WO2012176763A1 - Novel indazole derivative - Google Patents

Novel indazole derivative Download PDF

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WO2012176763A1
WO2012176763A1 PCT/JP2012/065609 JP2012065609W WO2012176763A1 WO 2012176763 A1 WO2012176763 A1 WO 2012176763A1 JP 2012065609 W JP2012065609 W JP 2012065609W WO 2012176763 A1 WO2012176763 A1 WO 2012176763A1
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group
alkoxy
optionally substituted
alkyl
substituted
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PCT/JP2012/065609
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French (fr)
Japanese (ja)
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伸也 臼井
貴士 ▲高▼田
幸博 西尾
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大日本住友製薬株式会社
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Publication of WO2012176763A1 publication Critical patent/WO2012176763A1/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
    • C07D401/02—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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • 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
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel indazole derivative which is a modulator of ⁇ 7 nicotinic acetylcholine receptor ( ⁇ 7 nAChR). Due to their pharmacological properties, the compounds of the present invention can be used for diseases related to cholinergic activity of the central nervous system (CNS) and / or peripheral nervous system (PNS), diseases related to smooth muscle contraction, endocrine diseases, diseases related to neurodegeneration, It may be useful for the treatment of diseases such as inflammation or pain and diseases related to withdrawal symptoms caused by addictive drug abuse.
  • CNS central nervous system
  • PNS peripheral nervous system
  • diseases related to smooth muscle contraction endocrine diseases
  • diseases related to neurodegeneration It may be useful for the treatment of diseases such as inflammation or pain and diseases related to withdrawal symptoms caused by addictive drug abuse.
  • ⁇ 7 nicotinic acetylcholine receptor represents a valid molecular target for neuroprotection.
  • neuroprotection can be achieved by developing an active agonist / positive modulator of the receptor (positive allosteric modulator: PAM).
  • PAM positive allosteric modulator
  • ⁇ 7 nicotinic receptor agonists have already been identified and evaluated as potential clues for the development of neuroprotective drugs.
  • the involvement of ⁇ 7 nicotinic acetylcholine receptors in inflammation has also been reported. From the above, the development of a novel modulator of the receptor is expected to be a novel treatment for nervous system diseases, psychiatric diseases and inflammatory diseases.
  • Patent Document 1 a modulator of ⁇ 7 nicotinic acetylcholine receptor ( ⁇ 7 nAChR), but the structure is different from the compound of the present invention (Patent Document 1 and Patent Document 2).
  • An object of the present invention is to provide a novel compound having a potent ⁇ 7 nicotinic acetylcholine receptor ( ⁇ 7 nAChR) regulating action and useful as a novel therapeutic and / or preventive agent for nervous system diseases, mental disorders and inflammatory diseases. Is to provide.
  • ⁇ 7 nAChR potent ⁇ 7 nicotinic acetylcholine receptor
  • an indazole derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof (hereinafter also referred to as “the compound of the present invention”) is provided.
  • halogen, hydroxyl, C 1- Alkoxy, -NR 8 R 9, -COOR 8 , -CONR 8 R 9, -NR 8 COR 9, are independently selected from the group consisting of -SO 2 NR 8 R 9 and -NR 8 SO 2 R 9 1 C 1-6 alkoxy optionally substituted with 5 substituents; halogen, hydroxyl group, C 1-6 alkoxy, —NR 8 R 9 , —COOR 8 , —CONR 8 R 9 , —NR 8 COR 9
  • W represents CR 3E or a nitrogen atom
  • R 2 is halogen, hydroxyl group, C 1-6 alkoxy, —NR 10 R 11 , —COOR 10 , —CONR 10 R 11 , —NR 10 COR 11 , —SO 2 NR 10 R 11 and —NR 10 SO 2 R C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of 11 ; halogen, hydroxyl, C 1-6 alkoxy, —NR 10 R 11 , —COOR 10 Substituted with 1 to 5 substituents independently selected from the group consisting of: —CONR 10 R 11 , —NR 10 COR 11 , —SO 2 NR 10 R 11 and —NR 10 SO 2 R 11 which may C 3-10 cycloalkyl, 4 to 10-membered saturated heterocyclic ring or 4 to 10-membered saturated heterocyclic ring - carbonyl -; hydrogen atom; a halogen, hydroxyl
  • R 8 to R 17 are the same or different, and when a plurality of R 8 to R 17 are present, each independently represents a hydrogen atom or C 1-6 alkyl optionally substituted with 1 to 5 fluorines, , R 8 and R 9 , R 10 and R 11 , R 12 and R 13 , R 14 and R 15 , R 16 and R 17 together form a 4- to 10-membered nitrogen-containing saturated heterocyclic ring.
  • n represents 1 or 2] Or a pharmaceutically acceptable salt thereof.
  • the optionally substituted alkyl, the optionally substituted cycloalkyl and the optionally substituted 4- to 10-membered saturated heterocyclic ring in Item 1 are each independently (1) optionally substituted aryl, (2) optionally substituted heteroaryl, (3) an optionally substituted 4- to 10-membered saturated heterocyclic ring, (4) optionally substituted C 3-10 cycloalkyl, (5) -CONR 18 R 19 (6) halogen, (7) hydroxyl group, (8) C 1-6 alkyl which may be substituted, (9) optionally substituted C 1-6 alkoxy, (10) optionally substituted C 1-6 alkylcarbonyl, (11) -N (R 18 ) COR 19 , and (12) -NR 18 R 19 , A group which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of: wherein the groups shown in (1) to (4) are the following Is a group which may be substituted with the same or different 1 to 5 substituents selected from the group consist
  • n is 1.
  • Item 3. The compound according to Item 1 or Item 2, or a pharmaceutically acceptable salt thereof.
  • R 4A , R 4B , R 5 and R 7 are the same or different and are aryl, heteroaryl, 4- to 10-membered saturated heterocycle, C 3-10 cycloalkyl, fluorine, hydroxyl group, 1-5 Substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy, C 1-6 alkylcarbonyl, and —NR 18 R 19 , optionally substituted with fluorine C 1-10 alkyl; C 3-10 cycloalkyl; 4- to 10-membered saturated heterocyclic ring; or a hydrogen atom (the aryl, heteroaryl, saturated heterocyclic ring and cycloalkyl are fluorine, hydroxyl group, C 1 -6 alkyl (the group may be substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, C 1-6 alkoxy and —NR 18 R 19 ), 1 to 5 Pieces of fluorine Optionally substituted with 1 to 5 substituorine Optionally
  • A is CR 1D .
  • Item 5 The compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.
  • W is CH.
  • Item 6 The compound according to any one of Items 1 to 5, or a pharmaceutically acceptable salt thereof.
  • [Claim 7] XYZ represents N—CO—NR 4A R 4B , CR 6 —CO—NR 4A R 4B , CR 6 —NR 7 —CO—NR 4A R 4B or CR 6 —NR 7 —COR 5 , Item 7.
  • R 2 is good fluorine, hydroxyl, optionally substituted with one to five substituents independently selected from the group consisting of C 1-6 alkoxy and -NR 10 R 11 C 1- 6 alkyl; C 3-10 cycloalkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, hydroxyl, C 1-6 alkoxy and —NR 10 R 11 or 4 A 10-membered saturated heterocyclic ring; a hydrogen atom; or a C 1-6 alkylcarbonyl.
  • Item 8 The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof.
  • R 1A , R 1B , R 1C, and R 1D are the same or different and are selected from fluorine, hydroxyl group, C 1-6 alkoxy, —NR 8 R 9 , —CONR 8 R 9, and —NR 8 COR 9.
  • 1-5 which may be C 1-6 alkyl substituted with a substituent selected independently from the group consisting; fluorine, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, -NR 8 R 9 , -CONR 8 R 9 and -NR 8 COR 9, an optionally substituted C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents, 4 to 10 membered saturated hetero A ring or a 4- to 10-membered saturated heterocyclic group —O—; independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy, —NR 8 R 9 , —CONR 8 R 9 and —NR 8 COR 9 With 1 to 5 substituents Which may be C 1-6 alkoxy; halogen, hydroxyl, C 1-6 alkoxy, -NR 8 R 9, 1 is independently selected from the group consisting of -CONR 8 R 9 and -NR 8 COR 9 ⁇ C 3-10 cycloalkoxy optionally substituted with 5
  • XYZ is N—CO—NR 4A R 4B , CR 6 —NR 7 —CO—NR 4A R 4B or CR 6 —NR 7 —COR 5 ;
  • Item 10 The compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof.
  • R 4A and R 4B are a hydrogen atom.
  • Item 11 The compound according to any one of Items 1 to 10, or a pharmaceutically acceptable salt thereof.
  • [Claim 12] C 1-6 alkyl in which R 3A , R 3B , R 3C , R 3D and R 3E are the same or different and may be substituted with 1 to 5 fluorines; C 1-6 alkoxy; A hydrogen atom; or fluorine, Item 12.
  • R 4A , R 4B , R 5 and R 7 are the same or different and are substituted with 4 to 10-membered saturated heterocyclic ring, C 3-10 cycloalkyl, fluorine, hydroxyl group, 1 to 5 fluorine atoms C 1-10 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of optionally substituted C 1-6 alkoxy and —NR 18 R 19 ; C 3-10 A cycloalkyl; a 4- to 10-membered saturated heterocycle; or a hydrogen atom (the saturated heterocycle and cycloalkyl are fluorine, hydroxyl, C 1-6 alkyl (the group is fluorine, C 1-6 alkoxy and —NR C 1-6 alkoxy optionally substituted with 1 to 5 fluorines, optionally substituted with 1 to 5 substituents independently selected from the group consisting of 18 R 19 , C 1 -6 alkylcarbonyl, or -N 18 may be substituted with 1 to
  • R 1A , R 1B , R 1C and R 1D are the same or different and are substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, hydroxyl group and C 1-6 alkoxy.
  • C 1-6 alkyl which may be substituted;
  • C 3-8 cycloalkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, hydroxyl group and C 1-6 alkoxy ; fluorine, hydroxyl and C 1-6 1 ⁇ 5 amino optionally substituted with a substituent C 1-6 alkoxy independently selected from the group consisting of alkoxy; from fluorine, hydroxyl and C 1-6 alkoxy
  • a C 3-10 cycloalkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of: a hydrogen atom; a hydroxyl group; a halogen; or a 4- to 10-membered saturated heterocyclic ring, Item 14.
  • R 6 is C 1-6 alkyl, C 1-6 alkoxy, fluorine or a hydrogen atom.
  • Item 15 The compound according to any one of Items 1 to 14, or a pharmaceutically acceptable salt thereof.
  • XYZ is N—CO—NR 4A R 4B or CR 6 —NR 7 —COR 5 ; Item 16. The compound according to any one of Items 1 to 15, or a pharmaceutically acceptable salt thereof.
  • R 4A , R 4B , R 5 and R 7 are the same or different and each represent a C 3-10 cycloalkyl; a 4- to 10-membered saturated heterocyclic ring; or a hydrogen atom (the saturated heterocyclic ring and Alkyl is fluorine, hydroxyl group, C 1-6 alkyl (the group may be substituted with 1 to 5 substituents independently selected from the group consisting of fluorine and C 1-6 alkoxy) or 1 (Optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy optionally substituted with 5 fluorines), wherein (1) R 4A and R 4B are not both hydrogen atoms, and (2) R 5 is not a hydrogen atom.
  • Item 18 The compound according to any one of Items 1 to 16, or a pharmaceutically acceptable salt thereof.
  • XYZ is N—CO—NR 4A R 4B .
  • Item 18 The compound according to any one of Items 1 to 17, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising the compound according to any one of items 1 to 18 or a pharmaceutically acceptable salt thereof.
  • a therapeutic agent for a disease caused by an abnormality in intracellular signal transduction involving acetylcholine comprising the compound according to any one of items 1 to 18 or a pharmaceutically acceptable salt thereof as an active ingredient Or a preventive agent.
  • the disease caused by an abnormality in intracellular signal transduction involving acetylcholine is a nervous system disease, a mental disease or an inflammatory disease.
  • Item 20 The therapeutic agent according to Item 20.
  • the nervous system disease, psychiatric disorder or inflammatory disease is dementia, schizophrenia, CIAS (cognitive impairment associated with schizophrenia), Alzheimer's disease, Down's syndrome, attention deficit disorder or cerebrovascular angiopathy.
  • An acetylcholine characterized by administering a therapeutically effective amount of the compound according to any one of items 1 to 18 or a pharmaceutically acceptable salt thereof to a patient in need of treatment.
  • the compound of the present invention can be used for nervous system diseases, psychiatric diseases and inflammatory diseases (for example, dementia, schizophrenia, CIAS (cognitive impairment associated with schizophrenia), Alzheimer's disease, Down's syndrome, attention deficit disorder, cerebrovascular angiopathy, etc. ) As a novel therapeutic agent and / or preventive agent.
  • the compound of the present invention is useful for the treatment and / or prevention of neurological diseases such as schizophrenia, mental diseases and the like as a concomitant drug with drugs classified as atypical antipsychotic drugs.
  • the compounds of the present invention may exist in the form of hydrates and / or solvates, these hydrates and / or solvates are also included in the compounds of the present invention.
  • solvates include ethanol solvates.
  • the compound of formula (I) may have one or more asymmetric carbon atoms and may cause geometric isomerism and axial chirality, and therefore exist as several stereoisomers. There is. In the present invention, these stereoisomers, mixtures thereof and racemates are included in the compound represented by the formula (I) of the present invention. In addition, a deuterium converter obtained by converting any one or two or more 1 H of the compound represented by the general formula (I) into 2 H (D) is also included in the compound represented by the general formula (I). Is done.
  • Alkyl means a linear or branched saturated hydrocarbon group, for example, “C 1-4 alkyl”, “C 1-6 alkyl” or “C 1-10 alkyl” Alkyl having 1 to 4, 1 to 6, or 1 to 10 carbon atoms is meant. Specific examples thereof include “C 1-4 alkyl” such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like.
  • C 1-6 alkyl in addition to the above, examples include pentyl, isopentyl, neopentyl, hexyl and the like, and in the case of “C 1-10 alkyl”, in addition to the above, heptyl, octyl and the like Is mentioned.
  • Cycloalkyl means a monocyclic or polycyclic saturated hydrocarbon.
  • C 3-10 cycloalkyl means a cyclic alkyl having 3 to 10 carbon atoms and is partially bridged.
  • spiro ring a part of which a spiro ring is constructed, or a part in which a condensed ring is formed with aryl or heteroaryl are also included.
  • Specific examples thereof include “C 3-10 cycloalkyl” such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, spiro [2,5] octane, and the like.
  • Cycloalkoxy means a group in which a monocyclic or polycyclic saturated hydrocarbon group similar to the above is interposed via an oxygen atom.
  • Alkoxy means a group in which a linear or branched saturated hydrocarbon group is interposed via an oxygen atom.
  • C 1-6 alkoxy means a group having 1 to 6 carbon atoms. Means alkoxy. Specific examples of “C 1-6 alkoxy” include methoxy, ethoxy, propoxy, isopropoxy, butyloxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like.
  • C 1-6 alkylcarbonyl are acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, iso-butylcarbonyl, etc. t- butylcarbonyl and the like. “C 1-3 alkylcarbonyl” is preferable, and acetyl is more preferable.
  • Halogen means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Among them, preferred is a fluorine atom or a chlorine atom.
  • aryl include phenyl, 1-naphthyl, 2-naphthyl, anthracene and the like. Of these, phenyl is preferable.
  • Heteroaryl is a monocyclic 5- to 7-membered aromatic heterocyclic group or bicyclic ring containing 1 to 4 atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom And an 8- to 11-membered aromatic heterocyclic group or a 3-ring 12- to 16-membered aromatic heterocyclic group.
  • the “4- to 10-membered saturated heterocyclic ring” means 4 to 10 atoms including 1 to 2 atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom.
  • the term means a monocyclic or bicyclic saturated heterocyclic ring, which includes a partially bridged structure, a partially spirolated ring, or a ring condensed with aryl or heteroaryl.
  • azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, tetrahydrofuran, tetrahydropyran and the like can be mentioned.
  • the “4- to 10-membered saturated heterocycle-carbonyl-” means a group in which a carbonyl is bonded to the 4- to 10-membered saturated heterocycle.
  • the “4- to 10-membered saturated heterocyclic ring —O—” means a group in which an oxygen atom is bonded to the 4- to 10-membered saturated heterocyclic ring.
  • A is preferably CR 1D .
  • XYZ is N—CO—NR 4A R 4B , CR 6 —CO—NR 4A R 4B , CR 6 —NR 7 —CO—NR 4A R 4B or CR 6.
  • —NR 7 —COR 5 is exemplified, more preferably N—CO—NR 4A R 4B or CR 6 —NR 7 —COR 5 is exemplified, and still more preferably, N—CO—NR 4A R 4B is exemplified.
  • R 1A to R 1D are preferably the same or different and independently selected from the group consisting of fluorine, hydroxyl group, C 1-6 alkoxy, —NR 8 R 9 , —CONR 8 R 9 and —NR 8 COR 9. that one to five substituents C 1-6 alkyl optionally substituted by group; fluorine, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, -NR 8 R 9, -CONR 8 R 9 and - C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of NR 8 COR 9 , 4 to 10 membered saturated heterocycle or 4 to 10 membered saturated A heterocyclic group —O—; 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy, —NR 8 R 9 , —CONR 8 R 9 and —NR 8 COR 9 Even if it is substituted with a group There C 1-6 alkoxy
  • C 1-6 alkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, hydroxyl group and C 1-6 alkoxy; fluorine, hydroxyl and C 1-6 1 ⁇ 5 amino which may be C 3-8 cycloalkyl substituted with a substituent independently selected from the group consisting of alkoxy; fluorine, the group consisting of hydroxyl and C 1-6 alkoxy C 1-6 alkoxy optionally substituted with 1 to 5 substituents independently selected from: 1 to 5 independently selected from the group consisting of fluorine, hydroxyl group and C 1-6 alkoxy C 3-10 cycloalkoxy which may be substituted with the following substituents: a hydrogen atom; a hydroxyl group; a halogen; or a 4- to 10-membered saturated heterocyclic ring.
  • fluorine and C 1-6 independently from the group consisting of alkoxy optionally substituted with 1 to 5 substituents selected C 1-6 alkyl; C 3-8 Cycloalkyl; C 1-6 alkoxy; C 3-10 cycloalkoxy; hydrogen atom; or halogen. Most preferably, it is the same or different and includes 1 to 5 fluorines optionally substituted with C 1-6 alkyl; C 1-6 alkoxy; C 3-10 cycloalkoxy; hydrogen atom; or halogen .
  • W is preferably CH.
  • R 2 is preferably C 1-6 alkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, hydroxyl group, C 1-6 alkoxy and —NR 10 R 11.
  • C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, hydroxyl group, C 1-6 alkoxy and —NR 10 R 11 ;
  • More preferable examples include C 1-6 alkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of fluorine and C 1-6 alkoxy, and more preferably , C 1-6 alkyl or a hydrogen atom, and most preferably a hydrogen atom.
  • R 3A , R 3B , R 3C , R 3D and R 3E are preferably the same or different and each is a C 1-6 alkyl or C 1-6 alkoxy optionally substituted with 1 to 5 fluorines; a hydrogen atom Or fluorine. More preferably, C 1-6 alkyl optionally substituted with 1 to 5 fluorines; a hydrogen atom; or fluorine is mentioned, and still more preferably C 1-6 alkyl; a hydrogen atom; or fluorine is mentioned. .
  • W is CH
  • the carbon atom of W may be substituted with the above substituent of R 3A , R 3B , R 3C or R 3D in the same manner as other carbon atoms of the ring to be formed.
  • R 4A , R 4B , R 5 , and R 7 are preferably the same or different and are aryl, heteroaryl, 4- to 10-membered saturated heterocyclic ring, C 3-10 cycloalkyl, fluorine, hydroxyl group, 1 to 5 Optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy, C 1-6 alkylcarbonyl, and —NR 18 R 19 , optionally substituted with fluorine Good C 1-10 alkyl; C 3-10 cycloalkyl; 4- to 10-membered saturated heterocycle; or a hydrogen atom (the aryl, heteroaryl, saturated heterocycle and cycloalkyl are fluorine, hydroxyl, C 1- 6 alkyl (said groups, fluorine may be substituted with one to five substituents independently selected from the group consisting of C 1-6 alkoxy and -NR 18 R 19), 1-5 Of fluorine substituted which may be C 1-6 alkoxy, optionally substituted
  • R 4A and R 4B are not both hydrogen atoms
  • R 5 is not a hydrogen atom. More preferably, it is the same or different and is a 4 to 10-membered saturated heterocyclic ring, C 3-10 cycloalkyl, fluorine, hydroxyl group, C 1-6 alkoxy optionally substituted with 1 to 5 fluorines, C 1 C 1-10 alkyl optionally substituted with 1-5 substituents independently selected from the group consisting of -6 alkylcarbonyl and —NR 18 R 19 ; C 3-10 cycloalkyl; 4-10 Or a hydrogen atom (the saturated heterocyclic ring and cycloalkyl are fluorine, hydroxyl, C 1-6 alkyl (the group is selected from the group consisting of fluorine, C 1-6 alkoxy and —NR 18 R 19); Optionally substituted with 1 to 5 substituents independently selected) C 1-6 alkoxy optionally substituted with 1 to 5 fluorines, C 1-6 alkylcarbonyl, or
  • any one of R ⁇ 4A> or R ⁇ 4B> is a hydrogen atom.
  • R 6 is preferably C 1-6 alkyl, C 1-6 alkoxy, hydroxyl group, fluorine or hydrogen atom. More preferably, a C1-6 alkoxy, a hydroxyl group, a fluorine, or a hydrogen atom is mentioned, More preferably, a fluorine or a hydrogen atom is mentioned.
  • R 8 to R 19 are the same or different and include a hydrogen atom or C 1-6 alkyl, preferably a hydrogen atom or C 1-4 alkyl.
  • Ar is preferably aryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkoxy and —NR 16 R 17. Can be mentioned. More preferable examples include aryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen and C 1-6 alkyl. As n, 1 or 2 is mentioned, Preferably 1 is mentioned.
  • the pharmaceutically acceptable salt of the compound represented by the formula (I) is a pharmaceutically acceptable acid addition of the compound of the formula (I) having a group capable of forming an acid addition salt in the structure.
  • Means salt Specific examples of acid addition salts include hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, phosphate and other inorganic acid salts, oxalate, malonate, maleate Acid, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate And organic acid salts such as glutamic acid salts and aspartic acid salts.
  • compound represented by a formula (I) has acidic functional groups, such as a carboxyl group
  • various bases and salts can be formed.
  • the pharmaceutically acceptable salt in this case include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts, and ammonium salts. These salts can be obtained by a conventional method such as recrystallization after mixing the compound of the present invention represented by formula (I) with a base.
  • the production method of the compound of the present invention is described below.
  • the compound of the present invention represented by the formula (I) can be produced, for example, by the following production methods A 1 to A 5 , B, C 1 or C 2 .
  • Compounds A1 and A1 represented by formulas [A1] and [A2] Compound A2 can be produced, for example, by the following production method.
  • Rx is an electron withdrawing group such as halogen or nitro; It means a hydrogen atom, P means an amino protecting group
  • 2-methylaniline (compound a1) in which A is CR 1D is, for example, Bioorganic & Medicinal Chemistry Letters 2002, 12 (20), 2925-2930, European Journal of Organic Chemistry 2010, 24, 4662-4670, International Publication No. 2009 / 001132 can be produced by the method described in the pamphlet or the like, or can be purchased as a commercial product.
  • 2-methyl-3-aminopyridine in which A is a nitrogen atom compound a1 can be produced, for example, by the method described in International Publication No. 2008/157404, International Publication No. 2009/088103, etc. Or it can be purchased as a commercial product.
  • Step A-1 In this step, compound a1 is reacted with a nitrite compound in an appropriate solvent in the presence of various acids and inorganic salts to obtain an azide compound, and then cyclized in the presence or absence of crown ether to give compound a2. It is a process to obtain.
  • the acid used in this step is selected from mineral acids such as hydrochloric acid, nitric acid and sulfuric acid, preferably hydrochloric acid, and the nitrite compound used in this step is preferably amyl nitrite or sodium nitrite Is mentioned.
  • the salt used in this step is selected from tetrafluoroborane sodium, potassium acetate, sodium acetate, sodium bicarbonate, tert-butoxypotassium, etc., preferably tetrafluoroborane sodium and potassium acetate.
  • the solvent used in this step is selected from the solvents exemplified below, and preferably water, acetic acid, chloroform or dichloromethane. This reaction can be similarly produced using the method described in Tetrahedron Lett. 2002, 43, 2695-2697, Tetrahedron 2006, 62, 7772-7775, and the like.
  • Step A-2 This step is a step for obtaining compound a3 by reacting compound a2 obtained in step A-1 with iodine in a suitable solvent in the presence of various bases.
  • the base used in this step is selected from the bases exemplified below, and preferably sodium hydroxide or potassium hydroxide.
  • the solvent used in this step is selected from the solvents exemplified below, and preferably dimethylformamide or chloroform.
  • Step A-3 This step is a step of obtaining compound a4 by coupling compound a3 obtained in step A-2 with compound a7 in the presence of a catalyst and a base.
  • the catalyst include those supported on a carrier such as a transition metal such as palladium, a salt thereof, a complex thereof, or a polymer.
  • the base used in this step is selected from the bases exemplified below, and preferably sodium carbonate or potassium carbonate.
  • the solvent used in this step is selected from the solvents exemplified below, preferably a mixed solvent of dioxane-water.
  • This reaction includes the method described in International Publication No. 2005/073219 pamphlet and the like, and can be similarly produced using this method. In this reaction, various boranoic acid reagents that proceed in the same manner as compound a7 can also be used.
  • Step A-4 This step is a step of reducing compound a4 obtained in step A-3 above in the presence of a catalyst to obtain compound a5.
  • a catalyst to obtain compound a5.
  • the reducing agent hydrogen, a salt of formic acid such as ammonium formate, or hydrazine can be used.
  • the catalyst include those supported on a carrier such as a transition metal such as palladium, nickel, rhodium, cobalt, platinum, a salt thereof, a complex thereof, or a polymer.
  • the solvent used in this process is selected from the solvent etc. which are illustrated to a postscript, Preferably ethanol or methanol is mentioned.
  • Step A-5 This step is a step of obtaining compound a6 by deprotecting the protecting group P of the amino group of compound a5 obtained in the above step A-4.
  • This step can be carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).
  • Step A-6 This step is a step of obtaining compound A1 by reacting compound a6 obtained in step A-5 with compound a8 or a9 in an appropriate solvent in the presence of various bases.
  • the base used in this step is selected from the bases exemplified below, and preferably diisopropylethylamine or triethylamine.
  • the solvent used in this step is selected from the solvents exemplified below, and preferably tetrahydrofuran or dimethylformamide is used.
  • Step A-7 In this step, compound A1 obtained in step A-6 is reacted with various alkyl halides, carboxylic acids, boranoic acids, acid chlorides, isocyanates, etc. in the presence or absence of various bases in an appropriate solvent.
  • the base used in this step is selected from bases exemplified below, and preferably sodium hydride, diisopropylethylamine, or sodium carbonate.
  • the solvent used in this step is selected from the solvents exemplified below.
  • the compound A1 ′ represented by the formula [A1 ′] in which XYZ is N—CO—NR 4A R 4B and W is CR 3E is:
  • it can also be produced by the following production method.
  • R 1A to R 1D , R 3A to R 3E , R 4A , R 4B and n are as defined in Item 1;
  • Ry means a C 1-6 alkyl group or amino protecting group,
  • Rz means a chlorine, bromine or iodine atom, and P means an amino protecting group
  • a 4-chloropiperidine derivative (compound a10) is produced by a method described in, for example, Heterocycles 1990, 31 (7), 1201-1204,1-1Journal of the Chemical Society, Perkin Transactions 2 1992, 6, 857-8. Or can be purchased as a commercial product.
  • Step A-8 This step is a step of obtaining alkylmagnesium compound a11 by reacting compound a10 with metal magnesium, a Grignard reagent, or the like.
  • the solvent used in this step is selected from the solvents exemplified below, and preferably tetrahydrofuran or diethyl ether.
  • Step A-9 This step is a step of obtaining compound a12 by reacting compound a11 obtained in the above step A-8 with a15 or a16 in a suitable solvent.
  • the solvent used in this step is selected from the solvents exemplified below, and preferably tetrahydrofuran or diethyl ether.
  • Step A-10 This step is a step of obtaining compound a13 by reacting compound a12 obtained in step A-9 with various electrophiles in the presence of various bases in an appropriate solvent.
  • electrophile phenyl chlorocarbonate, benzyloxycarbonyl chloride, di-t-butyl dicarbonate and the like can be used.
  • the base used in this step is selected from the bases exemplified below, and preferably sodium carbonate or potassium carbonate.
  • the solvent used in this step is preferably toluene or tetrahydrofuran.
  • Step A-11 the compound a13 obtained in the above step A-10 is reacted in the presence of various bases in the presence of only hydrazine in an appropriate solvent, or by reacting with hydrazine following addition of methylhydroxylamine.
  • compound a14 is obtained.
  • the base used in this step is selected from the bases exemplified below, and preferably pyridine or potassium carbonate.
  • the solvent used in this step is selected from the solvents exemplified below, and preferably pyridine or dimethoxyethane. This reaction includes the method described in Journal of Organic Chemistry 2006, 71 (21), 8166-8172, and can be produced according to this method.
  • Step A-12 This step is a step of obtaining the compound a6 ′ by deprotecting the protecting group P of the amino group of the compound a14 obtained in the step A-11.
  • This step can be carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).
  • Step A-13 This step is a step of converting the compound a6 ′ obtained in the step A-12 to the compound A1 ′ under the conditions according to the step A-6.
  • the compound A1 ′ represented by the formula [A1 ′] in which XYZ is N—CO—NR 4A R 4B and W is CR 3E is:
  • it can also be produced by the following production method.
  • R 1A to R 1D , R 3A to R 3E , R 4A , R 4B and n are as defined in Item 1; Rz represents a chlorine, bromine or iodine atom, and P represents an amino-protecting group
  • 2-Fluoro-bromobenzene and the like are disclosed in, for example, Bioorganic & Medicinal & Chemistry & Letters, 2011, 21 (24), 7434-7350, International Publication No. 2010/026124, International Publication No. 2007/082098 It can be produced by the methods described or can be purchased as a commercial product.
  • Step A-14 This step is a step of obtaining an aryllithium compound a18 by performing a halogen metal exchange reaction by reacting the compound a17 with alkyllithium or the like.
  • the alkyl lithium used in this step is preferably n-butyl lithium.
  • the solvent used in this step is selected from the solvents exemplified below, and preferably tetrahydrofuran or diethyl ether.
  • Step A-15 This step is a step of obtaining wine levamide a20 by reacting compound a19 with methoxymethylamine in an appropriate solvent in the presence of various condensing agents.
  • various condensing agents used in this step various condensing agents used in a conventional method can be used, but 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (including hydrochloride) is preferable. Is mentioned.
  • the solvent used in this step is selected from the solvents exemplified below.
  • Step A-16 This step is a step of obtaining compound a21 by reacting compound a20 with compound a18 in a suitable solvent.
  • the solvent used in this step is selected from the solvents exemplified below, preferably tetrahydrofuran or diethyl ether.
  • Step A-17 This step is a step of converting the compound a21 obtained in the step A-16 to the compound a22 under the conditions according to the step A-11.
  • Step A-18 This step is a step of converting the compound a22 obtained in the step A-17 to the compound a23 under the conditions according to the step A-12.
  • Step A-19 This step is a step of converting the compound a23 obtained in the step A-18 to the compound A1 ′ under the conditions according to the step A-6.
  • the compound A1 ′ represented by the formula [A1 ′] in which XYZ is N—CO—NR 4A R 4B and W is CR 3E is:
  • it can also be produced by the following production method.
  • Rx is an electron withdrawing group such as halogen, nitro or hydrogen; Means an atom, and P means an amino-protecting group
  • the 4-piperidylcarboxylic acid derivative (compound a25) can be produced, for example, by the method described in International Publication No. 2010/117323 pamphlet or can be purchased as a commercial product.
  • Step A-20 This step is a step of obtaining the thioester a26 by activating the carbonyl moiety of the compound a25 with various activating reagents or condensing agents and reacting the compound a30.
  • the activating reagent used in this step is preferably oxalyl chloride.
  • various condensing agents used in a conventional manner can be used. N'-dicyclohexylcarbodiimide.
  • the base used in this step is preferably diisopropylethylamine, and the solvent used in this step is selected from the solvents exemplified below.
  • Step A-21 This step is a step of obtaining compound a27 by reacting compound a26 with boranoic acid a31 in the presence of a palladium catalyst, a copper complex and a phosphorus ligand in an appropriate solvent.
  • the palladium catalyst used in this step is preferably trisdibenzylideneacetone bis-palladium, and the copper complex is preferably copper thiophenecarboxylate.
  • the phosphorus ligand is preferably triethyl phosphite, and the solvent is selected from the solvents exemplified below, and preferably tetrahydrofuran. Examples of the similar reaction include the methods described in Journal of the American Chemical Society 2007, 129 (5), 1132-1140, Journal of the American Chemical Society 2007, 129 (51), 15734-15735, etc. It can be similarly manufactured using this method.
  • Step A-22 This step is a step of converting compound a27 to compound a28 under the conditions according to the above step A-11.
  • Step A-23 This step is a step of converting compound a28 to compound a29 under the conditions according to the above step A-12.
  • Step A-24 This step is a step of converting compound a29 into compound A1 ′ under the conditions according to the above step A-6.
  • Compounds A3 and A3 represented by formulas [A3] and [A4] Compound A4 can be produced, for example, by the following production method. (In the formula, A, R 1A to R 1D , R 2 , R 3A to R 3D , R 4A , R 4B and n are as defined in Item 1, and Rx is an electron withdrawing group such as halogen or nitro It is a hydrogen atom.)
  • 3- (1-piperazinyl) -1H-indazole and the like include, for example, Organic Process Research & Development 2001, 5 (2), 179-183, International Publication No. 2010/054279, Organic Process Research & Development 2003, 7 (4), 521-532 or can be purchased as a commercial product.
  • Step A-25 This step is a step of converting compound a32 into compound A3 under the conditions according to the above step A-6.
  • Step A-26 This step is a step of converting the compound A3 obtained in the step A-25 to the compound A4 under the conditions according to the step A-7.
  • the 4-oxocyclohexanecarboxylate derivative (compound b1) can be obtained by a method described in, for example, Organic Syntheses 2007, 84, 233-241, Synlett 2000, 11, 1549-1552, International Publication No. 2010/141406, etc. It can be manufactured or purchased as a commercial product.
  • Step B-1 This step is a step of obtaining compound b2 by reacting compound b1 with compound b7 or b8 in an appropriate solvent in the presence of various bases.
  • the base used in this step is selected from the bases exemplified below, and preferably pyridine or potassium hexamethyldisilazide.
  • the solvent used in this process is selected from the solvent etc. which are illustrated to a postscript, Preferably toluene or tetrahydrofuran is mentioned.
  • This reaction includes the method described in Organic Process & Research & Development 2010, 14 (5), 1182-187, and can also be produced by this method.
  • Step B-2 This step is a step of coupling compound b2 obtained in step B-1 with compound b9 in the presence of a catalyst and a salt to obtain compound b3.
  • the catalyst include those supported on a carrier such as a transition metal such as palladium, a salt thereof, a complex thereof, or a polymer.
  • the salt used in this step is selected from potassium acetate, sodium acetate, silver acetate and the like, preferably potassium acetate.
  • the solvent used in this step is selected from the solvents exemplified below and preferably dimethyl sulfoxide and dimethoxyethane. Examples of this reaction include methods described in International Publication No. 2009/016462 pamphlet and the like, and can be produced in the same manner using this method.
  • Step B-3 This step is a step of converting the compound b3 obtained in the step B-2 into the compound b4 under the conditions according to the step A-3.
  • Step B-4 This step is a step of converting the compound b4 obtained in the step B-3 into the compound b5 under the conditions according to the step A-4.
  • Step B-5 This step is a step of converting the ester compound b5 obtained in the step B-4 to the corresponding carboxylic acid compound b6.
  • This step can be carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).
  • Step B-6 This step is a step of obtaining compound B1 by reacting compound b6 obtained in step B-5 with compound b10 in the presence of various condensing agents in an appropriate solvent.
  • various condensing agents used in this step various condensing agents used in a conventional method can be used, but 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (including hydrochloride) is preferable. Is mentioned.
  • the solvent used in this step is selected from the solvents exemplified below.
  • Step B-7 This step is a step of converting the compound B1 obtained in the step B-6 to the compound B2 under the conditions according to the step A-7.
  • Compound C1 can be produced, for example, by the following production method. (Wherein, A, R 1A ⁇ R 1D , R 2, R 3A ⁇ R 3D, R 5, R 6, Ar and n are as defined in claim 1, P is meant the amino-protecting group To do.)
  • the 4-aminocyclohexanecarboxylic acid derivative (compound c1) can be produced, for example, by the method described in Synthetic Communications 2002, 32 (13), 1985-1995, US Publication No. 2005/0020645, etc., or commercially available It can be purchased as a product.
  • Step C-1 This step is a step of converting compound c1 into the corresponding acid chloride compound c2 using a reagent such as oxalyl chloride, thionyl chloride and the like.
  • the solvent used in this step is selected from the solvents exemplified below, preferably dichloromethane or tetrahydrofuran.
  • Step C-2 This step is a step for producing the corresponding thioester c3 from compound c2 obtained in the above step C-1 using c8 in the presence of various bases in an appropriate solvent.
  • the base used in this step is selected from the bases exemplified below, and preferably triethylamine or diisopropylethylamine is used.
  • the solvent used in this step is selected from the solvents exemplified below, and preferably tetrahydrofuran or dichloromethane.
  • Step C-3 This step is a step of coupling compound c3 obtained in step C-2 with boronic acid compound c9 in the presence or absence of a catalyst and an organophosphorus compound to obtain compound c4.
  • the catalyst include those supported on a carrier such as transition metals such as palladium and copper, salts thereof, complexes thereof, and polymers.
  • the organophosphorus compound used in this step is preferably triethyl phosphite.
  • the solvent used in this step is selected from the solvents exemplified below, and preferably includes tetrahydrofuran. Examples of the reaction include those described in Journal of American Chemical Society 2007, 129 (5), 1132-1140, Bioorganic Medicinal Chemistry Letters 2007, 17, 5647-5651.
  • Step C-4 This step is a step of converting the compound c4 obtained in the step C-3 to the compound c5 under the conditions according to the step A-11.
  • Step C-5 This step is a step of converting the compound c5 obtained in the step C-4 into the compound c6 under the conditions according to the step A-7.
  • the compound represented by the formula (I) in which R 2 is a hydrogen atom does not carry out this step.
  • Step C-6 This step is a step of converting the compound c6 obtained in the step C-5 to the corresponding amine compound c7.
  • This step can be carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).
  • Step C-7 This step is a step of obtaining compound C1 by reacting compound c7 obtained in step C-6 with compound c10 or c11 in a suitable solvent in the presence of various condensing agents or bases.
  • various condensing agents used in this step various condensing agents used in a conventional method can be used, but 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (including hydrochloride) is preferable. Is mentioned.
  • the base used is selected from the bases exemplified below, and preferably diisopropylethylamine or triethylamine.
  • the solvent used in this step is selected from the solvents exemplified below, and preferably dimethylformamide or tetrahydrofuran.
  • a compound represented by the formula [C1] in which R 7 is not a hydrogen atom can also be produced by a method according to the above method.
  • A, R 1A to R 1D , R 2 , R 3A to R 3D , R 4A , R 4B , R 6 , R 7 and n are as defined in Item 1, Rx is halogen, nitro An electron withdrawing group such as hydrogen atom or a hydrogen atom, and X is a leaving group such as halogen.
  • Step C-8 This step is a step of converting the compound c7 obtained in the step C-6 to the compound C2 under the conditions according to the step A-6.
  • Step C-9 This step is a step of obtaining compound C3 by reacting compound c2 obtained in step C-8 with compound c12 in the presence of various bases in an appropriate solvent.
