WO2015152254A1 - Five-membered ring heteroaryl derivative - Google Patents

Five-membered ring heteroaryl derivative Download PDF

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Publication number
WO2015152254A1
WO2015152254A1 PCT/JP2015/060155 JP2015060155W WO2015152254A1 WO 2015152254 A1 WO2015152254 A1 WO 2015152254A1 JP 2015060155 W JP2015060155 W JP 2015060155W WO 2015152254 A1 WO2015152254 A1 WO 2015152254A1
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compound
alkyl
pharmaceutically acceptable
acceptable salt
optionally substituted
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PCT/JP2015/060155
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French (fr)
Japanese (ja)
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光貴 岩田
恭次 石田
尚明 島田
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大日本住友製薬株式会社
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Publication of WO2015152254A1 publication Critical patent/WO2015152254A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • A61K31/42—Oxazoles
    • 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
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/14—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing alicyclic rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a novel 5-membered heteroaryl derivative that 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, it is assumed that the development of novel modulators of the receptor will lead to novel treatments for nervous system diseases, psychiatric diseases and inflammatory diseases.
  • Patent Document 1 Patent Document 2, Patent Document 3, Patent Document 4
  • Patent Document 5 Patent Document 6
  • the problem to be solved by the present invention is a novel having a positive modulator action of a potent ⁇ 7 nicotinic acetylcholine receptor ( ⁇ 7 nAChR) and useful as a novel therapeutic agent for nervous system diseases, mental diseases and inflammatory diseases. It is to provide a compound.
  • ⁇ 7 nAChR potent ⁇ 7 nicotinic acetylcholine receptor
  • a novel compound represented by the following formula (I) has a positive modulator action of a potent ⁇ 7 nicotinic acetylcholine receptor ( ⁇ 7 nAChR).
  • ⁇ 7 nAChR potent ⁇ 7 nicotinic acetylcholine receptor
  • XYZ is N—COR 4A
  • R 4A is not C 3 alkyl substituted with 1 to 5 fluorines
  • R 3A and R 3B are both C 1-6 When alkyl, together with the nitrogen atom to which they are attached, is substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, C 1-6 alkyl and C 1-6 alkoxy. It may form a 4- to 10-membered nitrogen-containing saturated heterocyclic ring. Or a pharmaceutically acceptable salt thereof.
  • R 3A , R 3B , R 4A , R 4B and R 6 are the same or different and are independently selected from the group consisting of fluorine, C 1-6 alkoxy, and C 3-10 cycloalkyl.
  • C 1-6 alkyl optionally substituted with 1-5 substituents; 1-5 substituents independently selected from the group consisting of fluorine, C 1-6 alkoxy and C 1-6 alkyl in an optionally substituted C 3-10 cycloalkyl; saturated heterocyclic 4-10 membered; a or a hydrogen atom, wherein, (1) R 4A and R 4B are not hydrogen atom, (2) R 3A and R 3B are not simultaneously hydrogen atoms; (3) when B is B-3, W is an oxygen atom, and XYZ is N-COR 4A , R 4A is not methyl (4) A is unsubstituted phenyl and B is B- In it, W is an oxygen atom, when X-Y-Z is N-COR 4A
  • R 3A , R 3B and R 4A are the same or different and are each 1 to 5 substituents independently selected from the group consisting of fluorine, C 1-6 alkoxy and C 1-6 alkyl An optionally substituted C 3-10 cycloalkyl; a 4-10 membered saturated heterocycle; or a hydrogen atom, wherein R 3A and R 3B are not simultaneously a hydrogen atom and R 4A is not a hydrogen atom , Item 3.
  • R 4B is good fluorine, C 1-6 alkoxy, and C 3-10 optionally substituted with one to five substituents independently selected from the group consisting of cycloalkyl C 1- 6 alkyl, Item 4.
  • A is phenyl or pyridyl (the phenyl and the pyridyl are each substituted with fluorine, C 1-6 alkyl optionally substituted with 1 to 5 fluorine, and 1 to 5 fluorine. And optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy).
  • Item 5 The compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.
