2 together with adjacent carbon atoms; R 3 and R 4 together form ⁇ O, X is a single bond, Y is an oxygen atom, Z is an oxygen atom, R is an optionally substituted linear C 1-3 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group). (Preferably a straight-chain C 1-3 alkyl group), and ring A is represented by the following formula (2):
  • a nitrogen-containing heterocycle represented by R 8 is a hydrogen atom, a hydroxyl group, a fluorine atom, a methyl group, an ethyl group, or a methoxy group, A compound or a pharmaceutically acceptable salt thereof.
  • Compound H a is CH, b and c are the same or different and are CH or CR 5 (fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, propyl group, methoxy group or trifluoromethyl group); d is CH, R 1 and R 2 are the same or different and each represents a hydrogen atom, a fluorine atom, a hydroxyl group, or an optionally substituted C 1-6 alkyl group (particularly a C 1-3 alkyl group optionally substituted with a hydroxyl group).
  • R 1 and R 2 are bonded together to form a tetrahydropyran ring with R 1 and R 2 together with adjacent carbon atoms; R 3 and R 4 together form ⁇ O, X is methylene, Y is an oxygen atom, Z is an oxygen atom, R is an optionally substituted linear C 1-6 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group).
  • ring A is represented by the following formula (2):
  • a nitrogen-containing heterocycle represented by R 8 is a hydrogen atom, a hydroxyl group, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group, A compound or a pharmaceutically acceptable salt thereof.
  • Compound I a is CH, b and c are the same or different and are CH or CR 5 (fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, propyl group, methoxy group or trifluoromethyl group); d is CH, R 1 and R 2 are the same or different and each represents a hydrogen atom, a fluorine atom, a hydroxyl group, or an optionally substituted C 1-6 alkyl group (particularly a C 1-3 alkyl group optionally substituted with a hydroxyl group).
  • R 1 and R 2 are bonded together to form a tetrahydropyran ring with R 1 and R 2 together with adjacent carbon atoms; R 3 and R 4 together form ⁇ O, X is a single bond, Y is an oxygen atom, Z is an oxygen atom, R is an optionally substituted linear C 1-6 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group).
  • ring A is represented by the following formula (3):
  • a nitrogen-containing heterocyclic ring represented by A compound or a pharmaceutically acceptable salt thereof represented by A compound or a pharmaceutically acceptable salt thereof.
  • Compound J] a is CH, b and c are the same or different and are CH or CR 5 (fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, propyl group, methoxy group or trifluoromethyl group); d is CH, R 1 and R 2 are the same or different and each represents a hydrogen atom, a fluorine atom, a hydroxyl group, or an optionally substituted C 1-6 alkyl group (particularly a C 1-3 alkyl group optionally substituted with a hydroxyl group).
  • R 1 and R 2 are bonded together to form a tetrahydropyran ring with R 1 and R 2 together with adjacent carbon atoms; R 3 and R 4 together form ⁇ O, X is a single bond, Y is an oxygen atom, Z is an oxygen atom, R is an optionally substituted linear C 1-6 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group).
  • ring A is represented by the following formula (4):
  • a nitrogen-containing heterocyclic ring represented by A compound or a pharmaceutically acceptable salt thereof represented by A compound or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention represented by the general formula (1) can be produced by the following production method. Manufacturing method 1: following formula (5)
  • a method for producing a compound of the above formula (1) which comprises reacting a compound represented by the formula:
  • Reaction of a compound of formula (5) or a salt thereof with an available compound of formula (6) or a compound of formula (7) comprises sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborate, pyridine borane , 2-picoline borane and other commonly used reductive amination reagents can be used.
  • the reaction of the compound of formula (5) or a salt thereof with the compound of formula (6) or the compound of formula (7) is carried out without solvent or in a suitable solvent.
  • the solvent to be used include dichloromethane, tetrahydrofuran, dimethoxyethane, diethyl ether, dimethylformamide, methanol, ethanol, ethyl acetate and the like, and these reactions are used alone or in combination of two or more.
  • This reaction is performed in the presence of an acid or a base, if necessary.
  • the acid include acetic acid
  • examples of the base include triethylamine, and diisopropylethylamine.
  • condensing agents such as titanium tetraisopropoxide, can be used together as needed.
  • the reaction temperature is usually -78 ° C to 100 ° C.
  • the compound of the formula (5) or a salt thereof can be synthesized according to the following scheme 1 (the compound of the formula (1-4) in which R 3 and R 4 are combined to form ⁇ O).
  • Prot represents an amino-protecting group, and other symbols are as defined above.
  • Specific examples of amino-protecting groups include groups that form carbamates with amino groups such as tert-butoxycarbonyl and benzyloxycarbonyl groups, and amino groups and benzylamines such as benzyl and trityl groups. And the like.
  • Step 1 The compound of formula (1-2) can be produced by deprotecting the amino-protecting group of the compound of formula (1-1) according to a conventional method.
  • Step 2 The compound of formula (1-3) is produced by reacting the compound of formula (1-1) with a halogenating agent or alkylating agent corresponding to R 1 and R 2 in the presence of a base in an inert solvent.
  • a base include sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, sodium methoxide, sodium ethoxide, potassium tert-butoxide, lithium hexamethyldisilazide, potassium hexamethyl. And disilazide.
  • the inert solvent examples include tetrahydrofuran, dioxane, benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, dichloroethane, and the like, and these can be used in combination.
  • the reaction temperature is usually ⁇ 78 ° C. to 140 ° C., preferably ⁇ 78 ° C. to 100 ° C.
  • Step 3 This step is carried out by the same method as in step 1 of this scheme.
  • the compound of the formula (1-1) or a salt thereof can be synthesized according to the following scheme 2, 3, 4 or 5.
  • R ′ represents a C 1-6 alkyl group, and other symbols are as defined above.
  • Step 1 The compound of formula (2-2) can be produced by reacting an available compound of formula (2-1) with an alkyl halide in the presence of a base such as sodium hydride or cesium carbonate.
  • a base such as sodium hydride or cesium carbonate.
  • the solvent to be used include dimethylformamide, tetrahydrofuran, dichloromethane and the like, and they are used alone or in combination of two or more.
  • the reaction is usually carried out at -40 ° C to 40 ° C, preferably -10 ° C to 10 ° C.
  • Step 2 The compound of formula (2-3) can be produced by catalytic reduction of the compound of formula (2-2) using a metal catalyst such as palladium in a hydrogen atmosphere.
  • a metal catalyst such as palladium in a hydrogen atmosphere.
  • the solvent to be used include tetrahydrofuran, ethanol, methanol, acetic acid, ethyl acetate, dichloromethane, and the like.
  • a compound of formula (1-1) can be prepared by reacting a compound of formula (2-3) with an available compound of formula (2-4). This reaction can be performed according to the reductive amination conditions described above.
  • the reagent include commonly used reagents such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborate, pyridine borane, 2-picoline borane.
  • the solvent to be used include toluene, dichloromethane, tetrahydrofuran, dimethoxyethane, diethyl ether, dimethylformamide, methanol, ethanol, ethyl acetate, and the like. This reaction is performed in the presence of an acid or a base as necessary.
  • Examples of the acid include acetic acid, and examples of the base include triethylamine and diisopropylethylamine. Moreover, condensing agents, such as titanium tetraisopropoxide, can be used together as needed.
  • the reaction temperature is usually ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
  • Step 1 The compound of formula (3-2) can be produced by reacting the available 2-halogenated nitroaryl of formula (3-1) with a malonic acid diester in the presence of a base such as sodium hydride or cesium carbonate.
  • a base such as sodium hydride or cesium carbonate.
  • the solvent to be used include dimethylformamide, tetrahydrofuran, acetonitrile, dichloromethane and the like, and they are used alone or in combination of two or more.
  • the reaction is usually performed at ⁇ 20 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.
  • Step 2 The compound of formula (3-3) can be produced by catalytic reduction of the compound of formula (3-2) using a metal catalyst such as palladium or rhodium in a hydrogen atmosphere.
  • a metal catalyst such as palladium or rhodium in a hydrogen atmosphere.
  • the solvent to be used include tetrahydrofuran, ethanol, methanol, acetic acid, ethyl acetate, dichloromethane, and the like.
  • Step 3 This step is performed in the same manner as in Step 3 described in Scheme 2.
  • Step 4 The compound of formula (1-1) can be produced by heating and stirring the compound of formula (3-4) in the presence of an acid.
  • the acid include hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, 4-ethylbenzenesulfonic acid and the like, preferably p-toluenesulfonic acid, 4-ethylbenzenesulfonic acid and the like.
  • the solvent include dimethylformamide, tetrahydrofuran, dichloromethane, benzene, toluene, xylene and the like, preferably benzene and toluene. Two or more of these may be mixed and used.
  • the reaction is usually carried out at 0 ° C. to 200 ° C., preferably 70 ° C. to 140 ° C.
  • the compound of the formula (4-1) can be produced by reacting an available 2-halogenated acetic acid with a chlorinating agent such as thionyl chloride or oxalyl dichloride.
  • a chlorinating agent such as thionyl chloride or oxalyl dichloride.
  • the solvent to be used include dimethylformamide, tetrahydrofuran, chloroform, dichloromethane and the like, and these may be used alone or in combination of two or more.
  • Step 1 The compound of formula (4-3) can be produced by reacting the compound of formula (4-1) with an available compound of formula (4-2) in the presence of a base.
  • a base include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine and the like.
  • the solvent include dimethylformamide, tetrahydrofuran, acetonitrile, benzene, toluene, dichloromethane and the like, and preferably dimethylformamide, acetonitrile, dichloromethane and the like. Two or more of these may be mixed and used.
  • the reaction is usually carried out at ⁇ 20 ° C. to 120 ° C., preferably 0 ° C. to 70 ° C.
  • Step 2 The compound of formula (1-1) can be produced by reacting the compound of formula (4-3) in the presence of a metal catalyst such as palladium. That is, it can be produced by the method described in Tetrahedron Lett., 45, 8535-8537 (2004) or the like or a method analogous thereto.
  • a metal catalyst such as palladium
  • Step 1 The compound of formula (5-2) can be produced by reacting an available aniline derivative of formula (5-1) with a compound of formula (2-4) in the same manner as in Step 3 described in Scheme 2. it can.
  • Step 2 The compound of formula (5-3) can be produced by reacting the compound of formula (5-2) with chloroacetyl chloride in the presence of a base.
  • a base include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, pyridine and the like.
  • the solvent include dimethylformamide, tetrahydrofuran, acetonitrile, ethyl acetate, benzene, toluene, xylene, chloroform, dichloromethane, and the like, and two or more of these can be used in combination.
  • the reaction is usually carried out at ⁇ 20 ° C. to 140 ° C., preferably 20 ° C. to 100 ° C.
  • Step 3 The compound of formula (1-1) can be produced by reacting the compound of formula (5-3) in the presence of a Lewis acid in an inert solvent or in the absence of a solvent.
  • Lewis acids include zinc chloride and aluminum chloride.
  • the inert solvent include benzene, toluene, xylene, chlorobenzene, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide, and the like, and two or more of these can be used in combination.
  • the reaction is usually carried out at -20 ° C to 220 ° C, preferably 20 ° C to 200 ° C.
  • the compound of the formula (3) or a salt thereof can be synthesized according to the following scheme 6 (the compound of the formula (6-1) in which R 3 and R 4 together form ⁇ S).
  • Step 1 The compound of formula (6-1) can be produced by thioamidation of the compound of formula (1-4).
  • the thioamidation reagent to be used include Lawesson's reagent and phosphorus pentasulfide. This reaction is carried out without solvent or in a suitable solvent.
  • the solvent to be used include chloroform, dichloromethane, toluene, benzene, xylene, and the like, and two or more of these can be mixed and used.
  • a method for producing a compound of the above formula (1) which comprises reacting a compound of the above and an alkylating agent corresponding to R 1 and R 2 in the presence of a base in an inert solvent.
  • Examples of the base include sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, sodium methoxide, tert-butoxypotassium and the like.
  • Examples of the inert solvent include tetrahydrofuran, dioxane, benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, dichloroethane, and the like, and these can be used in combination.
  • the reaction is usually carried out at ⁇ 20 ° C. to 140 ° C., preferably 20 ° C. to 100 ° C.
  • Step 1 The compound of formula (7-3) is obtained by reacting the compound of formula (7-1) synthesized by the method of step 1 and step 2 described in production method 1, scheme 3 with the compound of formula (7-2). Can be manufactured. The reaction is carried out in the same manner as in Production method 1, step 3 described in scheme 2.
  • Step 2 A compound of formula (7-4) can be produced by reacting a compound of formula (7-3) with an alkylating agent corresponding to R 1 in the presence of a base in an inert solvent.
  • Examples of the base include sodium hydride, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, lithium hexamethyldisilazane, sodium hexamethyldisilazane, and the like.
  • Examples of the inert solvent include dimethylformamide, tetrahydrofuran, acetonitrile, benzene, toluene, dichloromethane and the like. You may use these in mixture of 2 or more types.
  • the reaction is usually carried out at ⁇ 20 ° C. to 120 ° C., preferably 0 ° C. to 120 ° C.
  • Step 3 This step is performed in the same manner as in step 4 described in Scheme 3.
  • Step 4 The compound of formula (1) can be produced by reacting the compound of formula (7-5) with an alkylating agent corresponding to R 2 in the same manner as in Step 1 described in this scheme.
  • Step 1 The compound of formula (8-2) is obtained by reacting N-ethyl-4-piperidone which is an available compound of formula (8-1) with an alkyl halide in the absence of a solvent or in a suitable solvent.
  • the alkyl halide include methyl iodide, ethyl iodide, methyl bromide, and ethyl bromide, and preferably methyl iodide.
  • the solvent to be used include acetone, toluene, chloroform, dichloromethane, ethyl acetate, hexane, and the like, and two or more of these can be mixed and used.
  • the reaction temperature is usually from ⁇ 20 ° C. to 140 ° C., preferably 0 ° C. to 50 ° C.
  • the compound of the formula (7-2) can be produced by reacting the compound of the formula (8-2) with an available amine of the formula (8-3) in a suitable solvent in the presence of a base.
  • a suitable solvent include sodium hydride, potassium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate.
  • the solvent to be used include water, ethanol, methanol, 2-propanol and the like, and two or more kinds thereof can be mixed and used.
  • the reaction temperature is usually 0 to 140 ° C, preferably 20 to 100 ° C.
  • Step 1 The compound of formula (9-3) can be produced by reacting an available compound of formula (9-1) with a compound of formula (9-2) with a nucleophile having an elimination ability.
  • the nucleophilic agent include sodium cyanide, potassium cyanide, triazole, tetrazole, dimethylaluminum cyanide and the like.
  • the solvent to be used include toluene, xylene, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethoxyethane, and the like, and two or more kinds thereof can be mixed and used.
  • the reaction temperature is usually from 0 ° C to 200 ° C, preferably from 20 ° C to 160 ° C.
  • Step 2 The compound of the formula (9-4) can be produced by reacting the compound of the formula (9-3) with an alkylating agent corresponding to R 8 .
  • the alkylating agent include alkyl lithium, alkyl magnesium chloride, alkyl magnesium bromide and the like corresponding to R 8 .
  • the solvent used include dimethylformamide, tetrahydrofuran, 1,4-dioxane, acetonitrile, benzene, toluene, chloroform, dichloromethane and the like. You may use these in mixture of 2 or more types.
  • the reaction is usually carried out at ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
  • Step 3 The compound of formula (9-5) can be produced by deprotecting the Boc group of the compound of formula (9-4) in the presence of an acid.
  • the acid include trifluoroacetic acid, hydrochloric acid, sulfuric acid and the like.
  • the solvent to be used include tetrahydrofuran, 1,4-dioxane, acetonitrile, benzene, toluene, chloroform, dichloromethane and the like.
  • the reaction is usually carried out at ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
  • Step 4 The compound of the formula (9-6) can be produced by reacting the compound of the formula (9-5) with carbonyl chloride or thiocarbonyl chloride corresponding to Y, Z and R in the presence of a base.
  • a base include sodium hydride, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, lithium hexamethyldisilazane, sodium hexamethyldisilazane, and the like.
  • the solvent include dimethylformamide, tetrahydrofuran, acetonitrile, benzene, toluene, dichloromethane and the like. You may use these in mixture of 2 or more types.
  • the reaction is usually carried out at ⁇ 20 ° C. to 120 ° C., preferably 0 ° C. to 120 ° C.
  • Step 5 The compound of formula (9-7) can be produced by deprotecting the acetal part of the compound of formula (9-6) in the presence of an acid.
  • the acid include trifluoroacetic acid, hydrochloric acid, sulfuric acid and the like.
  • the solvent to be used include tetrahydrofuran, 1,4-dioxane, acetonitrile, benzene, toluene, chloroform, dichloromethane and the like.
  • the reaction is usually carried out at -20 ° C to 160 ° C, preferably 0 ° C to 120 ° C.
  • Step 1 The compound of the formula (10-2) can be produced by dehydrating and condensing the compound of the formula (10-1) that is available to the compound of the formula (1-1) that can be synthesized according to the production method 1. .
  • This step is performed in the presence of an acid as necessary.
  • the acid include acetic acid, sulfuric acid, hydrochloric acid, zinc chloride, aluminum chloride, titanium chloride, titanium tetraisopropoxide and the like.
  • the solvent is used in the absence of a solvent or in a suitable solvent. Examples of the solvent used include benzene, toluene, xylene, chloroform, dichloromethane, tetrahydrofuran, diethyl ether, 1,4-dioxane, and the like. You may mix and use seeds or more.
  • the reaction temperature is usually ⁇ 20 ° C. to 200 ° C., preferably 20 ° C. to 140 ° C.
  • Step 2 The compound of the formula (10-3) can be produced by deprotecting the amino-protecting group from the compound of the formula (10-2) according to the same method as in Step 1 of Production Method 1 and Scheme 1. it can.
  • Step 3 The compound of the formula (10-4) can be produced by subjecting the compound of the formula (10-3) to a reductive amination reaction according to the same method as in Step 3 of Production Method 1 and Scheme 2. .
  • Step 4 The compound of the formula (1) can be produced by catalytic reduction of the compound of the formula (10-4) using a metal catalyst such as palladium or rhodium in the presence of a hydrogen atmosphere.
  • a metal catalyst such as palladium or rhodium
  • the solvent to be used include tetrahydrofuran, ethanol, methanol, acetic acid, ethyl acetate, chloroform, dichloromethane, and the like. These may be used alone or in combination of two or more.
  • the reaction temperature is usually 0 to 100 ° C., preferably 20 to 60 ° C.
  • Step 1 The compound of the formula (11-2) is obtained by converting an aniline derivative, which is a compound of the formula (11-1), and a compound of the formula (7-2), in the same manner as in Step 3 of Production Method 1 and Scheme 2.
  • an aniline derivative which is a compound of the formula (11-1)
  • a compound of the formula (7-2) in the same manner as in Step 3 of Production Method 1 and Scheme 2.
  • Step 2 The compound of the formula (11-3) can be produced by reacting the compound of the formula (11-2) with oxalyl dichloride in an appropriate solvent in the presence of an acid.
  • the acid include aluminum trichloride, zinc trichloride, titanium trichloride and the like.
  • the solvent include benzene, toluene, chloroform, dichloromethane, dichloroethane, and the like. These may be used alone or in combination of two or more.
  • the reaction temperature is usually ⁇ 20 ° C. to 200 ° C., preferably 0 ° C. to 120 ° C.
  • Step 3 The compound of formula (1) can be produced by reducing the carbonyl group of the compound of formula (11-3) with a suitable reducing agent in a solvent.
  • a suitable reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride and the like.
  • the solvent include methanol, ethanol, chloroform, dichloromethane, tetrahydrofuran, diethyl ether, and the like. These may be used alone or in combination of two or more.
  • the reaction temperature is usually from ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
  • Step 1 The compound of the formula (12-2) can be produced by reducing an indole derivative which is a compound of the formula (12-1) which is commercially available or can be synthesized by a method known to those skilled in the art to indoline.
  • the reducing agent is not particularly limited as long as it can reduce indole to indoline.
  • sodium cyanoborohydride can be used.
  • the solvent that can be used is not particularly limited as long as it can be used in this reaction, and examples thereof include dichloromethane and dichloroethane.
  • the reaction temperature is usually from ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
  • Step 2 The compound of the formula (12-3) can be produced by performing a reductive amination reaction between the compound of the formula (12-2) and the compound of the formula (12). This reaction can be carried out according to the conditions described in Production Method 1.
  • Step 3 The compound of the formula (12-4) can be produced by oxidizing the compound of the formula (12-3) with a suitable oxidizing agent in a solvent.
  • a suitable oxidizing agent include manganese dioxide.
  • the solvent include chloroform and dichloromethane. These may be used alone or in combination of two or more.
  • the reaction temperature is usually from ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
  • the compound of formula (1) can be produced by oxidizing the compound of formula (12-4) in a solvent with a suitable oxidizing agent.
  • the oxidizing agent is not particularly limited as long as it is a general oxidizing agent capable of oxidizing alkenes, and examples thereof include 2-iodoxybenzoic acid (IBX).
  • the solvent include acetonitrile and water, and these may be used alone or in combination of two or more.
  • cerium chloride or the like may be used.
  • the reaction temperature is usually from ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
  • a compound of formula (13-2) can be produced by reacting a compound of formula (13-1), which can be synthesized according to Scheme 7, with an alkyl halide formate in the presence of a base.
  • the base is not particularly limited as long as it can be used in this reaction, and examples thereof include diisopropylamine lithium amide (LDA).
  • Examples of the solvent that can be used include diethyl ether and tetrahydrofuran.
  • the reaction temperature is usually -80 ° C to 100 ° C, preferably -80 ° C to 50 ° C.
  • Step 2 The compound of formula (13-3) can be produced according to the method of Reference Example 93 by reacting the compound of formula (13-2) with a general fluorinating agent in the presence of a base.
  • the reaction conditions are preferably those for reacting with N-fluorobenzenesulfonimide at 0 to 50 ° C. in the presence of potassium carbonate in THF.
  • Step 3 The compound of the formula (1) can be produced by reducing the compound of the formula (13-3).
  • the reducing agent is not particularly limited as long as it can reduce only the ester, and examples thereof include lithium borohydride.
  • the solvent include tetrahydrofuran, diethyl ether, ethanol, methanol and the like, and these may be used alone or in combination of two or more.
  • the reaction temperature is usually from ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.
  • the compound of formula (1) obtained by the production method shown above is isolated and purified according to conventional methods such as extraction, column chromatography, recrystallization, and reprecipitation.
  • the extraction solvent include diethyl ether, ethyl acetate, chloroform, dichloromethane, toluene and the like.
  • Purification by column chromatography uses silica gel or alumina treated with acidic, basic or various chemical treatments, and examples of developing solvents include hexane / ethyl acetate, hexane / chloroform, ethyl acetate / methanol, chloroform / methanol, acetonitrile. / Water, methanol / water and the like.
  • each enantiomer can be separated and purified.
  • the compound of formula (1) having a hydroxyl group is produced by appropriately inserting a hydroxyl protecting step and a deprotecting step according to a conventional method in the production method described above.
  • the compound of formula (1) can be obtained in the form of a free base or an acid addition salt depending on the type of functional group present in the structural formula, the selection of the raw material compound, and the reaction treatment conditions. Can be converted to compounds. On the other hand, the compound of formula (1) can be converted into an acid addition salt by treating with various acids according to a conventional method.
  • Separation of the compound of the formula (1) into each enantiomer is performed by, for example, forming a diastereomeric salt according to a conventional method using an optically active acid, and then separating the diastereomeric salt into two free diastereomeric salts. This is done by converting.
  • optically active acid used as the optical resolution agent examples include (+)-or ( ⁇ )-camphoric acid, (1S)-(+)-or (1R)-( ⁇ )-camphor-10-sulfonic acid, L -(+)-Or D-(-)-tartaric acid, (+)-or (-)-mandelic acid, (S)-(-)-or (R)-(+)-malic acid, L-pyroglutamic acid , (S)-(+)-or (R)-( ⁇ )-1,1′-binaphthyl-2,2′-diyl, (+)-dibenzoyl-D-tartaric acid or ( ⁇ )-dibenzoyl-L- Examples include tartaric acid.
  • the compounds of the invention have a high selectivity and affinity for the muscarinic M 1 and M 4 receptors compared to the muscarinic M 2 , M 3 and M 5 receptor subtypes, and the selective muscarinic M 1 and M 4 is useful as receptor agonists.
  • the compounds of the invention also act at least in part as M 1 and M 4 agonists.
  • the compound of the present invention has an effect on diseases mediated by muscarinic M 1 and M 4 receptors, and is useful as a preventive and / or therapeutic agent for central diseases, particularly as an antipsychotic agent exhibiting excellent antipsychotic action. is there. Furthermore, since the compound of the present invention has selectivity for muscarinic receptors and other receptors, it can be expected to be used as a safe preventive and / or therapeutic agent for central diseases with fewer side effects than the prior agents. .
  • Disorders related to muscarinic M 1 receptors typically include cognitive impairment, forgetfulness, confusion, memory loss, attention deficit, visual defects, depression, pain, sleep disorders, psychosis, etc. It is done.
  • disorders related to muscarinic M 1 receptor is not limited to a mental disorder, for example, increased intraocular pressure is also related to the muscarinic M 1 receptor. Accordingly, non-psychiatric disorders are also included in the disorders targeted by the present invention.
  • Disorders related to muscarinic M 4 receptor is typically a mental disorder, for example, confusion, attention deficit, pain, sleep disorders, such as schizophrenia.
  • the disorders targeted by the compound or pharmaceutical composition of the present invention include, for example, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's disease, Friedreich's ataxia, Tourette's syndrome, Down's syndrome, pain Pick disease, dementia, clinical depression, age-related cognitive decline, attention deficit disorder, sudden infant death syndrome, glaucoma, cognitive impairment, amnesia, confusion, memory loss, visual deficit, depression, sleep disorder, psychosis Preferred are neurodegenerative diseases, attention deficit disorders, pain, Alzheimer's disease, schizophrenia and cognitive impairment, and particularly preferred are schizophrenia, Alzheimer's disease and cognitive impairment.
  • the administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration, and its daily dose varies depending on the type of compound, administration method, patient symptom / age, etc.
  • oral administration usually about 0.01 to 100 mg, more preferably about 0.1 to 10 mg per kg body weight of a human or mammal can be administered in 1 to several divided doses.
  • parenteral administration such as intravenous injection, usually, for example, about 1 ⁇ g to 10 mg, more preferably about 10 ⁇ g to 1 mg per kg body weight of a human or mammal can be administered.
  • the parenteral administration herein includes intravenous, intramuscular, subcutaneous, intranasal, intradermal, eye drop, intracerebral, intrarectal, intravaginal, intraperitoneal, and the like.
  • the administration period and interval of the pharmaceutical preparation are changed according to various situations, and are determined at any time according to the judgment of a doctor, but divided administration, daily administration, intermittent administration, short-term large-scale administration, repeated administration There are methods such as administration. For example, in the case of oral administration, it is desirable to divide and administer 1 to several times a day (particularly 2 to 3 times a day). Moreover, it can be administered as a sustained-release preparation or can be administered by intravenous infusion over a long period of time.
  • the compound of the present invention is usually administered in the form of a preparation prepared by mixing with a pharmaceutical carrier when used for pharmaceutical use as described above.
  • a pharmaceutical carrier a non-toxic substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention is used.
  • citric acid glutamic acid, glycine, lactose, inositol, glucose, mannitol, dextran, sorbitol, cyclodextrin, starch, partially pregelatinized magnesium, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, Carboxymethylcellulose calcium, ion exchange resin, methylcellulose, gelatin, gum arabic, pullulan, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, sodium alginate, light anhydrous silicic acid, stearic acid Magnesium, talc, tragacanth, bentonite, veegum, karuboki Vinyl polymer, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, fatty acid
  • Examples of the dosage form include tablets, capsules, granules, powders, solutions, syrups, suspensions, injections, suppositories, eye drops, ointments, coatings, patches, inhalants and the like. These preparations can be prepared according to a conventional method. Liquid preparations may be dissolved or suspended in water or other suitable medium when used. Tablets and granules may be coated by a known method.
  • aqueous solvents eg, distilled water, physiological saline, Ringer's solution, etc.
  • isotonic agents eg, glucose, D-sorbitol, D-mannitol, sodium chloride
  • stabilizers eg human serum albumin etc.
  • preservatives eg benzyl alcohol, chlorobutanol, methyl paraoxybenzoate, propyl paraoxybenzoate, phenol etc.
  • buffers eg phosphate buffer
  • soothing agents eg, benzalkonium chloride, procaine hydrochloride, etc.
  • these formulations may contain other therapeutically valuable ingredients.
  • the pharmaceutical preparation of the present invention can be produced according to a conventional method, and the content ratio of the compound of the present invention in the preparation is usually 0.01 to 50% (w / w). Specific examples are shown below.
  • Tablets, powders, granules, capsules For example, excipients, disintegrants, binders or lubricants are added to the compounds of the present invention and compression molded, and if necessary, taste masking, It can be produced by applying a coating for enteric or sustainable purposes.
  • a tablet it can be produced by mixing 20 mg of the compound of Example 1, 100 mg of lactose, 25 mg of crystalline cellulose and 1 mg of magnesium stearate, and tableting the resulting mixture.
  • the compound of the present invention is dissolved or suspended in a vegetable oil such as olive oil, sesame oil, cottonseed oil, corn oil, propylene glycol or the like as an aqueous injection together with a dispersing agent, preservative, tonicity agent and the like. It can be produced by turbidity or emulsification and molding as an oily injection.
  • a vegetable oil such as olive oil, sesame oil, cottonseed oil, corn oil, propylene glycol or the like
  • a dispersing agent preservative, tonicity agent and the like. It can be produced by turbidity or emulsification and molding as an oily injection.
  • Suppository produced by making the compound of the present invention into an oily or aqueous solid, semi-solid or liquid composition.
  • oily base used in such a composition examples include glycerides of higher fatty acids (for example, cacao butter, witepsols), intermediate fatty acids (for example, miglyols), or vegetable oils (for example, sesame oil, soybean oil, Cottonseed oil, etc.).
  • aqueous gel base examples include natural gums, cellulose derivatives, vinyl polymers, and acrylic acid polymers.
  • the compound was identified using proton nuclear magnetic resonance absorption spectrum ( 1 H-NMR), LC-MS, and the like.
  • the amino silica gel column made from Yamazen Co., Ltd. was used for the amino silica gel chromatography in a reference example and an Example.
  • LC-MS a system consisting of 2010EV and 2010HT (Shimadzu Corporation) or a system consisting of LC10ATVP (Shimadzu Corporation) and API150EX (Perkin Elmer) was used.
  • acetonitrile (1-99%) and 0.05% aqueous trifluoroacetic acid solution or methanol (10-99%) and 0.05% aqueous trifluoroacetic acid solution were used.
  • the retention time represents the time when the mass spectrum peak appears in the LC-MS measurement.
  • LC-MS is measured under various conditions, which are described in detail below.
  • Me represents a methyl group
  • Et represents an ethyl group
  • tBu represents a tert-butyl group
  • Boc represents a tert-butoxycarbonyl group.
  • Abbreviations used in NMR include s for single line, d for double line, dd for double double line, t for triple line, td for triple double line, q for quadruple line, and m for multiple line.
  • Line, br means broad
  • brd means broad double line
  • brt means broad triple line
  • J means coupling constant.
  • the compound of Reference Example 23 (1.0 g, 2.41 mmol) was dissolved in tert-butyl alcohol (24 ml), and palladium acetate (27 mg, 0.12 mmol), phenylboronic acid (29 mg, 0.24 mmol), X- Phos (114 mg, 0.24 mmol) and potassium carbonate (833 mg, 6.03 mmol) were added, and the mixture was stirred at 85 ° C. for 2 hours under a nitrogen atmosphere. 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. The organic layer was dried over magnesium sulfate, filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (237 mg, 35%).
  • the compound of Reference Example 22 (69 mg, 0.3 mmol) was dissolved in dichloromethane (3 mL), acetic acid (36 mg), 1-ethoxycarbonylpiperidin-4-one (57 mg), titanium tetraisopropoxide (427 mg). Was added at room temperature. After stirring for 10 minutes, sodium triacetoxyborohydride (127 mg) was added, and the mixture was stirred overnight with heating under reflux. After cooling to room temperature, a 25% aqueous ammonia solution was added to adjust the pH to 10. The filtrate filtered through Celite was separated, and the aqueous layer was extracted with chloroform. The organic layers were combined and washed with saturated brine.
  • Process 1 Using the compound of Reference Example 4 (436 mg, 2.02 mmol), an oily substance (547 mg, 85%) was obtained in the same manner as in Example 1.
  • Process 2 The compound (547 mg, 1.47 mmol) obtained in Step 1 was dissolved in dimethylformamide (8 ml), cesium carbonate (1.19 g, 3.68 mmol) was added, and the mixture was stirred at room temperature for 3 minutes. 1,3-dibromopropane (164 ⁇ l, 1.62 mmol) was added thereto, and the mixture was stirred at 70 ° C. for 3 hours.
  • the compound of Reference Example 16 (108 mg) was dissolved in dichloromethane (2 mL) and dimethoxyethane (2 mL), and 1-ethoxycarbonylpiperidin-4-one (86 mg) and titanium tetraisopropoxide (568 mg) were added at room temperature. Added in. After stirring at room temperature for 3 days, the mixture was cooled to ⁇ 78 ° C., methanol (0.5 mL) and sodium borohydride (39 mg) were added, and the temperature was slowly raised to room temperature. A 10% aqueous hydrochloric acid solution was added and stirred for 15 minutes, and then a 25% aqueous ammonia solution was added to adjust the pH to 10.
  • Process 2 The compound obtained in step 1 (210 mg) was dissolved in 4 mol / L hydrochloric acid-dioxane solution (5 mL) under ice cooling and stirred for 1 hour.
  • Example 11 4-( ⁇ 3- [1- (ethoxycarbonyl) piperidin-4-ylidene] -6-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl ⁇ piperidin-1-yl) piperidine- 1-ethyl carboxylate
  • Example 12 4-( ⁇ 3- [1- (ethoxycarbonyl) piperidin-4-yl] -6-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl ⁇ piperidin-1-yl) piperidine- 1-ethyl carboxylate
  • Example 11 The compound of Example 11 (18 mg) was dissolved in ethanol (1.5 ml), 10% Pd / C (100 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 5 hours. The reaction mixture was filtered through Celite, and the residue concentrated under reduced pressure was subjected to amino silica gel chromatography to obtain the title compound as an oily substance (2 mg).
  • LC-MS RT 7.1 min., M / z 567.2 (M + Na).
  • the compound of Reference Example 3 (200 mg) was dissolved in dichloromethane (9 ml), and 1-ethoxycarbonylazepan-4-one (154 mg), titanium tetraisopropoxide (392 mg), and acetic acid (66 mg) were added at room temperature. Added in. After stirring for 10 minutes, sodium triacetoxyborohydride (234 mg) was added and stirred with heating for 2 hours. After cooling to room temperature, a 25% aqueous ammonia solution was added to adjust the pH to 10. The filtrate filtered through Celite was separated, and the aqueous layer was extracted with chloroform. The organic layers were combined and washed with saturated brine.
  • Step 2 The compound obtained in Step 1 (3.4 g, 8.6 mmol) was dissolved in 4 mol / L hydrochloric acid-dioxane solution (11 ml) and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain the desired product, which was used in Step 3 as a crude product.
  • 3-Oxonortropane-8-carboxylic acid (3.3 g) was dissolved in methanol (50 ml) and water (5 ml), and ammonium formate (9.5 g) and 10% Pd / C (3.0 g) were added. For 24 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain the title compound (3.9 g, 74%).
  • Example 104 (3-endo) -3- [4- (3,6-Dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2 .1] Ethyl octane-8-carboxylate
  • Titanium tetraisopropoxide (425 mg) and acetone (87 mg) were added to a dichloromethane (2 mg) solution of the compound (100 mg) of Reference Example 33 and stirred at 50 ° C. overnight.
  • Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was filtered through celite, washed with chloroform, and extracted. The obtained organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (122 mg, quantitative).
  • Example 107 The compound of Example 107 (20 mg) was dissolved in methanol (1 ml), 10% palladium / carbon (10 mg) was added, and the mixture was stirred overnight under a hydrogen atmosphere. The reaction mixture was filtered through celite and concentrated under reduced pressure to give the title compound (13 mg, 65%).
  • Example 107 or Example 108 The following compounds were synthesized in the same manner as in Example 107 or Example 108 using the compounds of Reference Example 3, 31, 33 or 40 and the corresponding reagents.
  • Example 148 Using the compound of Example 1, 66-71, 75, 76, 104, 105, or 136, the following compound was obtained in the same manner as in Example 148.
  • Example 161 4- ⁇ 4- [3-Ethyl-3,6-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl ⁇ piperidine-1-carboxylate
  • Example 162 4- ⁇ 4- [6-Fluoro-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro (indole-3,4′-pyran) -1 (2H) -yl] piperidine-1- Yl ⁇ -4-methylpiperidine-1-carboxylate
  • Example 96 Using the compound of Example 96, 98 or 101, the following compound was obtained in the same manner as in Example 162.
  • Example 94 The following compound was obtained in the same manner as in Example 94 using the compound of Reference Example 73 or the compound of Reference Example 94.
  • the usefulness of the compound of the present invention as a medicine is proved by a pharmacological test capable of confirming pharmacological action, a pharmacokinetic test capable of confirming pharmacokinetics, and a safety test capable of confirming safety. These tests are not particularly limited as long as they can confirm physiological activity based on muscarinic M 1 and M 4 receptor operability and safety improvement by improving muscarinic receptor subtype selectivity. Proven by testing.
  • Examples of the pharmacological test include an in vitro muscarinic receptor agonist measurement test and an in vivo test for confirming an antipsychotic action and a cognitive impairment improving action.
  • Specific in vivo tests include an apomorphine-induced climbing test, methamphetamine-induced exercise amount.
  • Examples include an enhancement test, a prepulse inhibition test, a microdialysis test, a passive avoidance reaction test, and a Y maze type test.
  • Examples of the pharmacokinetic test include a blood concentration evaluation test, a brain migration evaluation test, a P-glycoprotein substrate recognition test, a drug interaction test, a drug metabolic pathway identification test, and a dansyl glutathione addition test.
  • safety tests include blood pressure and heart rate measurement tests, electrocardiogram measurement tests, rat taste aversion conditioning tests, salivary secretion measurement tests, body temperature Measurement tests, gastrointestinal symptom evaluation tests, covalent bonding tests, extrapyramidal symptom evaluation tests, general symptom observations, general toxicity tests and the like can be mentioned. These tests can generally be performed on mice, rats, dogs, and monkeys. Moreover, it can implement under awakening or anesthesia as needed.
  • the following test examples illustrate the usefulness of the compounds of the present invention as pharmaceuticals.
  • Test Example 1 In Vitro Efficacy Test of Human-type Muscarin M 1 -M 5 Receptor
  • Human m1 receptor expression plasmid pcDNA3.1_hM1
  • human m3 receptor expression plasmid pcDNA3.1_hM3
  • the human m2 receptor expression plasmid (pcDNA3.1_hM2), the human m4 receptor expression plasmid (pcDNA3.1_hM4) and the human m5 receptor expression plasmid (pcDNA3.1_hM5), together with the cDNA encoding the G ⁇ 16 gene, were introduced into CHO-K1 cells. After introduction, stable expression strains resistant to the selection drugs Zeocin and HygroGold were obtained.
  • Human m1 and human m3 receptor stably expressing cells at a rate of 4 ⁇ 10 4 cells / 100 ⁇ L / well, human m2, human m4 and human m5 receptor stably expressing cells at a rate of 2 ⁇ 10 4 cells / 100 ⁇ L / well The cells were seeded in a 96-well plate and cultured overnight in a CO 2 incubator. When each receptor stable expression cell becomes 100% confluent, it is increased transiently by addition of test compound at FLIPR TETRA (registered trademark) (Molecular Devices) using FLIPR Calcium 4 assay kit (Molecular Devices). The measured fluorescence intensity (RFU (max-min)) was measured. When the fluorescence intensity by the control agent acetylcholine (3 ⁇ M) was 100%, the relative value of the fluorescence intensity of each test compound was determined, and this was defined as the agonist activity (%).
  • FLIPR TETRA registered trademark
  • FLIPR Calcium 4 assay kit FLIPR Calcium 4 as
  • the compound of the present invention is administered subcutaneously, intraperitoneally or orally, and apomorphine is administered 20 minutes later (50 minutes in the case of oral administration). .
  • the behavior from 10 minutes to 30 minutes after apomorphine administration is observed, and the degree of climbing is scored and evaluated.
  • the inhibition rate (%) can be treated statistically by expressing it with a numerical value of 0-100.
  • Test Example 3 Rat Antimethamphetamine-Induced Momentum Activity Enhancement Evaluation: When methamphetamine (1 mg / kg) is administered intraperitoneally to rats, the amount of exercise increases for about 1 hour immediately after the administration. Such behavior is a pathological condition of positive symptoms of schizophrenia. It is thought to reflect a part.
  • the antipsychotic action can be evaluated by the degree to which the action of methamphetamine is antagonized when the compound of the present invention is administered to this model.
  • the compound of the present invention is administered subcutaneously, intraperitoneally or orally to male male Sprague-Dawley rats at 7 weeks of age, and methamphetamine is administered 30 minutes later (or 60 minutes in the case of oral administration).
  • the rat is transferred to a test cage (made of colorless transparent plastic), and the momentum is measured for 80 minutes after 10 minutes.
  • SuperMex Moromachi Machine Co., Ltd.
  • the total exercise amount for 80 minutes can be statistically processed by expressing the inhibition rate (%) as a numerical value of 0 to 100, based on the exercise amount of the methamphetamine single administration group.
  • Test Example 4 Rat Taste Aversion Conditioning Test After giving a solution having an inexperienced taste (conditioned stimulus, CS) and then injecting a drug that induces gastrointestinal disorders / nausea (unconditional stimulated muscles, US), the animal becomes CS and US Even if you give CS next time, you will refuse to take it because of its taste.
  • CS conditioned stimulus
  • US unconditional stimulated muscles
  • the experiment uses 9-week-old male Sprague-Dawley rats.
  • Training After 15 hours of water outage, training is performed to ensure water supply by presenting a water bottle with water to the rat for 1 hour. Thereafter, water is freely supplied for 8 hours, and water is stopped for 15 hours over the next day.
  • a water bottle containing 0.5% saccharin water (CS) was presented to rats under water-absorptive conditions for 1 hour, and immediately after removing the bottle, the compound (US) of the present invention was added. Subcutaneous, intraperitoneal or oral administration. Thereafter, water is freely supplied for 8 hours, and water is stopped for 15 hours over the next day.
  • CS saccharin water
  • the value obtained by dividing the saccharin intake at the time of the test by the saccharin intake at the time of conditioning is calculated, and the rate of decrease compared to that of the solvent-administered group is evaluated as the aversion reaction formation rate.
  • hERG Inhibition Test In CHO cells in which hERG (human ether-a-go-go) gene is stably expressed by whole cell patch clamp method using QPatch HT (Sophion Bioscience A / S) automatic patch clamp device hERG potassium current was recorded.
  • the hERG current is the tail current when the membrane potential is held at ⁇ 80 mV in the voltage clamp mode, depolarized to +20 mV for 5 seconds, then depolarized to +20 mV for 20 seconds, and then repolarized to ⁇ 50 mV for 5 seconds. Amplitude was evaluated. Stimulation was repeated every 15 seconds, and the experiment was performed at room temperature (22 ⁇ 2 ° C.).
  • the compound was cumulatively administered at a concentration of 4 per cell for 5 minutes, and the inhibition rate of the inhibited current was calculated as compared to the magnitude of the current before compound adaptation at each concentration, and the 50% inhibitory concentration was calculated using the Hill equation. (IC 50 [ ⁇ M]).
  • the following test solutions were used: extracellular solution (mM): 2 CaCl 2 , 1 MgCl 2 , 10 HEPES, 4 KCl, 145 NaCl, 10 glucose, intracellular solution (mM): 5.4 CaCl 2 , 1.8 MgCl 2 , 10 HEPES, 31 KOH, 10 EGTA, 120 KCl, 4ATP
  • the compounds of Comparative Examples 1 and 2 have no muscarinic receptor selectivity, and the compounds of the present invention in which the 1st nitrogen atom is bonded to piperidine and the 3rd position is a carbon atom are in terms of muscarinic receptor selectivity. It is clear that it is excellent.
  • the compound of Comparative Example 3 has very weak M 1 receptor activity, and the compound of the present invention in which the nitrogen atom at position 1 is bonded to piperidine and the carbon atom at position 3 is M 1 receptor activity. It is clear that it is superior.
  • the compound of the present invention selectively activates muscarinic M 1 and M 4 receptors, it has excellent central improving effects including antipsychotic effects, cognitive impairment improving effects, etc., and other muscarinic receptors or other Side effects through the receptor can be reduced. Therefore, the compound of the present invention can be a very useful medicament.

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Abstract

The present invention provides a fused-ring pyrrolidine derivative which selectively causes M1 and M4 muscarinic receptors to act and thereby produce an effect and which is reduced in side effects mediated by other muscarinic receptors or other receptors. The present invention relates to a compound represented by formula (1) (the symbols in formula (1) are as described in the description) or a pharmaceutically acceptable salt thereof, a medicinal composition containing the compound or salt thereof as an active ingredient, and a prophylactic and/or therapeutic agent for diseases mediated by muscarinic receptors which contains the compound or salt thereof.

Description

縮環ピロリジン誘導体Fused pyrrolidine derivatives
　本発明は、ムスカリン受容体作動性を有する新規な縮環ピロリジン誘導体およびそれらを有効成分とする医薬組成物に関する。本発明はまた、それらを含有するムスカリン受容体仲介疾患の予防および／または治療剤も提供する。 The present invention relates to novel fused pyrrolidine derivatives having muscarinic receptor activity and pharmaceutical compositions containing them as active ingredients. The present invention also provides a preventive and / or therapeutic agent for muscarinic receptor-mediated diseases containing them.
　神経伝達物質アセチルコリン受容体はニコチン受容体およびムスカリン受容体の２タイプのコリン作動性受容体が知られている。ムスカリン受容体は細胞膜結合Ｇタンパク質共役受容体（ＧＰＣＲ）であり、現在５個のサブタイプ(Ｍ１－Ｍ５)が知られている。これらＭ１－Ｍ５ムスカリン受容体は中枢および末梢組織に興奮性および抑制性制御を及ぼし、心拍、覚醒、認知、運動制御などを含む多くの生理的機能に関与する。 The neurotransmitter acetylcholine receptor is known to have two types of cholinergic receptors, nicotine receptor and muscarinic receptor. Muscarinic receptors are cell membrane-bound G protein-coupled receptors (GPCRs), and five subtypes (M 1 -M 5 ) are currently known. These M 1 -M 5 muscarinic receptors exert excitatory and inhibitory control on central and peripheral tissues and are involved in many physiological functions including heart rate, arousal, cognition, motor control and the like.
　ムスカリン受容体作動薬は鎮痛作用、記憶改善作用、抗精神病作用、認知障害改善作用など種々の薬理作用を有しており、それらの治療薬として使用できる可能性がある（非特許文献１）。しかしながら、カルバコールやピロカルピンのような従来のムスカリン受容体作動薬はムスカリン受容体サブタイプに対する選択性が低く、その結果副作用が、多く見られたため臨床への応用は限られている。 Muscarinic receptor agonists have various pharmacological actions such as analgesic action, memory improving action, antipsychotic action, and cognitive impairment improving action, and may be used as therapeutic agents for these (Non-Patent Document 1). However, conventional muscarinic receptor agonists such as carbachol and pilocarpine have low selectivity for muscarinic receptor subtypes, and as a result, many side effects have been observed, so their clinical application is limited.
　近年、ムスカリン受容体の分子クローニングおよびノックアウトマウスを使用する特定のサブタイプの生理学的役割の同定によって選択的ムスカリン受容体リガンドが新しい治療薬となりうる可能性が提示され、効果の増強および副作用の減少に必要な選択性プロファイルが研究されてきた。ザノメリン(xanomeline)は、ヒト統合失調症の陽性症状、陰性症状、認知障害のすべてに優れた臨床効果を示したことが報告されているが、Ｍ１およびＭ４ノックアウトマウスを用いた研究により、ザノメリンの抗精神病作用は主としてムスカリンＭ１およびＭ４受容体作動性を介していることが報告されている（非特許文献２）。 In recent years, molecular cloning of muscarinic receptors and identification of the physiological role of specific subtypes using knockout mice has shown the potential for selective muscarinic receptor ligands as new therapeutic agents, enhancing efficacy and reducing side effects The selectivity profile required for the study has been studied. Zanomerin (xanomeline) is of human schizophrenia positive symptoms, negative symptoms, but that all showed excellent clinical efficacy of cognitive impairment has been reported by studies with M 1 and M 4 knockout mice, It has been reported that the antipsychotic action of zanomeline is mainly mediated through muscarinic M 1 and M 4 receptor agonists (Non-patent Document 2).
　以上の理由から、特に中枢疾患治療剤としてムスカリンＭ１およびＭ４受容体に選択的に作動する薬剤の創出が、効果の増強および副作用の低減の観点から期待されている。 For these reasons, the creation of drugs that selectively act on muscarinic M 1 and M 4 receptors, particularly as therapeutic agents for central diseases, is expected from the viewpoint of enhancing effects and reducing side effects.
　特許文献１には、例えば、下記式で示されるオキシインドール化合物が開示されている。 Patent Document 1 discloses, for example, an oxindole compound represented by the following formula.
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000003
　当該化合物は、オキシインドール環の３位炭素原子がピペリジン環と結合している点で、オキシインドール環の１位窒素原子がピペリジン環と結合している本発明化合物と構造が異なる。また、ムスカリンＭ１およびＭ４受容体作動性およびムスカリン受容体選択性に関しては何ら具体的に開示も示唆もされていない。 The compound differs in structure from the compound of the present invention in which the 1-position nitrogen atom of the oxindole ring is bonded to the piperidine ring in that the 3-position carbon atom of the oxindole ring is bonded to the piperidine ring. Also, there is no specific disclosure or suggestion regarding muscarinic M 1 and M 4 receptor agonists and muscarinic receptor selectivity.
　また、特許文献２にはムスカリンＭ４受容体作動性を有する化合物として、例えば、下記式 Patent Document 2 discloses a compound having muscarinic M 4 receptor activity as, for example, the following formula:
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
で示されるベンズイミダゾリジノン化合物が開示されているが、当該化合物は、縮環ピロリジン化合物である本発明化合物と構造的に異なる。また、ムスカリンＭ１受容体作動性に関しては何ら具体的に開示も示唆もされていない。 Although the benzimidazolidinone compound shown by this is disclosed, this compound is structurally different from the compound of the present invention which is a condensed pyrrolidine compound. In addition, there is no specific disclosure or suggestion regarding muscarinic M 1 receptor agonism.
　また、特許文献３には、例えば、下記式 In Patent Document 3, for example, the following formula
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
で示されるオキシインドール化合物が開示されており、また特許文献４には、例えば、下記式 In addition, Patent Document 4 discloses, for example, the following formula:
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
で示されるオキシインドール化合物が開示されている。しかしながら、これらの化合物は、ピペリジン環の窒素原子にピロリジン環が結合している点で本発明化合物と構造的に異なる。また、当該化合物の作動性はムスカリンＭ１受容体選択的であり、ムスカリンＭ１およびＭ４の両受容体を選択的に作動するオキシインドール化合物に関しては何ら具体的に開示も示唆もされていない。 An oxindole compound is disclosed. However, these compounds are structurally different from the compounds of the present invention in that the pyrrolidine ring is bonded to the nitrogen atom of the piperidine ring. In addition, the agonist activity of the compound is selective for muscarinic M 1 receptor, and no specific disclosure or suggestion is made regarding an oxindole compound that selectively activates both muscarinic M 1 and M 4 receptors. .
国際公開第99/32481号パンフレットWO99 / 32481 pamphlet 国際公開第2001/27104号パンフレットInternational Publication No. 2001/27104 Pamphlet 国際公開第2007/142585号パンフレットInternational Publication No. 2007/142585 Pamphlet 国際公開第2009/110844号パンフレットInternational Publication No. 2009/110844 Pamphlet
　本発明は、選択的にムスカリンＭ１およびＭ４受容体を作動して、効果を発現するとともに、その他のムスカリン受容体または他の受容体を介する副作用が低減された縮環ピロリジン化合物を提供することを課題とする。 The present invention provides a fused-ring pyrrolidine compound that selectively activates muscarinic M 1 and M 4 receptors to express effects and has reduced side effects via other muscarinic receptors or other receptors. This is the issue.