  • the base used in this step is selected from the bases exemplified below, and preferably diisopropylamine or triethylamine.
  • the solvent used in this step is selected from the solvents exemplified below, and preferably dimethylformamide or tetrahydrofuran.
  • the base used in each step of each of the above production methods should be selected as appropriate depending on the reaction and the type of raw material compound.
  • alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate, sodium carbonate
  • Alkali carbonates such as potassium carbonate
  • metal hydrides such as sodium hydride and potassium hydride
  • alkali metal hydroxides such as sodium hydroxide and potassium hydroxide
  • sodium methoxide sodium t-butoxide
  • Alkali metal alkoxides organometallic bases such as butyl lithium and lithium diisopropylamide, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo [5.4.0]- Organic bases such as 7-undecene (DBU) Is mentioned.
  • DMAP 4-dimethylaminopyridine
  • the solvent used in each step of each of the above production methods should be selected as appropriate depending on the reaction and the type of raw material compound.
  • alcohols such as methanol, ethanol and isopropanol, acetone and methyl ketone, etc.
  • Ketones halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as tetrahydrofuran (THF) and dioxane, aromatic hydrocarbons such as toluene and benzene, aliphatic hydrocarbons such as hexane and heptane , Esters such as ethyl acetate, propyl acetate, amides such as N, N-dimethylformamide (DMF), N-methyl-2-pyrrolidone, sulfoxides such as dimethyl sulfoxide (DMSO), and acetonitrile Nitriles, and these solvents are simple Or it may be used by mixing 2 or more kinds.
  • organic bases such as methanol
  • the compound of the present invention represented by formula (I) or an intermediate thereof can be separated and purified by methods known to those skilled in the art. Examples include extraction, distribution, reprecipitation, column chromatography (for example, silica gel column chromatography, ion exchange column chromatography or preparative liquid chromatography) or recrystallization. Examples of the recrystallization solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as benzene and toluene, acetone and the like.
  • the recrystallization solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as benzene and toluene, acetone and the like.
  • Ketone solvents such as dichloromethane and chloroform
  • hydrocarbon solvents such as hexane
  • aprotic solvents such as dimethylformamide and acetonitrile
  • water or a mixed solvent of two or more selected from the above solvents
  • a mixed solvent of two or more selected from the above solvents Can be used.
  • the methods described in Experimental Chemistry Course (The Chemical Society of Japan, Maruzen) vol. 1 can be used.
  • the compound of the present invention represented by the formula (I) or a pharmaceutically acceptable salt thereof may have an asymmetry or may have a substituent having an asymmetric carbon.
  • Has optical isomers The compounds of the present invention include mixtures of these isomers and isolated ones, which can be produced according to ordinary methods. Examples of the production method include a method using a raw material having an asymmetric point, or a method of introducing asymmetry at an intermediate stage. For example, in the case of optical isomers, optical isomers can be obtained by using optically active raw materials or by performing optical resolution at an appropriate stage of the production process.
  • an alcohol solvent such as methanol, ethanol, 2-propanol or the like
  • An ether solvent such as diethyl ether, an ester solvent such as ethyl acetate, a hydrocarbon solvent such as toluene, an aprotic solvent such as acetonitrile, or a mixed solvent of two or more selected from the above solvents
  • optical activity For example, monocarboxylic acids such as mandelic acid, N-benzyloxyalanine and lactic acid, tartaric acid, dicarboxylic acids such as o-diisopropylidene tartaric acid and malic acid, and sulfonic acids such as camphorsulfonic acid and bromocamphorsulfonic acid
  • a diastereomer method in which a salt is formed using.
  • an optically active amine for example, 1-phenylethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine, etc.
  • the optical resolution can also be carried out by forming a salt using an organic amine).
  • the temperature at which the salt is formed is selected from the range from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to raise the temperature once to near the boiling point of the solvent. When the precipitated salt is collected by filtration, it can be cooled as necessary to improve the yield.
  • the amount of the optically active acid or amine used is suitably in the range of about 0.5 to about 2.0 equivalents, preferably in the range of about 1 equivalent, relative to the substrate.
  • Crystals in an inert solvent as necessary for example, alcohol solvents such as methanol, ethanol, 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, hydrocarbon solvents such as toluene, acetonitrile, etc. Or a mixed solvent of two or more selected from the above solvents) to obtain a highly pure optically active salt. Further, if necessary, an optically resolved salt can be treated with an acid or a base by a conventional method to obtain a free form.
  • an inert solvent for example, alcohol solvents such as methanol, ethanol, 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, hydrocarbon solvents such as toluene, acetonitrile, etc. Or a mixed solvent of two or more selected from the above solvents
  • the compounds of the present invention can be used for nervous system diseases, mental disorders and inflammatory diseases (eg, dementia, schizophrenia, CIAS (cognitive impairment associated with schizophrenia), Alzheimer's disease, Down's syndrome, attention deficit disorder, cerebrovascular angiopathy Etc.) and can be used as novel therapeutic agents and / or preventive agents.
  • the administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration, and the daily dose varies depending on the type of compound, administration method, patient symptom / age and the like.
  • oral administration usually about 0.01 to 1000 mg, more preferably about 0.1 to 500 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 0.01 mg to 300 mg, more preferably about 1 mg to 100 mg per kg body weight of a human or mammal can be administered.
  • Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, injections, suppositories, eye drops, ointments, coatings, patches, inhalants and the like.
  • These preparations can be prepared according to a conventional method. In the case of a liquid preparation, it may be dissolved or suspended in water, an appropriate aqueous solution or other appropriate medium at the time of use. Tablets and granules may be coated by a known method. In addition, these formulations may contain other therapeutically valuable ingredients.
  • the compound of the present invention can be used in combination with drugs classified as atypical antipsychotic drugs.
  • atypical antipsychotics include olanzapine, risperidone, paliperidone, quetiapine, ziprasidone, aripiprazole, asenapine, iloperidone, clozapine, sertindole, blonanserin and lurasidone.
  • High-performance liquid chromatograph / mass spectrometer The measurement conditions of LCMS are as follows, and the observed mass spectrometry value [MS (m / z)] is represented by MH + and the retention time is represented by Rt (minutes). In each actual measurement value, the measurement conditions used for measurement are indicated by A to C.
  • Measurement condition D Detection equipment: Perkin-Elmer Sciex API 150EX Massspectrometer (40eV)
  • HPLC Shimadzu LC 10ATVP
  • Solvent Liquid A: 0.035% TFA / CH 3 CN
  • Liquid B 0.05% TFA / H 2 O
  • UV 220 nm
  • Example 1 N-cyclohexyl-4- (6-fluoro-1H-indazol-3-yl) piperidine-1-carboxamide Cyclohexyl isocyanate (130 mg) was added to a tetrahydrofuran solution (30 ml) of Reference Example 1 (220 mg), and the mixture was stirred for 16 hours at room temperature. After completion of the reaction, the residue was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent; ethyl acetate) to obtain Example 1 (190 mg).
  • Example 2 N-cyclohexyl-4- (1-ethyl-6-fluoro-1H-indazol-3-yl) piperidine-1-carboxamide
  • Sodium hydride (9 mg) and bromoethane (25 mg) were added to a dimethylformamide solution (2 ml) of Example 1 (79 mg) at 0 ° C., and the mixture was stirred at 0 ° C. for 10 minutes.
  • the reaction solution was poured into water and extracted with ethyl acetate / hexane (3/2). The organic layer was dried over sodium sulfate and evaporated under reduced pressure.
  • Example 2 (43 mg) was obtained by refine
  • Example 3 (41 mg) was obtained by refine
  • 1 H-NMR 400 MHz, CD 3 OD: 1.15-1.90 (11H, brm), 2.90-2.80 (4H, m), 3.54 (2H, m), 4.14 (2H, m), 6.14 (1H, m ), 6.44 (1H, m), 6.72 (1H, m), 6.80 (1H, m).
  • Example 4 N-cyclohexyl-4- (3-1H-indazoyl) cyclohexanecarboxamide DIEA (350 ⁇ L) and cyclohexylamine (68 ⁇ L) were added to a DMF suspension (2 mL) of Reference Example 2 (98 mg), EDCI ⁇ HCl (112 mg) and HOBt (125 mg). Stir overnight. Liquid separation extraction was performed with CHCl 3 -water, and the obtained organic layer was washed with saturated brine and then dried over sodium sulfate.
  • Example 5 N- (cis-4- (3-1H-indazoyl) cyclohexyl) cyclohexanecarboxamide DIEA (175 ⁇ L) and cyclohexanecarboxylic acid (24 mg) were added to a DMF suspension (1.5 ml) of Reference Example 3 (43 mg), EDCI ⁇ HCl (56 mg) and HOBt (62 mg) at room temperature. Stir for 5 hours. Liquid separation extraction was performed with CH 2 Cl 2 -water, and the obtained organic layer was dried over sodium sulfate.
  • Example 6 4- (3-1H-indazoyl) cyclohexyl) -3-cyclohexylurea TEA (120 ⁇ L) and cyclohexyl isocyanate (24 ⁇ L) were added to a suspension of Reference Example 3 (58 mg) in THF (1.5 ml), and the mixture was stirred at room temperature for 15 hours. Liquid separation extraction was performed with CH 2 Cl 2 -water, and the obtained organic layer was dried over sodium sulfate. After evaporating the solvent under reduced pressure, Example 5 (30 mg) was obtained by purification with amino silica gel column chromatography (elution solvent; ethyl acetate).
  • Example 65 N- (trans-4-methoxycyclohexyl) -4- [7- (trifluoromethyl) -1H-indazol-3-yl] piperidine-1-carboxamide Phenyl (trans-4-methoxycyclohexyl) carbamate (71 mg) was added to acetonitrile solution (3 mL) of Reference Example 4 (103 mg), and the mixture was stirred at 80 ° C. for 16 hours. After completion of the reaction, the residue was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent; ethyl acetate) to give Example 65 (99 mg).
  • Example 66 46 mg.
  • the following compounds are envisaged. These are the corresponding amine compounds, 7- (1-methoxycyclopropyl) -3- (piperidin-4-yl) -1H-indazole or 7- (1-methoxyethyl) -3- (piperidin-4-yl) It can be synthesized by reacting and treating in the same manner as in Examples 1 to 3 and 65 to 67 using a urea reagent corresponding to -1H-indazole. The amine group can be synthesized by reacting and treating in the same manner as in Reference Example 5. As a similar reaction of methoxycyclopropylation, for example, the method described in International Publication No.
  • 2006/013048 pamphlet and the like is known and can be synthesized in the same manner.
  • methods described in International Publication No. 2011/138751 pamphlet, International Publication No. 2010/074089 pamphlet and the like are known, and can be synthesized in the same manner.
  • Test Example 1 PAM activity evaluation using human ⁇ 7 nACh receptor stable expression cells
  • Human ⁇ 7 nAChR stable expression cells Human ⁇ 7 nAChR stable expression cells were prepared and subjected to culture. Specifically, rat pituitary-derived GH4C1 cells (cat # CCL-82.2, ATCC, USA) were used as host cells.
  • Aequorin by introducing pcDNA3.1Zeo vector into which the nucleotide sequence encoding the protein of GenBank BAC81731 was inserted and pcDNA3.1 vector (cat # V790-20, invitrogen, Carlsbad, CA, USA) into which the human ⁇ 7 nAChR gene was inserted And human ⁇ 7 nAChR stably expressing cells were obtained.
  • Zeocin catalog # R25001, invitrogen, Carlsbad, CA, USA
  • Geneticin catalog # 10131-027, invitrogen, Carlsbad, CA, USA
  • the medium includes 2.5% fetal bovine serum (cat # 2917354, ICN Biomedicals, Inc, USA), 15% inactivated horse serum (cat # 26050-088, invitrogen, Carlsbad, CA, USA), 1 ⁇ g / mL Geneticin, Collagen Type1 using F-10 Nutrient Mixture (Ham) medium (cat # 11550-043, invitrogen, Carlsbad, CA, USA) containing 5 ⁇ g / mL Puromycin (cat # 14861-84, invitrogen, Carlsbad, CA, USA) Culturing was performed in a coat dish (cat # 4030-010, iwaki, Tokyo, Japan).
  • the medium was changed every 2-3 days, and the cells were collected by TrypLE Express (cat # 45604-021, invitrogen, Carlsbad, CA, USA) treatment every 7 days and subcultured. Seven days after passage, cells were collected by TrypLE Express treatment in a state of about 80% confluence, Hanks (cat # 14065-056, invitrogen, Carlsbad, CA, USA) / 20 mM Hepes (cat # 15630-080, invitrogen , Carlsbad, CA, USA) Suspended in a reaction medium consisting of Buffer (pH 7.4), F-10 Nutrient Mixture (Ham), 0.1 mg / mL Geneticin to 20000 cells / 25 ⁇ L / well, and a 384-well plate ( cat # 781090, Greiner, Germany).
  • Viviren (cat # E649X, Promega, Madison, WI, USA) was added to a final concentration of 4 ⁇ M (15 ⁇ L / well), and the mixture was allowed to stand for 4 hours at room temperature under light shielding after centrifugation.
  • test compound A DMSO solution having a concentration 1000 times the final concentration was prepared as a test compound, and this solution was added to Hanks / 20 mM HEPES / 0.2% BSA (cat # A3803, Sigma, St. Louis, MO, USA). The final concentration was adjusted to 6 times the final concentration.
  • PAM activity evaluation FDSS7000 (Hamamatsu Photonics) was used for the detection of the luminescent signal by ⁇ 7 nAChR stimulation. Test compounds were added to the plates to which cells and luminescent substrate had been added, and ACh at a concentration indicating EC 20 was added alone after 150 seconds. Rlu (Max-Min) was calculated by measuring the luminescence signal (center wavelength: 465 nm) for 138 seconds after addition of ACh, and the ratio of Rlu (Max-Min) between the control well and the test compound added well was defined as PAM activity. . Table 7 shows data of ⁇ 7 PAM activity of representative compounds.
  • the compound of the present invention had ⁇ 7 nAChR PAM activity in the PAM activity evaluation test.
  • Examples 1, 9, 33, 28, 33, 51, 98, 99, 128, 131, and 145 showed stronger PAM activity.
  • hERG potassium current in CHO cells stably expressing hERG (human ether-a-go-go) gene by whole cell patch clamp method using QPatch HT (Sophion Bioscience A / S) was recorded.
  • the hERG current is the amplitude of the tail current when the membrane potential is held at ⁇ 80 mV in the voltage clamp mode, depolarized to +20 mV for 5 seconds after being changed to ⁇ 50 mV for 20 milliseconds, and then repolarized to ⁇ 50 mV for 5 seconds. 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 for each cell for 5 minutes, the inhibition rate of the inhibited current was calculated as compared to the current before the compound adaptation at each concentration, and the 50% inhibitory concentration was calculated by the Hill equation. (IC 50 [ ⁇ M]).
  • Rat PK test 7-week-old rats were administered intravenously with physiological saline solution or orally with methylcellulose aqueous solution, and blood was collected at the following times, respectively.
  • Intravenous administration 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours and 24 hours
  • Oral administration 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours and 24 hours
  • Plasma obtained by centrifuging the collected blood at 3000 rpm ⁇ 10 minutes using a cooling centrifuge set at 4 ° C. was measured by HPLC, and pharmacokinetic parameters were calculated based on the obtained time curve.
  • Test Example 4 Evaluation of cognitive function using mouse novel object recognition test (hereinafter referred to as mORT) Decreased memory for known objects in a novel object recognition test using Slc: ddY mice (male, SLC Japan) weighing 25-30 g depending on the time interval between the first trial (training) and the second trial (test) When a second trial is performed 24 hours later, significant forgetting is observed. Therefore, the compound of the present invention was administered before the first trial, and the memory enhancing action in the second trial was evaluated.
  • mORT mouse novel object recognition test
  • the compound of the present invention has an effect of continuously improving the cognitive function from a very low dose.
  • the minimum effective dose of the compound of Example 131 was 0.3 mg / kg.
  • Test Example 5 Evaluation of improvement of cognitive impairment using rat Y-shaped maze test (hereinafter referred to as Y-maze test)
  • Y-maze test In a Y-shaped maze test using 280-300 g Slc: Wistar rats (male, SLC), memory impairment was caused by subcutaneous administration of 0.6 mg / kg Scopolamine HBr (cat # S0929, Sigma Aldrich, Japan)
  • a decrease in the spontaneous alternation behavior rate is observed. Therefore, the compound of the present invention was pretreated to evaluate the effect of improving memory impairment.
  • the compound of the present invention has an effect of continuously improving the cognitive function from a low dose.
  • the compound of Example 1 had a minimum effective dose of 3 mg / kg.
  • the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has a strong ⁇ 7 nicotinic acetylcholine receptor ( ⁇ 7 nAChR) modulating action, and the central nervous system ( CNS) and / or peripheral nervous system (PNS) cholinergic diseases, smooth muscle contraction diseases, endocrine diseases, neurodegenerative diseases, diseases such as inflammation or pain, and withdrawal symptoms caused by addictive drug abuse Useful for treatment of diseases and the like.
  • ⁇ 7 nAChR central nervous system
  • PNS peripheral nervous system

Abstract

Provided is a therapeutic agent for conditions involving the cholinergicity of the central nervous system (CNS) and/or peripheral nervous system (PNS), conditions involving smooth muscle contraction, endocrine conditions, conditions involving nerve degeneration, and the like; the therapeutic agent having a strong regulatory effect on the α7 nicotinic acetylcholine receptors (α7 nAChR), and containing a compound represented by formula (I) (where A represents CR1D or a nitrogen atom; X-Y-Z represents N-CO-NR4AR4B or the like; R1A, R1B, R1C, and R1D are the same or different and each represent a hydrogen atom or the like; W represents CH or a nitrogen atom; R2 represents a hydrogen atom or the like; R3A, R3B, R3C, and R3D are the same or different and represent a hydrogen atom or the like; R4A, R4B, R5, and R7 are the same or different and each represent an optionally substituted C3-10 cycloalkyl or the like, R6 are the same or different and each represent a hydrogen atom or the like; and n represents 1 or 2) or a pharmaceutically acceptable salt thereof.

Description

新規インダゾール誘導体New indazole derivatives
　本発明は、α７ニコチン性アセチルコリン受容体（α７ ｎＡＣｈＲ）の調節物質である新規なインダゾール誘導体に関する。それらの薬理学的特性から、本発明の化合物は、中枢神経系（ＣＮＳ）及び／又は末梢神経系（ＰＮＳ）のコリン作動性に関する疾患、平滑筋収縮に関する疾患、内分泌疾患、神経変性に関する疾患、炎症又は痛み等の疾患及び常習性の薬物乱用から引き起こされる禁断症状に関する疾患等の治療に有用であり得る。 The present invention relates to a novel indazole derivative which is a modulator of α7 nicotinic acetylcholine receptor (α7 nAChR). Due to their pharmacological properties, the compounds of the present invention can be used for diseases related to cholinergic activity of the central nervous system (CNS) and / or peripheral nervous system (PNS), diseases related to smooth muscle contraction, endocrine diseases, diseases related to neurodegeneration, It may be useful for the treatment of diseases such as inflammation or pain and diseases related to withdrawal symptoms caused by addictive drug abuse.
　近年、ニコチンの潜在的な神経保護効果が示されており、興奮毒性傷害、栄養欠乏、虚血、外傷、アミロイドベータ（Ａβ）媒介神経細胞死及びタンパク質凝集媒介神経変性を伴う動物及び培養細胞の様々な神経変性モデルが提唱されている。ニコチンが神経保護効果を呈する多くの例において、α７サブタイプ含有ニコチン性アセチルコリン受容体が活性化されていることが明らかになっている。これらは、ニコチンが神経保護効果を媒介するために役立つことが示唆され、α７サブタイプを含む受容体の直接的関与が想起されてきた。これらデータから、α７ニコチン性アセチルコリン受容体が、神経保護として妥当な分子標的の代表であることが示唆される。つまり、該受容体の活性なアゴニスト／正のモジュレーター（ポジティブアロステリックモジュレーター：ＰＡＭ）を開発することにより、神経保護が達成され得る。実際に、α７ニコチン性受容体アゴニストはすでに同定され、神経保護薬の開発のために可能性ある手がかりとして評価されている。また、近年α７ニコチン性アセチルコリン受容体の炎症への関与も、報告されている。以上のことから、該受容体の新規モジュレーターの開発は、神経系疾患、精神疾患及び炎症性疾患の新規な治療が想定される。 In recent years, the potential neuroprotective effects of nicotine have been shown, in animals and cultured cells with excitotoxic injury, nutrient deficiency, ischemia, trauma, amyloid beta (Aβ) mediated neuronal cell death and protein aggregation mediated neurodegeneration. Various neurodegenerative models have been proposed. In many instances where nicotine exhibits a neuroprotective effect, it has been shown that the α7 subtype-containing nicotinic acetylcholine receptor is activated. These have been suggested that nicotine helps to mediate neuroprotective effects, and direct involvement of receptors including the α7 subtype has been recalled. These data suggest that the α7 nicotinic acetylcholine receptor represents a valid molecular target for neuroprotection. Thus, neuroprotection can be achieved by developing an active agonist / positive modulator of the receptor (positive allosteric modulator: PAM). In fact, α7 nicotinic receptor agonists have already been identified and evaluated as potential clues for the development of neuroprotective drugs. In recent years, the involvement of α7 nicotinic acetylcholine receptors in inflammation has also been reported. From the above, the development of a novel modulator of the receptor is expected to be a novel treatment for nervous system diseases, psychiatric diseases and inflammatory diseases.
　これまでに、α７ニコチン性アセチルコリン受容体（α７ ｎＡＣｈＲ）の調節物質に関する開示はあるが、本願発明の化合物とは構造が異なる（特許文献１及び特許文献２）。 So far, there has been disclosure regarding a modulator of α7 nicotinic acetylcholine receptor (α7 nAChR), but the structure is different from the compound of the present invention (Patent Document 1 and Patent Document 2).
国際公開第２００３／０９３２５０号パンフレットInternational Publication No. 2003/093250 Pamphlet 国際公開第２００６／１３８５１０号パンフレットInternational Publication No. 2006/138510 Pamphlet
　本発明の課題は、強力なα７ニコチン性アセチルコリン受容体（α７ ｎＡＣｈＲ）の調節作用を有し、神経系疾患、精神疾患及び炎症性疾患の新規な治療剤及び／又は予防剤として有用な新規化合物を提供することにある。 An object of the present invention is to provide a novel compound having a potent α7 nicotinic acetylcholine receptor (α7 nAChR) regulating action and useful as a novel therapeutic and / or preventive agent for nervous system diseases, mental disorders and inflammatory diseases. Is to provide.
　本発明者らは、鋭意研究を行った結果、下記式（Ｉ）で表される新規化合物が強力なα７ニコチン性アセチルコリン受容体（α７ ｎＡＣｈＲ）の調節作用を有することを見出し、本発明を完成させた。本発明によれば、下記式（Ｉ）で表されるインダゾール誘導体又はその製薬学的に許容される塩（以下、「本発明の化合物」と称することもある）が提供される。 As a result of intensive studies, the present inventors have found that a novel compound represented by the following formula (I) has a potent α7 nicotinic acetylcholine receptor (α7 nAChR) regulating action, and completed the present invention. I let you. According to the present invention, an indazole derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof (hereinafter also referred to as “the compound of the present invention”) is provided.
［項１］
式（Ｉ）：
Figure JPOXMLDOC01-appb-C000002
 ［式中、
　Ａは、ＣＲ１Ｄ又は窒素原子を表し、
　Ｘ－Ｙ－Ｚは、Ｎ－ＣＯ－ＮＲ４ＡＲ４Ｂ、ＣＲ６－ＣＯ－ＮＲ４ＡＲ４Ｂ、ＣＲ６－ＮＲ７－ＣＯ－ＮＲ４ＡＲ４Ｂ、ＣＲ６－ＮＲ７－ＣＯＲ５又はＣＲ６－ＮＲ７－Ａｒを表し、
　Ｒ１Ａ、Ｒ１Ｂ、Ｒ１Ｃ及びＲ１Ｄは、同一又は異なって、ハロゲン、水酸基、Ｃ１－６アルコキシ、－ＮＲ８Ｒ９、－ＣＯＯＲ８、－ＣＯＮＲ８Ｒ９、－ＮＲ８ＣＯＲ９、－ＳＯ２ＮＲ８Ｒ９及び－ＮＲ８ＳＯ２Ｒ９からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；ハロゲン、水酸基、Ｃ１－６アルキル、Ｃ１－６アルコキシ、－ＮＲ８Ｒ９、－ＣＯＯＲ８、－ＣＯＮＲ８Ｒ９、－ＮＲ８ＣＯＲ９、－ＳＯ２ＮＲ８Ｒ９及び－ＮＲ８ＳＯ２Ｒ９からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルキル、４～１０員の飽和複素環若しくは４～１０員の飽和複素環基－Ｏ－；ハロゲン、水酸基、Ｃ１－６アルコキシ、－ＮＲ８Ｒ９、－ＣＯＯＲ８、－ＣＯＮＲ８Ｒ９、－ＮＲ８ＣＯＲ９、－ＳＯ２ＮＲ８Ｒ９及び－ＮＲ８ＳＯ２Ｒ９からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルコキシ；ハロゲン、水酸基、Ｃ１－６アルコキシ、－ＮＲ８Ｒ９、－ＣＯＯＲ８、－ＣＯＮＲ８Ｒ９、－ＮＲ８ＣＯＲ９、－ＳＯ２ＮＲ８Ｒ９及び－ＮＲ８ＳＯ２Ｒ９からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルコキシ；水素原子；水酸基；ハロゲン；ハロゲン、水酸基、Ｃ１－６アルキル、Ｃ１－６アルコキシ、－ＮＲ８Ｒ９、－ＣＯＯＲ８、－ＣＯＮＲ８Ｒ９及び－ＮＲ８ＣＯＲ９からなる群から独立して選択される１～５個の置換基で置換されていてもよいアリール若しくはヘテロアリール；ニトロ；－ＮＲ８Ｒ９；シアノ；－ＣＯＯＲ８；－ＣＯＮＲ８Ｒ９；－ＮＲ８ＣＯＲ９；－ＳＯ２ＮＲ８Ｒ９；又は－ＮＲ８ＳＯ２Ｒ９を表し、ここにおいて、Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＨＥｔであるとき、Ｒ１Ｂが－ＣＯ－ＮＨＥｔで置換されているアリール基ではなく、
　Ｗは、ＣＲ３Ｅ又は窒素原子を表し、
　Ｒ２は、ハロゲン、水酸基、Ｃ１－６アルコキシ、－ＮＲ１０Ｒ１１、－ＣＯＯＲ１０、－ＣＯＮＲ１０Ｒ１１、－ＮＲ１０ＣＯＲ１１、－ＳＯ２ＮＲ１０Ｒ１１及び－ＮＲ１０ＳＯ２Ｒ１１からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；ハロゲン、水酸基、Ｃ１－６アルコキシ、－ＮＲ１０Ｒ１１、－ＣＯＯＲ１０、－ＣＯＮＲ１０Ｒ１１、－ＮＲ１０ＣＯＲ１１、－ＳＯ２ＮＲ１０Ｒ１１及び－ＮＲ１０ＳＯ２Ｒ１１からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルキル、４～１０員の飽和複素環若しくは４～１０員の飽和複素環－カルボニル－；水素原子；ハロゲン、水酸基、Ｃ１－６アルキル、Ｃ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよいアリール若しくはヘテロアリール；Ｃ１－６アルキルカルボニル；－ＣＯＯＲ１０；－ＣＯＮＲ１０Ｒ１１；又はＳＯ２ＮＲ１０Ｒ１１を表し、
　Ｒ３Ａ、Ｒ３Ｂ、Ｒ３Ｃ、Ｒ３Ｄ及びＲ３Ｅは、同一又は異なって、ハロゲン、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１２Ｒ１３からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル若しくはＣ１－６アルコキシ；水素原子；ハロゲン；又は水酸基を表し、
　Ｒ４Ａ、Ｒ４Ｂ、Ｒ５及びＲ７は、同一又は異なって、置換されていてもよいＣ１－１０アルキル；置換されていてもよいＣ３－１０シクロアルキル（該基は、アリール又はヘテロアリールと縮環していてもよい）；置換されていてもよい４～１０員の飽和複素環（該基は、アリール又はヘテロアリールと縮環していてもよい）；置換されていてもよいアリール；置換されていてもよいヘテロアリール；又は水素原子を表し、ここにおいて、（１）Ｒ４Ａ及びＲ４Ｂは、一緒になって置換されていてもよい４～１０員の含窒素飽和複素環を形成していてもよく、（２）Ｒ４Ａ及びＲ４Ｂは、共に水素原子ではなく、（３）Ｒ５は、水素原子ではなく、
　Ｒ６は、同一又は異なって、ハロゲン、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１４Ｒ１５からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；ハロゲン、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１４Ｒ１５からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルキル若しくは４～１０員の飽和複素環；水素原子；ハロゲン；水酸基；又はＣ１－６アルコキシを表し、
　Ａｒは、ハロゲン、水酸基、Ｃ１－６アルキル、Ｃ１－６アルコキシ、－ＮＲ１６Ｒ１７、－ＣＯＯＲ１６、－ＣＯＮＲ１６Ｒ１７及び－ＮＲ１６ＣＯＲ１７からなる群から独立して選択される１～５個の置換基で置換されていてもよいアリール又はヘテロアリールを表し、
　Ｒ８～Ｒ１７は、同一又は異なって、また複数存在する場合にはそれぞれ独立して、水素原子又は１～５個のフッ素で置換されていてもよいＣ１－６アルキルを表し、ここにおいて、Ｒ８及びＲ９、Ｒ１０及びＲ１１、Ｒ１２及びＲ１３、Ｒ１４及びＲ１５、Ｒ１６及びＲ１７は一緒になって４～１０員の含窒素飽和複素環を形成していてもよく、
　ｎは、１又は２を表す］
で表される化合物又はその製薬学的に許容される塩。 [Claim 1]
Formula (I):
Figure JPOXMLDOC01-appb-C000002
 [Where:
A represents CR 1D or a nitrogen atom,
X—Y—Z represents N—CO—NR 4A R 4B , CR 6 —CO—NR 4A R 4B , CR 6 —NR 7 —CO—NR 4A R 4B , CR 6 —NR 7 —COR 5 or CR 6 Represents —NR 7 —Ar,
R 1A , R 1B , R 1C and R 1D are the same or different and are halogen, hydroxyl group, C 1-6 alkoxy, —NR 8 R 9 , —COOR 8 , —CONR 8 R 9 , —NR 8 COR 9 , C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of —SO 2 NR 8 R 9 and —NR 8 SO 2 R 9 ; halogen, hydroxyl group, C It consists of 1-6 alkyl, C 1-6 alkoxy, —NR 8 R 9 , —COOR 8 , —CONR 8 R 9 , —NR 8 COR 9 , —SO 2 NR 8 R 9 and —NR 8 SO 2 R 9. C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group, 4 to 10 membered saturated heterocyclic ring or 4 to 10 membered saturated heterocyclic group —O— ; halogen, hydroxyl, C 1- Alkoxy, -NR 8 R 9, -COOR 8 , -CONR 8 R 9, -NR 8 COR 9, are independently selected from the group consisting of -SO 2 NR 8 R 9 and -NR 8 SO 2 R 9 1 C 1-6 alkoxy optionally substituted with 5 substituents; halogen, hydroxyl group, C 1-6 alkoxy, —NR 8 R 9 , —COOR 8 , —CONR 8 R 9 , —NR 8 COR 9 A C 3-10 cycloalkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of -SO 2 NR 8 R 9 and -NR 8 SO 2 R 9 ; Hydroxyl group; halogen; halogen, hydroxyl group, C 1-6 alkyl, C 1-6 alkoxy, —NR 8 R 9 , —COOR 8 , —CONR 8 R 9 and —NR 8 COR 9 independently selected -NR 8 R 9 ; cyano; -COOR 8 ; -CONR 8 R 9 ; -NR 8 COR 9 ; -SO 2 NR 8 R 9 ; or —NR 8 SO 2 R 9 , wherein when XYZ is N—CO—NHEt, R 1B is not an aryl group substituted with —CO—NHEt. ,
W represents CR 3E or a nitrogen atom;
R 2 is halogen, hydroxyl group, C 1-6 alkoxy, —NR 10 R 11 , —COOR 10 , —CONR 10 R 11 , —NR 10 COR 11 , —SO 2 NR 10 R 11 and —NR 10 SO 2 R C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of 11 ; halogen, hydroxyl, C 1-6 alkoxy, —NR 10 R 11 , —COOR 10 Substituted with 1 to 5 substituents independently selected from the group consisting of: —CONR 10 R 11 , —NR 10 COR 11 , —SO 2 NR 10 R 11 and —NR 10 SO 2 R 11 which may C 3-10 cycloalkyl, 4 to 10-membered saturated heterocyclic ring or 4 to 10-membered saturated heterocyclic ring - carbonyl -; hydrogen atom; a halogen, hydroxyl, C 1-6 alkyl , 1-5 which may be substituted with a substituent aryl or heteroaryl are independently selected from the group consisting of C 1-6 alkoxy; C 1-6 alkylcarbonyl; -COOR 10; -CONR 10 R 11 ; or SO 2 NR 10 R 11 ,
R 3A , R 3B , R 3C , R 3D and R 3E are the same or different and are 1 to 5 independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy and —NR 12 R 13 A C 1-6 alkyl or C 1-6 alkoxy optionally substituted with a substituent of: a hydrogen atom; a halogen; or a hydroxyl group,
R 4A , R 4B , R 5 and R 7 are the same or different and may be substituted C 1-10 alkyl; optionally substituted C 3-10 cycloalkyl (the group may be aryl or hetero Optionally fused to aryl); optionally substituted 4-10 membered saturated heterocycle (the group optionally fused to aryl or heteroaryl); optionally substituted Aryl represents an optionally substituted heteroaryl; or represents a hydrogen atom, wherein (1) R 4A and R 4B are a 4- to 10-membered nitrogen-containing saturated heterocyclic ring that may be substituted together (2) R 4A and R 4B are not both hydrogen atoms, and (3) R 5 is not a hydrogen atom,
R 6 may be the same or different, halogen, hydroxyl, optionally substituted with one to five substituents independently selected from the group consisting of C 1-6 alkoxy and -NR 14 R 15 C 1 -6 alkyl; C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkoxy and —NR 14 R 15 ; Represents a 4- to 10-membered saturated heterocyclic ring; a hydrogen atom; a halogen; a hydroxyl group; or C 1-6 alkoxy,
Ar is independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkyl, C 1-6 alkoxy, —NR 16 R 17 , —COOR 16 , —CONR 16 R 17 and —NR 16 COR 17. Represents aryl or heteroaryl optionally substituted by 1 to 5 substituents,
R 8 to R 17 are the same or different, and when a plurality of R 8 to R 17 are present, each independently represents a hydrogen atom or C 1-6 alkyl optionally substituted with 1 to 5 fluorines, , R 8 and R 9 , R 10 and R 11 , R 12 and R 13 , R 14 and R 15 , R 16 and R 17 together form a 4- to 10-membered nitrogen-containing saturated heterocyclic ring. Well,
n represents 1 or 2]
Or a pharmaceutically acceptable salt thereof.
［項２］＜ｉ＞項１における置換されていてもよいアルキル、置換されていてもよいシクロアルキル及び置換されていてもよい４～１０員の飽和複素環が、それぞれ独立して、
　（１）置換されていてもよいアリール、
　（２）置換されていてもよいヘテロアリール、
　（３）置換されていてもよい４～１０員の飽和複素環、
　（４）置換されていてもよいＣ３－１０シクロアルキル、
　（５）－ＣＯＮＲ１８Ｒ１９
　（６）ハロゲン、
　（７）水酸基、
　（８）置換されていてもよいＣ１－６アルキル、
　（９）置換されていてもよいＣ１－６アルコキシ、
　（１０）置換されていてもよいＣ１－６アルキルカルボニル、
　（１１）－Ｎ（Ｒ１８）ＣＯＲ１９、及び
　（１２）－ＮＲ１８Ｒ１９、
からなる群から選択される同一又は異なる１～５個の置換基で置換されていてもよい基であり、ここにおいて、（１）～（４）に示す基は、後記（ａ）～（ｉ）からなる群から選択される同一又は異なる１～５個の置換基で置換されていてもよい基であり、（８）、（９）及び（１０）に示す基は、後記（ｂ）、（ｄ）、（ｅ）及びフッ素からなる群から選択される同一又は異なる１～５個の置換基で置換されていてもよい基であり、及び／又は、
　＜ｉｉ＞項１における置換されていてもよいアリール及び置換されていてもよいヘテロアリールが、それぞれ独立して、
　（ａ）ハロゲン、
　（ｂ）水酸基、
　（ｃ）置換されていてもよいＣ１－６アルキル、
　（ｄ）置換されていてもよいＣ１－６アルコキシ、
　（ｅ）－ＮＲ１８Ｒ１９、
　（ｆ）－Ｎ（Ｒ１８）ＣＯＲ１９、
　（ｇ）シアノ、及び
　（ｈ）－ＣＯＮＲ１８Ｒ１９、
　（ｉ）置換されていてもよいＣ１－６アルキルカルボニル、
からなる群から選択される同一又は異なる１～５個の置換基で置換されていてもよい基を意味し、ここにおいて、（ｃ）、（ｄ）及び（ｉ）は、－ＮＲ１８Ｒ１９、水酸基、Ｃ１－６アルコキシ及びフッ素からなる群から選択される同一又は異なる１～５個の置換基で置換されていてもよい基であり、
　Ｒ１８及びＲ１９が、それぞれ独立して、水素原子若しくは１～５個のフッ素で置換されていてもよいＣ１－１０アルキルであるか、又は、Ｒ１８とＲ１９は一緒になって４～１０員の含窒素飽和複素環を形成していてもよい、
項１に記載の化合物又はその製薬学的に許容される塩。 [Item 2] <i> The optionally substituted alkyl, the optionally substituted cycloalkyl and the optionally substituted 4- to 10-membered saturated heterocyclic ring in Item 1 are each independently
(1) optionally substituted aryl,
(2) optionally substituted heteroaryl,
(3) an optionally substituted 4- to 10-membered saturated heterocyclic ring,
(4) optionally substituted C 3-10 cycloalkyl,
(5) -CONR 18 R 19
(6) halogen,
(7) hydroxyl group,
(8) C 1-6 alkyl which may be substituted,
(9) optionally substituted C 1-6 alkoxy,
(10) optionally substituted C 1-6 alkylcarbonyl,
(11) -N (R 18 ) COR 19 , and (12) -NR 18 R 19 ,
A group which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of: wherein the groups shown in (1) to (4) are the following Is a group which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of: (8), (9) and (10), (D), (e) and a group which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of fluorine and / or
<Ii> The optionally substituted aryl and the optionally substituted heteroaryl in Item 1 are each independently
(A) halogen,
(B) a hydroxyl group,
(C) optionally substituted C 1-6 alkyl,
(D) an optionally substituted C 1-6 alkoxy,
(E) -NR 18 R 19 ,
(F) —N (R 18 ) COR 19 ,
(G) cyano, and (h) -CONR 18 R 19 ,
(I) an optionally substituted C 1-6 alkylcarbonyl,
Means a group which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of: wherein (c), (d) and (i) are —NR 18 R 19 , a hydroxyl group, a C 1-6 alkoxy and the same or different one to five substituents group which may be substituted by groups selected from the group consisting of fluorine,
R 18 and R 19 are each independently a hydrogen atom or C 1-10 alkyl optionally substituted with 1 to 5 fluorines, or R 18 and R 19 taken together 4 May form a 10-membered nitrogen-containing saturated heterocyclic ring,
Item 12. The compound according to Item 1 or a pharmaceutically acceptable salt thereof.
［項３］ｎが１である、
項１又は項２に記載の化合物又はその製薬学的に許容される塩。 [Item 3] n is 1.
Item 3. The compound according to Item 1 or Item 2, or a pharmaceutically acceptable salt thereof.