  • A is phenyl (the phenyl is each fluorine, C 1-6 alkyl optionally substituted with 1 to 5 fluorines, and C 1 optionally substituted with 1 to 5 fluorines) Optionally substituted with 1 to 5 substituents independently selected from the group consisting of -6 alkoxy.) Item 5.
  • A is pyridyl (the pyridyl is each fluorine, C 1-6 alkyl optionally substituted with 1 to 5 fluorines, and C 1 optionally substituted with 1 to 5 fluorines) Optionally substituted with 1 to 5 substituents independently selected from the group consisting of -6 alkoxy.) Item 5.
  • R 1 is a hydrogen atom; halogen; cyano; C 1-6 alkyl; or C 3-10 cycloalkyl.
  • Item 8 The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof.
  • R 1 is a hydrogen atom, chlorine or cyano.
  • Item 8 The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof.
  • R 1 is a hydrogen atom.
  • Item 8 The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof.
  • R 1 is chlorine.
  • Item 8 The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof.
  • W is an oxygen atom.
  • Item 12 The compound according to any one of Items 1 to 11 or a pharmaceutically acceptable salt thereof.
  • W is a sulfur atom.
  • Item 12 The compound according to any one of Items 1 to 11 or a pharmaceutically acceptable salt thereof.
  • R 2A , R 2B , R 2C , R 2D and R 5 are the same or different and are a hydrogen atom or C 1-6 alkyl, wherein R 2A , R 2B , R 2C , R When any two of 2D and R 5 are C 1-6 alkyl, the two alkyls may be combined together to form another ring with the ring to which the alkyl is attached, Item 14.
  • R 2A , R 2B , R 2C , R 2D and R 5 are all hydrogen atoms.
  • Item 14 The compound according to any one of Items 1 to 13, or a pharmaceutically acceptable salt thereof.
  • R 6 is optionally fluorine, C 1-6 alkoxy, and C 3-10 optionally substituted with one to five substituents independently selected from the group consisting of cycloalkyl C 1- 6 alkyl; or a hydrogen atom, Item 16.
  • R 6 is a hydrogen atom.
  • Item 16 The compound according to any one of Items 1 to 15, or a pharmaceutically acceptable salt thereof.
  • R 3B is a hydrogen atom
  • R 3A and R 4A are the same or different and are independently selected from the group consisting of fluorine, C 1-6 alkoxy and C 1-6 alkyl A C 3-10 cycloalkyl optionally substituted with 5 substituents; or a 4-10 membered saturated heterocycle, Item 18.
  • XYZ is N—CO—NR 3A R 3B or N—COR 4A .
  • Item 19 The compound according to any one of Items 1 to 18, or a pharmaceutically acceptable salt thereof.
  • XYZ is N—CO—NR 3A R 3B .
  • Item 19 The compound according to any one of Items 1 to 18, or a pharmaceutically acceptable salt thereof.
  • XYZ is N-COR 4A .
  • Item 19 The compound according to any one of Items 1 to 18, or a pharmaceutically acceptable salt thereof.
  • XYZ is CR 5 —CO—NR 3A R 3B .
  • Item 19 The compound according to any one of Items 1 to 18, or a pharmaceutically acceptable salt thereof.
  • XYZ is CR 5 —NR 6 —COR 4B .
  • Item 19 The compound according to any one of Items 1 to 18, or a pharmaceutically acceptable salt thereof.
  • B is B-1.
  • Item 24 The compound according to any one of Items 1 to 23 or a pharmaceutically acceptable salt thereof.
  • B is B-2.
  • Item 24 The compound according to any one of Items 1 to 23 or a pharmaceutically acceptable salt thereof.
  • [Section 26] B is B-3.
  • Item 24 The compound according to any one of Items 1 to 23 or a pharmaceutically acceptable salt thereof.
  • B is B-4.
  • Item 24 The compound according to any one of Items 1 to 23 or a pharmaceutically acceptable salt thereof.
  • [Item 28] B is B-5.
  • Item 24 The compound according to any one of Items 1 to 23 or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising the compound according to any one of items 1 to 29 or a pharmaceutically acceptable salt thereof.