　本発明者らは上記課題を解決するために鋭意検討した結果、特定の縮環ピロリジン構造を有する化合物が、選択的にムスカリンＭ１およびＭ４受容体を作動して、抗精神病作用、認知障害改善作用などを含む優れた中枢性疾患の改善効果を有すると共に、その他のムスカリン受容体または他の受容体を介する副作用を低減することを見出し、本発明を完成した。すなわち、本発明は、
［１］下記式（Ｉ） As a result of intensive studies to solve the above problems, the present inventors have found that a compound having a specific condensed pyrrolidine structure selectively activates muscarinic M 1 and M 4 receptors, thereby causing antipsychotic action and cognitive impairment. The present invention was completed by finding that it has an excellent effect of improving central diseases including an improving action and the like and reduces side effects via other muscarinic receptors or other receptors. That is, the present invention
[1] The following formula (I)
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
［式中、
ａ、ｂ、ｃおよびｄは、同一または異なって、それぞれＣＨまたはＣＲ５であり、
Ｒ５は、ハロゲン原子、Ｃ３－７シクロアルキル基、Ｃ６－１４アリール基、ヘテロアリール基、Ｃ６－１４アリールアルキル基、ヘテロアリールアルキル基、Ｃ２－６アルケニル基、Ｃ２－６アルキニル基、Ｃ１－６アルコキシ基、シアノ基、Ｃ１－６アルキルスルファニル基、アシル基、スルファモイル基、水酸基、アミノ基、ニトロ基、Ｃ１－６アルキルスルホニル基、または置換されていてもよいＣ１－６アルキル基であり、
Ｒ１およびＲ２は、同一または異なって、それぞれ水素原子、置換されていてもよいＣ１－６アルキル基、ハロゲン原子、水酸基、Ｃ３－７シクロアルキル基または３～７員の複素環基であるか、あるいはＲ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともにＣ３－７シクロアルカンまたは３～７員の複素環を形成するか、または一緒になって＝ＣＲ６Ｒ７を形成し、
Ｒ６およびＲ７は、同一または異なって、それぞれ水素原子、または置換されていてもよいＣ１－６アルキル基であるか、あるいはＲ６およびＲ７が互いに結合して、Ｒ６およびＲ７が隣接する炭素原子とともにＣ３－７シクロアルカンまたは３～７員の複素環を形成し、
Ｒ３およびＲ４は、一緒になって＝Ｏまたは＝Ｓを形成し、
Ｘは、単結合またはメチレンであり、
ＹおよびＺは、同一または異なって、それぞれ酸素原子または硫黄原子であり、
Ｒは、置換されていてもよいＣ１－６アルキル基、Ｃ２－６アルキニル基またはＣ２－６アルケニル基であり、
環Ａは、水酸基、ハロゲン原子、Ｃ１－６アルキル基およびＣ１－６アルコキシ基からなる群から選択される１～２個の置換基で置換されていてもよい６ないし７員の含窒素複素環である。］
で示される化合物またはその薬学的に許容される塩（以下、これらを化合物（Ｉ）ともいう）；
［２ａ］ｃがＣＲ５である、上記［１］に記載の化合物；
［２］Ｒ５が、ハロゲン原子、Ｃ１－６アルコキシ基、シアノ基、Ｃ１－６アルキルスルファニル基、水酸基、アミノ基、ニトロ基、または置換されていてもよいＣ１－６アルキル基である、上記［１］または［２ａ］に記載の化合物；
［３］Ｒ５が、フッ素原子、塩素原子、臭素原子、メチル基、エチル基、プロピル基、メトキシ基またはトリフルオロメチル基である、上記［１］または［２ａ］に記載の化合物；
［４ａ］環Ａが、下記式（２ａ） [Where:
a, b, c and d are the same or different and each is CH or CR 5 ;
R 5 represents a halogen atom, a C 3-7 cycloalkyl group, a C 6-14 aryl group, a heteroaryl group, a C 6-14 arylalkyl group, a heteroarylalkyl group, a C 2-6 alkenyl group, a C 2-6 Alkynyl group, C 1-6 alkoxy group, cyano group, C 1-6 alkylsulfanyl group, acyl group, sulfamoyl group, hydroxyl group, amino group, nitro group, C 1-6 alkylsulfonyl group, or optionally substituted A C 1-6 alkyl group,
R 1 and R 2 are the same or different and each represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, a halogen atom, a hydroxyl group, a C 3-7 cycloalkyl group, or a 3- to 7-membered heterocyclic group. Or R 1 and R 2 are bonded to each other so that R 1 and R 2 together with the adjacent carbon atom form a C 3-7 cycloalkane or a 3-7 membered heterocyclic ring, or together Form = CR 6 R 7
R 6 and R 7 are the same or different and are each a hydrogen atom or an optionally substituted C 1-6 alkyl group, or R 6 and R 7 are bonded to each other to form R 6 and R 7. Form a C 3-7 cycloalkane or a 3-7 membered heterocycle with adjacent carbon atoms,
R 3 and R 4 together form ═O or ═S;
X is a single bond or methylene,
Y and Z are the same or different and each represents an oxygen atom or a sulfur atom,
R is an optionally substituted C 1-6 alkyl group, a C 2-6 alkynyl group or a C 2-6 alkenyl group,
Ring A is a 6- to 7-membered nitrogen-containing group optionally substituted with 1 to 2 substituents selected from the group consisting of a hydroxyl group, a halogen atom, a C 1-6 alkyl group and a C 1-6 alkoxy group Heterocycle. ]
Or a pharmaceutically acceptable salt thereof (hereinafter, also referred to as compound (I));
[2a] The compound according to the above [1], wherein c is CR 5 ;
[2] R 5 is a halogen atom, a C 1-6 alkoxy group, a cyano group, a C 1-6 alkylsulfanyl group, a hydroxyl group, an amino group, a nitro group, or an optionally substituted C 1-6 alkyl group. A compound according to the above [1] or [2a];
[3] The compound according to [1] or [2a] above, wherein R 5 is a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a propyl group, a methoxy group or a trifluoromethyl group;
[4a] Ring A is represented by the following formula (2a)
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
で示される含窒素複素環である、上記［１］、［２ａ］、［２］または［３］に記載の化合物；
［４］環Ａが、下記式（２） The compound according to [1], [2a], [2] or [3], which is a nitrogen-containing heterocyclic ring represented by:
[4] Ring A is represented by the following formula (2)
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
［式中、Ｒ８は水素原子、水酸基、ハロゲン原子、Ｃ１－６アルキル基またはＣ１－６アルコキシ基である。］
で示される含窒素複素環である、上記［１］、［２ａ］、［２］または［３］に記載の化合物；
［５］Ｒ８が水素原子、Ｃ１－６アルキル基またはＣ１－６アルコキシ基である、上記［４］に記載の化合物；
［６ａ］Ｘが単結合である、上記［１］、［２ａ］、［２］、［３］、［４ａ］、［４］または［５］に記載の化合物；
［６］ｃおよびｂが、同一または異なってＣＨまたはＣＲ５である、上記［１］、［２ａ］、［２］、［３］、［４ａ］、［４］、［５］または［６ａ］に記載の化合物；
［７］ｃおよびｂのどちらか一方がＣＨ、もう一方がＣＲ５である、上記［１］、［２ａ］、［２］、［３］、［４ａ］、［４］、［５］または［６ａ］に記載の化合物；
［８］ＹおよびＺが、共に酸素原子である、上記［１］、［２ａ］、［２］、［３］、［４ａ］、［４］、［５］、［６ａ］、［６］または［７］に記載の化合物；
［９］Ｒ３およびＲ４が一緒になって＝Ｏを形成する、上記［１］、［２ａ］、［２］、［３］、［４ａ］、［４］、［５］、［６ａ］、［６］、［７］または［８］に記載の化合物；
［１０］Ｒ１およびＲ２が、同一または異なって、それぞれ水素原子、フッ素原子、水酸基、または置換されていてもよいＣ１－６アルキル基（特に水酸基で置換されていてもよいＣ１－３アルキル基）であるか、あるいはＲ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともにテトラヒドロピラン環を形成する、上記［１］、［２ａ］、［２］、［３］、［４ａ］、［４］、［５］、［６ａ］、［６］、［７］、［８］または［９］に記載の化合物；
［１１］Ｒが、置換されていてもよい直鎖のＣ１－６アルキル基である、上記［１］、［２ａ］、［２］、［３］、［４ａ］、［４］、［５］、［６ａ］、［６］、［７］、［８］、［９］または［１０］のいずれか一項に記載の化合物；
［１２］４－｛４－［２’－オキソスピロ（シクロヘキサン－１，３’－インドール）－１’（２’Ｈ）－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（５－クロロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（５－メチル－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（５－メチル－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（６－メチル－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（６－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（６－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
（１Ｒ，５Ｓ）－３－［４－（６－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
４－［４－（６－メトキシ－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－｛［４－（５－フルオロ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］メチル｝ピペリジン－１－カルボン酸エチル；
４－｛［４－（３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］メチル｝ピペリジン－１－カルボン酸エチル；
４－｛［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］メチル｝ピペリジン－１－カルボン酸エチル；
４－［４－（６－フルオロ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（６－エチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－｛［４－（５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］メチル｝ピペリジン－１－カルボン酸エチル；
４－｛［４－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］メチル｝ピペリジン－１－カルボン酸エチル；
４－［４－（６－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－４－メチルピペリジン－１－カルボン酸エチル；
４－［４－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－４－メチルピペリジン－１－カルボン酸エチル；
（３－ｅｎｄｏ）－３－［４－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
３－ｅｘｏ）－３－［４－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
３－ｅｎｄｏ）－３－［４－（６－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
（３－ｅｘｏ）－３－［４－（６－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
（３－ｅｎｄｏ）－３－［４－（３，６－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
４－｛４－［３－（ヒドロキシメチル）－６－メトキシ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－｛４－［３－（ヒドロキシメチル）－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
（３－ｅｎｄｏ）－３－［４－（６－メチル－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
４－［４－（３，３－ジフルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
（１Ｒ，５Ｓ）－３－［４－（３，３－ジフルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
４－［４－（３，３－ジフルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－４－メチルアゼパン－１－カルボン酸エチル；
４－［４－（３－ヒドロキシ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－４－メチルピペリジン－１－カルボン酸エチル；および
４－［４－（３－フルオロ－３－ヒドロキシメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－４－メチルピペリジン－１－カルボン酸エチル；
からなる群から選択される、上記［１］に記載の化合物またはその薬学的に許容される塩；
［１３］上記［１］、［２ａ］、［２］、［３］、［４ａ］、［４］、［５］、［６ａ］、［６］、［７］、［８］、［９］、［１０］、［１１］または［１２］に記載の化合物を含有する中枢疾患の予防および／または治療剤；
［１４］中枢疾患がアルツハイマー病および／または統合失調症である、上記［１３］に記載の予防および／または治療剤；
［１５］上記［１］、［２ａ］、［２］、［３］、［４ａ］、［４］、［５］、［６ａ］、［６］、［７］、［８］、［９］、［１０］、［１１］または［１２］に記載の化合物またはその薬学的に許容される塩および薬学的に許容される担体を含有する医薬組成物；
を提供する。 [Wherein R 8 represents a hydrogen atom, a hydroxyl group, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group. ]
The compound according to [1], [2a], [2] or [3], which is a nitrogen-containing heterocyclic ring represented by:
[5] The compound according to [4] above, wherein R 8 is a hydrogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group;
[6a] The compound according to [1], [2a], [2], [3], [4a], [4] or [5], wherein X is a single bond;
[6] The above [1], [2a], [2], [3], [4a], [4], [5] or [6a, wherein c and b are the same or different and are CH or CR 5 ] The compound according to
[7] The above [1], [2a], [2], [3], [4a], [4], [5] or any one of c and b is CH and the other is CR 5 The compound according to [6a];
[8] Y and Z are both oxygen atoms, [1], [2a], [2], [3], [4a], [4], [5], [6a], [6] Or the compound according to [7];
[9] R 3 and R 4 together form ═O, [1], [2a], [2], [3], [4a], [4], [5], [6a ], [6], [7] or a compound according to [8];
[10] R 1 and R 2 are the same or different and are each a hydrogen atom, a fluorine atom, a hydroxyl group, or an optionally substituted C 1-6 alkyl group (particularly an optionally substituted C 1- 1 3 alkyl group), or R 1 and R 2 are bonded to each other, and R 1 and R 2 together with adjacent carbon atoms form a tetrahydropyran ring, [1], [2a], [2] , [3], [4a], [4], [5], [6a], [6], [7], [8] or [9];
[11] The above [1], [2a], [2], [3], [4a], [4], [4], wherein R is an optionally substituted linear C 1-6 alkyl group 5], [6a], [6], [7], [8], [9] or the compound according to any one of [10];
[12] 4- {4- [2′-oxospiro (cyclohexane-1,3′-indole) -1 ′ (2′H) -yl] piperidin-1-yl} piperidine-1-carboxylate;
4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] ethyl azepane-1-carboxylate;
4- [4- (5-Chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (5-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (5-Methyl-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) -yl) piperidine-1- Yl] piperidine-1-carboxylate;
4- [4- (5-Methyl-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) -yl) piperidine-1- Yl] azepan-1-ethyl carboxylate;
4- [4- (6-Methyl-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) -yl) piperidine-1- Yl] piperidine-1-carboxylate;
Ethyl 4- [4- (6-methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate;
Ethyl 4- [4- (6-methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
(1R, 5S) -3- [4- (6-Methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2.1 ] Ethyl octane-8-carboxylate;
4- [4- (6-Methoxy-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) -yl) piperidine-1- Yl] piperidine-1-carboxylate;
4-{[4- (5-Fluoro-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] methyl} piperidine-1-carboxylate;
4-{[4- (3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] methyl} piperidine-1-carboxylate;
4-{[4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] methyl} piperidine-1-carboxylate;
4- [4- (6-Fluoro-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (6-Ethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4-{[4- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] methyl} piperidine-1-carboxylate;
4-{[4- (6-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
Ethyl 4- [4- (6-methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-methylpiperidine-1-carboxylate;
Ethyl 4- [4- (6-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-methylpiperidine-1-carboxylate;
(3-endo) -3- [4- (6-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2.1 ] Ethyl octane-8-carboxylate;
3-exo) -3- [4- (6-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2.1] Ethyl octane-8-carboxylate;
3-endo) -3- [4- (6-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2.1] Ethyl octane-8-carboxylate;
(3-exo) -3- [4- (6-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2.1 ] Ethyl octane-8-carboxylate;
(3-endo) -3- [4- (3,6-Dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2 .1] ethyl octane-8-carboxylate;
4- {4- [3- (hydroxymethyl) -6-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carvone Ethyl acid;
4- {4- [3- (hydroxymethyl) -3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylate;
(3-endo) -3- [4- (6-Methyl-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) — Yl) piperidin-1-yl] -8-azabicyclo [3.2.1] octane-8-carboxylate;
4- [4- (3,3-difluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
(1R, 5S) -3- [4- (3,3-Difluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2 .1] ethyl octane-8-carboxylate;
4- [4- (3,3-difluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate;
4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-ethyl methylazepan-1-carboxylate;
Ethyl 4- [4- (3-hydroxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-methylpiperidine-1-carboxylate; And 4- [4- (3-Fluoro-3-hydroxymethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-methylpiperidine-1-carboxylic acid ethyl;
The compound or pharmaceutically acceptable salt thereof according to the above [1], selected from the group consisting of:
[13] The above [1], [2a], [2], [3], [4a], [4], [5], [6a], [6], [7], [8], [9 ], [10], [11] or a preventive and / or therapeutic agent for central diseases comprising the compound according to [12];
[14] The preventive and / or therapeutic agent according to [13] above, wherein the central disease is Alzheimer's disease and / or schizophrenia;
[15] The above [1], [2a], [2], [3], [4a], [4], [5], [6a], [6], [7], [8], [9 ], [10], [11] or [12] or a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier;
I will provide a.
　本発明化合物は、抗精神病作用、認知障害改善作用などを含む優れた中枢性疾患の改善効果を示すため、新規な中枢性疾患の予防および／または治療剤として有用である。 The compound of the present invention exhibits an excellent effect of improving central diseases including an antipsychotic effect, a cognitive impairment improving effect, and the like, and thus is useful as a novel preventive and / or therapeutic agent for central diseases.
　本明細書における用語を以下に説明する。 The terms used in this specification are explained below.
　本発明の目的に関して、化学元素は元素周期表、CAS version, Handbook of Chemistry and Physics, 75th Edに従って同定する。さらに、有機化学の一般的原理は、“Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999および“March's Advanced Organic Chemistry”, 5th Ed., : Smith, M.B. and March, J., John Wiley ＆ Sons, New York: 2001に記載されており、それらの全内容を参照することができる。 For the purposes of the present invention, chemical elements are identified according to the Periodic Table of Elements, CAS version, Handbook of Chemistry and Physicals, 75th Ed. In addition, the general principles of organic chemistry are: “OrganicistChemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999 and “March's Advanced Organic Chemistry”, 5th Ed.,: Smith, MB and March, J. & John Sons, New York: 2001, all of which can be referenced.
　受容体サブタイプを特定する接頭辞がない用語「ムスカリン受容体」は、５種の受容体サブタイプＭ１－Ｍ５の１種以上を意味する。 The term “muscarinic receptor” without a prefix identifying a receptor subtype means one or more of the five receptor subtypes M 1 -M 5 .
　ムスカリン受容体に結合してムスカリン活性を増強する化合物は作動薬またはアゴニストと称される。ムスカリン受容体の活性を減少させる化合物は拮抗薬またはアンタゴニストと称される。アゴニストはムスカリン受容体と相互作用して該受容体が内因性リガンド結合に応答して細胞内シグナルを伝達する能力を増加させる。アンタゴニストはムスカリン受容体と相互作用し、該受容体上の結合部位(複数可)を内因性リガンド(複数可)または基質(複数可)と競合して、該受容体が内因性リガンド結合に応答して細胞内シグナルを伝達する能力を低下させる。 Compounds that bind to muscarinic receptors and enhance muscarinic activity are called agonists or agonists. Compounds that reduce the activity of muscarinic receptors are called antagonists or antagonists. Agonists interact with muscarinic receptors to increase their ability to transduce intracellular signals in response to endogenous ligand binding. Antagonists interact with the muscarinic receptor and compete for binding site (s) on the receptor with endogenous ligand (s) or substrate (s) and the receptor responds to endogenous ligand binding Reducing the ability to transmit intracellular signals.
　本明細書中、「Ｃ１－６アルキル基」という用語は、炭素数が１～６個の直鎖状または分枝鎖状の飽和炭化水素基を意味し、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、ペンチル基、イソペンチル基、ネオペンチル基およびｎ－ヘキシル基、ならびにそれらの構造異性体が挙げられ、中でも、Ｃ１－４アルキル基が好ましく、メチル基、エチル基、ｎ－プロピル基およびイソプロピル基がより好ましく、メチル基およびエチル基が特に好ましい。 In the present specification, the term “C 1-6 alkyl group” means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group and n-hexyl group, and structural isomers thereof, Among these, a C 1-4 alkyl group is preferable, a methyl group, an ethyl group, an n-propyl group, and an isopropyl group are more preferable, and a methyl group and an ethyl group are particularly preferable.
　本明細書中、「Ｃ２－６アルケニル基」という用語は、１個以上の二重結合を有する炭素数が２～６個の直鎖状または分枝鎖状の不飽和の脂肪族炭化水素基を意味し、例えば、エテニル基、プロペニル基、クロチル基、ブテニル基、ペンテニル基およびヘキセニル基、ならびにそれらの構造異性体や幾何異性体が挙げられる。二重結合の位置は炭素鎖上のどの位置であってもよい。中でも、Ｃ２－４アルケニル基が好ましい。 In the present specification, the term “C 2-6 alkenyl group” means a linear or branched unsaturated aliphatic hydrocarbon having 2 to 6 carbon atoms having one or more double bonds. Group, and includes, for example, ethenyl group, propenyl group, crotyl group, butenyl group, pentenyl group and hexenyl group, and structural isomers and geometric isomers thereof. The position of the double bond may be any position on the carbon chain. Of these, a C2-4 alkenyl group is preferable.
　本明細書中、「Ｃ２－６アルキニル基」という用語は、１個以上の三重結合を有する炭素数が２～６個の直鎖状または分枝鎖状の不飽和の脂肪族炭化水素基を意味し、例えば、エチニル基、プロピニル基、ブチニル基、ペンチニル基およびヘキシニル基、ならびにそれらの構造異性体が挙げられる。三重結合の位置は炭素鎖上のどの位置であってもよい。中でも、Ｃ２－４アルキニル基が好ましい。 In the present specification, the term “C 2-6 alkynyl group” means a linear or branched unsaturated aliphatic hydrocarbon group having 2 to 6 carbon atoms and having one or more triple bonds. And includes, for example, ethynyl group, propynyl group, butynyl group, pentynyl group and hexynyl group, and structural isomers thereof. The position of the triple bond may be any position on the carbon chain. Of these, a C 2-4 alkynyl group is preferable.
　本明細書中、「Ｃ３－７シクロアルキル基」という用語は、炭素原子のみで環を構成している３～７員の飽和または不飽和の脂肪族炭素環基を意味する。当該「Ｃ３－７シクロアルキル基」の具体例としては、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロペンテニル基、シクロペンタジエニル基、シクロヘキシル基、シクロヘキセニル基、１，３－シクロヘキサジエニル基、１，４－シクロヘキサジエニル基、シクロヘプチル基、シクロヘプテニル基、１，２－シクロヘプタジエニル基、１，３－シクロヘプタジエニル基および１，４－シクロヘプタジエニル基が挙げられ、中でも、Ｃ３－６シクロアルキル基が好ましい。また、当該「Ｃ３－７シクロアルキル基」は、芳香族π電子系が生じない限り、任意に1個以上の不飽和結合を有していてもよく、また、Ｃ６－１４アレーンと縮合していてもよい。 In the present specification, the term “C 3-7 cycloalkyl group” means a 3- to 7-membered saturated or unsaturated aliphatic carbocyclic group constituting a ring only with carbon atoms. Specific examples of the “C 3-7 cycloalkyl group” include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclopentenyl group, cyclopentadienyl group, cyclohexyl group, cyclohexenyl group, 1,3-cyclohexadienyl. Group, 1,4-cyclohexadienyl group, cycloheptyl group, cycloheptenyl group, 1,2-cycloheptadienyl group, 1,3-cycloheptadienyl group and 1,4-cycloheptadienyl group Of these, a C 3-6 cycloalkyl group is preferable. In addition, the “C 3-7 cycloalkyl group” may optionally have one or more unsaturated bonds as long as an aromatic π-electron system does not occur, and is condensed with a C 6-14 arene. You may do it.
　本明細書中、「複素環基」という用語は、環構成原子として酸素原子、硫黄原子および窒素原子からなる群より選択される１個以上のヘテロ原子を含む３～７員の飽和または不飽和の脂肪族環基を意味し、当該「複素環基」は、芳香族π電子系が生じない限り、任意に1個以上の不飽和結合を有していてもよく、また、Ｃ６－１４アレーンまたは複素環と縮合していてもよい。さらに、環構成メンバーとして、1個以上のカルボニルまたはチオカルボニルを含んでいてもよく、例えば、ラクタム、ラクトン、環式イミド、環式チオイミド、環式カルバメートなどの環状基も当該複素環基に含まれる。当該「複素環基」の結合位置は、ヘテロ原子上でも炭素原子上でもよく、Ｃ６－１４アレーンまたは複素環との縮合体の場合には、Ｃ６－１４アレーンまたは複素環の環上であってもよい。 In the present specification, the term “heterocyclic group” means 3 to 7-membered saturated or unsaturated containing one or more heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen atoms as ring-constituting atoms. The “heterocyclic group” may optionally have one or more unsaturated bonds as long as an aromatic π-electron system does not occur, and C 6-14 It may be condensed with an arene or a heterocyclic ring. Furthermore, the ring-constituting member may contain one or more carbonyl or thiocarbonyl. For example, a cyclic group such as lactam, lactone, cyclic imide, cyclic thioimide, and cyclic carbamate is also included in the heterocyclic group. It is. Binding position of the "heterocyclic group" may even on the carbon atoms also on hetero atoms, in the case of condensate of C 6-14 arene or heterocyclic ring, on a ring of C 6-14 arene or heterocyclic There may be.
　当該「複素環基」の具体例としては、例えば、テトラヒドロチオピラニル基、４Ｈ－ピラニル基、テトラヒドロピラニル基、ピペリジル基、１－エトキシカルボニルピペリジル基、１－エトキシカルボニルピペリジニリデニル基、１，３－ジオキシニル基、１，３－ジオキサニル基、１，４－ジオキシニル基、１，４－ジオキサニル基、ピペラジニル基、１，３－オキサチアニル基、１，４－オキサチイニル基、１，４－オキサチアニル基、テトラヒドロ－１，４－チアジニル基、２Ｈ－１，２－オキサジニル基、マレイミド基、スクシンイミド基、ジオキソピペラジニル基、ヒダントイン基、ジヒドロウラシル基、モルホリノ基、ヘキサヒドロ－１，３，５－トリアジニル基、テトラヒドロチエニル基、テトラヒドロフラニル基、ジヒドロフラニル基、オキセタニル基、ピロリニル基、ピロリジニル基、ピロリドニル基、ピロリジオニル基、ピラゾリニル基、ピラゾリジニル基、イミダゾリニル基、イミダゾリジニル基、１，３－ジオキソリル基、１，３－ジオキソラニル基、１，３－ジチオリル基、１，３－ジチオラニル基、イソオキサゾリニル基、イソオキサゾリジニル基、オキサゾリニル基、オキサゾリジニル基、チアゾリニル基、チアゾリジニル基および１，３－オキサチオラニル基が挙げられる。 Specific examples of the “heterocyclic group” include, for example, a tetrahydrothiopyranyl group, 4H-pyranyl group, tetrahydropyranyl group, piperidyl group, 1-ethoxycarbonylpiperidyl group, 1-ethoxycarbonylpiperidinylidenyl group, 1,3-dioxinyl group, 1,3-dioxanyl group, 1,4-dioxinyl group, 1,4-dioxanyl group, piperazinyl group, 1,3-oxathianyl group, 1,4-oxathiinyl group, 1,4-oxathianyl group Group, tetrahydro-1,4-thiazinyl group, 2H-1,2-oxazinyl group, maleimide group, succinimide group, dioxopiperazinyl group, hydantoin group, dihydrouracil group, morpholino group, hexahydro-1,3,5 -Triazinyl group, tetrahydrothienyl group, tetrahydrofuranyl group, dihydride Furanyl group, oxetanyl group, pyrrolinyl group, pyrrolidinyl group, pyrrolidonyl group, pyrrolidonyl group, pyrazolinyl group, pyrazolidinyl group, imidazolinyl group, imidazolidinyl group, 1,3-dioxolyl group, 1,3-dioxolanyl group, 1,3-dithiolyl group 1,3-dithiolanyl group, isoxazolinyl group, isoxazolidinyl group, oxazolinyl group, oxazolidinyl group, thiazolinyl group, thiazolidinyl group and 1,3-oxathiolanyl group.
　本明細書中、「Ｃ６－１４アリール基」という用語は、炭素数が６～１４の芳香族炭素環基を意味する。当該「Ｃ６－１４アリール基」は、少なくとも1つのＣ６－１４アレーンまたはＣ３－７シクロアルカンと縮合していてもよい。当該「Ｃ６－１４アリール基」の具体例としては、フェニル基、ナフチル基、フェナントリル基、アントリル基、フルオレニル基、テトラヒドロナフチル基、インデニル基およびインダニル基が挙げられ、中でも、フェニル基およびナフチル基が好ましく、フェニル基が特に好ましい。 In the present specification, the term “C 6-14 aryl group” means an aromatic carbocyclic group having 6 to 14 carbon atoms. The “C 6-14 aryl group” may be condensed with at least one C 6-14 arene or C 3-7 cycloalkane. Specific examples of the “C 6-14 aryl group” include a phenyl group, a naphthyl group, a phenanthryl group, an anthryl group, a fluorenyl group, a tetrahydronaphthyl group, an indenyl group and an indanyl group, and among them, a phenyl group and a naphthyl group. And a phenyl group is particularly preferable.
　当該「Ｃ６－１４アリール基」は、ハロゲン原子、水酸基、アミノ基、シアノ基、ニトロ基、Ｃ１－６アルキル－カルバモイル基、アシル基、Ｃ１－６アルコキシ基、置換されていてもよいＣ１－６アルキル基、モノまたはジＣ１－６アルキルアミノ基、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、スルファモイル基およびトリフルオロメチル基からなる群から選択される１個以上の任意の置換基を有してもよく、好ましくは、同一または異なった１個または２個の上記置換基を有するフェニル基である。Ｃ６－１４アリール基の代表例として、フェニル基、ハロゲン原子で置換されたフェニル基（例えば、３位または４位にハロゲン原子が置換されたフェニル基）、３－ヒドロキシフェニル基、４－ヒドロキシフェニル基、３－アミノフェニル基、４－アミノフェニル基、３－メチルフェニル基、４－メチルフェニル基、３－メトキシフェニル基、４－メトキシフェニル基、３－シアノフェニル基、４－シアノフェニル基、３，４－ジメチルフェニル基、ナフチル基、１－ヒドロキシナフチル基、４－（ヒドロキシメチル）フェニル基および４－（トリフルオロメチル)フェニル基が挙げられるが、これらに限られるわけではない。 The “C 6-14 aryl group” is a halogen atom, a hydroxyl group, an amino group, a cyano group, a nitro group, a C 1-6 alkyl-carbamoyl group, an acyl group, a C 1-6 alkoxy group or an optionally substituted group. C 1-6 alkyl group, a mono- or di-C 1-6 alkylamino group, C 1-6 alkylsulfanyl group, C 1-6 alkylsulfinyl group, C 1-6 alkylsulfonyl group, a sulfamoyl group and a trifluoromethyl group It may have one or more arbitrary substituents selected from the group consisting of, preferably a phenyl group having the same or different one or two substituents. Representative examples of the C 6-14 aryl group include a phenyl group, a phenyl group substituted with a halogen atom (for example, a phenyl group substituted with a halogen atom at the 3-position or 4-position), a 3-hydroxyphenyl group, 4-hydroxy Phenyl group, 3-aminophenyl group, 4-aminophenyl group, 3-methylphenyl group, 4-methylphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 3-cyanophenyl group, 4-cyanophenyl group 3,4-dimethylphenyl group, naphthyl group, 1-hydroxynaphthyl group, 4- (hydroxymethyl) phenyl group and 4- (trifluoromethyl) phenyl group, but are not limited thereto.
　本明細書中、「Ｃ６－１４アリールアルキル基」という用語は、Ｃ６－１４アリール基で置換されたＣ１－６アルキル基を意味する。 In this specification, the term “C 6-14 arylalkyl group” means a C 1-6 alkyl group substituted with a C 6-14 aryl group.
　本明細書中、「ヘテロアリール基」という用語は、環構成原子として酸素原子、硫黄原子および窒素原子からなる群より選択される１個以上のヘテロ原子を含む５～１０員の芳香族環基を意味する。「ヘテロアリール基」の具体例としては、例えば、フリル基、ベンゾフラニル基、チエニル基、ベンゾチオフェニル基、ピロリル基、ピリジル基、インドリル基、オキサゾリル基、ベンゾオキサゾリル基、イソオキサゾリル基、ベンゾイソオキサゾリル基、チアゾリル基、ベンゾチアゾリル基、イソチアゾリル基、イミダゾリル基、ベンゾイミダゾリル基、ピラゾリル基、インダゾリル基、テトラゾリル基、フラザニル基、１，２，３－オキサジアゾリル基、１，２，３－チアジアゾリル基、１，２，４－チアジアゾリル基、１，２，３－トリアゾリル基、１，２，４－トリアゾリル基、ベンゾトリアゾリル基、キノリニル基、イソキノリニル基、ピリダジニル基、ピリミジニル基、プリニル基、ピラジニル基、プテリジニル基、フェノキサゾリル基、ベンゾピラゾリル基、キノリジニル基、シンノリニル基、フタラジニル基、キナゾリニル基およびキノキサリニル基が挙げられ、中でも、５員および６員のヘテロアリール基が好ましい。当該「ヘテロアリール基」は、少なくとも1つのＣ６－１４アレーンまたは複素環と縮合していてもよい。 In the present specification, the term “heteroaryl group” means a 5- to 10-membered aromatic ring group containing one or more heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom as ring-constituting atoms. Means. Specific examples of the “heteroaryl group” include, for example, furyl group, benzofuranyl group, thienyl group, benzothiophenyl group, pyrrolyl group, pyridyl group, indolyl group, oxazolyl group, benzoxazolyl group, isoxazolyl group, benzoiso Oxazolyl group, thiazolyl group, benzothiazolyl group, isothiazolyl group, imidazolyl group, benzoimidazolyl group, pyrazolyl group, indazolyl group, tetrazolyl group, furazanyl group, 1,2,3-oxadiazolyl group, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,2,3-triazolyl group, 1,2,4-triazolyl group, benzotriazolyl group, quinolinyl group, isoquinolinyl group, pyridazinyl group, pyrimidinyl group, purinyl group, pyrazinyl group , Pteridinyl group, phenoxa Lil group, benzopyrazolyl group, quinolizinyl group, cinnolinyl group, phthalazinyl group, and quinazolinyl group and quinoxalinyl group. Among them, preferred heteroaryl groups 5- and 6-membered. The “heteroaryl group” may be condensed with at least one C 6-14 arene or heterocyclic ring.
　当該「ヘテロアリール基」は、ハロゲン原子、水酸基、アミノ基、シアノ基、ニトロ基、Ｃ１－６アルキル－カルバモイル基、アシル基、Ｃ１－６アルコキシ基、置換されていてもよいＣ１－６アルキル基、モノまたはジＣ１－６アルキルアミノ基、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、スルファモイル基およびトリフルオロメチル基からなる群より選択される1個以上の置換基を有してもよく、好ましくは、同一または異なった１個または２個の上記置換基を有していてもよい。最も典型的な置換基は、ハロゲン原子、水酸基、シアノ基、Ｃ１－６アルコキシ基、および置換されていてもよいＣ１－６アルキル基である。 The “heteroaryl group” is a halogen atom, a hydroxyl group, an amino group, a cyano group, a nitro group, a C 1-6 alkyl-carbamoyl group, an acyl group, a C 1-6 alkoxy group, an optionally substituted C 1 1- 6 alkyl group, a mono- or di-C 1-6 alkylamino group, C 1-6 alkylsulfanyl group, C 1-6 alkylsulfinyl group, C 1-6 alkylsulfonyl group, from a sulfamoyl group and a group consisting of a trifluoromethyl group It may have one or more selected substituents, and may preferably have one or two of the same or different substituents. The most typical substituents are a halogen atom, a hydroxyl group, a cyano group, a C 1-6 alkoxy group, and an optionally substituted C 1-6 alkyl group.
　本明細書中、「ヘテロアリールアルキル基」という用語は、ヘテロアリール基で置換されたＣ１－６アルキル基を意味する。 In this specification, the term “heteroarylalkyl group” means a C 1-6 alkyl group substituted with a heteroaryl group.
　本明細書中、「Ｃ１－６アルコキシ基」という用語は、Ｃ１－６アルキル基が結合した－Ｏ－を意味し、具体的には、メトキシ基、エトキシ基、ｎ－プロポキシ基、イソプロポキシ基、ｎ－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、イソペンチルオキシ基、ネオペンチルオキシ基およびヘキシルオキシ基が挙げられ、中でも、Ｃ１－３アルコキシ基が好ましく、メトキシ基およびエトキシ基が特に好ましい。 In this specification, the term “C 1-6 alkoxy group” means —O— to which a C 1-6 alkyl group is bonded, specifically, a methoxy group, an ethoxy group, an n-propoxy group, an iso Examples include propoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, and hexyloxy group, and among them, C 1-3 alkoxy group Are preferred, and methoxy and ethoxy groups are particularly preferred.
　本明細書中、「ハロゲン原子」という用語は、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。中でも、フッ素原子、臭素原子および塩素原子が好ましい。 In the present specification, the term “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Among these, a fluorine atom, a bromine atom and a chlorine atom are preferable.
　本明細書中、「Ｃ１－６アルキルスルファニル基」という用語は、Ｃ１－６アルキル基が結合した－Ｓ－を意味し、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（すなわち、アミルスルファニル）基、ヘキシルスルファニル基、イソプロピルスルファニル基、イソブチルスルファニル基、第２級ブチルスルファニル基、第３級ブチルスルファニル基、イソペンチルスルファニル基、ネオペンチルスルファニル基および第３級ペンチルスルファニル基が挙げられ、中でも、Ｃ１－３アルキルスルファニル基が好ましく、メチルスルファニル基およびエチルスルファニル基が特に好ましい。 In this specification, the term “C 1-6 alkylsulfanyl group” means —S— to which a C 1-6 alkyl group is bonded. Groups, pentylsulfanyl (ie, amylsulfanyl), hexylsulfanyl, isopropylsulfanyl, isobutylsulfanyl, secondary butylsulfanyl, tertiary butylsulfanyl, isopentylsulfanyl, neopentylsulfanyl and tertiary A primary pentylsulfanyl group is exemplified, among which a C 1-3 alkylsulfanyl group is preferable, and a methylsulfanyl group and an ethylsulfanyl group are particularly preferable.
　本明細書中、「アシル基」という用語は、「Ｃ１－６アルキル－カルボニル基」（Ｃ１－６アルキル基が結合した－ＣＯ－、例えば、アセチル基、プロピオニル基、ブチリル基、イソブチリル基、バレリル基、ピバロイル基、ヘキサノイル基およびヘプタノイル基）、「Ｃ６－１４アリール－カルボニル基」（Ｃ６－１４アリール基が結合した－ＣＯ－、例えば、ベンゾイル基およびナフトイル基）および「Ｃ６－１４アリールアルキル－カルボニル基」（Ｃ６－１４アリールアルキル基が結合した－ＣＯ－、例えば、ベンジルカルボニル基、２－フェニルエチルカルボニル基および３－フェニルプロピルカルボニル基）が挙げられ、中でも、アセチル基、プロピオニル基およびベンゾイル基が好ましい。当該「アシル基」中のベンゼン環およびナフタレン環はハロゲン原子、Ｃ１－６アルキル基、ニトロ基、シアノ基、水酸基およびＣ１－６アルコキシ基からなる群から選択される１～５個の置換基を有していてもよく、置換位置は特に限定されない。 In the present specification, the term “acyl group” means “C 1-6 alkyl-carbonyl group” (—CO— to which a C 1-6 alkyl group is bonded, such as acetyl group, propionyl group, butyryl group, isobutyryl group). , Valeryl group, pivaloyl group, hexanoyl group and heptanoyl group), “C 6-14 aryl-carbonyl group” (—CO— to which a C 6-14 aryl group is bonded, such as benzoyl group and naphthoyl group) and “C 6 -14 arylalkyl-carbonyl group "(-CO- to which a C 6-14 arylalkyl group is bonded, such as benzylcarbonyl group, 2-phenylethylcarbonyl group and 3-phenylpropylcarbonyl group), among which acetyl Groups, propionyl groups and benzoyl groups are preferred. The benzene ring and naphthalene ring in the “acyl group” are 1 to 5 substituents selected from the group consisting of a halogen atom, a C 1-6 alkyl group, a nitro group, a cyano group, a hydroxyl group, and a C 1-6 alkoxy group. It may have a group, and the substitution position is not particularly limited.
　本明細書中、「アミノ基」という用語は、アミノ基、およびＣ１－６アルキル基を有する２級または３級アミノ基であって、例えば、アミノ基、およびモノまたはジ－Ｃ１－６アルキルアミノ基（メチルアミノ基、ジメチルアミノ基、エチルアミノ基、ジエチルアミノ基、プロピルアミノ基、ジプロピルアミノ基、ブチルアミノ基、ジブチルアミノ基など）が挙げられ、中でも、アミノ基、およびモノまたはジ－Ｃ１－３アルキルアミノ基が好ましく、アミノ基、メチルアミノ基およびジメチルアミノ基が特に好ましい。 In the present specification, the term “amino group” refers to a secondary or tertiary amino group having an amino group and a C 1-6 alkyl group, such as an amino group and mono- or di-C 1-6. Examples include alkylamino groups (methylamino group, dimethylamino group, ethylamino group, diethylamino group, propylamino group, dipropylamino group, butylamino group, dibutylamino group, etc.). A —C 1-3 alkylamino group is preferred, and an amino group, a methylamino group and a dimethylamino group are particularly preferred.
　本明細書中、「Ｃ１－６アルキルスルホニル基」という用語は、Ｃ１－６アルキル基が結合した－ＳＯ２－を意味し、例えば、メチルスルホニル基、エチルスルホニル基、プロピルスルホニル基およひイソプロピルスルホニル基が挙げられ、中でも、Ｃ１－３アルキルスルホニル基が好ましく、メチルスルホニル基およびエチルスルホニル基が特に好ましい。 In this specification, the term “C 1-6 alkylsulfonyl group” means —SO 2 — to which a C 1-6 alkyl group is bonded, and examples thereof include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, and And a isopropylsulfonyl group. Among them, a C 1-3 alkylsulfonyl group is preferable, and a methylsulfonyl group and an ethylsulfonyl group are particularly preferable.
　本明細書中、「Ｃ１－６アルキルスルフィニル基」という用語は、Ｃ１－６アルキル基が結合した－ＳＯ－を意味し、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およびイソプロピルスルフィニル基が挙げられ、中でも、Ｃ１－３アルキルスルフィニル基が好ましい。 In this specification, the term “C 1-6 alkylsulfinyl group” means —SO— to which a C 1-6 alkyl group is bonded, and examples thereof include a methylsulfinyl group, an ethylsulfinyl group, a propylsulfinyl group, and an isopropylsulfinyl group. Among them, a C 1-3 alkylsulfinyl group is preferable.
　本明細書中、「スルファモイル基」という用語は、スルファモイル基（－ＳＯ２ＮＨ２）、およびスルファモイル基の窒素原子上の１個または２個の水素原子がＣ１－６アルキル基と置換した基を意味し、例えば、スルファモイル基、およびモノまたはジ－Ｃ１－６アルキルスルファモイル基（例えば、メチルスルファモイル基、ジメチルスルファモイル基、エチルスルファモイル基、ジエチルスルファモイル基、プロピルスルファモイル基、ジプロピルスルファモイル基、ブチルスルファモイル基およびジブチルスルファモイル基）が挙げられ、中でも、スルファモイル基およびモノまたはジ－Ｃ１－３アルキルスルファモイル基が好ましく、アミノ基、メチルスルファモイル基およびジメチルスルファモイル基が特に好ましい。 In this specification, the term “sulfamoyl group” means a sulfamoyl group (—SO 2 NH 2 ) and a group in which one or two hydrogen atoms on the nitrogen atom of the sulfamoyl group are substituted with a C 1-6 alkyl group. means, for example, a sulfamoyl group, and mono- or di -C 1-6 alkylsulfamoyl group (e.g., methylsulfamoyl group, dimethylsulfamoyl group, ethylsulfamoyl group, diethylsulfamoyl group, Propylsulfamoyl group, dipropylsulfamoyl group, butylsulfamoyl group and dibutylsulfamoyl group), among which sulfamoyl group and mono- or di-C 1-3 alkylsulfamoyl group are preferred, amino Particularly preferred are groups, methylsulfamoyl and dimethylsulfamoyl groups.
　本明細書中、「含窒素複素環」という用語は、環構成原子として、少なくとも１個の窒素原子を含む６ないし７員の飽和脂肪族環を意味し、さらに環構成原子として、酸素原子および硫黄原子から選択される１個以上のヘテロ原子を含有していてもよく、少なくとも1つのＣ６－１４アレーン、Ｃ３－７シクロアルカンまたは３～７員の複素環と縮合していてもよい。
　当該「含窒素複素環」の具体例としては、ピペリジン、ピペラジン、アゼパン、ジアゼパン、オキサゼパン、チアゼパン、モルホリンおよびチオモルホリンが挙げられる。 In the present specification, the term “nitrogen-containing heterocycle” means a 6- to 7-membered saturated aliphatic ring containing at least one nitrogen atom as a ring-constituting atom, and further oxygen atom and It may contain one or more heteroatoms selected from sulfur atoms and may be fused with at least one C 6-14 arene, C 3-7 cycloalkane or 3-7 membered heterocycle .
Specific examples of the “nitrogen-containing heterocycle” include piperidine, piperazine, azepan, diazepan, oxazepan, thiazepan, morpholine and thiomorpholine.
　本明細書中、「置換されていてもよいＣ１－６アルキル基」という用語は、置換可能な位置に、水酸基、Ｃ１－６アルキルスルファニル基、ハロゲン原子、アミノ基、ホルミル基、カルバモイル基、シアノ基、ニトロ基、Ｃ１－６アルコキシ基、Ｃ３－７シクロアルキル基および複素環基からなる群から選択される１～４個の原子または置換基で置換されていてもよいＣ１－６アルキル基を意味する。「置換されたＣ１－６アルキル基」の具体例としては、トリフルオロメチル基、フルオロメチル基、２－フルオロエチル基、メトキシエチル基、ヒドロキシメチル基、シクロプロピルメチル基、フリルメチル基、オキサゾリルメチル基およびテトラヒドロフリルメチル基が挙げられる。 In this specification, the term “optionally substituted C 1-6 alkyl group” means a hydroxyl group, C 1-6 alkylsulfanyl group, halogen atom, amino group, formyl group, carbamoyl group at a substitutable position. , cyano group, nitro group, C 1-6 alkoxy, C 3-7 cycloalkyl and heterocycle may be substituted with 1 to 4 atoms or substituents selected from the group consisting of group C 1 -6 means an alkyl group. Specific examples of the “substituted C 1-6 alkyl group” include a trifluoromethyl group, a fluoromethyl group, a 2-fluoroethyl group, a methoxyethyl group, a hydroxymethyl group, a cyclopropylmethyl group, a furylmethyl group, an oxa group. Examples include a zolylmethyl group and a tetrahydrofurylmethyl group.
　本明細書中、「Ｃ６－１４アレーン」という用語は、「Ｃ６－１４アリール基」に対応する環を意味する。
　本明細書中、「複素環」という用語は、「複素環基」に対応する環を意味する。
　本明細書中、「Ｃ３－７シクロアルカン」という用語は、「Ｃ３－７シクロアルキル基」に対応する環を意味する。 In the present specification, the term “C 6-14 arene” means a ring corresponding to “C 6-14 aryl group”.
In the present specification, the term “heterocycle” means a ring corresponding to “heterocyclic group”.
Herein, the term "C 3-7 cycloalkane" means a ring corresponding to the "C 3-7 cycloalkyl group".
　「塩」という用語は、アミンなどの官能基の塩基型を、適当な酸、例えば無機酸［例：ハロゲン化水素酸（例えば、塩酸、臭化水素酸、フッ化水素酸、ヨウ化水素酸）、または硫酸、硝酸、リン酸など］や、有機酸［例：酢酸、プロピオン酸、ヒドロ酢酸（hydroacetic acid）、２－ヒドロキシプロパン酸、２－オキソプロパン酸、エタン二酸、プロパン二酸、ブタン二酸、（Ｚ）－２－ブテン二酸、（Ｅ）－ブテン二酸、２－ヒドロキシブタン二酸、２，３－ジヒドロキシブタン二酸、２－ヒドロキシ－１，２，３－プロパントリカルボン酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、４－メチルベンゼンスルホン酸、シクロヘキサンスルファミン酸、２－ヒドロキシ安息香酸、４－アミノ－２－ヒドロキシ安息香酸、および当業者に知られている他の有機酸］で処理することによって得ることができる、薬学的に許容できる酸付加塩を意味する。 The term “salt” refers to the basic form of a functional group such as an amine and a suitable acid, such as an inorganic acid [eg, hydrohalic acid (eg, hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid). ), Or sulfuric acid, nitric acid, phosphoric acid, etc.], organic acids [eg acetic acid, propionic acid, hydroacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, ethanedioic acid, propanedioic acid, Butanedioic acid, (Z) -2-butenedioic acid, (E) -butenedioic acid, 2-hydroxybutanedioic acid, 2,3-dihydroxybutanedioic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid Acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, It can be obtained by treatment with another organic acid] known to beauty those skilled in the art, to mean a pharmaceutically acceptable acid addition salts.
　前記一般式（１）で表される本発明の化合物を更に具体的に開示するため、式（１）において用いられる各種記号につき、その好適な具体例を挙げて更に詳細に説明する。 In order to more specifically disclose the compound of the present invention represented by the general formula (1), the various symbols used in the formula (1) will be described in more detail with suitable specific examples.
　本発明の一般式（１）の化合物は、その置換基の態様によって、光学異性体、ジアステレオ異性体、幾何異性体等の立体異性体が存在する場合があるが、本発明の一般式（１）の化合物はこれら全ての立体異性体及びそれらの混合物をも包含する。 The compound of the general formula (1) of the present invention may have stereoisomers such as optical isomers, diastereoisomers and geometric isomers depending on the mode of the substituent. The compound of 1) also includes all these stereoisomers and mixtures thereof.
　前記一般式（１）において、ａ、ｂ、ｃおよびｄは、同一または異なって、それぞれＣＨまたはＣＲ５であり、好ましくは、ａおよびｄが、いずれもＣＨであり、かつｂおよびｃが、同一または異なって、ＣＨまたはＣＲ５である。ｃがＣＲ５のとき、ムスカリンＭ１およびＭ４受容体の選択性が向上し、また、薬物動態が改善される傾向にある。
　より好ましくは、ａおよびｄが、いずれもＣＨであり、ｂおよびｃのどちらか一方がＣＨ、もう一方がＣＲ５である。 In the general formula (1), a, b, c and d are the same or different and are each CH or CR 5 , preferably a and d are both CH, and b and c are same or different, CH or CR 5. When c is CR 5 , the selectivity of muscarinic M 1 and M 4 receptors is improved and the pharmacokinetics tends to be improved.
More preferably, a and d are both CH, and either of b and c is CH, the other is CR 5.
　前記一般式（１）において、Ｒ５は、ハロゲン原子、Ｃ３－７シクロアルキル基、Ｃ６－１４アリール基、ヘテロアリール基、Ｃ６－１４アリールアルキル基、ヘテロアリールアルキル基、Ｃ２－６アルケニル基、Ｃ２－６アルキニル基、Ｃ１－６アルコキシ基、シアノ基、Ｃ１－６アルキルスルファニル基、アシル基、スルファモイル基、水酸基、アミノ基、ニトロ基、Ｃ１－６アルキルスルホニル基、または置換されていてもよいＣ１－６アルキル基である。 In the general formula (1), R 5 represents a halogen atom, a C 3-7 cycloalkyl group, a C 6-14 aryl group, a heteroaryl group, a C 6-14 arylalkyl group, a heteroarylalkyl group, a C 2- 6 alkenyl group, C 2-6 alkynyl group, C 1-6 alkoxy group, cyano group, C 1-6 alkylsulfanyl group, acyl group, sulfamoyl group, hydroxyl group, amino group, nitro group, C 1-6 alkylsulfonyl group Or an optionally substituted C 1-6 alkyl group.
　Ｒ５は、好ましくは、ハロゲン原子、Ｃ２－６アルケニル基、Ｃ２－６アルキニル基、Ｃ１－６アルコキシ基、シアノ基、Ｃ１－６アルキルスルファニル基、アシル基、スルファモイル基、水酸基、アミノ基、ニトロ基、Ｃ１－６アルキルスルホニル基、または置換されていてもよいＣ１－６アルキル基（好ましくは、水酸基、Ｃ１－６アルキルスルファニル基、ハロゲン原子、シアノ基、ニトロ基およびメトキシ基からなる群から選択される１～４個の置換基で置換されていてもよい。）であり、
より好ましくは、ハロゲン原子、Ｃ１－６アルコキシ基、シアノ基、Ｃ１－６アルキルスルファニル基、水酸基、アミノ基、ニトロ基、または置換されていてもよいＣ１－６アルキル基（好ましくは、水酸基、Ｃ１－６アルキルスルファニル基、ハロゲン原子、シアノ基、ニトロ基およびメトキシ基からなる群から選択される１～４個の置換基で置換されていてもよい。）であり、
さらに好ましくは、ハロゲン原子、メチル基、エチル基、プロピル基、シアノ基、水酸基、メトキシ基またはトリフルオロメチル基であり、
特に好ましくは、フッ素原子、塩素原子、臭素原子、メチル基、エチル基、プロピル基、メトキシ基またはトリフルオロメチル基であり、
最も好ましくは、フッ素原子、塩素原子、臭素原子、メチル基、エチル基、プロピル基またはメトキシ基である。 R 5 is preferably a halogen atom, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 1-6 alkoxy group, a cyano group, a C 1-6 alkylsulfanyl group, an acyl group, a sulfamoyl group, a hydroxyl group, An amino group, a nitro group, a C 1-6 alkylsulfonyl group, or an optionally substituted C 1-6 alkyl group (preferably a hydroxyl group, a C 1-6 alkylsulfanyl group, a halogen atom, a cyano group, a nitro group, and And optionally substituted with 1 to 4 substituents selected from the group consisting of methoxy groups),
More preferably, a halogen atom, a C 1-6 alkoxy group, a cyano group, a C 1-6 alkylsulfanyl group, a hydroxyl group, an amino group, a nitro group, or an optionally substituted C 1-6 alkyl group (preferably And optionally substituted with 1 to 4 substituents selected from the group consisting of a hydroxyl group, a C 1-6 alkylsulfanyl group, a halogen atom, a cyano group, a nitro group and a methoxy group.
More preferably, a halogen atom, a methyl group, an ethyl group, a propyl group, a cyano group, a hydroxyl group, a methoxy group or a trifluoromethyl group,
Particularly preferably, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a propyl group, a methoxy group or a trifluoromethyl group,
Most preferably, they are a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a propyl group, or a methoxy group.
　前記一般式（１）において、Ｒ１およびＲ２は、同一または異なって、それぞれ水素原子、置換されていてもよいＣ１－６アルキル基、ハロゲン原子、水酸基、Ｃ３－７シクロアルキル基または３～７員の複素環基であるか、あるいはＲ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともにＣ３－７シクロアルカンまたは３～７員の複素環を形成するか、または一緒になって＝ＣＲ６Ｒ７を形成する。
　ここで、Ｒ６およびＲ７は、同一または異なって、それぞれ水素原子、または置換されていてもよいＣ１－６アルキル基であるか、あるいはＲ６およびＲ７が互いに結合して、Ｒ６およびＲ７が隣接する炭素原子とともにＣ３－７シクロアルカンまたは３～７員の複素環を形成する。 In the general formula (1), R 1 and R 2 are the same or different and each is a hydrogen atom, an optionally substituted C 1-6 alkyl group, a halogen atom, a hydroxyl group, a C 3-7 cycloalkyl group or A 3- to 7-membered heterocyclic group, or R 1 and R 2 are bonded to each other, and R 1 and R 2 together with an adjacent carbon atom form a C 3-7 cycloalkane or a 3- to 7-membered heterocyclic ring. Or together form ═CR 6 R 7 .
Here, R 6 and R 7 are the same or different and are each a hydrogen atom or an optionally substituted C 1-6 alkyl group, or R 6 and R 7 are bonded to each other, and R 6 And R 7 together with the adjacent carbon atom form a C 3-7 cycloalkane or a 3-7 membered heterocycle.
　Ｒ１およびＲ２は、好ましくは、同一または異なって、それぞれ水素原子、置換されていてもよいＣ１－６アルキル基、ハロゲン原子、水酸基、Ｃ３－７シクロアルキル基、または３～７員の複素環基であるか、あるいはＲ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともにＣ３－７シクロアルカンまたは３～７員の複素環を形成するか、またはＲ１およびＲ２が一緒になって＝ＣＲ６Ｒ７を形成し、
より好ましくは、同一または異なって、それぞれ水素原子、置換されていてもよいＣ１－６アルキル基、ハロゲン原子、水酸基、またはＣ３－７シクロアルキル基であるか、あるいはＲ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともにＣ３－７シクロアルカンまたは３～７員の複素環を形成し、
さらに好ましくは、同一または異なって、それぞれ水素原子、フッ素原子、塩素原子、臭素原子、水酸基、または置換されていてもよいＣ１－６アルキル基であるか、あるいはＲ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともにＣ３－７シクロアルカンまたは３～７員の複素環を形成し、
特に好ましくは、同一または異なって、それぞれ水素原子、フッ素原子、塩素原子、水酸基、または置換されていてもよいＣ１－６アルキル基（特に水酸基で置換されていてもよいＣ１－３アルキル基）であるか、あるいはＲ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともに３～７員の複素環を形成し、
特に一層好ましくは、同一または異なって、それぞれ水素原子、フッ素原子、水酸基、または置換されていてもよいＣ１－６アルキル基（特に水酸基で置換されていてもよいＣ１－３アルキル基）であるか、あるいはＲ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともにテトラヒドロピラン環を形成し、
最も好ましくは、同一または異なって、それぞれ水素原子、フッ素原子、水酸基、または水酸基で置換されていてもよいＣ１－３アルキル基（特にヒドロキシメチル）であるか、あるいはＲ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともにテトラヒドロピラン環を形成する。 R 1 and R 2 are preferably the same or different and each is a hydrogen atom, an optionally substituted C 1-6 alkyl group, a halogen atom, a hydroxyl group, a C 3-7 cycloalkyl group, or a 3-7 member. or a heterocyclic group, or R 1 and R 2 are bonded to each other, or R 1 and R 2 form a heterocyclic ring of C 3-7 cycloalkane or 3-7 membered together with the carbon atom adjacent, Or R 1 and R 2 together form ═CR 6 R 7 ,
More preferably, they are the same or different and each represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, a halogen atom, a hydroxyl group, or a C 3-7 cycloalkyl group, or R 1 and R 2 are Bonded to each other, R 1 and R 2 together with adjacent carbon atoms form a C 3-7 cycloalkane or a 3-7 membered heterocyclic ring;
More preferably, they are the same or different and each is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, or an optionally substituted C 1-6 alkyl group, or R 1 and R 2 are bonded to each other R 1 and R 2 together with adjacent carbon atoms form a C 3-7 cycloalkane or a 3-7 membered heterocycle,
Particularly preferably, they are the same or different and each is a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxyl group, or an optionally substituted C 1-6 alkyl group (particularly a C 1-3 alkyl group optionally substituted with a hydroxyl group). Or R 1 and R 2 are bonded together to form a 3- to 7-membered heterocycle with R 1 and R 2 together with adjacent carbon atoms;
Particularly preferably, they are the same or different and each is a hydrogen atom, a fluorine atom, a hydroxyl group, or an optionally substituted C 1-6 alkyl group (particularly a C 1-3 alkyl group optionally substituted with a hydroxyl group). Or R 1 and R 2 are bonded together to form a tetrahydropyran ring with R 1 and R 2 together with adjacent carbon atoms;
Most preferably, they are the same or different and each is a hydrogen atom, a fluorine atom, a hydroxyl group, or a C 1-3 alkyl group (particularly hydroxymethyl) optionally substituted with a hydroxyl group, or R 1 and R 2 are Together, R 1 and R 2 together with the adjacent carbon atoms form a tetrahydropyran ring.