［項４］Ｒ４Ａ、Ｒ４Ｂ、Ｒ５及びＲ７が、同一又は異なって、アリール、ヘテロアリール、４～１０員の飽和複素環、Ｃ３－１０シクロアルキル、フッ素、水酸基、１～５個のフッ素で置換されていてもよいＣ１－６アルコキシ、Ｃ１－６アルキルカルボニル及び－ＮＲ１８Ｒ１９からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－１０アルキル；Ｃ３－１０シクロアルキル；４～１０員の飽和複素環；又は水素原子であり（前記アリール、ヘテロアリール、飽和複素環及びシクロアルキルは、フッ素、水酸基、Ｃ１－６アルキル（該基は、フッ素、Ｃ１－６アルコキシ及び－ＮＲ１８Ｒ１９からなる群から独立して選択される１～５個の置換基で置換されていてもよい）、１～５個のフッ素で置換されていてもよいＣ１－６アルコキシ、Ｃ１－６アルキルカルボニル、及び－ＮＲ１８Ｒ１９からなる群から独立して選択される１～５個の置換基で置換されていてもよい）、ここにおいて、（１）Ｒ４Ａ及びＲ４Ｂは一緒になって４～１０員の含窒素飽和複素環（該環は、上記飽和複素環と同様の置換基で置換されていてもよい）を形成していてもよく、（２）Ｒ４Ａ及びＲ４Ｂは、共に水素原子ではなく、（３）Ｒ５は、水素原子ではない、
項１～３のいずれか一項に記載の化合物又はその製薬学的に許容される塩。 [Item 4] R 4A , R 4B , R 5 and R 7 are the same or different and are aryl, heteroaryl, 4- to 10-membered saturated heterocycle, C 3-10 cycloalkyl, fluorine, hydroxyl group, 1-5 Substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy, C 1-6 alkylcarbonyl, and —NR 18 R 19 , optionally substituted with fluorine C 1-10 alkyl; C 3-10 cycloalkyl; 4- to 10-membered saturated heterocyclic ring; or a hydrogen atom (the aryl, heteroaryl, saturated heterocyclic ring and cycloalkyl are fluorine, hydroxyl group, C 1 -6 alkyl (the group may be substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, C 1-6 alkoxy and —NR 18 R 19 ), 1 to 5 Pieces of fluorine Optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy, C 1-6 alkylcarbonyl, and —NR 18 R 19 ), Wherein (1) R 4A and R 4B are taken together to form a 4- to 10-membered nitrogen-containing saturated heterocycle (the ring may be substituted with the same substituent as the above-mentioned saturated heterocycle) (2) R 4A and R 4B are not both hydrogen atoms, and (3) R 5 is not a hydrogen atom.
Item 4. The compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof.
［項５］Ａが、ＣＲ１Ｄである、
項１～４のいずれか一項に記載の化合物又はその製薬学的に許容される塩。 [Claim 5] A is CR 1D .
Item 5. The compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.
［項６］Ｗが、ＣＨである、
項１～５のいずれか一項に記載の化合物又はその製薬学的に許容される塩。 [Item 6] W is CH.
Item 6. The compound according to any one of Items 1 to 5, or a pharmaceutically acceptable salt thereof.
［項７］Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ４ＡＲ４Ｂ、ＣＲ６－ＣＯ－ＮＲ４ＡＲ４Ｂ、ＣＲ６－ＮＲ７－ＣＯ－ＮＲ４ＡＲ４Ｂ又はＣＲ６－ＮＲ７－ＣＯＲ５である、
項１～６のいずれか一項に記載の化合物又はその製薬学的に許容される塩。 [Claim 7] XYZ represents N—CO—NR 4A R 4B , CR 6 —CO—NR 4A R 4B , CR 6 —NR 7 —CO—NR 4A R 4B or CR 6 —NR 7 —COR 5 ,
Item 7. The compound according to any one of Items 1 to 6, or a pharmaceutically acceptable salt thereof.
［項８］Ｒ２が、フッ素、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１０Ｒ１１からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；フッ素、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１０Ｒ１１からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルキル若しくは４～１０員の飽和複素環；水素原子；又はＣ１－６アルキルカルボニルである、
項１～７のいずれか一項に記載の化合物又はその製薬学的に許容される塩。 [Claim 8] R 2 is good fluorine, hydroxyl, optionally substituted with one to five substituents independently selected from the group consisting of C 1-6 alkoxy and -NR 10 R 11 C 1- 6 alkyl; C 3-10 cycloalkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, hydroxyl, C 1-6 alkoxy and —NR 10 R 11 or 4 A 10-membered saturated heterocyclic ring; a hydrogen atom; or a C 1-6 alkylcarbonyl.
Item 8. The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof.
［項９］Ｒ１Ａ、Ｒ１Ｂ、Ｒ１Ｃ及びＲ１Ｄが、同一又は異なって、フッ素、水酸基、Ｃ１－６アルコキシ、－ＮＲ８Ｒ９、－ＣＯＮＲ８Ｒ９及び－ＮＲ８ＣＯＲ９からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；フッ素、水酸基、Ｃ１－６アルキル、Ｃ１－６アルコキシ、－ＮＲ８Ｒ９、－ＣＯＮＲ８Ｒ９及び－ＮＲ８ＣＯＲ９からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルキル、４～１０員の飽和複素環若しくは４～１０員の飽和複素環基－Ｏ－；ハロゲン、水酸基、Ｃ１－６アルコキシ、－ＮＲ８Ｒ９、－ＣＯＮＲ８Ｒ９及び－ＮＲ８ＣＯＲ９からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルコキシ；ハロゲン、水酸基、Ｃ１－６アルコキシ、－ＮＲ８Ｒ９、－ＣＯＮＲ８Ｒ９及び－ＮＲ８ＣＯＲ９からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルコキシ；水素原子；水酸基；ハロゲン；－ＮＲ８Ｒ９；シアノ；－ＣＯＮＲ８Ｒ９；又は－ＮＲ８ＣＯＲ９である、
項１～８のいずれか一項に記載の化合物又はその製薬学的に許容される塩。 [Item 9] R 1A , R 1B , R 1C, and R 1D are the same or different and are selected from fluorine, hydroxyl group, C 1-6 alkoxy, —NR 8 R 9 , —CONR 8 R 9, and —NR 8 COR 9. 1-5 which may be C 1-6 alkyl substituted with a substituent selected independently from the group consisting; fluorine, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, -NR 8 R 9 , -CONR 8 R 9 and -NR 8 COR 9, an optionally substituted C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents, 4 to 10 membered saturated hetero A ring or a 4- to 10-membered saturated heterocyclic group —O—; independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy, —NR 8 R 9 , —CONR 8 R 9 and —NR 8 COR 9 With 1 to 5 substituents Which may be C 1-6 alkoxy; halogen, hydroxyl, C 1-6 alkoxy, -NR 8 R 9, 1 is independently selected from the group consisting of -CONR 8 R 9 and -NR 8 COR 9 ~ C 3-10 cycloalkoxy optionally substituted with 5 substituents; hydrogen atom; hydroxyl group; halogen; —NR 8 R 9 ; cyano; —CONR 8 R 9 ; or —NR 8 COR 9 .
Item 9. The compound according to any one of Items 1 to 8, or a pharmaceutically acceptable salt thereof.
［項１０］Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ４ＡＲ４Ｂ、ＣＲ６－ＮＲ７－ＣＯ－ＮＲ４ＡＲ４Ｂ又はＣＲ６－ＮＲ７－ＣＯＲ５である、
項１～９のいずれか一項に記載の化合物又はその製薬学的に許容される塩。 [Item 10] XYZ is N—CO—NR 4A R 4B , CR 6 —NR 7 —CO—NR 4A R 4B or CR 6 —NR 7 —COR 5 ;
Item 10. The compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof.
［項１１］Ｒ４Ａ又はＲ４Ｂのいずれか一方が水素原子である、
項１～１０のいずれか一項に記載の化合物又はその製薬学的に許容される塩。 [Item 11] Either one of R 4A and R 4B is a hydrogen atom.
Item 11. The compound according to any one of Items 1 to 10, or a pharmaceutically acceptable salt thereof.
［項１２］Ｒ３Ａ、Ｒ３Ｂ、Ｒ３Ｃ、Ｒ３Ｄ及びＲ３Ｅが、同一又は異なって、１～５個のフッ素で置換されていてもよいＣ１－６アルキル；Ｃ１－６アルコキシ；水素原子；又はフッ素である、
項１～１１のいずれか一項に記載の化合物又はその製薬学的に許容される塩。 [Claim 12] C 1-6 alkyl in which R 3A , R 3B , R 3C , R 3D and R 3E are the same or different and may be substituted with 1 to 5 fluorines; C 1-6 alkoxy; A hydrogen atom; or fluorine,
Item 12. The compound according to any one of Items 1 to 11, or a pharmaceutically acceptable salt thereof.
［項１３］Ｒ４Ａ、Ｒ４Ｂ、Ｒ５及びＲ７が、同一又は異なって、４～１０員の飽和複素環、Ｃ３－１０シクロアルキル、フッ素、水酸基、１～５個のフッ素で置換されていてもよいＣ１－６アルコキシ及び－ＮＲ１８Ｒ１９からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－１０アルキル；Ｃ３－１０シクロアルキル；４～１０員の飽和複素環；又は水素原子であり（前記飽和複素環及びシクロアルキルは、フッ素、水酸基、Ｃ１－６アルキル（該基はフッ素、Ｃ１－６アルコキシ及び－ＮＲ１８Ｒ１９からなる群から独立して選択される１～５個の置換基で置換されていてもよい）、１～５個のフッ素で置換されていてもよいＣ１－６アルコキシ、Ｃ１－６アルキルカルボニル、又は－ＮＲ１８Ｒ１９からなる群から独立して選択される１～５個の置換基で置換されていてもよい）、ここにおいて、（１）Ｒ４Ａ及びＲ４Ｂは一緒になって４～１０員の含窒素飽和複素環（該環は、上記飽和複素環と同様の置換基で置換されていてもよい）を形成していてもよく、（２）Ｒ４Ａ及びＲ４Ｂは、共に水素原子ではなく、（３）Ｒ５は、水素原子ではない、
項１～１２のいずれか一項に記載の化合物又はその製薬学的に許容される塩。 [Claim 13] R 4A , R 4B , R 5 and R 7 are the same or different and are substituted with 4 to 10-membered saturated heterocyclic ring, C 3-10 cycloalkyl, fluorine, hydroxyl group, 1 to 5 fluorine atoms C 1-10 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of optionally substituted C 1-6 alkoxy and —NR 18 R 19 ; C 3-10 A cycloalkyl; a 4- to 10-membered saturated heterocycle; or a hydrogen atom (the saturated heterocycle and cycloalkyl are fluorine, hydroxyl, C 1-6 alkyl (the group is fluorine, C 1-6 alkoxy and —NR C 1-6 alkoxy optionally substituted with 1 to 5 fluorines, optionally substituted with 1 to 5 substituents independently selected from the group consisting of 18 R 19 , C 1 -6 alkylcarbonyl, or -N 18 may be substituted with 1 to 5 substituents selected independently from the group consisting of R 19), wherein, (1) R 4A and R 4B are 4-10 membered together A nitrogen-containing saturated heterocyclic ring (which may be substituted with the same substituent as the saturated heterocyclic ring), and (2) R 4A and R 4B are not hydrogen atoms. (3) R 5 is not a hydrogen atom,
Item 13. The compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof.
［項１４］Ｒ１Ａ、Ｒ１Ｂ、Ｒ１Ｃ及びＲ１Ｄは、同一又は異なって、フッ素、水酸基及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；フッ素、水酸基及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－８シクロアルキル；フッ素、水酸基及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルコキシ；フッ素、水酸基及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルコキシ；水素原子；水酸基；ハロゲン；又は４～１０員の飽和複素環である、
項１～１３のいずれか一項に記載の化合物又はその製薬学的に許容される塩。 [Item 14] R 1A , R 1B , R 1C and R 1D are the same or different and are substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, hydroxyl group and C 1-6 alkoxy. C 1-6 alkyl which may be substituted; C 3-8 cycloalkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, hydroxyl group and C 1-6 alkoxy ; fluorine, hydroxyl and C 1-6 1 ~ 5 amino optionally substituted with a substituent C 1-6 alkoxy independently selected from the group consisting of alkoxy; from fluorine, hydroxyl and C 1-6 alkoxy A C 3-10 cycloalkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of: a hydrogen atom; a hydroxyl group; a halogen; or a 4- to 10-membered saturated heterocyclic ring,
Item 14. The compound according to any one of Items 1 to 13, or a pharmaceutically acceptable salt thereof.
［項１５］Ｒ６が、Ｃ１-６アルキル、Ｃ１-６アルコキシ、フッ素又は水素原子である、
項１～１４のいずれか一項に記載の化合物又はその製薬学的に許容される塩。 [Item 15] R 6 is C 1-6 alkyl, C 1-6 alkoxy, fluorine or a hydrogen atom.
Item 15. The compound according to any one of Items 1 to 14, or a pharmaceutically acceptable salt thereof.
［項１６］Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ４ＡＲ４Ｂ又はＣＲ６－ＮＲ７－ＣＯＲ５である、
項１～１５のいずれか一項に記載の化合物又はその製薬学的に許容される塩。 [Item 16] XYZ is N—CO—NR 4A R 4B or CR 6 —NR 7 —COR 5 ;
Item 16. The compound according to any one of Items 1 to 15, or a pharmaceutically acceptable salt thereof.
［項１７］Ｒ４Ａ、Ｒ４Ｂ、Ｒ５及びＲ７が、同一又は異なって、Ｃ３－１０シクロアルキル；４～１０員の飽和複素環；又は水素原子であり（前記飽和複素環及びシクロアルキルは、フッ素、水酸基、Ｃ１－６アルキル（該基はフッ素及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよい）又は１～５個のフッ素で置換されていてもよいＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよい）、ここにおいて、（１）Ｒ４Ａ及びＲ４Ｂは、共に水素原子ではなく、（２）Ｒ５は、水素原子ではない、
項１～１６のいずれか一項に記載の化合物又はその製薬学的に許容される塩。 [Item 17] R 4A , R 4B , R 5 and R 7 are the same or different and each represent a C 3-10 cycloalkyl; a 4- to 10-membered saturated heterocyclic ring; or a hydrogen atom (the saturated heterocyclic ring and Alkyl is fluorine, hydroxyl group, C 1-6 alkyl (the group may be substituted with 1 to 5 substituents independently selected from the group consisting of fluorine and C 1-6 alkoxy) or 1 (Optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy optionally substituted with 5 fluorines), wherein (1) R 4A and R 4B are not both hydrogen atoms, and (2) R 5 is not a hydrogen atom.
Item 18. The compound according to any one of Items 1 to 16, or a pharmaceutically acceptable salt thereof.
［項１８］Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ４ＡＲ４Ｂである、
項１～１７のいずれか一項に記載の化合物又はその製薬学的に許容される塩。 [Item 18] XYZ is N—CO—NR 4A R 4B .
Item 18. The compound according to any one of Items 1 to 17, or a pharmaceutically acceptable salt thereof.
［項１９］項１～１８のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩を含有する医薬組成物。 [Item 19] A pharmaceutical composition comprising the compound according to any one of items 1 to 18 or a pharmaceutically acceptable salt thereof.
［項２０］項１～１８のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩を有効成分とするアセチルコリンが関与する細胞内シグナル伝達の異常に起因する疾患の治療剤又は予防剤。 [Item 20] A therapeutic agent for a disease caused by an abnormality in intracellular signal transduction involving acetylcholine, comprising the compound according to any one of items 1 to 18 or a pharmaceutically acceptable salt thereof as an active ingredient Or a preventive agent.
［項２１］アセチルコリンが関与する細胞内シグナル伝達の異常に起因する疾患が、神経系疾患、精神疾患又は炎症性疾患である、
項２０に記載の治療剤。 [Item 21] The disease caused by an abnormality in intracellular signal transduction involving acetylcholine is a nervous system disease, a mental disease or an inflammatory disease.
Item 20. The therapeutic agent according to Item 20.
［項２２］神経系疾患、精神疾患又は炎症性疾患が、認知症、統合失調症、ＣＩＡＳ（統合失調症に伴う認知機能障害）、アルツハイマー病、ダウン症、注意欠陥障害又は脳血管アンギオパチーである、
項２１に記載の治療剤。 [Claim 22] The nervous system disease, psychiatric disorder or inflammatory disease is dementia, schizophrenia, CIAS (cognitive impairment associated with schizophrenia), Alzheimer's disease, Down's syndrome, attention deficit disorder or cerebrovascular angiopathy.
Item 22. The therapeutic agent according to Item 21.
［項２３］項１～１８のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩と、非定型抗精神病薬に分類される薬剤から選択される少なくとも１種以上の薬剤とを組み合わせてなる医薬。 [Item 23] At least one drug selected from the compound according to any one of Items 1 to 18 or a pharmaceutically acceptable salt thereof and a drug classified as an atypical antipsychotic drug A medicine that combines
［項２４］治療が必要な患者に、治療上の有効量の項１～１８のいずれか１項に記載の化合物又はその製薬学的に許容される塩を投与することを特徴とするアセチルコリンが関与する細胞内シグナル伝達の異常に起因する疾患の治療又は予防方法。 [Item 24] An acetylcholine characterized by administering a therapeutically effective amount of the compound according to any one of items 1 to 18 or a pharmaceutically acceptable salt thereof to a patient in need of treatment. A method for treating or preventing a disease caused by an abnormality in intracellular signaling involved.
［項２５］アセチルコリンが関与する細胞内シグナル伝達の異常に起因する疾患の治療又は予防のための項１～１８のいずれか１項に記載の化合物又はその製薬学的に許容される塩。 [Item 25] The compound according to any one of items 1 to 18 or a pharmaceutically acceptable salt thereof for the treatment or prevention of a disease caused by an abnormality in intracellular signal transduction involving acetylcholine.
［項２６］アセチルコリンが関与する細胞内シグナル伝達の異常に起因する疾患の治療又は予防に使用する、項１～１８のいずれか１項に記載の化合物又はその製薬学的に許容される塩を含む医薬組成物。 [Item 26] The compound according to any one of items 1 to 18 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease caused by an abnormality in intracellular signal transduction involving acetylcholine. A pharmaceutical composition comprising.
［項２７］アセチルコリンが関与する細胞内シグナル伝達の異常に起因する疾患の治療剤又は予防剤を製造するための項１～１８のいずれか１項に記載の化合物又はその製薬学的に許容される塩の使用。 [Item 27] The compound according to any one of items 1 to 18 or a pharmaceutically acceptable salt thereof for producing a therapeutic or prophylactic agent for a disease caused by an abnormality in intracellular signal transduction involving acetylcholine. Use of salt.
　本発明化合物は、神経系疾患、精神疾患及び炎症性疾患（例えば、認知症、統合失調症、ＣＩＡＳ（統合失調症に伴う認知機能障害）、アルツハイマー病、ダウン症、注意欠陥障害、脳血管アンギオパチー等）の新規な治療剤及び／又は予防剤として有用である。また、本発明化合物は、非定型抗精神病薬に分類される薬剤との併用剤として、統合失調症などの神経系疾患、精神疾患等の治療及び／又は予防に有用である。 The compound of the present invention can be used for nervous system diseases, psychiatric diseases and inflammatory diseases (for example, dementia, schizophrenia, CIAS (cognitive impairment associated with schizophrenia), Alzheimer's disease, Down's syndrome, attention deficit disorder, cerebrovascular angiopathy, etc. ) As a novel therapeutic agent and / or preventive agent. In addition, the compound of the present invention is useful for the treatment and / or prevention of neurological diseases such as schizophrenia, mental diseases and the like as a concomitant drug with drugs classified as atypical antipsychotic drugs.
　本発明の化合物は、水和物及び／又は溶媒和物の形で存在することもあるので、これらの水和物及び／又は溶媒和物もまた本発明の化合物に包含される。溶媒和物としてはエタノール溶媒和物などが挙げられる。 Since the compounds of the present invention may exist in the form of hydrates and / or solvates, these hydrates and / or solvates are also included in the compounds of the present invention. Examples of solvates include ethanol solvates.
　式（Ｉ）の化合物は、１個又は場合によりそれ以上の不斉炭素原子を有する場合があり、また幾何異性や軸性キラリティを生じることがあるので、数種の立体異性体として存在することがある。本発明においては、これらの立体異性体、それらの混合物及びラセミ体は本発明の式（Ｉ）で表される化合物に包含される。
　また、一般式（Ｉ）で表される化合物のいずれか１つ又は２つ以上の１Ｈを２Ｈ（Ｄ）に変換した重水素変換体も一般式（Ｉ）で表される化合物に包含される。 The compound of formula (I) may have one or more asymmetric carbon atoms and may cause geometric isomerism and axial chirality, and therefore exist as several stereoisomers. There is. In the present invention, these stereoisomers, mixtures thereof and racemates are included in the compound represented by the formula (I) of the present invention.
In addition, a deuterium converter obtained by converting any one or two or more 1 H of the compound represented by the general formula (I) into 2 H (D) is also included in the compound represented by the general formula (I). Is done.
　つぎに、本明細書における用語について以下に説明する。
　「アルキル」とは、直鎖状又は分枝鎖状の飽和炭化水素基を意味し、例えば、「Ｃ１－４アルキル」、「Ｃ１－６アルキル」又は「Ｃ１－１０アルキル」とは炭素原子数が１～４、１～６又は１～１０のアルキルを意味する。その具体例として、「Ｃ１－４アルキル」の場合には、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル等が挙げられる。「Ｃ１－６アルキル」の場合には、前記に加え、ぺンチル、イソペンチル、ネオペンチル、ヘキシル等が挙げられ、「Ｃ１－１０アルキル」の場合には、さらに前記に加え、ヘプチル、オクチル等が挙げられる。
　「シクロアルキル」とは、単環又は多環式飽和炭化水素を意味し、例えば「Ｃ３－１０シクロアルキル」とは炭素原子数が３～１０の環状アルキルを意味し、一部架橋された構造のもの、一部スピロ環を構築したもの又はアリール若しくはヘテロアリールと縮環を形成したものも含まれる。その具体例として、「Ｃ３－１０シクロアルキル」の場合には、シクロプロピル、シクロブチル、シクロペンチル、シクロへキシル、シクロヘプチル、シクロオクチル、アダマンチル、スピロ［２，５］オクタン等が挙げられる。また、「シクロアルコキシ」とは、上記と同様の単環又は多環式飽和炭化水素基が酸素原子を介している基を意味する。
　「アルコキシ」とは、直鎖状又は分枝鎖状の飽和炭化水素基が酸素原子を介している基を意味し、例えば、「Ｃ１－６アルコキシ」とは炭素原子数が１～６のアルコキシを意味する。その具体例として、「Ｃ１－６アルコキシ」の場合には、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブチルオキシ、ペンチルオキシ、イソペンチルオキシ、ネオペンチルオキシ、ヘキシルオキシ等が挙げられる。
　「Ｃ１－６アルキルカルボニル」の具体例としては、アセチル、エチルカルボニル、プロピルカルボニル、イソプロピルカルボニル、ブチルカルボニル、イソブチルカルボニル、ｔ－ブチルカルボニル等が挙げられる。好ましくは、「Ｃ１－３アルキルカルボニル」が挙げられ、さらに好ましくは、アセチルが挙げられる。 Next, terms used in this specification will be described below.
“Alkyl” means a linear or branched saturated hydrocarbon group, for example, “C 1-4 alkyl”, “C 1-6 alkyl” or “C 1-10 alkyl” Alkyl having 1 to 4, 1 to 6, or 1 to 10 carbon atoms is meant. Specific examples thereof include “C 1-4 alkyl” such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like. In the case of “C 1-6 alkyl”, in addition to the above, examples include pentyl, isopentyl, neopentyl, hexyl and the like, and in the case of “C 1-10 alkyl”, in addition to the above, heptyl, octyl and the like Is mentioned.
“Cycloalkyl” means a monocyclic or polycyclic saturated hydrocarbon. For example, “C 3-10 cycloalkyl” means a cyclic alkyl having 3 to 10 carbon atoms and is partially bridged. Those having a structure, a part of which a spiro ring is constructed, or a part in which a condensed ring is formed with aryl or heteroaryl are also included. Specific examples thereof include “C 3-10 cycloalkyl” such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, spiro [2,5] octane, and the like. “Cycloalkoxy” means a group in which a monocyclic or polycyclic saturated hydrocarbon group similar to the above is interposed via an oxygen atom.
“Alkoxy” means a group in which a linear or branched saturated hydrocarbon group is interposed via an oxygen atom. For example, “C 1-6 alkoxy” means a group having 1 to 6 carbon atoms. Means alkoxy. Specific examples of “C 1-6 alkoxy” include methoxy, ethoxy, propoxy, isopropoxy, butyloxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like.
Specific examples of the "C 1-6 alkylcarbonyl" are acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, iso-butylcarbonyl, etc. t- butylcarbonyl and the like. “C 1-3 alkylcarbonyl” is preferable, and acetyl is more preferable.
　「ハロゲン」とは、フッ素原子、塩素原子、臭素原子又はヨウ素原子を意味する。中でも好ましくは、フッ素原子又は塩素原子である。
　「アリール」としては、具体的にはフェニル、１－ナフチル、２－ナフチル、アントラセン等が挙げられる。中でも好ましくは、フェニルが挙げられる。
　「ヘテロアリール」としては、窒素原子、酸素原子及び硫黄原子からなる群から独立して選ばれる１から４個の原子を含む、単環の５～７員環の芳香族複素環基、２環の８～１１員の芳香族複素環基又は３環の１２～１６員の芳香族複素環基が挙げられる。具体的にはピリジル、ピリダジニル、イソチアゾリル、ピロリル、フリル、チエニル、チアゾリル、イミダゾリル、ピリミジニル、チアジアゾリル、ピラゾリル、オキサゾリル、イソオキサゾリル、ピラジニル、トリアジニル、トリアゾリル、イミダゾリジニル、オキサジアゾリル、トリアゾリル、テトラゾリル、インドリル、インダゾリル、クロメニル、キノリル、イソキノリル、ベンゾフラニル、ベンゾチエニル、ベンゾオキサゾリル、ベンゾチアゾリル、ベンズイソオキサゾリル、ベンズイソチアゾリル、ベンゾトリアゾリル、ベンズイミダゾリル、チオキサンテン、６，１１－ジヒドロジベンゾ［Ｂ，Ｅ］チエピニル等が挙げられる。好ましいヘテロアリールとしては、ピリジル、ピリミジニル、キノリル、及びイソキノリルが挙げられる。 “Halogen” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Among them, preferred is a fluorine atom or a chlorine atom.
Specific examples of “aryl” include phenyl, 1-naphthyl, 2-naphthyl, anthracene and the like. Of these, phenyl is preferable.
“Heteroaryl” is a monocyclic 5- to 7-membered aromatic heterocyclic group or bicyclic ring containing 1 to 4 atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom And an 8- to 11-membered aromatic heterocyclic group or a 3-ring 12- to 16-membered aromatic heterocyclic group. Specifically, pyridyl, pyridazinyl, isothiazolyl, pyrrolyl, furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, triazinyl, triazolyl, imidazolidinyl, oxadiazolyl, triazolyl, tetrazolyl, indolyl, indolyl, indolyl, indryl Quinolyl, isoquinolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzotriazolyl, benzimidazolyl, thioxanthene, 6,11-dihydrodibenzo [B, E] thiepinyl Etc. Preferred heteroaryls include pyridyl, pyrimidinyl, quinolyl, and isoquinolyl.
　「４～１０員の飽和複素環」とは、炭素原子以外に窒素原子、酸素原子及び硫黄原子からなる群から独立して選択される１～２個の原子を含む４～１０個の原子で構成される単環又は２環の飽和複素環を意味し、一部架橋された構造のもの、一部スピロ化されたもの又はアリール若しくはヘテロアリールと縮環を形成したものも含まれる。例えば、アゼチジン、ピロリジン、ピペリジン、ピペラジン、モルホリン、ホモピペリジン、テトラヒドロフラン、テトラヒドロピラン等が挙げられる。また、「４～１０員の飽和複素環－カルボニル－」とは、上記４～１０員の飽和複素環にカルボニルが結合した基を意味する。「４～１０員の飽和複素環－Ｏ－」とは、上記４～１０員の飽和複素環に酸素原子が結合した基を意味する。 The “4- to 10-membered saturated heterocyclic ring” means 4 to 10 atoms including 1 to 2 atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom. The term means a monocyclic or bicyclic saturated heterocyclic ring, which includes a partially bridged structure, a partially spirolated ring, or a ring condensed with aryl or heteroaryl. For example, azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, tetrahydrofuran, tetrahydropyran and the like can be mentioned. Further, the “4- to 10-membered saturated heterocycle-carbonyl-” means a group in which a carbonyl is bonded to the 4- to 10-membered saturated heterocycle. The “4- to 10-membered saturated heterocyclic ring —O—” means a group in which an oxygen atom is bonded to the 4- to 10-membered saturated heterocyclic ring.
　式（Ｉ）で表される本発明の化合物の中でも、Ａ、Ｘ－Ｙ－Ｚ、Ｒ１Ａ～Ｒ１Ｄ、Ｒ２、Ｒ３Ａ～Ｒ３Ｅ、Ｒ４Ａ、Ｒ４Ｂ、Ｒ５～Ｒ１９、Ａｒ及びｎで、好ましいものは以下のとおりであるが、本発明の技術的範囲は下記に挙げる化合物の範囲に限定されるものではない。 Among the compounds of the present invention represented by the formula (I), A, XYZ, R 1A to R 1D , R 2 , R 3A to R 3E , R 4A , R 4B , R 5 to R 19 , Preferred examples of Ar and n are as follows, but the technical scope of the present invention is not limited to the scope of the compounds listed below.
　Ａとして好ましくは、ＣＲ１Ｄが挙げられる。
　Ｘ－Ｙ－Ｚとして好ましくは、Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ４ＡＲ４Ｂ、ＣＲ６－ＣＯ－ＮＲ４ＡＲ４Ｂ、ＣＲ６－ＮＲ７－ＣＯ－ＮＲ４ＡＲ４Ｂ又はＣＲ６－ＮＲ７－ＣＯＲ５が挙げられ、より好ましくはＮ－ＣＯ－ＮＲ４ＡＲ４Ｂ又はＣＲ６－ＮＲ７－ＣＯＲ５が挙げられ、さらに好ましくは、Ｎ－ＣＯ－ＮＲ４ＡＲ４Ｂが挙げられる。 A is preferably CR 1D .
Preferably, XYZ is N—CO—NR 4A R 4B , CR 6 —CO—NR 4A R 4B , CR 6 —NR 7 —CO—NR 4A R 4B or CR 6. —NR 7 —COR 5 is exemplified, more preferably N—CO—NR 4A R 4B or CR 6 —NR 7 —COR 5 is exemplified, and still more preferably, N—CO—NR 4A R 4B is exemplified.
　Ｒ１Ａ～Ｒ１Ｄとして好ましくは、同一又は異なって、フッ素、水酸基、Ｃ１－６アルコキシ、－ＮＲ８Ｒ９、－ＣＯＮＲ８Ｒ９及び－ＮＲ８ＣＯＲ９からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；フッ素、水酸基、Ｃ１－６アルキル、Ｃ１－６アルコキシ、－ＮＲ８Ｒ９、－ＣＯＮＲ８Ｒ９及び－ＮＲ８ＣＯＲ９からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルキル、４～１０員の飽和複素環若しくは４～１０員の飽和複素環基－Ｏ－；ハロゲン、水酸基、Ｃ１－６アルコキシ、－ＮＲ８Ｒ９、－ＣＯＮＲ８Ｒ９及び－ＮＲ８ＣＯＲ９からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルコキシ；ハロゲン、水酸基、Ｃ１－６アルコキシ、－ＮＲ８Ｒ９、－ＣＯＮＲ８Ｒ９及び－ＮＲ８ＣＯＲ９からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルコキシ；水素原子；水酸基；ハロゲン；フッ素、Ｃ１－６アルキル、Ｃ１－６アルコキシ及び－ＮＲ８Ｒ９からなる群から独立して選択される１～５個の置換基で置換されていてもよいアリール若しくはヘテロアリール；－ＮＲ８Ｒ９；シアノ；－ＣＯＮＲ８Ｒ９；又は－ＮＲ８ＣＯＲ９が挙げられる。より好ましくは、同一又は異なって、フッ素、水酸基及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；フッ素、水酸基及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－８シクロアルキル；フッ素、水酸基及びＣ１－６アルコキシ からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルコキシ；フッ素、水酸基及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルコキシ；水素原子；水酸基；ハロゲン；又は４～１０員の飽和複素環が挙げられる。さらに好ましくは、同一又は異なって、フッ素及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；Ｃ３－８シクロアルキル；Ｃ１－６アルコキシ；Ｃ３－１０シクロアルコキシ；水素原子；又はハロゲンが挙げられる。最も好ましくは、同一又は異なって、１～５個のフッ素及で置換されていてもよいＣ１－６アルキル；Ｃ１－６アルコキシ；Ｃ３－１０シクロアルコキシ；水素原子；又はハロゲンが挙げられる。 R 1A to R 1D are preferably the same or different and independently selected from the group consisting of fluorine, hydroxyl group, C 1-6 alkoxy, —NR 8 R 9 , —CONR 8 R 9 and —NR 8 COR 9. that one to five substituents C 1-6 alkyl optionally substituted by group; fluorine, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, -NR 8 R 9, -CONR 8 R 9 and - C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of NR 8 COR 9 , 4 to 10 membered saturated heterocycle or 4 to 10 membered saturated A heterocyclic group —O—; 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy, —NR 8 R 9 , —CONR 8 R 9 and —NR 8 COR 9 Even if it is substituted with a group There C 1-6 alkoxy; halogen, hydroxyl, C 1-6 alkoxy, -NR 8 R 9, 1 ~ 5 substituents independently selected from the group consisting of -CONR 8 R 9 and -NR 8 COR 9 C 3-10 cycloalkoxy optionally substituted with a group; hydrogen atom; hydroxyl group; halogen; independently selected from the group consisting of fluorine, C 1-6 alkyl, C 1-6 alkoxy and —NR 8 R 9 -NR 8 R 9 ; cyano; -CONR 8 R 9 ; or -NR 8 COR 9 may be mentioned. More preferably, the same or different, C 1-6 alkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, hydroxyl group and C 1-6 alkoxy; fluorine, hydroxyl and C 1-6 1 ~ 5 amino which may be C 3-8 cycloalkyl substituted with a substituent independently selected from the group consisting of alkoxy; fluorine, the group consisting of hydroxyl and C 1-6 alkoxy C 1-6 alkoxy optionally substituted with 1 to 5 substituents independently selected from: 1 to 5 independently selected from the group consisting of fluorine, hydroxyl group and C 1-6 alkoxy C 3-10 cycloalkoxy which may be substituted with the following substituents: a hydrogen atom; a hydroxyl group; a halogen; or a 4- to 10-membered saturated heterocyclic ring. More preferably, identical or different, fluorine and C 1-6 independently from the group consisting of alkoxy optionally substituted with 1 to 5 substituents selected C 1-6 alkyl; C 3-8 Cycloalkyl; C 1-6 alkoxy; C 3-10 cycloalkoxy; hydrogen atom; or halogen. Most preferably, it is the same or different and includes 1 to 5 fluorines optionally substituted with C 1-6 alkyl; C 1-6 alkoxy; C 3-10 cycloalkoxy; hydrogen atom; or halogen .
　Ｗとして好ましくは、ＣＨが挙げられる。
　Ｒ２として好ましくは、フッ素、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１０Ｒ１１からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；フッ素、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１０Ｒ１１からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルキル、４～１０員の飽和複素環若しくは４～１０員の飽和複素環－カルボニル－；水素原子；又はＣ１－６アルキルカルボニルが挙げられる。より好ましくは、フッ素及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル又は水素原子が挙げられ、さらに好ましくは、Ｃ１－６アルキル又は水素原子が挙げられ、最も好ましくは水素原子が挙げられる。 W is preferably CH.
R 2 is preferably C 1-6 alkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, hydroxyl group, C 1-6 alkoxy and —NR 10 R 11. C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, hydroxyl group, C 1-6 alkoxy and —NR 10 R 11 ; A membered saturated heterocyclic ring or a 4- to 10-membered saturated heterocyclic ring-carbonyl-; a hydrogen atom; or a C 1-6 alkylcarbonyl. More preferable examples include C 1-6 alkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of fluorine and C 1-6 alkoxy, and more preferably , C 1-6 alkyl or a hydrogen atom, and most preferably a hydrogen atom.
　Ｒ３Ａ、Ｒ３Ｂ、Ｒ３Ｃ、Ｒ３Ｄ及びＲ３Ｅとして好ましくは、同一又は異なって、１～５個のフッ素で置換されていてもよいＣ１－６アルキル若しくはＣ１－６アルコキシ；水素原子；又はフッ素が挙げられる。より好ましくは、１～５個のフッ素で置換されていてもよいＣ１－６アルキル；水素原子；又はフッ素が挙げられ、さらに好ましくは、Ｃ１－６アルキル；水素原子；又はフッ素が挙げられる。なお、ＷがＣＨのとき、Ｗの炭素原子は、形成する環の他の炭素原子と同様に上記Ｒ３Ａ、Ｒ３Ｂ、Ｒ３Ｃ又はＲ３Ｄの置換基で置換されていてもよい。 R 3A , R 3B , R 3C , R 3D and R 3E are preferably the same or different and each is a C 1-6 alkyl or C 1-6 alkoxy optionally substituted with 1 to 5 fluorines; a hydrogen atom Or fluorine. More preferably, C 1-6 alkyl optionally substituted with 1 to 5 fluorines; a hydrogen atom; or fluorine is mentioned, and still more preferably C 1-6 alkyl; a hydrogen atom; or fluorine is mentioned. . When W is CH, the carbon atom of W may be substituted with the above substituent of R 3A , R 3B , R 3C or R 3D in the same manner as other carbon atoms of the ring to be formed.