  • CIAS cognitive impairment associated with schizophrenia
  • cognitive impairment mild cognitive impairment
  • memory impairment in schizophrenia Alzheimer's disease, Down's syndrome
  • attention deficit / hyperactivity disorder or cerebrovascular angiopathy or Item 31 A pharmaceutical composition according to Item 30, for treating and / or preventing learning disorders.
  • a pharmaceutical comprising the compound according to any one of items 1 to 29 or a pharmaceutically acceptable salt thereof and at least one drug selected from atypical antipsychotics .
  • [Item 35] Acetylcholine characterized by administering a therapeutically effective amount of the compound according to any one of Items 1 to 29 or a pharmaceutically acceptable salt thereof to a patient in need of treatment.
  • the compound of the present invention is useful as a therapeutic and / or prophylactic agent for diseases caused by abnormalities in intracellular signal transduction involving acetylcholine.
  • diseases caused by abnormal intracellular signal transduction involving acetylcholine include a neurological disease, a mental disease or an inflammatory disease.
  • neurological diseases, psychiatric diseases or inflammatory diseases include schizophrenia, Alzheimer's disease, Down's syndrome, attention deficit / hyperactivity disorder, or cerebrovascular angiopathy.
  • the compound of the present invention is (1) CIAS (cognitive dysfunction associated with schizophrenia), or (2) schizophrenia, Alzheimer's disease, Down's syndrome, attention deficit / hyperactivity disorder or cerebrovascular angiopathy, Useful for treating and / or preventing cognitive impairment, mild cognitive impairment, memory impairment or learning impairment.
  • CIAS cognitive dysfunction associated with schizophrenia
  • schizophrenia Alzheimer's disease, Down's syndrome, attention deficit / hyperactivity disorder or cerebrovascular angiopathy, Useful for treating and / or preventing cognitive impairment, mild cognitive impairment, memory impairment or learning impairment.
  • the compound of the present invention can be used in combination with an atypical antipsychotic agent for the purpose of the treatment and / or prevention.
  • the compound of the present invention may exist in the form of a hydrate and / or a solvate, a hydrate of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and / or Alternatively, solvates are also encompassed by the compounds of the present invention.
  • 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.
  • 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.
  • Crystalline polymorphisms may exist in the compound represented by the general formula (I) obtained as crystals and pharmaceutically acceptable salts thereof, and the compounds of the present invention may be in any crystalline form. included.
  • Alkyl means a linear or branched saturated hydrocarbon group.
  • C 1-4 alkyl or “C 1-6 alkyl” has 1 to 4 carbon atoms or Means 1-6 alkyl.
  • C 1-6 alkyl “C 1-4 alkyl” is preferable. Specific examples thereof include “C 1-4 alkyl” such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like.
  • pentyl, isopentyl, neopentyl, hexyl and the like can be mentioned.
  • Cycloalkyl means a group consisting of monocyclic or polycyclic saturated hydrocarbons.
  • C 3-10 cycloalkyl means a cyclic alkyl having 3 to 10 carbon atoms.
  • crosslinking is mentioned. Specific examples thereof include “C 3-10 cycloalkyl” such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl and the like.
  • Alkoxy means a group in which a linear or branched saturated hydrocarbon group is bonded to an oxygen atom, and is bonded to another moiety via the oxygen atom.
  • C 1-6 alkoxy means alkoxy having 1 to 6 carbon atoms. Specific examples of “C 1-6 alkoxy” include methoxy, ethoxy, propoxy, isopropoxy, butyloxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like.
  • 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.
  • 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.
  • Preferred 4- to 10-membered saturated heterocycles include tetrahydrofuran, tetrahydropyran, and oxetane. More preferred is tetrahydropyran.
  • the “4- to 10-membered nitrogen-containing saturated heterocycle” means 0 to 2 atoms independently selected from the group consisting of 1 to 2 nitrogen atoms, oxygen atoms and sulfur atoms in addition to carbon atoms.
  • a saturated heterocyclic ring composed of 4 to 10 atoms is included.