　具体的には、Ｒ１およびＲ２は、同一または異なって、それぞれ
(1)水素原子、
(2)(a)水酸基、
   (b)Ｃ１－６アルコキシ基（例、メトキシ）、
   (c)３～７員の複素環基（例、フリル、オキサゾリル、テトラヒドロフリル）、および
   (d)Ｃ３－７シクロアルキル基（例、シクロプロピル）
からなる群から選択される１～４個の置換基で置換されていてもよいＣ１－６アルキル基（例、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、１－エチルプロピル、１－プロピルブチル）、
(3)ハロゲン原子（例、フッ素原子、塩素原子、臭素原子）、
(4)水酸基、
(5)Ｃ３－７シクロアルキル基（例、シクロブチル、シクロペンチル）、または
(6)３～７員の複素環基（例、アゼチジニル、テトラヒドロピラニル、テトラヒドロフリル、オキセタニル）
であるか、あるいは
Ｒ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともに
(1)Ｃ３－７シクロアルカン（例、シクロプロパン、シクロブタン、シクロペンタン、シクロヘキサン）、または
(2)３～７員の複素環（例、テトラヒドロピラン）
を形成するか、または
Ｒ１およびＲ２が一緒になって、＝ＣＲ６Ｒ７（Ｒ６およびＲ７が、同一または異なって、それぞれ水素原子またはＣ１－６アルキル基（例、メチル、エチル、イソプロピル）であるか、Ｒ６およびＲ７が隣接する炭素原子とともに、Ｃ１－６アルコキシ－カルボニル基（例、エトキシカルボニル）で置換されていてもよい３～７員の複素環（例、ピペリジン）を形成する。）を形成する。 Specifically, R 1 and R 2 are the same or different,
(1) hydrogen atom,
(2) (a) a hydroxyl group,
(b) a C 1-6 alkoxy group (eg, methoxy),
(c) a 3- to 7-membered heterocyclic group (eg, furyl, oxazolyl, tetrahydrofuryl), and (d) a C 3-7 cycloalkyl group (eg, cyclopropyl)
A C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-ethylpropyl, 1-propyl) which may be substituted with 1 to 4 substituents selected from the group consisting of Butyl),
(3) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom),
(4) hydroxyl group,
(5) a C 3-7 cycloalkyl group (eg, cyclobutyl, cyclopentyl), or
(6) 3-7 membered heterocyclic group (eg, azetidinyl, tetrahydropyranyl, tetrahydrofuryl, oxetanyl)
Or R 1 and R 2 are bonded together, and R 1 and R 2 together with adjacent carbon atoms
(1) C 3-7 cycloalkane (eg, cyclopropane, cyclobutane, cyclopentane, cyclohexane), or
(2) 3-7 membered heterocycle (eg, tetrahydropyran)
Or R 1 and R 2 taken together are ═CR 6 R 7 (R 6 and R 7 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group (eg, methyl, Ethyl, isopropyl) or a 3-7 membered heterocycle (eg, R 6 and R 7 may be substituted with adjacent carbon atoms by a C 1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl)) , Piperidine).
　Ｒ１およびＲ２は、好ましくは、同一または異なって、それぞれ
(1)水素原子、
(2)(a)水酸基、
   (b)Ｃ１－６アルコキシ基（例、メトキシ）、
   (c)３～７員の複素環基（例、フリル、オキサゾリル、テトラヒドロフリル）、および
   (d)Ｃ３－７シクロアルキル基（例、シクロプロピル）
からなる群から選択される１～４個の置換基で置換されていてもよいＣ１－６アルキル基（例、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、１－エチルプロピル、１－プロピルブチル）、
(3)ハロゲン原子（例、フッ素原子、塩素原子、臭素原子）、
(4)水酸基、
(5)Ｃ３－７シクロアルキル基（例、シクロブチル、シクロペンチル）、または
(6)３～７員の複素環基（例、アゼチジニル、テトラヒドロピラニル、テトラヒドロフリル、オキセタニル）
であるか、あるいは
Ｒ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともに
(1)Ｃ３－７シクロアルカン（例、シクロプロパン、シクロブタン、シクロペンタン、シクロヘキサン）、または
(2)３～７員の複素環（例、テトラヒドロピラン）
を形成するか、または
Ｒ１およびＲ２が一緒になって、＝ＣＲ６Ｒ７（Ｒ６およびＲ７が、同一または異なって、それぞれ水素原子またはＣ１－６アルキル基（例、メチル、エチル、イソプロピル）であるか、Ｒ６およびＲ７が隣接する炭素原子とともに、Ｃ１－６アルコキシ－カルボニル基（例、エトキシカルボニル）で置換されていてもよい３～７員の複素環（例、ピペリジン）を形成する。）を形成する。 R 1 and R 2 are preferably the same or different,
(1) hydrogen atom,
(2) (a) a hydroxyl group,
(b) a C 1-6 alkoxy group (eg, methoxy),
(c) a 3- to 7-membered heterocyclic group (eg, furyl, oxazolyl, tetrahydrofuryl), and (d) a C 3-7 cycloalkyl group (eg, cyclopropyl)
A C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-ethylpropyl, 1-propyl) which may be substituted with 1 to 4 substituents selected from the group consisting of Butyl),
(3) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom),
(4) hydroxyl group,
(5) a C 3-7 cycloalkyl group (eg, cyclobutyl, cyclopentyl), or
(6) 3-7 membered heterocyclic group (eg, azetidinyl, tetrahydropyranyl, tetrahydrofuryl, oxetanyl)
Or R 1 and R 2 are bonded together, and R 1 and R 2 together with adjacent carbon atoms
(1) C 3-7 cycloalkane (eg, cyclopropane, cyclobutane, cyclopentane, cyclohexane), or
(2) 3-7 membered heterocycle (eg, tetrahydropyran)
Or R 1 and R 2 taken together are ═CR 6 R 7 (R 6 and R 7 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group (eg, methyl, Ethyl, isopropyl) or a 3-7 membered heterocycle (eg, R 6 and R 7 may be substituted with adjacent carbon atoms by a C 1-6 alkoxy-carbonyl group (eg, ethoxycarbonyl)) , Piperidine).
　Ｒ１およびＲ２は、より好ましくは、同一または異なって、それぞれ
(1)水素原子、
(2)(a)水酸基、
   (b)Ｃ１－６アルコキシ基（例、メトキシ）、
   (c)３～７員の複素環基（例、フリル、オキサゾリル、テトラヒドロフリル）、および
   (d)Ｃ３－７シクロアルキル基（例、シクロプロピル）
からなる群から選択される１～４個の置換基で置換されていてもよいＣ１－６アルキル基（例、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、１－エチルプロピル、１－プロピルブチル）、
(3)ハロゲン原子（例、フッ素原子、塩素原子、臭素原子）、
(4)水酸基、または
(5)Ｃ３－７シクロアルキル基（例、シクロブチル、シクロペンチル）
であるか、あるいは
Ｒ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともに
(1)Ｃ３－７シクロアルカン（例、シクロプロパン、シクロブタン、シクロペンタン、シクロヘキサン）、または
(2)３～７員の複素環（例、テトラヒドロピラン）
を形成する。 R 1 and R 2 are more preferably the same or different,
(1) hydrogen atom,
(2) (a) a hydroxyl group,
(b) a C 1-6 alkoxy group (eg, methoxy),
(c) a 3- to 7-membered heterocyclic group (eg, furyl, oxazolyl, tetrahydrofuryl), and (d) a C 3-7 cycloalkyl group (eg, cyclopropyl)
A C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-ethylpropyl, 1-propyl) which may be substituted with 1 to 4 substituents selected from the group consisting of Butyl),
(3) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom),
(4) hydroxyl group, or
(5) C 3-7 cycloalkyl group (eg, cyclobutyl, cyclopentyl)
Or R 1 and R 2 are bonded together, and R 1 and R 2 together with adjacent carbon atoms
(1) C 3-7 cycloalkane (eg, cyclopropane, cyclobutane, cyclopentane, cyclohexane), or
(2) 3-7 membered heterocycle (eg, tetrahydropyran)
Form.
　Ｒ１およびＲ２は、さらに好ましくは、同一または異なって、それぞれ
(1)水素原子、
(2)(a)水酸基、
   (b)Ｃ１－６アルコキシ基（例、メトキシ）、
   (c)３～７員の複素環基（例、フリル、オキサゾリル、テトラヒドロフリル）、および
   (d)Ｃ３－７シクロアルキル基（例、シクロプロピル）
からなる群から選択される１～４個の置換基で置換されていてもよいＣ１－６アルキル基（例、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、１－エチルプロピル、１－プロピルブチル）、
(3)フッ素原子、塩素原子または臭素原子、または
(4)水酸基
であるか、あるいは
Ｒ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともに
(1)Ｃ３－７シクロアルカン（例、シクロプロパン、シクロブタン、シクロペンタン、シクロヘキサン）、または
(2)３～７員の複素環（例、テトラヒドロピラン）
を形成する。 R 1 and R 2 are more preferably the same or different,
(1) hydrogen atom,
(2) (a) a hydroxyl group,
(b) a C 1-6 alkoxy group (eg, methoxy),
(c) a 3- to 7-membered heterocyclic group (eg, furyl, oxazolyl, tetrahydrofuryl), and (d) a C 3-7 cycloalkyl group (eg, cyclopropyl)
A C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-ethylpropyl, 1-propyl) which may be substituted with 1 to 4 substituents selected from the group consisting of Butyl),
(3) fluorine atom, chlorine atom or bromine atom, or
(4) is a hydroxyl group, or R 1 and R 2 are bonded to each other, and R 1 and R 2 together with adjacent carbon atoms
(1) C 3-7 cycloalkane (eg, cyclopropane, cyclobutane, cyclopentane, cyclohexane), or
(2) 3-7 membered heterocycle (eg, tetrahydropyran)
Form.
　Ｒ１およびＲ２は、特に好ましくは、同一または異なって、それぞれ
(1)水素原子、
(2)(a)水酸基、
   (b)Ｃ１－６アルコキシ基（例、メトキシ）、
   (c)３～７員の複素環基（例、フリル、オキサゾリル、テトラヒドロフリル）、および
   (d)Ｃ３－７シクロアルキル基（例、シクロプロピル）
からなる群から選択される１～４個の置換基で置換されていてもよいＣ１－６アルキル基（例、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、１－エチルプロピル、１－プロピルブチル、好ましくはＣ１－３アルキル基）（特に好ましくは水酸基で置換されていてもよいＣ１－３アルキル基）、
(3)フッ素原子または塩素原子、または
(4)水酸基
であるか、あるいは
Ｒ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともに、３～７員の複素環（例、テトラヒドロピラン）を形成する。 R 1 and R 2 are particularly preferably the same or different,
(1) hydrogen atom,
(2) (a) a hydroxyl group,
(b) a C 1-6 alkoxy group (eg, methoxy),
(c) a 3- to 7-membered heterocyclic group (eg, furyl, oxazolyl, tetrahydrofuryl), and (d) a C 3-7 cycloalkyl group (eg, cyclopropyl)
A C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-ethylpropyl, 1-propyl) which may be substituted with 1 to 4 substituents selected from the group consisting of butyl, preferably a C 1-3 alkyl group) (particularly preferably in C 1-3 alkyl group optionally substituted by a hydroxyl group),
(3) fluorine atom or chlorine atom, or
(4) It is a hydroxyl group, or R 1 and R 2 are bonded to each other, and R 1 and R 2 together with the adjacent carbon atom form a 3- to 7-membered heterocyclic ring (eg, tetrahydropyran).
　Ｒ１およびＲ２は、特に一層好ましくは、同一または異なって、それぞれ
(1)水素原子、
(2)(a)水酸基、
   (b)Ｃ１－６アルコキシ基（例、メトキシ）、
   (c)３～７員の複素環基（例、フリル、オキサゾリル、テトラヒドロフリル）、および
   (d)Ｃ３－７シクロアルキル基（例、シクロプロピル）
からなる群から選択される１～４個の置換基で置換されていてもよいＣ１－６アルキル基（例、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、１－エチルプロピル、１－プロピルブチル、好ましくはＣ１－３アルキル基）（特に好ましくは水酸基で置換されていてもよいＣ１－３アルキル基）、
(3)フッ素原子、または
(4)水酸基
であるか、あるいは
Ｒ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともに、テトラヒドロピラン環を形成する。 R 1 and R 2 are particularly preferably the same or different,
(1) hydrogen atom,
(2) (a) a hydroxyl group,
(b) a C 1-6 alkoxy group (eg, methoxy),
(c) a 3- to 7-membered heterocyclic group (eg, furyl, oxazolyl, tetrahydrofuryl), and (d) a C 3-7 cycloalkyl group (eg, cyclopropyl)
A C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-ethylpropyl, 1-propyl) which may be substituted with 1 to 4 substituents selected from the group consisting of butyl, preferably a C 1-3 alkyl group) (particularly preferably in C 1-3 alkyl group optionally substituted by a hydroxyl group),
(3) fluorine atom, or
(4) It is a hydroxyl group, or R 1 and R 2 are bonded to each other, and R 1 and R 2 together with the adjacent carbon atom form a tetrahydropyran ring.
　Ｒ１およびＲ２は、最も好ましくは、同一または異なって、それぞれ
(1)水素原子、
(2)水酸基で置換されていてもよいＣ１－３アルキル基（例、メチル、エチル、プロピル、イソプロピル、好ましくはメチル）（特に好ましくはヒドロキシメチル）、
(3)フッ素原子、または
(4)水酸基
であるか、あるいは
Ｒ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともに、テトラヒドロピラン環を形成する。 R 1 and R 2 are most preferably the same or different,
(1) hydrogen atom,
(2) a C 1-3 alkyl group optionally substituted with a hydroxyl group (eg, methyl, ethyl, propyl, isopropyl, preferably methyl) (particularly preferably hydroxymethyl),
(3) fluorine atom, or
(4) It is a hydroxyl group, or R 1 and R 2 are bonded to each other, and R 1 and R 2 together with the adjacent carbon atom form a tetrahydropyran ring.
　なお、Ｒ１およびＲ２が、共に水素原子以外の場合に、ｈＥＲＧ阻害が改善される傾向にある。 Note that hERG inhibition tends to be improved when R 1 and R 2 are both hydrogen atoms.
　前記一般式（１）において、環Ａは、水酸基、ハロゲン原子、Ｃ１－６アルキル基およびＣ１－６アルコキシ基からなる群から選択される１～２個の置換基で置換されていてもよい６ないし７員の含窒素複素環である。
　環Ａは、好ましくは、１～２個のＣ１－６アルキル基で置換されていてもよい６ないし７員の含窒素複素環（当該２個のＣ１－６アルキル基が結合してビシクロ環を形成してもよい）であり、
より好ましくは、下記式（２） In the general formula (1), ring A may be substituted with 1 to 2 substituents selected from the group consisting of a hydroxyl group, a halogen atom, a C 1-6 alkyl group and a C 1-6 alkoxy group. Good 6- to 7-membered nitrogen-containing heterocycle.
Ring A is preferably a 6- to 7-membered nitrogen-containing heterocyclic ring optionally substituted with 1 to 2 C 1-6 alkyl groups (the two C 1-6 alkyl groups are bonded to form a bicyclo A ring may be formed)
More preferably, the following formula (2)
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
で示される含窒素複素環である。 It is a nitrogen-containing heterocyclic ring shown by these.
　前記式（２）において、Ｒ８は、水素原子、水酸基、ハロゲン原子、Ｃ１－６アルキル基またはＣ１－６アルコキシ基である。
　Ｒ８は、好ましくは、水素原子、水酸基、フッ素原子、メチル基、エチル基、プロピル基、メトキシ基またはエトキシ基であり、より好ましくは、水素原子、水酸基、フッ素原子、メチル基、エチル基、メトキシ基であり、さらに好ましくは、水素原子、メチル基である。 In the formula (2), R 8 is a hydrogen atom, a hydroxyl group, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group.
R 8 is preferably a hydrogen atom, a hydroxyl group, a fluorine atom, a methyl group, an ethyl group, a propyl group, a methoxy group or an ethoxy group, more preferably a hydrogen atom, a hydroxyl group, a fluorine atom, a methyl group, an ethyl group, A methoxy group, more preferably a hydrogen atom or a methyl group.
　環Ａは、特に好ましくは、 Ring A is particularly preferably
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
または Or
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
で示される含窒素複素環である。 It is a nitrogen-containing heterocyclic ring shown by these.
　前記一般式（１）において、Ｒ３およびＲ４は、一緒になって＝Ｏまたは＝Ｓを形成する。
　Ｒ３およびＲ４は、好ましくは、一緒になって＝Ｏを形成する。 In the general formula (1), R 3 and R 4 together form ═O or ═S.
R 3 and R 4 are preferably taken together to form ═O.
　前記一般式（１）において、Ｘは、単結合またはメチレンである。 In the general formula (1), X is a single bond or methylene.
　前記一般式（１）において、ＹおよびＺは、同一または異なって、それぞれ酸素原子または硫黄原子である。
　Ｙは、好ましくは、酸素原子である。
　Ｚは、好ましくは、酸素原子である。 In the general formula (1), Y and Z are the same or different and each represents an oxygen atom or a sulfur atom.
Y is preferably an oxygen atom.
Z is preferably an oxygen atom.
　前記一般式（１）において、Ｒは、置換されていてもよいＣ１－６アルキル基、Ｃ２－６アルキニル基またはＣ２－６アルケニル基である。
　Ｒは、好ましくは、置換されていてもよいＣ１－６アルキル基（好ましくは、ハロゲン原子およびＣ１－６アルコキシ基からなる群から選択される１～４個の置換基で置換されていてもよい）、Ｃ２－６アルキニル基またはＣ２－６アルケニル基であり、
より好ましくは、置換されていてもよいＣ１－６アルキル基（好ましくは、ハロゲン原子およびＣ１－６アルコキシ基からなる群から選択される１～４個の置換基で置換されていてもよい）であり、
さらに好ましくは、置換されていてもよい直鎖のＣ１－６アルキル基（好ましくは、ハロゲン原子およびＣ１－６アルコキシ基からなる群から選択される１～４個の置換基で置換されていてもよい）であり、
さらにより好ましくは、置換されていてもよい直鎖のＣ１－３アルキル基（好ましくは、ハロゲン原子およびＣ１－６アルコキシ基からなる群から選択される１～４個の置換基で置換されていてもよい）であり、
さらに一層好ましくは、直鎖のＣ１－３アルキル基であり、
特に好ましくは、メチル基またはエチル基である。 In the general formula (1), R represents an optionally substituted C 1-6 alkyl group, a C 2-6 alkynyl group, or a C 2-6 alkenyl group.
R is preferably an optionally substituted C 1-6 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group). Or a C 2-6 alkynyl group or a C 2-6 alkenyl group,
More preferably, it may be substituted with an optionally substituted C 1-6 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group). ) And
More preferably, it may be a linear C 1-6 alkyl group which may be substituted (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group). May be)
Even more preferably, an optionally substituted straight chain C 1-3 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group). May be)
Even more preferably, it is a straight chain C 1-3 alkyl group,
Particularly preferred is a methyl group or an ethyl group.
　本発明化合物において、好ましい化合物としては、例えば、以下のような化合物が挙げられる。
［化合物Ａ］
ａが、ＣＨであり、
ｂが、ＣＨまたはＣＲ５（Ｒ５は、前記と同義である。）であり、
ｃが、ＣＲ５（Ｒ５は、前記と同義である。）であり、
ｄが、ＣＨであり、
Ｒ１およびＲ２が、同一または異なって、それぞれ水素原子、置換されていてもよいＣ１－６アルキル基、ハロゲン原子またはＣ３－７シクロアルキル基であるか、あるいはＲ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともにＣ３－７シクロアルカンまたは３～７員の複素環を形成し、
Ｒ３およびＲ４が、一緒になって＝Ｏまたは＝Ｓを形成し、
Ｘが、単結合であり、
Ｙが、酸素原子または硫黄原子であり、
Ｚが、酸素原子または硫黄原子であり、
Ｒが、置換されていてもよいＣ１－６アルキル基（好ましくは、ハロゲン原子およびＣ１－６アルコキシ基からなる群から選択される１～４個の置換基で置換されていてもよい）であり、かつ
環Ａが、１～２個のＣ１－６アルキル基で置換されていてもよい６ないし７員の含窒素複素環（当該２個のＣ１－６アルキル基が結合してビシクロ環を形成してもよい）である（好ましくは、ピペリジンまたはアゼパンである）、
化合物またはその薬学的に許容される塩。 In the compound of the present invention, examples of preferable compounds include the following compounds.
[Compound A]
a is CH,
b is CH or CR 5 (R 5 is as defined above);
c is CR 5 (R 5 is as defined above);
d is CH,
R 1 and R 2 are the same or different and are each a hydrogen atom, an optionally substituted C 1-6 alkyl group, a halogen atom or a C 3-7 cycloalkyl group, or R 1 and R 2 are Bonded together, R 1 and R 2 together with adjacent carbon atoms form a C 3-7 cycloalkane or a 3-7 membered heterocycle;
R 3 and R 4 together form ═O or ═S;
X is a single bond,
Y is an oxygen atom or a sulfur atom,
Z is an oxygen atom or a sulfur atom,
R is an optionally substituted C 1-6 alkyl group (preferably optionally substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group) And ring A is a 6- to 7-membered nitrogen-containing heterocyclic ring optionally substituted with 1 to 2 C 1-6 alkyl groups (the two C 1-6 alkyl groups are bonded to each other). (It may form a bicyclo ring) (preferably piperidine or azepane),
A compound or a pharmaceutically acceptable salt thereof.
［化合物Ｂ］
ａが、ＣＨであり、
ｂが、ＣＨまたはＣＲ５（Ｒ５は、前記と同義である。）であり、
ｃが、ＣＲ５（Ｒ５は、ハロゲン原子、Ｃ１－６アルコキシ基、シアノ基、Ｃ１－６アルキルスルファニル基、水酸基、アミノ基、ニトロ基または置換されていてもよいＣ１－６アルキル基（好ましくは、水酸基、Ｃ１－６アルキルスルファニル基、ハロゲン原子、シアノ基、ニトロ基およびメトキシ基からなる群から選択される１～４個の置換基で置換されていてもよい。）である）であり、
ｄが、ＣＨであり、
Ｒ１およびＲ２が、同一または異なって、それぞれ水素原子、または置換されていてもよいＣ１－６アルキル基であり、
Ｒ３およびＲ４が、一緒になって＝Ｏを形成し、
Ｘが、単結合であり、
Ｙが、酸素原子であり、
Ｚが、酸素原子であり、
Ｒが、置換されていてもよい直鎖のＣ１－６アルキル基（好ましくは、ハロゲン原子およびＣ１－６アルコキシ基からなる群から選択される１～４個の置換基で置換されていてもよい）であり、かつ
環Ａが、下記式（２ａ） [Compound B]
a is CH,
b is CH or CR 5 (R 5 is as defined above);
c is CR 5 (R 5 is a halogen atom, a C 1-6 alkoxy group, a cyano group, a C 1-6 alkylsulfanyl group, a hydroxyl group, an amino group, a nitro group, or an optionally substituted C 1-6 alkyl A group (preferably substituted with 1 to 4 substituents selected from the group consisting of a hydroxyl group, a C 1-6 alkylsulfanyl group, a halogen atom, a cyano group, a nitro group and a methoxy group). Is)
d is CH,
R 1 and R 2 are the same or different and each represents a hydrogen atom or an optionally substituted C 1-6 alkyl group;
R 3 and R 4 together form ═O,
X is a single bond,
Y is an oxygen atom,
Z is an oxygen atom,
R is an optionally substituted linear C 1-6 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group). And ring A is represented by the following formula (2a):
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
で示される含窒素複素環である、
化合物またはその薬学的に許容される塩。 A nitrogen-containing heterocyclic ring represented by
A compound or a pharmaceutically acceptable salt thereof.
［化合物Ｃ］
ａが、ＣＨであり、
ｂが、ＣＨであり、
ｃが、ＣＲ５（Ｒ５は、フッ素原子、塩素原子、臭素原子、メチル基、メトキシ基またはトリフルオロメチル基であり、好ましくは、フッ素原子、塩素原子、臭素原子、メチル基またはメトキシ基である。）であり、
ｄが、ＣＨであり、
Ｒ１およびＲ２が、同一または異なって、それぞれ水素原子またはＣ１－６アルキル基（好ましくは、Ｃ１－３アルキル基）であり、
Ｒ３およびＲ４が、一緒になって＝Ｏを形成し、
Ｘが、単結合であり、
Ｙが、酸素原子であり、
Ｚが、酸素原子であり、
Ｒが、置換されていてもよい直鎖のＣ１－３アルキル基（好ましくは、ハロゲン原子およびＣ１－６アルコキシ基からなる群から選択される１～４個の置換基で置換されていてもよい）（好ましくは、直鎖のＣ１－３アルキル基）であり、かつ
環Ａが、下記式（２ａ） [Compound C]
a is CH,
b is CH,
c is CR 5 (R 5 is a fluorine atom, chlorine atom, bromine atom, methyl group, methoxy group or trifluoromethyl group, preferably a fluorine atom, chlorine atom, bromine atom, methyl group or methoxy group; Yes.)
d is CH,
R 1 and R 2 are the same or different and each is a hydrogen atom or a C 1-6 alkyl group (preferably a C 1-3 alkyl group);
R 3 and R 4 together form ═O,
X is a single bond,
Y is an oxygen atom,
Z is an oxygen atom,
R is an optionally substituted linear C 1-3 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group). (Preferably a straight-chain C 1-3 alkyl group) and ring A is represented by the following formula (2a):
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
で示される含窒素複素環である、
化合物またはその薬学的に許容される塩。 A nitrogen-containing heterocyclic ring represented by
A compound or a pharmaceutically acceptable salt thereof.
［化合物Ｄ］
ａが、ＣＨであり、
ｂおよびｃが、同一または異なって、ＣＨまたはＣＲ５（フッ素原子、塩素原子、臭素原子、メチル基、エチル基、プロピル基、メトキシ基またはトリフルオロメチル基である。）であり、
ｄが、ＣＨであり、
Ｒ１およびＲ２が、同一または異なって、それぞれ水素原子、置換されていてもよいＣ１－６アルキル基、ハロゲン原子またはＣ３－７シクロアルキル基であるか、あるいはＲ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともにＣ３－７シクロアルカンまたは３～７員の複素環を形成し、
Ｒ３およびＲ４が、一緒になって＝Ｏまたは＝Ｓを形成し、
Ｘが、単結合またはメチレンであり、
Ｙが、酸素原子または硫黄原子であり、
Ｚが、酸素原子または硫黄原子であり、
Ｒが、置換されていてもよいＣ１－６アルキル基（好ましくは、ハロゲン原子およびＣ１－６アルコキシ基からなる群から選択される１～４個の置換基で置換されていてもよい）であり、かつ
環Ａが、水酸基、ハロゲン原子、Ｃ１－６アルキル基およびＣ１－６アルコキシ基からなる群から選択される１～２個の置換基で置換されていてもよい６ないし７員の含窒素複素環（当該２個のＣ１－６アルキル基が結合してビシクロ環を形成してもよい）である、
化合物またはその薬学的に許容される塩。 [Compound D]
a is CH,
b and c are the same or different and are CH or CR 5 (fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, propyl group, methoxy group or trifluoromethyl group);
d is CH,
R 1 and R 2 are the same or different and are each a hydrogen atom, an optionally substituted C 1-6 alkyl group, a halogen atom or a C 3-7 cycloalkyl group, or R 1 and R 2 are Bonded together, R 1 and R 2 together with adjacent carbon atoms form a C 3-7 cycloalkane or a 3-7 membered heterocycle;
R 3 and R 4 together form ═O or ═S;
X is a single bond or methylene,
Y is an oxygen atom or a sulfur atom,
Z is an oxygen atom or a sulfur atom,
R is an optionally substituted C 1-6 alkyl group (preferably optionally substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group) And ring A may be substituted with 1 to 2 substituents selected from the group consisting of a hydroxyl group, a halogen atom, a C 1-6 alkyl group and a C 1-6 alkoxy group. A membered nitrogen-containing heterocyclic ring (the two C 1-6 alkyl groups may be combined to form a bicyclo ring),
A compound or a pharmaceutically acceptable salt thereof.
［化合物Ｅ］
ａが、ＣＨであり、
ｂおよびｃが、同一または異なって、ＣＨまたはＣＲ５（フッ素原子、塩素原子、臭素原子、メチル基、エチル基、プロピル基、メトキシ基またはトリフルオロメチル基である。）であり、
ｄが、ＣＨであり、
Ｒ１およびＲ２が、同一または異なって、それぞれ水素原子、フッ素原子、水酸基、または置換されていてもよいＣ１－６アルキル基（特に水酸基で置換されていてもよいＣ１－３アルキル基）であるか、あるいはＲ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともにテトラヒドロピラン環を形成し、
Ｒ３およびＲ４が、一緒になって＝Ｏを形成し、
Ｘが、単結合であり、
Ｙが、酸素原子であり、
Ｚが、酸素原子であり、
Ｒが、置換されていてもよい直鎖のＣ１－６アルキル基（好ましくは、ハロゲン原子およびＣ１－６アルコキシ基からなる群から選択される１～４個の置換基で置換されていてもよい）であり、かつ
環Ａが、下記式（２） [Compound E]
a is CH,
b and c are the same or different and are CH or CR 5 (fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, propyl group, methoxy group or trifluoromethyl group);
d is CH,
R 1 and R 2 are the same or different and each represents a hydrogen atom, a fluorine atom, a hydroxyl group, or an optionally substituted C 1-6 alkyl group (particularly a C 1-3 alkyl group optionally substituted with a hydroxyl group). Or R 1 and R 2 are bonded together to form a tetrahydropyran ring with R 1 and R 2 together with adjacent carbon atoms;
R 3 and R 4 together form ═O,
X is a single bond,
Y is an oxygen atom,
Z is an oxygen atom,
R is an optionally substituted linear C 1-6 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group). And ring A is represented by the following formula (2):
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
で示される含窒素複素環であり、
Ｒ８が水素原子、水酸基、ハロゲン原子、Ｃ１－６アルキル基またはＣ１－６アルコキシ基である、
化合物またはその薬学的に許容される塩。 A nitrogen-containing heterocycle represented by
R 8 is a hydrogen atom, a hydroxyl group, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group,
A compound or a pharmaceutically acceptable salt thereof.
［化合物Ｆ］
ａが、ＣＨであり、
ｂが、ＣＨであり、
ｃが、ＣＲ５（フッ素原子、塩素原子、臭素原子、メチル基、エチル基、プロピル基、メトキシ基またはトリフルオロメチル基である。）であり、
ｄが、ＣＨであり、
Ｒ１およびＲ２が、同一または異なって、それぞれ水素原子、フッ素原子、水酸基、または置換されていてもよいＣ１－６アルキル基（特に水酸基で置換されていてもよいＣ１－３アルキル基）であるか、あるいはＲ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともにテトラヒドロピラン環を形成し、
Ｒ３およびＲ４が、一緒になって＝Ｏを形成し、
Ｘが、単結合であり、
Ｙが、酸素原子であり、
Ｚが、酸素原子であり、
Ｒが、置換されていてもよい直鎖のＣ１－３アルキル基（好ましくは、ハロゲン原子およびＣ１－６アルコキシ基からなる群から選択される１～４個の置換基で置換されていてもよい）（好ましくは、直鎖のＣ１－３アルキル基）であり、かつ
環Ａが、下記式（２） [Compound F]
a is CH,
b is CH,
c is CR 5 (fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, propyl group, methoxy group or trifluoromethyl group);
d is CH,
R 1 and R 2 are the same or different and each represents a hydrogen atom, a fluorine atom, a hydroxyl group, or an optionally substituted C 1-6 alkyl group (particularly a C 1-3 alkyl group optionally substituted with a hydroxyl group). Or R 1 and R 2 are bonded together to form a tetrahydropyran ring with R 1 and R 2 together with adjacent carbon atoms;
R 3 and R 4 together form ═O,
X is a single bond,
Y is an oxygen atom,
Z is an oxygen atom,
R is an optionally substituted linear C 1-3 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group). (Preferably a straight-chain C 1-3 alkyl group), and ring A is represented by the following formula (2):
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
で示される含窒素複素環であり、
Ｒ８が水素原子、水酸基、フッ素原子、メチル基、エチル基、メトキシ基である、
化合物またはその薬学的に許容される塩。 A nitrogen-containing heterocycle represented by
R 8 is a hydrogen atom, a hydroxyl group, a fluorine atom, a methyl group, an ethyl group, or a methoxy group,
A compound or a pharmaceutically acceptable salt thereof.
［化合物Ｇ］
ａが、ＣＨであり、
ｂが、ＣＲ５（フッ素原子、塩素原子、臭素原子、メチル基、エチル基、プロピル基、メトキシ基またはトリフルオロメチル基である。）であり、
ｃが、ＣＨであり、
ｄが、ＣＨであり、
Ｒ１およびＲ２が、同一または異なって、それぞれ水素原子、フッ素原子、水酸基、または置換されていてもよいＣ１－６アルキル基（特に水酸基で置換されていてもよいＣ１－３アルキル基）であるか、あるいはＲ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともにテトラヒドロピラン環を形成し、
Ｒ３およびＲ４が、一緒になって＝Ｏを形成し、
Ｘが、単結合であり、
Ｙが、酸素原子であり、
Ｚが、酸素原子であり、
Ｒが、置換されていてもよい直鎖のＣ１－３アルキル基（好ましくは、ハロゲン原子およびＣ１－６アルコキシ基からなる群から選択される１～４個の置換基で置換されていてもよい。）（好ましくは、直鎖のＣ１－３アルキル基）であり、かつ
環Ａが、下記式（２） [Compound G]
a is CH,
b is CR 5 (fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, propyl group, methoxy group, or trifluoromethyl group);
c is CH,
d is CH,
R 1 and R 2 are the same or different and each represents a hydrogen atom, a fluorine atom, a hydroxyl group, or an optionally substituted C 1-6 alkyl group (particularly a C 1-3 alkyl group optionally substituted with a hydroxyl group). Or R 1 and R 2 are bonded together to form a tetrahydropyran ring with R 1 and R 2 together with adjacent carbon atoms;
R 3 and R 4 together form ═O,
X is a single bond,
Y is an oxygen atom,
Z is an oxygen atom,
R is an optionally substituted linear C 1-3 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group). (Preferably a straight-chain C 1-3 alkyl group), and ring A is represented by the following formula (2):
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
で示される含窒素複素環であり、
Ｒ８が水素原子、水酸基、フッ素原子、メチル基、エチル基、メトキシ基である、
化合物またはその薬学的に許容される塩。 A nitrogen-containing heterocycle represented by
R 8 is a hydrogen atom, a hydroxyl group, a fluorine atom, a methyl group, an ethyl group, or a methoxy group,
A compound or a pharmaceutically acceptable salt thereof.
［化合物Ｈ］
ａが、ＣＨであり、
ｂおよびｃが、同一または異なって、ＣＨまたはＣＲ５（フッ素原子、塩素原子、臭素原子、メチル基、エチル基、プロピル基、メトキシ基またはトリフルオロメチル基である。）であり、
ｄが、ＣＨであり、
Ｒ１およびＲ２が、同一または異なって、それぞれ水素原子、フッ素原子、水酸基、または置換されていてもよいＣ１－６アルキル基（特に水酸基で置換されていてもよいＣ１－３アルキル基）であるか、あるいはＲ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともにテトラヒドロピラン環を形成し、
Ｒ３およびＲ４が、一緒になって＝Ｏを形成し、
Ｘが、メチレンであり、
Ｙが、酸素原子であり、
Ｚが、酸素原子であり、
Ｒが、置換されていてもよい直鎖のＣ１－６アルキル基（好ましくは、ハロゲン原子およびＣ１－６アルコキシ基からなる群から選択される１～４個の置換基で置換されていてもよい。）であり、かつ
環Ａが、下記式（２） [Compound H]
a is CH,
b and c are the same or different and are CH or CR 5 (fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, propyl group, methoxy group or trifluoromethyl group);
d is CH,
R 1 and R 2 are the same or different and each represents a hydrogen atom, a fluorine atom, a hydroxyl group, or an optionally substituted C 1-6 alkyl group (particularly a C 1-3 alkyl group optionally substituted with a hydroxyl group). Or R 1 and R 2 are bonded together to form a tetrahydropyran ring with R 1 and R 2 together with adjacent carbon atoms;
R 3 and R 4 together form ═O,
X is methylene,
Y is an oxygen atom,
Z is an oxygen atom,
R is an optionally substituted linear C 1-6 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group). And ring A is represented by the following formula (2):
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
で示される含窒素複素環であり、
Ｒ８が水素原子、水酸基、ハロゲン原子、Ｃ１－６アルキル基またはＣ１－６アルコキシ基である、
化合物またはその薬学的に許容される塩。 A nitrogen-containing heterocycle represented by
R 8 is a hydrogen atom, a hydroxyl group, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group,
A compound or a pharmaceutically acceptable salt thereof.
［化合物Ｉ］
ａが、ＣＨであり、
ｂおよびｃが、同一または異なって、ＣＨまたはＣＲ５（フッ素原子、塩素原子、臭素原子、メチル基、エチル基、プロピル基、メトキシ基またはトリフルオロメチル基である。）であり、
ｄが、ＣＨであり、
Ｒ１およびＲ２が、同一または異なって、それぞれ水素原子、フッ素原子、水酸基、または置換されていてもよいＣ１－６アルキル基（特に水酸基で置換されていてもよいＣ１－３アルキル基）であるか、あるいはＲ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともにテトラヒドロピラン環を形成し、
Ｒ３およびＲ４が、一緒になって＝Ｏを形成し、
Ｘが、単結合であり、
Ｙが、酸素原子であり、
Ｚが、酸素原子であり、
Ｒが、置換されていてもよい直鎖のＣ１－６アルキル基（好ましくは、ハロゲン原子およびＣ１－６アルコキシ基からなる群から選択される１～４個の置換基で置換されていてもよい。）であり、かつ
環Ａが、下記式（３） [Compound I]
a is CH,
b and c are the same or different and are CH or CR 5 (fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, propyl group, methoxy group or trifluoromethyl group);
d is CH,
R 1 and R 2 are the same or different and each represents a hydrogen atom, a fluorine atom, a hydroxyl group, or an optionally substituted C 1-6 alkyl group (particularly a C 1-3 alkyl group optionally substituted with a hydroxyl group). Or R 1 and R 2 are bonded together to form a tetrahydropyran ring with R 1 and R 2 together with adjacent carbon atoms;
R 3 and R 4 together form ═O,
X is a single bond,
Y is an oxygen atom,
Z is an oxygen atom,
R is an optionally substituted linear C 1-6 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group). And ring A is represented by the following formula (3):
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
で示される含窒素複素環である、
化合物またはその薬学的に許容される塩。 A nitrogen-containing heterocyclic ring represented by
A compound or a pharmaceutically acceptable salt thereof.
［化合物Ｊ］
ａが、ＣＨであり、
ｂおよびｃが、同一または異なって、ＣＨまたはＣＲ５（フッ素原子、塩素原子、臭素原子、メチル基、エチル基、プロピル基、メトキシ基またはトリフルオロメチル基である。）であり、
ｄが、ＣＨであり、
Ｒ１およびＲ２が、同一または異なって、それぞれ水素原子、フッ素原子、水酸基、または置換されていてもよいＣ１－６アルキル基（特に水酸基で置換されていてもよいＣ１－３アルキル基）であるか、あるいはＲ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともにテトラヒドロピラン環を形成し、
Ｒ３およびＲ４が、一緒になって＝Ｏを形成し、
Ｘが、単結合であり、
Ｙが、酸素原子であり、
Ｚが、酸素原子であり、
Ｒが、置換されていてもよい直鎖のＣ１－６アルキル基（好ましくは、ハロゲン原子およびＣ１－６アルコキシ基からなる群から選択される１～４個の置換基で置換されていてもよい。）であり、かつ
環Ａが、下記式（４） [Compound J]
a is CH,
b and c are the same or different and are CH or CR 5 (fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, propyl group, methoxy group or trifluoromethyl group);
d is CH,
R 1 and R 2 are the same or different and each represents a hydrogen atom, a fluorine atom, a hydroxyl group, or an optionally substituted C 1-6 alkyl group (particularly a C 1-3 alkyl group optionally substituted with a hydroxyl group). Or R 1 and R 2 are bonded together to form a tetrahydropyran ring with R 1 and R 2 together with adjacent carbon atoms;
R 3 and R 4 together form ═O,
X is a single bond,
Y is an oxygen atom,
Z is an oxygen atom,
R is an optionally substituted linear C 1-6 alkyl group (preferably substituted with 1 to 4 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group). And ring A is represented by the following formula (4):
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
で示される含窒素複素環である、
化合物またはその薬学的に許容される塩。 A nitrogen-containing heterocyclic ring represented by
A compound or a pharmaceutically acceptable salt thereof.