　Ｒ４Ａ、Ｒ４Ｂ、Ｒ５、及びＲ７として好ましくは、同一又は異なって、アリール、ヘテロアリール、４～１０員の飽和複素環、Ｃ３－１０シクロアルキル、フッ素、水酸基、１～５個のフッ素で置換されていてもよいＣ１－６アルコキシ、Ｃ１－６アルキルカルボニル及び－ＮＲ１８Ｒ１９からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－１０アルキル；Ｃ３－１０シクロアルキル；４～１０員の飽和複素環；又は水素原子であり（前記アリール、ヘテロアリール、飽和複素環及びシクロアルキルは、フッ素、水酸基、Ｃ１－６アルキル（該基は、フッ素、Ｃ１－６アルコキシ及び－ＮＲ１８Ｒ１９からなる群から独立して選択される１～５個の置換基で置換されていてもよい）、１～５個のフッ素で置換されていてもよいＣ１－６アルコキシ、Ｃ１－６アルキルカルボニル、及び－ＮＲ１８Ｒ１９からなる群から独立して選択される１～５個の置換基で置換されていてもよい）が挙げられ、ここにおいて、（１）Ｒ４Ａ及びＲ４Ｂは一緒になって４～１０員の含窒素飽和複素環（該環は、上記飽和複素環と同様の置換基で置換されていてもよい）を形成していてもよく、（２）Ｒ４Ａ及びＲ４Ｂは、共に水素原子ではなく、（３）Ｒ５は、水素原子ではない。より好ましくは、同一又は異なって、４～１０員の飽和複素環、Ｃ３－１０シクロアルキル、フッ素、水酸基、１～５個のフッ素で置換されていてもよいＣ１－６アルコキシ、Ｃ１－６アルキルカルボニル及び－ＮＲ１８Ｒ１９からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－１０アルキル；Ｃ３－１０シクロアルキル；４～１０員の飽和複素環；又は水素原子（前記飽和複素環及びシクロアルキルは、フッ素、水酸基、Ｃ１－６アルキル（該基は、フッ素、Ｃ１－６アルコキシ及び－ＮＲ１８Ｒ１９からなる群から独立して選択される１～５個の置換基で置換されていてもよい）、１～５個のフッ素で置換されていてもよいＣ１－６アルコキシ、Ｃ１－６アルキルカルボニル、又は－ＮＲ１６Ｒ１７からなる群から独立して選択される１～５個の置換基で置換されていてもよい）が挙げられる。さらに好ましくは、同一又は異なって、４～１０員の飽和複素環及びＣ３－１０シクロアルキルからなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－１０アルキル；Ｃ３－１０シクロアルキル；４～１０員の飽和複素環；又は水素原子であり（前記飽和複素環及びシクロアルキルは、フッ素、水酸基、Ｃ１－６アルキル（該基は、フッ素、Ｃ１－６アルコキシ及び－ＮＲ１８Ｒ１９からなる群から独立して選択される１～５個の置換基で置換されていてもよい）、１～５個のフッ素で置換されていてもよいＣ１－６アルコキシ、Ｃ１－６アルキルカルボニル、又は－ＮＲ１６Ｒ１７からなる群から独立して選択される１～５個の置換基で置換されていてもよい）が挙げられる。また、別の好ましい態様として、Ｒ４Ａ又はＲ４Ｂのいずれか一方が水素原子であることが挙げられる。 R 4A , R 4B , R 5 , and R 7 are preferably the same or different and are aryl, heteroaryl, 4- to 10-membered saturated heterocyclic ring, C 3-10 cycloalkyl, fluorine, hydroxyl group, 1 to 5 Optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy, C 1-6 alkylcarbonyl, and —NR 18 R 19 , optionally substituted with fluorine Good C 1-10 alkyl; C 3-10 cycloalkyl; 4- to 10-membered saturated heterocycle; or a hydrogen atom (the aryl, heteroaryl, saturated heterocycle and cycloalkyl are fluorine, hydroxyl, C 1- 6 alkyl (said groups, fluorine may be substituted with one to five substituents independently selected from the group consisting of C 1-6 alkoxy and -NR 18 R 19), 1-5 Of fluorine substituted which may be C 1-6 alkoxy, optionally substituted by C 1-6 alkylcarbonyl, and -NR 18 1 ~ 5 substituents selected independently from the group consisting of R 19 (1) R 4A and R 4B together are a 4- to 10-membered nitrogen-containing saturated heterocyclic ring (the ring is substituted with the same substituent as the above saturated heterocyclic ring). (2) R 4A and R 4B are not both hydrogen atoms, and (3) R 5 is not a hydrogen atom. More preferably, it is the same or different and is a 4 to 10-membered saturated heterocyclic ring, C 3-10 cycloalkyl, fluorine, hydroxyl group, C 1-6 alkoxy optionally substituted with 1 to 5 fluorines, C 1 C 1-10 alkyl optionally substituted with 1-5 substituents independently selected from the group consisting of -6 alkylcarbonyl and —NR 18 R 19 ; C 3-10 cycloalkyl; 4-10 Or a hydrogen atom (the saturated heterocyclic ring and cycloalkyl are fluorine, hydroxyl, C 1-6 alkyl (the group is selected from the group consisting of fluorine, C 1-6 alkoxy and —NR 18 R 19); Optionally substituted with 1 to 5 substituents independently selected) C 1-6 alkoxy optionally substituted with 1 to 5 fluorines, C 1-6 alkylcarbonyl, or — NR 16 And may be substituted with 1 to 5 substituents independently selected from the group consisting of R 17 ). More preferably, identical or different, 4-10 membered saturated heterocycle and C 3-10 optionally substituted with 1 to 5 substituents selected independently from the group consisting of cycloalkyl C 1 -10 alkyl; C 3-10 cycloalkyl; 4- to 10-membered saturated heterocycle; or a hydrogen atom (the saturated heterocycle and cycloalkyl are fluorine, hydroxyl, C 1-6 alkyl (the group is fluorine May be substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy and —NR 18 R 19 ), and may be substituted with 1 to 5 fluorines And may be substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy, C 1-6 alkylcarbonyl, or —NR 16 R 17 . Moreover, as another preferable aspect, it is mentioned that any one of R < 4A> or R <4B> is a hydrogen atom.
　Ｒ６として好ましくは、Ｃ１-６アルキル、Ｃ１-６アルコキシ、水酸基、フッ素又は水素原子が挙げられる。より好ましくは、Ｃ１-６アルコキシ、水酸基、フッ素又は水素原子が挙げられ、さらに好ましくは、フッ素又は水素原子が挙げられる。
　Ｒ８～Ｒ１９としては、同一又は異なって、水素原子又はＣ１－６アルキルが挙げられ、好ましくは、水素原子又はＣ１－４アルキルが挙げられる。
　Ａｒとして好ましくは、ハロゲン、Ｃ１－６アルキル、Ｃ１－６アルコキシ及び－ＮＲ１６Ｒ１７からなる群から独立して選択される１～３個の置換基で置換されていてもよいアリールが挙げられる。より好ましくは、ハロゲン及びＣ１－６アルキルからなる群から独立して選択される１～３個の置換基で置換されていてもよいアリールが挙げられる。
　ｎとしては、１又は２が挙げられ、好ましくは、１が挙げられる。 R 6 is preferably C 1-6 alkyl, C 1-6 alkoxy, hydroxyl group, fluorine or hydrogen atom. More preferably, a C1-6 alkoxy, a hydroxyl group, a fluorine, or a hydrogen atom is mentioned, More preferably, a fluorine or a hydrogen atom is mentioned.
R 8 to R 19 are the same or different and include a hydrogen atom or C 1-6 alkyl, preferably a hydrogen atom or C 1-4 alkyl.
Ar is preferably aryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkoxy and —NR 16 R 17. Can be mentioned. More preferable examples include aryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen and C 1-6 alkyl.
As n, 1 or 2 is mentioned, Preferably 1 is mentioned.
　式（Ｉ）で表される化合物の製薬学的に許容される塩とは、構造中に酸付加塩を形成しうる基を有する式（Ｉ）の化合物の製薬学的に許容される酸付加塩を意味する。酸付加塩の具体例としては、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硫酸塩、過塩素酸塩、リン酸塩等の無機酸塩、シュウ酸塩、マロン酸塩、マレイン酸塩、フマル酸塩、乳酸塩、リンゴ酸塩、クエン酸塩、酒石酸塩、安息香酸塩、トリフルオロ酢酸塩、酢酸塩、メタンスルホン酸塩、ｐ－トルエンスルホン酸塩、トリフルオロメタンスルホン酸塩等の有機酸塩、又はグルタミン酸塩、アスパラギン酸塩等のアミノ酸塩が挙げられる。
　式（Ｉ）で表される本発明化合物がカルボキシル基などの酸性官能基を有する場合、各種の塩基と塩を形成しうる。この場合の薬学的に許容される塩としては、ナトリウム塩、カリウム塩等のアルカリ金属塩、カルシウム塩等のアルカリ土類金属塩、又はアンモニウム塩等が挙げられる。これらの塩は、式（Ｉ）で表される本発明化合物を塩基と混合した後、再結晶などの常法により得ることができる。 The pharmaceutically acceptable salt of the compound represented by the formula (I) is a pharmaceutically acceptable acid addition of the compound of the formula (I) having a group capable of forming an acid addition salt in the structure. Means salt. Specific examples of acid addition salts include hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, phosphate and other inorganic acid salts, oxalate, malonate, maleate Acid, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate And organic acid salts such as glutamic acid salts and aspartic acid salts.
When this invention compound represented by a formula (I) has acidic functional groups, such as a carboxyl group, various bases and salts can be formed. Examples of the pharmaceutically acceptable salt in this case include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts, and ammonium salts. These salts can be obtained by a conventional method such as recrystallization after mixing the compound of the present invention represented by formula (I) with a base.
　なお、本明細書において記載の簡略化のために、次に挙げる略号を用いることもある。o－：ｏｒｔｈｏ－、ｍ－：ｍｅｔａ－、ｐ－：ｐａｒａ－、ｔ－：ｔｅｒｔ－、ｓ－：ｓｅｃ－、ＣＨＣｌ３：クロロホルム、ＣＨ２Ｃｌ２：ジクロロメタン、ＴＨＦ：テトラヒドロフラン、ＤＭＦ：Ｎ，Ｎ－ジメチルホルムアミド、ＤＭＳＯ：ジメチルスルホキシド、ＰＡＭ：ポジティブアロステリックモジュレーター、ＨＥＰＥＳ：Ｎ－２－ヒドロキンエチルピペラジン－Ｎ’－２－エタンスルホン酸、ＢＳＡ：牛血清アルブミン、ＦＤＳＳ：Ｆｕｎｃｔｉｏｎａｌ Ｄｒｕｇ Ｓｃｒｅｅｎｉｎｇ Ｓｙｓｔｅｍ、Ｂｏｃ：ｔｅｒｔ－ブトキシカルボニル、ｃ－Ｈｅｘ：シクロヘキシル、ｃ－Ｐｅｎ：シクロペンチル、ＥＤＣＩ・ＨＣｌ：Ｎ－（３－ジエチルアミノプロピル)－Ｎ’－エチルカルボジイミド 塩酸塩、ＨＯＢｔ：１－ヒドロキシベンゾトリアゾール、ＤＩＥＡ：ジイソプロピルエチルアミン、ＴＥＡ：トリエチルアミン Note that the following abbreviations may be used to simplify the description in this specification. o-: ortho-, m-: meta-, p-: para-, t-: tert-, s-: sec-, CHCl 3 : chloroform, CH 2 Cl 2 : dichloromethane, THF: tetrahydrofuran, DMF: N, N-dimethylformamide, DMSO: dimethyl sulfoxide, PAM: positive allosteric modulator, HEPES: N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid, BSA: bovine serum albumin, FDSS: Functional Drug Screening System, Boc : Tert-butoxycarbonyl, c-Hex: cyclohexyl, c-Pen: cyclopentyl, EDCI · HCl: N- (3-diethylaminopropyl) -N′-ethylcarbodiimide hydrochloride, HOBt: 1-hydride Alkoxy benzotriazoles, DIEA: diisopropylethylamine, TEA: Triethylamine
　本発明の化合物の製造方法について以下に述べる。式（Ｉ）で表される本発明の化合物は、例えば下記の製造法Ａ１～Ａ５、Ｂ、Ｃ１又はＣ２により製造することができる。 The production method of the compound of the present invention is described below. The compound of the present invention represented by the formula (I) can be produced, for example, by the following production methods A 1 to A 5 , B, C 1 or C 2 .
製造法Ａ １
　式（Ｉ）で表される化合物のうち、Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ４ＡＲ４Ｂであり、ＷがＣＨである式［Ａ１］及び［Ａ２］で表される化合物Ａ１及び化合物Ａ２は、例えば下記の製法により製造することができる。
Figure JPOXMLDOC01-appb-C000003
 （式中、Ａ、Ｒ１Ａ～Ｒ１Ｄ、Ｒ２、Ｒ３Ａ～Ｒ３Ｄ、Ｒ４Ａ、Ｒ４Ｂ及びｎは項１に定義されるとおりであり、Ｒxはハロゲン、ニトロ等の電子吸引基または水素原子を意味し、Ｐはアミノ基の保護基を意味する） Production method A 1
Of the compounds represented by formula (I), XYZ is N—CO—NR 4A R 4B and W is CH. Compounds A1 and A1 represented by formulas [A1] and [A2] Compound A2 can be produced, for example, by the following production method.
Figure JPOXMLDOC01-appb-C000003
 (In the formula, A, R 1A to R 1D , R 2 , R 3A to R 3D , R 4A , R 4B and n are as defined in Item 1, and Rx is an electron withdrawing group such as halogen or nitro; It means a hydrogen atom, P means an amino protecting group)
　ＡがＣＲ１Ｄの２－メチルアニリン（化合物ａ１）は、例えば、Bioorganic & Medicinal Chemistry Letters 2002, 12(20), 2925-2930、European Journal of Organic Chemistry 2010, 24, 4662-4670、国際公開第2009/001132号パンフレットなどに記載されている方法により製造できるか、又は市販品として購入できる。
　Ａが窒素原子の化合物ａ１である２－メチル－３－アミノピリジンは、例えば、国際公開第2008/157404号パンフレット、国際公開第2009/088103号パンフレットなどに記載されている方法により製造できるか、又は市販品として購入できる。 2-methylaniline (compound a1) in which A is CR 1D is, for example, Bioorganic & Medicinal Chemistry Letters 2002, 12 (20), 2925-2930, European Journal of Organic Chemistry 2010, 24, 4662-4670, International Publication No. 2009 / 001132 can be produced by the method described in the pamphlet or the like, or can be purchased as a commercial product.
2-methyl-3-aminopyridine in which A is a nitrogen atom compound a1 can be produced, for example, by the method described in International Publication No. 2008/157404, International Publication No. 2009/088103, etc. Or it can be purchased as a commercial product.
［Ａ－１工程］
　本工程は化合物ａ１に、種々の酸及び無機塩存在下、適当な溶媒中、亜硝酸化合物を反応させることによりアジド化合物を得た後、クラウンエーテル存在下又は非存在下で環化し化合物ａ２を得る工程である。本工程において使用される酸は、塩酸、硝酸、硫酸等の鉱酸から選択されるが、好ましくは塩酸が挙げられ、本工程において使用される亜硝酸化合物は好ましくは亜硝酸アミルまたは亜硝酸ナトリウムが挙げられる。本工程において使用される塩は、テトラフルオロボランナトリウム、酢酸カリウム、酢酸ナトリウム、炭酸水素ナトリウム、ｔｅｒｔ－ブトキシカリウム等から選択されるが、好ましくはテトラフルオロボランナトリウム、酢酸カリウムが挙げられる。本工程において使用される溶媒は、後記に例示する溶媒等から選択されるが、好ましくは水、酢酸、クロロホルム又はジクロロメタンが挙げられる。本反応は、Tetrahedron Lett. 2002, 43, 2695-2697、Tetrahedron 2006, 62, 7772-7775などに記載されている方法を用い同様に製造することができる。 [Step A-1]
In this step, compound a1 is reacted with a nitrite compound in an appropriate solvent in the presence of various acids and inorganic salts to obtain an azide compound, and then cyclized in the presence or absence of crown ether to give compound a2. It is a process to obtain. The acid used in this step is selected from mineral acids such as hydrochloric acid, nitric acid and sulfuric acid, preferably hydrochloric acid, and the nitrite compound used in this step is preferably amyl nitrite or sodium nitrite Is mentioned. The salt used in this step is selected from tetrafluoroborane sodium, potassium acetate, sodium acetate, sodium bicarbonate, tert-butoxypotassium, etc., preferably tetrafluoroborane sodium and potassium acetate. The solvent used in this step is selected from the solvents exemplified below, and preferably water, acetic acid, chloroform or dichloromethane. This reaction can be similarly produced using the method described in Tetrahedron Lett. 2002, 43, 2695-2697, Tetrahedron 2006, 62, 7772-7775, and the like.
［Ａ－２工程］
　本工程は上記Ａ－１工程で得られた化合物ａ２に、種々の塩基存在下、適当な溶媒中、ヨウ素を反応させることにより、化合物ａ３を得る工程である。本工程において使用される塩基は、後記に例示する塩基等から選択されるが、好ましくは水酸化ナトリウム又は水酸化カリウムが挙げられる。本工程において使用される溶媒は、後記に例示する溶媒等から選択されるが、好ましくはジメチルホルムアミド又はクロロホルムが挙げられる。 [Step A-2]
This step is a step for obtaining compound a3 by reacting compound a2 obtained in step A-1 with iodine in a suitable solvent in the presence of various bases. The base used in this step is selected from the bases exemplified below, and preferably sodium hydroxide or potassium hydroxide. The solvent used in this step is selected from the solvents exemplified below, and preferably dimethylformamide or chloroform.
［Ａ－３工程］
　本工程は上記Ａ－２工程で得られた化合物ａ３に触媒及び塩基存在下、化合物ａ７とカップリングし化合物ａ４を得る工程である。触媒としては、パラジウムなどの遷移金属やその塩、その錯体、ポリマーなどの担体に担持させたものを挙げることができる。本工程において使用される塩基は、後記に例示する塩基等から選択されるが、好ましくは炭酸ナトリウム又は炭酸カリウム等が挙げられる。本工程において使用される溶媒は、後記に例示する溶媒等から選択されるが、好ましくはジオキサン－水の混合溶媒が挙げられる。本反応は、国際公開第2005/073219号パンフレットなどに記載されている方法が挙げられ、本方法を用い同様に製造することができる。なお、本反応においては、化合物ａ７と同様に反応が進行する各種ボラン酸試薬も使用することができる。 [Step A-3]
This step is a step of obtaining compound a4 by coupling compound a3 obtained in step A-2 with compound a7 in the presence of a catalyst and a base. Examples of the catalyst include those supported on a carrier such as a transition metal such as palladium, a salt thereof, a complex thereof, or a polymer. The base used in this step is selected from the bases exemplified below, and preferably sodium carbonate or potassium carbonate. The solvent used in this step is selected from the solvents exemplified below, preferably a mixed solvent of dioxane-water. This reaction includes the method described in International Publication No. 2005/073219 pamphlet and the like, and can be similarly produced using this method. In this reaction, various boranoic acid reagents that proceed in the same manner as compound a7 can also be used.
［Ａ－４工程］
　本工程は上記Ａ－３工程で得られた化合物ａ４に触媒存在下で還元し化合物ａ５を得る工程である。還元剤としては水素、蟻酸アンモニウムなどの蟻酸の塩、ヒドラジンを用いることができる。触媒としては、パラジウム、ニッケル、ロジウム、コバルト、白金等の遷移金属やその塩、その錯体、ポリマーなどの担体に担持させたものを挙げることができる。本工程において使用される溶媒は、後記に例示する溶媒等から選択されるが、好ましくはエタノール又はメタノールが挙げられる。 [Step A-4]
This step is a step of reducing compound a4 obtained in step A-3 above in the presence of a catalyst to obtain compound a5. As the reducing agent, hydrogen, a salt of formic acid such as ammonium formate, or hydrazine can be used. Examples of the catalyst include those supported on a carrier such as a transition metal such as palladium, nickel, rhodium, cobalt, platinum, a salt thereof, a complex thereof, or a polymer. Although the solvent used in this process is selected from the solvent etc. which are illustrated to a postscript, Preferably ethanol or methanol is mentioned.
［Ａ－５工程］
　本工程は上記Ａ－４工程で得られた化合物ａ５のアミノ基の保護基Ｐを、脱保護することにより、化合物ａ６を得る工程である。本工程はProtective Groups in Organic Synthesis（Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年）に記載されている方法等に準じて行うことができる。 [Step A-5]
This step is a step of obtaining compound a6 by deprotecting the protecting group P of the amino group of compound a5 obtained in the above step A-4. This step can be carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).
［Ａ－６工程］
　本工程は上記Ａ－５工程で得られた化合物ａ６に、種々の塩基存在下、適当な溶媒中、化合物ａ８又はａ９を反応させることにより、化合物Ａ１を得る工程である。本工程において使用される塩基は、後記に例示する塩基等から選択されるが、好ましくはジイソプロピルエチルアミン又はトリエチルアミンが挙げられる。本工程において使用される溶媒は、後記に例示する溶媒等から選択されるが、好ましくはテトラヒドロフラン又はジメチルホルムアミドが挙げられる。 [Step A-6]
This step is a step of obtaining compound A1 by reacting compound a6 obtained in step A-5 with compound a8 or a9 in an appropriate solvent in the presence of various bases. The base used in this step is selected from the bases exemplified below, and preferably diisopropylethylamine or triethylamine. The solvent used in this step is selected from the solvents exemplified below, and preferably tetrahydrofuran or dimethylformamide is used.
［Ａ－７工程］
　本工程は上記Ａ－６工程で得られた化合物Ａ１に、種々の塩基存在下又は非存在下、適当な溶媒中、各種アルキルハライド、カルボン酸、ボラン酸、酸クロライド、イソシアネート等と反応させることにより、化合物Ａ２を得る工程である。本工程において使用される塩基は、後記に例示する塩基等から選択されるが、好ましくは水素化ナトリウム、ジイソプロピルエチルアミン又は炭酸ナトリウムが挙げられる。本工程において使用される溶媒は、後記に例示する溶媒等から選択される。 [Step A-7]
In this step, compound A1 obtained in step A-6 is reacted with various alkyl halides, carboxylic acids, boranoic acids, acid chlorides, isocyanates, etc. in the presence or absence of various bases in an appropriate solvent. To obtain compound A2. The base used in this step is selected from bases exemplified below, and preferably sodium hydride, diisopropylethylamine, or sodium carbonate. The solvent used in this step is selected from the solvents exemplified below.
製造法Ａ ２
　式（Ｉ）で表される化合物のうち、Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ４ＡＲ４Ｂであり、ＷがＣＲ３Ｅである式［Ａ１’］で表される化合物Ａ１’は、例えば下記の製法によっても製造することができる。
Figure JPOXMLDOC01-appb-C000004
 （式中、Ａ、Ｒ１Ａ～Ｒ１Ｄ、Ｒ３Ａ～Ｒ３Ｅ、Ｒ４Ａ、Ｒ４Ｂ及びｎは項１に定義されるとおりであり、Ｒxはハロゲン、ニトロ等の電子吸引基または水素原子を意味し、ＲｙはＣ１－６のアルキル基又はアミノ基の保護基を意味し、Ｒzは塩素、臭素又はヨウ素原子を意味し、Ｐはアミノ基の保護基を意味する） Production method A 2
Among the compounds represented by the formula (I), the compound A1 ′ represented by the formula [A1 ′] in which XYZ is N—CO—NR 4A R 4B and W is CR 3E is: For example, it can also be produced by the following production method.
Figure JPOXMLDOC01-appb-C000004
 (In the formula, A, R 1A to R 1D , R 3A to R 3E , R 4A , R 4B and n are as defined in Item 1; Ry means a C 1-6 alkyl group or amino protecting group, Rz means a chlorine, bromine or iodine atom, and P means an amino protecting group)
　４－クロロピペリジン誘導体（化合物ａ１０）は、例えば、Heterocycles 1990, 31(7), 1201-1204、 Journal of the Chemical Society, Perkin Transactions 2 1992, 6, 857-8などに記載されている方法により製造できるか、又は市販品として購入できる。 A 4-chloropiperidine derivative (compound a10) is produced by a method described in, for example, Heterocycles 1990, 31 (7), 1201-1204,1-1Journal of the Chemical Society, Perkin Transactions 2 1992, 6, 857-8. Or can be purchased as a commercial product.
［Ａ－８工程］
　本工程は化合物ａ１０に、金属マグネシウム、グリニャード試薬等を反応させることにより、アルキルマグネシウム化合物ａ１１を得る工程である。本工程において使用される溶媒は、後記に例示する溶媒等から選択されるが、好ましくはテトラヒドロフラン又はジエチルエーテルが挙げられる。 [Step A-8]
This step is a step of obtaining alkylmagnesium compound a11 by reacting compound a10 with metal magnesium, a Grignard reagent, or the like. The solvent used in this step is selected from the solvents exemplified below, and preferably tetrahydrofuran or diethyl ether.
［Ａ－９工程］
　本工程は上記Ａ－８工程で得られた化合物ａ１１に、適当な溶媒中、ａ１５又はａ１６を反応させることにより、化合物ａ１２を得る工程である。本工程において使用される溶媒は、後記に例示する溶媒等から選択されるが、好ましくはテトラヒドロフラン又はジエチルエーテルが挙げられる。 [Step A-9]
This step is a step of obtaining compound a12 by reacting compound a11 obtained in the above step A-8 with a15 or a16 in a suitable solvent. The solvent used in this step is selected from the solvents exemplified below, and preferably tetrahydrofuran or diethyl ether.
［Ａ－１０工程］
　本工程は上記Ａ－９工程で得られた化合物ａ１２に、種々の塩基存在下、適当な溶媒中、種々の求電子剤と反応させることにより、化合物ａ１３を得る工程である。求電子剤としては、クロロ炭酸フェニル、塩化ベンジルオキシカルボニル、ジ－ｔ－ブチルジカルボナート等を用いることができる。本工程において使用される塩基は、後記に例示する塩基等から選択されるが、好ましくは炭酸ナトリウム又は炭酸カリウム等が挙げられる。本工程において使用される溶媒は、好ましくはトルエン又はテトラヒドロフランが挙げられる。 [Step A-10]
This step is a step of obtaining compound a13 by reacting compound a12 obtained in step A-9 with various electrophiles in the presence of various bases in an appropriate solvent. As the electrophile, phenyl chlorocarbonate, benzyloxycarbonyl chloride, di-t-butyl dicarbonate and the like can be used. The base used in this step is selected from the bases exemplified below, and preferably sodium carbonate or potassium carbonate. The solvent used in this step is preferably toluene or tetrahydrofuran.
［Ａ－１１工程］
　本工程は上記Ａ－１０工程で得られた化合物ａ１３に、種々の塩基存在下、適当な溶媒中にヒドラジンのみ存在下反応させるか、又は、メチルヒドロキシルアミン添加に続きヒドラジンと反応させることにより、化合物ａ１４を得る工程である。本工程において使用される塩基は、後記に例示する塩基等から選択されるが、好ましくはピリジン又は炭酸カリウム等が挙げられる。本工程において使用される溶媒は、後記に例示する溶媒等から選択されるが、好ましくはピリジン又はジメトキシエタンが挙げられる。本反応は、Journal of Organic Chemistry 2006, 71(21）, 8166-8172に記載されている方法が挙げられ、本方法に準じて製造することができる。 [Step A-11]
In this step, the compound a13 obtained in the above step A-10 is reacted in the presence of various bases in the presence of only hydrazine in an appropriate solvent, or by reacting with hydrazine following addition of methylhydroxylamine. In this step, compound a14 is obtained. The base used in this step is selected from the bases exemplified below, and preferably pyridine or potassium carbonate. The solvent used in this step is selected from the solvents exemplified below, and preferably pyridine or dimethoxyethane. This reaction includes the method described in Journal of Organic Chemistry 2006, 71 (21), 8166-8172, and can be produced according to this method.
［Ａ－１２工程］
　本工程は上記Ａ－１１工程で得られた化合物ａ１４のアミノ基の保護基Ｐを、脱保護することにより、化合物ａ６’を得る工程である。本工程はProtective Groups in Organic Synthesis（Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年）に記載されている方法等に準じて行うことができる。 [Step A-12]
This step is a step of obtaining the compound a6 ′ by deprotecting the protecting group P of the amino group of the compound a14 obtained in the step A-11. This step can be carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).
［Ａ－１３工程］
　本工程は上記Ａ－１２工程で得られた化合物ａ６’を上記Ａ－６工程に準じた条件で化合物Ａ１’へ変換する工程である。 [Step A-13]
This step is a step of converting the compound a6 ′ obtained in the step A-12 to the compound A1 ′ under the conditions according to the step A-6.
製造法Ａ ３
　式（Ｉ）で表される化合物のうち、Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ４ＡＲ４Ｂであり、ＷがＣＲ３Ｅである式［Ａ１’］で表される化合物Ａ１’は、例えば下記の製法によっても製造することができる。
Figure JPOXMLDOC01-appb-C000005
 （式中、Ａ、Ｒ１Ａ～Ｒ１Ｄ、Ｒ３Ａ～Ｒ３Ｅ、Ｒ４Ａ、Ｒ４Ｂ及びｎは項１に定義されるとおりであり、Ｒxはハロゲン、ニトロ等の電子吸引基または水素原子を意味し、Ｒｚは塩素、臭素またはヨウ素原子を意味し、Ｐはアミノ基の保護基を意味する） Production method A 3
Among the compounds represented by the formula (I), the compound A1 ′ represented by the formula [A1 ′] in which XYZ is N—CO—NR 4A R 4B and W is CR 3E is: For example, it can also be produced by the following production method.
Figure JPOXMLDOC01-appb-C000005
 (In the formula, A, R 1A to R 1D , R 3A to R 3E , R 4A , R 4B and n are as defined in Item 1; Rz represents a chlorine, bromine or iodine atom, and P represents an amino-protecting group)
　２-フルオロ-ブロモベンゼン等（化合物ａ１７）は、例えば、Bioorganic & Medicinal Chemistry Letters, 2011, 21(24), 7344-7350、国際公開第2010/026124号パンフレット、国際公開第2007/082098号パンフレットに記載されている方法により製造できるか、又は市販品として購入できる。 2-Fluoro-bromobenzene and the like (compound a17) are disclosed in, for example, Bioorganic & Medicinal & Chemistry & Letters, 2011, 21 (24), 7434-7350, International Publication No. 2010/026124, International Publication No. 2007/082098 It can be produced by the methods described or can be purchased as a commercial product.
［Ａ－１４工程］
　本工程は化合物ａ１７に、アルキルリチウム等を反応させることにより、ハロゲン金属交換反応を行い、アリールリチウム化合物ａ１８を得る工程である。本工程において使用されるアルキルリチウムは、好ましくはｎ－ブチルリチウム等が挙げられる。本工程において使用される溶媒は、後記に例示する溶媒等から選択されるが、好ましくはテトラヒドロフラン又はジエチルエーテルが挙げられる。 [Step A-14]
This step is a step of obtaining an aryllithium compound a18 by performing a halogen metal exchange reaction by reacting the compound a17 with alkyllithium or the like. The alkyl lithium used in this step is preferably n-butyl lithium. The solvent used in this step is selected from the solvents exemplified below, and preferably tetrahydrofuran or diethyl ether.
［Ａ－１５工程］
　本工程は化合物ａ１９に、種々の縮合剤存在下、適当な溶媒中、メトキシメチルアミンを反応させることにより、ワインレブアミドａ２０を得る工程である。本工程において使用される縮合剤は、常法で使用される種々の縮合剤を使用することができるが、好ましくは１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド（塩酸塩を含む）が挙げられる。本工程において使用される溶媒は、後記に例示する溶媒等から選択される。 [Step A-15]
This step is a step of obtaining wine levamide a20 by reacting compound a19 with methoxymethylamine in an appropriate solvent in the presence of various condensing agents. As the condensing agent used in this step, various condensing agents used in a conventional method can be used, but 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (including hydrochloride) is preferable. Is mentioned. The solvent used in this step is selected from the solvents exemplified below.
［Ａ－１６工程］
　本工程は化合物ａ２０に、適当な溶媒中、化合物ａ１８を反応させることにより、化合物ａ２１を得る工程である。本工程において使用される溶媒は、後記に例示する溶媒等から選択されが、好ましくはテトラヒドロフラン又はジエチルエーテルが挙げられる。 [Step A-16]
This step is a step of obtaining compound a21 by reacting compound a20 with compound a18 in a suitable solvent. The solvent used in this step is selected from the solvents exemplified below, preferably tetrahydrofuran or diethyl ether.
［Ａ－１７工程］
　本工程は上記Ａ－１６工程で得られた化合物ａ２１を上記Ａ－１１工程に準じた条件で化合物ａ２２へ変換する工程である。 [Step A-17]
This step is a step of converting the compound a21 obtained in the step A-16 to the compound a22 under the conditions according to the step A-11.
［Ａ－１８工程］
　本工程は上記Ａ－１７工程で得られた化合物ａ２２を上記Ａ－１２工程に準じた条件で化合物ａ２３へ変換する工程である。 [Step A-18]
This step is a step of converting the compound a22 obtained in the step A-17 to the compound a23 under the conditions according to the step A-12.
［Ａ－１９工程］
　本工程は上記Ａ－１８工程で得られた化合物ａ２３を上記Ａ－６工程に準じた条件で化合物Ａ１’へ変換する工程である。 [Step A-19]
This step is a step of converting the compound a23 obtained in the step A-18 to the compound A1 ′ under the conditions according to the step A-6.
製造法Ａ ４
　式（Ｉ）で表される化合物のうち、Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ４ＡＲ４Ｂであり、ＷがＣＲ３Ｅである式［Ａ１’］で表される化合物Ａ１’は、例えば下記の製法によっても製造することができる。
Figure JPOXMLDOC01-appb-C000006
 （式中、Ａ、Ｒ１Ａ～Ｒ１Ｄ、Ｒ３Ａ～Ｒ３Ｅ、Ｒ４Ａ、Ｒ４Ｂ、Ａｒ及びｎは項１に定義されるとおりであり、Ｒxはハロゲン、ニトロ等の電子吸引基または水素原子を意味し、Ｐはアミノ基の保護基を意味する） Production Method A 4
Among the compounds represented by the formula (I), the compound A1 ′ represented by the formula [A1 ′] in which XYZ is N—CO—NR 4A R 4B and W is CR 3E is: For example, it can also be produced by the following production method.
Figure JPOXMLDOC01-appb-C000006
 (In the formula, A, R 1A to R 1D , R 3A to R 3E , R 4A , R 4B , Ar and n are as defined in Item 1; Rx is an electron withdrawing group such as halogen, nitro or hydrogen; Means an atom, and P means an amino-protecting group)
　４－ピペリジルカルボン酸誘導体（化合物ａ２５）は、例えば、国際公開第2010/117323号パンフレットなどに記載されている方法により製造できるか、又は市販品として購入できる。 The 4-piperidylcarboxylic acid derivative (compound a25) can be produced, for example, by the method described in International Publication No. 2010/117323 pamphlet or can be purchased as a commercial product.
［Ａ－２０工程］
　本工程は化合物ａ２５を種々の活性化試薬または縮合剤でカルボニル部位を活性化し、化合物ａ３０を反応させることにより、チオエステルａ２６を得る工程である。本工程において使用される活性化試薬は好ましくはオギザリルクロライドが挙げられ、本工程において使用される縮合剤は常法で使用される種々の縮合剤を使用することができるが、好ましくはＮ，Ｎ’－ジシクロヘキシルカルボジイミドが挙げられる。本工程において使用される塩基は、好ましくはジイソプロピルエチルアミンが挙げられ、本工程において使用される溶媒は、後記に例示する溶媒等から選択される。 [Step A-20]
This step is a step of obtaining the thioester a26 by activating the carbonyl moiety of the compound a25 with various activating reagents or condensing agents and reacting the compound a30. The activating reagent used in this step is preferably oxalyl chloride. As the condensing agent used in this step, various condensing agents used in a conventional manner can be used. N'-dicyclohexylcarbodiimide. The base used in this step is preferably diisopropylethylamine, and the solvent used in this step is selected from the solvents exemplified below.
［Ａ－２１工程］
　本工程は化合物ａ２６に、適当な溶媒中、パラジウム触媒、銅錯体、リン配位子存在下、ボラン酸ａ３１と反応させることにより、化合物ａ２７を得る工程である。本工程において使用されるパラジウム触媒は好ましくはトリスジベンジリデンアセトンビスパラジウムが挙げられ、銅錯体は好ましくはチオフェンカルボン酸銅が挙げられる。リン配位子として、好ましくは亜リン酸トリエチルが挙げられ、溶媒は、後記に例示する溶媒等から選択されが、好ましくはテトラヒドロフランが挙げられる。類似反応として、例えば、Journal of the American Chemical Society 2007, 129(5), 1132-1140、Journal of the American Chemical Society 2007, 129(51), 15734-15735などに記載されている方法が挙げられ、本方法を用い同様に製造することができる。 [Step A-21]
This step is a step of obtaining compound a27 by reacting compound a26 with boranoic acid a31 in the presence of a palladium catalyst, a copper complex and a phosphorus ligand in an appropriate solvent. The palladium catalyst used in this step is preferably trisdibenzylideneacetone bis-palladium, and the copper complex is preferably copper thiophenecarboxylate. The phosphorus ligand is preferably triethyl phosphite, and the solvent is selected from the solvents exemplified below, and preferably tetrahydrofuran. Examples of the similar reaction include the methods described in Journal of the American Chemical Society 2007, 129 (5), 1132-1140, Journal of the American Chemical Society 2007, 129 (51), 15734-15735, etc. It can be similarly manufactured using this method.
［Ａ－２２工程］
　本工程は化合物ａ２７を上記Ａ－１１工程に準じた条件で化合物ａ２８へ変換する工程である。 [Step A-22]
This step is a step of converting compound a27 to compound a28 under the conditions according to the above step A-11.
［Ａ－２３工程］
　本工程は化合物ａ２８を上記Ａ－１２工程に準じた条件で化合物ａ２９へ変換する工程である。 [Step A-23]
This step is a step of converting compound a28 to compound a29 under the conditions according to the above step A-12.
［Ａ－２４工程］
　本工程は化合物ａ２９を上記Ａ－６工程に準じた条件で化合物Ａ１’へ変換する工程である。 [Step A-24]
This step is a step of converting compound a29 into compound A1 ′ under the conditions according to the above step A-6.
製造法Ａ ５
　式（Ｉ）で表される化合物のうち、Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ４ＡＲ４Ｂであり、ＷがＮである式［Ａ３］及び［Ａ４］で表される化合物Ａ３及び化合物Ａ４は、例えば下記の製法により製造することができる。
Figure JPOXMLDOC01-appb-C000007
 （式中、Ａ、Ｒ１Ａ～Ｒ１Ｄ、Ｒ２、Ｒ３Ａ～Ｒ３Ｄ、Ｒ４Ａ、Ｒ４Ｂ及びｎは項１に定義されるとおりであり、Ｒxはハロゲン、ニトロ等の電子吸引基または水素原子である。） Production method A 5
Of the compounds represented by formula (I), XYZ is N—CO—NR 4A R 4B and W is N. Compounds A3 and A3 represented by formulas [A3] and [A4] Compound A4 can be produced, for example, by the following production method.
Figure JPOXMLDOC01-appb-C000007
 (In the formula, A, R 1A to R 1D , R 2 , R 3A to R 3D , R 4A , R 4B and n are as defined in Item 1, and Rx is an electron withdrawing group such as halogen or nitro It is a hydrogen atom.)
　３－（１－ピペラジニル）－１Ｈ－インダゾール等（化合物ａ３２）は、例えば、Organic Process Research & Development 2001, 5(2), 179-183、国際公開第2010/054279号パンフレット、Organic Process Research & Development 2003, 7(4), 521-532 に記載されている方法により製造できるか、又は市販品として購入できる。 3- (1-piperazinyl) -1H-indazole and the like (compound a32) include, for example, Organic Process Research & Development 2001, 5 (2), 179-183, International Publication No. 2010/054279, Organic Process Research & Development 2003, 7 (4), 521-532 or can be purchased as a commercial product.
［Ａ－２５工程］
　本工程は化合物ａ３２を、上記Ａ－６工程に準じた条件で化合物Ａ３へ変換する工程である。 [Step A-25]
This step is a step of converting compound a32 into compound A3 under the conditions according to the above step A-6.
［Ａ－２６工程］
　本工程は上記Ａ－２５工程で得られた化合物Ａ３を上記Ａ－７工程に準じた条件で化合物Ａ４へ変換する工程である。 [Step A-26]
This step is a step of converting the compound A3 obtained in the step A-25 to the compound A4 under the conditions according to the step A-7.
製造法Ｂ
　式（Ｉ）で表される化合物のうち、Ｘ－Ｙ－Ｚが、ＣＲ６－ＣＯ－ＮＲ４ＡＲ４Ｂであり、ＷがＣＨである式［Ｂ１］及び［Ｂ２］で表される化合物Ｂ１及びＢ２は、例えば下記の製法により製造することができる。
Figure JPOXMLDOC01-appb-C000008
 （式中、Ａ、Ｒ１Ａ～Ｒ１Ｄ、Ｒ２、Ｒ３Ａ～Ｒ３Ｄ、Ｒ４Ａ、Ｒ４Ｂ、Ｒ６及びｎは項１に定義されるとおりであり、Ｒｘは、Ｃ１－６アルキル基を意味する） Manufacturing method B
Of the compounds represented by the formula (I), the compound B1 represented by the formulas [B1] and [B2] in which XYZ is CR 6 —CO—NR 4A R 4B and W is CH. And B2 can be produced, for example, by the following production method.
Figure JPOXMLDOC01-appb-C000008
 (In the formula, A, R 1A to R 1D , R 2 , R 3A to R 3D , R 4A , R 4B , R 6 and n are as defined in Item 1; R x is C 1-6 Means an alkyl group)
　４－オキソシクロヘキサンカルボキシレート誘導体（化合物ｂ１）は、例えば、Organic Syntheses 2007, 84, 233-241、Synlett 2000, 11, 1549-1552、国際公開第2010/141406号パンフレットなどに記載されている方法により製造できるか、又は市販品として購入できる。 The 4-oxocyclohexanecarboxylate derivative (compound b1) can be obtained by a method described in, for example, Organic Syntheses 2007, 84, 233-241, Synlett 2000, 11, 1549-1552, International Publication No. 2010/141406, etc. It can be manufactured or purchased as a commercial product.