  • azetidine, pyrrolidine, piperidine, piperazine, homopiperidine and the like can be mentioned.
  • Preferred examples of the 4 to 10-membered nitrogen-containing saturated heterocyclic ring include saturated heterocyclic rings composed of 4 to 10 atoms containing one nitrogen atom in addition to the carbon atom.
  • azetidine, pyrrolidine, piperidine and the like can be mentioned.
  • A, B, W, XYZ, R 1 , R 2A , R 2B , R 2C , R 2D , R 3A , R 3B , R 4A , R 4B , R 5 and R 6 are preferably as follows, but the technical scope of the present invention is not limited to the scope of the compounds listed below.
  • X—Y—Z is preferably N—CO—NR 3A R 3B , N—COR 4A , CR 5 —CO—NR 3A R 3B or CR 5 —NR 6 —COR 4B . More preferably, N—CO—NR 3A R 3B , N—COR 4A or CR 5 —NR 6 —COR 4B may be mentioned. More preferred is N—CO—NR 3A R 3B or N—COR 4A .
  • A is preferably phenyl or pyridyl (the phenyl and pyridyl are each substituted with halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1 to 5 fluorine, and 1 to 5 fluorine. And optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy. More preferably, phenyl or pyridyl (the phenyl and the pyridyl are each substituted with fluorine, chlorine, C 1-6 alkyl optionally substituted with 1 to 5 fluorine, and 1 to 5 fluorine. And optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy.
  • it is 1 to 5 substituents independently selected from the group consisting of fluorine, chlorine, C 1-6 alkyl optionally substituted with 1 to 3 fluorine and C 1-6 alkoxy.
  • substituents independently selected from the group consisting of fluorine, chlorine, C 1-6 alkyl optionally substituted with 1 to 3 fluorine and C 1-6 alkoxy.
  • Examples include optionally substituted phenyl.
  • phenyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine and C 1-6 alkoxy.
  • B is preferably B-1, B-2, B-3, B-4 or B-5. More preferred is B-1, B-4 or B-5. More preferred is B-1 or B-4.
  • W is preferably an oxygen atom or a sulfur atom. More preferably, an oxygen atom is mentioned.
  • R 1 is preferably a hydrogen atom; halogen; cyano; or halogen, hydroxyl, C 3-10 cycloalkyl optionally substituted with 1 to 5 fluorines, C 1-6 alkoxy, and 4 to 10 membered saturation And C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of heterocycles. More preferably, a hydrogen atom, halogen, or cyano is mentioned. More preferably, a hydrogen atom, chlorine, or cyano is mentioned. Most preferably, a hydrogen atom or chlorine is mentioned.
  • R 2A , R 2B , R 2C , R 2D and R 5 are preferably the same or different and include a hydrogen atom, fluorine, a hydroxyl group or C 1-6 alkyl.
  • R 2A , R 2B , R 2C , R 2D and R 5 are C 1-6 alkyl optionally substituted with 1 to 5 fluorines, the two alkyls together To form a ring different from the ring to which the alkyl is bonded.
  • R 2A , R 2B , R 2C , R 2D and R 5 are more preferably the same or different and include a hydrogen atom or C 1-6 alkyl.
  • R 2A , R 2B , R 2C , R 2D and R 5 are C 1-6 alkyl
  • the two alkyls are joined together to form a ring to which the alkyl is bonded Another ring may be formed.
  • R 2A , R 2B , R 2C , R 2D and R 5 are more preferably a hydrogen atom.
  • R 3A , R 3B and R 4A are preferably the same or different and are halogen, hydroxyl group, C 1-6 alkoxy, C 3-10 cycloalkyl and a 4- to 10-membered saturated heterocyclic ring (provided that a carbonyl group is present on the ring).