　本発明の化合物としては、
４－［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（３，３－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（３，３－ジエチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（３－エチル－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（３，３－ジプロピル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－｛４－［２’－オキソスピロ（シクロプロパン－１，３’－インドール）－１’（２’Ｈ）－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－｛４－［２’－オキソスピロ（シクロブタン－１，３’－インドール）－１’（２’Ｈ）－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－｛４－［２’－オキソスピロ（シクロペンタン－１，３’－インドール）－１’（２’Ｈ）－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－｛４－［２’－オキソスピロ（シクロヘキサン－１，３’－インドール）－１’（２’Ｈ）－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－｛４－［２’－オキソスピロ（テトラヒドロピラン－４，３’－インドール）－１’（２’Ｈ）－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－［４－（３，３－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］メチルピペリジン－１－カルボン酸エチル；
４－｛４－［２’－オキソスピロ（シクロプロパン－１，３’－インドール）－１’（２’Ｈ）－イル］ピペリジン－１－イル｝メチルピペリジン－１－カルボン酸エチル；
３－［４－（３，３－ジエチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
４－［４－（３，３－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸メチル；
４－［４－（３，３－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸イソプロピル；
４－［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（６－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（６－フルオロ－３，３－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（５－クロロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（５－フルオロ－３，３－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－（｛３－［１－（エトキシカルボニル）ピペリジン－４－イリデン］－６－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝ピペリジン－１－イル）ピペリジン－１－カルボン酸エチル；
４－（｛３－［１－（エトキシカルボニル）ピペリジン－４－イル］－６－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝ピペリジン－１－イル）ピペリジン－１－カルボン酸エチル；
１－エチルチオカルボニル－４－［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン；
４－［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸　２－フルオロエチル；
４－［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸　２－プロペニル；
４－［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸　２－メトキシエチル；
４－［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸ブチル；
１－メチルチオカルボニル－４－［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン；
４－［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸プロピル；
４－［４－（５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（３，３－ジメチル－２－オキソ－２，３－ジヒドロ－５－フルオロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（３，３－ジメチル－２－チオキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（５－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－[４－（５－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル]ピペリジン－１－カルボン酸エチル；
４－[４－（５－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル]アゼパン－１－カルボン酸エチル；
３０：４－｛４－［３，３－ビス（３－メトキシプロピル）－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝アゼパン－１－カルボン酸エチル；
４－｛４－［５－フルオロ－３，３－ビス（ヒドロキシメチル）－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－［４－（５－ブロモ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（５－ブロモ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（５－クロロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（５－クロロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸メチル；
４－［４－（５－フルオロ－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（５－フルオロ－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（５’－クロロ－２’－オキソスピロ－［シクロプロパン－１，３’－インドール］－１’（２’Ｈ）－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（５’－クロロ－２’－オキソスピロ－［シクロプロパン－１，３’－インドール］－１’（２’Ｈ）－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸メチル；
４－［４－（５’－クロロ－２’－オキソスピロ－［シクロプロパン－１，３’－インドール］－１’（２’Ｈ）－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（５’－フルオロ－２’－オキソスピロ－［シクロプロパン－１，３’－インドール］－１’（２’Ｈ）－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（５’－フルオロ－２’－オキソスピロ－［シクロプロパン－１，３’－インドール］－１’（２’Ｈ）－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸メチル；
４－［４－（５’－フルオロ－２’－オキソスピロ－［シクロプロパン－１，３’－インドール］－１’（２’Ｈ）－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（５－メチル－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（５－メチル－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（５’－メチル－２’－オキソスピロ－［シクロプロパン－１，３’－インドール］－１’（２’Ｈ）－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（５’－メチル－２’－オキソスピロ－［シクロプロパン－１，３’－インドール］－１’（２’Ｈ）－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（３，３，６－トリメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（３，３，６－トリメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸メチル；
４－［４－（３，３，６－トリメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（６’－メチル－２’－オキソスピロ－［シクロプロパン－１，３’－インドール］－１’（２’Ｈ）－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（６’－メチル－２’－オキソスピロ－［シクロプロパン－１，３’－インドール］－１’（２’Ｈ）－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸メチル；
４－［４－（６’－メチル－２’－オキソスピロ－［シクロプロパン－１，３’－インドール］－１’（２’Ｈ）－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（６－メチル－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（６－メチル－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（６－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（６－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸メチル；
４－［４－（６－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
（１Ｒ，５Ｓ）－３－［４－（６－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
４－｛［４－（６－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］メチル｝ピペリジン－１－カルボン酸エチル；
４－［４－（６－メトキシ－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（６－メトキシ－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
（１Ｒ，５Ｓ）－３－［４－（６－メトキシ－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
４－［４－（５－クロロ－６－フルオロ－３，３－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（３，６－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（３，６－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸メチル；
４－［４－（３，６－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（５－フルオロ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－｛［４－（５－フルオロ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］メチル｝ピペリジン－１－カルボン酸エチル；
４－｛［４－（３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］メチル｝ピペリジン－１－カルボン酸エチル；
４－［４－（５－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－｛［４－（５－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］メチル｝ピペリジン－１－カルボン酸エチル；
４－｛［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］メチル｝ピペリジン－１－カルボン酸エチル；
４－［４－（６－フルオロ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（６－フルオロ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸メチル；
４－［４－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸メチル；
４－［４－（６－ブロモ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（６－ブロモ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（６－ブロモ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸メチル；
４－［４－（６－エチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（６－エチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（２－オキソ－６－プロピル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－｛［４－（５－クロロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］メチル｝ピペリジン－１－カルボン酸エチル；
（１Ｒ，５Ｓ）－３－［４－（５－クロロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
４－｛［４－（５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］メチル｝ピペリジン－１－カルボン酸エチル；
（１Ｒ，５Ｓ）－３－［４－（５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
４－［４－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－｛［４－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］メチル｝ピペリジン－１－カルボン酸エチル；
４－｛［４－（６－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］メチル｝ピペリジン－１－カルボン酸エチル；
４－［４－（６－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（５－フルオロ－３，３－ジメチル－２－チオキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（６－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－４－メチルピペリジン－１－カルボン酸エチル；
４－［４－（６－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－４－メチルピペリジン－１－カルボン酸エチル；
４－［４－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－４－メチルピペリジン－１－カルボン酸エチル；
４－［４－（６－メトキシ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－４－メチルピペリジン－１－カルボン酸エチル；
（３－ｅｎｄｏ）－３－［４－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
（３－ｅｘｏ）－３－［４－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
（３－ｅｎｄｏ）－３－［４－（６－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
（３－ｅｘｏ）－３－［４－（６－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
（３－ｅｎｄｏ）－３－［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
（３－ｅｘｏ）－３－［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
（３－ｅｎｄｏ）－３－［４－（３，６－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
（３－ｅｎｄｏ）－３－［４－（６－フルオロ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
（３－ｅｎｄｏ）－３－［４－（５－フルオロ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
４－｛４－［５－フルオロ－２－オキソ－３－（プロパン－２－イリデン）－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－｛４－［５－フルオロ－２－オキソ－３－（プロパン－２－イル）－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝アゼパン－１－カルボン酸エチル；
４－｛４－［（３Ｚ）－３－エチリデン－５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝アゼパン－１－カルボン酸エチル；
４－［４－（３－エチル－５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－｛４－［（３Ｚ）－５－フルオロ－３－（２－メチルプロピリデン）－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－｛４－［５－フルオロ－３－（２－メチルプロピル）－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－［４－（３－シクロペンチル－５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－｛４－［（３Ｚ）－５－フルオロ－２－オキソ－３－プロピリデン－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝アゼパン－１－カルボン酸エチル；
４－［４－（５－フルオロ－２－オキソ－３－プロピル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－｛４－［５－フルオロ－２－オキソ－３－（テトラヒドロ－２Ｈ－ピラン－４－イル）－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－｛４－［（３Ｚ）－５－クロロ－３－エチリデン－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－｛４－［５－フルオロ－３－（オキセタン－３－イル）－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－｛４－［５－フルオロ－２－オキソ－３ー（テトラヒドロフラン－３－イル）－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－｛４－［３－（オキセタン－３－イル）－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－｛４－［３－（アゼチジン－３－イル）－５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－｛４－［５－フルオロ－３－（オキセタン－３－イル）－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸メチル；
４－［４－（３－シクロブチル－５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（３－エチル－６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸メチル；
４－｛４－［６－メチル－２－オキソ－３－（プロパン－２－イル）－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸メチル；
４－｛４－［５－フルオロ－２－オキソ－３－（プロパン－２－イル）－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸メチル；
４－［４－（３－エチル－５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－｛４－［２－オキソ－３－（プロパン－２－イル）－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－［４－（３－シクロブチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（３－シクロペンチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（２－オキソ－３－プロピル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－｛４－［２－オキソ－３－（テトラヒドロ－２Ｈ－ピラン－４－イル）－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－｛４－［２－オキソ－３－（ペンタン－３－イル）－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－｛４－［２－オキソ－３－（テトラヒドロフラン－３－イルメチル）－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－｛４－［３－（シクロプロピルメチル）－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－［４－（３－エチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（３－エチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－｛４－［３－（１，３－オキサゾール－２－イルメチル）－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－｛４－［２－オキソ－３－（プロパン－２－イル）－２，３－ジヒドロ－１Ｈ－インドール－１－イル］アゼパン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－［４－（２－オキソ－３－プロピル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－｛４－［２－オキソ－３－（テトラヒドロフラン－３－イル）－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝アゼパン－１－カルボン酸エチル；
４－｛４－［３－（ヘプタン－４－イル）－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝アゼパン－１－カルボン酸エチル；
４－｛４－［２－オキソ－３－（テトラヒドロ－２Ｈ－ピラン－４－イル）－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝アゼパン－１－カルボン酸エチル；
４－｛４－［２－オキソ－３－（ペンタン－３－イル）－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝アゼパン－１－カルボン酸エチル；
４－｛４－［２－オキソ－３－（テトラヒドロフラン－３－イル）－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－［４－（３－ブチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－｛４－［３－（フラン－３－イルメチル）－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－｛４－［３－（ヒドロキシメチル）－６－メトキシ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－｛４－［３－（ヒドロキシメチル）－３，６－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－｛４－［５－フルオロ－３－（ヒドロキシメチル）－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝アゼパン－１－カルボン酸エチル；
４－｛４－［３－（ヒドロキシメチル）－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝メチルピペリジン－１－カルボン酸エチル；
４－｛４－［５－フルオロ－３－（ヒドロキシメチル）－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝メチルピペリジン－１－カルボン酸エチル；
４－｛４－［６－フルオロ－３－（ヒドロキシメチル）－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－｛４－［６－フルオロ－３－（ヒドロキシメチル）－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝アゼパン－１－カルボン酸エチル；
４－｛４－［３－（ヒドロキシメチル）－３，６－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－｛４－［３－（ヒドロキシメチル）－３，６－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝アゼパン－１－カルボン酸エチル；
４－｛４－［３－（ヒドロキシメチル）－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
（３－ｅｎｄｏ）－３－｛４－［６－フルオロ－３－（ヒドロキシメチル）－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
（３－ｅｎｄｏ）－３－｛４－［３－（ヒドロキシメチル）－３，６－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
４－｛４－［３－エチル－３－（ヒドロキシメチル）－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－［４－（３－エチル－３，６－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（６－フルオロ－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］メチルピペリジン－１－カルボン酸エチル；
４－［４－（６－メチル－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］メチルピペリジン－１－カルボン酸エチル；
（３－ｅｎｄｏ）－３－［４－（６－メチル－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
（３－ｅｘｏ）－３－［４－（６－フルオロ－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
４－［４－（３－ヒドロキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸ブチル－２－イン；
４－［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸２－ブロモエチル；
４－［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸２－クロロエチル；
４－［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸２－プロピル；
４－［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸メチル；
４－［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸メチル；
４－［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸プロピル－２－イン；
４－［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸ブチル－２－イル；
４－［４－（６－クロロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸２－フルオロエチル；
４－［４－（５－クロロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸２－プロピル；
４－［４－（５－クロロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸プロピル－２－エン；
４－［４－（５－クロロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸２－メトキシエタン；
４－［４－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸プロピル－２－エン；
４－［４－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸２－フルオロエチル；
４－［４－（５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸２－メトキシエタン；
４－［４－（５－クロロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸メチル；
４－［４－（３，３－ジフルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
（１Ｒ，５Ｓ）－３－［４－（３，３－ジフルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
４－［４－（３，３－ジフルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
（１Ｒ，５Ｓ）－３－｛４－［３－（ヒドロキシメチル）－６－メトキシ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
４－｛４－［３－（ヒドロキシメチル）－６－メトキシ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝アゼパン－１－カルボン酸エチル；
４－｛４－［５－フルオロ－３－（ヒドロキシメチル）－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－［４－（６－フルオロ－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（６－フルオロ－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（３，６－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（６－フルオロ－３メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（６－フルオロ－３メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－４－メチルアゼパン－１－カルボン酸エチル；
４－［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－４－メチルピペリジン－１－カルボン酸エチル；
４－［４－（５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－４－メチルピペリジン－１－カルボン酸エチル；
４－［４－（５－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－４－メチルピペリジン－１－カルボン酸エチル；
４－［４－（５－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－４－メチルピペリジン－１－カルボン酸エチル；
（１Ｒ，５Ｓ）－３－｛４－［５－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
（１Ｒ，５Ｓ）－３－｛４－［５－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
４－［４－（３－ヒドロキシ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－４－メチルピペリジン－１－カルボン酸エチル；
４－［４－（３－ヒドロキシ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－４－メチルピペリジン－１－カルボン酸メチル；
４－［４－（３－フルオロ－３－ヒドロキシメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－４－メチルピペリジン－１－カルボン酸エチル；および
４－［４－（３－フルオロ－３－ヒドロキシメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－４－メチルピペリジン－１－カルボン酸メチル；
等が好ましい。 As the compound of the present invention,
4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (3-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
Ethyl 4- [4- (3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
Ethyl 4- [4- (3,3-diethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (3-Ethyl-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (3,3-dipropyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- {4- [2′-oxospiro (cyclopropane-1,3′-indole) -1 ′ (2′H) -yl] piperidin-1-yl} piperidine-1-carboxylate;
4- {4- [2′-oxospiro (cyclobutane-1,3′-indole) -1 ′ (2′H) -yl] piperidin-1-yl} piperidine-1-carboxylate;
4- {4- [2′-oxospiro (cyclopentane-1,3′-indole) -1 ′ (2′H) -yl] piperidin-1-yl} piperidine-1-carboxylate;
4- {4- [2′-oxospiro (cyclohexane-1,3′-indole) -1 ′ (2′H) -yl] piperidin-1-yl} piperidine-1-carboxylate;
4- {4- [2′-oxospiro (tetrahydropyran-4,3′-indole) -1 ′ (2′H) -yl] piperidin-1-yl} piperidine-1-carboxylate;
Ethyl 4- [4- (3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] methylpiperidine-1-carboxylate;
4- {4- [2′-oxospiro (cyclopropane-1,3′-indole) -1 ′ (2′H) -yl] piperidin-1-yl} methylpiperidine-1-carboxylate;
3- [4- (3,3-Diethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2.1] octane-8 -Ethyl carboxylate;
Methyl 4- [4- (3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] ethyl azepane-1-carboxylate;
4- [4- (6-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (6-Fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (5-Chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
Ethyl 4- [4- (5-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (5-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4-({3- [1- (ethoxycarbonyl) piperidin-4-ylidene] -6-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl} piperidin-1-yl) piperidine- 1-ethyl carboxylate;
4-({3- [1- (ethoxycarbonyl) piperidin-4-yl] -6-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl} piperidin-1-yl) piperidine- 1-ethyl carboxylate;
1-ethylthiocarbonyl-4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine;
4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylic acid 2-fluoroethyl;
4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylic acid 2-propenyl;
4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylic acid 2-methoxyethyl;
4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
1-methylthiocarbonyl-4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine;
4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (5-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate;
Ethyl 4- [4- (3,3-dimethyl-2-oxo-2,3-dihydro-5-fluoro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate;
Ethyl 4- [4- (3,3-dimethyl-2-thioxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
Ethyl 4- [4- (5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (6-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
Ethyl 4- [4- (5-methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
Ethyl 4- [4- (5-methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepan-1-carboxylate;
30: 4- {4- [3,3-bis (3-methoxypropyl) -2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} azepan-1-carboxylic acid ethyl;
4- {4- [5-Fluoro-3,3-bis (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylic acid ethyl;
4- [4- (5-Bromo-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (5-Bromo-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate;
4- [4- (5-Chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate;
4- [4- (5-Chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (5-Fluoro-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) -yl) piperidine-1- Yl] piperidine-1-carboxylate;
4- [4- (5-Fluoro-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) -yl) piperidine-1- Yl] azepan-1-ethyl carboxylate;
4- [4- (5′-Chloro-2′-oxospiro- [cyclopropane-1,3′-indole] -1 ′ (2′H) -yl) piperidin-1-yl] piperidine-1-carboxylic acid ethyl;
4- [4- (5′-Chloro-2′-oxospiro- [cyclopropane-1,3′-indole] -1 ′ (2′H) -yl) piperidin-1-yl] piperidine-1-carboxylic acid Methyl;
4- [4- (5′-Chloro-2′-oxospiro- [cyclopropane-1,3′-indole] -1 ′ (2′H) -yl) piperidin-1-yl] azepan-1-carboxylic acid ethyl;
4- [4- (5′-Fluoro-2′-oxospiro- [cyclopropane-1,3′-indole] -1 ′ (2′H) -yl) piperidin-1-yl] piperidine-1-carboxylic acid ethyl;
4- [4- (5′-Fluoro-2′-oxospiro- [cyclopropane-1,3′-indole] -1 ′ (2′H) -yl) piperidin-1-yl] piperidine-1-carboxylic acid Methyl;
4- [4- (5′-Fluoro-2′-oxospiro- [cyclopropane-1,3′-indole] -1 ′ (2′H) -yl) piperidin-1-yl] azepan-1-carboxylic acid ethyl;
4- [4- (5-Methyl-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) -yl) piperidine-1- Yl] piperidine-1-carboxylate;
4- [4- (5-Methyl-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) -yl) piperidine-1- Yl] azepan-1-ethyl carboxylate;
4- [4- (5′-Methyl-2′-oxospiro- [cyclopropane-1,3′-indole] -1 ′ (2′H) -yl) piperidin-1-yl] piperidine-1-carboxylic acid ethyl;
4- [4- (5′-Methyl-2′-oxospiro- [cyclopropane-1,3′-indole] -1 ′ (2′H) -yl) piperidin-1-yl] azepan-1-carboxylic acid ethyl;
4- [4- (3,3,6-trimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (3,3,6-trimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
Ethyl 4- [4- (3,3,6-trimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate;
4- [4- (6′-Methyl-2′-oxospiro- [cyclopropane-1,3′-indole] -1 ′ (2′H) -yl) piperidin-1-yl] piperidine-1-carboxylic acid ethyl;
4- [4- (6′-Methyl-2′-oxospiro- [cyclopropane-1,3′-indole] -1 ′ (2′H) -yl) piperidin-1-yl] piperidine-1-carboxylic acid Methyl;
4- [4- (6′-Methyl-2′-oxospiro- [cyclopropane-1,3′-indole] -1 ′ (2′H) -yl) piperidin-1-yl] azepan-1-carboxylic acid ethyl;
4- [4- (6-Methyl-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) -yl) piperidine-1- Yl] piperidine-1-carboxylate;
4- [4- (6-Methyl-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) -yl) piperidine-1- Yl] azepan-1-ethyl carboxylate;
4- [4- (6-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate;
Ethyl 4- [4- (6-methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (6-Methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
Ethyl 4- [4- (6-methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate;
(1R, 5S) -3- [4- (6-Methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2.1 ] Ethyl octane-8-carboxylate;
4-{[4- (6-methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
4- [4- (6-Methoxy-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) -yl) piperidine-1- Yl] piperidine-1-carboxylate;
4- [4- (6-Methoxy-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) -yl) piperidine-1- Yl] azepan-1-ethyl carboxylate;
(1R, 5S) -3- [4- (6-Methoxy-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) — Yl) piperidin-1-yl] -8-azabicyclo [3.2.1] octane-8-carboxylate;
4- [4- (5-Chloro-6-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylic acid ethyl;
4- [4- (3,6-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
Methyl 4- [4- (3,6-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
Ethyl 4- [4- (3,6-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate;
Ethyl 4- [4- (5-fluoro-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate;
4-{[4- (5-Fluoro-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] methyl} piperidine-1-carboxylate;
4-{[4- (3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] methyl} piperidine-1-carboxylate;
4- [4- (5-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate;
4-{[4- (5-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] methyl} piperidine-1-carboxylate;
4-{[4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] methyl} piperidine-1-carboxylate;
4- [4- (6-Fluoro-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (6-Fluoro-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate;
4- [4- (5-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (6-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (6-Bromo-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (6-Bromo-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate;
4- [4- (6-Bromo-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (6-Ethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (6-Ethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate;
Ethyl 4- [4- (2-oxo-6-propyl-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4-{[4- (5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] methyl} piperidine-1-carboxylate;
(1R, 5S) -3- [4- (5-Chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2.1 ] Ethyl octane-8-carboxylate;
4-{[4- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] methyl} piperidine-1-carboxylate;
(1R, 5S) -3- [4- (5-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2.1 ] Ethyl octane-8-carboxylate;
4- [4- (6-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate;
4-{[4- (6-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
4-{[4- (6-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] methyl} piperidine-1-carboxylate;
Ethyl 4- [4- (6-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate;
4- [4- (5-Fluoro-3,3-dimethyl-2-thioxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
Ethyl 4- [4- (6-methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-methylpiperidine-1-carboxylate;
4- [4- (6-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-methylpiperidine-1-carboxylate;
Ethyl 4- [4- (6-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-methylpiperidine-1-carboxylate;
4- [4- (6-Methoxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-methylpiperidine-1-carboxylate;
(3-endo) -3- [4- (6-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2.1 ] Ethyl octane-8-carboxylate;
(3-exo) -3- [4- (6-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2.1 ] Ethyl octane-8-carboxylate;
(3-endo) -3- [4- (6-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2.1 ] Ethyl octane-8-carboxylate;
(3-exo) -3- [4- (6-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2.1 ] Ethyl octane-8-carboxylate;
(3-endo) -3- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2.1] octane-8 -Ethyl carboxylate;
(3-exo) -3- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2.1] octane-8 -Ethyl carboxylate;
(3-endo) -3- [4- (3,6-Dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2 .1] ethyl octane-8-carboxylate;
(3-endo) -3- [4- (6-Fluoro-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3 2.1] ethyl octane-8-carboxylate;
(3-endo) -3- [4- (5-Fluoro-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3 2.1] ethyl octane-8-carboxylate;
4- {4- [5-Fluoro-2-oxo-3- (propane-2-ylidene) -2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylic acid ethyl;
4- {4- [5-Fluoro-2-oxo-3- (propan-2-yl) -2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} azepan-1-carboxylic acid ethyl;
4- {4-[(3Z) -3-ethylidene-5-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} azepane-1-carboxylate;
Ethyl 4- [4- (3-ethyl-5-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- {4-[(3Z) -5-fluoro-3- (2-methylpropylidene) -2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine- 1-ethyl carboxylate;
4- {4- [5-Fluoro-3- (2-methylpropyl) -2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylate ethyl ;
4- [4- (3-Cyclopentyl-5-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- {4-[(3Z) -5-fluoro-2-oxo-3-propylidene-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} azepane-1-carboxylate;
4- [4- (5-Fluoro-2-oxo-3-propyl-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- {4- [5-Fluoro-2-oxo-3- (tetrahydro-2H-pyran-4-yl) -2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine- 1-ethyl carboxylate;
4- {4-[(3Z) -5-chloro-3-ethylidene-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylate;
4- {4- [5-Fluoro-3- (oxetane-3-yl) -2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylic acid ethyl;
4- {4- [5-Fluoro-2-oxo-3- (tetrahydrofuran-3-yl) -2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylic acid ethyl;
4- {4- [3- (oxetane-3-yl) -2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylate;
4- {4- [3- (azetidin-3-yl) -5-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylic acid ethyl;
4- {4- [5-Fluoro-3- (oxetane-3-yl) -2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylic acid Methyl;
4- [4- (3-cyclobutyl-5-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (3-Ethyl-6-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- {4- [6-Methyl-2-oxo-3- (propan-2-yl) -2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylic acid Methyl;
4- {4- [5-Fluoro-2-oxo-3- (propan-2-yl) -2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylic acid Methyl;
Ethyl 4- [4- (3-ethyl-5-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- {4- [2-oxo-3- (propan-2-yl) -2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylate;
4- [4- (3-cyclobutyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (3-Cyclopentyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
Ethyl 4- [4- (2-oxo-3-propyl-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- {4- [2-oxo-3- (tetrahydro-2H-pyran-4-yl) -2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylic acid ethyl;
4- {4- [2-oxo-3- (pentan-3-yl) -2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylate;
4- {4- [2-oxo-3- (tetrahydrofuran-3-ylmethyl) -2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylate;
4- {4- [3- (cyclopropylmethyl) -2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylate;
4- [4- (3-Ethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (3-Ethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate;
4- {4- [3- (1,3-oxazol-2-ylmethyl) -2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylic acid ethyl;
4- {4- [2-oxo-3- (propan-2-yl) -2,3-dihydro-1H-indol-1-yl] azepan-1-yl} piperidine-1-carboxylate;
4- [4- (2-oxo-3-propyl-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate;
4- {4- [2-oxo-3- (tetrahydrofuran-3-yl) -2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} azepane-1-carboxylate;
4- {4- [3- (heptan-4-yl) -2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} azepane-1-carboxylate;
4- {4- [2-oxo-3- (tetrahydro-2H-pyran-4-yl) -2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} azepan-1-carboxylic acid ethyl;
4- {4- [2-oxo-3- (pentan-3-yl) -2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} azepane-1-carboxylate;
4- {4- [2-oxo-3- (tetrahydrofuran-3-yl) -2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylate;
4- [4- (3-Butyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- {4- [3- (furan-3-ylmethyl) -2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylate;
4- {4- [3- (hydroxymethyl) -6-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carvone Ethyl acid;
4- {4- [3- (Hydroxymethyl) -3,6-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylate ;
4- {4- [5-Fluoro-3- (hydroxymethyl) -3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} azepan-1-carvone Ethyl acid;
Ethyl 4- {4- [3- (hydroxymethyl) -3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} methylpiperidine-1-carboxylate;
4- {4- [5-Fluoro-3- (hydroxymethyl) -3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} methylpiperidine-1- Ethyl carboxylate;
4- {4- [6-Fluoro-3- (hydroxymethyl) -3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carvone Ethyl acid;
4- {4- [6-Fluoro-3- (hydroxymethyl) -3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} azepan-1-carvone Ethyl acid;
4- {4- [3- (Hydroxymethyl) -3,6-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylate ;
4- {4- [3- (hydroxymethyl) -3,6-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} azepan-1-carboxylate ethyl ;
4- {4- [3- (hydroxymethyl) -3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylate;
(3-endo) -3- {4- [6-Fluoro-3- (hydroxymethyl) -3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl } -8-Azabicyclo [3.2.1] octane-8-carboxylate;
(3-endo) -3- {4- [3- (hydroxymethyl) -3,6-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl}- Ethyl 8-azabicyclo [3.2.1] octane-8-carboxylate;
4-ethyl 4- {4- [3-ethyl-3- (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylate;
4- [4- (3-Ethyl-3,6-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (6-Fluoro-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) -yl) piperidine-1- Yl] methyl piperidine-1-carboxylate;
4- [4- (6-Methyl-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) -yl) piperidine-1- Yl] methyl piperidine-1-carboxylate;
(3-endo) -3- [4- (6-Methyl-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) — Yl) piperidin-1-yl] -8-azabicyclo [3.2.1] octane-8-carboxylate;
(3-exo) -3- [4- (6-Fluoro-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) — Yl) piperidin-1-yl] -8-azabicyclo [3.2.1] octane-8-carboxylate;
4- [4- (3-hydroxy-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate butyl-2-yne;
4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate 2-bromoethyl;
4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate 2-chloroethyl;
4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate 2-propyl;
Methyl 4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] ethyl azepane-1-carboxylate;
4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate methyl;
4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepan-1-propyl-2-carboxylate;
4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepan-1-butyl-2-carboxylate;
4- [4- (6-Chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate 2-fluoroethyl;
4- [4- (5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate; 2-propyl;
4- [4- (5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidin-1-carboxylic acid propyl-2-ene;
4- [4- (5-chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylic acid 2-methoxyethane;
4- [4- (6-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidin-1-carboxylic acid propyl-2-ene;
4- [4- (6-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate 2-fluoroethyl;
4- [4- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylic acid 2-methoxyethane;
4- [4- (5-Chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate methyl;
4- [4- (3,3-difluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
(1R, 5S) -3- [4- (3,3-Difluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2 .1] ethyl octane-8-carboxylate;
4- [4- (3,3-difluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate;
(1R, 5S) -3- {4- [3- (Hydroxymethyl) -6-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl } -8-Azabicyclo [3.2.1] octane-8-carboxylate;
4- {4- [3- (hydroxymethyl) -6-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} azepan-1-carvone Ethyl acid;
4- {4- [5-Fluoro-3- (hydroxymethyl) -3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carvone Ethyl acid;
4- [4- (6-Fluoro-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) -yl) piperidine-1- Yl] azepan-1-ethyl carboxylate;
4- [4- (6-Fluoro-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) -yl) piperidine-1- Yl] piperidine-1-carboxylate;
Ethyl 4- [4- (3,6-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate;
4- [4- (6-Fluoro-3methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (6-Fluoro-3methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate;
4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-ethyl methylazepan-1-carboxylate;
Ethyl 4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-methylpiperidine-1-carboxylate;
Ethyl 4- [4- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-methylpiperidine-1-carboxylate;
Ethyl 4- [4- (5-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-methylpiperidine-1-carboxylate;
4- [4- (5-methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-methylpiperidine-1-carboxylate;
(1R, 5S) -3- {4- [5-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} -8-azabicyclo [3.2.1 ] Ethyl octane-8-carboxylate;
(1R, 5S) -3- {4- [5-Methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} -8-azabicyclo [3.2.1 ] Ethyl octane-8-carboxylate;
Ethyl 4- [4- (3-hydroxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-methylpiperidine-1-carboxylate;
4- [4- (3-Hydroxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-methylpiperidine-1-carboxylate;
4- [4- (3-Fluoro-3-hydroxymethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-methylpiperidine-1-carboxylate ethyl ;and
4- [4- (3-Fluoro-3-hydroxymethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-methylpiperidine-1-carboxylate methyl ;
Etc. are preferable.
　また、４－｛４－［２’－オキソスピロ（シクロヘキサン－１，３’－インドール）－１’（２’Ｈ）－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（５－クロロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（５－メチル－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（５－メチル－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（６－メチル－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（６－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（６－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
（１Ｒ，５Ｓ）－３－［４－（６－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
４－［４－（６－メトキシ－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－｛［４－（５－フルオロ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］メチル｝ピペリジン－１－カルボン酸エチル；
４－｛［４－（３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］メチル｝ピペリジン－１－カルボン酸エチル；
４－｛［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］メチル｝ピペリジン－１－カルボン酸エチル；
４－［４－（６－フルオロ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－［４－（６－エチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
４－｛［４－（５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］メチル｝ピペリジン－１－カルボン酸エチル；
４－｛［４－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］メチル｝ピペリジン－１－カルボン酸エチル；
４－［４－（６－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－４－メチルピペリジン－１－カルボン酸エチル；
４－［４－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－４－メチルピペリジン－１－カルボン酸エチル；
（３－ｅｎｄｏ）－３－［４－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
３－ｅｘｏ）－３－［４－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
３－ｅｎｄｏ）－３－［４－（６－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
（３－ｅｘｏ）－３－［４－（６－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
（３－ｅｎｄｏ）－３－［４－（３，６－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
４－｛４－［３－（ヒドロキシメチル）－６－メトキシ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
４－｛４－［３－（ヒドロキシメチル）－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
（３－ｅｎｄｏ）－３－［４－（６－メチル－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
４－［４－（３，３－ジフルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
（１Ｒ，５Ｓ）－３－［４－（３，３－ジフルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
４－［４－（３，３－ジフルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
４－［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－４－メチルアゼパン－１－カルボン酸エチル；
４－［４－（３－ヒドロキシ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－４－メチルピペリジン－１－カルボン酸エチル；および
４－［４－（３－フルオロ－３－ヒドロキシメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－４－メチルピペリジン－１－カルボン酸エチル；
等がより好ましい。 And 4- {4- [2′-oxospiro (cyclohexane-1,3′-indole) -1 ′ (2′H) -yl] piperidin-1-yl} piperidine-1-carboxylate;
4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] ethyl azepane-1-carboxylate;
4- [4- (5-Chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (5-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (5-Methyl-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) -yl) piperidine-1- Yl] piperidine-1-carboxylate;
4- [4- (5-Methyl-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) -yl) piperidine-1- Yl] azepan-1-ethyl carboxylate;
4- [4- (6-Methyl-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) -yl) piperidine-1- Yl] piperidine-1-carboxylate;
Ethyl 4- [4- (6-methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate;
Ethyl 4- [4- (6-methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
(1R, 5S) -3- [4- (6-Methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2.1 ] Ethyl octane-8-carboxylate;
4- [4- (6-Methoxy-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) -yl) piperidine-1- Yl] piperidine-1-carboxylate;
4-{[4- (5-Fluoro-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] methyl} piperidine-1-carboxylate;
4-{[4- (3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] methyl} piperidine-1-carboxylate;
4-{[4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] methyl} piperidine-1-carboxylate;
4- [4- (6-Fluoro-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4- [4- (6-Ethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
4-{[4- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] methyl} piperidine-1-carboxylate;
4-{[4- (6-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
Ethyl 4- [4- (6-methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-methylpiperidine-1-carboxylate;
Ethyl 4- [4- (6-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-methylpiperidine-1-carboxylate;
(3-endo) -3- [4- (6-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2.1 ] Ethyl octane-8-carboxylate;
3-exo) -3- [4- (6-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2.1] Ethyl octane-8-carboxylate;
3-endo) -3- [4- (6-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2.1] Ethyl octane-8-carboxylate;
(3-exo) -3- [4- (6-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2.1 ] Ethyl octane-8-carboxylate;
(3-endo) -3- [4- (3,6-Dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2 .1] ethyl octane-8-carboxylate;
4- {4- [3- (hydroxymethyl) -6-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carvone Ethyl acid;
4- {4- [3- (hydroxymethyl) -3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylate;
(3-endo) -3- [4- (6-Methyl-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) — Yl) piperidin-1-yl] -8-azabicyclo [3.2.1] octane-8-carboxylate;
4- [4- (3,3-difluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
(1R, 5S) -3- [4- (3,3-Difluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2 .1] ethyl octane-8-carboxylate;
4- [4- (3,3-difluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate;
4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-ethyl methylazepan-1-carboxylate;
Ethyl 4- [4- (3-hydroxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-methylpiperidine-1-carboxylate; And 4- [4- (3-Fluoro-3-hydroxymethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-methylpiperidine-1-carboxylic acid ethyl;
Etc. are more preferable.
　次に本発明の化合物の製造法について以下に説明する。一般式（１）で示される本発明の化合物は以下の製法により製造することができる。
製法１：下記式（５） Next, a method for producing the compound of the present invention will be described below. The compound of the present invention represented by the general formula (1) can be produced by the following production method.
Manufacturing method 1: following formula (5)
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
の化合物またはその塩と下記式（６） Or a salt thereof and the following formula (6)
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
または下記式（７） Or the following formula (7)
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
で示される化合物を反応させることからなる前記式（１）の化合物を製造する方法。 A method for producing a compound of the above formula (1), which comprises reacting a compound represented by the formula:
　式（５）の化合物またはその塩と入手可能な式（６）の化合物または式（７）の化合物との反応は、水素化ホウ素ナトリウム、シアノ水素化ホウ素ナトリウム、トリアセトキシボラン酸ナトリウム、ピリジンボラン、２－ピコリンボランなどの汎用される還元的アミノ化試薬を用いて行うことができる。 Reaction of a compound of formula (5) or a salt thereof with an available compound of formula (6) or a compound of formula (7) comprises sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborate, pyridine borane , 2-picoline borane and other commonly used reductive amination reagents can be used.
　式（５）の化合物またはその塩と式（６）の化合物または式（７）の化合物との反応は無溶媒または適当な溶媒中で行われる。使用する溶媒はジクロロメタン、テトラヒドロフラン、ジメトキシエタン、ジエチルエーテル、ジメチルホルムアミド、メタノール、エタノール、酢酸エチルなどが挙げられ、これらの反応は単独または２種以上を混合して用いられる。本反応は必要に応じて酸または塩基の存在下で行われ、例えば酸としては酢酸、塩基としてはトリエチルアミン、ジイソプロピルエチルアミンなどが挙げられる。また必要に応じてチタンテトライソプロポキシドなどの縮合剤を併用することができる。また、反応温度は通常－７８℃から１００℃である。 The reaction of the compound of formula (5) or a salt thereof with the compound of formula (6) or the compound of formula (7) is carried out without solvent or in a suitable solvent. Examples of the solvent to be used include dichloromethane, tetrahydrofuran, dimethoxyethane, diethyl ether, dimethylformamide, methanol, ethanol, ethyl acetate and the like, and these reactions are used alone or in combination of two or more. This reaction is performed in the presence of an acid or a base, if necessary. Examples of the acid include acetic acid, examples of the base include triethylamine, and diisopropylethylamine. Moreover, condensing agents, such as titanium tetraisopropoxide, can be used together as needed. The reaction temperature is usually -78 ° C to 100 ° C.
　前記式（５）の化合物またはその塩は下記スキーム１に従って合成することができる（Ｒ３およびＲ４が一緒になって＝Ｏを形成する式（１－４）の化合物）。 The compound of the formula (5) or a salt thereof can be synthesized according to the following scheme 1 (the compound of the formula (1-4) in which R 3 and R 4 are combined to form ═O).
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
（式中、Ｐｒｏｔはアミノ基の保護基を表し、その他の記号は前記と同義である。）
　アミノ基の保護基の具体例としては、例えばｔｅｒｔ－ブトキシカルボニル基、ベンジルオキシカルボニル基などのアミノ基とカルバメート類を形成する基や、ベンジル基やトリチル基などのアミノ基とベンジルアミン類を形成する基などが挙げられる。 (In the formula, Prot represents an amino-protecting group, and other symbols are as defined above.)
Specific examples of amino-protecting groups include groups that form carbamates with amino groups such as tert-butoxycarbonyl and benzyloxycarbonyl groups, and amino groups and benzylamines such as benzyl and trityl groups. And the like.
工程１：
　式（１－２）の化合物は式（１－１）の化合物のアミノ基の保護基を常法に従って脱保護することで製造することができる。 Step 1:
The compound of formula (1-2) can be produced by deprotecting the amino-protecting group of the compound of formula (1-1) according to a conventional method.
工程２：
　式（１－３）の化合物は式（１－１）の化合物とＲ１およびＲ２に対応するハロゲン化剤またはアルキル化剤等を塩基存在下、不活性溶媒中で反応させることで製造することができる。塩基としては、例えば水素化ナトリウム、水素化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、トリエチルアミン、ジイソプロピルエチルアミン、ナトリウムメトキシド、ナトリウムエトキシド、カリウムｔｅｒｔ－ブトキシド、リチウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジド等が挙げられる。不活性溶媒としては、例えばテトラヒドロフラン、ジオキサン、ベンゼン、トルエン、キシレン、ジメチルホルムアミド、ジメチルスルホキシド、クロロホルム、ジクロロメタン、ジクロロエタン等が挙げられ、これらを２種以上混合して用いることもできる。反応温度は通常－７８℃から１４０℃で行われ、好ましくは－７８℃から１００℃である。 Step 2:
The compound of formula (1-3) is produced by reacting the compound of formula (1-1) with a halogenating agent or alkylating agent corresponding to R 1 and R 2 in the presence of a base in an inert solvent. be able to. Examples of the base include sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, sodium methoxide, sodium ethoxide, potassium tert-butoxide, lithium hexamethyldisilazide, potassium hexamethyl. And disilazide. Examples of the inert solvent include tetrahydrofuran, dioxane, benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, dichloroethane, and the like, and these can be used in combination. The reaction temperature is usually −78 ° C. to 140 ° C., preferably −78 ° C. to 100 ° C.
工程３：
　本工程は本スキームの工程１と同様の方法によって行われる。 Step 3:
This step is carried out by the same method as in step 1 of this scheme.
　前記式（１－１）の化合物またはその塩は下記スキーム２、３、４または５に従って合成することができる。 The compound of the formula (1-1) or a salt thereof can be synthesized according to the following scheme 2, 3, 4 or 5.
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
（式中、Ｒ’はＣ１－６アルキル基を表し、その他の記号は前記と同義である。） (In the formula, R ′ represents a C 1-6 alkyl group, and other symbols are as defined above.)
工程１：
　式（２－２）の化合物は入手可能な式（２－１）の化合物を水素化ナトリウムや炭酸セシウムなどの塩基存在下でアルキルハライドと反応させることで製造することができる。使用する溶媒としては、例えばジメチルホルムアミド、テトラヒドロフラン、ジクロロメタンなどが挙げられ、単独または２種以上を混合して用いられる。反応は通常－４０℃から４０℃で行われ、好ましくは－１０℃から１０℃である。 Step 1:
The compound of formula (2-2) can be produced by reacting an available compound of formula (2-1) with an alkyl halide in the presence of a base such as sodium hydride or cesium carbonate. Examples of the solvent to be used include dimethylformamide, tetrahydrofuran, dichloromethane and the like, and they are used alone or in combination of two or more. The reaction is usually carried out at -40 ° C to 40 ° C, preferably -10 ° C to 10 ° C.
工程２：
　式（２－３）の化合物は式（２－２）の化合物を水素雰囲気下パラジウムなどの金属触媒を用いて接触還元することで製造することができる。使用する溶媒としては、例えばテトラヒドロフラン、エタノール、メタノール、酢酸、酢酸エチル、ジクロロメタンなどが挙げられ、単独または２種以上を混合して用いられる。 Step 2:
The compound of formula (2-3) can be produced by catalytic reduction of the compound of formula (2-2) using a metal catalyst such as palladium in a hydrogen atmosphere. Examples of the solvent to be used include tetrahydrofuran, ethanol, methanol, acetic acid, ethyl acetate, dichloromethane, and the like.
工程３：
　式（１－１）の化合物は式（２－３）の化合物を入手可能な式（２－４）の化合物と反応させることで製造することができる。該反応は上述する還元的アミノ化の条件に準じて行うことができる。試薬としては、例えば水素化ホウ素ナトリウム、シアノ水素化ホウ素ナトリウム、トリアセトキシボラン酸ナトリウム、ピリジンボラン、２－ピコリンボランなどの汎用される試薬が挙げられる。使用する溶媒としては、例えばトルエン、ジクロロメタン、テトラヒドロフラン、ジメトキシエタン、ジエチルエーテル、ジメチルホルムアミド、メタノール、エタノール、酢酸エチルなどが挙げられ、単独または２種以上を混合して用いられる。本反応は必要に応じて酸または塩基の存在下で行われ、酸としては、例えば酢酸、塩基としては、例えばトリエチルアミン、ジイソプロピルエチルアミンなどが挙げられる。また必要に応じてチタンテトライソプロポキシドなどの縮合剤を併用することができる。また、反応温度は通常－２０℃から１００℃で、好ましくは０℃から８０℃である。 Step 3:
A compound of formula (1-1) can be prepared by reacting a compound of formula (2-3) with an available compound of formula (2-4). This reaction can be performed according to the reductive amination conditions described above. Examples of the reagent include commonly used reagents such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborate, pyridine borane, 2-picoline borane. Examples of the solvent to be used include toluene, dichloromethane, tetrahydrofuran, dimethoxyethane, diethyl ether, dimethylformamide, methanol, ethanol, ethyl acetate, and the like. This reaction is performed in the presence of an acid or a base as necessary. Examples of the acid include acetic acid, and examples of the base include triethylamine and diisopropylethylamine. Moreover, condensing agents, such as titanium tetraisopropoxide, can be used together as needed. The reaction temperature is usually −20 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
（式中、Ｘ１はハロゲン原子を表し、その他の記号は前記と同義である。） (Wherein X 1 represents a halogen atom, and other symbols are as defined above.)
工程１：
　式（３－２）の化合物は入手可能な式（３－１）の２－ハロゲン化ニトロアリールを水素化ナトリウムや炭酸セシウムなどの塩基存在下でマロン酸ジエステルと反応させることで製造することができる。使用する溶媒としては、例えばジメチルホルムアミド、テトラヒドロフラン、アセトニトリル、ジクロロメタンなどが挙げられ、単独または２種以上を混合して用いられる。反応は通常－２０℃から１５０℃で行われ、好ましくは０℃から１００℃である。 Step 1:
The compound of formula (3-2) can be produced by reacting the available 2-halogenated nitroaryl of formula (3-1) with a malonic acid diester in the presence of a base such as sodium hydride or cesium carbonate. it can. Examples of the solvent to be used include dimethylformamide, tetrahydrofuran, acetonitrile, dichloromethane and the like, and they are used alone or in combination of two or more. The reaction is usually performed at −20 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.
工程２：
　式（３－３）の化合物は式（３－２）の化合物を水素雰囲気下パラジウムやロジウム等の金属触媒を用いて接触還元することで製造することができる。使用する溶媒としては、例えばテトラヒドロフラン、エタノール、メタノール、酢酸、酢酸エチル、ジクロロメタンなどが挙げられ、単独または２種以上を混合して用いられる。 Step 2:
The compound of formula (3-3) can be produced by catalytic reduction of the compound of formula (3-2) using a metal catalyst such as palladium or rhodium in a hydrogen atmosphere. Examples of the solvent to be used include tetrahydrofuran, ethanol, methanol, acetic acid, ethyl acetate, dichloromethane, and the like.
工程３：
　本工程はスキーム２記載の工程３と同様の方法によって行われる。 Step 3:
This step is performed in the same manner as in Step 3 described in Scheme 2.
工程４：
　式（１－１）の化合物は式（３－４）の化合物を酸存在下で加熱攪拌することで製造することができる。酸としては塩酸、硫酸、りん酸、ｐ－トルエンスルホン酸、４－エチルベンゼンスルホン酸などが挙げられ、好ましくはｐ－トルエンスルホン酸、４－エチルベンゼンスルホン酸などが挙げられる。溶媒としては、例えばジメチルホルムアミド、テトラヒドロフラン、ジクロロメタン、ベンゼン、トルエン、キシレンなどが挙げられ、好ましくはベンゼン、トルエンが挙げられる。またこれらを２種以上混合して用いることもできる。反応は通常０℃から２００℃で行われ、好ましくは７０℃から１４０℃である。 Step 4:
The compound of formula (1-1) can be produced by heating and stirring the compound of formula (3-4) in the presence of an acid. Examples of the acid include hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, 4-ethylbenzenesulfonic acid and the like, preferably p-toluenesulfonic acid, 4-ethylbenzenesulfonic acid and the like. Examples of the solvent include dimethylformamide, tetrahydrofuran, dichloromethane, benzene, toluene, xylene and the like, preferably benzene and toluene. Two or more of these may be mixed and used. The reaction is usually carried out at 0 ° C. to 200 ° C., preferably 70 ° C. to 140 ° C.
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
（式中、Ｘ２はハロゲン原子を表し、その他の記号は前記と同義である。） (Wherein X 2 represents a halogen atom, and other symbols are as defined above.)
　式（４－１）の化合物は入手可能な２－ハロゲン化酢酸を塩化チオニルや二塩化オキサリルなどの塩素化剤と反応させることで製造することができる。使用する溶媒としては、例えばジメチルホルムアミド、テトラヒドロフラン、クロロホルム、ジクロロメタンなどが挙げられ、単独または２種以上を混合して用いられる。 The compound of the formula (4-1) can be produced by reacting an available 2-halogenated acetic acid with a chlorinating agent such as thionyl chloride or oxalyl dichloride. Examples of the solvent to be used include dimethylformamide, tetrahydrofuran, chloroform, dichloromethane and the like, and these may be used alone or in combination of two or more.
工程１：
　式（４－３）の化合物は式（４－１）の化合物と入手可能な式（４－２）の化合物を塩基存在下で反応させることで製造することができる。塩基としては、例えば水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、トリエチルアミン、ジイソプロピルエチルアミンなどが挙げられる。溶媒としては、例えばジメチルホルムアミド、テトラヒドロフラン、アセトニトリル、ベンゼン、トルエン、ジクロロメタンなどが挙げられ、好ましくはジメチルホルムアミド、アセトニトリル、ジクロロメタンなどが挙げられる。またこれらを２種以上混合して用いることもできる。反応は通常－２０℃から１２０℃で行われ、好ましくは０℃から７０℃である。 Step 1:
The compound of formula (4-3) can be produced by reacting the compound of formula (4-1) with an available compound of formula (4-2) in the presence of a base. Examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine and the like. Examples of the solvent include dimethylformamide, tetrahydrofuran, acetonitrile, benzene, toluene, dichloromethane and the like, and preferably dimethylformamide, acetonitrile, dichloromethane and the like. Two or more of these may be mixed and used. The reaction is usually carried out at −20 ° C. to 120 ° C., preferably 0 ° C. to 70 ° C.
工程２：
　式（１－１）の化合物は式（４－３）の化合物をパラジウムなどの金属触媒存在下反応させることで製造することができる。すなわちTetrahedron Lett., 45, 8535-8537 (2004)等記載の方法あるいはそれに準じた方法によって製造することができる。 Step 2:
The compound of formula (1-1) can be produced by reacting the compound of formula (4-3) in the presence of a metal catalyst such as palladium. That is, it can be produced by the method described in Tetrahedron Lett., 45, 8535-8537 (2004) or the like or a method analogous thereto.
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
（式中の各記号は前記と同義である。） (Each symbol in the formula is as defined above.)
工程１：
　式（５－２）の化合物は入手可能な式（５－１）のアニリン誘導体と式（２－４）の化合物をスキーム２記載の工程３と同様の方法で反応せることで製造することができる。 Step 1:
The compound of formula (5-2) can be produced by reacting an available aniline derivative of formula (5-1) with a compound of formula (2-4) in the same manner as in Step 3 described in Scheme 2. it can.
工程２：
　式（５－３）の化合物は式（５－２）の化合物とクロロアセチルクロリドを塩基存在下で反応させることにより製造することができる。塩基としては、例えば水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、トリエチルアミン、ジイソプロピルエチルアミン、ピリジンなどが挙げられる。溶媒としては、例えばジメチルホルムアミド、テトラヒドロフラン、アセトニトリル、酢酸エチル、ベンゼン、トルエン、キシレン、クロロホルム、ジクロロメタンなどが挙げられ、これらを２種以上混合して用いることもできる。反応は通常－２０℃から１４０℃で行われ、好ましくは２０℃から１００℃である。 Step 2:
The compound of formula (5-3) can be produced by reacting the compound of formula (5-2) with chloroacetyl chloride in the presence of a base. Examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, pyridine and the like. Examples of the solvent include dimethylformamide, tetrahydrofuran, acetonitrile, ethyl acetate, benzene, toluene, xylene, chloroform, dichloromethane, and the like, and two or more of these can be used in combination. The reaction is usually carried out at −20 ° C. to 140 ° C., preferably 20 ° C. to 100 ° C.
工程３：
　式（１－１）の化合物は式（５－３）の化合物をルイス酸存在下、不活性溶媒中、もしくは無溶媒中で反応させることで製造することができる。ルイス酸としては塩化亜鉛、塩化アルミニウムなどが挙げられる。不活性溶媒としては、例えばベンゼン、トルエン、キシレン、クロロベンゼン、クロロホルム、ジクロロメタン、ジメチルホルムアミド、ジメチルスルホキシドなどが挙げられ、これらを２種以上混合して用いることもできる。反応は通常－２０℃から２２０℃で行われ、好ましくは２０℃から２００℃である。 Step 3:
The compound of formula (1-1) can be produced by reacting the compound of formula (5-3) in the presence of a Lewis acid in an inert solvent or in the absence of a solvent. Examples of Lewis acids include zinc chloride and aluminum chloride. Examples of the inert solvent include benzene, toluene, xylene, chlorobenzene, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide, and the like, and two or more of these can be used in combination. The reaction is usually carried out at -20 ° C to 220 ° C, preferably 20 ° C to 200 ° C.
　前記式（３）の化合物またはその塩は下記スキーム６に従って合成することができる（Ｒ３およびＲ４が一緒になって＝Ｓを形成する式（６－１）の化合物）。 The compound of the formula (3) or a salt thereof can be synthesized according to the following scheme 6 (the compound of the formula (6-1) in which R 3 and R 4 together form ═S).
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
（式中の各記号は前記と同義である。） (Each symbol in the formula is as defined above.)
工程１：
　式（６－１）の化合物は式（１－４）の化合物をチオアミド化することで製造することができる。使用するチオアミド化の試薬としては、例えばLawesson試薬、五硫化リンなどが挙げられる。この反応は無溶媒または適当な溶媒中で行われる。使用する溶媒としては、例えばクロロホルム、ジクロロメタン、トルエン、ベンゼン、キシレンなどが挙げられ、これらを２種以上混合して用いることも出来る。 Step 1:
The compound of formula (6-1) can be produced by thioamidation of the compound of formula (1-4). Examples of the thioamidation reagent to be used include Lawesson's reagent and phosphorus pentasulfide. This reaction is carried out without solvent or in a suitable solvent. Examples of the solvent to be used include chloroform, dichloromethane, toluene, benzene, xylene, and the like, and two or more of these can be mixed and used.
　前記式（７）の化合物は入手可能な下記式（８） The compound of the formula (7) is available in the following formula (8)
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
の化合物を公知の方法、例えば新実験化学講座１５巻（丸善、１９７８年）等に記載されている方法あるいはそれに準じた方法で酸化することによって製造することができる。 Can be produced by oxidation by a known method, for example, the method described in New Experimental Chemistry Course Vol. 15 (Maruzen, 1978) or the like.
製法２：下記式（９） Manufacturing method 2: following formula (9)
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
の化合物とＲ１およびＲ２に対応するアルキル化剤等を塩基存在下、不活性溶媒中で反応させることからなる前記式（１）の化合物を製造する方法。 A method for producing a compound of the above formula (1), which comprises reacting a compound of the above and an alkylating agent corresponding to R 1 and R 2 in the presence of a base in an inert solvent.
　塩基としては、例えば水素化ナトリウム、水素化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、トリエチルアミン、ジイソプロピルエチルアミン、ナトリウムメトキシド、ｔｅｒｔ－ブトキシカリウム等が挙げられる。不活性溶媒としては、例えばテトラヒドロフラン、ジオキサン、ベンゼン、トルエン、キシレン、ジメチルホルムアミド、ジメチルスルホキシド、クロロホルム、ジクロロメタン、ジクロロエタン等が挙げられ、これらを２種以上混合して用いることもできる。反応は通常－２０℃から１４０℃で行われ、好ましくは２０℃から１００℃である。 Examples of the base include sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, sodium methoxide, tert-butoxypotassium and the like. Examples of the inert solvent include tetrahydrofuran, dioxane, benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, dichloroethane, and the like, and these can be used in combination. The reaction is usually carried out at −20 ° C. to 140 ° C., preferably 20 ° C. to 100 ° C.
製法３：下記スキーム７ Production Method 3: Scheme 7 below
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
（式中の記号は前記と同義である。） (The symbols in the formula are as defined above.)
に従って、前記式（１）を製造する方法。 According to the method of manufacturing the formula (1).
工程１：
　式（７－３）の化合物は、製法１、スキーム３記載の工程１および工程２の方法により合成される式（７－１）の化合物を式（７－２）の化合物と反応させることで製造することができる。該反応は製法１、スキーム２記載の工程３と同様の方法によって行われる。
工程２：
　式（７－４）の化合物は、式（７－３）の化合物と、Ｒ１に対応するアルキル化剤を、塩基存在下、不活性溶媒中で反応させることで製造することができる。 Step 1:
The compound of formula (7-3) is obtained by reacting the compound of formula (7-1) synthesized by the method of step 1 and step 2 described in production method 1, scheme 3 with the compound of formula (7-2). Can be manufactured. The reaction is carried out in the same manner as in Production method 1, step 3 described in scheme 2.
Step 2:
A compound of formula (7-4) can be produced by reacting a compound of formula (7-3) with an alkylating agent corresponding to R 1 in the presence of a base in an inert solvent.
　塩基としては、例えば、水素化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、トリエチルアミン、ジイソプロピルエチルアミン、リチウムヘキサメチルジシラザン、ナトリウムヘキサメチルジシラザンなどが挙げられる。不活性溶媒としては、例えば、ジメチルホルムアミド、テトラヒドロフラン、アセトニトリル、ベンゼン、トルエン、ジクロロメタンなどが挙げられる。これらは２種以上混合して用いても良い。反応は通常－２０℃から１２０℃で行われ、好ましくは０℃から１２０℃である。 Examples of the base include sodium hydride, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, lithium hexamethyldisilazane, sodium hexamethyldisilazane, and the like. Examples of the inert solvent include dimethylformamide, tetrahydrofuran, acetonitrile, benzene, toluene, dichloromethane and the like. You may use these in mixture of 2 or more types. The reaction is usually carried out at −20 ° C. to 120 ° C., preferably 0 ° C. to 120 ° C.
工程３：
　本工程は、スキーム３記載の工程４と同様の方法によって行われる。 Step 3:
This step is performed in the same manner as in step 4 described in Scheme 3.
工程４：
　式（１）の化合物は式（７－５）の化合物に対し、Ｒ２に対応するアルキル化剤を、本スキーム記載の工程１と同様の方法で反応させることで製造することが出来る。 Step 4:
The compound of formula (1) can be produced by reacting the compound of formula (7-5) with an alkylating agent corresponding to R 2 in the same manner as in Step 1 described in this scheme.
　下記式（７－２）
Figure JPOXMLDOC01-appb-C000033
 Following formula (7-2)
Figure JPOXMLDOC01-appb-C000033
は下記スキーム８または９に従って合成することができる。 Can be synthesized according to Scheme 8 or 9 below.
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
（式中の記号は前記と同義である。） (The symbols in the formula are as defined above.)
工程１：
　式（８－２）の化合物は、入手可能な式（８－１）の化合物であるＮ－エチル－４－ピペリドンを無溶媒、または適当な溶媒中、アルキルハライドと反応させ、４級アンモニウム塩とすることにより製造することが出来る。アルキルハライドとしては、例えばヨウ化メチル、ヨウ化エチル、臭化メチル、臭化エチル等が挙げられ、好ましくはヨウ化メチルが挙げられる。使用する溶媒としては、例えばアセトン、トルエン、クロロホルム、ジクロロメタン、酢酸エチル、ヘキサン等が挙げられ、これらを２種以上混合して用いることもできる。反応温度は通常－２０℃から１４０℃で行われ、好ましくは０℃から５０℃である。 Step 1:
The compound of formula (8-2) is obtained by reacting N-ethyl-4-piperidone which is an available compound of formula (8-1) with an alkyl halide in the absence of a solvent or in a suitable solvent. Can be manufactured. Examples of the alkyl halide include methyl iodide, ethyl iodide, methyl bromide, and ethyl bromide, and preferably methyl iodide. Examples of the solvent to be used include acetone, toluene, chloroform, dichloromethane, ethyl acetate, hexane, and the like, and two or more of these can be mixed and used. The reaction temperature is usually from −20 ° C. to 140 ° C., preferably 0 ° C. to 50 ° C.
工程２
　式（７－２）の化合物は式（８－２）の化合物と入手可能な式（８－３）のアミンを、適当な溶媒中、塩基存在下反応させることで製造することができる。塩基としては、例えば水素化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウムが挙げられる。使用する溶媒としては、例えば水、エタノール、メタノール、２－プロパノール等が挙げられ、これらを２種以上混合して用いることもできる。反応温度は通常０℃から１４０℃で行われ、好ましくは２０℃から１００℃である。 Process 2
The compound of the formula (7-2) can be produced by reacting the compound of the formula (8-2) with an available amine of the formula (8-3) in a suitable solvent in the presence of a base. Examples of the base include sodium hydride, potassium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate. Examples of the solvent to be used include water, ethanol, methanol, 2-propanol and the like, and two or more kinds thereof can be mixed and used. The reaction temperature is usually 0 to 140 ° C, preferably 20 to 100 ° C.
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
（式中、Ｌは脱離基を表し、その他の記号は前記と同義である。） (In the formula, L represents a leaving group, and other symbols are as defined above.)
工程１：
　式（９－３）の化合物は入手可能な式（９－１）の化合物と、式（９－２）の化合物を、脱離能を有する求核剤と反応させることで製造することができる。求核剤としては、例えばシアン化ナトリウム、シアン化カリウム、トリアゾール、テトラゾール、ジメチルアルミニウムシアニド等が挙げられる。使用する溶媒としては、例えばトルエン、キシレン、テトラヒドロフラン、１，４－ジオキサン、アセトニトリル、ジメトキシエタン等が挙げられ、これらを２種以上混合して用いることもできる。反応温度は通常０℃から２００℃で行われ、好ましくは２０℃から１６０℃である。 Step 1:
The compound of formula (9-3) can be produced by reacting an available compound of formula (9-1) with a compound of formula (9-2) with a nucleophile having an elimination ability. . Examples of the nucleophilic agent include sodium cyanide, potassium cyanide, triazole, tetrazole, dimethylaluminum cyanide and the like. Examples of the solvent to be used include toluene, xylene, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethoxyethane, and the like, and two or more kinds thereof can be mixed and used. The reaction temperature is usually from 0 ° C to 200 ° C, preferably from 20 ° C to 160 ° C.
工程２：
　式（９－４）の化合物は式（９－３）の化合物と、Ｒ８に対応するアルキル化剤を反応させることで製造することができる。アルキル化剤としては、例えば、Ｒ８に対応するアルキルリチウム、アルキルマグネシウムクロリド、アルキルマグネシウムブロミド等が挙げられる。使用する溶媒としては、例えばジメチルホルムアミド、テトラヒドロフラン、１，４－ジオキサン、アセトニトリル、ベンゼン、トルエン、クロロホルム、ジクロロメタンなどが挙げられる。これらは２種以上混合して用いても良い。反応は通常－２０℃から１００℃で行われ、好ましくは０℃から８０℃である。 Step 2:
The compound of the formula (9-4) can be produced by reacting the compound of the formula (9-3) with an alkylating agent corresponding to R 8 . Examples of the alkylating agent include alkyl lithium, alkyl magnesium chloride, alkyl magnesium bromide and the like corresponding to R 8 . Examples of the solvent used include dimethylformamide, tetrahydrofuran, 1,4-dioxane, acetonitrile, benzene, toluene, chloroform, dichloromethane and the like. You may use these in mixture of 2 or more types. The reaction is usually carried out at −20 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
工程３：
　式（９－５）の化合物は式（９－４）の化合物のＢｏｃ基を酸存在下脱保護することで製造することができる。酸としては、トリフルオロ酢酸、塩酸、硫酸等が挙げられる。使用する溶媒としては、テトラヒドロフラン、１，４－ジオキサン、アセトニトリル、ベンゼン、トルエン、クロロホルム、ジクロロメタン等が挙げられる。反応は通常－２０℃から１００℃で行われ、好ましくは０℃から８０℃である。 Step 3:
The compound of formula (9-5) can be produced by deprotecting the Boc group of the compound of formula (9-4) in the presence of an acid. Examples of the acid include trifluoroacetic acid, hydrochloric acid, sulfuric acid and the like. Examples of the solvent to be used include tetrahydrofuran, 1,4-dioxane, acetonitrile, benzene, toluene, chloroform, dichloromethane and the like. The reaction is usually carried out at −20 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
工程４：
　式（９－６）の化合物は式（９－５）の化合物と、塩基存在下Ｙ、ＺおよびＲに対応するカルボニルクロリドもしくはチオカルボニルクロリドを反応させることで製造することができる。塩基としては、例えば水素化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、トリエチルアミン、ジイソプロピルエチルアミン、リチウムヘキサメチルジシラザン、ナトリウムヘキサメチルジシラザンなどが挙げられる。溶媒としては、例えばジメチルホルムアミド、テトラヒドロフラン、アセトニトリル、ベンゼン、トルエン、ジクロロメタンなどが挙げられる。これらは２種以上混合して用いても良い。反応は通常－２０℃から１２０℃で行われ、好ましくは０℃から１２０℃である。 Step 4:
The compound of the formula (9-6) can be produced by reacting the compound of the formula (9-5) with carbonyl chloride or thiocarbonyl chloride corresponding to Y, Z and R in the presence of a base. Examples of the base include sodium hydride, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, diisopropylethylamine, lithium hexamethyldisilazane, sodium hexamethyldisilazane, and the like. Examples of the solvent include dimethylformamide, tetrahydrofuran, acetonitrile, benzene, toluene, dichloromethane and the like. You may use these in mixture of 2 or more types. The reaction is usually carried out at −20 ° C. to 120 ° C., preferably 0 ° C. to 120 ° C.
工程５：
　式（９－７）の化合物は式（９－６）の化合物のアセタール部分を酸存在下脱保護することで製造することができる。酸としては、トリフルオロ酢酸、塩酸、硫酸等が挙げられる。使用する溶媒としては、テトラヒドロフラン、１，４－ジオキサン、アセトニトリル、ベンゼン、トルエン、クロロホルム、ジクロロメタン等が挙げられる。反応は通常－２０℃から１６０℃で行われ、好ましくは０℃から１２０℃である。 Step 5:
The compound of formula (9-7) can be produced by deprotecting the acetal part of the compound of formula (9-6) in the presence of an acid. Examples of the acid include trifluoroacetic acid, hydrochloric acid, sulfuric acid and the like. Examples of the solvent to be used include tetrahydrofuran, 1,4-dioxane, acetonitrile, benzene, toluene, chloroform, dichloromethane and the like. The reaction is usually carried out at -20 ° C to 160 ° C, preferably 0 ° C to 120 ° C.
製法４：下記スキーム１０ Production Method 4: Scheme 10 below
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
（式中の記号は前記と同義である。） (The symbols in the formula are as defined above.)
に従って、前記式（１）を製造する方法。 According to the method of manufacturing the formula (1).
工程１：
　式（１０－２）の化合物は、製法１の方法に従って合成できる式（１－１）の化合物に対し、入手可能な式（１０－１）の化合物を脱水縮合することで製造することができる。 Step 1:
The compound of the formula (10-2) can be produced by dehydrating and condensing the compound of the formula (10-1) that is available to the compound of the formula (1-1) that can be synthesized according to the production method 1. .
　本工程は必要に応じて酸存在下で行われ、酸としては例えば、酢酸、硫酸、塩酸、塩化亜鉛、塩化アルミニウム、塩化チタン、チタニウムテトライソプロポキシドなどが挙げられる。また、無溶媒または適当な溶媒中で行われ、使用する溶媒としては、例えばベンゼン、トルエン、キシレン、クロロホルム、ジクロロメタン、テトラヒドロフラン、ジエチルエーテル、１，４－ジオキサンなどが挙げられ、これらを単独または２種以上混合して用いても良い。反応温度は通常－２０℃から２００℃で行われ、好ましくは２０℃から１４０℃である。 This step is performed in the presence of an acid as necessary. Examples of the acid include acetic acid, sulfuric acid, hydrochloric acid, zinc chloride, aluminum chloride, titanium chloride, titanium tetraisopropoxide and the like. The solvent is used in the absence of a solvent or in a suitable solvent. Examples of the solvent used include benzene, toluene, xylene, chloroform, dichloromethane, tetrahydrofuran, diethyl ether, 1,4-dioxane, and the like. You may mix and use seeds or more. The reaction temperature is usually −20 ° C. to 200 ° C., preferably 20 ° C. to 140 ° C.
工程２：
　式（１０－３）の化合物は、式（１０－２）の化合物に対し、製法１、スキーム１記載の工程１と同様の方法に従ってアミノ基の保護基を脱保護することで製造することができる。 Step 2:
The compound of the formula (10-3) can be produced by deprotecting the amino-protecting group from the compound of the formula (10-2) according to the same method as in Step 1 of Production Method 1 and Scheme 1. it can.