［Ｂ－１工程］
　本工程は化合物ｂ１に、種々の塩基存在下、適当な溶媒中、化合物ｂ７又はｂ８と反応させることにより化合物ｂ２を得る工程である。本工程において使用される塩基は、後記に例示する塩基等から選択されるが、好ましくはピリジン又はカリウムヘキサメチルジシラジドが挙げられる。本工程において使用される溶媒は、後記に例示する溶媒等から選択されるが、好ましくはトルエン又はテトラヒドロフランが挙げられる。本反応は、Organic Process & Research & Development 2010, 14(5）, 1182-187に記載されている方法が挙げられ、本方法により製造することもできる。 [Step B-1]
This step is a step of obtaining compound b2 by reacting compound b1 with compound b7 or b8 in an appropriate solvent in the presence of various bases. The base used in this step is selected from the bases exemplified below, and preferably pyridine or potassium hexamethyldisilazide. Although the solvent used in this process is selected from the solvent etc. which are illustrated to a postscript, Preferably toluene or tetrahydrofuran is mentioned. This reaction includes the method described in Organic Process & Research & Development 2010, 14 (5), 1182-187, and can also be produced by this method.
［Ｂ－２工程］
　本工程は上記Ｂ－１工程で得られた化合物ｂ２に、触媒及び塩存在下、化合物ｂ９とカップリングし化合物ｂ３を得る工程である。触媒としては、パラジウムなどの遷移金属やその塩、その錯体、ポリマーなどの担体に担持させたものを挙げることができる。本工程において使用される塩は、酢酸カリウム、酢酸ナトリウム、酢酸銀等から選択されるが、好ましくは酢酸カリウムが挙げられる。本工程において使用される溶媒は、後記に例示する溶媒等から選択されるが、好ましくはジメチルスルホキシド及びジメトキシエタンが挙げられる。本反応は、国際公開第2009/016462号公開パンフレットなどに記載されている方法が挙げられ、本方法を用い同様に製造することができる。 [Step B-2]
This step is a step of coupling compound b2 obtained in step B-1 with compound b9 in the presence of a catalyst and a salt to obtain compound b3. Examples of the catalyst include those supported on a carrier such as a transition metal such as palladium, a salt thereof, a complex thereof, or a polymer. The salt used in this step is selected from potassium acetate, sodium acetate, silver acetate and the like, preferably potassium acetate. The solvent used in this step is selected from the solvents exemplified below and preferably dimethyl sulfoxide and dimethoxyethane. Examples of this reaction include methods described in International Publication No. 2009/016462 pamphlet and the like, and can be produced in the same manner using this method.
［Ｂ－３工程］
　本工程は上記Ｂ－２工程で得られた化合物ｂ３を、上記Ａ－３工程に準じた条件で化合物ｂ４へ変換する工程である。 [Step B-3]
This step is a step of converting the compound b3 obtained in the step B-2 into the compound b4 under the conditions according to the step A-3.
［Ｂ－４工程］
　本工程は上記Ｂ－３工程で得られた化合物ｂ４を、上記Ａ－４工程に準じた条件で化合物ｂ５へ変換する工程である。 [Step B-4]
This step is a step of converting the compound b4 obtained in the step B-3 into the compound b5 under the conditions according to the step A-4.
［Ｂ－５工程］
　本工程は上記Ｂ－４工程で得られたエステル化合物ｂ５を、対応するカルボン酸化合物ｂ６に変換する工程である。本工程はProtective Groups in Organic Synthesis（Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年）に記載されている方法等に準じて行うことができる。 [Step B-5]
This step is a step of converting the ester compound b5 obtained in the step B-4 to the corresponding carboxylic acid compound b6. This step can be carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).
［Ｂ－６工程］
　本工程は上記Ｂ－５工程で得られた化合物ｂ６に、種々の縮合剤存在下、適当な溶媒中、化合物ｂ１０を反応させることにより、化合物Ｂ１を得る工程である。本工程において使用される縮合剤は、常法で使用される種々の縮合剤を使用することができるが、好ましくは１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド（塩酸塩を含む）が挙げられる。本工程において使用される溶媒は、後記に例示する溶媒等から選択される。 [Step B-6]
This step is a step of obtaining compound B1 by reacting compound b6 obtained in step B-5 with compound b10 in the presence of various condensing agents in an appropriate solvent. As the condensing agent used in this step, various condensing agents used in a conventional method can be used, but 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (including hydrochloride) is preferable. Is mentioned. The solvent used in this step is selected from the solvents exemplified below.
［Ｂ－７工程］
　本工程は上記Ｂ－６工程で得られた化合物Ｂ１を、上記Ａ－７工程に準じた条件で化合物Ｂ２へ変換する工程である。 [Step B-7]
This step is a step of converting the compound B1 obtained in the step B-6 to the compound B2 under the conditions according to the step A-7.
製造法Ｃ １
　式（Ｉ）で表される化合物のうち、Ｘ－Ｙ－ＺがＣＲ６－ＮＲ７－ＣＯＲ５であり、Ｒ７が水素原子であり、ＷがＣＨである式［Ｃ１］で表される化合物Ｃ１は、例えば下記の製法により製造することができる。
Figure JPOXMLDOC01-appb-C000009
 （式中、Ａ、Ｒ１Ａ～Ｒ１Ｄ、Ｒ２、Ｒ３Ａ～Ｒ３Ｄ、Ｒ５、Ｒ６、Ａｒ及びｎは項１に定義されるとおりであり、Ｐはアミノ基の保護基を意味する。） Production method C 1
Of the compounds represented by formula (I), XYZ is CR 6 —NR 7 —COR 5 , R 7 is a hydrogen atom, and W is CH. Compound C1 can be produced, for example, by the following production method.
Figure JPOXMLDOC01-appb-C000009
 (Wherein, A, R 1A ~ R 1D , R 2, R 3A ~ R 3D, R 5, R 6, Ar and n are as defined in claim 1, P is meant the amino-protecting group To do.)
　４－アミノシクロヘキサンカルボン酸誘導体（化合物ｃ１）は、例えば、Synthetic Communications 2002, 32(13), 1985-1995、米国公開第2005/0020645号パンフレットなどに記載されている方法により製造できるか、又は市販品として購入できる。 The 4-aminocyclohexanecarboxylic acid derivative (compound c1) can be produced, for example, by the method described in Synthetic Communications 2002, 32 (13), 1985-1995, US Publication No. 2005/0020645, etc., or commercially available It can be purchased as a product.
［Ｃ－１工程］
　本工程は化合物ｃ１を、オキサリルクロライド、チオニルクロライド等の試薬を用いて、対応する酸クロライド化合物ｃ２に変換する工程である。本工程において使用される溶媒は、後記に例示する溶媒等から選択されるが、好ましくはジクロロメタン又はテトラヒドロフラン等が挙げられる。 [Step C-1]
This step is a step of converting compound c1 into the corresponding acid chloride compound c2 using a reagent such as oxalyl chloride, thionyl chloride and the like. The solvent used in this step is selected from the solvents exemplified below, preferably dichloromethane or tetrahydrofuran.
［Ｃ－２工程］
　本工程は上記Ｃ－１工程で得られた化合物ｃ２を、種々の塩基存在下、適当な溶媒中、ｃ８を用いて対応するチオエステルｃ３を製造する工程である。本工程において使用される塩基は、後記に例示する塩基等から選択されるが、好ましくはトリエチルアミン又はジイソプロピルエチルアミン等が挙げられる。本工程において使用される溶媒は、後記に例示する溶媒等から選択されるが好ましくはテトラヒドロフラン又はジクロロメタンが挙げられる。 [Step C-2]
This step is a step for producing the corresponding thioester c3 from compound c2 obtained in the above step C-1 using c8 in the presence of various bases in an appropriate solvent. The base used in this step is selected from the bases exemplified below, and preferably triethylamine or diisopropylethylamine is used. The solvent used in this step is selected from the solvents exemplified below, and preferably tetrahydrofuran or dichloromethane.
［Ｃ－３工程］
　本工程は上記Ｃ－２工程で得られた化合物ｃ３に触媒及び有機リン化合物存在下又は非存在下、ボロン酸化合物ｃ９とカップリングし化合物ｃ４を得る工程である。触媒としては、パラジウム及び銅などの遷移金属やその塩、その錯体、ポリマーなどの担体に担持させたものを挙げられる。本工程において使用される有機リン化合物は、好ましくは亜リン酸トリエチル等が挙げられる。本工程において使用される溶媒は、後記に例示する溶媒等から選択されるが、好ましくはテトラヒドロフランが挙げられる。本反応は、Journal of American Chemical Society 2007, 129(5）,1132-1140、 Bioorganic Medicinal Chemistry Letters 2007, 17, 5647-5651 に記載されている方法が挙げられる。 [Step C-3]
This step is a step of coupling compound c3 obtained in step C-2 with boronic acid compound c9 in the presence or absence of a catalyst and an organophosphorus compound to obtain compound c4. Examples of the catalyst include those supported on a carrier such as transition metals such as palladium and copper, salts thereof, complexes thereof, and polymers. The organophosphorus compound used in this step is preferably triethyl phosphite. The solvent used in this step is selected from the solvents exemplified below, and preferably includes tetrahydrofuran. Examples of the reaction include those described in Journal of American Chemical Society 2007, 129 (5), 1132-1140, Bioorganic Medicinal Chemistry Letters 2007, 17, 5647-5651.
［Ｃ－４工程］
　本工程は上記Ｃ－３工程で得られた化合物ｃ４を、上記Ａ－１１工程に準じた条件で化合物ｃ５へ変換する工程である。 [Step C-4]
This step is a step of converting the compound c4 obtained in the step C-3 to the compound c5 under the conditions according to the step A-11.
［Ｃ－５工程］
　本工程は上記Ｃ－４工程で得られた化合物ｃ５を、上記Ａ－７工程に準じた条件で化合物ｃ６へ変換する工程である。Ｒ２が、水素原子である式（Ｉ）で表される化合物は本工程を実施しない。 [Step C-5]
This step is a step of converting the compound c5 obtained in the step C-4 into the compound c6 under the conditions according to the step A-7. The compound represented by the formula (I) in which R 2 is a hydrogen atom does not carry out this step.
［Ｃ－６工程］
　本工程は上記Ｃ－５工程で得られた化合物ｃ６を対応するアミン化合物ｃ７に変換する工程である。本工程はProtective Groups in Organic Synthesis（Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年）に記載されている方法等に準じて行うことができる。 [Step C-6]
This step is a step of converting the compound c6 obtained in the step C-5 to the corresponding amine compound c7. This step can be carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).
［Ｃ－７工程］
　本工程は上記Ｃ－６工程で得られた化合物ｃ７に、種々の縮合剤又は塩基存在下、適当な溶媒中、化合物ｃ１０又はｃ１１を反応させることにより、化合物Ｃ１を得る工程である。本工程において使用される縮合剤は、常法で使用される種々の縮合剤を使用することができるが、好ましくは１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド（塩酸塩を含む）が挙げられる。また使用される塩基は、後記に例示する塩基等から選択されるが、好ましくはジイソプロピルエチルアミン又はトリエチルアミンが挙げられる。本工程において使用される溶媒は、後記に例示する溶媒等から選択されるが、好ましくはジメチルホルムアミド又はテトラヒドロフランが挙げられる。
　Ｒ７が、水素原子でない式［Ｃ１］で表される化合物も上記方法に準じた方法により製造することができる。 [Step C-7]
This step is a step of obtaining compound C1 by reacting compound c7 obtained in step C-6 with compound c10 or c11 in a suitable solvent in the presence of various condensing agents or bases. As the condensing agent used in this step, various condensing agents used in a conventional method can be used, but 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (including hydrochloride) is preferable. Is mentioned. The base used is selected from the bases exemplified below, and preferably diisopropylethylamine or triethylamine. The solvent used in this step is selected from the solvents exemplified below, and preferably dimethylformamide or tetrahydrofuran.
A compound represented by the formula [C1] in which R 7 is not a hydrogen atom can also be produced by a method according to the above method.
製造法Ｃ ２
　式（Ｉ）で表される化合物のうち、Ｘ－Ｙ－ＺがＣＲ６－ＮＲ７－ＣＯＮＲ４ＡＲ４Ｂであり、ＷがＣＨである式［Ｃ２］及び［Ｃ３］で表される化合物Ｃ２及びＣ３は、例えば下記の製法によって製造することができる。
Figure JPOXMLDOC01-appb-C000010
 （式中、Ａ、Ｒ１Ａ～Ｒ１Ｄ、Ｒ２、Ｒ３Ａ～Ｒ３Ｄ、Ｒ４Ａ、Ｒ４Ｂ、Ｒ６、Ｒ７及びｎは項１に定義されるとおりであり、Ｒxはハロゲン、ニトロ等の電子吸引基または水素原子であり、Ｘはハロゲン等の脱離基である。） Production method C 2
Of the compounds represented by the formula (I), the compound C2 represented by the formulas [C2] and [C3] in which XYZ is CR 6 —NR 7 —CONR 4A R 4B and W is CH. And C3 can be produced, for example, by the following production method.
Figure JPOXMLDOC01-appb-C000010
 (In the formula, A, R 1A to R 1D , R 2 , R 3A to R 3D , R 4A , R 4B , R 6 , R 7 and n are as defined in Item 1, Rx is halogen, nitro An electron withdrawing group such as hydrogen atom or a hydrogen atom, and X is a leaving group such as halogen.)
［Ｃ－８工程］
　本工程は上記Ｃ－６工程で得られた化合物ｃ７を、上記Ａ－６工程に準じた条件で化合物Ｃ２へ変換する工程である。 [Step C-8]
This step is a step of converting the compound c7 obtained in the step C-6 to the compound C2 under the conditions according to the step A-6.
［Ｃ－９工程］
　本工程は上記Ｃ－８工程で得られた化合物Ｃ２に、種々の塩基存在下、適当な溶媒中、化合物ｃ１２を反応させることにより、化合物Ｃ３を得る工程である。本工程において使用される塩基は、後記に例示する塩基等から選択されるが、好ましくはジイソプロピルアミン又はトリエチルアミンが挙げられる。本工程において使用される溶媒は、後記に例示する溶媒等から選択されるが、好ましくはジメチルホルムアミド又はテトラヒドロフランが挙げられる。 [Step C-9]
This step is a step of obtaining compound C3 by reacting compound c2 obtained in step C-8 with compound c12 in the presence of various bases in an appropriate solvent. The base used in this step is selected from the bases exemplified below, and preferably diisopropylamine or triethylamine. The solvent used in this step is selected from the solvents exemplified below, and preferably dimethylformamide or tetrahydrofuran.
　上記の各製造法の各工程において使用される塩基は、反応や原料化合物の種類等によって適時選択されるべきであるが、例えば重炭酸ナトリウム、重炭酸カリウムのような重炭酸アルカリ類、炭酸ナトリウム、炭酸カリウムのような炭酸アルカリ類、水素化ナトリウム、水素化カリウムのような金属水素化類、水酸化ナトリウム、水酸化カリウムのようなアルカリ金属水酸化物、ナトリウムメトキシド、ナトリウムｔ-ブトキシドのようなアルカリ金属アルコキシド類、ブチルリチウム、リチウムジイソプロピルアミドのような有機金属塩基類、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、４－ジメチルアミノピリジン（ＤＭＡＰ）、１，８－ジアザビシクロ［５．４．０］－７－ウンデセン（ＤＢＵ）のような有機塩基類が挙げられる。 The base used in each step of each of the above production methods should be selected as appropriate depending on the reaction and the type of raw material compound. For example, alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate, sodium carbonate , Alkali carbonates such as potassium carbonate, metal hydrides such as sodium hydride and potassium hydride, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium methoxide, sodium t-butoxide Alkali metal alkoxides, organometallic bases such as butyl lithium and lithium diisopropylamide, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo [5.4.0]- Organic bases such as 7-undecene (DBU) Is mentioned.
　上記の各製造法の各工程において使用される溶媒は、反応や原料化合物の種類等によって適時選択されるべきであるが、例えばメタノール、エタノール、イソプロパノールのようなアルコール類、アセトン、メチルケトンのようなケトン類、塩化メチレン、クロロホルムのようなハロゲン化炭化水素類、テトラヒドロフラン（ＴＨＦ）、ジオキサンのようなエーテル類、トルエン、ベンゼンのような芳香族炭化水素類、ヘキサン、ヘプタンのような脂肪族炭化水素類、酢酸エチル、酢酸プロピルのようなエステル類、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、Ｎ－メチル－２－ピロリドンのようなアミド類、ジメチルスルホキシド（ＤＭＳＯ）のようなスルホキシド類、アセトニトリルのようなニトリル類が挙げられ、これらの溶媒は単独又は２種類以上混合して用いることができる。また反応の種類によっては、有機塩基類を溶媒として用いてもよい。 The solvent used in each step of each of the above production methods should be selected as appropriate depending on the reaction and the type of raw material compound. For example, alcohols such as methanol, ethanol and isopropanol, acetone and methyl ketone, etc. Ketones, halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as tetrahydrofuran (THF) and dioxane, aromatic hydrocarbons such as toluene and benzene, aliphatic hydrocarbons such as hexane and heptane , Esters such as ethyl acetate, propyl acetate, amides such as N, N-dimethylformamide (DMF), N-methyl-2-pyrrolidone, sulfoxides such as dimethyl sulfoxide (DMSO), and acetonitrile Nitriles, and these solvents are simple Or it may be used by mixing 2 or more kinds. Depending on the type of reaction, organic bases may be used as a solvent.
　式（Ｉ）で表される本発明化合物又はその中間体は、当業者にとって公知の方法で分離、精製することができる。例えば、抽出、分配、再沈殿、カラムクロマトグラフィー（例えば、シリカゲルカラムクロマトグラフィー、イオン交換カラムクロマトグラフィー若しくは分取液体クロマトグラフィー）又は再結晶などが挙げられる。再結晶溶媒としては例えば、メタノール、エタノール、２－プロパノール等のアルコール系溶媒、ジエチルエーテル等のエーテル系溶媒、酢酸エチル等のエステル系溶媒、ベンゼン、トルエン等の芳香族炭化水素系溶媒、アセトン等のケトン系溶媒、ジクロロメタン、クロロホルム等のハロゲン系溶媒、ヘキサン等の炭化水素系溶媒、ジメチルホルムアミド、アセトニトリル等の非プロトン系溶媒、水、又は上記溶媒から選択される２種以上の混合溶媒などを用いることができる。その他の精製方法としては、実験化学講座（日本化学会編、丸善）１巻などに記載された方法などを用いることができる。 The compound of the present invention represented by formula (I) or an intermediate thereof can be separated and purified by methods known to those skilled in the art. Examples include extraction, distribution, reprecipitation, column chromatography (for example, silica gel column chromatography, ion exchange column chromatography or preparative liquid chromatography) or recrystallization. Examples of the recrystallization solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as benzene and toluene, acetone and the like. Ketone solvents, halogen solvents such as dichloromethane and chloroform, hydrocarbon solvents such as hexane, aprotic solvents such as dimethylformamide and acetonitrile, water, or a mixed solvent of two or more selected from the above solvents Can be used. As other purification methods, the methods described in Experimental Chemistry Course (The Chemical Society of Japan, Maruzen) vol. 1 can be used.
　式（Ｉ）で表される本発明化合物またそれらの薬学的に許容される塩には、不斉が生じる場合又は不斉炭素を有する置換基を有する場合があり、そのような化合物にあっては光学異性体が存在する。本発明化合物にはこれらの各異性体の混合物や単離されたものも含まれ、通常の方法に従って製造することができる。製造方法としては例えば、不斉点を有する原料を用いる方法か、又は途中の段階で不斉を導入する方法が挙げられる。例えば、光学異性体の場合、光学活性な原料を用いるか、製造工程の適当な段階で光学分割などを行うことで、光学異性体を得ることができる。光学分割法としては例えば、式（Ｉ）で表される化合物又はその中間体が、塩基性官能基を有する場合には、不活性溶媒中（例えばメタノール、エタノール、２－プロパノール等のアルコール系溶媒、ジエチルエーテル等のエーテル系溶媒、酢酸エチル等のエステル系溶媒、トルエン等の炭化水素系溶媒、アセトニトリル等の非プロトン系溶媒、又は上記溶媒から選択される２種以上の混合溶媒）、光学活性な酸（例えば、マンデル酸、Ｎ－ベンジルオキシアラニン、乳酸等のモノカルボン酸、酒石酸、ｏ－ジイソプロピリデン酒石酸、リンゴ酸等のジカルボン酸、カンファースルフォン酸、ブロモカンファースルホン酸等のスルホン酸）を用いて塩を形成させるジアステレオマー法が挙げられる。式（Ｉ）で表される本発明化合物の中間体が、カルボキシル基などの酸性官能基を有する場合には、光学活性なアミン（例えば１－フェニルエチルアミン、キニン、キニジン、シンコニジン、シンコニン、ストリキニーネ等の有機アミン）を用いて、塩を形成させることにより、光学分割を行うこともできる。 The compound of the present invention represented by the formula (I) or a pharmaceutically acceptable salt thereof may have an asymmetry or may have a substituent having an asymmetric carbon. Has optical isomers. The compounds of the present invention include mixtures of these isomers and isolated ones, which can be produced according to ordinary methods. Examples of the production method include a method using a raw material having an asymmetric point, or a method of introducing asymmetry at an intermediate stage. For example, in the case of optical isomers, optical isomers can be obtained by using optically active raw materials or by performing optical resolution at an appropriate stage of the production process. As the optical resolution method, for example, when the compound represented by the formula (I) or an intermediate thereof has a basic functional group, an alcohol solvent such as methanol, ethanol, 2-propanol or the like is used. An ether solvent such as diethyl ether, an ester solvent such as ethyl acetate, a hydrocarbon solvent such as toluene, an aprotic solvent such as acetonitrile, or a mixed solvent of two or more selected from the above solvents), optical activity (For example, monocarboxylic acids such as mandelic acid, N-benzyloxyalanine and lactic acid, tartaric acid, dicarboxylic acids such as o-diisopropylidene tartaric acid and malic acid, and sulfonic acids such as camphorsulfonic acid and bromocamphorsulfonic acid) And a diastereomer method in which a salt is formed using. When the intermediate of the compound of the present invention represented by the formula (I) has an acidic functional group such as a carboxyl group, an optically active amine (for example, 1-phenylethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine, etc.) The optical resolution can also be carried out by forming a salt using an organic amine).
　塩を形成させる温度としては、室温から溶媒の沸点までの範囲から選択される。光学純度を向上させるためには、一旦、溶媒の沸点付近まで温度を上げることが望ましい。析出した塩を濾取する際、必要に応じて冷却し、収率を向上させることができる。光学活性な酸又はアミンの使用量は、基質に対し約０．５～約２．０当量の範囲、好ましくは１当量前後の範囲が適当である。必要に応じ結晶を不活性溶媒中（例えばメタノール、エタノール、２－プロパノール等のアルコール系溶媒、ジエチルエーテル等のエーテル系溶媒、酢酸エチル等のエステル系溶媒、トルエン等の炭化水素系溶媒、アセトニトリル等の非プロトン系溶媒、又は上記溶媒から選択される２種以上の混合溶媒）で再結晶し、高純度の光学活性な塩を得ることもできる。また、必要に応じて光学分割した塩を通常の方法で酸又は塩基で処理し、フリー体として得ることもできる。 The temperature at which the salt is formed is selected from the range from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to raise the temperature once to near the boiling point of the solvent. When the precipitated salt is collected by filtration, it can be cooled as necessary to improve the yield. The amount of the optically active acid or amine used is suitably in the range of about 0.5 to about 2.0 equivalents, preferably in the range of about 1 equivalent, relative to the substrate. Crystals in an inert solvent as necessary (for example, alcohol solvents such as methanol, ethanol, 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, hydrocarbon solvents such as toluene, acetonitrile, etc. Or a mixed solvent of two or more selected from the above solvents) to obtain a highly pure optically active salt. Further, if necessary, an optically resolved salt can be treated with an acid or a base by a conventional method to obtain a free form.
　本発明の化合物は、神経系疾患、精神疾患及び炎症性疾患（例えば、認知症、統合失調症、ＣＩＡＳ（統合失調症に伴う認知機能障害）、アルツハイマー病、ダウン症、注意欠陥障害、脳血管アンギオパチー等）の新規な治療剤及び／又は予防剤となり得る。本発明の化合物の投与経路としては、経口投与、非経口投与又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。例えば、経口投与の場合は、通常、ヒト又は哺乳動物１ｋｇ体重当たり約０．０１～１０００ｍｇ、更に好ましくは約０．１～５００ｍｇを１～数回に分けて投与することができる。静注等の非経口投与の場合は、通常、例えば、ヒト又は哺乳動物１ｋｇ体重当たり約０．０１ｍｇ～３００ｍｇ、更に好ましくは約１ｍｇ～１００ｍｇを投与することができる。 The compounds of the present invention can be used for nervous system diseases, mental disorders and inflammatory diseases (eg, dementia, schizophrenia, CIAS (cognitive impairment associated with schizophrenia), Alzheimer's disease, Down's syndrome, attention deficit disorder, cerebrovascular angiopathy Etc.) and can be used as novel therapeutic agents and / or preventive agents. The administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration, and the daily dose varies depending on the type of compound, administration method, patient symptom / age and the like. For example, in the case of oral administration, usually about 0.01 to 1000 mg, more preferably about 0.1 to 500 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 0.01 mg to 300 mg, more preferably about 1 mg to 100 mg per kg body weight of a human or mammal can be administered.
　剤型としては、錠剤、カプセル剤、顆粒剤、散剤、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従って調製することができる。なお、液体製剤にあっては、用時、水、適当な水溶液又は他の適当な媒体に溶解又は懸濁する形であってもよい。また、錠剤及び顆粒剤は周知の方法でコーティングしてもよい。更に、これらの製剤は治療上価値ある他の成分を含有してもよい。 Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, injections, suppositories, eye drops, ointments, coatings, patches, inhalants and the like. These preparations can be prepared according to a conventional method. In the case of a liquid preparation, it may be dissolved or suspended in water, an appropriate aqueous solution or other appropriate medium at the time of use. Tablets and granules may be coated by a known method. In addition, these formulations may contain other therapeutically valuable ingredients.
　本発明の化合物は、非定型抗精神病薬に分類される薬剤と併用することができる。非定型抗精神病薬としては、例えば、オランザピン、リスペリドン、パリペリドン、ケチアピン、ジプラシドン、アリピプラゾール、アセナピン、イロペリドン、クロザピン、セルティンドール、ブロナンセリン及びルラシドンが挙げられる。 The compound of the present invention can be used in combination with drugs classified as atypical antipsychotic drugs. Examples of atypical antipsychotics include olanzapine, risperidone, paliperidone, quetiapine, ziprasidone, aripiprazole, asenapine, iloperidone, clozapine, sertindole, blonanserin and lurasidone.
　以下に参考例、実施例及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。なお、化合物の同定は元素分析値、マス・スペクトル、高速液体クロマト質量分析計；ＬＣＭＳ、ＩＲスペクトル、ＮＭＲスペクトル、高速液体クロマトグラフィー（ＨＰＬＣ）等により行った。 Hereinafter, the present invention will be described more specifically with reference to reference examples, examples and test examples, but these examples do not limit the present invention. The compound was identified by elemental analysis, mass spectrum, high performance liquid chromatography / mass spectrometer; LCMS, IR spectrum, NMR spectrum, high performance liquid chromatography (HPLC) and the like.
　明細書の記載を簡略化するために参考例、実施例及び実施例中の表において以下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、Ｐｈはフェニルを意味する。ＴＦＡはトリフルオロ酢酸を意味する。ＮＭＲに用いられる記号としては、ｓは一重線、ｄは二重線、ｄｄは二重の二重線、ｔは三重線、ｔｄは三重線の二重線、ｑは四重線、ｍは多重線、ｂｒは幅広い、ｂｒｓは幅広い一重線、ｂｒｓは幅広い多重線及びＪは結合定数を意味する。 In order to simplify the description of the specification, the following abbreviations may be used in the reference examples, examples, and tables in the examples. As abbreviations used as substituents, Me means methyl and Ph means phenyl. TFA means trifluoroacetic acid. The symbols used in NMR are as follows: s is a single line, d is a double line, dd is a double double line, t is a triple line, td is a triple double line, q is a quadruple line, m is Multiple line, br is broad, brs is wide single line, brs is wide multiple line, and J is coupling constant.
　高速液体クロマト質量分析計；ＬＣＭＳの測定条件は、以下の通りであり、観察された質量分析の値［ＭＳ（ｍ／ｚ）］をＭＨ＋で、保持時間をＲｔ（分）で示す。なお、各実測値においては、測定に用いた測定条件をＡ～Ｃで付記する。 High-performance liquid chromatograph / mass spectrometer: The measurement conditions of LCMS are as follows, and the observed mass spectrometry value [MS (m / z)] is represented by MH + and the retention time is represented by Rt (minutes). In each actual measurement value, the measurement conditions used for measurement are indicated by A to C.
測定条件Ａ：
検出機器：APIシリーズ用Agilent 1100シリーズ (applied Biosystems社製)
ＨＰＬＣ：API 150EX LC/MS system (applied Biosystems社製)
Ｃｏｌｕｍｎ：YMC CombiScreen Hydrosphere C18 (S-5μM, 12 nm, 4.6×50 mm)
Ｓｏｌｖｅｎｔ：Ａ液：0.05 % TFA／H2O、Ｂ液：0.05 % TFA／MeOH
Ｇｒａｄｉｅｎｔ Ｃｏｎｄｉｔｉｏｎ：
　　0.0-6.0分；Ａ／Ｂ＝75：25～1：99（linear gradient）
Ｆｌｏｗ ｒａｔｅ：3.5 mL／分
ＵＶ：254 nm Measurement condition A:
Detection equipment: Agilent 1100 series for API series (Applied Biosystems)
HPLC: API 150EX LC / MS system (Applied Biosystems)
Column: YMC CombiScreen Hydrosphere C18 (S-5μM, 12 nm, 4.6 × 50 mm)
Solvent: Liquid A: 0.05% TFA / H 2 O, Liquid B: 0.05% TFA / MeOH
Gradient Condition:
0.0-6.0 min; A / B = 75: 25 to 1:99 (linear gradient)
Flow rate: 3.5 mL / min UV: 254 nm
測定条件Ｂ：
検出機器：APIシリーズ用Agilent 1100シリーズ (applied Biosystems社製)
ＨＰＬＣ：API 150EX LC/MS system (applied Biosystems社製)
Ｃｏｌｕｍｎ：YMC CombiScreen Hydrosphere C18 (S-5μM, 12 nm, 4.6×50 mm)
Ｓｏｌｖｅｎｔ：Ａ液：0.05 % TFA／H2O、Ｂ液：0.05 % TFA／MeOH
Ｇｒａｄｉｅｎｔ Ｃｏｎｄｉｔｉｏｎ：
　　0.0-6.0分；Ａ／Ｂ＝90：10～1：99（linear gradient）
Ｆｌｏｗ ｒａｔｅ：3.5 mL／分
ＵＶ：254、220 nm Measurement condition B:
Detection equipment: Agilent 1100 series for API series (Applied Biosystems)
HPLC: API 150EX LC / MS system (Applied Biosystems)
Column: YMC CombiScreen Hydrosphere C18 (S-5μM, 12 nm, 4.6 × 50 mm)
Solvent: Liquid A: 0.05% TFA / H 2 O, Liquid B: 0.05% TFA / MeOH
Gradient Condition:
0.0-6.0 min; A / B = 90: 10 to 1:99 (linear gradient)
Flow rate: 3.5 mL / min UV: 254, 220 nm
測定条件Ｃ：
検出機器, ＨＰＬＣ：LCMS-2010EV (島津社製)
Ｃｏｌｕｍｎ：Xtimate (3μM, 2.1×30 mm) (Welch Materials社製)
Ｓｏｌｖｅｎｔ：Ａ液：0.019 % TFA／H2O、Ｂ液：0.038 % TFA／MeOH
Ｇｒａｄｉｅｎｔ Ｃｏｎｄｉｔｉｏｎ：
　　0.0-1.35分；Ａ／Ｂ＝90：10～20：80（linear gradient）
    1.35-2.25分；Ａ／Ｂ＝20：80
Ｆｌｏｗ ｒａｔｅ：0.8 mL/分
ＵＶ：220 nm
カラム温度：50℃ Measurement condition C:
Detector, HPLC: LCMS-2010EV (Shimadzu)
Column: Xtimate (3μM, 2.1 × 30 mm) (Welch Materials)
Solvent: Liquid A: 0.019% TFA / H 2 O, Liquid B: 0.038% TFA / MeOH
Gradient Condition:
0.0-1.35 minutes; A / B = 90: 10-20: 80 (linear gradient)
1.35-2.25 minutes; A / B = 20: 80
Flow rate: 0.8 mL / min UV: 220 nm
Column temperature: 50 ° C
測定条件Ｄ：
検出機器：Perkin-Elmer Sciex API 150EX Massspectrometer（40eV）
ＨＰＬＣ：Shimadzu LC 10ATVP
Ｃｏｌｕｍｎ：Shiseido CAPCELL PAK C18 ACR（S-5μm，4.6 mm×50 mm）
Ｓｏｌｖｅｎｔ：Ａ液：0.035 % TFA／CH3CN、Ｂ液：0.05 % TFA／H2O
Ｇｒａｄｉｅｎｔ Ｃｏｎｄｉｔｉｏｎ：
　　0.0-0.5分；Ａ／Ｂ＝1：99
　　0.5-4.8分；Ａ／Ｂ＝99：1
　　4.8-5.0分；Ａ／Ｂ＝99：1
Ｆｌｏｗ ｒａｔｅ：3.5 mL／分
ＵＶ：220 nm
カラム温度：40℃ Measurement condition D:
Detection equipment: Perkin-Elmer Sciex API 150EX Massspectrometer (40eV)
HPLC: Shimadzu LC 10ATVP
Column: Shiseido CAPCELL PAK C18 ACR (S-5μm, 4.6 mm x 50 mm)
Solvent: Liquid A: 0.035% TFA / CH 3 CN, Liquid B: 0.05% TFA / H 2 O
Gradient Condition:
0.0-0.5 min; A / B = 1: 99
0.5-4.8 min; A / B = 99: 1
4.8-5.0 min; A / B = 99: 1
Flow rate: 3.5 mL / min UV: 220 nm
Column temperature: 40 ° C
測定条件Ｅ：
検出機器：島津 LCMS-2020
Ｃｏｌｕｍｎ：Phenomenex Kinetex（1.7μm C18，50 mm×2.10 mm）
Ｓｏｌｖｅｎｔ：Ａ液：MeOH、Ｂ液：0.05 % TFA／H2O
Ｇｒａｄｉｅｎｔ Ｃｏｎｄｉｔｉｏｎ：
　　0.0分；Ａ／Ｂ＝３０：７０
　　0.0-1.9分；Ａ／Ｂ＝99：1
　　1.9-3.0分；Ａ／Ｂ＝30：70
Ｆｌｏｗ ｒａｔｅ：0.5 mL／分
ＵＶ：220 nm
カラム温度：40℃ Measurement condition E:
Detector: Shimadzu LCMS-2020
Column: Phenomenex Kinetex (1.7μm C18, 50 mm x 2.10 mm)
Solvent: A solution: MeOH, B solution: 0.05% TFA / H 2 O
Gradient Condition:
0.0 min; A / B = 30: 70
0.0-1.9 min; A / B = 99: 1
1.9-3.0 minutes; A / B = 30: 70
Flow rate: 0.5 mL / min UV: 220 nm
Column temperature: 40 ° C
測定条件Ｆ：
ＬＣＭＳ：Waters ACQUITY UltraPerfomanc LC-PDA-ELSD-SQD
Ｃｏｌｕｍｎ：
Waters ACQUITY UPLC BEH C18 1.7 m, 2.1×30 mm（Part．No.186002349）
Ｓｏｌｖｅｎｔ：Ａ液：0.05 %ギ酸／H2O、Ｂ液：CH3CN
Ｇｒａｄｉｅｎｔ Ｃｏｎｄｉｔｉｏｎ：
　　0.0分；Ａ／Ｂ＝90：10
　　0.0-1.3分；Ａ／Ｂ＝5：95
Ｆｌｏｗ ｒａｔｅ：0.80 mL／分
ＵＶ：220、254 nm
カラム温度：40℃ Measurement condition F:
LCMS: Waters ACQUITY UltraPerfomanc LC-PDA-ELSD-SQD
Column:
Waters ACQUITY UPLC BEH C18 1.7 m, 2.1 × 30 mm (Part. No.186002349)
Solvent: A solution: 0.05% formic acid / H 2 O, B solution: CH 3 CN
Gradient Condition:
0.0 min; A / B = 90: 10
0.0-1.3 min; A / B = 5: 95
Flow rate: 0.80 mL / min UV: 220, 254 nm
Column temperature: 40 ° C
測定条件Ｇ：(２ＦＬＣＭＳ)
ＬＣＭＳ：Waters ACQUITYTM UltraPerformance LC
Ｃｏｌｕｍｎ：Waters ACQUITY UPLC BEH Phenyl 1.7μm 2.1×50 mm
Ｓｏｌｖｅｎｔ：Ａ液:0.05 %ギ酸／H2O、Ｂ液:0.05 %ギ酸／CH3CN
Ｇｒａｄｉｅｎｔ Ｃｏｎｄｉｔｉｏｎ：
　　0.0分；Ａ／Ｂ＝90：10
　　0.0-1.5分；Ａ／Ｂ＝1：99
　　1.5-2.0分；Ａ／Ｂ＝90：10
Ｆｌｏｗ ｒａｔｅ：0.75 mL／分
ＵＶ：220、254 nm
カラム温度：40℃ Measurement condition G: (2FLCMS)
LCMS: Waters ACQUITYTM UltraPerformance LC
Column: Waters ACQUITY UPLC BEH Phenyl 1.7μm 2.1 × 50 mm
Solvent: A solution: 0.05% formic acid / H 2 O, B solution: 0.05% formic acid / CH 3 CN
Gradient Condition:
0.0 min; A / B = 90: 10
0.0-1.5 min; A / B = 1: 99
1.5-2.0 minutes; A / B = 90: 10
Flow rate: 0.75 mL / min UV: 220, 254 nm
Column temperature: 40 ° C
測定条件Ｈ：
ＬＣＭＳ：島津LCMS-2010EV
Ｃｏｌｕｍｎ：Shiseido CAPCELL PAK C18 MGII（4.6 mm×50 mm）
Ｓｏｌｖｅｎｔ：Ａ液：MeOH、Ｂ液：0.05 % TFA／H2O
Ｇｒａｄｉｅｎｔ Ｃｏｎｄｉｔｉｏｎ：
　　0.0-1.0分；Ａ／Ｂ＝30：70
　　1.0-7.0分；Ａ／Ｂ＝99：1
　　7.1-12.0分；Ａ／Ｂ＝30：70
Ｆｌｏｗ ｒａｔｅ：2.8 mL／分
ＵＶ：220 nm
カラム温度：40℃ Measurement condition H:
LCMS: Shimadzu LCMS-2010EV
Column: Shiseido CAPCELL PAK C18 MGII (4.6 mm x 50 mm)
Solvent: A solution: MeOH, B solution: 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 minutes; A / B = 30: 70
Flow rate: 2.8 mL / min UV: 220 nm
Column temperature: 40 ° C
参考例１
６－フルオロ－３－（４－ピペリジニル）－１Ｈ－インダゾール
Figure JPOXMLDOC01-appb-C000011
 Reference example 1
6-Fluoro-3- (4-piperidinyl) -1H-indazole
Figure JPOXMLDOC01-appb-C000011
ａ）フェニル ４－（２，４－ジフルオロベンゾイル）ピペリジン－１－カルボキシレート（化合物Ｑ１）の製造
　（２，４－ジフルオロフェニル）（１－メチル－４－ピペリジニル)メタノン（1.31 g）のトルエン溶液（25 ml）にクロロ炭酸フェニル（0.861 g）を加え、次いで、炭酸カリウム（0.829 g）を加えて９０℃で２時間加熱攪拌した。反応終了後、酢酸エチル－飽和炭酸水素ナトリウム水溶液で分液抽出し、有機層を硫酸ナトリウムで乾燥後、減圧留去した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：メタノール＝１００：３）で精製することにより化合物Ｑ１（0.722 g）を得た。
1H-NMR (400 MHz, CDCl3): 1.76 (2H, brs), 2.00 (2H, brm), 3.08-3.11 (1H, brm), 3.36-3.32 (1H, brm), 4.32 (2H, brs), 6.94-6.86 (1H, m), 7.03-6.97 (1H, m), 7.11 (2H, m), 7.20 (1H, m), 7.36 (2H, m), 7.89 (1H, m). a) Preparation of phenyl 4- (2,4-difluorobenzoyl) piperidine-1-carboxylate (Compound Q1) (2,4-difluorophenyl) (1-methyl-4-piperidinyl) methanone (1.31 g) in toluene solution (25 ml) was added phenyl chlorocarbonate (0.861 g), then potassium carbonate (0.829 g) was added, and the mixture was stirred with heating at 90 ° C. for 2 hr. After completion of the reaction, the mixture was extracted with ethyl acetate-saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried over sodium sulfate and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; chloroform: methanol = 100: 3) to obtain Compound Q1 (0.722 g).
1 H-NMR (400 MHz, CDCl 3 ): 1.76 (2H, brs), 2.00 (2H, brm), 3.08-3.11 (1H, brm), 3.36-3.32 (1H, brm), 4.32 (2H, brs) , 6.94-6.86 (1H, m), 7.03-6.97 (1H, m), 7.11 (2H, m), 7.20 (1H, m), 7.36 (2H, m), 7.89 (1H, m).
ｂ）フェニル ４－（６－フルオロ－１Ｈ－インダゾール－３－イル）ピペリジン－１－カルボキシレート（化合物Ｑ２）の製造
　化合物Ｑ１（810 mg）のピリジン溶液（8 ml）にヒドラジン１水和物（234 mg）を加え、マイクロウエーブ照射下、１５０℃で１時間加熱攪拌した。反応終了後、酢酸エチル－水で分液抽出し、有機層を硫酸ナトリウムで乾燥後、減圧留去した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル＝１：１）で精製することにより化合物Ｑ２（390 mg）を得た。
1H-NMR (400 MHz, CDCl3): 2.10-2.07 (4H, brm), 3.28-3.22 (3H, brm), 4.43 (2H, brs), 6.93 (1H, m), 7.07 (3H, m), 7.22-7.13 (1H, m), 7.37 (2H, m), 7.70 (1H, m). b) Preparation of phenyl 4- (6-fluoro-1H-indazol-3-yl) piperidine-1-carboxylate (Compound Q2) Hydrazine monohydrate (8 ml) in a pyridine solution (8 ml) of Compound Q1 (810 mg) 234 mg) was added, and the mixture was heated and stirred at 150 ° C. for 1 hour under microwave irradiation. After completion of the reaction, the mixture was extracted with ethyl acetate-water, and the organic layer was dried over sodium sulfate and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 1: 1) to obtain Compound Q2 (390 mg).
1 H-NMR (400 MHz, CDCl 3 ): 2.10-2.07 (4H, brm), 3.28-3.22 (3H, brm), 4.43 (2H, brs), 6.93 (1H, m), 7.07 (3H, m) , 7.22-7.13 (1H, m), 7.37 (2H, m), 7.70 (1H, m).
ｃ）６－フルオロ－３－（４－ピペリジニル）－１Ｈ－インダゾール（参考例１）の製造
　化合物Ｑ２（630 mg）の水／エタノール溶液（19 mL／19 mL）に水酸化カリウム（3.12 g）を加え、９０℃で１５時間加熱攪拌した。反応終了後、酢酸エチル－水で分液抽出し、有機層を硫酸ナトリウムで乾燥後、減圧留去し、参考例１（350 mg）を得た。
1H-NMR (400 MHz, CDCl3): 1.93 (2H, m), 2.02 (2H, brm), 2.83 (2H, m), 3.18 (1H, m), 3.24 (2H, m), 6.91 (1H, td, J = 9.0, 9.0, 7.9 Hz), 7.09 (1H, dd, J = 9.0, 2.2 Hz), 7.73 (1H, dd, J = 9.0, 5.1 Hz). c) Preparation of 6-fluoro-3- (4-piperidinyl) -1H-indazole (Reference Example 1) Compound Q2 (630 mg) in water / ethanol solution (19 mL / 19 mL) and potassium hydroxide (3.12 g) And heated and stirred at 90 ° C. for 15 hours. After completion of the reaction, the mixture was extracted with ethyl acetate-water, and the organic layer was dried over sodium sulfate and evaporated under reduced pressure to give Reference Example 1 (350 mg).
1 H-NMR (400 MHz, CDCl 3 ): 1.93 (2H, m), 2.02 (2H, brm), 2.83 (2H, m), 3.18 (1H, m), 3.24 (2H, m), 6.91 (1H , td, J = 9.0, 9.0, 7.9 Hz), 7.09 (1H, dd, J = 9.0, 2.2 Hz), 7.73 (1H, dd, J = 9.0, 5.1 Hz).
参考例２
４－（１Ｈ－インダゾール－３－イル）シクロヘキサンカルボン酸
Figure JPOXMLDOC01-appb-C000012
 Reference example 2
4- (1H-indazol-3-yl) cyclohexanecarboxylic acid
Figure JPOXMLDOC01-appb-C000012
ａ）エチル ４－（トリフルオロメチルスルホニルオキシ）－３－シクロヘキセンカルボキシレート（化合物Ｑ３）の製造
　ピリジン（2.08 mL）のトルエン溶液（70 ml）に窒素雰囲気下、Ｔｆ２Ｏ（4.39 mL）を３０分で滴下した。反応溶液に、エチル－４－オキソシクロヘキサンカルボキシレート（4.00 g）のトルエン溶液（3.0 mL）を添加し、窒素雰囲気下、４０℃で１日加熱攪拌した。反応終了後、トルエン－水で分液抽出し、有機層を乾燥後、減圧留去した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル＝４：１）で精製することにより化合物Ｑ３（3.98 g）を得た。
1H-NMR (400 MHz, CDCl3): 1.24 (3H, t, J = 8.0 Hz), 1.89 (1H, m), 2.01 (1H, m), 2.38 (4H, brm), 2.56 (1H, m), 3.68 (1H, brs), 4.13 (2H, q, J = 8.0 Hz), 5.74 (1H, s)． a) Preparation of ethyl 4- (trifluoromethylsulfonyloxy) -3-cyclohexenecarboxylate (Compound Q3) Tf 2 O (4.39 mL) was added to a toluene solution (70 ml) of pyridine (2.08 mL) under a nitrogen atmosphere. Added dropwise in minutes. To the reaction solution was added a toluene solution (3.0 mL) of ethyl-4-oxocyclohexanecarboxylate (4.00 g), and the mixture was heated and stirred at 40 ° C. for 1 day under a nitrogen atmosphere. After completion of the reaction, the mixture was extracted with toluene-water, and the organic layer was dried and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 4: 1) to obtain Compound Q3 (3.98 g).
1 H-NMR (400 MHz, CDCl 3 ): 1.24 (3H, t, J = 8.0 Hz), 1.89 (1H, m), 2.01 (1H, m), 2.38 (4H, brm), 2.56 (1H, m ), 3.68 (1H, brs), 4.13 (2H, q, J = 8.0 Hz), 5.74 (1H, s).
ｂ）エチル ４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボラン－２－イル）－３－シクロヘキセンカルボキシレート（化合物Ｑ４）の製造
　化合物Ｑ３（3.15 g）のＤＭＳＯ溶液（40 ml）にビス(ピナコレート)ジボラン（2.51 g）、酢酸カリウム（3.06 g）及び１，１’－ビス（ジフェニルホスフィノ）フェロセンパラジウムジクロライド（458 mg）を添加後、窒素ガス雰囲気下５０℃にて３時間加熱攪拌した。反応終了後、酢酸エチル－水で分液抽出し、有機層を乾燥後、減圧留去した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル＝５：１）で精製することにより化合物Ｑ４（1.95 g）を得た。
1H-NMR (400 MHz, CDCl3): 1.22 (15H, m), 1.57 (1H, s), 1.97 (1H, s), 2.09 (1H, s), 2.22 (1H, s), 2.31 (2H, s), 2.46 (1H, s), 4.10 (2H, q, J = 7.1 Hz), 6.51 (1H, s). b) Preparation of ethyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) -3-cyclohexenecarboxylate (compound Q4) Compound Q3 (3.15 g) in DMSO (40 ml) was added with bis (pinacolato) diborane (2.51 g), potassium acetate (3.06 g) and 1,1′-bis (diphenylphosphino) ferrocene palladium dichloride (458 mg), and then at 50 ° C. under nitrogen gas atmosphere And stirred for 3 hours. After completion of the reaction, the mixture was extracted with ethyl acetate-water, and the organic layer was dried and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 5: 1) to obtain Compound Q4 (1.95 g).
1 H-NMR (400 MHz, CDCl 3 ): 1.22 (15H, m), 1.57 (1H, s), 1.97 (1H, s), 2.09 (1H, s), 2.22 (1H, s), 2.31 (2H , s), 2.46 (1H, s), 4.10 (2H, q, J = 7.1 Hz), 6.51 (1H, s).
ｃ）エチル ４－（３－１Ｈ－インダゾイル）―３－シクロヘキセンカルボキシレート（化合物Ｑ５）の製造
　化合物Ｑ４（1.57 g）の水／イソプロパノール溶液（4 mL／12 ml）に３－ヨードインダゾール（976 mg）、炭酸水素ナトリウム(672 mg)、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）ジクロライド（232 mg）を添加後、窒素ガス雰囲気下マイクロ波照射下、１４０℃にて１時間加熱攪拌した。反応終了後、濾過によりＰｄを取り除いた後、酢酸エチル－水で分液抽出し、有機層を乾燥後、減圧留去した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル＝４：３）で精製することにより化合物Ｑ５（769 mg）を得た。
1H-NMR (400 MHz, CDCl3): 1.27 (3H, t, J = 7.1 Hz), 1.83-1.93 (1H, brm), 2.23 (1H, m), 2.58 (2H, t, J = 9.5 Hz), 2.69 (2H, m), 2.89 (1H, m), 4.17 (2H, q, J = 7.2 Hz), 6.57 (1H, s), 7.17 (1H, t, J = 8.0 Hz), 7.37 (1H, t, J = 8.0 Hz), 7.45 (1H, d, J = 8.0 Hz), 7.92 (1H, d, J = 8.0 Hz). c) Preparation of ethyl 4- (3-1H-indazoyl) -3-cyclohexenecarboxylate (compound Q5) 3-iodoindazole (976 mg) in a water / isopropanol solution (4 mL / 12 ml) of compound Q4 (1.57 g) ), Sodium bicarbonate (672 mg) and bis (triphenylphosphine) palladium (II) dichloride (232 mg) were added, and the mixture was heated and stirred at 140 ° C. for 1 hour under microwave irradiation in a nitrogen gas atmosphere. After completion of the reaction, Pd was removed by filtration, followed by liquid separation extraction with ethyl acetate-water, and the organic layer was dried and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 4: 3) to obtain Compound Q5 (769 mg).
1 H-NMR (400 MHz, CDCl 3 ): 1.27 (3H, t, J = 7.1 Hz), 1.83-1.93 (1H, brm), 2.23 (1H, m), 2.58 (2H, t, J = 9.5 Hz ), 2.69 (2H, m), 2.89 (1H, m), 4.17 (2H, q, J = 7.2 Hz), 6.57 (1H, s), 7.17 (1H, t, J = 8.0 Hz), 7.37 (1H , t, J = 8.0 Hz), 7.45 (1H, d, J = 8.0 Hz), 7.92 (1H, d, J = 8.0 Hz).
ｄ）エチル ４－（３－１Ｈ－インダゾイル）シクロヘキサンカルボキシレート（化合物Ｑ６）の製造
　上記の実験で得られた化合物Ｑ５（1.48 g）のエタノール溶液（40 ml）に、酸化プラチナ（ＩＶ）（148 mg）を加え、４．５ａｔｍの水素ガス雰囲気下３日間、接触還元した。反応終了後、セライト濾過し、ろ液を減圧留去した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル＝３：１）で精製することにより化合物Ｑ６（961 mg）を得た。
1H-NMR (400 MHz, CDCl3): 1.22 (3H, t, J = 7.2 Hz), 1.67-2.21 (8H, brm), 2.67 (1H, m), 3.19 (1H, m), 4.16 (2H, q, J = 7.2 Hz), 7.12 (1H, m), 7.35 (1H, m), 7.43 (1H, d, J = 8.0 Hz), 7.74 (1H, d, J = 8.0 Hz). d) Preparation of ethyl 4- (3-1H-indazoyl) cyclohexanecarboxylate (Compound Q6) To an ethanol solution (40 ml) of Compound Q5 (1.48 g) obtained in the above experiment, platinum (IV) oxide (148 mg) was added, and catalytic reduction was performed in a hydrogen gas atmosphere of 4.5 atm for 3 days. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 3: 1) to obtain Compound Q6 (961 mg).
1 H-NMR (400 MHz, CDCl 3 ): 1.22 (3H, t, J = 7.2 Hz), 1.67-2.21 (8H, brm), 2.67 (1H, m), 3.19 (1H, m), 4.16 (2H , q, J = 7.2 Hz), 7.12 (1H, m), 7.35 (1H, m), 7.43 (1H, d, J = 8.0 Hz), 7.74 (1H, d, J = 8.0 Hz).
ｅ）４－（３－１Ｈ－インダゾイル）シクロヘキサンカルボン酸（参考例２）の製造
　上記の実験で得られた化合物Ｑ６（757 mg）のエタノール溶液（8.5 ml）に、２ｍｏｌ／Ｌの水酸化ナトリウム水溶液（4.17 mL）を加え、室温にて１日攪拌した。反応終了後、水に注ぎ、酢酸エチルで洗浄した。水層を１０％クエン酸水溶液で酸性にした後、酢酸エチルで抽出した。有機層を乾燥後、減圧留去することにより参考例２（676 mg）を得た。
1H-NMR (400 MHz, CD3OD): 1.76-2.26 (8H, brm), 3.17 (1H, m), 3.72 (1H, m), 3.92-3.89 (1H, m), 5.46 (1H, m), 7.07 (1H, m), 7.33 (1H, m), 7.44 (1H, d, J = 8.3 Hz),7.75 (1H, d, J = 8.3 Hz). e) Preparation of 4- (3-1H-indazoyl) cyclohexanecarboxylic acid (Reference Example 2) 2 mol / L sodium hydroxide was added to an ethanol solution (8.5 ml) of compound Q6 (757 mg) obtained in the above experiment. Aqueous solution (4.17 mL) was added, and the mixture was stirred at room temperature for 1 day. After completion of the reaction, it was poured into water and washed with ethyl acetate. The aqueous layer was acidified with 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer was dried and evaporated under reduced pressure to give Reference Example 2 (676 mg).
1 H-NMR (400 MHz, CD 3 OD): 1.76-2.26 (8H, brm), 3.17 (1H, m), 3.72 (1H, m), 3.92-3.89 (1H, m), 5.46 (1H, m ), 7.07 (1H, m), 7.33 (1H, m), 7.44 (1H, d, J = 8.3 Hz), 7.75 (1H, d, J = 8.3 Hz).
参考例３
シス－４－（３－インダゾイル）シクロヘキシルアミン（参考例３）
Figure JPOXMLDOC01-appb-C000013
 Reference example 3
Cis-4- (3-indazoyl) cyclohexylamine (Reference Example 3)
Figure JPOXMLDOC01-appb-C000013
ａ）フェニル シス－Ｓ－４－（ベンジルオキシカルボニル）シクロヘキサンチオカルボキシレート（化合物Ｑ７）の製造
　４－（ベンジルオキシカルボニル）シクロヘキサンカルボン酸（832 mg）のＣＨ２Ｃｌ２溶液（15.0 ml）に０℃にて、オキサリルクロライド（399 μL）を滴下した。反応溶液に室温下、少量のＤＭＦ溶液を加え、室温にて１時間攪拌した。溶媒を減圧留去後、ＴＨＦ（12.0 mL）、チオフェノール（314 μL）及びトリエチルアミン（1.35 mL）を添加し、室温にて１．５時間攪拌した。反応終了後、酢酸エチル－水で分液抽出し、得られた有機層を飽和食塩水で洗浄した後、硫酸ナトリウムで乾燥した。溶媒を減圧留去した後、得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル＝３：１）で精製することにより化合物Ｑ７（1.16 g）を得た。
1H-NMR (400 MHz, CDCl3)：1.75-1.84 (8H, brm), 2.74 (1H, s), 3.75 (1H, s), 4.81 (1H, s), 5.07 (2H, s), 7.31-7.39 (10H, brm). a) Preparation of phenyl cis-S-4- (benzyloxycarbonyl) cyclohexanethiocarboxylate (Compound Q7) 4- (benzyloxycarbonyl) cyclohexanecarboxylic acid (832 mg) in CH 2 Cl 2 solution (15.0 ml) was 0. At 0 ° C., oxalyl chloride (399 μL) was added dropwise. A small amount of DMF solution was added to the reaction solution at room temperature, and the mixture was stirred at room temperature for 1 hour. After the solvent was distilled off under reduced pressure, THF (12.0 mL), thiophenol (314 μL) and triethylamine (1.35 mL) were added, and the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, the mixture was extracted with ethyl acetate-water, and the obtained organic layer was washed with saturated brine and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 3: 1) to obtain Compound Q7 (1.16 g).
1 H-NMR (400 MHz, CDCl3): 1.75-1.84 (8H, brm), 2.74 (1H, s), 3.75 (1H, s), 4.81 (1H, s), 5.07 (2H, s), 7.31- 7.39 (10H, brm).
ｂ）ベンジル シス－４－（２－フルオロベンゾイル）シクロヘキシルカルバメート（化合物Ｑ８）の製造
　上記の実験で得られた化合物Ｑ７（370 mg）のＴＨＦ溶液（10 ml）に、２－フルオロフェニルボロン酸（168 mg）、チオフェン－２－カルボン酸銅（Ｉ）（229 mg）、トリス（ジベンジリデンアセトン）ビスパラジウム（92 mg）及び亜リン酸トリエチル（17 mg）を加え、３０℃にて１６時間攪拌した。反応終了後、濾過し、得られたろ液を酢酸エチル－水で分液抽出した。有機層を飽和食塩水で洗浄した後、硫酸ナトリウムで乾燥した。溶媒を減圧留去した後、得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル＝２：１）で精製することにより化合物Ｑ８（297 mg）を得た。
1H-NMR (400 MHz, CDCl3)：7.70 (1H, m), 7.47 (1H, m), 7.31 (5H, m), 7.20 (1H, m), 7.09 (1H, m), 5.06 (2H, s), 4.88 (1H, br), 3.78 (1H, s), 3.22 (1H, m), 1.60-1.80 (8H, brm). b) Preparation of benzyl cis-4- (2-fluorobenzoyl) cyclohexylcarbamate (Compound Q8) To a THF solution (10 ml) of Compound Q7 (370 mg) obtained in the above experiment was added 2-fluorophenylboronic acid ( 168 mg), copper (I) thiophene-2-carboxylate (229 mg), tris (dibenzylideneacetone) bispalladium (92 mg) and triethyl phosphite (17 mg) were added, and the mixture was stirred at 30 ° C. for 16 hours. did. After completion of the reaction, the mixture was filtered, and the obtained filtrate was subjected to liquid separation extraction with ethyl acetate-water. The organic layer was washed with saturated brine and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 2: 1) to obtain Compound Q8 (297 mg).
1 H-NMR (400 MHz, CDCl3): 7.70 (1H, m), 7.47 (1H, m), 7.31 (5H, m), 7.20 (1H, m), 7.09 (1H, m), 5.06 (2H, s), 4.88 (1H, br), 3.78 (1H, s), 3.22 (1H, m), 1.60-1.80 (8H, brm).
ｃ）ベンジル シス－４－（３－１Ｈ－インダゾイル）シクロヘキシルカルバメート（化合物Ｑ９）の製造
　上記の実験で得られた化合物Ｑ８（263 mg）のピリジン溶液（3 ml）に、ヒドラジン１水和物（74 mg）を加え、マイクロウエーブ照射下、１５０℃で１時間加熱攪拌した。反応終了後、酢酸エチル－水で分液抽出し、有機層を硫酸ナトリウムで乾燥後、減圧留去した。得られた残査をアミノシリカゲルカラムクロマトグラフィー （溶出溶媒；クロロホルム：酢酸エチル＝４：１）で精製することにより化合物Ｑ９（109 mg）を得た。
1H-NMR (400 MHz, CDCl3): 1.75-2.00 (8H, brm), 3.19 (1H, m), 3.93 (1H, m), 5.09 (3H, m), 7.08 (1H, m), 7.28-7.45 (7H, brm), 7.70 (1H, d, J = 8.3 Hz). c) Preparation of benzyl cis-4- (3-1H-indazoyl) cyclohexylcarbamate (Compound Q9) To a pyridine solution (3 ml) of Compound Q8 (263 mg) obtained in the above experiment, hydrazine monohydrate ( 74 mg) was added, and the mixture was heated and stirred at 150 ° C. for 1 hour under microwave irradiation. After completion of the reaction, the mixture was extracted with ethyl acetate-water, and the organic layer was dried over sodium sulfate and evaporated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; chloroform: ethyl acetate = 4: 1) to obtain Compound Q9 (109 mg).
1 H-NMR (400 MHz, CDCl 3): 1.75-2.00 (8H, brm), 3.19 (1H, m), 3.93 (1H, m), 5.09 (3H, m), 7.08 (1H, m), 7.28 -7.45 (7H, brm), 7.70 (1H, d, J = 8.3 Hz).
ｄ）シス－４－（３－１Ｈ－インダゾイル）シクロヘキシルアミン（参考例３）の製造
　上記の実験で得られた化合物Ｑ９（100 mg）のエタノール溶液（40 ml）に、Ｐｄ（ＯＨ）２（10 mg）を加え、水素ガス雰囲気下１日間接触還元した。反応終了後、セライト濾過し、ろ液を減圧留去することにより参考例３（62 mg）を得た。
1H-NMR (400 MHz, CD3OD): 1.86-2.02 (6H, m), 2.21 (2H, m), 3.38 (2H, m), 7.09 (1H, m), 7.33 (1H, m), 7.45 (1H, d, J = 8.3 Hz), 7.75 (1H, d, J = 8.3 Hz). d) Preparation of cis-4- (3-1H-indazoyl) cyclohexylamine (Reference Example 3) To an ethanol solution (40 ml) of compound Q9 (100 mg) obtained in the above experiment, Pd (OH) 2 ( 10 mg) was added, and catalytic reduction was performed for 1 day in a hydrogen gas atmosphere. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was distilled off under reduced pressure to obtain Reference Example 3 (62 mg).
1 H-NMR (400 MHz, CD 3 OD): 1.86-2.02 (6H, m), 2.21 (2H, m), 3.38 (2H, m), 7.09 (1H, m), 7.33 (1H, m), 7.45 (1H, d, J = 8.3 Hz), 7.75 (1H, d, J = 8.3 Hz).
参考例４
３－（ピペリジン－４－イル）－７－（トリフルオロメチル）－１Ｈ－インダゾール
Figure JPOXMLDOC01-appb-C000014
 Reference example 4
3- (Piperidin-4-yl) -7- (trifluoromethyl) -1H-indazole
Figure JPOXMLDOC01-appb-C000014
ａ）［２－フルオロ－３－（トリフルオロメチル）フェニル］リチウム（化合物Ｑ１０）の製造
　２－フルオロ－１－ヨード－３－（トリフルオロメチル）ベンゼン（5.00 g）の脱水テトラヒドロフラン溶液（50 mL）にｎ－ブチルリチウム（1.56 mmol／L ｎ－ヘキサン溶液, 11.0 ｍL）を－７６℃にて滴下した。反応溶液を１時間、－７６℃にて攪拌し、化合物Ｑ１０溶液を得た。本溶液をそのままｃ）工程にて使用した。 a) Preparation of [2-fluoro-3- (trifluoromethyl) phenyl] lithium (Compound Q10) Dehydrated tetrahydrofuran solution (50 mL) of 2-fluoro-1-iodo-3- (trifluoromethyl) benzene (5.00 g) N-butyllithium (1.56 mmol / L n-hexane solution, 11.0 mL) was added dropwise at -76 ° C. The reaction solution was stirred at −76 ° C. for 1 hour to obtain a compound Q10 solution. This solution was directly used in step c).
ｂ）ｔｅｒｔ－ブチル ４－［メトキシ（メチル）カルバモイル］ピペリジン－１－カルボキシレート（化合物Ｑ１１）の製造
　１－（ｔｅｒｔ－ブトキシカルボニル）ピペリジン－４－カルボン酸（3.94 g）、ＥＤＣＩ・ＨＣｌ（4.59 g）及びＨＯＢｔ（3.23 g）のＤＭＦ懸濁溶液（65 mL）にＤＩＥＡ（11.3 mL）及びメトキシメチルアミン塩酸塩（1.74 g）を加えて、室温で一晩撹拌した。酢酸エチル－水で分液抽出し、得られた有機層を飽和食塩水で洗浄した後、硫酸ナトリウムで乾燥した。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー（溶出溶媒:ヘキサン：酢酸エチル＝４：３）で精製することにより化合物Ｑ１１（3.54 g）を得た。
1H-NMR (400 MHz, CDCl3): 1.94 (9H, s), 1.55-1.70 (4H, m), 2.75 (2H, m), 3.16 (3H, s), 3.69 (3H, s), 4.13 (2H, m). b) Preparation of tert-butyl 4- [methoxy (methyl) carbamoyl] piperidine-1-carboxylate (Compound Q11) 1- (tert-Butoxycarbonyl) piperidine-4-carboxylic acid (3.94 g), EDCI · HCl (4.59) DIEA (11.3 mL) and methoxymethylamine hydrochloride (1.74 g) were added to a DMF suspension solution (65 mL) of g) and HOBt (3.23 g), and the mixture was stirred overnight at room temperature. Liquid separation extraction was performed with ethyl acetate-water, and the obtained organic layer was washed with saturated brine, and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 4: 3) to obtain Compound Q11 (3.54 g).
1 H-NMR (400 MHz, CDCl 3 ): 1.94 (9H, s), 1.55-1.70 (4H, m), 2.75 (2H, m), 3.16 (3H, s), 3.69 (3H, s), 4.13 (2H, m).
ｃ）ｔｅｒｔ－ブチル ４－｛［２－フルオロ－３－（トリフルオロメチル）フェニル］カルボニル｝ピペリジン－１－カルボキシレート（化合物Ｑ１２）の製造
　化合物Ｑ１０溶液に化合物Ｑ１１（2.34 g）の脱水テトラヒドロフラン溶液（１0 mL）を－７６℃にて滴下した。反応溶液を２．５時間、－７６℃にて攪拌した後、飽和塩化アンモニウム水溶液を－７６℃にて添加した。酢酸エチル－水で分液抽出し、得られた有機層を飽和食塩水で洗浄した後、硫酸ナトリウムで乾燥した。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー（溶出溶媒：ヘキサン：酢酸エチル＝４：１）で精製することにより化合物Ｑ１２（2.80 g）を得た。
1H-NMR (400 MHz, CDCl3):.1.44 (9H, s), 1.70 (2H, m), 1.89 (2H, m), 2.86 (2H, m), 3.24 (1H, m), 4.11 (2H, m), 7.34 (1H, t, J = 8.0 Hz), 7.78 (1H, t, J = 8.0 Hz), 7.93 (1H, t, J = 8.0 Hz). c) Preparation of tert-butyl 4-{[2-fluoro-3- (trifluoromethyl) phenyl] carbonyl} piperidine-1-carboxylate (Compound Q12) Dehydrated tetrahydrofuran solution of Compound Q11 (2.34 g) in Compound Q10 solution (10 mL) was added dropwise at -76 ° C. The reaction solution was stirred for 2.5 hours at -76 ° C, and then a saturated aqueous ammonium chloride solution was added at -76 ° C. Liquid separation extraction was performed with ethyl acetate-water, and the obtained organic layer was washed with saturated brine, and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 4: 1) to obtain Compound Q12 (2.80 g).
1 H-NMR (400 MHz, CDCl 3 ): 1.44 (9H, s), 1.70 (2H, m), 1.89 (2H, m), 2.86 (2H, m), 3.24 (1H, m), 4.11 ( 2H, m), 7.34 (1H, t, J = 8.0 Hz), 7.78 (1H, t, J = 8.0 Hz), 7.93 (1H, t, J = 8.0 Hz).
ｄ）ｔｅｒｔ－ブチル ４－［７－（トリフルオロメチル）－１Ｈ－インダゾール－３－イル］ピペリジン－１－カルボキシレート（化合物Ｑ１３）の製造
　化合物Ｑ１２（2.79 g）のピリジン溶液（12 mL）にヒドラジン１水和物（0.924 g）を加え、マイクロウエーブ照射下、１５０℃で２時間加熱攪拌した。反応終了後、酢酸エチル－水で分液抽出し、有機層を硫酸ナトリウムで乾燥後、減圧留去した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル＝２：１）で精製することにより化合物Ｑ１３（2.70 g）を得た。
1H-NMR (400 MHz, CDCl3): 1.47 (9H, s), 1.85-2.05 (4H, m), 2.92 (2H, m), 3.26 (2H, m), 4.24 (2H, m), 7.20 (1H, m), 7.63 (1H, d, J = 8.0 Hz), 7.92 (1H, d, J = 8.0 Hz). d) Preparation of tert-butyl 4- [7- (trifluoromethyl) -1H-indazol-3-yl] piperidine-1-carboxylate (Compound Q13) To a pyridine solution (12 mL) of Compound Q12 (2.79 g) Hydrazine monohydrate (0.924 g) was added, and the mixture was stirred with heating at 150 ° C. for 2 hours under microwave irradiation. After completion of the reaction, the mixture was extracted with ethyl acetate-water, and the organic layer was dried over sodium sulfate and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 2: 1) to obtain Compound Q13 (2.70 g).
1 H-NMR (400 MHz, CDCl 3 ): 1.47 (9H, s), 1.85-2.05 (4H, m), 2.92 (2H, m), 3.26 (2H, m), 4.24 (2H, m), 7.20 (1H, m), 7.63 (1H, d, J = 8.0 Hz), 7.92 (1H, d, J = 8.0 Hz).
ｅ）３－（ピペリジン－４－イル）－７－（トリフルオロメチル）－１Ｈ－インダゾール（参考例４）の製造
　化合物Ｑ１３（1.23 ｇ）のメタノール（20 mL）溶液に４ｍｏｌ／Ｌ塩化水素／酢酸エチル溶液（3.56 mL）を加え、室温にて２０時間攪拌した。溶媒を留去し、残渣を酢酸エチルで洗浄し、析出した結晶をろ取して、参考例４（730 mg）を得た。 e) Preparation of 3- (piperidin-4-yl) -7- (trifluoromethyl) -1H-indazole (Reference Example 4) Compound M13 (1.23 g) in methanol (20 mL) solution in 4 mol / L hydrogen chloride / Ethyl acetate solution (3.56 mL) was added and stirred at room temperature for 20 hours. The solvent was distilled off, the residue was washed with ethyl acetate, and the precipitated crystals were collected by filtration to give Reference Example 4 (730 mg).
参考例５
７－（メトキシメチル）－３－（ピペリジン－４－イル）－１Ｈ－インダゾール塩酸塩
Figure JPOXMLDOC01-appb-C000015
 Reference Example 5
7- (Methoxymethyl) -3- (piperidin-4-yl) -1H-indazole hydrochloride
Figure JPOXMLDOC01-appb-C000015
ａ）１Ｈ－インダゾール－７－イルメタノール（化合物Ｑ１４）の製造
　水素化リチウムアルミニウム（2.03 g）のテトラヒドロフラン（80 mL）懸濁液に０℃にて７－メトキシカルボニルインダゾール（8.00 g）のテトラヒドロフラン（20 ｍL）溶液を滴下した。同温にて１５分間攪拌後、反応液に水（2.03 ｍL）、１５％水酸化ナトリウム水溶液（2.03 mL）および水（6.09 mL）を順に加えて５分間攪拌した。不溶物をろ去し、ろ液を減圧留去して、化合物Ｑ１４（5.61ｇ）を得た。
1H-NMR (DMSO-d6, 300MHz) δ: 4.80 (2H, s), 5.26 (1H, br s), 7.07 (1H, t, J = 7.5 Hz), 7.26-7.34 (1H, m), 7.63 (1H, d, J = 8.1 Hz), 8.05 (1H, s), 13.00 (1H, br s). a) Preparation of 1H-indazol-7-ylmethanol (Compound Q14) To a suspension of lithium aluminum hydride (2.03 g) in tetrahydrofuran (80 mL) at 0 ° C. in tetrahydrofuran (7-methoxycarbonylindazole (8.00 g)) 20 mL) solution was added dropwise. After stirring at the same temperature for 15 minutes, water (2.03 mL), 15% aqueous sodium hydroxide (2.03 mL) and water (6.09 mL) were sequentially added to the reaction mixture, and the mixture was stirred for 5 minutes. Insoluble material was removed by filtration, and the filtrate was distilled off under reduced pressure to obtain Compound Q14 (5.61 g).
1 H-NMR (DMSO-d 6 , 300 MHz) δ: 4.80 (2H, s), 5.26 (1H, br s), 7.07 (1H, t, J = 7.5 Hz), 7.26-7.34 (1H, m), 7.63 (1H, d, J = 8.1 Hz), 8.05 (1H, s), 13.00 (1H, br s).
ｂ）３－ヨード－７－（メトキシメチル）－１Ｈ－インダゾール（化合物Ｑ１５）の製造
　化合物Ｑ１４（4.00 g）のジクロロメタン（30 mL）懸濁液に塩化チオニル（3.94 mL）を加えた。室温にて２時間攪拌後、溶媒を減圧留去し、残渣にメタノール（30 mL）およびナトリウムメトキシド（2.92 g）を加え、１８時間加熱還流した。反応液を室温に戻し、水（100 mL）を加えて、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。残渣をＮ，Ｎ－ジメチルホルムアミド（30 mL）に溶かし、水酸化カリウム（3.03 g）およびヨウ素（7.17 g）を加え、室温にて３時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層をチオ硫酸ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥し、ろ過して溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出液：ヘキサン／酢酸エチル＝１００／０～５０／５０）で精製して、化合物Ｑ１５（6.99 ｇ）を得た。
1H-NMR (CDCl3, 300mHz) δ: 3.44 (3H, s), 4.85 (2H, s), 7.13-7.29 (2H, m), 7.42-7.49 (1H, m), 10.83 (1H, br s). b) Preparation of 3-iodo-7- (methoxymethyl) -1H-indazole (Compound Q15) Thionyl chloride (3.94 mL) was added to a suspension of Compound Q14 (4.00 g) in dichloromethane (30 mL). After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure, methanol (30 mL) and sodium methoxide (2.92 g) were added to the residue, and the mixture was heated to reflux for 18 hours. The reaction solution was returned to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in N, N-dimethylformamide (30 mL), potassium hydroxide (3.03 g) and iodine (7.17 g) were added, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium thiosulfate solution, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 100/0 to 50/50) to obtain Compound Q15 (6.99 g).
1 H-NMR (CDCl 3 , 300mHz) δ: 3.44 (3H, s), 4.85 (2H, s), 7.13-7.29 (2H, m), 7.42-7.49 (1H, m), 10.83 (1H, br s ).
ｃ）ｔｅｒｔ－ブチル ４－［７－（メトキシメチル）－１Ｈ－インダゾール－３－イル］－３，６－ジヒドロピリジン－１(２Ｈ)－カルボキシレート（化合物Ｑ１６）の製造
　化合物Ｑ１５（1.32 g）、１－Ｎ－Ｂｏｃ－４－（４，４，５，５－テトラメチル－［１，３，２］－ジオキサボロラン－２－イル）－３，３－ジヒドロ－２Ｈ－ピリジン（1.98ｇ）、炭酸水素ナトリウム（770 mg）、ジクロロ（ビストリフェニルホスフィン）パラジウム（321 mg）、イソプロパノール（12 mL）および水（4 mL）の混合液をマイクロウェーブ照射下１４０℃にて１時間攪拌した。反応液を室温に戻し、水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥後、ろ過して溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィー（溶出液：ヘキサン／酢酸エチル＝１００／０～５０／５０）で精製し化合物Ｑ１６（1.46 g）を得た。
1H-NMR (CDCl3, 300mHz) δ: 1.51 (9H, s), 2.75-2.90 (2H, m), 3.42 (3H, s), 3.64-3.79 (2H, m), 4.13-4.27 (2H, m), 4.85 (2H, s), 6.48 (1H, br s), 7.06-7.37 (2H, m), 7.86 (1H, d, J = 8.0 Hz). c) Preparation of tert-butyl 4- [7- (methoxymethyl) -1H-indazol-3-yl] -3,6-dihydropyridine-1 (2H) -carboxylate (Compound Q16) Compound Q15 (1.32 g) 1-N-Boc-4- (4,4,5,5-tetramethyl- [1,3,2] -dioxaborolan-2-yl) -3,3-dihydro-2H-pyridine (1.98 g), carbonic acid A mixture of sodium hydride (770 mg), dichloro (bistriphenylphosphine) palladium (321 mg), isopropanol (12 mL) and water (4 mL) was stirred at 140 ° C. for 1 hour under microwave irradiation. The reaction solution was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 100/0 to 50/50) to obtain Compound Q16 (1.46 g).
1 H-NMR (CDCl 3 , 300mHz) δ: 1.51 (9H, s), 2.75-2.90 (2H, m), 3.42 (3H, s), 3.64-3.79 (2H, m), 4.13-4.27 (2H, m), 4.85 (2H, s), 6.48 (1H, br s), 7.06-7.37 (2H, m), 7.86 (1H, d, J = 8.0 Hz).
ｄ）ｔｅｒｔ－ブチル ４－［７－（メトキシメチル）－１Ｈ－インダゾール－３－イル］ピペリジン－１－カルボキシレート（化合物Ｑ１７）の製造
　化合物Ｑ１６（300 mg）をメタノール／テトラヒドロフラン（１０／１）に溶かし、パラジウム炭素エチレンジアミン錯体（300 mg）を加え、水素雰囲気下２７時間攪拌した。反応液をセライトろ過し、溶媒を減圧留去して、化合物Ｑ１７（286 mg）を得た。
1H-NMR (CDCl3, 300mHz) δ: 1.49 (9H, s), 1.83-2.18 (4H, m), 2.80-3.06 (2H, m), 3.14-3.33 (1H, m), 3.42 (3H, s), 4.12-4.40 (2H, m), 4.82 (2H, s), 6.99-7.22 (2H, m), 7.62-7.77 (1H, m), 10.30 (1H, br s). d) Preparation of tert-butyl 4- [7- (methoxymethyl) -1H-indazol-3-yl] piperidine-1-carboxylate (Compound Q17) Compound Q16 (300 mg) was dissolved in methanol / tetrahydrofuran (10/1) Then, palladium carbon ethylenediamine complex (300 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 27 hours. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain Compound Q17 (286 mg).
1 H-NMR (CDCl 3 , 300mHz) δ: 1.49 (9H, s), 1.83-2.18 (4H, m), 2.80-3.06 (2H, m), 3.14-3.33 (1H, m), 3.42 (3H, s), 4.12-4.40 (2H, m), 4.82 (2H, s), 6.99-7.22 (2H, m), 7.62-7.77 (1H, m), 10.30 (1H, br s).