工程３：
　式（１０－４）の化合物は、式（１０－３）の化合物に対し、製法１、スキーム２記載の工程３と同様の方法に従って、還元的アミノ化反応を行うことで製造することができる。 Step 3:
The compound of the formula (10-4) can be produced by subjecting the compound of the formula (10-3) to a reductive amination reaction according to the same method as in Step 3 of Production Method 1 and Scheme 2. .
工程４：
　式（１）の化合物は、式（１０－４）の化合物に対し、水素雰囲気存在下パラジウムやロジウム等の金属触媒を用いて接触還元することで製造することができる。使用する溶媒としては、例えばテトラヒドロフラン、エタノール、メタノール、酢酸、酢酸エチル、クロロホルム、ジクロロメタンなどが挙げられ、これらは単独または２種以上を混合して用いても良い。反応温度は通常０℃から１００℃で行われ、好ましくは２０℃から６０℃である。 Step 4:
The compound of the formula (1) can be produced by catalytic reduction of the compound of the formula (10-4) using a metal catalyst such as palladium or rhodium in the presence of a hydrogen atmosphere. Examples of the solvent to be used include tetrahydrofuran, ethanol, methanol, acetic acid, ethyl acetate, chloroform, dichloromethane, and the like. These may be used alone or in combination of two or more. The reaction temperature is usually 0 to 100 ° C., preferably 20 to 60 ° C.
製法５：下記スキーム１１ Production Method 5: Scheme 11 below
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
（式中の記号は前記と同義である。） (The symbols in the formula are as defined above.)
に従って、前記式（１）を製造する方法。 According to the method of manufacturing the formula (1).
工程１：
　式（１１－２）の化合物は、入手可能な式（１１－１）の化合物であるアニリン誘導体と、式（７－２）の化合物を、製法１、スキーム２記載の工程３と同様の方法に従って、製造することができる。 Step 1:
The compound of the formula (11-2) is obtained by converting an aniline derivative, which is a compound of the formula (11-1), and a compound of the formula (7-2), in the same manner as in Step 3 of Production Method 1 and Scheme 2. Can be manufactured according to
工程２：
　式（１１－３）の化合物は、式（１１－２）の化合物と、二塩化オキサリルを、適当な溶媒中、酸存在下反応させることで製造することができる。酸としては例えば三塩化アルミニウム、三塩化亜鉛、三塩化チタンなどが挙げられる。溶媒としてはベンゼン、トルエン、クロロホルム、ジクロロメタン、ジクロロエタンなどが挙げられ、これらを単独または２種以上混合して用いても良い。反応温度は通常－２０℃から２００℃で行われ、好ましくは０℃から１２０℃である。 Step 2:
The compound of the formula (11-3) can be produced by reacting the compound of the formula (11-2) with oxalyl dichloride in an appropriate solvent in the presence of an acid. Examples of the acid include aluminum trichloride, zinc trichloride, titanium trichloride and the like. Examples of the solvent include benzene, toluene, chloroform, dichloromethane, dichloroethane, and the like. These may be used alone or in combination of two or more. The reaction temperature is usually −20 ° C. to 200 ° C., preferably 0 ° C. to 120 ° C.
工程３：
　式（１）の化合物は、式（１１－３）の化合物に対し、溶媒中、適当な還元剤でカルボニル基を還元することで製造することができる。還元剤としては、例えば水素化ホウ素ナトリウム、水素化ホウ素リチウム、水素化リチウムアルミニウムなどが挙げられる。溶媒としてはメタノール、エタノール、クロロホルム、ジクロロメタン、テトラヒドロフラン、ジエチルエーテルなどが挙げられ、これらを単独または２種以上混合して用いても良い。反応温度は通常－２０℃から１００℃で行われ、好ましくは０℃から８０℃である。 Step 3:
The compound of formula (1) can be produced by reducing the carbonyl group of the compound of formula (11-3) with a suitable reducing agent in a solvent. Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride and the like. Examples of the solvent include methanol, ethanol, chloroform, dichloromethane, tetrahydrofuran, diethyl ether, and the like. These may be used alone or in combination of two or more. The reaction temperature is usually from −20 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
製法６：下記スキーム１２ Production method 6: Scheme 12 below
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
（式中の記号は前記と同義である。） (The symbols in the formula are as defined above.)
に従って、前記式（１）を製造する方法。 According to the method of manufacturing the formula (1).
工程１：
　式（１２－２）の化合物は、市販または当業者にとって公知の方法で合成可能な式（１２－１）の化合物であるインドール誘導体を、インドリンに還元して製造することができる。還元剤としては、インドールをインドリンに還元できるものであれば特に限定されないが、例えばシアノ水素化ホウ素ナトリウムなどを用いることができる。使用しうる溶媒は本反応に使用しうるものであれば特に限定されないが、例えばジクロロメタンやジクロロエタンなどが挙げられる。反応温度は通常－２０℃から１００℃で行われ、好ましくは０℃から８０℃である。 Step 1:
The compound of the formula (12-2) can be produced by reducing an indole derivative which is a compound of the formula (12-1) which is commercially available or can be synthesized by a method known to those skilled in the art to indoline. The reducing agent is not particularly limited as long as it can reduce indole to indoline. For example, sodium cyanoborohydride can be used. The solvent that can be used is not particularly limited as long as it can be used in this reaction, and examples thereof include dichloromethane and dichloroethane. The reaction temperature is usually from −20 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
工程２：
　式（１２－３）の化合物は、式（１２－２）の化合物と、式（１２）の化合物とを還元的アミノ化反応を行なうことで製造することができる。本反応は製法１に記載される条件に従って実施することができる。 Step 2:
The compound of the formula (12-3) can be produced by performing a reductive amination reaction between the compound of the formula (12-2) and the compound of the formula (12). This reaction can be carried out according to the conditions described in Production Method 1.
工程３：
　式（１２－４）の化合物は、式（１２－３）の化合物を溶媒中、適当な酸化剤で酸化することで製造することができる。酸化剤としては、例えば二酸化マンガンなどが挙げられる。溶媒としてはクロロホルム、ジクロロメタンなどが挙げられ、これらを単独または２種以上混合して用いても良い。反応温度は通常－２０℃から１００℃で行われ、好ましくは０℃から８０℃である。 Step 3:
The compound of the formula (12-4) can be produced by oxidizing the compound of the formula (12-3) with a suitable oxidizing agent in a solvent. Examples of the oxidizing agent include manganese dioxide. Examples of the solvent include chloroform and dichloromethane. These may be used alone or in combination of two or more. The reaction temperature is usually from −20 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
工程４：
　式（１）の化合物は、式（１２－４）の化合物を溶媒中、適当な酸化剤で酸化することで製造することができる。酸化剤はアルケンを酸化できる一般的な酸化剤であれば特に限定されないが、例えば２－ヨードキシ安息香酸（ＩＢＸ）が挙げられる。溶媒としてはアセトニトリル、水などが挙げられ、これらを単独または２種以上混合して用いても良い。添加剤として、塩化セリウムなどを用いても良い。反応温度は通常－２０℃から１００℃で行われ、好ましくは０℃から８０℃である。 Step 4:
The compound of formula (1) can be produced by oxidizing the compound of formula (12-4) in a solvent with a suitable oxidizing agent. The oxidizing agent is not particularly limited as long as it is a general oxidizing agent capable of oxidizing alkenes, and examples thereof include 2-iodoxybenzoic acid (IBX). Examples of the solvent include acetonitrile and water, and these may be used alone or in combination of two or more. As an additive, cerium chloride or the like may be used. The reaction temperature is usually from −20 ° C. to 100 ° C., preferably 0 ° C. to 80 ° C.
製法７：下記スキーム１３ Production Method 7: Scheme 13 below
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
（式中の記号は前記と同義である。） (The symbols in the formula are as defined above.)
に従って、前記式（１）を製造する方法。 According to the method of manufacturing the formula (1).
工程１：
　式（１３－２）の化合物は、スキーム７に従って合成可能な式（１３－１）の化合物を、塩基存在下ハロゲン化ギ酸アルキルと反応させて製造することができる。塩基は本反応に用いることが可能なものであれば特に限定されないが、例えばジイソプロピルアミンリチウムアミド（ＬＤＡ）が挙げられる。使用しうる溶媒は、例えばジエチルエーテルやテトラヒドロフランなどが挙げられる。反応温度は通常－８０℃から１００℃で行われ、好ましくは－８０℃から５０℃である。 Step 1:
A compound of formula (13-2) can be produced by reacting a compound of formula (13-1), which can be synthesized according to Scheme 7, with an alkyl halide formate in the presence of a base. The base is not particularly limited as long as it can be used in this reaction, and examples thereof include diisopropylamine lithium amide (LDA). Examples of the solvent that can be used include diethyl ether and tetrahydrofuran. The reaction temperature is usually -80 ° C to 100 ° C, preferably -80 ° C to 50 ° C.
工程２：
　式（１３－３）の化合物は、参考例９３の方法に準じて、式（１３－２）の化合物を塩基存在下一般的なフッ素化剤と反応させて製造することができる。反応条件としては、炭酸カリウム存在下、ＴＨＦ中でＮ－フルオロベンゼンスルホンイミドと０～５０℃で反応させる条件が好適である。 Step 2:
The compound of formula (13-3) can be produced according to the method of Reference Example 93 by reacting the compound of formula (13-2) with a general fluorinating agent in the presence of a base. The reaction conditions are preferably those for reacting with N-fluorobenzenesulfonimide at 0 to 50 ° C. in the presence of potassium carbonate in THF.
工程３：
　式（１）の化合物は、式（１３－３）の化合物を還元することで製造することができる。還元剤としてはエステルのみを還元できるものであれば特に限定されないが、例えば水素化ホウ素リチウムなどが挙げられる。溶媒としてはテトラヒドロフラン、ジエチルエーテル、エタノール、メタノールなどが挙げられ、これらを単独または２種以上混合して用いても良い。反応温度は通常－２０℃から１００℃で行われ、好ましくは０℃から５０℃である。 Step 3:
The compound of the formula (1) can be produced by reducing the compound of the formula (13-3). The reducing agent is not particularly limited as long as it can reduce only the ester, and examples thereof include lithium borohydride. Examples of the solvent include tetrahydrofuran, diethyl ether, ethanol, methanol and the like, and these may be used alone or in combination of two or more. The reaction temperature is usually from −20 ° C. to 100 ° C., preferably 0 ° C. to 50 ° C.
　上記で示す製造方法で得られた式（１）の化合物は、抽出、カラムクロマトグラフィー、再結晶、再沈殿のような常法に従って単離・精製される。抽出溶媒としては、例えばジエチルエーテル、酢酸エチル、クロロホルム、ジクロロメタン、トルエン等が挙げられる。カラムクロマトグラフィーによる精製は、酸性、塩基性もしくは各種化学処理をしたシリカゲルまたはアルミナ等を用いて、展開溶媒としては、例えばヘキサン／酢酸エチル、ヘキサン／クロロホルム、酢酸エチル／メタノール、クロロホルム／メタノール、アセトニトリル／水、メタノール／水等が挙げられる。 The compound of formula (1) obtained by the production method shown above is isolated and purified according to conventional methods such as extraction, column chromatography, recrystallization, and reprecipitation. Examples of the extraction solvent include diethyl ether, ethyl acetate, chloroform, dichloromethane, toluene and the like. Purification by column chromatography uses silica gel or alumina treated with acidic, basic or various chemical treatments, and examples of developing solvents include hexane / ethyl acetate, hexane / chloroform, ethyl acetate / methanol, chloroform / methanol, acetonitrile. / Water, methanol / water and the like.
　式（１）の化合物がラセミ体である場合は、光学活性カラムを用いるクロマトグラフィー、光学活性な酸並びに合成キラル分割剤などによる光学分割方法、優先晶出法、ジアステレオマー法等の常法に従って、それぞれのエナンチオマーへと分離・精製することができる。 When the compound of formula (1) is a racemate, conventional methods such as chromatography using an optically active column, an optically active method using an optically active acid and a synthetic chiral resolving agent, a preferential crystallization method, a diastereomeric method, etc. According to the above, each enantiomer can be separated and purified.
　水酸基を有する式（１）の化合物は、上記で示す製造方法において、常法に従った水酸基の保護工程と脱保護工程を適宜挿入することにより製造される。 The compound of formula (1) having a hydroxyl group is produced by appropriately inserting a hydroxyl protecting step and a deprotecting step according to a conventional method in the production method described above.
　式（１）の化合物は、構造式中に存在する官能基の種類、原料化合物の選定、反応処理条件により、遊離塩基または酸付加塩の形で得られるが、常法に従って式（１）の化合物に変換することができる。一方、式（１）の化合物は、常法に従って各種の酸と処理することにより酸付加塩に導くことができる。 The compound of formula (1) can be obtained in the form of a free base or an acid addition salt depending on the type of functional group present in the structural formula, the selection of the raw material compound, and the reaction treatment conditions. Can be converted to compounds. On the other hand, the compound of formula (1) can be converted into an acid addition salt by treating with various acids according to a conventional method.
　式（１）の化合物の各エナンチオマーへの分離は、例えば光学活性酸を用い常法に従ってジアステレオマー塩を形成させた後、２種のジアステレオマー塩に分離し、次いでこれを遊離塩基に変換させることにより行われる。光学分割剤として用いられる光学活性酸としては、例えば（＋）－または（－）－ショウノウ酸、（１Ｓ）－（＋）－または（１Ｒ）－（－）－ショウノウ－１０－スルホン酸、Ｌ－（＋）－またはＤ－（－）－酒石酸、（＋）－または（－）－マンデル酸、（Ｓ）－（－）－または（Ｒ）－（＋）－リンゴ酸、Ｌ－ピログルタミン酸、（Ｓ）－（＋）－または（Ｒ）－（－）－１，１’－ビナフチル－２，２’－ジイル、（＋）－ジベンゾイル－Ｄ－酒石酸または（－）－ジベンゾイル－Ｌ－酒石酸等が挙げられる。 Separation of the compound of the formula (1) into each enantiomer is performed by, for example, forming a diastereomeric salt according to a conventional method using an optically active acid, and then separating the diastereomeric salt into two free diastereomeric salts. This is done by converting. Examples of the optically active acid used as the optical resolution agent include (+)-or (−)-camphoric acid, (1S)-(+)-or (1R)-(−)-camphor-10-sulfonic acid, L -(+)-Or D-(-)-tartaric acid, (+)-or (-)-mandelic acid, (S)-(-)-or (R)-(+)-malic acid, L-pyroglutamic acid , (S)-(+)-or (R)-(−)-1,1′-binaphthyl-2,2′-diyl, (+)-dibenzoyl-D-tartaric acid or (−)-dibenzoyl-L- Examples include tartaric acid.
　本発明の化合物はムスカリンＭ２、Ｍ３およびＭ５受容体サブタイプと比較して、ムスカリンＭ１およびＭ４受容体に対して高い選択性および親和性を持ち、選択的なムスカリンＭ１およびＭ４受容体作動薬として有用である。また本発明の化合物は少なくとも部分的にＭ１およびＭ４作動薬として作用する。 The compounds of the invention have a high selectivity and affinity for the muscarinic M 1 and M 4 receptors compared to the muscarinic M 2 , M 3 and M 5 receptor subtypes, and the selective muscarinic M 1 and M 4 is useful as receptor agonists. The compounds of the invention also act at least in part as M 1 and M 4 agonists.
　本発明の化合物は、ムスカリンＭ１およびＭ４受容体が仲介する疾患に対して効果を示し、中枢疾患の予防および／または治療薬、特に優れた抗精神病作用を発現する抗精神病剤として有用である。
　さらに本発明の化合物はムスカリン受容体選択性およびその他の受容体に対する選択性を有することから、先行剤と比べて副作用が少ない安全な中枢疾患の予防および／または治療薬として使用することが期待できる。 The compound of the present invention has an effect on diseases mediated by muscarinic M 1 and M 4 receptors, and is useful as a preventive and / or therapeutic agent for central diseases, particularly as an antipsychotic agent exhibiting excellent antipsychotic action. is there.
Furthermore, since the compound of the present invention has selectivity for muscarinic receptors and other receptors, it can be expected to be used as a safe preventive and / or therapeutic agent for central diseases with fewer side effects than the prior agents. .
　ムスカリンＭ１受容体に関係する障害は、典型的には、精神障害であり、例えば、認知障害、健忘、錯乱、記憶喪失、注意欠陥、視覚欠陥、うつ、疼痛、睡眠障害、精神病などが挙げられる。 Disorders related to muscarinic M 1 receptors, typically a mental disorder, for example, include cognitive impairment, forgetfulness, confusion, memory loss, attention deficit, visual defects, depression, pain, sleep disorders, psychosis, etc. It is done.
　また、ムスカリンＭ１受容体に関係する障害は精神障害であるとは限らず、例えば、眼内圧上昇もムスカリンＭ１受容体に関係している。したがって本発明の対象となる障害には非精神障害も含まれる。 Moreover, disorders related to muscarinic M 1 receptor is not limited to a mental disorder, for example, increased intraocular pressure is also related to the muscarinic M 1 receptor. Accordingly, non-psychiatric disorders are also included in the disorders targeted by the present invention.
　ムスカリンＭ４受容体に関係する障害は、典型的には精神障害であり、例えば、錯乱、注意欠陥、疼痛、睡眠障害、統合失調症などが挙げられる。 Disorders related to muscarinic M 4 receptor is typically a mental disorder, for example, confusion, attention deficit, pain, sleep disorders, such as schizophrenia.
　従って、本発明の化合物または医薬組成物が対象とする障害としては、例えば、神経変性疾患、アルツハイマー病、パーキンソン病、統合失調症、ハンチントン病、フリードライヒ運動失調症、トゥレット症候群、ダウン症候群、疼痛、ピック病、痴呆、臨床的抑うつ、加齢性認知機能低下、注意欠陥障害、乳児突然死症候群、緑内障、認知障害、健忘、錯乱、記憶喪失、視覚欠陥、うつ、睡眠障害、精神病などが挙げられ、好ましくは神経変性疾患、注意欠陥障害、疼痛、アルツハイマー病、統合失調症、認知障害であり、特に好ましくは統合失調症、アルツハイマー病、認知障害である。 Accordingly, the disorders targeted by the compound or pharmaceutical composition of the present invention include, for example, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's disease, Friedreich's ataxia, Tourette's syndrome, Down's syndrome, pain Pick disease, dementia, clinical depression, age-related cognitive decline, attention deficit disorder, sudden infant death syndrome, glaucoma, cognitive impairment, amnesia, confusion, memory loss, visual deficit, depression, sleep disorder, psychosis Preferred are neurodegenerative diseases, attention deficit disorders, pain, Alzheimer's disease, schizophrenia and cognitive impairment, and particularly preferred are schizophrenia, Alzheimer's disease and cognitive impairment.
　本発明の化合物の投与経路としては、経口投与、非経口投与または直腸内投与のいずれでもよく、その一日投与量は、化合物の種類、投与方法、患者の症状・年齢等により異なるが、例えば、経口投与の場合は、通常、ヒトまたは哺乳動物１ｋｇ体重あたり約０．０１～１００ｍｇ、更に好ましくは、約０．１～１０ｍｇを１～数回に分けて投与することができる。静注などの非経口投与の場合は、通常、例えば、ヒトまたは哺乳動物１ｋｇ体重あたり約１μｇ～１０ｍｇ、更に好ましくは約１０μｇ～１ｍｇを投与することができる。ここでいう非経口投与には、静脈内、筋肉内、皮下、鼻腔内、皮内、点眼、脳内、直腸内、腟内および腹腔内などへの投与を含む。 The administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration, and its daily dose varies depending on the type of compound, administration method, patient symptom / age, etc. In the case of oral administration, usually about 0.01 to 100 mg, more preferably about 0.1 to 10 mg per kg body weight of a human or mammal can be administered in 1 to several divided doses. In the case of parenteral administration such as intravenous injection, usually, for example, about 1 μg to 10 mg, more preferably about 10 μg to 1 mg per kg body weight of a human or mammal can be administered. The parenteral administration herein includes intravenous, intramuscular, subcutaneous, intranasal, intradermal, eye drop, intracerebral, intrarectal, intravaginal, intraperitoneal, and the like.
　前記医薬製剤の投与期間および間隔は、種々の状況に応じて変更されるものであり、医師の判断により随時判断されるものであるが、分割投与、連日投与、間歇投与、短期大量投与、反復投与などの方法がある。例えば、経口投与の場合は、１日１ないし数回（特に１日２ないし３回）に分割して投与することが望ましい。また、徐放性の製剤として投与することや長時間かけて点滴静注することも可能である。 The administration period and interval of the pharmaceutical preparation are changed according to various situations, and are determined at any time according to the judgment of a doctor, but divided administration, daily administration, intermittent administration, short-term large-scale administration, repeated administration There are methods such as administration. For example, in the case of oral administration, it is desirable to divide and administer 1 to several times a day (particularly 2 to 3 times a day). Moreover, it can be administered as a sustained-release preparation or can be administered by intravenous infusion over a long period of time.
　本発明の化合物は、上記のごとき医薬用途に使用する場合、通常、製剤用担体と混合して調製された製剤の形で投与される。製剤用担体としては、製剤分野において常用され、かつ本発明の化合物と反応しない無毒性の物質が用いられる。具体的には、クエン酸、グルタミン酸、グリシン、乳糖、イノシトール、ブドウ糖、マンニトール、デキストラン、ソルビトール、シクロデキストリン、デンプン、部分アルファー化マグネシウム、合成ケイ酸アルミニウム、結晶セルロース、カルボキシメチルセルロースナトリウム、ヒドロキシプロピルデンプン、カルボキシメチルセルロースカルシウム、イオン交換樹脂、メチルセルロース、ゼラチン、アラビアゴム、プルラン、ヒドロキシプロピルセルロース、低置換度ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、ポリビニルアルコール、アルギン酸、アルギン酸ナトリウム、軽質無水ケイ酸、ステアリン酸マグネシウム、タルク、トラガント、ベントナイト、ビーガム、カルボキシビニルポリマー、酸化チタン、ソルビタン脂肪酸エステル、ラウリル硫酸ナトリウム、グリセリン、脂肪酸グリセリンエステル、精製ラノリン、グリセロゼラチン、ポリソルベート、マクロゴール、植物油、ロウ、プロピレングルコール、エタノール、ベンジルアルコール、塩化ナトリウム、水酸化ナトリウム、塩酸、水等が挙げられる。 The compound of the present invention is usually administered in the form of a preparation prepared by mixing with a pharmaceutical carrier when used for pharmaceutical use as described above. As the pharmaceutical carrier, a non-toxic substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention is used. Specifically, citric acid, glutamic acid, glycine, lactose, inositol, glucose, mannitol, dextran, sorbitol, cyclodextrin, starch, partially pregelatinized magnesium, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, Carboxymethylcellulose calcium, ion exchange resin, methylcellulose, gelatin, gum arabic, pullulan, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, sodium alginate, light anhydrous silicic acid, stearic acid Magnesium, talc, tragacanth, bentonite, veegum, karuboki Vinyl polymer, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, fatty acid glycerin ester, purified lanolin, glycerogelatin, polysorbate, macrogol, vegetable oil, wax, propylene glycol, ethanol, benzyl alcohol, sodium chloride, sodium hydroxide , Hydrochloric acid, water and the like.
　剤型としては、錠剤、カプセル剤、顆粒剤、散剤、液剤、シロップ剤、懸濁剤、注射剤、坐剤、点眼剤、軟膏剤、塗布剤、貼付剤、吸入剤等が挙げられる。これらの製剤は常法にしたがって調製することができる。液体製剤にあっては、用時、水または他の適当な媒体に溶解または懸濁する形であってもよい。また、錠剤および顆粒剤は周知の方法でコーティングしてもよい。非経口製剤、例えば、注射剤を製造する際には、水性溶剤（例：蒸留水、生理食塩水、リンゲル液等）、等張化剤（例：ブドウ糖、Ｄ－ソルビトール、Ｄ－マンニトール、塩化ナトリウム等）、安定化剤（例：ヒト血清アルブミン等）、防腐剤（例：ベンジルアルコール、クロロブタノール、パラオキシ安息香酸メチル、パラオキシ安息香酸プロピル、フェノール等）、緩衝剤（例：リン酸塩緩衝液、酢酸ナトリウム緩衝液等）、無痛化剤（例：塩化ベンザルコニウム、塩酸プロカイン等）を適宜配合することができる。更に、これらの製剤は治療上価値のある他の成分を含有していてもよい。 Examples of the dosage form include tablets, capsules, granules, powders, solutions, syrups, suspensions, injections, suppositories, eye drops, ointments, coatings, patches, inhalants and the like. These preparations can be prepared according to a conventional method. Liquid preparations may be dissolved or suspended in water or other suitable medium when used. Tablets and granules may be coated by a known method. When producing parenteral preparations such as injections, aqueous solvents (eg, distilled water, physiological saline, Ringer's solution, etc.), isotonic agents (eg, glucose, D-sorbitol, D-mannitol, sodium chloride) Etc.), stabilizers (eg human serum albumin etc.), preservatives (eg benzyl alcohol, chlorobutanol, methyl paraoxybenzoate, propyl paraoxybenzoate, phenol etc.), buffers (eg phosphate buffer) , Sodium acetate buffer, etc.) and soothing agents (eg, benzalkonium chloride, procaine hydrochloride, etc.) can be appropriately blended. In addition, these formulations may contain other therapeutically valuable ingredients.
　本発明の医薬製剤は常法に従って製造することができ、製剤中の本発明の化合物の含有割合は通常０.０１～５０％（w／w）である。具体例を以下に示す。 The pharmaceutical preparation of the present invention can be produced according to a conventional method, and the content ratio of the compound of the present invention in the preparation is usually 0.01 to 50% (w / w). Specific examples are shown below.
（１）錠剤、散剤、顆粒剤、カプセル剤：本発明の化合物に、例えば賦形剤、崩壊剤、結合剤または滑沢剤などを添加して圧縮成型し、次いで必要により、味のマスキング、腸溶性あるいは持続性を目的とするコーティングを行うことにより製造することができる。
　例えば錠剤の場合、実施例１の化合物２０ｍｇ、乳糖１００ｍｇ、結晶セルロース２５ｍｇおよびステアリン酸マグネシウム１ｍｇを混合し、得られた混合物を打錠することにより製造できる。
（２）注射剤：本発明の化合物を、例えば分散剤、保存剤、等張化剤などと共に水性注射剤として、あるいはオリーブ油、ゴマ油、綿実油、コーン油等の植物油、プロピレングリコール等に溶解、懸濁あるいは乳化して油性注射剤として成型することにより製造することができる。
（３）座剤：本発明の化合物を油性または水性の固状、半固状あるいは液状の組成物とすることにより製造される。このような組成物に用いる油性基剤としては、例えば、高級脂肪酸のグリセリド（例えば、カカオ脂、ウイテプゾル類など）、中級脂肪酸（例えば、ミグリオール類など）、あるいは植物油（例えば、ゴマ油、大豆油、綿実油など）などが挙げられる。水性ゲル基剤としては、例えば天然ガム類、セルロース誘導体、ビニール重合体、アクリル酸重合体などが挙げられる。 (1) Tablets, powders, granules, capsules: For example, excipients, disintegrants, binders or lubricants are added to the compounds of the present invention and compression molded, and if necessary, taste masking, It can be produced by applying a coating for enteric or sustainable purposes.
For example, in the case of a tablet, it can be produced by mixing 20 mg of the compound of Example 1, 100 mg of lactose, 25 mg of crystalline cellulose and 1 mg of magnesium stearate, and tableting the resulting mixture.
(2) Injection: The compound of the present invention is dissolved or suspended in a vegetable oil such as olive oil, sesame oil, cottonseed oil, corn oil, propylene glycol or the like as an aqueous injection together with a dispersing agent, preservative, tonicity agent and the like. It can be produced by turbidity or emulsification and molding as an oily injection.
(3) Suppository: produced by making the compound of the present invention into an oily or aqueous solid, semi-solid or liquid composition. Examples of the oily base used in such a composition include glycerides of higher fatty acids (for example, cacao butter, witepsols), intermediate fatty acids (for example, miglyols), or vegetable oils (for example, sesame oil, soybean oil, Cottonseed oil, etc.). Examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, and acrylic acid polymers.
　以下に参考例、実施例および試験例を挙げて本発明を更に具体的に説明するが、これらは本発明を限定するものではない。化合物の同定はプロトン核磁気共鳴吸収スペクトル（１Ｈ－ＮＭＲ）、ＬＣ－ＭＳ等を用いて行った。なお、参考例および実施例におけるアミノシリカゲルクロマトグラフィーは、山善株式会社製のアミノシリカゲルカラムを用いた。ＬＣ－ＭＳは２０１０ＥＶと２０１０ＨＴからなるシステム(島津製作所)またはＬＣ１０ＡＴＶＰ（島津製作所）とＡＰＩ１５０ＥＸ（Ｐｅｒｋｉｎ　Ｅｌｍｅｒ）からなるシステムを用いた。ＬＣ－ＭＳの移動相はアセトニトリル（１～９９％）と０．０５％トリフルオロ酢酸水溶液またはメタノール（１０～９９％）と０．０５％トリフルオロ酢酸水溶液を用いた。リテンションタイム（Ｒ.Ｔ.）はＬＣ－ＭＳ測定におけるマススペクトルピークが現れた時間を表す。 Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples and Test Examples, but these do not limit the present invention. The compound was identified using proton nuclear magnetic resonance absorption spectrum ( 1 H-NMR), LC-MS, and the like. In addition, the amino silica gel column made from Yamazen Co., Ltd. was used for the amino silica gel chromatography in a reference example and an Example. For LC-MS, a system consisting of 2010EV and 2010HT (Shimadzu Corporation) or a system consisting of LC10ATVP (Shimadzu Corporation) and API150EX (Perkin Elmer) was used. As the mobile phase of LC-MS, acetonitrile (1-99%) and 0.05% aqueous trifluoroacetic acid solution or methanol (10-99%) and 0.05% aqueous trifluoroacetic acid solution were used. The retention time (R.T.) represents the time when the mass spectrum peak appears in the LC-MS measurement.
　ＬＣ－ＭＳは種々の条件で測定しており、それらを以下に詳細に記す。
条件Ａ：
ＬＣＭＳ：
島津ＬＣＭＳ－２０１０ＥＶ
Ｃｏｌｕｍｎ：
Ｓｈｉｓｅｉｄｏ　ＣＡＰＣＥＬＬ　ＰＡＫ　Ｃ１８　ＭＧII（４．６ｍｍ×５０ｍｍ）
Ｓｏｌｖｅｎｔ：
Ａ液：ＭｅＯＨ、Ｂ液：０．０５％ＴＦＡ／Ｈ２Ｏ
Ｇｒａｄｉｅｎｔ　Ｃｏｎｄｉｔｉｏｎ：
０．０－１．０ｍｉｎ；Ａ／Ｂ　＝　３０：７０
１．０－７．０ｍｉｎ；Ａ／Ｂ　＝　９９：１
７．１－１２．０ｍｉｎ；Ａ／Ｂ　＝　３０：７０
Ｆｌｏｗ　ｒａｔｅ：
２．８ｍＬ／ｍｉｎ
ＵＶ：    
２２０ｎｍ
カラム温度：
４０℃ LC-MS is measured under various conditions, which are described in detail below.
Condition A:
LCMS:
Shimadzu LCMS-2010EV
Column:
Shiseido CAPCELL PAK C18 MGII (4.6 mm x 50 mm)
Solvent:
Liquid A: MeOH, liquid B: 0.05% TFA / H 2 O
Gradient Condition:
0.0-1.0 min; A / B = 30: 70
1.0-7.0 min; A / B = 99: 1
7.1-12.0 min; A / B = 30: 70
Flow rate:
2.8 mL / min
UV:
220nm
Column temperature:
40 ° C
条件Ｂ：
検出機器：
ＡＰＩシリーズ用Ａｇｉｌｅｎｔ　１１００シリーズ（Ａｐｐｌｉｅｄ　Ｂｉｏｓｙｓｔｅｍｓ社製）
ＨＰＬＣ：
ＡＰＩ１５０ＥＸ　ＬＣ／ＭＳ　ｓｙｓｔｅｍ（Ａｐｐｌｉｅｄ　Ｂｉｏｓｙｓｔｅｍｓ社製）
Ｃｏｌｕｍｎ：
ＹＭＣ　ＣｏｍｂｉＳｃｒｅｅｎ　ＯＤＳ－Ａ（Ｓ－５μＭ，１２ｎｍ，４．６ｘ５０ｍｍ）
Ｓｏｌｖｅｎｔ：
Ａ液：０．０５％ＴＦＡ／Ｈ２Ｏ、Ｂ液：０．０３５％ＴＦＡ／ＭｅＯＨ
Ｇｒａｄｉｅｎｔ　Ｃｏｎｄｉｔｉｏｎ：
０．０－０．５ｍｉｎ；Ａ／Ｂ＝９０：１０
０．５－４．２ｍｉｎ；Ａ／Ｂ＝１：９９
４．２－４．４ｍｉｎ；Ａ／Ｂ＝９９：１
Ｆｌｏｗ　ｒａｔｅ：
１．８ｍＬ／ｍｉｎ
ＵＶ：
２２０ｎｍ Condition B:
Detection equipment:
Agilent 1100 series for API series (Applied Biosystems)
HPLC:
API150EX LC / MS system (Applied Biosystems)
Column:
YMC CombiScreen ODS-A (S-5μM, 12nm, 4.6x50mm)
Solvent:
Liquid A: 0.05% TFA / H 2 O, Liquid B: 0.035% TFA / MeOH
Gradient Condition:
0.0-0.5 min; A / B = 90: 10
0.5-4.2 min; A / B = 1: 99
4.2-4.4 min; A / B = 99: 1
Flow rate:
1.8mL / min
UV:
220nm
条件Ｃ：
ＬＣＭＳ：
島津ＬＣＭＳ－２０１０ＥＶ
Ｃｏｌｕｍｎ：
Ｘｉｍａｔｅ　Ｃ１８　３．０mｍ　２．１ｍｍ×３０ｍｍ
Ｓｏｌｖｅｎｔ：
Ａ液：０．０１９％ＴＦＡ／Ｈ２Ｏ、Ｂ液：０．０３８％ＴＦＡ／ＣＨ３ＣＮ
Ｇｒａｄｉｅｎｔ　Ｃｏｎｄｉｔｉｏｎ：
０．０ｍｉｎ；Ａ／Ｂ＝９０：１０
０．０－１．３５ｍｉｎ；Ａ／Ｂ＝２０：８０
１．３５－２．２５ｍｉｎ；Ａ／Ｂ＝２０：８０
２．２５－２．２６ｍｉｎ；Ａ／Ｂ＝９０：１０
２．２６－３．００ｍｉｎ；Ａ／Ｂ＝９０：１０
Ｆｌｏｗ　ｒａｔｅ：
０．８ｍＬ／ｍｉｎ
ＵＶ：    
２２０ｎｍ
カラム温度：
５０℃ Condition C:
LCMS:
Shimadzu LCMS-2010EV
Column:
Ximate C18 3.0mm 2.1mm x 30mm
Solvent:
Liquid A: 0.019% TFA / H 2 O, Liquid B: 0.038% TFA / CH 3 CN
Gradient Condition:
0.0 min; A / B = 90: 10
0.0-1.35 min; A / B = 20: 80
1.35-2.25 min; A / B = 20: 80
2.25 to 2.26 min; A / B = 90: 10
2.26-3.00 min; A / B = 90: 10
Flow rate:
0.8mL / min
UV:
220nm
Column temperature:
50 ° C
　実験項に特に記載が無い場合、条件はＡを使用した。 If there is no particular description in the experimental section, A was used as the condition.
　また、明細書の記載を簡略化するために参考例、実施例および表中において次に示すような略号を用いることもある。
　置換基として用いられる略号としては、Ｍｅはメチル基、Ｅｔはエチル基、ｔＢｕはｔｅｒｔ－ブチル基、Ｂｏｃはｔｅｒｔ－ブトキシカルボニル基を意味する。 In order to simplify the description, the following abbreviations may be used in Reference Examples, Examples and Tables.
As abbreviations used as substituents, Me represents a methyl group, Et represents an ethyl group, tBu represents a tert-butyl group, and Boc represents a tert-butoxycarbonyl group.
　ＮＭＲに用いられる略号としては、ｓは一重線、ｄは二重線、ｄｄは二重の二重線、ｔは三重線、ｔｄは三重の二重線、ｑは四重線、ｍは多重線、ｂｒは幅広い、ｂｒｄは幅広い二重線、ｂｒｔは幅広い三重線およびＪは結合定数を意味する。 Abbreviations used in NMR include s for single line, d for double line, dd for double double line, t for triple line, td for triple double line, q for quadruple line, and m for multiple line. Line, br means broad, brd means broad double line, brt means broad triple line, and J means coupling constant.
参考例１
２－ニトロフェニル酢酸メチル Reference example 1
2-Nitrophenylacetic acid methyl ester
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
　２－ニトロフェニル酢酸(200 g)のメタノール(1.3 L)溶液に硫酸(15 mL)を室温で滴下した。反応液を加熱還流下16時間攪拌した。室温に冷却後、30%炭酸水素ナトリウム水溶液(500 mL)で中和し、減圧濃縮した。残渣を酢酸エチルで抽出し、飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、減圧濃縮して目的物を得た(150 g, 70%)。 Sulfuric acid (15 L) was added dropwise at room temperature to a solution of 2-nitrophenylacetic acid (200 L) in methanol (1.3 L). The reaction solution was stirred for 16 hours under heating to reflux. After cooling to room temperature, the mixture was neutralized with 30% aqueous sodium hydrogen carbonate solution (500 mL) and concentrated under reduced pressure. The residue was extracted with ethyl acetate and washed with saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the desired product (150 g, 70%).
参考例２
２－アミノフェニル酢酸メチル Reference example 2
2-aminophenylacetic acid methyl ester
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
　参考例１の化合物(100 g)のメタノール(1.5 L)溶液にパラジウム－炭素(12 g)を加えた。反応容器を水素置換し、室温で終夜攪拌した。パラジウム－炭素をセライトで濾去し、減圧濃縮して目的物(73 g, 86%)を得た。 Palladium-carbon (12 g) was added to a methanol (1.5 L) solution of the compound of Reference Example 1 (100 g). The reaction vessel was purged with hydrogen and stirred at room temperature overnight. Palladium-carbon was filtered off through celite and concentrated under reduced pressure to obtain the desired product (73 g, 86%).
参考例３
４－（２－オキソ－２，３－ジヒドロインドール－１－イル）ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル Reference example 3
Tert-Butyl 4- (2-oxo-2,3-dihydroindol-1-yl) piperidine-1-carboxylate
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
　参考例２の化合物(150 g)をジクロロメタン(2.5 L)に溶解し、１－ｔｅｒｔ－ブトキシカルボニル－４－ピペリドン(217.5 g)を室温で加えた。２時間攪拌後、５～１０℃に冷却し、トリアセトキシ水素化ホウ素ナトリウム(320 g)を加え、室温下７２時間撹拌した。反応液に氷水(500 mL)を加え、３０％水酸化ナトリウム水溶液でpHを11とし、トルエンで抽出した。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ー（石油エーテル／酢酸エチル＝20/1）にて精製し、目的物を得た(125 g, 43%)。 The compound of Reference Example 2 (150 g) was dissolved in dichloromethane (2.5 L), and 1-tert-butoxycarbonyl-4-piperidone (217.5 g) was added at room temperature. After stirring for 2 hours, the mixture was cooled to 5 to 10 ° C., sodium triacetoxyborohydride (320 g) was added, and the mixture was stirred at room temperature for 72 hours. Ice water (500 mL) was added to the reaction mixture, the pH was adjusted to 11 with 30% aqueous sodium hydroxide solution, and the mixture was extracted with toluene. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20/1) to obtain the desired product (125 g, 43%).
参考例４
４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン Reference example 4
4- (2-Oxo-2,3-dihydro-1H-indol-1-yl) piperidine
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
　参考例３の化合物(2.0 ｇ)をジクロロメタン(25 ml)に溶解し、氷浴下トリフルオロ酢酸(4.0 ml)を加えた。徐々に昇温し、室温で終夜撹拌した。反応液に4mol/L NaOH水溶液を加え、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮し、表題化合物を得た(1.35 g) 。 The compound of Reference Example 3 (2.0 g) was dissolved in dichloromethane (25 ml), and trifluoroacetic acid (4.0 ml) was added in an ice bath. The temperature was gradually raised, and the mixture was stirred at room temperature overnight. A 4 mol / L aqueous NaOH solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (1.35 g).
参考例５
４－（３，３－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル Reference Example 5
4- (3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidine-1-carboxylate tert-butyl
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044
　参考例３で得られた化合物(316 mg)をジメチルホルムアミド(5 mL)に溶かし、窒素置換後氷冷した。5分攪拌した後に、水素化ナトリウム(55%、105 mg)を少しずつ加えた。気泡が出なくなったところでヨウ化メチル(341 mg)を滴下した。室温で2時間攪拌し、飽和塩化アンモニウム水溶液(5 mL)を加えた。酢酸エチルで抽出した有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝9/1～4/1）で精製し、目的物(350 mg)を得た。 The compound (316 mg) obtained in Reference Example 3 was dissolved in dimethylformamide (5 mL), purged with nitrogen and ice-cooled. After stirring for 5 minutes, sodium hydride (55%, 105 mg) was added in small portions. When no bubbles were generated, methyl iodide (341 mg) was added dropwise. The mixture was stirred at room temperature for 2 hours, and saturated aqueous ammonium chloride solution (5 mL) was added. The organic layer extracted with ethyl acetate was washed with saturated brine. The residue obtained after drying over anhydrous sodium sulfate and concentration under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 9 / 1-4 / 1) to obtain the desired product (350 mg).
参考例６
４－（３，３－ジメチル－２－オキソ－２,３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン Reference Example 6
4- (3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidine
　参考例５の化合物を用いて、参考例４と同様の方法に従って表題化合物を得た。 The title compound was obtained in the same manner as in Reference Example 4 using the compound of Reference Example 5.
参考例７
４－（３，３－ジエチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル Reference Example 7
4- (3,3-Diethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidine-1-carboxylate tert-butyl
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046
　参考例３で得られた化合物(40 g)をジメチルホルムアミド(320 mL)に溶かし、窒素置換後氷冷した。5分攪拌した後に、水素化ナトリウム(55%, 6 g)を少しずつ加えた。気泡が出なくなったところでヨウ化エチル(25.2 g)を滴下した。室温で2時間攪拌し、飽和塩化アンモニウム水溶液を加えた。酢酸エチルで抽出した有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（石油エーテル／酢酸エチル＝50/1～20/1）で精製し、目的物(6.5g, 29％)を得た。 The compound (40 g) obtained in Reference Example 3 was dissolved in dimethylformamide (320 置換 mL), purged with nitrogen and cooled with ice. After stirring for 5 minutes, sodium hydride (55%, 6 g) was added in small portions. When no bubbles were generated, ethyl iodide (25.2 g) was added dropwise. The mixture was stirred at room temperature for 2 hours, and a saturated aqueous ammonium chloride solution was added. The organic layer extracted with ethyl acetate was washed with saturated brine. The residue obtained after drying over anhydrous sodium sulfate and concentration under reduced pressure was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1-20 / 1) to obtain the desired product (6.5 g, 29%). It was.
参考例８
４－（３－エチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル Reference Example 8
4- (3-Ethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidine-1-carboxylate tert-butyl
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047
　参考例７の副生成物として得られた(5.4 g, 25%)。 た Obtained as a by-product of Reference Example 7 (5.4 g, 25%).
参考例９
４－（３－エチル－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル Reference Example 9
4- (3-Ethyl-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidine-1-carboxylate tert-butyl
Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048
　参考例８の化合物(11 g)のジメチルホルムアミド(50 mL)溶液を窒素置換後氷冷した。10分攪拌した後に水素化ナトリウム(55%, 2 g)を少しずつ加えた。気泡が出なくなったところでヨウ化メチル(7.05 g)を滴下した。室温で２時間攪拌し、飽和塩化アンモニウム水溶液を加えた。酢酸エチルで抽出した有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥後、減圧濃縮して目的物(10.5 g)を得た。 A solution of the compound of Reference Example 8 (11 g) in dimethylformamide (50 ml) was purged with nitrogen and cooled with ice. After stirring for 10 minutes, sodium hydride (55%, 2 g) was added in small portions. When no bubbles were generated, methyl iodide (7.05 g) was added dropwise. The mixture was stirred at room temperature for 2 hours, and a saturated aqueous ammonium chloride solution was added. The organic layer extracted with ethyl acetate was washed with saturated brine. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the desired product (10.5 g).
参考例１０
４－（３－エチル－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン Reference Example 10
4- (3-Ethyl-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidine
Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049
　参考例９の化合物を用いて、参考例４と同様の方法に従って表題化合物を得た。 The title compound was obtained in the same manner as in Reference Example 4 using the compound of Reference Example 9.
参考例１１
４－（２－オキソ－３，３－ジプロピル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル Reference Example 11
4- (2-oxo-3,3-dipropyl-2,3-dihydro-1H-indol-1-yl) piperidine-1-carboxylate tert-butyl
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050
　参考例３の化合物と、ヨウ化メチルの代わりにヨウ化プロピルを用いて、参考例５と同様の方法に従って表題化合物を得た。 The title compound was obtained in the same manner as in Reference Example 5 using the compound of Reference Example 3 and propyl iodide instead of methyl iodide.
参考例１２
４－（２－オキソ－３，３－ジプロピル－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン Reference Example 12
4- (2-oxo-3,3-dipropyl-2,3-dihydro-1H-indol-1-yl) piperidine
Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000051
　参考例１１の化合物を用いて、参考例４と同様の方法に従って表題化合物を得た。 The title compound was obtained in the same manner as in Reference Example 4 using the compound of Reference Example 11.
参考例１３
４－[２’－オキソスピロ（シクロプロパン－１，３’－インドール）－１’（２’Ｈ）－イル]ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル Reference Example 13
4- [2′-oxospiro (cyclopropane-1,3′-indole) -1 ′ (2′H) -yl] piperidine-1-carboxylate tert-butyl
Figure JPOXMLDOC01-appb-C000052
Figure JPOXMLDOC01-appb-C000052
　参考例３の化合物と、ヨウ化メチルの代わりに１，２－ジブロモエタンを用いて、参考例５と同様の方法に従って表題化合物を得た(81%)。 Using the compound of Reference Example 3 and 1,2-dibromoethane instead of methyl iodide, the title compound was obtained in the same manner as in Reference Example 5 (81%).
参考例１４
４－[２’－オキソスピロ（シクロプロパン－１，３’－インドール）－１’（２’Ｈ）－イル]ピペリジン Reference Example 14
4- [2′-oxospiro (cyclopropane-1,3′-indole) -1 ′ (2′H) -yl] piperidine
Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000053
　参考例１３の化合物を用いて、参考例４と同様の方法に従って表題化合物を得た。 The title compound was obtained in the same manner as in Reference Example 4 using the compound of Reference Example 13.
参考例１５
４－[２’－オキソスピロ（シクロペンタン－１，３’－インドール）－１’（２’Ｈ）－イル]ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル Reference Example 15
4- [2′-oxospiro (cyclopentane-1,3′-indole) -1 ′ (2′H) -yl] piperidine-1-carboxylate tert-butyl
Figure JPOXMLDOC01-appb-C000054
Figure JPOXMLDOC01-appb-C000054
　参考例３の化合物と、ヨウ化メチルの代わりに１，４－ジブロモブタンを用いて、参考例５と同様の方法に従って表題化合物を得た(71%)。 Using the compound of Reference Example 3 and 1,4-dibromobutane instead of methyl iodide, the title compound was obtained in the same manner as in Reference Example 5 (71%).
参考例１６
４－[２’－オキソスピロ（シクロペンタン－１，３’－インドール）－１’（２’Ｈ）－イル]ピペリジン Reference Example 16
4- [2′-oxospiro (cyclopentane-1,3′-indole) -1 ′ (2′H) -yl] piperidine
Figure JPOXMLDOC01-appb-C000055
Figure JPOXMLDOC01-appb-C000055
　参考例１５の化合物を用いて、参考例４と同様の方法に従って表題化合物を得た。 The title compound was obtained in the same manner as in Reference Example 4 using the compound of Reference Example 15.
参考例１７
４－[２’－オキソスピロ（シクロヘキサン－１，３’－インドール）－１’（２’Ｈ）－イル]ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル Reference Example 17
4- [2′-oxospiro (cyclohexane-1,3′-indole) -1 ′ (2′H) -yl] piperidine-1-carboxylate tert-butyl
Figure JPOXMLDOC01-appb-C000056
Figure JPOXMLDOC01-appb-C000056
　参考例３の化合物と、ヨウ化メチルの代わりに１，５－ジブロモペンタンを用いて、参考例５と同様の方法に従って表題化合物を得た(82%)。 Using the compound of Reference Example 3 and 1,5-dibromopentane instead of methyl iodide, the title compound was obtained in the same manner as in Reference Example 5 (82%).
参考例１８
４－[２’－オキソスピロ（シクロヘキサン－１，３’－インドール）－１’（２’Ｈ）－イル]ピペリジン Reference Example 18
4- [2′-oxospiro (cyclohexane-1,3′-indole) -1 ′ (2′H) -yl] piperidine
Figure JPOXMLDOC01-appb-C000057
Figure JPOXMLDOC01-appb-C000057
　参考例１７の化合物を用いて、参考例４と同様の方法に従って表題化合物を得た。 The title compound was obtained in the same manner as in Reference Example 4 using the compound of Reference Example 17.
参考例１９
４－[２’－オキソスピロ（テトラヒドロピラン－４，３’－インドール）－１’（２’Ｈ）－イル]ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル Reference Example 19
4- [2′-oxospiro (tetrahydropyran-4,3′-indole) -1 ′ (2′H) -yl] piperidine-1-carboxylate tert-butyl
Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000058
　参考例３の化合物と、ヨウ化メチルの代わりにビス（２－ブロモエチル）エーテルを用いて、参考例５と同様の方法に従って表題化合物を得た。 The title compound was obtained in the same manner as in Reference Example 5 using the compound of Reference Example 3 and bis (2-bromoethyl) ether instead of methyl iodide.
参考例２０
４－[２’－オキソスピロ（テトラヒドロピラン－４，３’－インドール）－１’（２’Ｈ）－イル]ピペリジン Reference Example 20
4- [2′-oxospiro (tetrahydropyran-4,3′-indole) -1 ′ (2′H) -yl] piperidine
Figure JPOXMLDOC01-appb-C000059
Figure JPOXMLDOC01-appb-C000059
　参考例１９の化合物を用いて、参考例４と同様の方法に従って表題化合物を得た。 The title compound was obtained in the same manner as in Reference Example 4 using the compound of Reference Example 19.
参考例２１
４－（３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル Reference Example 21
4- (3-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidine-1-carboxylate tert-butyl
Figure JPOXMLDOC01-appb-C000060
Figure JPOXMLDOC01-appb-C000060
　参考例３の化合物(40 g)のテトラヒドロフラン(1 L)溶液にヘキサメチルリン酸トリアミド(288 mL)を加え、窒素雰囲気下－78℃に冷却した。ヘキサメチルジシラザンリチウムアミドのテトラヒドロフラン溶液(1等量)を滴下し２時間攪拌した後にヨウ化メチル(1.2等量)を加え5時間攪拌した。飽和塩化アンモニウム水溶液を加えた後に、水層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した。減圧濃縮して得られた油状物質をシリカゲルカラムクロマトグラフィー（石油エーテル／酢酸エチル＝50/1～20/1）に付し、目的物を白色固体として得た(13.5 g)。 To a solution of the compound of Reference Example 3 (40 g) in tetrahydrofuran (1 L) was added hexamethylphosphoric triamide (288 mL), and the mixture was cooled to -78 ° C under a nitrogen atmosphere. A tetrahydrofuran solution (1 equivalent) of hexamethyldisilazane lithium amide was added dropwise and stirred for 2 hours, and then methyl iodide (1.2 equivalents) was added and stirred for 5 hours. After adding saturated aqueous ammonium chloride solution, the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The oily substance obtained by concentration under reduced pressure was subjected to silica gel column chromatography (petroleum ether / ethyl acetate = 50/1 to 20/1) to obtain the desired product as a white solid (13.5 g).
参考例２２
４－（３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン Reference Example 22
4- (3-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidine
Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-C000061
　参考例２１の化合物を用いて、参考例４と同様の方法に従って表題化合物を得た。 The title compound was obtained in the same manner as in Reference Example 4 using the compound of Reference Example 21.
参考例２３
４－｛[（２－ブロモ－４－フルオロフェニル）アセチル]アミノ｝ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル Reference Example 23
4-{[(2-Bromo-4-fluorophenyl) acetyl] amino} piperidine-1-carboxylate tert-butyl
Figure JPOXMLDOC01-appb-C000062
Figure JPOXMLDOC01-appb-C000062
　２－ブロモ－４－フルオロフェニル酢酸(2.0 g, 8.58 mmol)に塩化チオニル(10 ml)を加え、80℃で5時間撹拌した。反応溶液を減圧濃縮し、アセトニトリル(30 ml)、炭酸カリウム(1.42 g, 10.30 mmol)、４－アミノ－１－ｔｅｒｔ－ブトキシカルボニルピペリジン(1.89 g, 9.44 mmol)を加え、室温で終夜撹拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。硫酸マグネシウムで乾燥後、セライト濾過し、濾液を減圧濃縮した。得られた固体をヘキサン、酢酸エチルで洗浄し、表題化合物を得た(2.67 g, 75%)。
1H-NMR (CDCl3, 400 MHz) δ1.19-1.29 (m, 2H), 1.44 (s, 9H), 1.82-1.90 (d, J = 12.7 Hz, 2H), 2.77-2.90 (br, 2H), 3.64 (s, 2H), 3.88-4.03 (br, 2H), 5.27-5.33(br, 1H), 7.02-7.08 (td, J = 8.3, 2.7 Hz, 1H), 7.30-7.36 (m, 2H).
LC-MS: R.T. 8.3 min., m/z 361.0 (M-tBu). Thionyl chloride (10 ml) was added to 2-bromo-4-fluorophenylacetic acid (2.0 g, 8.58 mmol), and the mixture was stirred at 80 ° C. for 5 hours. The reaction solution was concentrated under reduced pressure, acetonitrile (30 ml), potassium carbonate (1.42 g, 10.30 mmol), 4-amino-1-tert-butoxycarbonylpiperidine (1.89 g, 9.44 mmol) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The extract was dried over magnesium sulfate and filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained solid was washed with hexane and ethyl acetate to give the title compound (2.67 g, 75%).
1 H-NMR (CDCl 3 , 400 MHz) δ1.19-1.29 (m, 2H), 1.44 (s, 9H), 1.82-1.90 (d, J = 12.7 Hz, 2H), 2.77-2.90 (br, 2H ), 3.64 (s, 2H), 3.88-4.03 (br, 2H), 5.27-5.33 (br, 1H), 7.02-7.08 (td, J = 8.3, 2.7 Hz, 1H), 7.30-7.36 (m, 2H ).
LC-MS: RT 8.3 min., M / z 361.0 (M-tBu).