ｅ）７－（メトキシメチル）－３－（ピペリジン－４－イル)－１Ｈ－インダゾール塩酸塩（参考例５）の製造
　化合物Ｑ１７（1.23 ｇ）のメタノール（20 mL）溶液に４規定塩化水素／酢酸エチル溶液（3.56 mL）を加え、室温にて２０時間攪拌した。溶媒を留去し、残渣を酢酸エチルで洗浄し、析出した結晶をろ取して、参考例５（730 mg）得た。
1H-NMR (DMSO-d6, 300 MHz) δ: 1.99-2.24 (4H, m), 2.94-3.19 (2H, m), 3.21-3.49 (2H, m), 3.31 (3H, s), 4.67 (2H, s), 6.98-7.14 (1H, m), 7.20-7.31 (1H, m), 7.70-7.88 (1H, m), 8.77-9.17 (2H, m). e) Preparation of 7- (methoxymethyl) -3- (piperidin-4-yl) -1H-indazole hydrochloride (Reference Example 5) To a solution of compound Q17 (1.23 g) in methanol (20 mL) was added 4N hydrogen chloride / Ethyl acetate solution (3.56 mL) was added and stirred at room temperature for 20 hours. The solvent was distilled off, the residue was washed with ethyl acetate, and the precipitated crystals were collected by filtration to give Reference Example 5 (730 mg).
1 H-NMR (DMSO-d 6 , 300 MHz) δ: 1.99-2.24 (4H, m), 2.94-3.19 (2H, m), 3.21-3.49 (2H, m), 3.31 (3H, s), 4.67 (2H, s), 6.98-7.14 (1H, m), 7.20-7.31 (1H, m), 7.70-7.88 (1H, m), 8.77-9.17 (2H, m).
参考例６
７－メチル－３－（ピペリジン－４－イル）－１Ｈ－インダゾール塩酸塩
Figure JPOXMLDOC01-appb-C000016
 Reference Example 6
7-Methyl-3- (piperidin-4-yl) -1H-indazole hydrochloride
Figure JPOXMLDOC01-appb-C000016
ａ）ベンジル ４－［（フェニルスルファニル）カルボニル］ピペリジン－１－カルボキシレート（化合物Ｑ１８）の製造
　１－［（ベンジロキシ）カルボニル］ピペリジン－４－カルボン酸（2.63 g）のジクロロメタン溶液（30 mL）に０℃にて、オキサリルクロライド（1.33 mL）を滴下した。反応溶液に室温下、少量のＤＭＦ溶液を加え、室温にて３時間攪拌した。溶媒を減圧留去後、ＴＨＦ（30 mL）、チオフェノール（1.02 mL）及びトリエチルアミン（4.50 mL）を添加し、室温にて１６時間攪拌した。反応終了後、酢酸エチル－水で分液抽出し、得られた有機層を飽和食塩水で洗浄した後、硫酸ナトリウムで乾燥した。溶媒を減圧留去した後、得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル＝４：１）で精製することにより化合物Ｑ１８（3.15 g）を得た。
1H-NMR (400 MHz, CDCl3)：1.73 (2H, m), 1.95 (2H, m), 2.73 (1H, m), 2.92 (2H, m), 4.18 (2H, br), 5.11 (2H, s), 7.24-7.48 (10H, brm). a) Preparation of benzyl 4-[(phenylsulfanyl) carbonyl] piperidine-1-carboxylate (Compound Q18) 1-[(Benzyloxy) carbonyl] piperidine-4-carboxylic acid (2.63 g) in dichloromethane solution (30 mL) Oxalyl chloride (1.33 mL) was added dropwise at 0 ° C. A small amount of DMF solution was added to the reaction solution at room temperature, and the mixture was stirred at room temperature for 3 hours. After evaporating the solvent under reduced pressure, THF (30 mL), thiophenol (1.02 mL) and triethylamine (4.50 mL) were added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was extracted with ethyl acetate-water, and the obtained organic layer was washed with saturated brine and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 4: 1) to obtain Compound Q18 (3.15 g).
1 H-NMR (400 MHz, CDCl 3 ): 1.73 (2H, m), 1.95 (2H, m), 2.73 (1H, m), 2.92 (2H, m), 4.18 (2H, br), 5.11 (2H , s), 7.24-7.48 (10H, brm).
ｂ）ベンジル ４－［（３－ブロモ－２－フルオロフェニル）カルボニル］ピペリジン－１－カルボキシレート（化合物Ｑ１９）の製造
　上記の実験で得られた化合物Ｑ１８（10.67 g）のＴＨＦ溶液（225 mL）に、（３－ブロモ－２－フルオロフェニル）ボロン酸（7.87 g）、チオフェン－２－カルボン酸銅（Ｉ）（6.87 g）、トリス（ジベンジリデンアセトン）ビスパラジウム（2.75 g）及び亜リン酸トリエチル（495 mg）を加え、３０℃にて１日間攪拌した。反応終了後、セライト濾過し、得られたろ液を酢酸エチル－水で分液抽出した。有機層を飽和食塩水で洗浄した後、硫酸ナトリウムで乾燥した。溶媒を減圧留去した後、得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル＝３：１）で精製することにより化合物 Ｑ１９（7.97 mg）を得た。
1H-NMR (400 MHz, CDCl3)：1.55-1.67 (2H, brm), 1.88 (2H, m), 2.94 (2H, m), 3.25 (1H, m), 4.18 (2H, br), 7.11 (1H, t, 8.0 Hz), 7.64-7.73 (2H, m). b) Preparation of benzyl 4-[(3-bromo-2-fluorophenyl) carbonyl] piperidine-1-carboxylate (Compound Q19) Compound Q18 (10.67 g) obtained in the above experiment in THF (225 mL) (3-bromo-2-fluorophenyl) boronic acid (7.87 g), copper (I) thiophene-2-carboxylate (6.87 g), tris (dibenzylideneacetone) bispalladium (2.75 g) and phosphorous acid Triethyl (495 mg) was added, and the mixture was stirred at 30 ° C. for 1 day. After completion of the reaction, the mixture was filtered through Celite, and the obtained filtrate was subjected to liquid separation extraction with ethyl acetate-water. The organic layer was washed with saturated brine and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 3: 1) to obtain Compound Q19 (7.97 mg).
1 H-NMR (400 MHz, CDCl 3 ): 1.55-1.67 (2H, brm), 1.88 (2H, m), 2.94 (2H, m), 3.25 (1H, m), 4.18 (2H, br), 7.11 (1H, t, 8.0 Hz), 7.64-7.73 (2H, m).
ｃ）ベンジル ４－（７－ブロモ－１Ｈ－インダゾール－３－イル）ピペリジン－１－カルボキシレート（化合物Ｑ２０）の製造
　化合物Ｑ１９（3.99 g）のピリジン溶液（15 mL）にヒドラジン１水和物（1.18 g）を加え、マイクロウエーブ照射下、１５０℃で２時間加熱攪拌した。反応終了後、酢酸エチル－水で分液抽出し、有機層を硫酸ナトリウムで乾燥後、減圧留去した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル＝２：１）で精製することにより化合物Ｑ２０（6.61 g）を得た。
1H-NMR (400 MHz, CDCl3): 1.94-2.03 (4H, m), 3.02 (2H, br), 3.23 (1H, m), 4.31 (2H, br), 5.15 (2H, s), 7.01 (1H, t, J = 8.0 Hz), 7.23-7.38 (5H, m), 7.51 (1H, d, J = 8.0 Hz), 7.66 (1H, d, J = 8.0 Hz). c) Preparation of benzyl 4- (7-bromo-1H-indazol-3-yl) piperidine-1-carboxylate (Compound Q20) Hydrazine monohydrate (15 mL) in a pyridine solution (15 mL) of Compound Q19 (3.99 g) 1.18 g) was added, and the mixture was heated and stirred at 150 ° C. for 2 hours under microwave irradiation. After completion of the reaction, the mixture was extracted with ethyl acetate-water, and the organic layer was dried over sodium sulfate and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 2: 1) to obtain Compound Q20 (6.61 g).
1 H-NMR (400 MHz, CDCl 3 ): 1.94-2.03 (4H, m), 3.02 (2H, br), 3.23 (1H, m), 4.31 (2H, br), 5.15 (2H, s), 7.01 (1H, t, J = 8.0 Hz), 7.23-7.38 (5H, m), 7.51 (1H, d, J = 8.0 Hz), 7.66 (1H, d, J = 8.0 Hz).
ｄ）ベンジル ４－（７－メチル－１Ｈ－インダゾール－３－イル）ピペリジン－１－カルボキシレート（化合物Ｑ２１）の製造
　上記の実験で得られた化合物Ｑ２０（1.66 g）のジオキサン溶液（32 mL）に、水（8 mL）、炭酸セシウム（3.90 g）、トリメチルボロキシン（552 mg）、１，１’－ビス（ジフェニルホスフィノ）フェロセンパラジウムジクロライド（587 mg）を添加後、窒素ガス雰囲気下９０℃にて１８時間加熱攪拌した。濾過後、得られたろ液を酢酸エチル－水で分液抽出した。有機層を飽和食塩水で洗浄した後、硫酸ナトリウムで乾燥した。溶媒を減圧留去した後、得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル＝３：１）で精製することにより化合物Ｑ２１（842 mg）を得た。
1H-NMR (400 MHz, CDCl3)：1.90-2.10 (2H, br), 2.52 (3H, s), 3.01 (2H, br), 3.27 (1H, s), 3.25 (1H, m), 4.31 (2H, br), 5.15 (2H, s), 7.06 (1H, t, 8.0 Hz), 7.07 (1H, t, 8.0 Hz), 7.29-7.38 (5H, m), 7.56 (1H, d, 8.0 Hz). d) Preparation of benzyl 4- (7-methyl-1H-indazol-3-yl) piperidine-1-carboxylate (Compound Q21) Dioxane solution (32 mL) of Compound Q20 (1.66 g) obtained in the above experiment Water (8 mL), cesium carbonate (3.90 g), trimethylboroxine (552 mg), 1,1′-bis (diphenylphosphino) ferrocene palladium dichloride (587 mg), and then added under nitrogen gas atmosphere 90 The mixture was stirred at 18 ° C. for 18 hours. After filtration, the obtained filtrate was subjected to liquid separation extraction with ethyl acetate-water. The organic layer was washed with saturated brine and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 3: 1) to obtain Compound Q21 (842 mg).
1 H-NMR (400 MHz, CDCl 3 ): 1.90-2.10 (2H, br), 2.52 (3H, s), 3.01 (2H, br), 3.27 (1H, s), 3.25 (1H, m), 4.31 (2H, br), 5.15 (2H, s), 7.06 (1H, t, 8.0 Hz), 7.07 (1H, t, 8.0 Hz), 7.29-7.38 (5H, m), 7.56 (1H, d, 8.0 Hz ).
ｅ）７－メチル－３－（ピペリジン－４－イル）－１Ｈ－インダゾール（参考例６）の製造
　化合物Ｑ２１（1.23ｇ）のエタノール（20 mL）溶液に水酸化パラジウム／炭素 （100 mg）を加え、室温にて１８時間攪拌した。セライトにて濾過後、溶媒を留去し、参考例６（513 mg）を得た。 e) Preparation of 7-methyl-3- (piperidin-4-yl) -1H-indazole (Reference Example 6) Compound Q21 (1.23 g) in ethanol (20 mL) was added palladium hydroxide / carbon (100 mg). The mixture was further stirred at room temperature for 18 hours. After filtration through celite, the solvent was distilled off to obtain Reference Example 6 (513 mg).
実施例１
Ｎ－シクロヘキシル－４－（６－フルオロ－１Ｈ－インダゾール－３－イル）ピペリジン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000017
 　参考例１（220 mg）のテトラヒドロフラン溶液（30 ml）にシクロヘキシルイソシアネート（130 mg）を添加し、１６時間室温で攪拌した。反応終了後、減圧留去し、得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；酢酸エチル）で精製することにより実施例１（190 mg）を得た。
1H-NMR (400 MHz, CD3OD): 1.15-1.36 (5H, m), 1.64 (1H, m), 1.76 (2H, m), 1.90-1.83 (4H, m), 1.99 (2H, m), 2.96 (2H, m), 3.28 (1H, m), 3.54 (1H, m), 4.16 (2H, m), 6.15 (1H, m), 6.90 (1H, td, J = 9.0, 2.2 Hz), 7.12 (1H, dd, J = 9.0, 2.2 Hz), 7.77 (1H, dd, J = 9.0, 5.1 Hz). Example 1
N-cyclohexyl-4- (6-fluoro-1H-indazol-3-yl) piperidine-1-carboxamide
Figure JPOXMLDOC01-appb-C000017
 Cyclohexyl isocyanate (130 mg) was added to a tetrahydrofuran solution (30 ml) of Reference Example 1 (220 mg), and the mixture was stirred for 16 hours at room temperature. After completion of the reaction, the residue was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent; ethyl acetate) to obtain Example 1 (190 mg).
1 H-NMR (400 MHz, CD 3 OD): 1.15-1.36 (5H, m), 1.64 (1H, m), 1.76 (2H, m), 1.90-1.83 (4H, m), 1.99 (2H, m ), 2.96 (2H, m), 3.28 (1H, m), 3.54 (1H, m), 4.16 (2H, m), 6.15 (1H, m), 6.90 (1H, td, J = 9.0, 2.2 Hz) , 7.12 (1H, dd, J = 9.0, 2.2 Hz), 7.77 (1H, dd, J = 9.0, 5.1 Hz).
実施例２
Ｎ－シクロヘキシル－４－（１－エチル－６－フルオロ－１Ｈ－インダゾール－３－イル）ピペリジン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000018
 　実施例１（79 mg）のジメチルホルムアミド溶液（2 ml）に０℃にて水素化ナトリウム（9 mg）及びブロモエタン（25 mg）を添加し、１０分間０℃で攪拌した。反応終了後、反応溶液を水に注ぎ、酢酸エチル／ヘキサン（３／２）で抽出し、有機層を硫酸ナトリウムで乾燥後、減圧留去した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；酢酸エチル）で精製することにより実施例２（43 mg）を得た。
1H-NMR (400 MHz, CDCl3): 1.05-1.26 (3H, brm), 1.45 (1H, m), 1.45 (3H, t, J = 7.3 Hz), 1.60-1.74 (3H, m), 1.99 (6H, brm), 2.96 (2H, m), 3.18 (1H, m), 3.68 (1H, m), 4.07 (2H, m), 4.29 (2H, q, J = 7.3 Hz), 4.38 (1H, m), 6.86 (1H, td, J = 9.0, 2.1 Hz), 6.99 (1H, dd, J = 9.0, 2.1 Hz), 7.64 (1H, dd, J = 9.0, 5.1 Hz). Example 2
N-cyclohexyl-4- (1-ethyl-6-fluoro-1H-indazol-3-yl) piperidine-1-carboxamide
Figure JPOXMLDOC01-appb-C000018
 Sodium hydride (9 mg) and bromoethane (25 mg) were added to a dimethylformamide solution (2 ml) of Example 1 (79 mg) at 0 ° C., and the mixture was stirred at 0 ° C. for 10 minutes. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate / hexane (3/2). The organic layer was dried over sodium sulfate and evaporated under reduced pressure. Example 2 (43 mg) was obtained by refine | purifying the obtained residue with silica gel column chromatography (elution solvent; ethyl acetate).
1 H-NMR (400 MHz, CDCl 3 ): 1.05-1.26 (3H, brm), 1.45 (1H, m), 1.45 (3H, t, J = 7.3 Hz), 1.60-1.74 (3H, m), 1.99 (6H, brm), 2.96 (2H, m), 3.18 (1H, m), 3.68 (1H, m), 4.07 (2H, m), 4.29 (2H, q, J = 7.3 Hz), 4.38 (1H, m), 6.86 (1H, td, J = 9.0, 2.1 Hz), 6.99 (1H, dd, J = 9.0, 2.1 Hz), 7.64 (1H, dd, J = 9.0, 5.1 Hz).
実施例３
Ｎ－シクロヘキシル－４－（６－フルオロ－１Ｈ－インダゾール－３－イル）ピペラジン－１－カルボキシアミド
Figure JPOXMLDOC01-appb-C000019
 　６－フルオロ－３－（１－ピペラジニル）－１Ｈ－インダゾール ２塩酸塩（58 mg）のテトラヒドロフラン溶液（2 ml）にシクロヘキシルイソシアネート（25 mg）を添加し、１２時間室温で攪拌した。反応終了後、水に反応溶液を注ぎ、得られた混合溶液を酢酸エチルで抽出し、得られた有機層を硫酸ナトリウムで乾燥後、減圧留去した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；酢酸エチル）で精製することにより実施例３（41 mg）を得た。
1H-NMR (400 MHz, CD3OD): 1.15-1.90 (11H, brm), 2.90-2.80 (4H, m), 3.54 (2H, m), 4.14 (2H, m), 6.14 (1H, m), 6.44 (1H, m), 6.72 (1H, m), 6.80 (1H, m). Example 3
N-cyclohexyl-4- (6-fluoro-1H-indazol-3-yl) piperazine-1-carboxamide
Figure JPOXMLDOC01-appb-C000019
 Cyclohexyl isocyanate (25 mg) was added to a tetrahydrofuran solution (2 ml) of 6-fluoro-3- (1-piperazinyl) -1H-indazole dihydrochloride (58 mg), and the mixture was stirred for 12 hours at room temperature. After completion of the reaction, the reaction solution was poured into water, the resulting mixed solution was extracted with ethyl acetate, and the resulting organic layer was dried over sodium sulfate and evaporated under reduced pressure. Example 3 (41 mg) was obtained by refine | purifying the obtained residue with silica gel column chromatography (elution solvent; ethyl acetate).
1 H-NMR (400 MHz, CD 3 OD): 1.15-1.90 (11H, brm), 2.90-2.80 (4H, m), 3.54 (2H, m), 4.14 (2H, m), 6.14 (1H, m ), 6.44 (1H, m), 6.72 (1H, m), 6.80 (1H, m).
実施例４
Ｎ－シクロヘキシル－４－（３－１Ｈ－インダゾイル）シクロヘキサンカルボキシアミド
Figure JPOXMLDOC01-appb-C000020
 　参考例２（98 mg）、ＥＤＣＩ・ＨＣｌ（112 mg）及びＨＯＢｔ（125 mg）のＤＭＦ懸濁溶液（2 mL）に ＤＩＥＡ（350 μL）及びシクロヘキシルアミン（68 μL）を加えて、室温で一晩撹拌した。ＣＨＣｌ３－水で分液抽出し、得られた有機層を飽和食塩水で洗浄した後硫酸ナトリウムで乾燥した。溶媒を減圧留去した後、シリカゲルカラムクロマトグラフィー（溶出溶媒:ヘキサン：酢酸エチル＝３：１）で精製することにより実施例２（29 mg）を得た。
1H-NMR (400 MHz, CDCl3): 7.80 (1H, d, J = 8.3 Hz), 7.44 (1H, d, J = 8.3 Hz), 7.33 (1H, dd, J = 8.3, 7.2 Hz), 7.07 (1H, dd, J = 8.3, 7.2 Hz), 3.64 (1H, m), 2.46 (1H, m), 2.35 (2H, m), 2.03 (2H, m), 1.85 (4H, m), 1.67-1.77 (6H, brm), 1.15-1.40 (4H, m). Example 4
N-cyclohexyl-4- (3-1H-indazoyl) cyclohexanecarboxamide
Figure JPOXMLDOC01-appb-C000020
 DIEA (350 μL) and cyclohexylamine (68 μL) were added to a DMF suspension (2 mL) of Reference Example 2 (98 mg), EDCI · HCl (112 mg) and HOBt (125 mg). Stir overnight. Liquid separation extraction was performed with CHCl 3 -water, and the obtained organic layer was washed with saturated brine and then dried over sodium sulfate. After distilling off the solvent under reduced pressure, Example 2 (29 mg) was obtained by purification by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 3: 1).
1 H-NMR (400 MHz, CDCl 3 ): 7.80 (1H, d, J = 8.3 Hz), 7.44 (1H, d, J = 8.3 Hz), 7.33 (1H, dd, J = 8.3, 7.2 Hz), 7.07 (1H, dd, J = 8.3, 7.2 Hz), 3.64 (1H, m), 2.46 (1H, m), 2.35 (2H, m), 2.03 (2H, m), 1.85 (4H, m), 1.67 -1.77 (6H, brm), 1.15-1.40 (4H, m).
実施例５
Ｎ－（シス－４－（３－１Ｈ－インダゾイル）シクロヘキシル）シクロヘキサンカルボキシアミド
Figure JPOXMLDOC01-appb-C000021
 　参考例３（43 mg）、ＥＤＣＩ・ＨＣｌ（56 mg）とＨＯＢｔ（62 mg）のＤＭＦ懸濁溶液（1.5 ml）にＤＩＥＡ（175 μL）及びシクロヘキサンカルボン酸（24 mg）を加えて、室温で５時間撹拌した。ＣＨ２Ｃｌ２－水で分液抽出し、得られた有機層を硫酸ナトリウムで乾燥した。溶媒を減圧留去した後、アミノシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル＝１：４）で精製することにより実施例４（18 mg）を得た。
1H-NMR (400 MHz, CDCl3)：1.22-1.26 (2H, m), 1.41 (2H, m), 1.65 (2H, s), 1.75-2.05 (12H, m), 3.21 (1H, m), 4.15 (1H, m), 5.64 (1H, m), 7.13 (1H, m), 7.36 (1H, m), 7.44 (1H, d, J = 8.3 Hz), 7.71 (1H, d, J = 8.3 Hz), 9.85 (1H, s). Example 5
N- (cis-4- (3-1H-indazoyl) cyclohexyl) cyclohexanecarboxamide
Figure JPOXMLDOC01-appb-C000021
 DIEA (175 μL) and cyclohexanecarboxylic acid (24 mg) were added to a DMF suspension (1.5 ml) of Reference Example 3 (43 mg), EDCI · HCl (56 mg) and HOBt (62 mg) at room temperature. Stir for 5 hours. Liquid separation extraction was performed with CH 2 Cl 2 -water, and the obtained organic layer was dried over sodium sulfate. After the solvent was distilled off under reduced pressure, Example 4 (18 mg) was obtained by purification by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate = 1: 4).
1 H-NMR (400 MHz, CDCl 3 ): 1.22-1.26 (2H, m), 1.41 (2H, m), 1.65 (2H, s), 1.75-2.05 (12H, m), 3.21 (1H, m) , 4.15 (1H, m), 5.64 (1H, m), 7.13 (1H, m), 7.36 (1H, m), 7.44 (1H, d, J = 8.3 Hz), 7.71 (1H, d, J = 8.3 Hz), 9.85 (1H, s).
実施例６
１－（４－（３－１Ｈ－インダゾイル）シクロヘキシル）－３－シクロヘキシルウレア
Figure JPOXMLDOC01-appb-C000022
 　参考例３(58 mg)のＴＨＦ懸濁溶液（1.5 ml）にＴＥＡ（120 μL）及びシクロヘキシルイソシアネート（24 μL）を加えて、室温で１５時間撹拌した。ＣＨ２Ｃｌ２－水で分液抽出し、得られた有機層を硫酸ナトリウムで乾燥した。溶媒を減圧留去した後、アミノシリカゲルカラムクロマトグラフィー（溶出溶媒；酢酸エチル）で精製することにより実施例５（30 mg）を得た。
1H-NMR (400 MHz, CDCl3)：1.07 (2H, m), 1.25 (2H, m), 1.57-1.93 (12H, brm), 3.14 (1H, m), 3.46 (1H, m), 3.91 (1H, m), 4.12 (1H, m), 4.49 (1H, m), 7.08 (1H, m), 7.31 (1H, m), 7.38 (1H, m), 7.66 (1H, m). Example 6
1- (4- (3-1H-indazoyl) cyclohexyl) -3-cyclohexylurea
Figure JPOXMLDOC01-appb-C000022
 TEA (120 μL) and cyclohexyl isocyanate (24 μL) were added to a suspension of Reference Example 3 (58 mg) in THF (1.5 ml), and the mixture was stirred at room temperature for 15 hours. Liquid separation extraction was performed with CH 2 Cl 2 -water, and the obtained organic layer was dried over sodium sulfate. After evaporating the solvent under reduced pressure, Example 5 (30 mg) was obtained by purification with amino silica gel column chromatography (elution solvent; ethyl acetate).
1 H-NMR (400 MHz, CDCl 3 ): 1.07 (2H, m), 1.25 (2H, m), 1.57-1.93 (12H, brm), 3.14 (1H, m), 3.46 (1H, m), 3.91 (1H, m), 4.12 (1H, m), 4.49 (1H, m), 7.08 (1H, m), 7.31 (1H, m), 7.38 (1H, m), 7.66 (1H, m).
実施例８～５１
　対応する原料化合物を用いて実施例１～３と同様に反応・処理し、表１に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000024
 Examples 8 to 51
Reaction and treatment were carried out in the same manner as in Examples 1 to 3 using the corresponding starting compounds, and the compounds shown in Table 1 were obtained.
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000024
実施例５２～６０
　対応する原料化合物を用いて実施例４と同様に反応・処理し、表２に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000025
 Examples 52-60
Reaction and treatment were performed in the same manner as in Example 4 using the corresponding starting compounds, and the compounds shown in Table 2 were obtained.
Figure JPOXMLDOC01-appb-T000025
実施例６１～６４
　対応する原料化合物を用いて実施例５及び６と同様に反応・処理し、表３に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000026
 Examples 61-64
Reaction and treatment were performed in the same manner as in Examples 5 and 6 using the corresponding starting compounds, and the compounds shown in Table 3 were obtained.
Figure JPOXMLDOC01-appb-T000026
実施例６５
Ｎ－（トランス－４－メトキシシクロヘキシル）－４－［７－（トリフルオロメチル）－１Ｈ－インダゾール－３－イル］ピペリジン－１－カルボキサミド
Figure JPOXMLDOC01-appb-C000027
 　参考例４（103 mg）のアセトニトリル溶液（3 mL）にフェニル（トランス－４－メトキシシクロヘキシル）カルバメート（71 mg）を添加し、１６時間８０℃で攪拌した。反応終了後、減圧留去し、得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；酢酸エチル）で精製することにより実施例６５（99 mg）を得た。
1H-NMR (400 MHz, CD3OD): 1.45-1.62 (4H, m), 1.65-1.85 (4H, m), 1.90-2.07 (4H, m), 2.98 (2H, m), 3.10-3.20 (5H, m), 3.76 (1H, br), 4.04 (2H, m), 4.54 (1H, br), 7.21 (1H, m), 7.63 (1H, d, J = 8.0 Hz), 7.92 (1H, d, J = 8.0 Hz). Example 65
N- (trans-4-methoxycyclohexyl) -4- [7- (trifluoromethyl) -1H-indazol-3-yl] piperidine-1-carboxamide
Figure JPOXMLDOC01-appb-C000027
 Phenyl (trans-4-methoxycyclohexyl) carbamate (71 mg) was added to acetonitrile solution (3 mL) of Reference Example 4 (103 mg), and the mixture was stirred at 80 ° C. for 16 hours. After completion of the reaction, the residue was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent; ethyl acetate) to give Example 65 (99 mg).
1 H-NMR (400 MHz, CD 3 OD): 1.45-1.62 (4H, m), 1.65-1.85 (4H, m), 1.90-2.07 (4H, m), 2.98 (2H, m), 3.10-3.20 (5H, m), 3.76 (1H, br), 4.04 (2H, m), 4.54 (1H, br), 7.21 (1H, m), 7.63 (1H, d, J = 8.0 Hz), 7.92 (1H, d, J = 8.0 Hz).
実施例６６
Ｎ－［（１Ｓ）－２，２－ジフルオロシクロヘキシル］－４－［７－（メトキシメチル）－１Ｈ－インダゾール－３－イル］ピペリジン－１－カルボキサミドの製造
Figure JPOXMLDOC01-appb-C000028
 　参考例５（80 mg）およびジイソプロピルエチルアミン（216 μL）のアセトニトリル（2mL）溶液にフェニル［（１Ｓ）－２，２－フルオロシクロヘキシル］カルバメート（64 mg）を加え１４時間加熱還流した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出液：ヘキサン／酢酸エチル＝５０／５０～０／１００）で精製して、実施例６６(46 mg)を得た。
1H-NMR (CDCl3, 300 MHz) δ: 1.16-1.60 (4H, m), 1.60-1.90 (2H, m), 1.93-2.31 (6H, m), 2.97-3.15 (2H, m), 3.21-3.38 (1H, m), 3.42 (3H, s), 4.02-4.32 (3H, m), 4.73 (1H, d, J = 8.4 Hz), 4.83 (2H, s), 7.03-7.13 (1H, m), 7.14-7.22 (1H, m), 7.69 (1H, d, J = 7.5 Hz). Example 66
Preparation of N-[(1S) -2,2-difluorocyclohexyl] -4- [7- (methoxymethyl) -1H-indazol-3-yl] piperidine-1-carboxamide
Figure JPOXMLDOC01-appb-C000028
 Phenyl [(1S) -2,2-fluorocyclohexyl] carbamate (64 mg) was added to a solution of Reference Example 5 (80 mg) and diisopropylethylamine (216 μL) in acetonitrile (2 mL), and the mixture was heated to reflux for 14 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 50 / 50-0 / 100) to give Example 66 (46 mg).
1 H-NMR (CDCl 3 , 300 MHz) δ: 1.16-1.60 (4H, m), 1.60-1.90 (2H, m), 1.93-2.31 (6H, m), 2.97-3.15 (2H, m), 3.21 -3.38 (1H, m), 3.42 (3H, s), 4.02-4.32 (3H, m), 4.73 (1H, d, J = 8.4 Hz), 4.83 (2H, s), 7.03-7.13 (1H, m ), 7.14-7.22 (1H, m), 7.69 (1H, d, J = 7.5 Hz).
実施例６７
Ｎ－［（１Ｒ）－２，２－ジフルオロシクロヘキシル］－４－（７－メチル－１Ｈ－インダゾール－３－イル）ピペリジン－１－カルボキサミドの製造
Figure JPOXMLDOC01-appb-C000029
 　参考例６（43 mg）およびジイソプロピルエチルアミン（140 μL）のアセトニトリル（1.5 mL）溶液にフェニル［（１Ｒ）－２，２－フルオロシクロヘキシル］カルバメート（49 mg）を加え１４時間加熱還流した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（溶出液：酢酸エチル）で精製して、実施例５（49 mg）を得た。
1H-NMR (CDCl3, 300MHz) δ: 1.36-1.50 (4H, m), 1.60-1.85 (4H, m), 1.95-2.10 (6H, m), 2.52 (3H, s), 3.02 (2H, m), 3.31 (1H, m), 4.02-4.15 (4H, m), 4.72 (1H, m), 7.08 (1H, t, J = 8.0 Hz), 7.18 (1H, d, J = 8.0 Hz), 7.59 (1H, d, J = 8.0 Hz). Example 67
Preparation of N-[(1R) -2,2-difluorocyclohexyl] -4- (7-methyl-1H-indazol-3-yl) piperidine-1-carboxamide
Figure JPOXMLDOC01-appb-C000029
 Phenyl [(1R) -2,2-fluorocyclohexyl] carbamate (49 mg) was added to a solution of Reference Example 6 (43 mg) and diisopropylethylamine (140 μL) in acetonitrile (1.5 mL), and the mixture was heated to reflux for 14 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give Example 5 (49 mg).
1 H-NMR (CDCl 3 , 300 MHz) δ: 1.36-1.50 (4H, m), 1.60-1.85 (4H, m), 1.95-2.10 (6H, m), 2.52 (3H, s), 3.02 (2H, m), 3.31 (1H, m), 4.02-4.15 (4H, m), 4.72 (1H, m), 7.08 (1H, t, J = 8.0 Hz), 7.18 (1H, d, J = 8.0 Hz), 7.59 (1H, d, J = 8.0 Hz).
実施例６８～７８
　対応する原料化合物を用いて実施例１～３、６５～６７と同様に反応・処理し、表４に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000031
 Examples 68-78
The corresponding starting materials were used and reacted and treated in the same manner as in Examples 1 to 3 and 65 to 67 to obtain the compounds shown in Table 4.
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000031
実施例７９～３４０
　対応する原料化合物を用いて実施例１～３、６５～６７と同様に反応・処理し、表５に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000047
 Examples 79-340
The corresponding starting materials were used and reacted and treated in the same manner as in Examples 1 to 3 and 65 to 67 to obtain the compounds shown in Table 5.
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000047
　以上の実施例の他に以下に示す化合物が想定される。
Figure JPOXMLDOC01-appb-C000048
 　これらは、対応するアミン化合物、７－（１－メトキシシクロプロピル）－３－（ピペリジン－４－イル）－１Ｈ－インダゾール又は７－（１－メトキシエチル）－３－（ピペリジン－４－イル）－１Ｈ－インダゾールと対応するウレア化試薬を用いて実施例１～３、６５～６７と同様に反応・処理することで合成できる。また、上記アミン群は参考例５と同様に反応・処理することで合成できる。メトキシシクロプロピル化の類似反応として、例えば、国際公開第2006/013048号パンフレットなどに記載されている方法が既知であり、同様に合成することができる。メトキシエチル化の類似反応として、例えば、国際公開第2011/138751号パンフレット、国際公開第2010/074089号パンフレットなどに記載されている方法が既知であり、同様に合成することができる。 In addition to the above examples, the following compounds are envisaged.
Figure JPOXMLDOC01-appb-C000048
 These are the corresponding amine compounds, 7- (1-methoxycyclopropyl) -3- (piperidin-4-yl) -1H-indazole or 7- (1-methoxyethyl) -3- (piperidin-4-yl) It can be synthesized by reacting and treating in the same manner as in Examples 1 to 3 and 65 to 67 using a urea reagent corresponding to -1H-indazole. The amine group can be synthesized by reacting and treating in the same manner as in Reference Example 5. As a similar reaction of methoxycyclopropylation, for example, the method described in International Publication No. 2006/013048 pamphlet and the like is known and can be synthesized in the same manner. As a similar reaction of methoxyethylation, for example, methods described in International Publication No. 2011/138751 pamphlet, International Publication No. 2010/074089 pamphlet and the like are known, and can be synthesized in the same manner.
試験例
　以下に、本発明の代表的化合物の薬理試験結果を示し、該化合物についての薬理作用を説明するが、本発明はこれらの試験例に限定されるものではない。 Test Examples Hereinafter, pharmacological test results of representative compounds of the present invention will be shown and the pharmacological action of the compounds will be described. However, the present invention is not limited to these test examples.
試験例１ヒトα７ ｎＡＣｈ受容体安定発現細胞を用いたＰＡＭ活性評価
（１）ヒトα７ ｎＡＣｈＲ安定発現細胞
　ヒトα７ ｎＡＣｈＲ安定発現細胞を作製し、培養に供した。具体的には、宿主細胞としてラット下垂体由来ＧＨ４Ｃ１細胞（cat#CCL-82.2, ATCC, USA）を用いた。GenBank BAC81731の蛋白をコードする塩基配列を挿入したpcDNA3.1Zeoベクターの導入、およびヒトα７ ｎＡＣｈＲ遺伝子を挿入したpcDNA3.1ベクター（cat#V790-20, invitrogen, Carlsbad，CA，USA）の導入によりエクオリンおよびヒトα７ ｎＡＣｈＲ安定発現細胞を得た。選別にはそれぞれZeocin（cat#R25001, invitrogen, Carlsbad，CA，USA）およびGeneticin（cat#10131-027, invitrogen, Carlsbad，CA，USA）を用いた。
　培地には２．５％ウシ胎児血清（cat#2917354, ICN Biomedicals, Inc, USA）、１５％非働化ウマ血清（cat#26050-088, invitrogen, Carlsbad，CA，USA）、1μｇ／ｍＬ Geneticin、5μｇ／ｍＬ Puromycin（cat#14861-84, invitrogen, Carlsbad，CA，USA）を含むF-10 Nutrient Mixture（Ham）培地（cat#11550-043, invitrogen, Carlsbad，CA，USA）を用い、コラーゲンType1コートディッシュ（cat#4030-010, iwaki, Tokyo, Japan）にて培養を行った。培養中、２－３日毎に培地交換を行い、7日毎にTrypLE Express（cat# 45604-021, invitrogen, Carlsbad，CA，USA）処理にて細胞を回収し、継代培養を行った。
　継代から７日後、約８０％コンフルエントな状態でTrypLE Express処理にて細胞を回収し、Hanks（cat#14065-056, invitrogen, Carlsbad，CA，USA）／２０ｍＭ Hepes（cat#15630-080, invitrogen, Carlsbad，CA，USA）Buffer（pH 7.4）、F-10 Nutrient Mixture（Ham）、０．１ｍｇ／ｍＬ Geneticinからなる反応培地にて20000 cells/25μL/wellとなるように懸濁し、384ｗｅｌｌプレート（cat#781090, Greiner,Germany）に播種した。
　播種翌日、Viviren（cat#E649X, Promega, Madison，WI，USA）を終濃度４μＭとなるように添加し（15μL/well）、遠心後4時間室温、遮光下で静置した。 Test Example 1 PAM activity evaluation using human α7 nACh receptor stable expression cells (1) Human α7 nAChR stable expression cells Human α7 nAChR stable expression cells were prepared and subjected to culture. Specifically, rat pituitary-derived GH4C1 cells (cat # CCL-82.2, ATCC, USA) were used as host cells. Aequorin by introducing pcDNA3.1Zeo vector into which the nucleotide sequence encoding the protein of GenBank BAC81731 was inserted and pcDNA3.1 vector (cat # V790-20, invitrogen, Carlsbad, CA, USA) into which the human α7 nAChR gene was inserted And human α7 nAChR stably expressing cells were obtained. For selection, Zeocin (cat # R25001, invitrogen, Carlsbad, CA, USA) and Geneticin (cat # 10131-027, invitrogen, Carlsbad, CA, USA) were used.
The medium includes 2.5% fetal bovine serum (cat # 2917354, ICN Biomedicals, Inc, USA), 15% inactivated horse serum (cat # 26050-088, invitrogen, Carlsbad, CA, USA), 1 μg / mL Geneticin, Collagen Type1 using F-10 Nutrient Mixture (Ham) medium (cat # 11550-043, invitrogen, Carlsbad, CA, USA) containing 5 μg / mL Puromycin (cat # 14861-84, invitrogen, Carlsbad, CA, USA) Culturing was performed in a coat dish (cat # 4030-010, iwaki, Tokyo, Japan). During the culture, the medium was changed every 2-3 days, and the cells were collected by TrypLE Express (cat # 45604-021, invitrogen, Carlsbad, CA, USA) treatment every 7 days and subcultured.
Seven days after passage, cells were collected by TrypLE Express treatment in a state of about 80% confluence, Hanks (cat # 14065-056, invitrogen, Carlsbad, CA, USA) / 20 mM Hepes (cat # 15630-080, invitrogen , Carlsbad, CA, USA) Suspended in a reaction medium consisting of Buffer (pH 7.4), F-10 Nutrient Mixture (Ham), 0.1 mg / mL Geneticin to 20000 cells / 25 μL / well, and a 384-well plate ( cat # 781090, Greiner, Germany).
On the day after seeding, Viviren (cat # E649X, Promega, Madison, WI, USA) was added to a final concentration of 4 μM (15 μL / well), and the mixture was allowed to stand for 4 hours at room temperature under light shielding after centrifugation.
（２）試験化合物の調製
　試験化合物は最終濃度の1000倍濃度のＤＭＳＯ溶液を作製し、この溶液をHanks／20 mM HEPES／0.2％BSA（cat#A3803, Sigma，St.Louis, MO, USA）にて最終濃度の６倍濃度に調製した。 (2) Preparation of test compound A DMSO solution having a concentration 1000 times the final concentration was prepared as a test compound, and this solution was added to Hanks / 20 mM HEPES / 0.2% BSA (cat # A3803, Sigma, St. Louis, MO, USA). The final concentration was adjusted to 6 times the final concentration.
（３）ＰＡＭ活性評価
　α７ ｎＡＣｈＲ刺激による発光シグナルの検出にはFDSS7000（浜松ホトニクス）を用いた。細胞及び発光基質を添加したプレートに試験化合物を添加し、１５０秒後に単独処置でＥＣ２０を示す濃度のＡＣｈを添加した。ＡＣｈ添加後１３８秒間発光シグナル（中心波長：465 nm）を測定してＲｌｕ（Ｍａｘ－Ｍｉｎ）を算出し、コントロールｗｅｌｌと試験化合物添加ｗｅｌｌとのＲｌｕ（Ｍａｘ－Ｍｉｎ）の比をＰＡＭ活性とした。代表的化合物のα７ ＰＡＭ活性のデータを表６に示す。 (3) PAM activity evaluation FDSS7000 (Hamamatsu Photonics) was used for the detection of the luminescent signal by α7 nAChR stimulation. Test compounds were added to the plates to which cells and luminescent substrate had been added, and ACh at a concentration indicating EC 20 was added alone after 150 seconds. Rlu (Max-Min) was calculated by measuring the luminescence signal (center wavelength: 465 nm) for 138 seconds after addition of ACh, and the ratio of Rlu (Max-Min) between the control well and the test compound added well was defined as PAM activity. . Table 7 shows data of α7 PAM activity of representative compounds.
Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000050
Figure JPOXMLDOC01-appb-T000050
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000052
　表６に示すように、本発明の化合物はＰＡＭ活性評価試験においてα７ ｎＡＣｈＲのＰＡＭ活性を有した。特に、実施例１、９、３３、２８、３３、５１、９８、９９、１２８、１３１、１４５は、より強いＰＡＭ活性を示した。 As shown in Table 6, the compound of the present invention had α7 nAChR PAM activity in the PAM activity evaluation test. In particular, Examples 1, 9, 33, 28, 33, 51, 98, 99, 128, 131, and 145 showed stronger PAM activity.
試験例２．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、４ ＡＴＰ Test Example 2 hERG potassium current in CHO cells stably expressing hERG (human ether-a-go-go) gene by whole cell patch clamp method using QPatch HT (Sophion Bioscience A / S) Was recorded. The hERG current is the amplitude of the tail current when the membrane potential is held at −80 mV in the voltage clamp mode, depolarized to +20 mV for 5 seconds after being changed to −50 mV for 20 milliseconds, and then repolarized to −50 mV for 5 seconds. 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 for each cell for 5 minutes, the inhibition rate of the inhibited current was calculated as compared to the current before the compound adaptation at each concentration, and the 50% inhibitory concentration was calculated by 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, 4 ATP
　実施例化合物を用いて、試験例２に従って行ったｈＥＲＧ阻害試験の結果を以下に示す。
Figure JPOXMLDOC01-appb-T000053
 The result of the hERG inhibition test conducted according to Test Example 2 using the Example compounds is shown below.
Figure JPOXMLDOC01-appb-T000053
試験例３．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：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：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分離機をもちいて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ーを算出した。 Test Example 3 Rat PK test 7-week-old rats were administered intravenously with physiological saline solution or orally with methylcellulose aqueous solution, and blood was collected at the following times, respectively.
Intravenous administration: 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours and 24 hours Oral administration: 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours and 24 hours Plasma obtained by centrifuging the collected blood at 3000 rpm × 10 minutes using a cooling centrifuge set at 4 ° C. was measured by HPLC, and pharmacokinetic parameters were calculated based on the obtained time curve.
　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１３１の化合物の生物学的利用率は６６％であった。 This test proves that the compound of the present invention is excellent in pharmacokinetics. For example, the bioavailability of the compound of Example 131 was 66%.
試験例４．マウス新奇物体認識試験を用いた認知機能評価（以下、ｍＯＲＴとする）
　体重２５－３０ｇのＳｌｃ：ｄｄＹマウス（雄性、日本エスエルシー）を用いた新奇物体認識試験において、第一試行（トレーニング）と第二試行（テスト）の間隔時間依存的に、既知物体に対する記憶低下が認められ、２４時間後に第二試行を行った場合、顕著な忘却が認められる。そこで本発明化合物を第一試行前に投与し、第２試行における記憶増強作用を評価した。 Test Example 4 Evaluation of cognitive function using mouse novel object recognition test (hereinafter referred to as mORT)
Decreased memory for known objects in a novel object recognition test using Slc: ddY mice (male, SLC Japan) weighing 25-30 g depending on the time interval between the first trial (training) and the second trial (test) When a second trial is performed 24 hours later, significant forgetting is observed. Therefore, the compound of the present invention was administered before the first trial, and the memory enhancing action in the second trial was evaluated.
　この試験により本発明化合物は極めて低用量から、持続的に認知機能改善効果を有することを証明することができ、例えば実施例１３１の化合物は最小有効用量は０．３ｍｇ／ｋｇであった。 This test proves that the compound of the present invention has an effect of continuously improving the cognitive function from a very low dose. For example, the minimum effective dose of the compound of Example 131 was 0.3 mg / kg.
試験例５．ラットＹ字型迷路試験を用いた認知障害の改善評価（以下、Ｙ－ｍａzｅ試験とする）
　２８０－３００ｇのＳｌｃ：Ｗｉｓｔａｒラット（雄性、日本エスエルシー）を用いたＹ字型迷路試験において、０．６ｍｇ／ｋｇのＳｃｏｐｏｌａｍｉｎｅ ＨＢｒ（cat#S0929, Sigma Aldrich, Japan）皮下投与により記憶障害が惹起され、自発交替行動率の低下が認められる。そこで本発明化合物を前処置し、記憶障害改善作用を評価した。 Test Example 5 Evaluation of improvement of cognitive impairment using rat Y-shaped maze test (hereinafter referred to as Y-maze test)
In a Y-shaped maze test using 280-300 g Slc: Wistar rats (male, SLC), memory impairment was caused by subcutaneous administration of 0.6 mg / kg Scopolamine HBr (cat # S0929, Sigma Aldrich, Japan) In addition, a decrease in the spontaneous alternation behavior rate is observed. Therefore, the compound of the present invention was pretreated to evaluate the effect of improving memory impairment.
　この試験により本発明化合物は低用量から、持続的に認知機能改善効果を有することを証明することができ、例えば実施例１の化合物は最小有効用量は３ｍｇ／ｋｇであった。 From this test, it was proved that the compound of the present invention has an effect of continuously improving the cognitive function from a low dose. For example, the compound of Example 1 had a minimum effective dose of 3 mg / kg.
　以上で説明したように、式（Ｉ）で表される化合物、又はその製薬学上許容される塩は、強いα７ニコチン性アセチルコリン受容体（α７ ｎＡＣｈＲ）の調節作用を有し、中枢神経系（ＣＮＳ）及び／又は末梢神経系（ＰＮＳ）のコリン作動性に関する疾患、平滑筋収縮に関する疾患、内分泌疾患、神経変性に関する疾患、炎症又は痛み等の疾患及び常習性の薬物乱用から引き起こされる禁断症状に関する疾患等の治療に有用である。 As described above, the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has a strong α7 nicotinic acetylcholine receptor (α7 nAChR) modulating action, and the central nervous system ( CNS) and / or peripheral nervous system (PNS) cholinergic diseases, smooth muscle contraction diseases, endocrine diseases, neurodegenerative diseases, diseases such as inflammation or pain, and withdrawal symptoms caused by addictive drug abuse Useful for treatment of diseases and the like.

Claims (27)

  1. 　式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000001
     ［式中、
    　Ａは、ＣＲ１Ｄ又は窒素原子を表し、
    　Ｘ－Ｙ－Ｚは、Ｎ－ＣＯ－ＮＲ４ＡＲ４Ｂ、ＣＲ６－ＣＯ－ＮＲ４ＡＲ４Ｂ、ＣＲ６－ＮＲ７－ＣＯ－ＮＲ４ＡＲ４Ｂ、ＣＲ６－ＮＲ７－ＣＯＲ５又はＣＲ６－ＮＲ７－Ａｒを表し、
    　Ｒ１Ａ、Ｒ１Ｂ、Ｒ１Ｃ及びＲ１Ｄは、同一又は異なって、ハロゲン、水酸基、Ｃ１－６アルコキシ、－ＮＲ８Ｒ９、－ＣＯＯＲ８、－ＣＯＮＲ８Ｒ９、－ＮＲ８ＣＯＲ９、－ＳＯ２ＮＲ８Ｒ９及び－ＮＲ８ＳＯ２Ｒ９からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；ハロゲン、水酸基、Ｃ１－６アルキル、Ｃ１－６アルコキシ、－ＮＲ８Ｒ９、－ＣＯＯＲ８、－ＣＯＮＲ８Ｒ９、－ＮＲ８ＣＯＲ９、－ＳＯ２ＮＲ８Ｒ９及び－ＮＲ８ＳＯ２Ｒ９からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルキル、４～１０員の飽和複素環若しくは４～１０員の飽和複素環基－Ｏ－；ハロゲン、水酸基、Ｃ１－６アルコキシ、－ＮＲ８Ｒ９、－ＣＯＯＲ８、－ＣＯＮＲ８Ｒ９、－ＮＲ８ＣＯＲ９、－ＳＯ２ＮＲ８Ｒ９及び－ＮＲ８ＳＯ２Ｒ９からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルコキシ；ハロゲン、水酸基、Ｃ１－６アルコキシ、－ＮＲ８Ｒ９、－ＣＯＯＲ８、－ＣＯＮＲ８Ｒ９、－ＮＲ８ＣＯＲ９、－ＳＯ２ＮＲ８Ｒ９及び－ＮＲ８ＳＯ２Ｒ９からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルコキシ；水素原子；水酸基；ハロゲン；ハロゲン、水酸基、Ｃ１－６アルキル、Ｃ１－６アルコキシ、－ＮＲ８Ｒ９、－ＣＯＯＲ８、－ＣＯＮＲ８Ｒ９及び－ＮＲ８ＣＯＲ９からなる群から独立して選択される１～５個の置換基で置換されていてもよいアリール若しくはヘテロアリール；ニトロ；－ＮＲ８Ｒ９；シアノ；－ＣＯＯＲ８；－ＣＯＮＲ８Ｒ９；－ＮＲ８ＣＯＲ９；－ＳＯ２ＮＲ８Ｒ９；又は－ＮＲ８ＳＯ２Ｒ９を表し、ここにおいて、Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＨＥｔであるとき、Ｒ１Ｂが－ＣＯ－ＮＨＥｔで置換されているアリール基ではなく、
    　Ｗは、ＣＲ３Ｅ又は窒素原子を表し、
    　Ｒ２は、ハロゲン、水酸基、Ｃ１－６アルコキシ、－ＮＲ１０Ｒ１１、－ＣＯＯＲ１０、－ＣＯＮＲ１０Ｒ１１、－ＮＲ１０ＣＯＲ１１、－ＳＯ２ＮＲ１０Ｒ１１及び－ＮＲ１０ＳＯ２Ｒ１１からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；ハロゲン、水酸基、Ｃ１－６アルコキシ、－ＮＲ１０Ｒ１１、－ＣＯＯＲ１０、－ＣＯＮＲ１０Ｒ１１、－ＮＲ１０ＣＯＲ１１、－ＳＯ２ＮＲ１０Ｒ１１及び－ＮＲ１０ＳＯ２Ｒ１１からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルキル、４～１０員の飽和複素環若しくは４～１０員の飽和複素環－カルボニル－；水素原子；ハロゲン、水酸基、Ｃ１－６アルキル、Ｃ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよいアリール若しくはヘテロアリール；Ｃ１－６アルキルカルボニル；－ＣＯＯＲ１０；－ＣＯＮＲ１０Ｒ１１；又はＳＯ２ＮＲ１０Ｒ１１を表し、
    　Ｒ３Ａ、Ｒ３Ｂ、Ｒ３Ｃ、Ｒ３Ｄ及びＲ３Ｅは、同一又は異なって、ハロゲン、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１２Ｒ１３からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル若しくはＣ１－６アルコキシ；水素原子；ハロゲン；又は水酸基を表し、
    　Ｒ４Ａ、Ｒ４Ｂ、Ｒ５及びＲ７は、同一又は異なって、置換されていてもよいＣ１－１０アルキル；置換されていてもよいＣ３－１０シクロアルキル（該基は、アリール又はヘテロアリールと縮環していてもよい）；置換されていてもよい４～１０員の飽和複素環（該基は、アリール又はヘテロアリールと縮環していてもよい）；置換されていてもよいアリール；置換されていてもよいヘテロアリール；又は水素原子を表し、ここにおいて、（１）Ｒ４Ａ及びＲ４Ｂは、一緒になって置換されていてもよい４～１０員の含窒素飽和複素環を形成していてもよく、（２）Ｒ４Ａ及びＲ４Ｂは、共に水素原子ではなく、（３）Ｒ５は、水素原子ではなく、
    　Ｒ６は、同一又は異なって、ハロゲン、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１４Ｒ１５からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；ハロゲン、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１４Ｒ１５からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルキル若しくは４～１０員の飽和複素環；水素原子；ハロゲン；水酸基；又はＣ１－６アルコキシを表し、
    　Ａｒは、ハロゲン、水酸基、Ｃ１－６アルキル、Ｃ１－６アルコキシ、－ＮＲ１６Ｒ１７、－ＣＯＯＲ１６、－ＣＯＮＲ１６Ｒ１７及び－ＮＲ１６ＣＯＲ１７からなる群から独立して選択される１～５個の置換基で置換されていてもよいアリール又はヘテロアリールを表し、
    　Ｒ８～Ｒ１７は、同一又は異なって、また複数存在する場合にはそれぞれ独立して、水素原子又は１～５個のフッ素で置換されていてもよいＣ１－６アルキルを表し、ここにおいて、Ｒ８及びＲ９、Ｒ１０及びＲ１１、Ｒ１２及びＲ１３、Ｒ１４及びＲ１５、Ｒ１６及びＲ１７は一緒になって４～１０員の含窒素飽和複素環を形成していてもよく、
    　ｎは、１又は２を表す］
    で表される化合物又はその製薬学的に許容される塩。     Formula (I):
    Figure JPOXMLDOC01-appb-C000001
     [Where:
    A represents CR 1D or a nitrogen atom,
    X—Y—Z represents N—CO—NR 4A R 4B , CR 6 —CO—NR 4A R 4B , CR 6 —NR 7 —CO—NR 4A R 4B , CR 6 —NR 7 —COR 5 or CR 6 Represents —NR 7 —Ar,
    R 1A , R 1B , R 1C and R 1D are the same or different and are halogen, hydroxyl group, C 1-6 alkoxy, —NR 8 R 9 , —COOR 8 , —CONR 8 R 9 , —NR 8 COR 9 , C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of —SO 2 NR 8 R 9 and —NR 8 SO 2 R 9 ; halogen, hydroxyl group, C It consists of 1-6 alkyl, C 1-6 alkoxy, —NR 8 R 9 , —COOR 8 , —CONR 8 R 9 , —NR 8 COR 9 , —SO 2 NR 8 R 9 and —NR 8 SO 2 R 9. C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group, 4 to 10 membered saturated heterocyclic ring or 4 to 10 membered saturated heterocyclic group —O— ; halogen, hydroxyl, C 1- Alkoxy, -NR 8 R 9, -COOR 8 , -CONR 8 R 9, -NR 8 COR 9, are independently selected from the group consisting of -SO 2 NR 8 R 9 and -NR 8 SO 2 R 9 1 C 1-6 alkoxy optionally substituted with 5 substituents; halogen, hydroxyl group, C 1-6 alkoxy, —NR 8 R 9 , —COOR 8 , —CONR 8 R 9 , —NR 8 COR 9 A C 3-10 cycloalkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of -SO 2 NR 8 R 9 and -NR 8 SO 2 R 9 ; Hydroxyl group; halogen; halogen, hydroxyl group, C 1-6 alkyl, C 1-6 alkoxy, —NR 8 R 9 , —COOR 8 , —CONR 8 R 9 and —NR 8 COR 9 independently selected -NR 8 R 9 ; cyano; -COOR 8 ; -CONR 8 R 9 ; -NR 8 COR 9 ; -SO 2 NR 8 R 9 ; or —NR 8 SO 2 R 9 , wherein when XYZ is N—CO—NHEt, R 1B is not an aryl group substituted with —CO—NHEt. ,
    W represents CR 3E or a nitrogen atom;
    R 2 is halogen, hydroxyl group, C 1-6 alkoxy, —NR 10 R 11 , —COOR 10 , —CONR 10 R 11 , —NR 10 COR 11 , —SO 2 NR 10 R 11 and —NR 10 SO 2 R C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of 11 ; halogen, hydroxyl, C 1-6 alkoxy, —NR 10 R 11 , —COOR 10 Substituted with 1 to 5 substituents independently selected from the group consisting of: —CONR 10 R 11 , —NR 10 COR 11 , —SO 2 NR 10 R 11 and —NR 10 SO 2 R 11 which may C 3-10 cycloalkyl, 4 to 10-membered saturated heterocyclic ring or 4 to 10-membered saturated heterocyclic ring - carbonyl -; hydrogen atom; a halogen, hydroxyl, C 1-6 alkyl , 1-5 which may be substituted with a substituent aryl or heteroaryl are independently selected from the group consisting of C 1-6 alkoxy; C 1-6 alkylcarbonyl; -COOR 10; -CONR 10 R 11 ; or SO 2 NR 10 R 11 ,
    R 3A , R 3B , R 3C , R 3D and R 3E are the same or different and are 1 to 5 independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy and —NR 12 R 13 A C 1-6 alkyl or C 1-6 alkoxy optionally substituted with a substituent of: a hydrogen atom; a halogen; or a hydroxyl group,
    R 4A , R 4B , R 5 and R 7 are the same or different and may be substituted C 1-10 alkyl; optionally substituted C 3-10 cycloalkyl (the group may be aryl or hetero Optionally fused to aryl); optionally substituted 4-10 membered saturated heterocycle (the group optionally fused to aryl or heteroaryl); optionally substituted Aryl represents an optionally substituted heteroaryl; or represents a hydrogen atom, wherein (1) R 4A and R 4B are a 4- to 10-membered nitrogen-containing saturated heterocyclic ring that may be substituted together (2) R 4A and R 4B are not both hydrogen atoms, and (3) R 5 is not a hydrogen atom,
    R 6 may be the same or different, halogen, hydroxyl, optionally substituted with one to five substituents independently selected from the group consisting of C 1-6 alkoxy and -NR 14 R 15 C 1 -6 alkyl; C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkoxy and —NR 14 R 15 ; Represents a 4- to 10-membered saturated heterocyclic ring; a hydrogen atom; a halogen; a hydroxyl group; or C 1-6 alkoxy,
    Ar is independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkyl, C 1-6 alkoxy, —NR 16 R 17 , —COOR 16 , —CONR 16 R 17 and —NR 16 COR 17. Represents aryl or heteroaryl optionally substituted by 1 to 5 substituents,
    R 8 to R 17 are the same or different, and when a plurality of R 8 to R 17 are present, each independently represents a hydrogen atom or C 1-6 alkyl optionally substituted with 1 to 5 fluorines, , R 8 and R 9 , R 10 and R 11 , R 12 and R 13 , R 14 and R 15 , R 16 and R 17 together form a 4- to 10-membered nitrogen-containing saturated heterocyclic ring. Well,
    n represents 1 or 2]
    Or a pharmaceutically acceptable salt thereof.
  2. 　＜ｉ＞項１における置換されていてもよいアルキル、置換されていてもよいシクロアルキル及び置換されていてもよい４～１０員の飽和複素環が、それぞれ独立して、
    　（１）置換されていてもよいアリール、
    　（２）置換されていてもよいヘテロアリール、
    　（３）置換されていてもよい４～１０員の飽和複素環、
    　（４）置換されていてもよいＣ３－１０シクロアルキル、
    　（５）－ＣＯＮＲ１８Ｒ１９
    　（６）ハロゲン、
    　（７）水酸基、
    　（８）置換されていてもよいＣ１－６アルキル、
    　（９）置換されていてもよいＣ１－６アルコキシ、
    　（１０）置換されていてもよいＣ１－６アルキルカルボニル、
    　（１１）－Ｎ（Ｒ１８）ＣＯＲ１９、及び
    　（１２）－ＮＲ１８Ｒ１９、
    からなる群から選択される同一又は異なる１～５個の置換基で置換されていてもよい基であり、ここにおいて、（１）～（４）に示す基は、後記（ａ）～（ｉ）からなる群から選択される同一又は異なる１～５個の置換基で置換されていてもよい基であり、（８）、（９）及び（１０）に示す基は、後記（ｂ）、（ｄ）、（ｅ）及びフッ素からなる群から選択される同一又は異なる１～５個の置換基で置換されていてもよい基であり、及び／又は、
    　＜ｉｉ＞項１における置換されていてもよいアリール及び置換されていてもよいヘテロアリールが、それぞれ独立して、
    　（ａ）ハロゲン、
    　（ｂ）水酸基、
    　（ｃ）置換されていてもよいＣ１－６アルキル、
    　（ｄ）置換されていてもよいＣ１－６アルコキシ、
    　（ｅ）－ＮＲ１８Ｒ１９、
    　（ｆ）－Ｎ（Ｒ１８）ＣＯＲ１９、
    　（ｇ）シアノ、及び
    　（ｈ）－ＣＯＮＲ１８Ｒ１９、
    　（ｉ）置換されていてもよいＣ１－６アルキルカルボニル、
    からなる群から選択される同一又は異なる１～５個の置換基で置換されていてもよい基を意味し、ここにおいて、（ｃ）、（ｄ）及び（ｉ）は、－ＮＲ１８Ｒ１９、水酸基、Ｃ１－６アルコキシ及びフッ素からなる群から選択される同一又は異なる１～５個の置換基で置換されていてもよい基であり、
    　Ｒ１８及びＲ１９が、それぞれ独立して、水素原子若しくは１～５個のフッ素で置換されていてもよいＣ１－１０アルキルであるか、又は、Ｒ１８とＲ１９は一緒になって４～１０員の含窒素飽和複素環を形成していてもよい、
    請求項１に記載の化合物又はその製薬学的に許容される塩。     <I> The optionally substituted alkyl, the optionally substituted cycloalkyl, and the optionally substituted 4- to 10-membered saturated heterocyclic ring in Item 1 are each independently
    (1) optionally substituted aryl,
    (2) optionally substituted heteroaryl,
    (3) an optionally substituted 4- to 10-membered saturated heterocyclic ring,
    (4) optionally substituted C 3-10 cycloalkyl,
    (5) -CONR 18 R 19
    (6) halogen,
    (7) hydroxyl group,
    (8) C 1-6 alkyl which may be substituted,
    (9) optionally substituted C 1-6 alkoxy,
    (10) optionally substituted C 1-6 alkylcarbonyl,
    (11) -N (R 18 ) COR 19 , and (12) -NR 18 R 19 ,
    A group which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of: wherein the groups shown in (1) to (4) are the following Is a group which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of: (8), (9) and (10), (D), (e) and a group which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of fluorine and / or
    <Ii> The optionally substituted aryl and the optionally substituted heteroaryl in Item 1 are each independently
    (A) halogen,
    (B) a hydroxyl group,
    (C) optionally substituted C 1-6 alkyl,
    (D) an optionally substituted C 1-6 alkoxy,
    (E) -NR 18 R 19 ,
    (F) —N (R 18 ) COR 19 ,
    (G) cyano, and (h) -CONR 18 R 19 ,
    (I) an optionally substituted C 1-6 alkylcarbonyl,
    Means a group which may be substituted with the same or different 1 to 5 substituents selected from the group consisting of: wherein (c), (d) and (i) are —NR 18 R 19 , a hydroxyl group, a C 1-6 alkoxy and the same or different one to five substituents group which may be substituted by groups selected from the group consisting of fluorine,
    R 18 and R 19 are each independently a hydrogen atom or C 1-10 alkyl optionally substituted with 1 to 5 fluorines, or R 18 and R 19 taken together 4 May form a 10-membered nitrogen-containing saturated heterocyclic ring,
    The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
  3. 　ｎが１である、
    請求項１又は項２に記載の化合物又はその製薬学的に許容される塩。     n is 1,
    The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.
  4. 　Ｒ４Ａ、Ｒ４Ｂ、Ｒ５及びＲ７が、同一又は異なって、アリール、ヘテロアリール、４～１０員の飽和複素環、Ｃ３－１０シクロアルキル、フッ素、水酸基、１～５個のフッ素で置換されていてもよいＣ１－６アルコキシ、Ｃ１－６アルキルカルボニル及び－ＮＲ１８Ｒ１９からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－１０アルキル；Ｃ３－１０シクロアルキル；４～１０員の飽和複素環；又は水素原子であり（前記アリール、ヘテロアリール、飽和複素環及びシクロアルキルは、フッ素、水酸基、Ｃ１－６アルキル（該基は、フッ素、Ｃ１－６アルコキシ及び－ＮＲ１８Ｒ１９からなる群から独立して選択される１～５個の置換基で置換されていてもよい）、１～５個のフッ素で置換されていてもよいＣ１－６アルコキシ、Ｃ１－６アルキルカルボニル、及び－ＮＲ１８Ｒ１９からなる群から独立して選択される１～５個の置換基で置換されていてもよい）、ここにおいて、（１）Ｒ４Ａ及びＲ４Ｂは一緒になって４～１０員の含窒素飽和複素環（該環は、上記飽和複素環と同様の置換基で置換されていてもよい）を形成していてもよく、（２）Ｒ４Ａ及びＲ４Ｂは、共に水素原子ではなく、（３）Ｒ５は、水素原子ではない、
    請求項１～３のいずれか一項に記載の化合物又はその製薬学的に許容される塩。     R 4A , R 4B , R 5 and R 7 are the same or different and are aryl, heteroaryl, 4-10 membered saturated heterocycle, C 3-10 cycloalkyl, fluorine, hydroxyl group, 1-5 fluorines. optionally substituted C 1-6 alkoxy, C 1-6 alkylcarbonyl and -NR 18 may be substituted with 1 to 5 substituents selected independently from the group consisting of R 19 C 1 -10 alkyl; C 3-10 cycloalkyl; 4 to 10-membered saturated heterocyclic ring; or a hydrogen atom (the aryl, heteroaryl, saturated heterocyclic ring and cycloalkyl are fluorine, hydroxyl group, C 1-6 alkyl ( The group may be substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, C 1-6 alkoxy and —NR 18 R 19 ). Replaced Optionally substituted by 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy, C 1-6 alkylcarbonyl, and —NR 18 R 19 ), Here, (1) R 4A and R 4B together form a 4- to 10-membered nitrogen-containing saturated heterocyclic ring (the ring may be substituted with the same substituent as the saturated heterocyclic ring). (2) R 4A and R 4B are not both hydrogen atoms, and (3) R 5 is not a hydrogen atom.
    The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.
  5. 　Ａが、ＣＲ１Ｄである、
    請求項１～４のいずれか一項に記載の化合物又はその製薬学的に許容される塩。     A is CR 1D ,
    The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.
  6. 　Ｗが、ＣＨである、
    請求項１～５のいずれか一項に記載の化合物又はその製薬学的に許容される塩。     W is CH,
    The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.
  7. 　Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ４ＡＲ４Ｂ、ＣＲ６－ＣＯ－ＮＲ４ＡＲ４Ｂ、ＣＲ６－ＮＲ７－ＣＯ－ＮＲ４ＡＲ４Ｂ又はＣＲ６－ＮＲ７－ＣＯＲ５である、
    請求項１～６のいずれか一項に記載の化合物又はその製薬学的に許容される塩。     XYZ is N—CO—NR 4A R 4B , CR 6 —CO—NR 4A R 4B , CR 6 —NR 7 —CO—NR 4A R 4B or CR 6 —NR 7 —COR 5 ;
    The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.
  8. 　Ｒ２が、フッ素、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１０Ｒ１１からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；フッ素、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１０Ｒ１１からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルキル若しくは４～１０員の飽和複素環；水素原子；又はＣ１－６アルキルカルボニルである、
    請求項１～７のいずれか一項に記載の化合物又はその製薬学的に許容される塩。     R 2 is fluorine, hydroxyl, C 1-6 alkoxy and -NR 10 may be substituted with 1 to 5 substituents selected independently from the group consisting of R 11 C 1-6 alkyl; fluorine C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of hydroxyl group, C 1-6 alkoxy and —NR 10 R 11, or 4 to 10 membered A saturated heterocyclic ring; a hydrogen atom; or C 1-6 alkylcarbonyl.
    The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.
  9. 　Ｒ１Ａ、Ｒ１Ｂ、Ｒ１Ｃ及びＲ１Ｄが、同一又は異なって、フッ素、水酸基、Ｃ１－６アルコキシ、－ＮＲ８Ｒ９、－ＣＯＮＲ８Ｒ９及び－ＮＲ８ＣＯＲ９からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；フッ素、水酸基、Ｃ１－６アルキル、Ｃ１－６アルコキシ、－ＮＲ８Ｒ９、－ＣＯＮＲ８Ｒ９及び－ＮＲ８ＣＯＲ９からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルキル、４～１０員の飽和複素環若しくは４～１０員の飽和複素環基－Ｏ－；ハロゲン、水酸基、Ｃ１－６アルコキシ、－ＮＲ８Ｒ９、－ＣＯＮＲ８Ｒ９及び－ＮＲ８ＣＯＲ９からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルコキシ；ハロゲン、水酸基、Ｃ１－６アルコキシ、－ＮＲ８Ｒ９、－ＣＯＮＲ８Ｒ９及び－ＮＲ８ＣＯＲ９からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルコキシ；水素原子；水酸基；ハロゲン；－ＮＲ８Ｒ９；シアノ；－ＣＯＮＲ８Ｒ９；又は－ＮＲ８ＣＯＲ９である、
    請求項１～８のいずれか一項に記載の化合物又はその製薬学的に許容される塩。     R 1A , R 1B , R 1C and R 1D are the same or different and independent from the group consisting of fluorine, hydroxyl group, C 1-6 alkoxy, —NR 8 R 9 , —CONR 8 R 9 and —NR 8 COR 9. and 1-5 which may be C 1-6 alkyl substituted with a substituent selected; fluorine, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, -NR 8 R 9, -CONR 8 C 3-10 cycloalkyl, 4-10 membered saturated heterocycle optionally substituted with 1-5 substituents independently selected from the group consisting of R 9 and —NR 8 COR 9, 10-membered saturated heterocyclic group —O—; 1 to independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy, —NR 8 R 9 , —CONR 8 R 9 and —NR 8 COR 9 Substituted with 5 substituents Which may be C 1-6 alkoxy; halogen, hydroxyl, C 1-6 alkoxy, -NR 8 R 9, 1 ~ 5 substituents independently selected from the group consisting of -CONR 8 R 9 and -NR 8 COR 9 A C 3-10 cycloalkoxy optionally substituted with a substituent of: a hydrogen atom; a hydroxyl group; a halogen; —NR 8 R 9 ; cyano; —CONR 8 R 9 ; or —NR 8 COR 9 .
    The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.
  10. 　Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ４ＡＲ４Ｂ、ＣＲ６－ＮＲ７－ＣＯ－ＮＲ４ＡＲ４Ｂ又はＣＲ６－ＮＲ７－ＣＯＲ５である、
    請求項１～９のいずれか一項に記載の化合物又はその製薬学的に許容される塩。     XYZ is N—CO—NR 4A R 4B , CR 6 —NR 7 —CO—NR 4A R 4B or CR 6 —NR 7 —COR 5 ;
    The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.
  11. 　Ｒ４Ａ又はＲ４Ｂのいずれか一方が水素原子である、
    請求項１～１０のいずれか一項に記載の化合物又はその製薬学的に許容される塩。     Either one of R 4A or R 4B is a hydrogen atom,
    The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.
  12. 　Ｒ３Ａ、Ｒ３Ｂ、Ｒ３Ｃ、Ｒ３Ｄ及びＲ３Ｅが、同一又は異なって、１～５個のフッ素で置換されていてもよいＣ１－６アルキル；Ｃ１－６アルコキシ；水素原子；又はフッ素である、
    請求項１～１１のいずれか一項に記載の化合物又はその製薬学的に許容される塩。     R 1A , R 3B , R 3C , R 3D and R 3E are the same or different and may be substituted with 1 to 5 fluorine atoms; C 1-6 alkyl; C 1-6 alkoxy; hydrogen atom; or Is fluorine,
    The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.
  13. 　Ｒ４Ａ、Ｒ４Ｂ、Ｒ５及びＲ７が、同一又は異なって、４～１０員の飽和複素環、Ｃ３－１０シクロアルキル、フッ素、水酸基、１～５個のフッ素で置換されていてもよいＣ１－６アルコキシ及び－ＮＲ１８Ｒ１９からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－１０アルキル；Ｃ３－１０シクロアルキル；４～１０員の飽和複素環；又は水素原子であり（前記飽和複素環及びシクロアルキルは、フッ素、水酸基、Ｃ１－６アルキル（該基はフッ素、Ｃ１－６アルコキシ及び－ＮＲ１８Ｒ１９からなる群から独立して選択される１～５個の置換基で置換されていてもよい）、１～５個のフッ素で置換されていてもよいＣ１－６アルコキシ、Ｃ１－６アルキルカルボニル、又は－ＮＲ１８Ｒ１９からなる群から独立して選択される１～５個の置換基で置換されていてもよい）、ここにおいて、（１）Ｒ４Ａ及びＲ４Ｂは一緒になって４～１０員の含窒素飽和複素環（該環は、上記飽和複素環と同様の置換基で置換されていてもよい）を形成していてもよく、（２）Ｒ４Ａ及びＲ４Ｂは、共に水素原子ではなく、（３）Ｒ５は、水素原子ではない、
    請求項１～１２のいずれか一項に記載の化合物又はその製薬学的に許容される塩。     R 4A , R 4B , R 5 and R 7 may be the same or different and may be substituted with a 4 to 10-membered saturated heterocyclic ring, C 3-10 cycloalkyl, fluorine, a hydroxyl group, or 1 to 5 fluorine atoms. C 1-10 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy and —NR 18 R 19 ; C 3-10 cycloalkyl; 4 A 10-membered saturated heterocycle; or a hydrogen atom (the saturated heterocycle and cycloalkyl are fluorine, hydroxyl, C 1-6 alkyl (the group is derived from fluorine, C 1-6 alkoxy and —NR 18 R 19) Optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy, C 1-6 alkylcarbonyl optionally substituted with 1 to 5 fluorines , or -NR 18 R It may be substituted with 1 to 5 substituents selected independently from the group consisting of 9), wherein, (1) R 4A and R 4B are nitrogen-containing 4-10 membered together A saturated heterocyclic ring (which may be substituted with the same substituent as the saturated heterocyclic ring), and (2) R 4A and R 4B are not hydrogen atoms, 3) R 5 is not a hydrogen atom,
    The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.
  14. 　Ｒ１Ａ、Ｒ１Ｂ、Ｒ１Ｃ及びＲ１Ｄは、同一又は異なって、フッ素、水酸基及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；フッ素、水酸基及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－８シクロアルキル；フッ素、水酸基及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルコキシ；フッ素、水酸基及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルコキシ；水素原子；水酸基；ハロゲン；又は４～１０員の飽和複素環である、
    請求項１～１３のいずれか一項に記載の化合物又はその製薬学的に許容される塩。     R 1A , R 1B , R 1C and R 1D are the same or different and may be substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, hydroxyl group and C 1-6 alkoxy. Good C 1-6 alkyl; C 3-8 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, hydroxyl and C 1-6 alkoxy; fluorine, hydroxyl And C 1-6 alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy; independent from the group consisting of fluorine, hydroxyl group and C 1-6 alkoxy A C 3-10 cycloalkoxy optionally substituted with 1 to 5 substituents selected as above; a hydrogen atom; a hydroxyl group; a halogen; or a 4- to 10-membered saturated heterocyclic ring,
    The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.
  15. 　Ｒ６が、Ｃ１-６アルキル、Ｃ１-６アルコキシ、フッ素又は水素原子である、
    請求項１～１４のいずれか一項に記載の化合物又はその製薬学的に許容される塩。     R 6 is C 1-6 alkyl, C 1-6 alkoxy, fluorine or a hydrogen atom,
    The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.
  16. 　Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ４ＡＲ４Ｂ又はＣＲ６－ＮＲ７－ＣＯＲ５である、
    請求項１～１５のいずれか一項に記載の化合物又はその製薬学的に許容される塩。     XYZ is N—CO—NR 4A R 4B or CR 6 —NR 7 —COR 5 ;
    The compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.
  17. 　Ｒ４Ａ、Ｒ４Ｂ、Ｒ５及びＲ７が、同一又は異なって、Ｃ３－１０シクロアルキル；４～１０員の飽和複素環；又は水素原子であり（前記飽和複素環及びシクロアルキルは、フッ素、水酸基、Ｃ１－６アルキル（該基はフッ素及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよい）又は１～５個のフッ素で置換されていてもよいＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよい）、ここにおいて、（１）Ｒ４Ａ及びＲ４Ｂは、共に水素原子ではなく、（２）Ｒ５は、水素原子ではない、
    請求項１～１６のいずれか一項に記載の化合物又はその製薬学的に許容される塩。     R 4A , R 4B , R 5 and R 7 are the same or different and are a C 3-10 cycloalkyl; a 4-10 membered saturated heterocycle; or a hydrogen atom (the saturated heterocycle and cycloalkyl are fluorine , A hydroxyl group, C 1-6 alkyl (the group may be substituted with 1 to 5 substituents independently selected from the group consisting of fluorine and C 1-6 alkoxy) or 1 to 5 (Optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy optionally substituted with fluorine), wherein (1) R 4A and R 4B Are not both hydrogen atoms, (2) R 5 is not a hydrogen atom,
    The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof.
  18. 　Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ４ＡＲ４Ｂである、
    請求項１～１７のいずれか一項に記載の化合物又はその製薬学的に許容される塩。     XYZ is N—CO—NR 4A R 4B ;
    The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17.
  19. 　請求項１～１８のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩を含有する医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof.
  20. 　請求項１～１８のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩を有効成分とするアセチルコリンが関与する細胞内シグナル伝達の異常に起因する疾患の治療剤又は予防剤。 A therapeutic or prophylactic agent for a disease caused by an abnormality in intracellular signal transduction involving acetylcholine, comprising the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof as an active ingredient .
  21. 　アセチルコリンが関与する細胞内シグナル伝達の異常に起因する疾患が、神経系疾患、精神疾患又は炎症性疾患である、
    請求項２０に記載の治療剤。     The disease caused by an abnormality in intracellular signal transduction involving acetylcholine is a nervous system disease, mental disease or inflammatory disease,
    The therapeutic agent of Claim 20.
  22. 　神経系疾患、精神疾患又は炎症性疾患が、認知症、統合失調症、ＣＩＡＳ（統合失調症に伴う認知機能障害）、アルツハイマー病、ダウン症、注意欠陥障害又は脳血管アンギオパチーである、
    請求項２１に記載の治療剤。     The nervous system disease, psychiatric disease or inflammatory disease is dementia, schizophrenia, CIAS (cognitive impairment associated with schizophrenia), Alzheimer's disease, Down's syndrome, attention deficit disorder or cerebrovascular angiopathy,
    The therapeutic agent according to claim 21.
  23. 　請求項１～１８のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩と、非定型抗精神病薬に分類される薬剤から選択される少なくとも１種以上の薬剤とを組み合わせてなる医薬。 A combination of the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof and at least one drug selected from drugs classified as atypical antipsychotic drugs The medicine which becomes.
  24. 　治療が必要な患者に、治療上の有効量の請求項１～１８のいずれか１項に記載の化合物又はその製薬学的に許容される塩を投与することを特徴とするアセチルコリンが関与する細胞内シグナル伝達の異常に起因する疾患の治療又は予防方法。 A cell involving acetylcholine, characterized in that a therapeutically effective amount of the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof is administered to a patient in need of treatment A method for treating or preventing a disease caused by abnormal signal transduction.
  25. 　アセチルコリンが関与する細胞内シグナル伝達の異常に起因する疾患の治療又は予防のための請求項１～１８のいずれか１項に記載の化合物又はその製薬学的に許容される塩。 The compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof for the treatment or prevention of a disease caused by an abnormality in intracellular signal transduction involving acetylcholine.
  26. 　アセチルコリンが関与する細胞内シグナル伝達の異常に起因する疾患の治療又は予防に使用する、請求項１～１８のいずれか１項に記載の化合物又はその製薬学的に許容される塩を含む医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease caused by an abnormality in intracellular signal transduction involving acetylcholine. object.
  27. 　アセチルコリンが関与する細胞内シグナル伝達の異常に起因する疾患の治療剤又は予防剤を製造するための請求項１～１８のいずれか１項に記載の化合物又はその製薬学的に許容される塩の使用。 The compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof for producing a therapeutic or prophylactic agent for a disease caused by an abnormality in intracellular signal transduction involving acetylcholine. use.
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