参考例２４
４－（６－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル Reference Example 24
4- (6-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidine-1-carboxylate tert-butyl
Figure JPOXMLDOC01-appb-C000063
Figure JPOXMLDOC01-appb-C000063
　参考例２３の化合物(1.0 g, 2.41 mmol)をｔｅｒｔ－ブチルアルコール(24 ml)に溶解し、そこに酢酸パラジウム(27 mg, 0.12 mmol)、フェニルボロン酸(29 mg, 0.24 mmol)、Ｘ－Ｐｈｏｓ(114 mg, 0.24 mmol)、炭酸カリウム(833 mg, 6.03 mmol)を加え、窒素雰囲気下85℃で2時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄した。有機層を硫酸マグネシウムで乾燥後、セライト濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製し、表題化合物を得た(237 mg, 35%)。 The compound of Reference Example 23 (1.0 g, 2.41 mmol) was dissolved in tert-butyl alcohol (24 ml), and palladium acetate (27 mg, 0.12 mmol), phenylboronic acid (29 mg, 0.24 mmol), X- Phos (114 mg, 0.24 mmol) and potassium carbonate (833 mg, 6.03 mmol) were added, and the mixture was stirred at 85 ° C. for 2 hours under a nitrogen atmosphere. 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. The organic layer was dried over magnesium sulfate, filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (237 mg, 35%).
参考例２５
４－（６－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン Reference Example 25
4- (6-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidine
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000064
　参考例２４の化合物を用いて、参考例４と同様の方法に従って表題化合物を得た(86%)。 The title compound was obtained in the same manner as in Reference Example 4 using the compound of Reference Example 24 (86%).
参考例２６
４－（６－フルオロ－３，３－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル Reference Example 26
4- (6-Fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidine-1-carboxylate tert-butyl
Figure JPOXMLDOC01-appb-C000065
Figure JPOXMLDOC01-appb-C000065
　参考例２４の化合物を用いて、参考例５と同様の方法に従って表題化合物を得た(33%)。 The title compound was obtained in the same manner as in Reference Example 5 using the compound of Reference Example 24 (33%).
参考例２７
４－（６－フルオロ－３，３－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン Reference Example 27
4- (6-Fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidine
Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-C000066
　参考例２６の化合物を用いて、参考例４と同様の方法に従って表題化合物を得た。 The title compound was obtained in the same manner as in Reference Example 4 using the compound of Reference Example 26.
参考例２８
２－（５－クロロ－２－ニトロフェニル）－１，３－プロパン二酸ジｔｅｒｔ－ブチル Reference Example 28
2- (5-Chloro-2-nitrophenyl) -1,3-propanedioic acid ditert-butyl ester
Figure JPOXMLDOC01-appb-C000067
Figure JPOXMLDOC01-appb-C000067
　水素化ナトリウム(55% in oil, 634 mg, 14.54 mmol)をジメチルホルムアミド(20 ml)に懸濁し、氷浴下マロン酸ジｔｅｒｔ-ブチル(2.10 ml, 9.40 mmol)を加え40分撹拌した。そこに４－クロロ－２－フルオロニトロベンゼン(1.5 g, 8.55 mmol)のジメチルホルムアミド(10 ml)溶液を加え、徐々に室温に昇温し、終夜撹拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥後、セライト濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製し、表題化合物を得た(3.30 g)。 Sodium hydride (55% in oil, 634 mg, 14.54 mmol) was suspended in dimethylformamide (20 ml), di-tert-butyl malonate (2.10 ml, 9.40 mmol) was added in an ice bath and stirred for 40 minutes. To this was added a solution of 4-chloro-2-fluoronitrobenzene (1.5 g, 8.55 mmol) in dimethylformamide (10 ml), gradually warmed to room temperature, and stirred overnight. 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. The organic layer was dried over sodium sulfate, filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (3.30 g).
参考例２９
２－（２－アミノ－５－クロロフェニル）－１，３－プロパン二酸ジｔｅｒｔ－ブチル Reference Example 29
2- (2-Amino-5-chlorophenyl) -1,3-propanedioic acid ditert-butyl ester
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000068
　参考例２８の化合物(3.30 g)をエタノール(30 ml)に溶解し、10%ロジウムカーボン(3.0 g)を加え、水素雰囲気下4時間撹拌した。反応液を濾過し、減圧濃縮することで表題化合物を得た(2.72 g)。 The compound of Reference Example 28 (3.30 g) was dissolved in ethanol (30 ml), 10% rhodium carbon (3.0 g) was added, and the mixture was stirred for 4 hours in a hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure to obtain the title compound (2.72 g).
参考例３０
２－（２－｛[１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル]アミノ｝－５－クロロフェニルプロパン）－１，３－二酸ジｔｅｒｔ－ブチル Reference Example 30
2- (2-{[1- (tert-Butoxycarbonyl) piperidin-4-yl] amino} -5-chlorophenylpropane) -1,3-diacid di-tert-butyl
Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000069
　参考例２９の化合物(1.50 g, 4.39 mmol)をジクロロメタン(20 ml)に溶解し、１－ｔｅｒｔ－ブトキシカルボニル－４－ピペリドン(751 mg, 4.39 mmol)、酢酸(527 mg, 8,78 mmol)、トリアセトキシ水素化ホウ素ナトリウム(1.86 g, 8.78 mmol)を加え、室温下終夜撹拌した。反応液に2mol/L水酸化ナトリウム水溶液を加え、クロロホルムで抽出し、有機層を飽和食塩水で洗浄した。硫酸ナトリウムで乾燥後、セライト濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製し、表題化合物を得た(1.10 g, 48%)。 The compound of Reference Example 29 (1.50 g, 4.39 mmol) was dissolved in dichloromethane (20 ml), 1-tert-butoxycarbonyl-4-piperidone (751 mg, 4.39 mmol), acetic acid (527 mg, 8,78 mmol) , Sodium triacetoxyborohydride (1.86 g, 8.78 mmol) was added, and the mixture was stirred at room temperature overnight. A 2 mol / L aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine. The extract was dried over sodium sulfate, filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (1.10 g, 48%).
参考例３１
４－（５－クロロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル Reference Example 31
4- (5-Chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidine-1-carboxylate tert-butyl
Figure JPOXMLDOC01-appb-C000070
Figure JPOXMLDOC01-appb-C000070
　参考例３０の化合物(1.10 g, 2.09 mmol)をトルエン(15 ml)に溶解し、ｐ－エチルベンゼンスルホン酸(3.90 g, 20.95 mmol)を加え140℃にて5時間撹拌した。反応液を減圧濃縮し、氷浴下テトラヒドロフラン(15 ml)、トリエチルアミン(3.2 ml, 22.99 mmol)、ジ－ｔｅｒｔ－ブチルジカーボネート(912 mg, 4.18 mmol)を加え、2時間撹拌した。反応液に2mol/L水酸化ナトリウム水溶液を加え、クロロホルムで抽出し、有機層を飽和食塩水で洗浄した。硫酸ナトリウムで乾燥後、セライト濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製し、表題化合物を得た(435 mg, 59%)。 The compound of Reference Example 30 (1.10 g, 2.09 mmol) was dissolved in toluene (15 ス ル ホ ン ml), p-ethylbenzenesulfonic acid (3.90 g, 20.95 mmol) was added, and the mixture was stirred at 140 ° C for 5 hours. The reaction mixture was concentrated under reduced pressure, tetrahydrofuran (15 ml), triethylamine (3.2 ml, 22.99 mmol) and di-tert-butyl dicarbonate (912 mg, 4.18 mmol) were added in an ice bath, and the mixture was stirred for 2 hr. A 2 mol / L aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine. The extract was dried over sodium sulfate, filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (435 mg, 59%).
参考例３２
４－（５―クロロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン Reference Example 32
4- (5-Chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidine
Figure JPOXMLDOC01-appb-C000071
Figure JPOXMLDOC01-appb-C000071
　参考例３１の化合物を用いて、参考例４と同様の方法に従って表題化合物を得た。 The title compound was obtained in the same manner as in Reference Example 4 using the compound of Reference Example 31.
参考例３３
４－（５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル Reference Example 33
4- (5-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidine-1-carboxylate tert-butyl
Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000072
　４－クロロ－２－フルオロニトロベンゼンの代わりに２，４－ジフルオロニトロベンゼンを用い、参考例２８－３１と同様の方法に従って表題化合物を得た。 Using 2,4-difluoronitrobenzene instead of 4-chloro-2-fluoronitrobenzene, the title compound was obtained in the same manner as in Reference Examples 28-31.
参考例３４
４－（５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン Reference Example 34
4- (5-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidine
Figure JPOXMLDOC01-appb-C000073
Figure JPOXMLDOC01-appb-C000073
　参考例３３の化合物を用いて、参考例４と同様の方法に従って表題化合物を得た。 The title compound was obtained in the same manner as in Reference Example 4 using the compound of Reference Example 33.
参考例３５
４－（５－フルオロ－３，３－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン Reference Example 35
4- (5-Fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidine
Figure JPOXMLDOC01-appb-C000074
Figure JPOXMLDOC01-appb-C000074
　参考例３３の化合物を用いて、参考例５および参考例４と同様の方法に従って表題化合物を合成した。 Using the compound of Reference Example 33, the title compound was synthesized according to the same method as Reference Example 5 and Reference Example 4.
参考例３６
３，３－ジメチル－１－（ピペリジン－４－イル）－１，３－ジヒドロ－２Ｈ－インドール－２－チオン Reference Example 36
3,3-Dimethyl-1- (piperidin-4-yl) -1,3-dihydro-2H-indole-2-thione
Figure JPOXMLDOC01-appb-C000075
Figure JPOXMLDOC01-appb-C000075
　参考例６の化合物(162 mg)、Lawesson試薬(804 mg)をトルエン(7 ml)に溶かし、120℃で6時間撹拌した。反応液をセライト濾過し、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ーにて精製し、表題化合物を得た(216 mg)。 The compound of Reference Example 6 (162 mg) and Lawesson reagent (804 mg) were dissolved in toluene (7 ml) and stirred at 120 ° C. for 6 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (216 mg).
参考例３７
４－（５－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン Reference Example 37
4- (5-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidine
Figure JPOXMLDOC01-appb-C000076
Figure JPOXMLDOC01-appb-C000076
　４－クロロ－２－フルオロニトロベンゼンの代わりに２－フルオロ－４－メチルニトロベンゼンを用い、参考例２８－３１と同様の方法に従って、表題化合物を得た。 Using 2-fluoro-4-methylnitrobenzene instead of 4-chloro-2-fluoronitrobenzene, the title compound was obtained in the same manner as in Reference Example 28-31.
参考例３８
４－（５－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン Reference Example 38
4- (5-Methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidine
Figure JPOXMLDOC01-appb-C000077
Figure JPOXMLDOC01-appb-C000077
　４－クロロ－２－フルオロニトロベンゼンの代わりに２－フルオロ－４－メトキシニトロベンゼンを用い、参考例２８－３１と同様の方法に従って、表題化合物を得た。 Using 2-fluoro-4-methoxynitrobenzene instead of 4-chloro-2-fluoronitrobenzene, the title compound was obtained in the same manner as in Reference Example 28-31.
実施例１
４－[４－（３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル]ピペリジン－１－カルボン酸エチル Example 1
4- [4- (3-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate ethyl
　参考例２２の化合物(69 mg, 0.3 mmol)をジクロロメタン(3 mL)に溶かし、酢酸(36 mg)、１－エトキシカルボニルピペリジン－４－オン(57 mg)、チタンテトライソプロポキシド(427 mg)を室温で加えた。10分攪拌した後に、トリアセトキシ水素化ホウ素ナトリウム(127 mg)を加え、加熱還流下で終夜撹拌した。室温に冷却後、25%アンモニア水溶液を加えてpHを10にした。セライト濾過した濾液を分液し、水層をクロロホルムで抽出した。有機層を合わせ、飽和食塩水で洗浄した。無水硫酸ナトリウム水溶液で乾燥後、減圧濃縮して得られた残渣をアミノシリカゲルカラムクロマトグラフィーに付し（ヘキサン／酢酸エチル＝9/1～酢酸エチル）、油状物質として目的物を得た(81 mg, 70%)。エタノールに溶かし、フマル酸(24 mg)を加えた後に減圧濃縮した。得られた固体をジイソプロピルエーテルでトリチュレートした後に濾取し、表題化合物のフマル酸塩(90 mg)を得た。
1H-NMR (300MHz, CD3OD) δ1.26 (3H, t, J = 7.1Hz), 1.42 (3H, d, J = 7.7Hz), 1.55-1.75 (2H, m), 1.9-2.0 (2H,m), 2.05-2.15 (2H, m), 2.7-2.95 (4H, m), 3.09 (2H, t, J = 12Hz), 3.46 (1H, m), 3.5-3.6 (2H, m), 4.12 (2H, q, J = 7.1Hz), 4.25-4.45 (3H, m), 6.72 (2H, s), 7.07 (1H, t, J = 7.4Hz), 7.18 (1H, m), 7.29 (2H, m).
LC-MS: R.T. 6.4 min, m/z 386.2 (M+1). The compound of Reference Example 22 (69 mg, 0.3 mmol) was dissolved in dichloromethane (3 mL), acetic acid (36 mg), 1-ethoxycarbonylpiperidin-4-one (57 mg), titanium tetraisopropoxide (427 mg). Was added at room temperature. After stirring for 10 minutes, sodium triacetoxyborohydride (127 mg) was added, and the mixture was stirred overnight with heating under reflux. After cooling to room temperature, a 25% aqueous ammonia solution was added to adjust the pH to 10. The filtrate filtered through Celite was separated, and the aqueous layer was extracted with chloroform. The organic layers were combined and washed with saturated brine. The residue obtained after drying with anhydrous sodium sulfate aqueous solution and concentration under reduced pressure was subjected to amino silica gel column chromatography (hexane / ethyl acetate = 9/1 to ethyl acetate) to obtain the desired product as an oily substance (81 mg , 70%). After dissolving in ethanol, fumaric acid (24 mg) was added, and the mixture was concentrated under reduced pressure. The obtained solid was triturated with diisopropyl ether and collected by filtration to give the fumarate salt (90 mg) of the title compound.
1 H-NMR (300MHz, CD 3 OD) δ1.26 (3H, t, J = 7.1Hz), 1.42 (3H, d, J = 7.7Hz), 1.55-1.75 (2H, m), 1.9-2.0 ( 2H, m), 2.05-2.15 (2H, m), 2.7-2.95 (4H, m), 3.09 (2H, t, J = 12Hz), 3.46 (1H, m), 3.5-3.6 (2H, m), 4.12 (2H, q, J = 7.1Hz), 4.25-4.45 (3H, m), 6.72 (2H, s), 7.07 (1H, t, J = 7.4Hz), 7.18 (1H, m), 7.29 (2H , m).
LC-MS: RT 6.4 min, m / z 386.2 (M + 1).
実施例２
４－[４－（３，３－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル]ピペリジン－１－カルボン酸エチル Example 2
4- [4- (3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate ethyl
Figure JPOXMLDOC01-appb-C000079
Figure JPOXMLDOC01-appb-C000079
　参考例６の化合物を用いて、実施例２と同様の方法に従って、塩酸塩として表題化合物を得た(344 mg)。
LC-MS: R.T. 1.2 min, m/z 400.4 (M+1). The title compound was obtained as a hydrochloride (344 mg) according to the same method as in Example 2 using the compound of Reference Example 6.
LC-MS: RT 1.2 min, m / z 400.4 (M + 1).
実施例３
４－[４－（３－エチル－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル]ピペリジン－１－カルボン酸エチル Example 3
4- [4- (3-Ethyl-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate ethyl
Figure JPOXMLDOC01-appb-C000080
Figure JPOXMLDOC01-appb-C000080
　参考例１０の化合物を用いて、実施例１と同様の方法に従って、トリフルオロ酢酸塩として表題化合物を得た(17 mg)。
LC-MS: R.T. 4.8 min, m/z 414.8 (M+1). The title compound was obtained as a trifluoroacetate salt using the compound of Reference Example 10 according to the same method as in Example 1 (17 mg).
LC-MS: RT 4.8 min, m / z 414.8 (M + 1).
実施例４
４－[４－（３，３－ジプロピル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル]ピペリジン－１－カルボン酸エチル Example 4
4- [4- (3,3-Dipropyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate ethyl
Figure JPOXMLDOC01-appb-C000081
Figure JPOXMLDOC01-appb-C000081
　参考例１２の化合物を用いて、実施例１と同様の方法に従って表題化合物を得た(8.6 mg)。
LC-MS: R.T. 4.1 min, m/z 456.6 (M+1). The title compound was obtained in the same manner as in Example 1 using the compound of Reference Example 12 (8.6 mg).
LC-MS: RT 4.1 min, m / z 456.6 (M + 1).
実施例５
４－｛４－[２’－オキソスピロ（シクロプロパン－１，３’－インドール）－１’（２’Ｈ）－イル]ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル Example 5
4- {4- [2′-oxospiro (cyclopropane-1,3′-indole) -1 ′ (2′H) -yl] piperidin-1-yl} piperidine-1-carboxylate ethyl
Figure JPOXMLDOC01-appb-C000082
Figure JPOXMLDOC01-appb-C000082
　参考例１４の化合物を用いて、実施例１と同様の方法に従って、フマル酸塩として表題化合物を得た。
1H-NMR (300MHz, CD3OD) δ1.25 (3H, t, J = 7.1Hz), 1.45-1.75 (6H, m), 1.96-2.18 (5H, m), 2.8-2.95 (5H,m), 3.19 (2H, t, J = 12Hz), 3.31 (2H, m), 3.45 (1H, m), 3.64 (2H, d, J = 12Hz), 4.12 (2H, q, J = 7.1Hz), 4.2-4.35 (3H, m), 4.57 (1H, m), 6.73 (2H, s), 6.95 (1H, m), 7.03 (1H, t, J = 7.4Hz), 7.29 (2H, m).
LC-MS R.T. 6.3 min, m/z 398.2 (M+1). The title compound was obtained as a fumarate salt in the same manner as in Example 1 using the compound of Reference Example 14.
1 H-NMR (300MHz, CD 3 OD) δ1.25 (3H, t, J = 7.1Hz), 1.45-1.75 (6H, m), 1.96-2.18 (5H, m), 2.8-2.95 (5H, m ), 3.19 (2H, t, J = 12Hz), 3.31 (2H, m), 3.45 (1H, m), 3.64 (2H, d, J = 12Hz), 4.12 (2H, q, J = 7.1Hz), 4.2-4.35 (3H, m), 4.57 (1H, m), 6.73 (2H, s), 6.95 (1H, m), 7.03 (1H, t, J = 7.4Hz), 7.29 (2H, m).
LC-MS RT 6.3 min, m / z 398.2 (M + 1).
実施例６
４－｛４－[２’－オキソスピロ（シクロブタン－１，３’－インドール）－１’（２’Ｈ）－イル]ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル Example 6
4- {4- [2′-oxospiro (cyclobutane-1,3′-indole) -1 ′ (2′H) -yl] piperidin-1-yl} piperidine-1-carboxylate ethyl
Figure JPOXMLDOC01-appb-C000083
Figure JPOXMLDOC01-appb-C000083
工程１
　参考例４の化合物(436 mg, 2.02 mmol)を用いて、実施例１と同様の方法に従って油状物質(547 mg, 85%)を得た。
工程２
　工程１で得られた化合物(547 mg, 1.47 mmol)をジメチルホルムアミド(8 ml)に溶解し、炭酸セシウム(1.19 g, 3.68 mmol)を加え室温で3分撹拌した。そこに１，３－ジブロモプロパン(164 μl, 1.62 mmol)を加え、70℃で3時間撹拌した。反応液に水、4mol/L水酸化ナトリウム水溶液を加え、クロロホルムで抽出し、有機層を水で洗浄した。硫酸ナトリウムで乾燥後、セライト濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製し、表題化合物を得た(60 mg, 10%)。
1H-NMR (CDCl3, 400 MHz) δ1.22-1.30 (t, J = 7.1 Hz, 3H), 1.63-1.75 (m, 2H), 1.85-1.96 (br, 2H), 2.10-2.2.40 (m, 6H), 2.54-2.66 (m, 2H), 2.71-2.89 (br, 2H), 2.90-3.09 (br, 4H), 3.40-3.51 (br, 1H), 3.66 (s, 2H), 4.08-4.16 (q, J = 7.1 Hz, 2H), 4.22-4.44 (br, 2H), 4.61-4.73 (br, 1H), 7.07-7.12 (t, J = 7.7 Hz, 1H), 7.22-7.26 (t, J = 7.7 Hz, 1H), 7.33-7.36 (d, J = 8.0 Hz, 1H), 7.43-7.52 (d, J = 6.4 Hz, 1H).
LC-MS: R.T. 6.8 min., m/z 412.2 (M+1). Process 1
Using the compound of Reference Example 4 (436 mg, 2.02 mmol), an oily substance (547 mg, 85%) was obtained in the same manner as in Example 1.
Process 2
The compound (547 mg, 1.47 mmol) obtained in Step 1 was dissolved in dimethylformamide (8 ml), cesium carbonate (1.19 g, 3.68 mmol) was added, and the mixture was stirred at room temperature for 3 minutes. 1,3-dibromopropane (164 μl, 1.62 mmol) was added thereto, and the mixture was stirred at 70 ° C. for 3 hours. Water and a 4 mol / L sodium hydroxide aqueous solution were added to the reaction solution, followed by extraction with chloroform, and the organic layer was washed with water. The extract was dried over sodium sulfate, filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (60 mg, 10%).
1 H-NMR (CDCl 3 , 400 MHz) δ1.22-1.30 (t, J = 7.1 Hz, 3H), 1.63-1.75 (m, 2H), 1.85-1.96 (br, 2H), 2.10-2.2.40 (m, 6H), 2.54-2.66 (m, 2H), 2.71-2.89 (br, 2H), 2.90-3.09 (br, 4H), 3.40-3.51 (br, 1H), 3.66 (s, 2H), 4.08 -4.16 (q, J = 7.1 Hz, 2H), 4.22-4.44 (br, 2H), 4.61-4.73 (br, 1H), 7.07-7.12 (t, J = 7.7 Hz, 1H), 7.22-7.26 (t , J = 7.7 Hz, 1H), 7.33-7.36 (d, J = 8.0 Hz, 1H), 7.43-7.52 (d, J = 6.4 Hz, 1H).
LC-MS: RT 6.8 min., M / z 412.2 (M + 1).
実施例７
４－｛４－[２’－オキソスピロ（シクロペンタン－１，３’－インドール）－１’（２’Ｈ）－イル]ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル Example 7
4- {4- [2′-oxospiro (cyclopentane-1,3′-indole) -1 ′ (2′H) -yl] piperidin-1-yl} piperidine-1-carboxylate ethyl
Figure JPOXMLDOC01-appb-C000084
Figure JPOXMLDOC01-appb-C000084
　参考例１６の化合物(108 mg)をジクロロメタン(2 mL)およびジメトキシエタン(2 mL)に溶かし、１－エトキシカルボニルピペリジン－４－オン(86 mg)、チタンテトライソプロポキシド(568 mg)を室温で加えた。室温で3日攪拌した後に、－78℃に冷却してメタノール(0.5 mL)、水素化ホウ素ナトリウム(39 mg)を加え、ゆっくりと室温まで昇温した。10%塩酸水溶液を加えて15分攪拌した後に、25%アンモニア水溶液を加えてpHを10にした。セライト濾過した濾液を分液し、水層をクロロホルムで抽出した。有機層を合わせ、飽和食塩水で洗浄した。無水硫酸ナトリウム水溶液で乾燥後、減圧濃縮して得られた残渣をアミノシリカゲルカラムクロマトグラフィーに付し（ヘキサン／酢酸エチル＝9/1～酢酸エチル）、油状物質として目的物を得た(58 mg)。エタノールに溶かし、フマル酸(16 mg)を加えた後に減圧濃縮した。得られた固体をジイソプロピルエーテルでトリチュレートした後に濾取し、表題化合物のフマル酸塩(60 mg)を得た。
LC-MS: R.T. 2.5 min, m/z 426.6 (M+1). The compound of Reference Example 16 (108 mg) was dissolved in dichloromethane (2 mL) and dimethoxyethane (2 mL), and 1-ethoxycarbonylpiperidin-4-one (86 mg) and titanium tetraisopropoxide (568 mg) were added at room temperature. Added in. After stirring at room temperature for 3 days, the mixture was cooled to −78 ° C., methanol (0.5 mL) and sodium borohydride (39 mg) were added, and the temperature was slowly raised to room temperature. A 10% aqueous hydrochloric acid solution was added and stirred for 15 minutes, and then a 25% aqueous ammonia solution was added to adjust the pH to 10. The filtrate filtered through Celite was separated, and the aqueous layer was extracted with chloroform. The organic layers were combined and washed with saturated brine. The residue obtained after drying with anhydrous sodium sulfate aqueous solution and concentration under reduced pressure was subjected to amino silica gel column chromatography (hexane / ethyl acetate = 9/1 to ethyl acetate) to obtain the desired product as an oily substance (58 mg). ). After dissolving in ethanol, fumaric acid (16 mg) was added, and the mixture was concentrated under reduced pressure. The obtained solid was triturated with diisopropyl ether and collected by filtration to give the fumarate salt (60 mg) of the title compound.
LC-MS: RT 2.5 min, m / z 426.6 (M + 1).
実施例８
４－｛４－[２’－オキソスピロ（シクロヘキサン－１，３’－インドール）－１’（２’Ｈ）－イル]ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル Example 8
4- {4- [2′-oxospiro (cyclohexane-1,3′-indole) -1 ′ (2′H) -yl] piperidin-1-yl} piperidine-1-carboxylate ethyl
Figure JPOXMLDOC01-appb-C000085
Figure JPOXMLDOC01-appb-C000085
　参考例１８の化合物を用いて、実施例９と同様の方法に従って表題化合物を得た(58 mg)。
LC-MS R.T. 3.4 min, m/z 440.5 (M+1). The title compound was obtained in the same manner as in Example 9 using the compound of Reference Example 18 (58 mg).
LC-MS RT 3.4 min, m / z 440.5 (M + 1).
実施例９
４－｛４－[２’－オキソスピロ（テトラヒドロピラン－４，３’－インドール）－１’（２’Ｈ）－イル]ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル Example 9
4- {4- [2′-oxospiro (tetrahydropyran-4,3′-indole) -1 ′ (2′H) -yl] piperidin-1-yl} piperidine-1-carboxylate
Figure JPOXMLDOC01-appb-C000086
Figure JPOXMLDOC01-appb-C000086
　参考例２０の化合物を用いて、実施例９と同様の方法に従って表題化合物を得た(105 mg)。
LC-MS: R.T. 4.2 min, m/z 442.5 (M+1). The title compound was obtained in the same manner as in Example 9 using the compound of Reference Example 20 (105 mg).
LC-MS: RT 4.2 min, m / z 442.5 (M + 1).
実施例１０
４－[４－（３，３－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル]ピペリジン－１－カルボン酸メチル Example 10
4- [4- (3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate methyl
Figure JPOXMLDOC01-appb-C000087
Figure JPOXMLDOC01-appb-C000087
工程１
　参考例６の化合物(244 mg)、１－ｔｅｒｔ－ブトキシカルボニル－４－ピペリドン(239 mg)、および酢酸(0.5mL)をメタノール(4.5 mL)に溶かし、室温で２－ピコリンボラン(107 mg)を加えた。室温で終夜攪拌した後に、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム～クロロホルム／メタノール＝9/1）に付し、油状物質(430 mg)を得た。
工程２
　工程１で得られた化合物(210 mg)を氷冷下4mol/Lの塩酸－ジオキサン溶液(5 mL)に溶かし、１時間攪拌した。反応液を減圧濃縮して油状物質(100 mg)を得た。
工程３
　工程２で得られた化合物(50 mg)およびトリエチルアミンをテトラヒドロフラン(5 mL)に溶かし、クロロギ酸メチルを氷冷下滴下した。室温に昇温し、終夜攪拌した後に水を加えた。25%アンモニア水溶液でpHを10とした。クロロホルムで抽出した有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥して減圧濃縮した。得られた残渣をシリカゲルクロマトグラフィー（クロロホルム～クロロホルム／メタノール＝9/1）に付し、油状物質として目的物を得た(21 mg)。
LC-MS: R.T. 0.7 min, m/z 386.5 (M+1). Process 1
The compound of Reference Example 6 (244 mg), 1-tert-butoxycarbonyl-4-piperidone (239 mg), and acetic acid (0.5 mL) were dissolved in methanol (4.5 mL) and 2-picoline borane (107 mg) at room temperature. Was added. After stirring overnight at room temperature, the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform to chloroform / methanol = 9/1) to obtain an oily substance (430 mg).
Process 2
The compound obtained in step 1 (210 mg) was dissolved in 4 mol / L hydrochloric acid-dioxane solution (5 mL) under ice cooling and stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain an oily substance (100 mg).
Process 3
The compound obtained in step 2 (50 mg) and triethylamine were dissolved in tetrahydrofuran (5 mL), and methyl chloroformate was added dropwise under ice cooling. After warming to room temperature and stirring overnight, water was added. The pH was adjusted to 10 with 25% aqueous ammonia. The organic layer extracted with chloroform was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography (chloroform to chloroform / methanol = 9/1) to obtain the desired product as an oily substance (21 mg).
LC-MS: RT 0.7 min, m / z 386.5 (M + 1).
実施例１１
４－（｛３－[１－(エトキシカルボニル)ピペリジン－４－イリデン]－６－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝ピペリジン－１－イル）ピペリジン－１－カルボン酸エチル Example 11
4-({3- [1- (ethoxycarbonyl) piperidin-4-ylidene] -6-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl} piperidin-1-yl) piperidine- 1-ethyl carboxylate
Figure JPOXMLDOC01-appb-C000088
Figure JPOXMLDOC01-appb-C000088
　参考例２５の化合物を用いて、実施例１と同様の反応に従って表題化合物を得た(37 mg)。
1H-NMR (CDCl3, 400 MHz) δ1.16-1.31 (m, 6H), 1.62-1.74 (br, 2H), 1.82-1.91 (d, J = 11.5 Hz, 2H), 2.10-2.29 (br, 2H), 2.75-3.22 (m, 9H), 3.35-3.78 (m, 10H), 4.03-4.21 (m, 4H), 4.74-4.89 (br, 1H), 6.95-7.04 (m, 1H), 7.21-7.23 (m, 1H), 7.53 (s, 1H).
LC-MS: R.T. 7.2 min., m/z 565.2 (M+Na). The title compound was obtained in the same manner as in Example 1 using the compound of Reference Example 25 (37 mg).
1 H-NMR (CDCl 3 , 400 MHz) δ1.16-1.31 (m, 6H), 1.62-1.74 (br, 2H), 1.82-1.91 (d, J = 11.5 Hz, 2H), 2.10-2.29 (br , 2H), 2.75-3.22 (m, 9H), 3.35-3.78 (m, 10H), 4.03-4.21 (m, 4H), 4.74-4.89 (br, 1H), 6.95-7.04 (m, 1H), 7.21 -7.23 (m, 1H), 7.53 (s, 1H).
LC-MS: RT 7.2 min., M / z 565.2 (M + Na).
実施例１２
４－（｛３－[１－(エトキシカルボニル)ピペリジン－４－イル]－６－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル｝ピペリジン－１－イル）ピペリジン－１－カルボン酸エチル Example 12
4-({3- [1- (ethoxycarbonyl) piperidin-4-yl] -6-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl} piperidin-1-yl) piperidine- 1-ethyl carboxylate
Figure JPOXMLDOC01-appb-C000089
Figure JPOXMLDOC01-appb-C000089
　実施例１１の化合物(18 mg)をエタノール(1.5 ml)に溶かし、10% Pd/C (100 mg)を加え、水素雰囲気下5時間撹拌した。反応液をセライト濾過し、減圧濃縮した残渣をアミノシリカゲルクロマトグラフィーに付し、油状物質として表題化合物を得た(2 mg)。
LC-MS: R.T. 7.1 min., m/z 567.2 (M+Na). The compound of Example 11 (18 mg) was dissolved in ethanol (1.5 ml), 10% Pd / C (100 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 5 hours. The reaction mixture was filtered through Celite, and the residue concentrated under reduced pressure was subjected to amino silica gel chromatography to obtain the title compound as an oily substance (2 mg).
LC-MS: RT 7.1 min., M / z 567.2 (M + Na).
実施例１３
４－[４－（６－フルオロ－３，３－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル]ピペリジン－１－カルボン酸エチル Example 13
4- [4- (6-Fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate
Figure JPOXMLDOC01-appb-C000090
Figure JPOXMLDOC01-appb-C000090
　参考例２７の化合物を用いて、実施例１と同様の方法に従って表題化合物を得た(25 mg)。
1H-NMR (CDCl3, 400 MHz) δ1.21-1.28 (t, J = 7.1 Hz, 3H), 1.33 (s, 6H), 1.65-1.87 (m, 6H), 2.29-2.44 (m, 4H), 2.47-2.58 (m, 1H), 2.71-2.82 (m, 2H), 2.99-3.10 (m, 2H), 4.09-4.14 (q, J = 7.1 Hz, 2H), 4.17-4.32 (br, 3H), 6.67-6.74 (td, J = 9.6, 2.1 Hz, 1H), 6.91-6.94 (dd, J = 9.6, 2.2 Hz, 1H), 7.07-7.14 (dd, J = 8.3, 5.6 Hz, 1H).
LC-MS: R.T. 6.7 min., m/z 418.2 (M+1). The title compound was obtained in the same manner as in Example 1 using the compound of Reference Example 27 (25 mg).
1 H-NMR (CDCl 3 , 400 MHz) δ1.21-1.28 (t, J = 7.1 Hz, 3H), 1.33 (s, 6H), 1.65-1.87 (m, 6H), 2.29-2.44 (m, 4H ), 2.47-2.58 (m, 1H), 2.71-2.82 (m, 2H), 2.99-3.10 (m, 2H), 4.09-4.14 (q, J = 7.1 Hz, 2H), 4.17-4.32 (br, 3H ), 6.67-6.74 (td, J = 9.6, 2.1 Hz, 1H), 6.91-6.94 (dd, J = 9.6, 2.2 Hz, 1H), 7.07-7.14 (dd, J = 8.3, 5.6 Hz, 1H).
LC-MS: RT 6.7 min., M / z 418.2 (M + 1).
実施例１４
４－[４－（５－フルオロ－３，３－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル]ピペリジン－１－カルボン酸エチル Example 14
4- [4- (5-Fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate
Figure JPOXMLDOC01-appb-C000091
Figure JPOXMLDOC01-appb-C000091
　参考例３５の化合物を用いて、実施例１と同様の方法に従って表題化合物を得た(40 mg)。
1H-NMR (CDCl3, 400 MHz) δ1.20-1.25 (t, J = 7.1 Hz, 3H), 1.33 (s, 6H), 1.61-1.79 (br, 2H), 1.80-1.91 (br, 2H), 2.19-2.42 (br, 2H), 2.71-2.87 (br, 2H), 2.88-3.00 (br, 2H), 3.21-3.41 (br, 3H), 3.52-3.62 (br, 2H), 4.08-4.13 (q, J = 7.1 Hz, 2H), 4.24-4.45 (br, 2H), 4.62-4.73 (br, 1H), 6.88-6.92 (dd, J = 7.8, 2.4 Hz, 1H), 6.99-7.05 (br, 1H), 7.77-7.83 (br, 1H).
LC-MS: R.T. 6.8 min., m/z 418.2 (M+1). The title compound was obtained in the same manner as in Example 1 using the compound of Reference Example 35 (40 mg).
1 H-NMR (CDCl 3 , 400 MHz) δ1.20-1.25 (t, J = 7.1 Hz, 3H), 1.33 (s, 6H), 1.61-1.79 (br, 2H), 1.80-1.91 (br, 2H ), 2.19-2.42 (br, 2H), 2.71-2.87 (br, 2H), 2.88-3.00 (br, 2H), 3.21-3.41 (br, 3H), 3.52-3.62 (br, 2H), 4.08-4.13 (q, J = 7.1 Hz, 2H), 4.24-4.45 (br, 2H), 4.62-4.73 (br, 1H), 6.88-6.92 (dd, J = 7.8, 2.4 Hz, 1H), 6.99-7.05 (br , 1H), 7.77-7.83 (br, 1H).
LC-MS: RT 6.8 min., M / z 418.2 (M + 1).
実施例１５
４－[４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル]アゼパン－１－カルボン酸エチル Example 15
Ethyl 4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepan-1-carboxylate
Figure JPOXMLDOC01-appb-C000092
Figure JPOXMLDOC01-appb-C000092
　参考例３の化合物(200 mg)をジクロロメタン(9 ml)に溶かし、１－エトキシカルボニルアゼパン－４－オン(154 mg)、チタンテトライソプロポキシド(392 mg)、酢酸(66 mg)を室温で加えた。10分撹拌後トリアセトキシ水素化ホウ素ナトリウム(234 mg)を加え、2時間加熱撹拌した。室温に冷却後、25%アンモニア水溶液を加えてpHを10にした。セライト濾過した濾液を分液し、水層をクロロホルムで抽出した。有機層を合わせ、飽和食塩水で洗浄した。無水硫酸ナトリウム水溶液で乾燥後、減圧濃縮して得られた残渣をアミノシリカゲルカラムクロマトグラフィーに付し（ヘキサン／酢酸エチル＝9/1～酢酸エチル）、油状物質として目的物を得た(152 mg)。エタノールに溶かし、フマル酸(45 mg)を加えた後に減圧濃縮した。得られた固体をジエチルエーテルでトリチュレートした後に濾取し、表題化合物のフマル酸塩(194 mg)を得た。
1H-NMR (DMSO-d6, 400 MHz) δ1.14-1.19 (td, J = 7.1, 3.4 Hz, 3H), 1.37-1.52 (br, 2H), 1.56-1.68 (br, 3H), 1.74-1.99 (m, 3H), 2.30-2.42 (br, 2H), 2.43-2.58 (m, 2H), 2.63-2.72 (br, 1H), 2.91-3.01 (br, 2H), 3.18-3.29 (br, 2H), 3.33-3.53 (m, 4H), 3.98-4.07 (q, J = 7.1 Hz,2H), 4.10-4.22 (br, 1H), 6.58 (s, 2H, fumaric acid), 6.93-7.00 (t, J = 7.3 Hz, 1H), 7.12-7.25 (m, 3H).
LC-MS: R.T. 6.0 min., m/z 386.3 (M+1). The compound of Reference Example 3 (200 mg) was dissolved in dichloromethane (9 ml), and 1-ethoxycarbonylazepan-4-one (154 mg), titanium tetraisopropoxide (392 mg), and acetic acid (66 mg) were added at room temperature. Added in. After stirring for 10 minutes, sodium triacetoxyborohydride (234 mg) was added and stirred with heating for 2 hours. After cooling to room temperature, a 25% aqueous ammonia solution was added to adjust the pH to 10. The filtrate filtered through Celite was separated, and the aqueous layer was extracted with chloroform. The organic layers were combined and washed with saturated brine. The residue obtained after drying over anhydrous sodium sulfate and concentration under reduced pressure was subjected to amino silica gel column chromatography (hexane / ethyl acetate = 9/1 to ethyl acetate) to give the desired product as an oily substance (152 mg ). After dissolving in ethanol, fumaric acid (45 mg) was added, and the mixture was concentrated under reduced pressure. The obtained solid was triturated with diethyl ether and collected by filtration to give the fumarate salt (194 mg) of the title compound.
1 H-NMR (DMSO-d 6 , 400 MHz) δ1.14-1.19 (td, J = 7.1, 3.4 Hz, 3H), 1.37-1.52 (br, 2H), 1.56-1.68 (br, 3H), 1.74 -1.99 (m, 3H), 2.30-2.42 (br, 2H), 2.43-2.58 (m, 2H), 2.63-2.72 (br, 1H), 2.91-3.01 (br, 2H), 3.18-3.29 (br, 2H), 3.33-3.53 (m, 4H), 3.98-4.07 (q, J = 7.1 Hz, 2H), 4.10-4.22 (br, 1H), 6.58 (s, 2H, fumaric acid), 6.93-7.00 (t , J = 7.3 Hz, 1H), 7.12-7.25 (m, 3H).
LC-MS: RT 6.0 min., M / z 386.3 (M + 1).
実施例１６
１－エチルスルファニルカルボニル－４－[４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル]ピペリジン Example 16
1-ethylsulfanylcarbonyl-4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine
Figure JPOXMLDOC01-appb-C000093
Figure JPOXMLDOC01-appb-C000093
工程１
　参考例３の化合物(2.9g, 13mmol)、１－ｔｅｒｔ－ブトキシカルボニル－４－ピペリドン(2.7g, 13mmol)、酢酸(3.1ml, 54mmol)、およびチタンテトライソプロポキシド(20ml, 67mmol)をジクロロメタン(50ml)に溶かし、トリアセトキシ水素化ホウ素ナトリウム(5.7g, 27mmol)を室温で少しずつ加えた。50℃で4時間攪拌した後に、28%アンモニア水溶液を加え、セライト濾過した後、酢酸エチルで抽出した。水および飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残渣をアミノシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝10/0～0/10）に付し、目的物(3.4g, 64%)を得た。
工程２
　工程１で得られた化合物(3.4g, 8.6mmol)を4mol/Lの塩酸－ジオキサン溶液(11ml)に溶かし、室温で終夜攪拌した。反応液を減圧濃縮して目的物を得、粗生成物のまま工程３に用いた。
工程３
　工程２で得られた化合物(50mg, 0.13mmol)をジクロロメタン(1.5ml)に懸濁し、ピリジン(0.054ml, 0.67mmol)を加えた後、エチルチオカルボニルクロリド(0.021ml, 0.20mmol)を少しずつ加えた。室温で終夜攪拌した後に、クロロホルムを加え、水で洗浄した。有機層を減圧濃縮し、得られた残渣を逆相高速液体クロマトグラフィー（0.035%トリフルオロ酢酸－アセトニトリル/0.05%トリフルオロ酢酸－水＝1%～95%）に付し、油状物質として目的物を得た(6.1mg)。
LC-MS: R.T. 2.8 min, m/z 388.5 (M+1). Process 1
The compound of Reference Example 3 (2.9 g, 13 mmol), 1-tert-butoxycarbonyl-4-piperidone (2.7 g, 13 mmol), acetic acid (3.1 ml, 54 mmol), and titanium tetraisopropoxide (20 ml, 67 mmol) were dissolved in dichloromethane. (50 ml) and sodium triacetoxyborohydride (5.7 g, 27 mmol) was added in portions at room temperature. After stirring at 50 ° C. for 4 hours, 28% aqueous ammonia solution was added, and the mixture was filtered through celite and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to amino silica gel column chromatography (hexane / ethyl acetate = 10/0 to 0/10) to obtain the desired product (3.4 g, 64%).
Process 2
The compound obtained in Step 1 (3.4 g, 8.6 mmol) was dissolved in 4 mol / L hydrochloric acid-dioxane solution (11 ml) and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain the desired product, which was used in Step 3 as a crude product.
Process 3
The compound obtained in Step 2 (50 mg, 0.13 mmol) was suspended in dichloromethane (1.5 ml), pyridine (0.054 ml, 0.67 mmol) was added, and then ethylthiocarbonyl chloride (0.021 ml, 0.20 mmol) was added little by little. added. After stirring overnight at room temperature, chloroform was added and washed with water. The organic layer was concentrated under reduced pressure, and the obtained residue was subjected to reverse phase high performance liquid chromatography (0.035% trifluoroacetic acid-acetonitrile / 0.05% trifluoroacetic acid-water = 1% to 95%) to give the desired product as an oily substance. (6.1 mg) was obtained.
LC-MS: RT 2.8 min, m / z 388.5 (M + 1).
実施例１７
４－[４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル]ピペリジン－１－カルボン酸　２－フルオロエチル Example 17
4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylic acid 2-fluoroethyl
Figure JPOXMLDOC01-appb-C000094
Figure JPOXMLDOC01-appb-C000094
　参考例３の化合物と、エチルチオカルボニルクロリドの代わりにクロロギ酸２－フルオロメチルを用いて、実施例１６と同様の方法に従って、表題化合物(17mg)を得た。
LC-MS: R.T. 2.6 min, m/z 390.5 (M+1). The title compound (17 mg) was obtained in the same manner as in Example 16 using the compound of Reference Example 3 and 2-fluoromethyl chloroformate instead of ethylthiocarbonyl chloride.
LC-MS: RT 2.6 min, m / z 390.5 (M + 1).
実施例１８
４－[４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル]ピペリジン－１－カルボン酸　２－プロペニル Example 18
4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylic acid 2-propenyl
Figure JPOXMLDOC01-appb-C000095
Figure JPOXMLDOC01-appb-C000095
　参考例３の化合物（50mg, 0.23mmol)、１－アリロキシカルボニル－４－ピペリドン(0.042ml, 0.23mmol)、酢酸(0.053ml, 0.93mmol)、およびチタンテトライソプロポキシド(0.34ml, 1.2mmol)をジクロロメタン(2ml)に溶かし、トリアセトキシ水素化ホウ素ナトリウム(98mg, 0.46mmol)を室温で少しずつ加えた。50℃で5時間攪拌した後に、28%アンモニア水溶液、クロロホルムを加え、セライト濾過した後、水層を除去し、水で洗浄して、減圧濃縮した。残渣を逆相高速液体クロマトグラフィー（0.035%トリフルオロ酢酸－アセトニトリル/0.05%トリフルオロ酢酸－水＝1%～95%）に付し、油状物質として目的物(17mg, 19%)を得た。
LC-MS: R.T. 2.8 min, m/z 384.5 (M+1). The compound of Reference Example 3 (50 mg, 0.23 mmol), 1-allyloxycarbonyl-4-piperidone (0.042 ml, 0.23 mmol), acetic acid (0.053 ml, 0.93 mmol), and titanium tetraisopropoxide (0.34 ml, 1.2 mmol) ) Was dissolved in dichloromethane (2 ml) and sodium triacetoxyborohydride (98 mg, 0.46 mmol) was added in portions at room temperature. After stirring at 50 ° C. for 5 hours, 28% aqueous ammonia solution and chloroform were added, and the mixture was filtered through Celite. Then, the aqueous layer was removed, washed with water, and concentrated under reduced pressure. The residue was subjected to reverse phase high performance liquid chromatography (0.035% trifluoroacetic acid-acetonitrile / 0.05% trifluoroacetic acid-water = 1% to 95%) to obtain the desired product (17 mg, 19%) as an oily substance.
LC-MS: RT 2.8 min, m / z 384.5 (M + 1).
実施例１９
４－[４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル]ピペリジン－１－カルボン酸　２－メトキシエチル Example 19
4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylic acid 2-methoxyethyl
Figure JPOXMLDOC01-appb-C000096
Figure JPOXMLDOC01-appb-C000096
　参考例３の化合物と、エチルチオカルボニルクロリドの代わりにクロロギ酸２－メトキシエチルを用いて、実施例１６と同様の方法に従って表題化合物(3.8mg)を得た。
LC-MS: R.T. 2.5 min, m/z 402.6 (M+1). The title compound (3.8 mg) was obtained in the same manner as in Example 16 using the compound of Reference Example 3 and 2-methoxyethyl chloroformate instead of ethylthiocarbonyl chloride.
LC-MS: RT 2.5 min, m / z 402.6 (M + 1).
実施例２０
１－メチルスルファニルカルボニル－４－[４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル]ピペリジン Example 20
1-methylsulfanylcarbonyl-4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine
Figure JPOXMLDOC01-appb-C000097
Figure JPOXMLDOC01-appb-C000097
　参考例３の化合物と、エチルチオカルボニルクロリドの代わりにメチルチオカルボニルクロリドを用いて、実施例１６と同様の方法に従って表題化合物(19mg)を得た。
LC-MS: R.T. 2.6 min, m/z 374.5 (M+1). The title compound (19 mg) was obtained in the same manner as in Example 16 using the compound of Reference Example 3 and methylthiocarbonyl chloride instead of ethylthiocarbonyl chloride.
LC-MS: RT 2.6 min, m / z 374.5 (M + 1).
実施例２１
４－[４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル]ピペリジン－１－カルボン酸プロピル Example 21
4- [4- (2-Oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate
Figure JPOXMLDOC01-appb-C000098
Figure JPOXMLDOC01-appb-C000098
　参考例３の化合物と、エチルチオカルボニルクロリドの代わりにクロロギ酸プロピルを用いて、実施例１６と同様の方法に従って表題化合物(15mg)を得た。
LC-MS: R.T. 2.8 min, m/z 386.6 (M+1). The title compound (15 mg) was obtained in the same manner as in Example 16 using the compound of Reference Example 3 and propyl chloroformate instead of ethylthiocarbonyl chloride.
LC-MS: RT 2.8 min, m / z 386.6 (M + 1).
実施例２２
４－[４－（５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル]アゼパン－１－カルボン酸エチル Example 22
4- [4- (5-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate ethyl
Figure JPOXMLDOC01-appb-C000099
Figure JPOXMLDOC01-appb-C000099
　参考例３４の化合物を用いて、実施例１５と同様の方法に従って、表題化合物のフマル酸塩を得た(86 mg)。
1H-NMR (DMSO-d6, 400 MHz) δ1.12-1.20 (td, J = 7.1, 3.2 Hz, 3H), 1.38-1.51 (m, 2H), 1.58-1.69 (m, 3H), 1.78-2.01 (m, 3H), 2.32-2.44 (m, 2H), 2.50-2.62 (m, 2H), 2.70-2.78 (br, 1H), 2.95-3.04 (br, 2H), 3.18-3.30 (br, 2H), 3.39-3.50 (m, 2H), 3.55 (s, 2H), 4.00-4.09 (q, J = 7.1 Hz, 2H), 4.13-4.23 (br, 1H), 6.57 (s, 2H, fumaric acid), 7.00-7.09 (t, J = 9.0 Hz, 1H), 7.11-7.20 (m, 2H).
LC-MS: R.T. 6.1 min., m/z 404.2 (M+1). The fumarate salt of the title compound was obtained in the same manner as in Example 15 using the compound of Reference Example 34 (86 mg).
1 H-NMR (DMSO-d 6 , 400 MHz) δ1.12-1.20 (td, J = 7.1, 3.2 Hz, 3H), 1.38-1.51 (m, 2H), 1.58-1.69 (m, 3H), 1.78 -2.01 (m, 3H), 2.32-2.44 (m, 2H), 2.50-2.62 (m, 2H), 2.70-2.78 (br, 1H), 2.95-3.04 (br, 2H), 3.18-3.30 (br, 2H), 3.39-3.50 (m, 2H), 3.55 (s, 2H), 4.00-4.09 (q, J = 7.1 Hz, 2H), 4.13-4.23 (br, 1H), 6.57 (s, 2H, fumaric acid ), 7.00-7.09 (t, J = 9.0 Hz, 1H), 7.11-7.20 (m, 2H).
LC-MS: RT 6.1 min., M / z 404.2 (M + 1).
実施例２３
４－[４－（３，３－ジメチル－２－オキソ－２，３－ジヒドロ－５－フルオロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル]アゼパン－１－カルボン酸エチル Example 23
4- [4- (3,3-Dimethyl-2-oxo-2,3-dihydro-5-fluoro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate ethyl
Figure JPOXMLDOC01-appb-C000100
Figure JPOXMLDOC01-appb-C000100
　参考例３５の化合物を用いて、実施例１５と同様の方法に従って表題化合物のフマル酸塩を得た(156 mg)。
1H-NMR (DMSO-d6, 400 MHz) δ1.13-1.19 (td, J = 7.1, 3.2 Hz, 3H), 1.24 (s, 6H), 1.37-1.51 (br, 2H), 1.57-1.68 (d, J = 11.0 Hz, 3H), 1.76-2.00 (m, 3H), 2.29-2.41 (br, 2H), 2.50-2.60 (m, 2H), 2.68-2.75 (br, 1H), 2.94-3.03 (m, 2H), 3.18-3.29 (br, 2H), 3.40-3.52 (m, 2H), 4.00-4.07 (q, J = 7.1 Hz, 2H), 4.11-4.22 (br, 1H), 6.58 (s, 2H, fumaric acid), 7.00-7.05 (td, J = 9.3, 2.7 Hz, 1H), 7.15-7.21 (m, 1H), 7.30-7.33 (dd, J = 8.3, 2.7 Hz, 1H).
LC-MS: R.T. 6.9 min., m/z 432.2 (M+1). Using the compound of Reference Example 35, the fumarate salt of the title compound was obtained in the same manner as in Example 15 (156 mg).
1 H-NMR (DMSO-d 6 , 400 MHz) δ1.13-1.19 (td, J = 7.1, 3.2 Hz, 3H), 1.24 (s, 6H), 1.37-1.51 (br, 2H), 1.57-1.68 (d, J = 11.0 Hz, 3H), 1.76-2.00 (m, 3H), 2.29-2.41 (br, 2H), 2.50-2.60 (m, 2H), 2.68-2.75 (br, 1H), 2.94-3.03 (m, 2H), 3.18-3.29 (br, 2H), 3.40-3.52 (m, 2H), 4.00-4.07 (q, J = 7.1 Hz, 2H), 4.11-4.22 (br, 1H), 6.58 (s , 2H, fumaric acid), 7.00-7.05 (td, J = 9.3, 2.7 Hz, 1H), 7.15-7.21 (m, 1H), 7.30-7.33 (dd, J = 8.3, 2.7 Hz, 1H).
LC-MS: RT 6.9 min., M / z 432.2 (M + 1).
実施例２４
４－[４－（３，３－ジメチル－２－チオキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル]ピペリジン－１－カルボン酸エチル Example 24
4- [4- (3,3-Dimethyl-2-thioxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate ethyl
Figure JPOXMLDOC01-appb-C000101
Figure JPOXMLDOC01-appb-C000101
　参考例３６の化合物を用いて、実施例１と同様の方法に従って表題化合物を得た(1 mg)。
LC-MS: R.T. 7.12 min., m/z 416.3 (M+1). The title compound was obtained in the same manner as in Example 1 using the compound of Reference Example 36 (1 mg).
LC-MS: RT 7.12 min., M / z 416.3 (M + 1).
実施例２５
４－[４－（５－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル]ピペリジン－１－カルボン酸エチル Example 25
4- [4- (5-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate ethyl
Figure JPOXMLDOC01-appb-C000102
Figure JPOXMLDOC01-appb-C000102
　参考例３７の化合物を用いて、実施例１と同様の方法に従って表題化合物を得た(149 mg)。
1H-NMR (DMSO-d6, 400 MHz) δ1.12-1.21 (t, J = 7.1 Hz, 3H), 1.21-1.38 (m, 2H), 1.54 (s, 2H), 1.68-1.77 (d, J = 11.2 Hz, 2H), 2.21-2.32 (m, 2H), 2.43-2.54 (m, 5H), 2.64-2.83 (br, 2H), 2.89-3.00 (d, J = 6.4 Hz, 2H), 3.32 (s, 1H), 3.46 (s, 2H), 3.95-4.10 (m, 5H), 6.97-7.10 (m, 3H).
LC-MS: R.T. 6.2 min., m/z 386.2 (M+1). The title compound was obtained in the same manner as in Example 1 using the compound of Reference Example 37 (149 mg).
1 H-NMR (DMSO-d 6 , 400 MHz) δ1.12-1.21 (t, J = 7.1 Hz, 3H), 1.21-1.38 (m, 2H), 1.54 (s, 2H), 1.68-1.77 (d , J = 11.2 Hz, 2H), 2.21-2.32 (m, 2H), 2.43-2.54 (m, 5H), 2.64-2.83 (br, 2H), 2.89-3.00 (d, J = 6.4 Hz, 2H), 3.32 (s, 1H), 3.46 (s, 2H), 3.95-4.10 (m, 5H), 6.97-7.10 (m, 3H).
LC-MS: RT 6.2 min., M / z 386.2 (M + 1).
実施例２６
４－[４－（５－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル]ピペリジン－１－カルボン酸エチル Example 26
4- [4- (5-Methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate ethyl
Figure JPOXMLDOC01-appb-C000103
Figure JPOXMLDOC01-appb-C000103
　参考例３８の化合物を用いて、実施例１と同様の方法に従って表題化合物のフマル酸塩を得た(160 mg)。
1H-NMR (DMSO-d6, 400 MHz) δ1.12-1.20 (td, J = 7.1, 2.2 Hz, 3H), 1,31-1,43 (m, 2H), 1.56-1.62 (m, 2H), 1.75-1.84 (d, J = 11.4 Hz, 2H), 2.30-2.63 (m, 4H), 2.64-2.82 (m, 3H), 3.02-3.11 (d, J = 10.7 Hz, 2H), 3.49 (s, 2H), 3.69 (s, 3H), 3.96-4.08 (q, J = 7.1 Hz, 4H), 4.09-4.21 (m, 1H), 6.59 (s, 2H, fumaric acid), 6.75-6.80 (d, J = 8.1 Hz, 1H), 6.91 (s, 1H), 7.03-7.07 (d, J = 8.1 Hz, 1H).
LC-MS: R.T. 5.7 min., m/z 402.2 (M+1). The fumarate salt of the title compound was obtained using the compound of Reference Example 38 according to the same method as in Example 1 (160 mg).
1 H-NMR (DMSO-d 6 , 400 MHz) δ1.12-1.20 (td, J = 7.1, 2.2 Hz, 3H), 1,31-1,43 (m, 2H), 1.56-1.62 (m, 2H), 1.75-1.84 (d, J = 11.4 Hz, 2H), 2.30-2.63 (m, 4H), 2.64-2.82 (m, 3H), 3.02-3.11 (d, J = 10.7 Hz, 2H), 3.49 (s, 2H), 3.69 (s, 3H), 3.96-4.08 (q, J = 7.1 Hz, 4H), 4.09-4.21 (m, 1H), 6.59 (s, 2H, fumaric acid), 6.75-6.80 ( d, J = 8.1 Hz, 1H), 6.91 (s, 1H), 7.03-7.07 (d, J = 8.1 Hz, 1H).
LC-MS: RT 5.7 min., M / z 402.2 (M + 1).
実施例２７
４－[４－（５－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル]アゼパン－１－カルボン酸エチル Example 27
4- [4- (5-Methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate ethyl
Figure JPOXMLDOC01-appb-C000104
Figure JPOXMLDOC01-appb-C000104
　参考例３８の化合物を用いて、実施例１５と同様の方法に従って表題化合物のフマル酸塩を得た(131 mg)。
1H-NMR (DMSO-d6, 400 MHz) δ1.13-1.20 (td, J = 7.1, 3.4 Hz, 3H), 1.39-1.50 (m, 2H), 1.52-1.70 (m, 3H), 1.73-1.88 (m, 1H), 1.89-2.03 (m, 2H), 2.31-2.42 (m, 2H), 2.55-2.69 (m, 2H), 2.71-2.80 (m, 1H), 2.96-3.05 (m, 2H), 3.17-3.30 (br, 2H), 3.39-3.52 (m, 4H), 3.69 (s, 3H), 4.00-4.06 (q, J = 7.1 Hz, 2H), 4.16-4.27 (m, 1H), 6.58 (s, 2H, fumaric acid), 6.73-6.78 (d, J = 8.1 Hz, 1H), 6.90 (s, 1H), 7.08-7.12 (d, J = 8.1 Hz, 1H).
LC-MS: R.T. 5.9 min., m/z 438.2 (M+Na). The fumarate salt of the title compound was obtained in the same manner as in Example 15 using the compound of Reference Example 38 (131 mg).
1 H-NMR (DMSO-d 6 , 400 MHz) δ1.13-1.20 (td, J = 7.1, 3.4 Hz, 3H), 1.39-1.50 (m, 2H), 1.52-1.70 (m, 3H), 1.73 -1.88 (m, 1H), 1.89-2.03 (m, 2H), 2.31-2.42 (m, 2H), 2.55-2.69 (m, 2H), 2.71-2.80 (m, 1H), 2.96-3.05 (m, 2H), 3.17-3.30 (br, 2H), 3.39-3.52 (m, 4H), 3.69 (s, 3H), 4.00-4.06 (q, J = 7.1 Hz, 2H), 4.16-4.27 (m, 1H) , 6.58 (s, 2H, fumaric acid), 6.73-6.78 (d, J = 8.1 Hz, 1H), 6.90 (s, 1H), 7.08-7.12 (d, J = 8.1 Hz, 1H).
LC-MS: RT 5.9 min., M / z 438.2 (M + Na).
実施例２８
４－[４－（５－クロロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル]ピペリジン－１－カルボン酸エチル Example 28
4- [4- (5-Chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate ethyl
Figure JPOXMLDOC01-appb-C000105
Figure JPOXMLDOC01-appb-C000105
　参考例３２の化合物を用いて、実施例１と同様の方法に従って、フマル酸塩として表題化合物を得た(73 mg)。
1H-NMR (CDCl3, 400 MHz) δ1.22-1.29 (t, J = 7.1 Hz, 3H), 1.65-1.77 (m, 2H), 1.90-1.98 (d, J = 12.0 Hz, 2H), 2.13-2.28 (br, 2H), 2.76-2.90 (br, 2H), 2.93-3.08 (br, 2H), 3.09-3.21 (m, 2H), 3.38-3.48 (m, 1H), 3.56 (s, 2H), 3.61-3.70 (d, J = 10.5 Hz, 2H), 4.10-4.18 (q, J = 7.1 Hz, 2H), 4.30-4.45 (br, 2H), 4.69-4.81 (m, 1H), 7.20-7.25 (m, 1H), 7.26-7.32 (d, J = 8.3 Hz, 1H), 7.54-7.58 (d, J = 8.3 Hz, 1H).
LC-MS: R.T. 6.6 min., m/z 406.1 (M+1). The title compound was obtained as a fumarate salt in the same manner as in Example 1 using the compound of Reference Example 32 (73 mg).
1 H-NMR (CDCl 3 , 400 MHz) δ1.22-1.29 (t, J = 7.1 Hz, 3H), 1.65-1.77 (m, 2H), 1.90-1.98 (d, J = 12.0 Hz, 2H), 2.13-2.28 (br, 2H), 2.76-2.90 (br, 2H), 2.93-3.08 (br, 2H), 3.09-3.21 (m, 2H), 3.38-3.48 (m, 1H), 3.56 (s, 2H ), 3.61-3.70 (d, J = 10.5 Hz, 2H), 4.10-4.18 (q, J = 7.1 Hz, 2H), 4.30-4.45 (br, 2H), 4.69-4.81 (m, 1H), 7.20- 7.25 (m, 1H), 7.26-7.32 (d, J = 8.3 Hz, 1H), 7.54-7.58 (d, J = 8.3 Hz, 1H).
LC-MS: RT 6.6 min., M / z 406.1 (M + 1).
実施例２９
４－[４－（５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル]ピペリジン－１－カルボン酸エチル Example 29
4- [4- (5-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate ethyl
Figure JPOXMLDOC01-appb-C000106
Figure JPOXMLDOC01-appb-C000106
　参考例３４の化合物を用いて、実施例１と同様の方法に従って表題化合物を得た(12 mg)。
1H-NMR (CDCl3, 400 MHz) δ1.23-1.31 (t, J = 7.1 Hz, 3H), 1.63-1.76 (m, 2H), 1.88-1.99 (d, J = 12.2 Hz, 2H), 2.15-2.31 (br, 2H), 2.75-2.91 (br, 2H), 2.91-3.09 (br, 2H), 3.11-3.28 (m, 2H), 3.31-3.43 (m, 1H), 3.56 (s, 2H), 3.60-3.69 (d, J = 11.5 Hz, 2H), 4.11-4.18 (q, J = 7.1 Hz, 2H), 4.27-4.50 (br, 2H), 4.71-4.82 (br, 1H), 6.93-7.09 (m, 2H), 7.63-7.69 (m, 1H).
LC-MS: R.T. 5.9 min., m/z 390.1 (M+1). The title compound was obtained in the same manner as in Example 1 using the compound of Reference Example 34 (12 mg).
1 H-NMR (CDCl 3 , 400 MHz) δ1.23-1.31 (t, J = 7.1 Hz, 3H), 1.63-1.76 (m, 2H), 1.88-1.99 (d, J = 12.2 Hz, 2H), 2.15-2.31 (br, 2H), 2.75-2.91 (br, 2H), 2.91-3.09 (br, 2H), 3.11-3.28 (m, 2H), 3.31-3.43 (m, 1H), 3.56 (s, 2H ), 3.60-3.69 (d, J = 11.5 Hz, 2H), 4.11-4.18 (q, J = 7.1 Hz, 2H), 4.27-4.50 (br, 2H), 4.71-4.82 (br, 1H), 6.93- 7.09 (m, 2H), 7.63-7.69 (m, 1H).
LC-MS: RT 5.9 min., M / z 390.1 (M + 1).
実施例３０
４－｛４－［３，３－ビス（３－メトキシプロピル）－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－1－イル］ピペリジン－１－イル｝アゼパン－１－カルボン酸エチル Example 30
4- {4- [3,3-Bis (3-methoxypropyl) -2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} azepan-1-carboxylate ethyl
Figure JPOXMLDOC01-appb-C000107
Figure JPOXMLDOC01-appb-C000107
　実施例１５の化合物を用いて、１，３－ジブロモプロパンの代わりに１－ヨード－３－メトキシプロパンを用いて、実施例６工程２と同様の方法に従い、表題化合物を得た。
LC-MS: R.T. 1.2 min, m/z 530.1 (M+1). 条件Ｃ Using the compound of Example 15 and substituting 1-iodo-3-methoxypropane for 1,3-dibromopropane, the title compound was obtained in the same manner as in Step 2 of Example 6.
LC-MS: RT 1.2 min, m / z 530.1 (M + 1). Condition C
実施例３１
４－｛４－［５－フルオロ－３，３－ビス（ヒドロキシメチル）－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル Example 31
4- {4- [5-Fluoro-3,3-bis (hydroxymethyl) -2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylic acid ethyl
Figure JPOXMLDOC01-appb-C000108
Figure JPOXMLDOC01-appb-C000108
　実施例２９の化合物を用いて、１，３－ジブロモプロパンの代わりにパラホルムアルデヒドを用いて、実施例６工程２と同様の方法に従い、表題化合物を得た。
1H-NMR (CDCl3, 400 MHz) δ7.17(m, 2H), 6.99(m, 1H), 4.16(m, 2H), 3.95(m, 4H), 3.10(m, 3H), 2.75(m, 2H), 2.51-2.39(m, 5H), 1.82(m, 2H), 1.71(m, 2H), 1.63(m, 2H), 1.44(m, 2H), 1.26(t, 3H).
LC-MS: R.T. 6.2 min, m/z 450 (M+1). 条件Ａ Using the compound of Example 29 and substituting paraformaldehyde for 1,3-dibromopropane, the title compound was obtained in the same manner as in Step 2 of Example 6.
1 H-NMR (CDCl 3 , 400 MHz) δ7.17 (m, 2H), 6.99 (m, 1H), 4.16 (m, 2H), 3.95 (m, 4H), 3.10 (m, 3H), 2.75 ( m, 2H), 2.51-2.39 (m, 5H), 1.82 (m, 2H), 1.71 (m, 2H), 1.63 (m, 2H), 1.44 (m, 2H), 1.26 (t, 3H).
LC-MS: RT 6.2 min, m / z 450 (M + 1). Condition A
参考例３９－４５ Reference Example 39-45
　対応する入手可能な原料を用いて、参考例２８－３１と同様の方法に従って、下記化合物を得た。 The following compounds were obtained in the same manner as in Reference Examples 28-31 using the corresponding available raw materials.
Figure JPOXMLDOC01-appb-T000109
Figure JPOXMLDOC01-appb-T000109
参考例４６－５１ Reference Example 46-51
　参考例３９－４１、４３－４５の化合物を用いて、参考例４と同様の方法に従って、下記化合物を得た。 The following compounds were obtained in the same manner as in Reference Example 4 using the compounds of Reference Examples 39-41 and 43-45.
Figure JPOXMLDOC01-appb-T000110
Figure JPOXMLDOC01-appb-T000110
参考例５２－６１ Reference Example 52-61
　参考例３１、３３、３７、３９または４０の化合物を用いて、参考例１３、参考例２０または参考例３５と同様の方法に従って、下記化合物を得た。 Using the compound of Reference Example 31, 33, 37, 39 or 40, the following compound was obtained according to the same method as Reference Example 13, Reference Example 20 or Reference Example 35.
Figure JPOXMLDOC01-appb-T000111
Figure JPOXMLDOC01-appb-T000111
参考例６２
５－フルオロ－３，３－ジメチル－１－（ピペリジン－４－イル）１，３－ジヒドロ－２Ｈ－インドール－２－チオン Reference Example 62
5-Fluoro-3,3-dimethyl-1- (piperidin-4-yl) 1,3-dihydro-2H-indole-2-thione
Figure JPOXMLDOC01-appb-C000112
Figure JPOXMLDOC01-appb-C000112
　参考例３５の化合物を用いて、参考例３６と同様の方法に従って、表題化合物を得た。 The title compound was obtained in the same manner as in Reference Example 36 using the compound of Reference Example 35.
参考例６２
２－（２－アミノ－４－メトキシフェニル）－１，３－プロパン二酸ジｔｅｒｔ－ブチル Reference Example 62
2- (2-Amino-4-methoxyphenyl) -1,3-propanedioic acid ditert-butyl ester
Figure JPOXMLDOC01-appb-C000113
Figure JPOXMLDOC01-appb-C000113
　４－クロロ－２－フルオロニトロベンゼンの代わりに２－クロロ－５－メトキシニトロベンゼンを用い、参考例２８および参考例２９と同様の方法に従って表題化合物を得た。 Using 2-chloro-5-methoxynitrobenzene instead of 4-chloro-2-fluoronitrobenzene, the title compound was obtained in the same manner as in Reference Example 28 and Reference Example 29.
参考例６３
２－（２－｛［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル]アミノ｝－４－メトキシフェニル）－１，３－プロパン二酸ジｔｅｒｔ－ブチル Reference Example 63
2- (2-{[1- (tert-butoxycarbonyl) piperidin-4-yl] amino} -4-methoxyphenyl) -1,3-propanedioic acid ditert-butyl ester
Figure JPOXMLDOC01-appb-C000114
Figure JPOXMLDOC01-appb-C000114
　参考例６２の化合物を用いて、参考例３０と同様の方法に従って表題化合物を得た。 The title compound was obtained in the same manner as in Reference Example 30 using the compound of Reference Example 62.
参考例６４
２－（２－｛［１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－イル]アミノ｝－４－メトキシフェニル）（メチル）－１，３－プロパン二酸ジｔｅｒｔ－ブチル Reference Example 64
2- (2-{[1- (tert-butoxycarbonyl) piperidin-4-yl] amino} -4-methoxyphenyl) (methyl) -1,3-propanedioic acid ditert-butyl ester
Figure JPOXMLDOC01-appb-C000115
Figure JPOXMLDOC01-appb-C000115
　参考例６３の化合物 (2.0 g)をジメチルホルムアミド (20 ml)に溶解し、氷浴下水素化ナトリウム (185 mg)を加え、10分撹拌した。そこにヨウ化メチル (600 mg)を加え、室温で5時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。硫酸ナトリウムで乾燥後、セライト濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製し、表題化合物を得た (1.29 g, 63%)。 Compound の (2.0 g) of Reference Example 63 was dissolved in dimethylformamide (20 ml), sodium hydride (185 mg) was added in an ice bath, and the mixture was stirred for 10 minutes. Thereto was added methyl iodide (600 mg), and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The extract was dried over sodium sulfate, filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (1.29 g, 63%).
参考例６５
４－（６－メトキシ－３－メチル－２－オキソー２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル Reference Example 65
4- (6-Methoxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidine-1-carboxylate tert-butyl
Figure JPOXMLDOC01-appb-C000116
Figure JPOXMLDOC01-appb-C000116
　参考例６４の化合物を用いて、参考例３１と同様の方法に従って、表題化合物を得た。 The title compound was obtained in the same manner as in Reference Example 31 using the compound of Reference Example 64.
参考例６６
６－メトキシ－３－メチル－１－（ピペリジン－１－イル）－１，３－ジヒドロ－２Ｈ－インドール－２－オン Reference Example 66
6-Methoxy-3-methyl-1- (piperidin-1-yl) -1,3-dihydro-2H-indol-2-one
Figure JPOXMLDOC01-appb-C000117
Figure JPOXMLDOC01-appb-C000117
　参考例６５の化合物を用いて、参考例４と同様の方法に従って、表題化合物を得た。 The title compound was obtained in the same manner as in Reference Example 4 using the compound of Reference Example 65.
参考例６７－６９ Reference Example 67-69
　対応する市販の原料を用いて、参考例６２－６６と同様の方法に従って、下記化合物を得た Using the corresponding commercially available raw material, the following compound was obtained according to the same method as in Reference Example 62-66.
Figure JPOXMLDOC01-appb-T000118
Figure JPOXMLDOC01-appb-T000118
実施例３２－９３ Examples 32-93
　参考例４、２２、３２、３４、３７、４６－６２、６７－６９の化合物を用いて、実施例１または実施例１５と同様の方法に従って、下記化合物を得た。1－エトキシカルボニルピペリジンの代わりに、１－メトキシカルボニルピペリジン－４－オン、３－オキソノルトロパン－８－カルボン酸エチル、または１－エトキシカルボニル－４－ホルミルピペリジンを使用したものもある。 Using the compounds of Reference Examples 4, 22, 32, 34, 37, 46-62, and 67-69, the following compounds were obtained in the same manner as in Example 1 or Example 15. Some use 1-methoxycarbonylpiperidin-4-one, ethyl 3-oxonortropane-8-carboxylate, or 1-ethoxycarbonyl-4-formylpiperidine instead of 1-ethoxycarbonylpiperidine.
Figure JPOXMLDOC01-appb-T000119
Figure JPOXMLDOC01-appb-T000119
Figure JPOXMLDOC01-appb-T000120
Figure JPOXMLDOC01-appb-T000120
Figure JPOXMLDOC01-appb-T000121
Figure JPOXMLDOC01-appb-T000121
Figure JPOXMLDOC01-appb-T000122
Figure JPOXMLDOC01-appb-T000122
Figure JPOXMLDOC01-appb-T000123
Figure JPOXMLDOC01-appb-T000123
Figure JPOXMLDOC01-appb-T000124
Figure JPOXMLDOC01-appb-T000124
Figure JPOXMLDOC01-appb-T000125
Figure JPOXMLDOC01-appb-T000125
Figure JPOXMLDOC01-appb-T000126
Figure JPOXMLDOC01-appb-T000126
参考例７０
４－（１，４－ジオキサ－８－アザスピロ［４．５］デカン－８－イル）－４－メチルピペリジン－１－カルボン酸ｔｅｒｔ－ブチル Reference Example 70
4- (1,4-Dioxa-8-azaspiro [4.5] decan-8-yl) -4-methylpiperidine-1-carboxylate tert-butyl
Figure JPOXMLDOC01-appb-C000127
Figure JPOXMLDOC01-appb-C000127
　４－ピペリドンエチレンアセタール (32 g)、Ｎ－Ｂｏｃ－４－ピペリドン (40 g)、１，２，３－トリアゾール (17 g)をトルエン (200 ml)に溶解し、ディーンスターク装置を介して脱水しながら8時間加熱還流した。反応液を室温に冷やし、メチルマグネシウムブロミド (200 mmol, 3 M in ether)の テトラヒドロフラン(200 ml)溶液を、反応液が24℃以下になるように加え、室温で1時間撹拌した。反応液に20%塩化アンモニウム水溶液 (500 ml)を、反応液の温度が30℃以下になるように加えた。酢酸エチルで抽出し、2 mol/L 水酸化ナトリウム、および水で洗浄し、有機層を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製し、表題化合物を得た (20 g, 29%)。 4-piperidone ethylene acetal (32 g), N-Boc-4-piperidone (40 g), 1,2,3-triazole (17 g) were dissolved in toluene (200 ml) and passed through a Dean-Stark apparatus. The mixture was heated to reflux for 8 hours while dehydrating. The reaction solution was cooled to room temperature, and a solution of methylmagnesium bromide (200 mmol, 3 M in ether) in tetrahydrofuran (200 ml) was added so that the reaction solution became 24 ° C or lower, and the mixture was stirred at room temperature for 1 hour. To the reaction solution, 20% aqueous ammonium chloride solution (500 ml) was added so that the temperature of the reaction solution was 30 ° C. or lower. The mixture was extracted with ethyl acetate, washed with 2 mol / L sodium hydroxide and water, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (20 g, 29%).
参考例７１
４－（１，４－ジオキサ－８－アザスピロ［４．５］デカン－８－イル）－４－メチルピペリジン塩酸塩 Reference Example 71
4- (1,4-Dioxa-8-azaspiro [4.5] decan-8-yl) -4-methylpiperidine hydrochloride
Figure JPOXMLDOC01-appb-C000128
Figure JPOXMLDOC01-appb-C000128
　参考例７０の化合物 (14 g)を１，４－ジオキサン (100 ml)に溶解し、6 mol/L 塩酸 (100 ml)を加え、室温で10時間撹拌した。反応液を減圧濃縮し、表題化合物を得た (10 g)。 The compound の (14 g) of Reference Example 70 was dissolved in 1,4-dioxane (100 ml), 6 mol / L HCl (100 ml) was added, and the mixture was stirred at room temperature for 10 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound (10 g).
参考例７２
４－（１，４－ジオキサ－８－アザスピロ［４．５］デカン－８－イル）－４－メチルピペリジン－１－カルボン酸エチル Reference Example 72
Ethyl 4- (1,4-dioxa-8-azaspiro [4.5] decan-8-yl) -4-methylpiperidine-1-carboxylate
Figure JPOXMLDOC01-appb-C000129
Figure JPOXMLDOC01-appb-C000129
　参考例７１の化合物 (5 g)を水 (50 ml)、テトラヒドロフラン (50 ml)に溶解し、炭酸ナトリウム (11 g)を加えた。反応液を室温で30分撹拌後、クロロギ酸エチル (2.9 g)を加え、室温で10時間撹拌した。反応液をジクロロメタンで抽出し、硫酸ナトリウムで乾燥後、減圧濃縮することで、表題化合物を得た (6 g)。 Compound of Example 71 (5 g) was dissolved in water (50 ml) and tetrahydrofuran (50 ml), and sodium carbonate (11 g) was added. The reaction mixture was stirred at room temperature for 30 min, ethyl chloroformate (2.9 g) was added, and the mixture was stirred at room temperature for 10 hr. The reaction mixture was extracted with dichloromethane, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (6 g).
参考例７３
４－（４－オキソピペリジン－１－イル）－４－メチルピペリジン－１－カルボン酸エチル Reference Example 73
Ethyl 4- (4-oxopiperidin-1-yl) -4-methylpiperidine-1-carboxylate
Figure JPOXMLDOC01-appb-C000130
Figure JPOXMLDOC01-appb-C000130
　参考例７２の化合物 (6.0 g)を１，４－ジオキサン (240 ml)に溶解し、6 mol/L 塩酸 (240 ml)を加え、15時間加熱還流した。反応液を室温に冷却し、10%水酸化ナトリウム水溶液を加えた。ジクロロメタンで抽出後、硫酸ナトリウムで乾燥し、減圧濃縮することで表題化合物を得た (5.1 g)。 The compound の (6.0 g) of Reference Example 72 was dissolved in 1,4-dioxane (240 ml), 6 mol / L HCl (240 ml) was added, and the mixture was heated to reflux for 15 hours. The reaction solution was cooled to room temperature and 10% aqueous sodium hydroxide solution was added. After extraction with dichloromethane, drying over sodium sulfate and concentration under reduced pressure gave the title compound (5.1 g).
参考例７４
４－（４－オキソピペリジン－１－イル）－４－メチルピペリジン－１－カルボン酸メチル Reference Example 74
4- (4-Oxopiperidin-1-yl) -4-methylpiperidine-1-carboxylate methyl
Figure JPOXMLDOC01-appb-C000131
Figure JPOXMLDOC01-appb-C000131
　参考例７１の化合物を用いて、クロロギ酸エチルの代わりにクロロギ酸メチルを使用し、参考例７２－７３と同様の方法に従って表題化合物を得た。 Using the compound of Reference Example 71, methyl chloroformate was used instead of ethyl chloroformate, and the title compound was obtained in the same manner as in Reference Examples 72-73.
参考例７５
２－（２－｛１－[（１－エトキシカルボニル）－４－メチルピペリジン－４－イル]－ピペリジン－４－イル｝アミノ－４－メトキシフェニル）－１，３－プロパン二酸ジｔｅｒｔ－ブチル Reference Example 75
2- (2- {1-[(1-ethoxycarbonyl) -4-methylpiperidin-4-yl] -piperidin-4-yl} amino-4-methoxyphenyl) -1,3-propanedioic acid ditert- Butyl
Figure JPOXMLDOC01-appb-C000132
Figure JPOXMLDOC01-appb-C000132
　参考例６２の化合物と、参考例７３の化合物を用いて、参考例３０と同様の方法に従って表題化合物を得た。 The title compound was obtained in the same manner as in Reference Example 30 using the compound of Reference Example 62 and the compound of Reference Example 73.
実施例９４
４－［４－（６－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル]－４－メチルピペリジン－１－カルボン酸エチル Example 94
4- [4- (6-Methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-methylpiperidine-1-carboxylate ethyl
Figure JPOXMLDOC01-appb-C000133
Figure JPOXMLDOC01-appb-C000133
　参考例７５の化合物 (115 mg)、４－エチルベンゼンスルホン酸 (145 mg)をトルエン (2 ml)に溶解し、125℃で3時間撹拌した。反応液に4 mol/L 水酸化ナトリウムを加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、硫酸ナトリウムで乾燥し、セライト濾過した。濾液を減圧濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することで表題化合物をフマル酸塩として得た (40 mg)。
LC-MS: R.T. 5.5 min., m/z 430.2 (M+H). 条件Ａ。
1H-NMR (CD3OD, 400 MHz) δ1.25-1.30 (t, J = 7.0 Hz, 3H), 1.45 (s, 3H), 1.79-1.86 (m, 2H), 1.94-2.06 (m, 4H), 2.74-2.85 (m, 2H), 3.05-3.15 (m, 4H), 3.48 (s, 2H), 2.68-2.74 (m, 2H), 3.81 (s, 3H), 4.11-4.19 (q, J = 7.0 Hz, 4H), 4.34-4.47 (br 1H), 6.60-6.64 (d, J = 8.0 Hz, 1H), 6.71 (s 2H, fumaric acid), 6.80 (s, 1H), 7.16-7.20 (d, J = 8.0 Hz, 1H). The compound of Reference Example 75 (115 mg) and 4-ethylbenzenesulfonic acid (145 mg) were dissolved in toluene (2 ml) and stirred at 125 ° C. for 3 hours. 4 mol / L sodium hydroxide was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, and filtered through celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound as a fumarate salt (40 mg).
LC-MS: RT 5.5 min., M / z 430.2 (M + H). Condition A.
1 H-NMR (CD 3 OD, 400 MHz) δ1.25-1.30 (t, J = 7.0 Hz, 3H), 1.45 (s, 3H), 1.79-1.86 (m, 2H), 1.94-2.06 (m, 4H), 2.74-2.85 (m, 2H), 3.05-3.15 (m, 4H), 3.48 (s, 2H), 2.68-2.74 (m, 2H), 3.81 (s, 3H), 4.11-4.19 (q, J = 7.0 Hz, 4H), 4.34-4.47 (br 1H), 6.60-6.64 (d, J = 8.0 Hz, 1H), 6.71 (s 2H, fumaric acid), 6.80 (s, 1H), 7.16-7.20 ( d, J = 8.0 Hz, 1H).
実施例９５－９６ Examples 95-96
　対応する中間体を用いて、実施例９４と同様の方法に従って、下記化合物を得た。 The following compound was obtained in the same manner as in Example 94 using the corresponding intermediate.
Figure JPOXMLDOC01-appb-T000134
Figure JPOXMLDOC01-appb-T000134
参考例７６
２－（２－｛１－[（１－エトキシカルボニル）－４－メチルピペリジン－４－イル]－ピペリジン－４－イル｝アミノ－４－メトキシフェニル）（メチル）－１，３－プロパン二酸ジｔｅｒｔ－ブチル Reference Example 76
2- (2- {1-[(1-ethoxycarbonyl) -4-methylpiperidin-4-yl] -piperidin-4-yl} amino-4-methoxyphenyl) (methyl) -1,3-propanedioic acid Di-tert-butyl
Figure JPOXMLDOC01-appb-C000135
Figure JPOXMLDOC01-appb-C000135
　参考例７５の化合物を用いて、参考例６４と同様の方法に従って表題化合物を得た。 The title compound was obtained in the same manner as in Reference Example 64 using the compound of Reference Example 75.
実施例９７
４－［４－（６－メトキシ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル]－４－メチルピペリジン－１－カルボン酸エチル Example 97
4- [4- (6-Methoxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-methylpiperidine-1-carboxylate ethyl
Figure JPOXMLDOC01-appb-C000136
Figure JPOXMLDOC01-appb-C000136
　参考例７６の化合物を用いて、実施例９４と同様の方法に従って表題化合物を得た。
LC-MS: R.T. 5.5 min., m/z 430.20 (M+1). 条件Ａ。 The title compound was obtained in the same manner as in Example 94 using the compound of Reference Example 76.
LC-MS: RT 5.5 min., M / z 430.20 (M + 1). Condition A.
参考例７７
（３－ｅｎｄｏ）－３－アミノ－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル Reference Example 77
(3-endo) -3-Amino-8-azabicyclo [3.2.1] octane-8-carboxylate ethyl
Figure JPOXMLDOC01-appb-C000137
Figure JPOXMLDOC01-appb-C000137
　３－オキソノルトロパン－８－カルボン酸 (3.3 g)をメタノール (50 ml)と水 (5 ml)に溶解し、ギ酸アンモニウム (9.5 g)と10%Pd/C (3.0 g)を加え、室温で24時間撹拌した。反応液を濾過し、減圧濃縮することで、表題化合物を得た (3.9 g, 74%)。 3-Oxonortropane-8-carboxylic acid (3.3 g) was dissolved in methanol (50 ml) and water (5 ml), and ammonium formate (9.5 g) and 10% Pd / C (3.0 g) were added. For 24 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain the title compound (3.9 g, 74%).
参考例７８
１－エチルメチル－４－オキソピペリジニウムヨージド Reference Example 78
1-ethylmethyl-4-oxopiperidinium iodide
Figure JPOXMLDOC01-appb-C000138
Figure JPOXMLDOC01-appb-C000138
　１－エチル－４－ピペリドン (5.0 g)をアセトン (80 ml)に溶解し、室温下ヨウ化メチル (3.18 ml)を加え、2.5時間撹拌した。析出した固体を濾取し、減圧下乾燥することで、表題化合物を得た(9.11 g, 86%)。 1-Ethyl-4-piperidone (5.0 g) was dissolved in acetone (80 ml), methyl iodide (3.18 ml) was added at room temperature, and the mixture was stirred for 2.5 hours. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (9.11 g, 86%).
参考例７９
（３－ｅｎｄｏ）－３－（４－オキソピペリジン－１－イル）－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル Reference Example 79
(3-endo) -3- (4-Oxopiperidin-1-yl) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure JPOXMLDOC01-appb-C000139
Figure JPOXMLDOC01-appb-C000139
　参考例７７の化合物 (2.0 g)をエタノール (60 ml)と水 (30 ml)に溶解し、参考例７８の化合物 (2.7 g)と炭酸カリウム (2.8 g)を加え、24時間加熱還流した。反応液を室温に冷却し、溶媒を減圧濃縮した。得られた残渣を酢酸エチルで抽出し、水で洗浄後、有機層を硫酸ナトリウムで乾燥した。セライト濾過後、濾液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーにて精製し、表題化合物を得た (1.9 g, 67%)。 Compound (2.0 g) of Reference Example 77 was dissolved in ethanol (60 ml) and water candy (30 ml), Compound (2.7 g) of Reference Example 78 and potassium carbonate (2.8 g) were added, and the mixture was heated to reflux for 24 hours. The reaction solution was cooled to room temperature, and the solvent was concentrated under reduced pressure. The obtained residue was extracted with ethyl acetate, washed with water, and the organic layer was dried over sodium sulfate. After filtration through celite, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain the title compound (1.9 g, 67%).
参考例８０
２―［（３－ｅｘｏ）－８－メチル－８－アザビシクロ［３．２．１］オクタン－３－イル］－１Ｈ－イソインドール－１，３（２Ｈ）－ジオン Reference Example 80
2-[(3-exo) -8-Methyl-8-azabicyclo [3.2.1] octane-3-yl] -1H-isoindole-1,3 (2H) -dione
Figure JPOXMLDOC01-appb-C000140
Figure JPOXMLDOC01-appb-C000140
　トロピン (15.0 g)、フタルイミド (18.8 g)、およびトリフェニルホスフィン (42.0 g)をテトラヒドロフランに溶解し、０℃に冷却後、ジイソプロピルアゾジカルボキシレート (31.3 ml)を加え、室温に昇温した後20時間撹拌した。反応液を1 mol/L 塩酸水溶液で抽出し、酢酸エチルで洗浄した。水槽に炭酸ナトリウムを加え、溶液を塩基性にした後、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥し、セライト濾過後、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することで、表題化合物を得た (8.0 g, 28%)。 Tropin (15.0 g), phthalimide (18.8 g), and triphenylphosphine (42.0 g) were dissolved in tetrahydrofuran, cooled to 0 ° C, diisopropyl azodicarboxylate (31.3 ml) was added, and the temperature was raised to room temperature. Stir for 20 hours. The reaction mixture was extracted with 1 mol / L hydrochloric acid aqueous solution and washed with ethyl acetate. Sodium carbonate was added to the water bath to make the solution basic, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate, filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (8.0 kg, 28%).
参考例８１
（３－ｅｘｏ）－３－（１，３－ジオキソ－１，３－ジヒドロ－２Ｈ－イソインドール－２－イル）－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル Reference Example 81
(3-exo) -3- (1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure JPOXMLDOC01-appb-C000141
Figure JPOXMLDOC01-appb-C000141
　参考例８０の化合物 (8.0 g)をトルエンに溶解し、室温下クロロギ酸エチル (4.3 ml)を滴下した後、10分後昇温し、24時間加熱還流した。室温に冷却後、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、硫酸ナトリウムで乾燥後、セライト濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することで、表題化合物を得た (4.9 g, 50%)。 The compound の (8.0 g) of Reference Example 80 was dissolved in toluene, and after adding ethyl chloroformate (4.3 滴下 ml) dropwise at room temperature, the temperature was raised after 10 minutes and the mixture was heated to reflux for 24 hours. After cooling to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (4.9 g, 50%).
参考例８２
（３－ｅｘｏ）－３－アミノ－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル Reference Example 82
(3-exo) -3-Amino-8-azabicyclo [3.2.1] octane-8-carboxylate ethyl
Figure JPOXMLDOC01-appb-C000142
Figure JPOXMLDOC01-appb-C000142
　参考例８１の化合物 (4.9 ｇ)をエタノール (50 ml)に溶解し、ヒドラジン１水和物を加えた後に昇温し、24時間加熱還流した。反応液を室温に冷却後、減圧濃縮した。得られた固体をエタノールで3回洗浄し、濾液を減圧濃縮することで白色固体を得た。得られた固体を酢酸エチルに溶解した後に濾過し、濾液を減圧濃縮することで、表題化合物を得た (2.9 g, 定量的)。 The compound の (4.9 g) of Reference Example 81 was dissolved in ethanol (50 ml), hydrazine monohydrate was added, the temperature was raised, and the mixture was heated to reflux for 24 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The obtained solid was washed three times with ethanol, and the filtrate was concentrated under reduced pressure to obtain a white solid. The obtained solid was dissolved in ethyl acetate and filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (2.9 g, quantitative).
参考例８３
（３－ｅｘｏ）－３－（４－オキソピペリジン－１－イル）－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル Reference Example 83
(3-exo) -3- (4-Oxopiperidin-1-yl) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure JPOXMLDOC01-appb-C000143
Figure JPOXMLDOC01-appb-C000143
　参考例８２の化合物を用いて、参考例７９と同様の方法に従って、表題化合物を得た。 The title compound was obtained in the same manner as in Reference Example 79 using the compound of Reference Example 82.
参考例８４
２－（２－｛１－［（３－ｅｎｄｏ）－８－（エトキシカルボニル）－８－アザビシクロ［３．２．１］オクタン－３－イル］－ピペリジン－４－イル｝アミノ－４－メチルフェニル）－１，３－プロパン二酸ジｔｅｒｔ－ブチル Reference Example 84
2- (2- {1-[(3-endo) -8- (ethoxycarbonyl) -8-azabicyclo [3.2.1] octane-3-yl] -piperidin-4-yl} amino-4-methyl Phenyl) -1,3-propanedioic acid ditert-butyl
Figure JPOXMLDOC01-appb-C000144
Figure JPOXMLDOC01-appb-C000144
　参考例４７の合成中間体と、参考例７９を用いて、参考例３０と同様の方法に従って表題化合物を得た。 Using the synthesis intermediate of Reference Example 47 and Reference Example 79, the title compound was obtained in the same manner as in Reference Example 30.
実施例９８
（３－ｅｎｄｏ）－３－［４－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル Example 98
(3-endo) -3- [4- (6-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2.1 ] Ethyl octane-8-carboxylate
Figure JPOXMLDOC01-appb-C000145
Figure JPOXMLDOC01-appb-C000145
　参考例８４の化合物を用いて、実施例９４と同様の反応に従って表題化合物を得た。
1H-NMR (CDCl3, 400 MHz) δ 1.27 (t, J = 7.1 Hz, 3H), 1.50-1.76 (m, 4H), 1.85-2.09 (m, 6H), 2.10-2.30 (m, 2H), 2.37 (s, 3H), 2.33-2.49 (m, 2H), 3.22 (d, J = 11.2 Hz, 2H), 4.09-4.42 (m, 5H), 6.83 (d, J = 7.3 Hz, 1H), 6.91 (s, 1H), 7.11 (d, J = 7.3 Hz, 1H).
LC-MS: R.T. 3.3 min., m/z 412.3 (M+1). 条件Ｂ。 The title compound was obtained in the same manner as in Example 94 using the compound of Reference Example 84.
1 H-NMR (CDCl 3 , 400 MHz) δ 1.27 (t, J = 7.1 Hz, 3H), 1.50-1.76 (m, 4H), 1.85-2.09 (m, 6H), 2.10-2.30 (m, 2H) , 2.37 (s, 3H), 2.33-2.49 (m, 2H), 3.22 (d, J = 11.2 Hz, 2H), 4.09-4.42 (m, 5H), 6.83 (d, J = 7.3 Hz, 1H), 6.91 (s, 1H), 7.11 (d, J = 7.3 Hz, 1H).
LC-MS: RT 3.3 min., M / z 412.3 (M + 1). Condition B.
実施例９９－１０３ Examples 99-103
　対応する中間体と、参考例７９または参考例８３の化合物を用いて、実施例９８と同様の方法に従って下記化合物を得た。 The following compound was obtained in the same manner as in Example 98 using the corresponding intermediate and the compound of Reference Example 79 or Reference Example 83.
Figure JPOXMLDOC01-appb-T000146
Figure JPOXMLDOC01-appb-T000146
参考例８５
２－（２－｛１－［（３－ｅｎｄｏ）－８－（エトキシカルボニル）－８－アザビシクロ［３．２．１］オクタン－３－イル］－ピペリジン－４－イル｝アミノ－４－メチルフェニル）（メチル）－１，３－プロパン二酸ジｔｅｒｔ－ブチル Reference Example 85
2- (2- {1-[(3-endo) -8- (ethoxycarbonyl) -8-azabicyclo [3.2.1] octane-3-yl] -piperidin-4-yl} amino-4-methyl Phenyl) (methyl) -1,3-propanedioic acid di-tert-butyl
Figure JPOXMLDOC01-appb-C000147
Figure JPOXMLDOC01-appb-C000147
　参考例８４の化合物を用いて、参考例６４と同様の方法に従って、表題化合物を得た。 The title compound was obtained in the same manner as in Reference Example 64 using the compound of Reference Example 84.
実施例１０４
（３－ｅｎｄｏ）－３－［４－（３，６－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル Example 104
(3-endo) -3- [4- (3,6-Dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2 .1] Ethyl octane-8-carboxylate
Figure JPOXMLDOC01-appb-C000148
Figure JPOXMLDOC01-appb-C000148
　参考例８５の化合物を用いて、実施例９４と同様の方法に従って、表題化合物を得た。
1H-NMR (CDCl3, 400 MHz) δ 1.20 (t, J = 7.1 Hz, 3H), 1.36, 1.38 (s, 3H, ratio = 1 : 1), 2.55-2.68 (m, 4H), 2.02-2.76 (m, 6H), 2.21-2.04 (m, 2H), 2.31 (s, 3H), 2.41-2.31 (m, 2H), 3.12-3.32 (m, 4H), 4.07 (q, J = 7.1 Hz, 2H), 4.13-4.28 (m, 1H), 6.78 (d, J = 7.4 Hz, 1H), 6.84 (s, 1H), 7.04 (d, J = 7.4 Hz, 1H).
LC-MS: R.T. 6.1 min., m/z 426.2 (M+1). 条件Ａ。 The title compound was obtained in the same manner as in Example 94 using the compound of Reference Example 85.
1 H-NMR (CDCl 3 , 400 MHz) δ 1.20 (t, J = 7.1 Hz, 3H), 1.36, 1.38 (s, 3H, ratio = 1: 1), 2.55-2.68 (m, 4H), 2.02- 2.76 (m, 6H), 2.21-2.04 (m, 2H), 2.31 (s, 3H), 2.41-2.31 (m, 2H), 3.12-3.32 (m, 4H), 4.07 (q, J = 7.1 Hz, 2H), 4.13-4.28 (m, 1H), 6.78 (d, J = 7.4 Hz, 1H), 6.84 (s, 1H), 7.04 (d, J = 7.4 Hz, 1H).
LC-MS: RT 6.1 min., M / z 426.2 (M + 1). Condition A.
実施例１０５－１０６ Examples 105-106
　対応する中間体を用いて、実施例１０４と同様の方法に従って下記化合物を得た。 The following compound was obtained in the same manner as in Example 104 using the corresponding intermediate.
Figure JPOXMLDOC01-appb-T000149
Figure JPOXMLDOC01-appb-T000149
参考例８６
４－［５－フルオロ－２－オキソ－３－（プロパン－２－イリデン）－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル Reference Example 86
4- [5-Fluoro-2-oxo-3- (propane-2-ylidene) -2,3-dihydro-1H-indol-1-yl] piperidine-1-carboxylate tert-butyl
Figure JPOXMLDOC01-appb-C000150
Figure JPOXMLDOC01-appb-C000150
　参考例３３の化合物 (100 mg)のジクロロメタン (2 ml)溶液に、チタニウムテトライソプロポキシド (425 mg)、アセトン (87 mg)を加え、50℃で終夜撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、セライト濾過し、クロロホルムで洗浄、抽出した。得られた有機層を硫酸ナトリウムで乾燥し、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ーにて精製し、表題化合物を得た (122 mg, 定量的)。 Titanium tetraisopropoxide (425 mg) and acetone (87 mg) were added to a dichloromethane (2 mg) solution of the compound (100 mg) of Reference Example 33 and stirred at 50 ° C. overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was filtered through celite, washed with chloroform, and extracted. The obtained organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (122 mg, quantitative).
参考例８７
４－［５－フルオロ－２－オキソ－３－（プロパン－２－イリデン）－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン Reference Example 87
4- [5-Fluoro-2-oxo-3- (propane-2-ylidene) -2,3-dihydro-1H-indol-1-yl] piperidine
Figure JPOXMLDOC01-appb-C000151
Figure JPOXMLDOC01-appb-C000151
　参考例８６の化合物を用いて、参考例４と同様の方法に従って、表題化合物を得た。 The title compound was obtained in the same manner as in Reference Example 4 using the compound of Reference Example 86.
実施例１０７
４－｛４－［５－フルオロ－２－オキソ－３－（プロパン－２－イリデン）－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル Example 107
4- {4- [5-Fluoro-2-oxo-3- (propane-2-ylidene) -2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylic acid ethyl
Figure JPOXMLDOC01-appb-C000152
Figure JPOXMLDOC01-appb-C000152
　参考例８７の化合物を用いて、実施例１と同様の方法に従って、表題化合物を得た。
1H-NMR (CDCl3, 400 MHz) δ1.26 (m, 3H), 1.44-1.84 (m, 14H), 2.48-2.36 (m, 5H), 2.76 (t, 2H), 3.02-3.15 (m, 4H), 3.77-3.87 (m, 5H), 4.18 (m, 4H), 6.90 (m, 1H), 7.06 (m, 1H), 7.29 (m, 1H).
LC-MS: R.T. 6.8 min., m/z 430 (M+H). 条件Ａ。 The title compound was obtained in the same manner as in Example 1 using the compound of Reference Example 87.
1 H-NMR (CDCl 3 , 400 MHz) δ1.26 (m, 3H), 1.44-1.84 (m, 14H), 2.48-2.36 (m, 5H), 2.76 (t, 2H), 3.02-3.15 (m , 4H), 3.77-3.87 (m, 5H), 4.18 (m, 4H), 6.90 (m, 1H), 7.06 (m, 1H), 7.29 (m, 1H).
LC-MS: RT 6.8 min., M / z 430 (M + H). Condition A.
実施例１０８
４－｛４－［５－フルオロ－２－オキソ－３－（プロパン－２－イル）－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル Example 108
4- {4- [5-Fluoro-2-oxo-3- (propan-2-yl) -2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylic acid ethyl
Figure JPOXMLDOC01-appb-C000153
Figure JPOXMLDOC01-appb-C000153
　実施例１０７の化合物 (20 mg)をメタノール (1 ml)に溶解し、10%パラジウム/炭素 (10 mg)を加え、水素雰囲気下終夜撹拌した。反応液をセライト濾過し、減圧濃縮することで、表題化合物 (13 mg, 65%)を得た。
1H-NMR (CDCl3, 400 MHz) δ0.83 (d, 3H), 1.06 (d, 3H), 1.26 (t, 3H), 1.42 (m, 2H), 1.67-1.83 (m, 6H), 2.36-2.48 (m, 5H), 2.75 (t, 2H), 3.02 (m, 2H), 3.32 (m, 1H), 4.10-4.27 (m, 5H), 6.90 (m, 1H), 6.95 (m, 1H), 7.05 (m, 1H).
LC-MS: R.T. 7.0 min., m/z 432 (M+H). 条件Ａ。 The compound of Example 107 (20 mg) was dissolved in methanol (1 ml), 10% palladium / carbon (10 mg) was added, and the mixture was stirred overnight under a hydrogen atmosphere. The reaction mixture was filtered through celite and concentrated under reduced pressure to give the title compound (13 mg, 65%).
1 H-NMR (CDCl 3 , 400 MHz) δ0.83 (d, 3H), 1.06 (d, 3H), 1.26 (t, 3H), 1.42 (m, 2H), 1.67-1.83 (m, 6H), 2.36-2.48 (m, 5H), 2.75 (t, 2H), 3.02 (m, 2H), 3.32 (m, 1H), 4.10-4.27 (m, 5H), 6.90 (m, 1H), 6.95 (m, 1H), 7.05 (m, 1H).
LC-MS: RT 7.0 min., M / z 432 (M + H). Condition A.
実施例１０９－１４７ Examples 109-147
　参考例３、３１、３３または４０の化合物と、対応する試薬を用いて、実施例１０７または実施例１０８と同様の方法に従って、下記化合物を合成した。 The following compounds were synthesized in the same manner as in Example 107 or Example 108 using the compounds of Reference Example 3, 31, 33 or 40 and the corresponding reagents.
Figure JPOXMLDOC01-appb-T000154
Figure JPOXMLDOC01-appb-T000154
Figure JPOXMLDOC01-appb-T000155
Figure JPOXMLDOC01-appb-T000155
Figure JPOXMLDOC01-appb-T000156
Figure JPOXMLDOC01-appb-T000156
Figure JPOXMLDOC01-appb-T000157
Figure JPOXMLDOC01-appb-T000157
参考例８８
４－｛４－［６－メトキシ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル Reference Example 88
4- {4- [6-Methoxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylate ethyl
Figure JPOXMLDOC01-appb-C000158
Figure JPOXMLDOC01-appb-C000158
　参考例６６の化合物を用いて、実施例１と同様の方法に従って表題化合物を得た。 The title compound was obtained in the same manner as in Example 1 using the compound of Reference Example 66.
実施例１４８
４－｛４－［３－ヒドロキシメチル－６－メトキシ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル Example 148
4- {4- [3-Hydroxymethyl-6-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylate
Figure JPOXMLDOC01-appb-C000159
Figure JPOXMLDOC01-appb-C000159
　参考例８８の化合物 (33 mg)、炭酸カリウム (33 mg)、パラホルムアルデヒド (21 mg)をテトラヒドロフラン (2 ml)に溶解し、６０℃で２時間撹拌した。反応液を濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製し、表題化合物をフマル酸塩として得た (19 mg, 43%)。
1H-NMR (CD3OD, 400 MHz) δ1.14-1.21 (t, J = 7.1 Hz, 3H), 1.23-1.27 (t, J = 7.2 Hz, 3H), 1.58-1.66 (m 2H), 1.91-1.98 (m, 2H), 2.04-2.11 (m, 2H), 2.70-2.92 (br 4H), 3.00-3.09 (m, 2H), 3.44-3.51 (q, J = 7.2 Hz, 1H), 3.51-3.58 (m, 2H), 3.73 (s, 2H), 3.81 (s, 3H), 4.08-4.15 (q, J = 7.1 Hz, 2H), 4.23-4.36 (m, 3H), 6.62-6.65 (dd J = 8.1 Hz, 2.2 Hz, 1H), 6.79-6.81 (d, J = 2.2 Hz, 1H), 7.18-7.22 (d, J = 8.1 Hz, 1H).
LC-MS: R.T. 5.7 min., m/z 446.2 (M+H). 条件Ａ。 The compound of Reference Example 88 (33 mg), potassium carbonate (33 mg) and paraformaldehyde (21 mg) were dissolved in tetrahydrofuran (2 ml) and stirred at 60 ° C. for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a fumarate salt (19 mg, 43%).
1 H-NMR (CD 3 OD, 400 MHz) δ1.14-1.21 (t, J = 7.1 Hz, 3H), 1.23-1.27 (t, J = 7.2 Hz, 3H), 1.58-1.66 (m 2H), 1.91-1.98 (m, 2H), 2.04-2.11 (m, 2H), 2.70-2.92 (br 4H), 3.00-3.09 (m, 2H), 3.44-3.51 (q, J = 7.2 Hz, 1H), 3.51 -3.58 (m, 2H), 3.73 (s, 2H), 3.81 (s, 3H), 4.08-4.15 (q, J = 7.1 Hz, 2H), 4.23-4.36 (m, 3H), 6.62-6.65 (dd J = 8.1 Hz, 2.2 Hz, 1H), 6.79-6.81 (d, J = 2.2 Hz, 1H), 7.18-7.22 (d, J = 8.1 Hz, 1H).
LC-MS: RT 5.7 min., M / z 446.2 (M + H). Condition A.
実施例１４９－１６０ Examples 149-160
　実施例１、６６－７１、７５、７６、１０４、１０５または１３６の化合物を用いて、実施例１４８と同様の方法に従って下記化合物を得た。 Using the compound of Example 1, 66-71, 75, 76, 104, 105, or 136, the following compound was obtained in the same manner as in Example 148.
Figure JPOXMLDOC01-appb-T000160
Figure JPOXMLDOC01-appb-T000160
Figure JPOXMLDOC01-appb-T000161
Figure JPOXMLDOC01-appb-T000161
実施例１６１
４－｛４－［３－エチル－３，６－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル Example 161
4- {4- [3-Ethyl-3,6-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylate
Figure JPOXMLDOC01-appb-C000162
Figure JPOXMLDOC01-appb-C000162
　実施例１の化合物を用いて、パラホルムアルデヒドの代わりに、ヨウ化エチルを用いて、実施例１４８と同様の方法に従って、表題化合物をフマル酸塩として得た。
1H-NMR (DMSO-d6, 400 MHz) δ0.39-0.44 (t, J = 7.2 Hz, 3H), 1.14-1.19 (t, J = 7.2 Hz, 6H), 1.28-1.39 (m, 2H), 1.51-1.58 (br, 2H), 1.67-1.73 (q, J = 7.2 Hz, 2H), 1.74-1.80 (m, 2H), 2.31 (s, 3H), 2.31-2.40 (m, 4H), 2.58-2.65 (m, 1H), 1.69-2.80 (br, 2H), 2.97-3.00 (br, 2H), 3.97-4.08 (q, J = 7.2 Hz, 5H), 6.59 (s, 2H, fumaric acid), 6.80-6.84 (d, J =7.4 Hz, 1H), 6.95 (s, 1H), 7.11-7.14 (d, J = 7.4 Hz, 1H).
LC-MS: R.T. 6.9 min., m/z 428.2 (M+H). 条件Ａ。 The title compound was obtained as a fumarate salt in the same manner as in Example 148 using ethyl iodide in place of paraformaldehyde.
1 H-NMR (DMSO-d 6 , 400 MHz) δ0.39-0.44 (t, J = 7.2 Hz, 3H), 1.14-1.19 (t, J = 7.2 Hz, 6H), 1.28-1.39 (m, 2H ), 1.51-1.58 (br, 2H), 1.67-1.73 (q, J = 7.2 Hz, 2H), 1.74-1.80 (m, 2H), 2.31 (s, 3H), 2.31-2.40 (m, 4H), 2.58-2.65 (m, 1H), 1.69-2.80 (br, 2H), 2.97-3.00 (br, 2H), 3.97-4.08 (q, J = 7.2 Hz, 5H), 6.59 (s, 2H, fumaric acid) , 6.80-6.84 (d, J = 7.4 Hz, 1H), 6.95 (s, 1H), 7.11-7.14 (d, J = 7.4 Hz, 1H).
LC-MS: RT 6.9 min., M / z 428.2 (M + H). Condition A.
実施例１６２
４－｛４－［６－フルオロ－２－オキソ－２´，３´，５´，６´－テトラヒドロスピロ（インドール－３，４´－ピラン）－１（２Ｈ）－イル］ピペリジン－１－イル｝－４－メチルピペリジン－１－カルボン酸エチル Example 162
4- {4- [6-Fluoro-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro (indole-3,4′-pyran) -1 (2H) -yl] piperidine-1- Yl} -4-methylpiperidine-1-carboxylate
Figure JPOXMLDOC01-appb-C000163
Figure JPOXMLDOC01-appb-C000163
　実施例９５の化合物を用いて、１，３－ジブロモプロパンの代わりに、ビス（２－ブロモエチル）エーテルを用いて、実施例６工程２と同様の方法に従って、表題化合物を得た。
LC-MS: R.T. 5.5 min., m/z 474.2 (M+H). 条件Ａ。 Using the compound of Example 95 and substituting bis (2-bromoethyl) ether for 1,3-dibromopropane, the title compound was obtained in the same manner as in Step 2 of Example 6.
LC-MS: RT 5.5 min., M / z 474.2 (M + H). Condition A.
実施例１６３－１６５ Examples 163-165
　実施例９６、９８または１０１の化合物を用いて、実施例１６２と同様の方法に従い、下記化合物を得た。 Using the compound of Example 96, 98 or 101, the following compound was obtained in the same manner as in Example 162.
Figure JPOXMLDOC01-appb-T000164
Figure JPOXMLDOC01-appb-T000164
参考例８９
４－（４－オキソピペリジン－１－イル）ピペリジン－１－カルボン酸エチル Reference Example 89
4- (4-Oxopiperidin-1-yl) piperidine-1-carboxylate ethyl
Figure JPOXMLDOC01-appb-C000165
Figure JPOXMLDOC01-appb-C000165
　入手可能な１－エトキシカルボニル－４－ピペリドンと、参考例７８の化合物を用いて、参考例７９と同様の方法に従って、表題化合物を得た。 The title compound was obtained in the same manner as in Reference Example 79 using 1-ethoxycarbonyl-4-piperidone that was available and the compound of Reference Example 78.
参考例９０
４－［４－（４－クロロフェニル）アミノピペリジン－１－イル］ピペリジン－１－カルボン酸エチル Reference Example 90
Ethyl 4- [4- (4-chlorophenyl) aminopiperidin-1-yl] piperidine-1-carboxylate
Figure JPOXMLDOC01-appb-C000166
Figure JPOXMLDOC01-appb-C000166
　パラ－クロロアニリン (752 mg)、参考例８９の化合物 (1.5 g)をジクロロメタン (10 ml)に溶解し、トリアセトキシ水素化ホウ素ナトリウム (1.6 g)、酢酸 (500 mg)を加え、室温で6時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。得られた有機層を硫酸水素ナトリウムで乾燥し、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ーにて精製し、表題化合物を得た (1.6 g, 74%)。 Para-chloroaniline (752 mg), Compound の (1.5 g) of Reference Example 89 was dissolved in dichloromethane (10 ml), sodium triacetoxyborohydride (1.6 g) and acetic acid (500 mg) were added. Stir for hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The obtained organic layer was dried over sodium hydrogen sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (1.6 g, 74%).
参考例９１
４－｛４－［５－クロロ－２，３－ジオキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル Reference Example 91
4- {4- [5-Chloro-2,3-dioxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylate ethyl
Figure JPOXMLDOC01-appb-C000167
Figure JPOXMLDOC01-appb-C000167
　参考例９０の化合物 (1.6 g)をジエチルエーテル (50 ml)に溶解し、二塩化オキサリル (1.1 ml)を加え、2時間加熱還流した。反応液を室温に戻し、減圧濃縮した後、ジクロロメタン (50 ml)に溶解させ、氷冷下三塩化アルミニウム (3.48 g)を加えた。その後室温で2時間撹拌後、飽和炭酸水素ナトリウムを加えた。反応液をセライト濾過し、濾液を減圧濃縮後、シリカゲルカラムクロマトグラフィーにて精製し、表題化合物を得た。 Compound (1.6 g) of Reference Example 90 was dissolved in diethyl ether (50 ml), oxalyl dichloride (1.1 ml) was added, and the mixture was heated to reflux for 2 hours. The reaction solution was returned to room temperature, concentrated under reduced pressure, dissolved in dichloromethane (50 ml), and aluminum trichloride (3.48 g) was added under ice cooling. After stirring at room temperature for 2 hours, saturated sodium hydrogen carbonate was added. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound.
参考例９２
４－｛４－［５－クロロ－３－ヒドロキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル Reference Example 92
4- {4- [5-Chloro-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylate
Figure JPOXMLDOC01-appb-C000168
Figure JPOXMLDOC01-appb-C000168
　参考例９１の化合物 (150 mg)をメタノール (3 ml)に溶解し、氷冷下水素化ホウ素ナトリウム (67 mg)を加え、1時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を硫酸ナトリウムで乾燥し、減圧濃縮することにより、表題化合物を得た (85 mg, 56%)。 Compound の (150 mg) of Reference Example 91 was dissolved in methanol (3 ml), sodium borohydride (67 mg) was added under ice cooling, and the mixture was stirred for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (85 mg, 56%).
実施例１６６
４－｛４－［３－ヒドロキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル Example 166
4- {4- [3-Hydroxy-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylate
Figure JPOXMLDOC01-appb-C000169
Figure JPOXMLDOC01-appb-C000169
　パラ－クロロアニリンの代わりにアニリンを用いて、参考例９０－９２と同様の方法に従って、表題化合物を得た。
1H-NMR (CDCl3, 400 MHz) δ1.26 (m, 3H), 1.47 (m, 3H), 1.62 (m, 2H), 1.80 (m, 2H), 2.28-2.38 (m, 4H), 2.75 (m, 2H), 2.93 (m, 1H), 3.04 (m 2H), 4.10-4.16 (m, 4H), 4.99 (s, 1H), 7.06-7.10 (m, 3H), 7.46 (m, 1H).
LC-MS: R.T. 3.1 min., m/z 388 (M+H). 条件Ａ。 The title compound was obtained in the same manner as in Reference Examples 90-92 using aniline instead of para-chloroaniline.
1 H-NMR (CDCl 3 , 400 MHz) δ1.26 (m, 3H), 1.47 (m, 3H), 1.62 (m, 2H), 1.80 (m, 2H), 2.28-2.38 (m, 4H), 2.75 (m, 2H), 2.93 (m, 1H), 3.04 (m 2H), 4.10-4.16 (m, 4H), 4.99 (s, 1H), 7.06-7.10 (m, 3H), 7.46 (m, 1H ).
LC-MS: RT 3.1 min., M / z 388 (M + H). Condition A.
実施例１６７－１７１ Examples 167-171
　実施例１６記載の工程３と同様の方法に従い、エチルチオカルボニルクロリドの代わりに、入手可能なクロロギ酸エステルを用いて、下記化合物を合成した。 In the same manner as in Step 3 described in Example 16, the following compound was synthesized using an available chloroformate instead of ethylthiocarbonyl chloride.
Figure JPOXMLDOC01-appb-T000170
Figure JPOXMLDOC01-appb-T000170
実施例１７２－１７５ Examples 172-175
　実施例１６記載の工程１－３と同様の方法に従い、１－ｔｅｒｔ－ブトキシカルボニル－４－ピペリドンの代わりに、１－ｔｅｒｔブトキシカルボニル－４－アゼパノンを用い、またエチルチオカルボニルクロリドの代わりに、入手可能なクロロギ酸エステルを用いて、下記化合物を合成した。 According to the same method as in Step 1-3 described in Example 16, substituting 1-tert-butoxycarbonyl-4-azepanone for 1-tert-butoxycarbonyl-4-piperidone, and instead of ethylthiocarbonyl chloride, The following compounds were synthesized using available chloroformate esters.
Figure JPOXMLDOC01-appb-T000171
Figure JPOXMLDOC01-appb-T000171
実施例１７６－１８２ Examples 176-182
　参考例３２または４７の化合物を用いて、実施例１６記載の工程１－３と同様の方法に従い、エチルチオカルボニルクロリドの代わりに、入手可能なクロロギ酸エステルを用いて、下記化合物を合成した。 Using the compound of Reference Example 32 or 47 and following the same method as in Step 1-3 described in Example 16, the following compound was synthesized using an available chloroformate instead of ethylthiocarbonyl chloride.
Figure JPOXMLDOC01-appb-T000172
Figure JPOXMLDOC01-appb-T000172
実施例１８３
４－｛４－［５－クロロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝アゼパン－１－カルボン酸メチル Example 183
4- {4- [5-Chloro-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} azepane-1-carboxylate methyl
Figure JPOXMLDOC01-appb-C000173
Figure JPOXMLDOC01-appb-C000173
　参考例３２の化合物を用いて、実施例１６記載の工程１－３と同様の方法に従い、１－ｔｅｒｔ－ブトキシカルボニル－４－ピペリドンの代わりに、１－ｔｅｒｔブトキシカルボニル－４－アゼパノンを用い、またエチルチオカルボニルクロリドの代わりに、クロロギ酸メチルを用いて、表題化合物のフマル酸塩を得た。
1H-NMR (DMSO-d6, 400 MHz) δ1.01-1.09 (m, 1H), 1.12-1.18 (td, J = 7.1, 3.3 Hz), 1.38-1.40 (m 2H), 1.55-1.65 (m, 3H), 1.77-1.97 (m, 3H), 2.28-2.40 (m, 2H), 2.50-2.58 (m, 1H), 2.63-2.70 (br, 1H), 2.91-2.99 (br, 1H), 3.18-3.27 (br, 2H), 3.40-3.50 (m, 2H), 3.55 (s, 2H), 3.99-4.07 (q, J = 7.1 Hz, 2H), 4.10-4.20 (br, 1H), 6.58 (s, 2H, fumaric acid), 7.16-7.19 (dd, J = 8.4, 3.2 Hz, 1H), 7.25-7.30 (d, J = 8.4 Hz, 1H), 7.31-7.32 (d, J = 3.2 Hz, 1H).
LC-MS: R.T. 6.3 min., m/z 442.2 (M+Na). 条件Ａ。 Using the compound of Reference Example 32 and following the same method as in Step 1-3 described in Example 16, substituting 1-tert-butoxycarbonyl-4-azepanone for 1-tert-butoxycarbonyl-4-piperidone, The fumarate salt of the title compound was obtained using methyl chloroformate instead of ethylthiocarbonyl chloride.
1 H-NMR (DMSO-d 6 , 400 MHz) δ1.01-1.09 (m, 1H), 1.12-1.18 (td, J = 7.1, 3.3 Hz), 1.38-1.40 (m 2H), 1.55-1.65 ( m, 3H), 1.77-1.97 (m, 3H), 2.28-2.40 (m, 2H), 2.50-2.58 (m, 1H), 2.63-2.70 (br, 1H), 2.91-2.99 (br, 1H), 3.18-3.27 (br, 2H), 3.40-3.50 (m, 2H), 3.55 (s, 2H), 3.99-4.07 (q, J = 7.1 Hz, 2H), 4.10-4.20 (br, 1H), 6.58 ( s, 2H, fumaric acid), 7.16-7.19 (dd, J = 8.4, 3.2 Hz, 1H), 7.25-7.30 (d, J = 8.4 Hz, 1H), 7.31-7.32 (d, J = 3.2 Hz, 1H ).
LC-MS: RT 6.3 min., M / z 442.2 (M + Na). Condition A.
参考例９３
４－（３，３－ジフルオロ－２－オキソ－２，３－ジヒドロインドール－１－イル）ピペリジン－１－カルボン酸ｔｅｒｔ－ブチル Reference Example 93
4- (3,3-Difluoro-2-oxo-2,3-dihydroindol-1-yl) piperidine-1-carboxylate tert-butyl
Figure JPOXMLDOC01-appb-C000174
Figure JPOXMLDOC01-appb-C000174
　参考例３の化合物(340 mg)をジメチルホルムアミド(5 ml)に溶解し、氷浴下水素化ナトリウム(141 mg)を加え、1分撹拌した。その後Ｎ－フルオロベンゼンスルホンイミド(1.02 g)を加え、室温に昇温し、2.5時間撹拌した。反応液に水を加え、クロロホルムで抽出し、有機層を水、飽和食塩水で洗浄した。硫酸ナトリウムで乾燥後、セライト濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィーにて精製することで、表題化合物を得た(338 mg, 89%)。 The compound of Reference Example 3 (340 mg) was dissolved in dimethylformamide (5 ml), sodium hydride (141 mg) was added in an ice bath, and the mixture was stirred for 1 minute. Thereafter, N-fluorobenzenesulfonimide (1.02 g) was added, the temperature was raised to room temperature, and the mixture was stirred for 2.5 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine. The extract was dried over sodium sulfate, filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (338 mg, 89%).
実施例１８４－１８６ Examples 184-186
　参考例９３の化合物を用いて、参考例４、実施例３０－９３と同様の方法に従って、下記化合物を合成した。 Using the compound of Reference Example 93, the following compounds were synthesized according to the same method as Reference Example 4 and Examples 30-93.
Figure JPOXMLDOC01-appb-T000175
Figure JPOXMLDOC01-appb-T000175
実施例１８７－１８９ Examples 187-189
　実施例１４９－１６０と同様の方法に従って、下記化合物を得た。 The following compound was obtained according to the same method as in Examples 149-160.
Figure JPOXMLDOC01-appb-T000176
Figure JPOXMLDOC01-appb-T000176
実施例１９０－１９１ Examples 190-191
　実施例１６３－１６５と同様の方法に従って、下記化合物を得た。 The following compound was obtained in the same manner as in Examples 163 to 165.
Figure JPOXMLDOC01-appb-T000177
Figure JPOXMLDOC01-appb-T000177
実施例１９２－１９４ Examples 192-194
　参考例６７または６９の化合物を用いて、実施例１と同様の方法に従い、下記化合物を得た。 The following compound was obtained in the same manner as in Example 1 using the compound of Reference Example 67 or 69.
Figure JPOXMLDOC01-appb-T000178
Figure JPOXMLDOC01-appb-T000178
参考例９４
４－（４－オキソピペリジン－１－イル）－４－メチルアゼパン－１－カルボン酸エチル Reference Example 94
Ethyl 4- (4-oxopiperidin-1-yl) -4-methylazepan-1-carboxylate
Figure JPOXMLDOC01-appb-C000179
Figure JPOXMLDOC01-appb-C000179
　Ｎ－Ｂｏｃ－４－ピペリドンの代わりに、Ｎ－Ｂｏｃ－４－アゼパノンを用いて、参考例７０－７３と同様の方法に従って、表題化合物を合成した。 The title compound was synthesized in the same manner as in Reference Examples 70-73 using N-Boc-4-azepanone instead of N-Boc-4-piperidone.
実施例１９５－１９９ Examples 195-199
　参考例７３の化合物または参考例９４の化合物を用いて、実施例９４と同様の方法に従って、下記化合物を得た。 The following compound was obtained in the same manner as in Example 94 using the compound of Reference Example 73 or the compound of Reference Example 94.
実施例２００－２０２ Examples 200-202
　参考例３７の化合物または参考例３８の化合物を用いて、実施例１と同様の方法に従って、下記化合物を得た。 The following compound was obtained in the same manner as in Example 1 using the compound of Reference Example 37 or the compound of Reference Example 38.
Figure JPOXMLDOC01-appb-T000181
Figure JPOXMLDOC01-appb-T000181
実施例２０３－２０４ Examples 203-204
　製法６、スキーム１２記載の一般的な方法に準じて、下記化合物を合成した。 The following compounds were synthesized according to the general method described in Production Method 6 and Scheme 12.
Figure JPOXMLDOC01-appb-T000182
Figure JPOXMLDOC01-appb-T000182
実施例２０５－２０６ Examples 205-206
　製法７、スキーム１３記載の一般的な方法に準じて、下記化合物を合成した。 The following compounds were synthesized according to the general methods described in Production Method 7 and Scheme 13.
Figure JPOXMLDOC01-appb-T000183
Figure JPOXMLDOC01-appb-T000183
　本発明の化合物の医薬としての有用性は、薬理作用を確認できる薬理試験、体内動態を確認できる薬物動態試験、安全性を確認できる安全性試験により証明される。これらの試験は、ムスカリンＭ１およびＭ４受容体作動性に基づく生理活性およびムスカリン受容体サブタイプ選択性を向上させることによる安全性向上を確認できるものであれば特に限定されないが、例えば以下の試験により証明される。薬理試験としては、ｉｎ　ｖｉｔｒｏのムスカリン受容体作動性測定試験、抗精神病作用や認知障害改善作用を確認するｉｎ　ｖｉｖｏ試験が挙げられ、具体的なｉｎ　ｖｉｖｏ試験としてはアポモルフィン誘発クライミング試験、メタンフェタミン誘発運動量亢進試験、プレパルス抑制試験、マイクロダイアリシス試験、受動的回避反応試験、Ｙ迷路型試験などが挙げられる。薬物動態試験としては、例えば血中濃度評価試験、脳移行性評価試験、Ｐ－糖タンパク基質認識試験、薬物相互作用試験、薬物代謝経路同定試験、ダンシルグルタチオン付加試験などが挙げられる。安全性試験としては、ｈＥＲＧ阻害試験、細胞毒性試験、Ａｍｅｓ試験などのｉｎ　ｖｉｔｒｏ試験に加えて、血圧や心拍数の測定試験、心電図測定試験、ラット味覚嫌悪条件付け試験、唾液分泌量測定試験、体温測定試験、消化器症状評価試験、共有結合試験、錐体外路症状評価試験、一般症状観察、一般毒性試験などが挙げられる。これらの試験は一般にマウス、ラット、イヌ、およびサルで行なうことができる。また、必要に応じて覚醒または麻酔下で実施することができる。下記試験例により、本発明の化合物の医薬としての有用性を説明する。 The usefulness of the compound of the present invention as a medicine is proved by a pharmacological test capable of confirming pharmacological action, a pharmacokinetic test capable of confirming pharmacokinetics, and a safety test capable of confirming safety. These tests are not particularly limited as long as they can confirm physiological activity based on muscarinic M 1 and M 4 receptor operability and safety improvement by improving muscarinic receptor subtype selectivity. Proven by testing. Examples of the pharmacological test include an in vitro muscarinic receptor agonist measurement test and an in vivo test for confirming an antipsychotic action and a cognitive impairment improving action. Specific in vivo tests include an apomorphine-induced climbing test, methamphetamine-induced exercise amount. Examples include an enhancement test, a prepulse inhibition test, a microdialysis test, a passive avoidance reaction test, and a Y maze type test. Examples of the pharmacokinetic test include a blood concentration evaluation test, a brain migration evaluation test, a P-glycoprotein substrate recognition test, a drug interaction test, a drug metabolic pathway identification test, and a dansyl glutathione addition test. In addition to in vitro tests such as hERG inhibition tests, cytotoxicity tests, and Ames tests, safety tests include blood pressure and heart rate measurement tests, electrocardiogram measurement tests, rat taste aversion conditioning tests, salivary secretion measurement tests, body temperature Measurement tests, gastrointestinal symptom evaluation tests, covalent bonding tests, extrapyramidal symptom evaluation tests, general symptom observations, general toxicity tests and the like can be mentioned. These tests can generally be performed on mice, rats, dogs, and monkeys. Moreover, it can implement under awakening or anesthesia as needed. The following test examples illustrate the usefulness of the compounds of the present invention as pharmaceuticals.
試験例１　ヒト型ムスカリンＭ１－Ｍ５受容体のｉｎ　ｖｉｔｒｏ作動性試験
　各受容体に対する作動性は、各受容体安定発現細胞における細胞内カルシウム濃度の変化を、蛍光強度を指標として評価した。ヒトｍ１受容体発現プラスミド（ｐｃＤＮＡ３．１＿ｈＭ１）あるいはヒトｍ３受容体発現プラスミド（ｐｃＤＮＡ３．１＿ｈＭ３）をＣＨＯ－Ｋ１細胞に導入し、限界希釈法にてＧｅｎｅｔｉｃｉｎ耐性の安定発現株を取得した。ヒトｍ２受容体発現プラスミド（ｐｃＤＮＡ３．１＿ｈＭ２）、ヒトｍ４受容体発現プラスミド（ｐｃＤＮＡ３．１＿ｈＭ４）およびヒトｍ５受容体発現プラスミド（ｐｃＤＮＡ３．１＿ｈＭ５）は、それぞれＧα１６遺伝子をコードするｃＤＮＡと共にＣＨＯ－Ｋ１細胞に導入し、選択薬剤ＺｅｏｃｉｎおよびＨｙｇｒｏＧｏｌｄ耐性の安定発現株を取得した。ヒトｍ１およびヒトｍ３受容体安定発現細胞は４×１０４ｃｅｌｌｓ／１００μＬ／ｗｅｌｌの割合で、ヒトｍ２、ヒトｍ４およびヒトｍ５受容体安定発現細胞は２×１０４ｃｅｌｌｓ／１００μＬ／ｗｅｌｌの割合で９６－ｗｅｌｌ　ｐｌａｔｅに播き込み、ＣＯ２インキュベーターにて一晩培養した。各受容体安定発現細胞が１００％コンフルエントになればＦＬＩＰＲ　Ｃａｌｃｉｕｍ　４　ａｓｓａｙ　ｋｉｔ（Ｍｏｌｅｃｕｌａｒ　Ｄｅｖｉｃｅｓ社）を用い、ＦＬＩＰＲＴＥＴＲＡ（登録商標）（Ｍｏｌｅｃｕｌａｒ Ｄｅｖｉｃｅｓ社）にて、被検化合物添加により一過性に上昇した蛍光強度（ＲＦＵ（ｍａｘ－ｍｉｎ））を測定した。コントロール薬剤アセチルコリン（３μＭ）による蛍光強度を１００％としたとき、各被検化合物の蛍光強度の相対値を求め、これをアゴニスト活性（％）とした。 Test Example 1 In Vitro Efficacy Test of Human-type Muscarin M 1 -M 5 Receptor For the operability for each receptor, the change in intracellular calcium concentration in each receptor stably expressing cell was evaluated using the fluorescence intensity as an index. Human m1 receptor expression plasmid (pcDNA3.1_hM1) or human m3 receptor expression plasmid (pcDNA3.1_hM3) was introduced into CHO-K1 cells, and geneticin-resistant stable expression strains were obtained by the limiting dilution method. The human m2 receptor expression plasmid (pcDNA3.1_hM2), the human m4 receptor expression plasmid (pcDNA3.1_hM4) and the human m5 receptor expression plasmid (pcDNA3.1_hM5), together with the cDNA encoding the Gα16 gene, were introduced into CHO-K1 cells. After introduction, stable expression strains resistant to the selection drugs Zeocin and HygroGold were obtained. Human m1 and human m3 receptor stably expressing cells at a rate of 4 × 10 4 cells / 100 μL / well, human m2, human m4 and human m5 receptor stably expressing cells at a rate of 2 × 10 4 cells / 100 μL / well The cells were seeded in a 96-well plate and cultured overnight in a CO 2 incubator. When each receptor stable expression cell becomes 100% confluent, it is increased transiently by addition of test compound at FLIPR TETRA (registered trademark) (Molecular Devices) using FLIPR Calcium 4 assay kit (Molecular Devices). The measured fluorescence intensity (RFU (max-min)) was measured. When the fluorescence intensity by the control agent acetylcholine (3 μM) was 100%, the relative value of the fluorescence intensity of each test compound was determined, and this was defined as the agonist activity (%).
　実施例化合物を用いて、試験例１に従って行ったヒト型ムスカリン受容体のｉｎ　ｖｉｔｒｏ薬理試験の結果を以下に示す。 The results of an in vitro pharmacological test of human muscarinic receptors carried out according to Test Example 1 using Example compounds are shown below.
Figure JPOXMLDOC01-appb-T000184
Figure JPOXMLDOC01-appb-T000184
Figure JPOXMLDOC01-appb-T000185
Figure JPOXMLDOC01-appb-T000185
Figure JPOXMLDOC01-appb-T000186
Figure JPOXMLDOC01-appb-T000186
Figure JPOXMLDOC01-appb-T000187
Figure JPOXMLDOC01-appb-T000187
Figure JPOXMLDOC01-appb-T000188
Figure JPOXMLDOC01-appb-T000188
Figure JPOXMLDOC01-appb-T000189
Figure JPOXMLDOC01-appb-T000189
Figure JPOXMLDOC01-appb-T000190
Figure JPOXMLDOC01-appb-T000190
Figure JPOXMLDOC01-appb-T000191
Figure JPOXMLDOC01-appb-T000191
試験例２　マウス抗アポモルフィン誘発クライミング作用評価
　マウスをクライミングケージ（ステンレス製、直径１１．８ｃｍ×高さ１３．５ｃｍの円柱形）に入れ、アポモルフィン（１ｍｇ／ｋｇ）を皮下投与すると、ケージを登る行動（クライミング）を示すことから、本行動は統合失調症の陽性症状の病態の一部を反映すると考えられている。本モデルに対して本発明化合物を投与した際のアポモルフィンの作用を拮抗する程度によって抗精神病作用を評価することができる。５週齢の雄性ｄｄＹマウスを３０分間クライミングケージ内で馴化させた後、本発明化合物を皮下、腹腔内または経口投与し、２０分後（経口投与の場合は５０分後）にアポモルフィンを投与する。アポモルフィン投与後１０分後から３０分後までの行動を観察し、クライミングの程度をスコア化して評価する。アポモルフィン単独投与群のスコアを基準とし、抑制率（％）を０～１００の数値で表すことによって統計学的に処理することができる。 Test Example 2 Evaluation of Climbing Action Induced by Mouse Anti-Apomorphine Mouse When a mouse is placed in a climbing cage (made of stainless steel, cylindrical shape with a diameter of 11.8 cm and a height of 13.5 cm) and apomorphine (1 mg / kg) is administered subcutaneously, the behavior of climbing the cage (Climbing) indicates that this behavior reflects some of the positive symptoms of schizophrenia. The antipsychotic action can be evaluated based on the degree of antagonizing the action of apomorphine when the compound of the present invention is administered to this model. After acclimation of a 5-week-old male ddY mouse in a climbing cage for 30 minutes, the compound of the present invention is administered subcutaneously, intraperitoneally or orally, and apomorphine is administered 20 minutes later (50 minutes in the case of oral administration). . The behavior from 10 minutes to 30 minutes after apomorphine administration is observed, and the degree of climbing is scored and evaluated. Based on the score of the apomorphine single administration group as a reference, the inhibition rate (%) can be treated statistically by expressing it with a numerical value of 0-100.
　実施例化合物を用いて、試験例２に従って行ったｉｎ　ｖｉｖｏ試験の結果を以下に示す。 The results of an in vivo test performed according to Test Example 2 using the Example compound are shown below.
Figure JPOXMLDOC01-appb-T000192
Figure JPOXMLDOC01-appb-T000192
試験例３　ラット抗メタンフェタミン誘発運動量亢進作用評価
　ラットにメタンフェタミン（１ｍｇ／ｋｇ）を腹腔内投与すると直後から１時間程度運動量が亢進することから、このような行動は統合失調症の陽性症状の病態の一部を反映すると考えられている。本モデルに対して本発明化合物を投与した際の、メタンフェタミンの作用を拮抗する程度によって抗精神病作用を評価することができる。７週齢の雄性Ｓｐｒａｇｕｅ－Ｄａｗｌｅｙラットに対して、本発明化合物を皮下、腹腔内または経口投与し、３０分後（経口投与の場合は６０分後）にメタンフェタミンを投与する。同時にラットをテストケージ（無色透明プラスチック製）に移し、１０分後から８０分間の運動量を測定する。測定にはＳｕｐｅｒＭｅｘ（室町機械株式会社製）を用いる。８０分間の総運動量はメタンフェタミン単独投与群の運動量を基準とし、抑制率（％）を０～１００の数値で表すことによって統計学的に処理することができる。 Test Example 3 Rat Antimethamphetamine-Induced Momentum Activity Enhancement Evaluation: When methamphetamine (1 mg / kg) is administered intraperitoneally to rats, the amount of exercise increases for about 1 hour immediately after the administration. Such behavior is a pathological condition of positive symptoms of schizophrenia. It is thought to reflect a part. The antipsychotic action can be evaluated by the degree to which the action of methamphetamine is antagonized when the compound of the present invention is administered to this model. The compound of the present invention is administered subcutaneously, intraperitoneally or orally to male male Sprague-Dawley rats at 7 weeks of age, and methamphetamine is administered 30 minutes later (or 60 minutes in the case of oral administration). At the same time, the rat is transferred to a test cage (made of colorless transparent plastic), and the momentum is measured for 80 minutes after 10 minutes. SuperMex (Muromachi Machine Co., Ltd.) is used for the measurement. The total exercise amount for 80 minutes can be statistically processed by expressing the inhibition rate (%) as a numerical value of 0 to 100, based on the exercise amount of the methamphetamine single administration group.
　実施例化合物を用いて、試験例３に従って行ったin vivo試験の結果を以下に示す。 The results of the in vivo test performed according to Test Example 3 using the Example compound are shown below.
Figure JPOXMLDOC01-appb-T000193
Figure JPOXMLDOC01-appb-T000193
試験例４　ラット味覚嫌悪条件付け試験
　未経験の味を有する溶液（ｃｏｎｄｉｔｉｏｎｅｄ　ｓｔｉｍｕｌｕｓ、ＣＳ）を与えた後で、胃腸障害・嘔気などを誘発する薬物（ｕｎｃｏｎｄｉｔｉｏｎｅｄ ｓｔｉｍｕｌｕｓ、ＵＳ）を注射すると、動物はＣＳとＵＳの結びつきを学習し、次にＣＳを与えてもその味を手がかりとして摂取を拒否する。このような条件付けモデルを用いることによって、本発明化合物の嘔気誘発作用を評価することができる。
　実験には９週齢の雄性Ｓｐｒａｇｕｅ－Ｄａｗｌｅｙラットを用いる。
ｉ）トレーニング
　１５時間の絶水後、ラットに水の入った給水瓶を１時間提示することによって確実に給水するようにトレーニングを行う。その後８時間自由に給水させ、翌日にかけて１５時間絶水する。
ii）条件付け
　前日と同時刻に、絶水条件下のラットに０．５％のサッカリン水（ＣＳ）の入った給水瓶を１時間提示し、瓶を取り去った直後に本発明化合物（ＵＳ）を皮下、腹腔内または経口投与する。その後８時間自由に給水させ、翌日にかけて１５時間絶水する。
iii）試験
　絶水条件下のラットに前日と同様に０．５％のサッカリン水（ＣＳ）の入った給水瓶を１時間提示する。
　個体ごとに試験時のサッカリン摂取量を条件付け時のサッカリン摂取量で割った値を算出し、溶媒投与群のそれと比較して減少した割合を嫌悪反応形成率として評価する。 Test Example 4 Rat Taste Aversion Conditioning Test After giving a solution having an inexperienced taste (conditioned stimulus, CS) and then injecting a drug that induces gastrointestinal disorders / nausea (unconditional stimulated muscles, US), the animal becomes CS and US Even if you give CS next time, you will refuse to take it because of its taste. By using such a conditioning model, the nausea-inducing action of the compound of the present invention can be evaluated.
The experiment uses 9-week-old male Sprague-Dawley rats.
i) Training After 15 hours of water outage, training is performed to ensure water supply by presenting a water bottle with water to the rat for 1 hour. Thereafter, water is freely supplied for 8 hours, and water is stopped for 15 hours over the next day.
ii) Conditioning At the same time as the previous day, a water bottle containing 0.5% saccharin water (CS) was presented to rats under water-absorptive conditions for 1 hour, and immediately after removing the bottle, the compound (US) of the present invention was added. Subcutaneous, intraperitoneal or oral administration. Thereafter, water is freely supplied for 8 hours, and water is stopped for 15 hours over the next day.
iii) Test Rats under water-absent conditions are presented with a water bottle containing 0.5% saccharin water (CS) for 1 hour as in the previous day.
For each individual, the value obtained by dividing the saccharin intake at the time of the test by the saccharin intake at the time of conditioning is calculated, and the rate of decrease compared to that of the solvent-administered group is evaluated as the aversion reaction formation rate.
　実施例化合物を用いて、試験例４に従って行ったin vivo試験の結果を以下に示す。 The results of the in vivo test performed according to Test Example 4 using the example compounds are shown below.
Figure JPOXMLDOC01-appb-T000194
Figure JPOXMLDOC01-appb-T000194
試験例５　ｈＥＲＧ阻害試験
　自動パッチクランプ装置QPatch HT (Sophion Bioscience A/S)を用いて、ホールセルパッチクランプ法により、hERG（human ether-a-go-go）遺伝子を安定発現させたCHO細胞におけるhERGカリウム電流を記録した。hERG電流は、ボルテージクランプモードで膜電位を－80ｍＶに保持し、20ミリ秒間－50ｍＶにした後5秒間+20ｍＶに脱分極させ、続いて5秒間－50ｍＶに再分極させた時のテール電流の振幅を評価した。刺激は15秒おきに繰り返し行い、実験は室温（22±2℃）で行った。化合物は1細胞あたり4濃度を各濃度5分間累積投与し、各濃度における化合物適応前の電流の大きさと較べて阻害された電流の阻害率を算出し、Hill式により50％阻害濃度を計算した（IC50［μＭ］）。試験溶液は以下のものを用いた：細胞外溶液（ｍＭ）：２ ＣａＣｌ２、１ ＭｇＣｌ２、１０ ＨＥＰＥＳ、４ ＫＣｌ、１４５ ＮａＣｌ、１０グルコース、細胞内溶液（ｍＭ）：５.４ ＣａＣｌ２、１.８ ＭｇＣｌ２、１０ ＨＥＰＥＳ、３１ ＫＯＨ、１０ ＥＧＴＡ、１２０ ＫＣｌ、４ＡＴＰ Test Example 5 hERG Inhibition Test In CHO cells in which hERG (human ether-a-go-go) gene is stably expressed by whole cell patch clamp method using QPatch HT (Sophion Bioscience A / S) automatic patch clamp device hERG potassium current was recorded. The hERG current is the tail current when the membrane potential is held at −80 mV in the voltage clamp mode, depolarized to +20 mV for 5 seconds, then depolarized to +20 mV for 20 seconds, and then repolarized to −50 mV for 5 seconds. Amplitude was evaluated. Stimulation was repeated every 15 seconds, and the experiment was performed at room temperature (22 ± 2 ° C.). The compound was cumulatively administered at a concentration of 4 per cell for 5 minutes, and the inhibition rate of the inhibited current was calculated as compared to the magnitude of the current before compound adaptation at each concentration, and the 50% inhibitory concentration was calculated using the Hill equation. (IC 50 [μM]). The following test solutions were used: extracellular solution (mM): 2 CaCl 2 , 1 MgCl 2 , 10 HEPES, 4 KCl, 145 NaCl, 10 glucose, intracellular solution (mM): 5.4 CaCl 2 , 1.8 MgCl 2 , 10 HEPES, 31 KOH, 10 EGTA, 120 KCl, 4ATP
　実施例化合物を用いて、試験例５に従って行ったｈＥＲＧ阻害試験の結果を以下に示す。 Results of hERG inhibition test conducted in accordance with Test Example 5 using Example compounds are shown below.
Figure JPOXMLDOC01-appb-T000195
Figure JPOXMLDOC01-appb-T000195
試験例６　ラットＰＫ試験
　７週齢のラットに対して、本発明化合物を生理食塩水溶液にて静脈投与またはメチルセルロース水溶液にて経口投与し、それぞれ以下の時間で血液を採取した。
静脈投与：投与後５分、１５分、３０分、１時間、２時間、４時間、６時間および２４時間
経口投与：投与後１５分、３０分、１時間、２時間、４時間、６時間および２４時間
　採取した血液を４℃に設定した冷却遠心器を用いて３０００ｒｐｍ×１０分間遠心分離することで得た血漿をＨＰＬＣにて測定し、得られたタイムカーブを元に薬物動態パラメータを算出した。 Test Example 6 Rat PK Test To 7-week-old rats, the compound of the present invention was intravenously administered with a physiological saline solution or orally with a methylcellulose solution, and blood was collected at the following times.
Intravenous administration: 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours and 24 hours after administration Oral administration: 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours after administration And the plasma obtained by centrifuging the collected blood by centrifuging at 3000 rpm for 10 minutes using a cooling centrifuge set at 4 ° C. was measured by HPLC, and the pharmacokinetic parameters were calculated based on the obtained time curve did.
　この試験により本発明化合物が薬物動態的に優れていることを証明することができ、例えば実施例２８の生物学的利用率は７９％であった。 This test proves that the compound of the present invention is excellent in pharmacokinetics. For example, the bioavailability of Example 28 was 79%.
　また、上記試験例１の方法を用いて、本発明と構造的に近似する公知の化合物を比較例として、ムスカリンＭ１－Ｍ４受容体に対する作動性を測定し、本願の実施例化合物との比較を行った。 In addition, using the method of Test Example 1 above, using a known compound structurally similar to the present invention as a comparative example, the operability against the muscarinic M 1 -M 4 receptor was measured, and A comparison was made.
　特許文献１に開示されている化合物群で、本発明と構造的に近似する化合物は、例えば下記比較例１および比較例２で表される。 In the compound group disclosed in Patent Document 1, compounds structurally similar to the present invention are represented by, for example, Comparative Example 1 and Comparative Example 2 below.
Figure JPOXMLDOC01-appb-C000196
Figure JPOXMLDOC01-appb-C000196
Figure JPOXMLDOC01-appb-C000197
Figure JPOXMLDOC01-appb-C000197
Figure JPOXMLDOC01-appb-T000198
Figure JPOXMLDOC01-appb-T000198
　表３３より比較例１および２の化合物はムスカリン受容体選択性が全く無く、１位窒素原子がピペリジンと結合し、かつ３位が炭素原子である本発明化合物がムスカリン受容体選択性の面で優れていることは明らかである。 From Table 33, the compounds of Comparative Examples 1 and 2 have no muscarinic receptor selectivity, and the compounds of the present invention in which the 1st nitrogen atom is bonded to piperidine and the 3rd position is a carbon atom are in terms of muscarinic receptor selectivity. It is clear that it is excellent.
　特許文献２に開示されている化合物群で、本発明と構造的に近似する化合物は、例えば比較例３で表される。 In the compound group disclosed in Patent Document 2, a compound structurally similar to the present invention is represented by, for example, Comparative Example 3.
Figure JPOXMLDOC01-appb-C000199
Figure JPOXMLDOC01-appb-C000199
Figure JPOXMLDOC01-appb-T000200
Figure JPOXMLDOC01-appb-T000200
　表３４より比較例３の化合物はＭ１受容体作動性が非常に弱く、１位窒素原子がピペリジンと結合し、かつ３位が炭素原子である本発明化合物がＭ１受容体作動性の面で優れていることは明らかである。 From Table 34, the compound of Comparative Example 3 has very weak M 1 receptor activity, and the compound of the present invention in which the nitrogen atom at position 1 is bonded to piperidine and the carbon atom at position 3 is M 1 receptor activity. It is clear that it is superior.
　特許文献３に開示されている化合物群で、本発明と構造的に近似する化合物は、例えば比較例４で表される。 In the group of compounds disclosed in Patent Document 3, a compound structurally similar to the present invention is represented by Comparative Example 4, for example.
Figure JPOXMLDOC01-appb-C000201
Figure JPOXMLDOC01-appb-C000201
Figure JPOXMLDOC01-appb-T000202
Figure JPOXMLDOC01-appb-T000202
　表３５より比較例４の化合物はＭ４受容体作動性が非常に弱く、本発明化合物がＭ４受容体作動性の面で優れていることは明らかである。 The compounds of Table 35 Comparative Example 4 M 4 receptor agonist is very weak, it is clear that the present invention compounds are superior in terms of M 4 receptor agonist.
　特許文献４に開示されている化合物群で、本発明と構造的に近似する化合物は、例えば比較例５および比較例６で表される。 In the compound group disclosed in Patent Document 4, compounds structurally similar to the present invention are represented by, for example, Comparative Example 5 and Comparative Example 6.
Figure JPOXMLDOC01-appb-C000203
Figure JPOXMLDOC01-appb-C000203
Figure JPOXMLDOC01-appb-C000204
Figure JPOXMLDOC01-appb-C000204
　比較例５および比較例６は特許文献４にてＭ４受容体作動性が非常に弱いことが開示されており、本発明化合物がＭ４受容体作動性の面で優れていることは明らかである。 In Comparative Example 5 and Comparative Example 6, it is disclosed in Patent Document 4 that M 4 receptor agonist is very weak, and it is clear that the compound of the present invention is superior in terms of M 4 receptor agonist. is there.
　本発明の化合物は、選択的にムスカリンＭ１およびＭ４受容体を作動するので、抗精神病作用、認知障害改善作用などを含む優れた中枢改善効果を有すると共に、その他のムスカリン受容体または他の受容体を介する副作用を低減することができる。従って、本発明の化合物は、非常に有用な医薬となり得る。 Since the compound of the present invention selectively activates muscarinic M 1 and M 4 receptors, it has excellent central improving effects including antipsychotic effects, cognitive impairment improving effects, etc., and other muscarinic receptors or other Side effects through the receptor can be reduced. Therefore, the compound of the present invention can be a very useful medicament.

Claims (15)

  1. 　下記式（１）
    Figure JPOXMLDOC01-appb-C000001
    ［式中、
    ａ、ｂ、ｃおよびｄは、同一または異なって、それぞれＣＨまたはＣＲ５であり、
    Ｒ５は、ハロゲン原子、Ｃ３－７シクロアルキル基、Ｃ６－１４アリール基、ヘテロアリール基、Ｃ６－１４アリールアルキル基、ヘテロアリールアルキル基、Ｃ２－６アルケニル基、Ｃ２－６アルキニル基、Ｃ１－６アルコキシ基、シアノ基、Ｃ１－６アルキルスルファニル基、アシル基、スルファモイル基、水酸基、アミノ基、ニトロ基、Ｃ１－６アルキルスルホニル基、または置換されていてもよいＣ１－６アルキル基であり、
    Ｒ１およびＲ２は、同一または異なって、それぞれ水素原子、置換されていてもよいＣ１－６アルキル基、ハロゲン原子、水酸基、Ｃ３－７シクロアルキル基または３～７員の複素環基であるか、あるいはＲ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともにＣ３－７シクロアルカンまたは３～７員の複素環を形成するか、または一緒になって＝ＣＲ６Ｒ７を形成し、
    Ｒ６およびＲ７は、同一または異なって、それぞれ水素原子、または置換されていてもよいＣ１－６アルキル基であるか、あるいはＲ６およびＲ７が互いに結合して、Ｒ６およびＲ７が隣接する炭素原子とともにＣ３－７シクロアルカンまたは３～７員の複素環を形成し、
    Ｒ３およびＲ４は、一緒になって＝Ｏまたは＝Ｓを形成し、
    Ｘは、単結合またはメチレンであり、
    ＹおよびＺは、同一または異なって、それぞれ酸素原子または硫黄原子であり、
    Ｒは、置換されていてもよいＣ１－６アルキル基、Ｃ２－６アルキニル基またはＣ２－６アルケニル基であり、
    環Ａは、水酸基、ハロゲン原子、Ｃ１－６アルキル基およびＣ１－６アルコキシ基からなる群から選択される１～２個の置換基で置換されていてもよい６ないし７員の含窒素複素環である。］
    で示される化合物またはその薬学的に許容される塩。     Following formula (1)
    Figure JPOXMLDOC01-appb-C000001
    [Where:
    a, b, c and d are the same or different and each is CH or CR 5 ;
    R 5 represents a halogen atom, a C 3-7 cycloalkyl group, a C 6-14 aryl group, a heteroaryl group, a C 6-14 arylalkyl group, a heteroarylalkyl group, a C 2-6 alkenyl group, a C 2-6 Alkynyl group, C 1-6 alkoxy group, cyano group, C 1-6 alkylsulfanyl group, acyl group, sulfamoyl group, hydroxyl group, amino group, nitro group, C 1-6 alkylsulfonyl group, or optionally substituted A C 1-6 alkyl group,
    R 1 and R 2 are the same or different and each represents a hydrogen atom, an optionally substituted C 1-6 alkyl group, a halogen atom, a hydroxyl group, a C 3-7 cycloalkyl group, or a 3- to 7-membered heterocyclic group. Or R 1 and R 2 are bonded to each other so that R 1 and R 2 together with the adjacent carbon atom form a C 3-7 cycloalkane or a 3-7 membered heterocyclic ring, or together Form = CR 6 R 7
    R 6 and R 7 are the same or different and are each a hydrogen atom or an optionally substituted C 1-6 alkyl group, or R 6 and R 7 are bonded to each other to form R 6 and R 7. Form a C 3-7 cycloalkane or a 3-7 membered heterocycle with adjacent carbon atoms,
    R 3 and R 4 together form ═O or ═S;
    X is a single bond or methylene,
    Y and Z are the same or different and each represents an oxygen atom or a sulfur atom,
    R is an optionally substituted C 1-6 alkyl group, a C 2-6 alkynyl group or a C 2-6 alkenyl group,
    Ring A is a 6- to 7-membered nitrogen-containing group optionally substituted with 1 to 2 substituents selected from the group consisting of a hydroxyl group, a halogen atom, a C 1-6 alkyl group and a C 1-6 alkoxy group Heterocycle. ]
    Or a pharmaceutically acceptable salt thereof.
  2. 　Ｒ５が、ハロゲン原子、Ｃ１－６アルコキシ基、シアノ基、Ｃ１－６アルキルスルファニル基、水酸基、アミノ基、ニトロ基、または置換されていてもよいＣ１－６アルキル基である、請求項１に記載の化合物； R 5 is a halogen atom, a C 1-6 alkoxy group, a cyano group, a C 1-6 alkylsulfanyl group, a hydroxyl group, an amino group, a nitro group, or an optionally substituted C 1-6 alkyl group, Item 1. A compound according to Item 1;
  3. 　Ｒ５が、フッ素原子、塩素原子、臭素原子、メチル基、エチル基、プロピル基、メトキシ基またはトリフルオロメチル基である、請求項１に記載の化合物。 The compound according to claim 1, wherein R 5 is a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a propyl group, a methoxy group or a trifluoromethyl group.
  4. 　環Ａが、下記式（２）
    Figure JPOXMLDOC01-appb-C000002
    ［式中、Ｒ８は水素原子、水酸基、ハロゲン原子、Ｃ１－６アルキル基またはＣ１－６アルコキシ基である。］で示される、請求項１～３のいずれか一項に記載の化合物。     Ring A is represented by the following formula (2)
    Figure JPOXMLDOC01-appb-C000002
    [Wherein R 8 represents a hydrogen atom, a hydroxyl group, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group. The compound according to any one of claims 1 to 3, which is represented by the formula:
  5. 　Ｒ８が水素原子、Ｃ１－６アルキル基またはＣ１－６アルコキシ基である、請求項１～４のいずれか一項に記載の化合物。 The compound according to any one of claims 1 to 4, wherein R 8 is a hydrogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group.
  6. 　ｃおよびｂが、同一または異なってＣＨまたはＣＲ５である、請求項１～５のいずれか一項に記載の化合物。 The compound according to any one of claims 1 to 5, wherein c and b are the same or different and are CH or CR 5 .
  7. 　ｃおよびｂのどちらか一方がＣＨ、もう一方がＣＲ５である、請求項１～５のいずれか一項に記載の化合物。 c and either of b is CH, the other is CR 5, the compounds according to any one of claims 1 to 5.
  8. 　ＹおよびＺが、共に酸素原子である、請求項１～７のいずれか一項に記載の化合物。 The compound according to any one of claims 1 to 7, wherein Y and Z are both oxygen atoms.
  9. 　Ｒ３およびＲ４が一緒になって＝Ｏを形成する、請求項１～８のいずれか一項に記載の化合物。 The compound according to any one of claims 1 to 8, wherein R 3 and R 4 together form = 0.
  10. 　Ｒ１およびＲ２が、同一または異なって、それぞれ水素原子、フッ素原子、水酸基、または置換されていてもよいＣ１－６アルキル基であるか、あるいはＲ１およびＲ２が互いに結合して、Ｒ１およびＲ２が隣接する炭素原子とともにテトラヒドロピラン環を形成する、請求項１～９のいずれか一項に記載の化合物。 R 1 and R 2 are the same or different and are each a hydrogen atom, a fluorine atom, a hydroxyl group, or an optionally substituted C 1-6 alkyl group, or R 1 and R 2 are bonded to each other; The compound according to any one of claims 1 to 9, wherein R 1 and R 2 together with adjacent carbon atoms form a tetrahydropyran ring.
  11. 　Ｒが、置換されていてもよい直鎖のＣ１－６アルキル基である、請求項１～１０のいずれか一項に記載の化合物。 The compound according to any one of claims 1 to 10, wherein R is an optionally substituted linear C 1-6 alkyl group.
  12. 　４－｛４－［２’－オキソスピロ（シクロヘキサン－１，３’－インドール）－１’（２’Ｈ）－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
    ４－［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
    ４－［４－（５－クロロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
    ４－［４－（５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
    ４－［４－（５－メチル－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
    ４－［４－（５－メチル－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
    ４－［４－（６－メチル－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
    ４－［４－（６－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
    ４－［４－（６－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
    （１Ｒ，５Ｓ）－３－［４－（６－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
    ４－［４－（６－メトキシ－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
    ４－｛［４－（５－フルオロ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］メチル｝ピペリジン－１－カルボン酸エチル；
    ４－｛［４－（３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］メチル｝ピペリジン－１－カルボン酸エチル；
    ４－｛［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］メチル｝ピペリジン－１－カルボン酸エチル；
    ４－［４－（６－フルオロ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
    ４－［４－（６－エチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
    ４－｛［４－（５－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］メチル｝ピペリジン－１－カルボン酸エチル；
    ４－｛［４－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］メチル｝ピペリジン－１－カルボン酸エチル；
    ４－［４－（６－メトキシ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－４－メチルピペリジン－１－カルボン酸エチル；
    ４－［４－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－４－メチルピペリジン－１－カルボン酸エチル；
    （３－ｅｎｄｏ）－３－［４－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
    ３－ｅｘｏ）－３－［４－（６－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
    ３－ｅｎｄｏ）－３－［４－（６－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
    （３－ｅｘｏ）－３－［４－（６－フルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
    （３－ｅｎｄｏ）－３－［４－（３，６－ジメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
    ４－｛４－［３－（ヒドロキシメチル）－６－メトキシ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
    ４－｛４－［３－（ヒドロキシメチル）－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル］ピペリジン－１－イル｝ピペリジン－１－カルボン酸エチル；
    （３－ｅｎｄｏ）－３－［４－（６－メチル－２－オキソ－２’，３’，５’，６’－テトラヒドロスピロ［インドール－３，４’－ピラン］－１（２Ｈ）－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
    ４－［４－（３，３－ジフルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］ピペリジン－１－カルボン酸エチル；
    （１Ｒ，５Ｓ）－３－［４－（３，３－ジフルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－８－アザビシクロ［３．２．１］オクタン－８－カルボン酸エチル；
    ４－［４－（３，３－ジフルオロ－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］アゼパン－１－カルボン酸エチル；
    ４－［４－（２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－４－メチルアゼパン－１－カルボン酸エチル；
    ４－［４－（３－ヒドロキシ－３－メチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－４－メチルピペリジン－１－カルボン酸エチル；および
    ４－［４－（３－フルオロ－３－ヒドロキシメチル－２－オキソ－２，３－ジヒドロ－１Ｈ－インドール－１－イル）ピペリジン－１－イル］－４－メチルピペリジン－１－カルボン酸エチル；
    からなる群から選択される、請求項１に記載の化合物またはその薬学的に許容される塩。     4- {4- [2′-oxospiro (cyclohexane-1,3′-indole) -1 ′ (2′H) -yl] piperidin-1-yl} piperidine-1-carboxylate;
    4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] ethyl azepane-1-carboxylate;
    4- [4- (5-Chloro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
    4- [4- (5-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
    4- [4- (5-Methyl-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) -yl) piperidine-1- Yl] piperidine-1-carboxylate;
    4- [4- (5-Methyl-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) -yl) piperidine-1- Yl] azepan-1-ethyl carboxylate;
    4- [4- (6-Methyl-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) -yl) piperidine-1- Yl] piperidine-1-carboxylate;
    Ethyl 4- [4- (6-methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate;
    Ethyl 4- [4- (6-methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
    (1R, 5S) -3- [4- (6-Methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2.1 ] Ethyl octane-8-carboxylate;
    4- [4- (6-Methoxy-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) -yl) piperidine-1- Yl] piperidine-1-carboxylate;
    4-{[4- (5-Fluoro-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] methyl} piperidine-1-carboxylate;
    4-{[4- (3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] methyl} piperidine-1-carboxylate;
    4-{[4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] methyl} piperidine-1-carboxylate;
    4- [4- (6-Fluoro-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
    4- [4- (6-Ethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
    4-{[4- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] methyl} piperidine-1-carboxylate;
    4-{[4- (6-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] methyl} ethyl piperidine-1-carboxylate;
    Ethyl 4- [4- (6-methoxy-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-methylpiperidine-1-carboxylate;
    Ethyl 4- [4- (6-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-methylpiperidine-1-carboxylate;
    (3-endo) -3- [4- (6-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2.1 ] Ethyl octane-8-carboxylate;
    3-exo) -3- [4- (6-Methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2.1] Ethyl octane-8-carboxylate;
    3-endo) -3- [4- (6-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2.1] Ethyl octane-8-carboxylate;
    (3-exo) -3- [4- (6-Fluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2.1 ] Ethyl octane-8-carboxylate;
    (3-endo) -3- [4- (3,6-Dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2 .1] ethyl octane-8-carboxylate;
    4- {4- [3- (hydroxymethyl) -6-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carvone Ethyl acid;
    4- {4- [3- (hydroxymethyl) -3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl] piperidin-1-yl} piperidine-1-carboxylate;
    (3-endo) -3- [4- (6-Methyl-2-oxo-2 ′, 3 ′, 5 ′, 6′-tetrahydrospiro [indole-3,4′-pyran] -1 (2H) — Yl) piperidin-1-yl] -8-azabicyclo [3.2.1] octane-8-carboxylate;
    4- [4- (3,3-difluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] piperidine-1-carboxylate;
    (1R, 5S) -3- [4- (3,3-Difluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -8-azabicyclo [3.2 .1] ethyl octane-8-carboxylate;
    4- [4- (3,3-difluoro-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] azepane-1-carboxylate;
    4- [4- (2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-ethyl methylazepan-1-carboxylate;
    Ethyl 4- [4- (3-hydroxy-3-methyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-methylpiperidine-1-carboxylate; And 4- [4- (3-Fluoro-3-hydroxymethyl-2-oxo-2,3-dihydro-1H-indol-1-yl) piperidin-1-yl] -4-methylpiperidine-1-carboxylic acid ethyl;
    The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of:
  13. 　請求項１～１２のいずれか一項に記載の化合物を含有する中枢疾患の予防および／または治療剤。 A preventive and / or therapeutic agent for central diseases comprising the compound according to any one of claims 1 to 12.
  14. 　中枢疾患がアルツハイマー病および／または統合失調症である、請求項１２に記載の予防および／または治療剤。 The preventive and / or therapeutic agent according to claim 12, wherein the central disease is Alzheimer's disease and / or schizophrenia.
  15. 　請求項１～１２のいずれか一項に記載の化合物またはその薬学的に許容される塩および薬学的に許容される担体を含有する医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
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