  • C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of: a halogen, a hydroxyl group, C 1-6 alkoxy and C 1-6 alkyl C 3-10 cycloalkyl optionally substituted with 1-5 substituents independently selected from the group consisting of: 4-10 membered saturated heterocycle optionally substituted with C 1-6 alkyl Or a hydrogen atom, wherein (1) R 4A is not a hydrogen atom, (2) R 3A and R 3B are not simultaneously a hydrogen atom, (3) B is B-3, and W is An oxygen atom, X- When -Z is N-COR 4A is, R 4A is not methyl, (4) A a is unsubstituted phenyl, B is B-4, W is an oxygen atom, X-Y- When Z is N—COR 4A , R 4A is not C 3 alkyl substituted with 1 to 5 fluorines.
  • R 3A , R 3B and R 4A are the same or different and are 1 to 5 substituents independently selected from the group consisting of fluorine, C 1-6 alkoxy and C 3-10 cycloalkyl C 1-6 alkyl optionally substituted with 1-6 alkyls independently selected from the group consisting of fluorine, C 1-6 alkoxy and C 1-6 alkyl C 3-10 cycloalkyl; a 4-10 membered saturated heterocycle; or a hydrogen atom, where (1) R 4A is not a hydrogen atom and (2) R 3A and R 3B are simultaneously a hydrogen atom And (3) when B is B-3, W is an oxygen atom, and XYZ is N—COR 4A , R 4A is not methyl and (4) A is unsubstituted Phenyl, B is B-4, W is An atom, X-Y-Z is and when is N-COR 4A, R 4A is not C 3 alkyl substituted with 1-5 fluorine.
  • R 3A , R 3B and R 4A are the same or different and substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, C 1-6 alkoxy and C 1-6 alkyl A C 3-10 cycloalkyl which may be substituted ; a 4 to 10 membered saturated heterocyclic ring; or a hydrogen atom, wherein R 3A and R 3B are not simultaneously a hydrogen atom and R 4A is not a hydrogen atom .
  • R 3A and R 4A the same or different, fluorine and C 1-6 optionally substituted with 1-5 substituents independently selected from the group consisting of alkoxy C 3-10 Examples include cycloalkyl or a 4- to 10-membered saturated heterocyclic ring.
  • R 3B includes a hydrogen atom.
  • R 4A is not C 3 alkyl substituted with 1 to 5 fluorines means that “R 4A is substituted with 1 to 5 fluorines, It is not C 3 alkyl not substituted with a substituent ”.
  • R 4B is preferably selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy, C 3-10 cycloalkyl and a 4-10 membered saturated heterocyclic ring not substituted with a carbonyl group.
  • C 1-6 alkyl optionally substituted with 5 substituents; 1-5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy and C 1-6 alkyl C 3-10 cycloalkyl which may be substituted with a 4-10 membered saturated heterocyclic ring which may be substituted with C 1-6 alkyl.
  • fluorine, C 1-6 alkoxy, and C 3-10 1 ⁇ 5 amino optionally substituted with a substituent C 1-6 alkyl independently selected from the group consisting of cycloalkyl; fluorine C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy and C 1-6 alkyl; or 4-10 membered saturation Heterocycles are mentioned. More preferable examples include C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, C 1-6 alkoxy, and C 3-10 cycloalkyl. It is done. Most preferred is C 1-6 alkyl optionally substituted with 1 to 5 fluorines.
  • R 6 is preferably selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy, C 3-10 cycloalkyl and a 4-10 membered saturated heterocyclic ring not substituted with a carbonyl group.
  • C 1-6 alkyl optionally substituted with 5 substituents; 1-5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy and C 1-6 alkyl
  • fluorine, C 1-6 alkoxy, and C 3-10 1 ⁇ 5 amino optionally substituted with a substituent C 1-6 alkyl independently selected from the group consisting of cycloalkyl; fluorine C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy and C 1-6 alkyl; A ring; or a hydrogen atom. More preferably, fluorine, C 1-6 alkoxy, and C 3-10 1 ⁇ 5 amino C 1-6 alkyl optionally substituted with a substituent selected independently from the group consisting of cycloalkyl; or A hydrogen atom is mentioned. Most preferably, a hydrogen atom is mentioned.
  • preferred compounds include the following compounds or pharmaceutically acceptable salts thereof.
  • (A) is mentioned as a preferable aspect.
  • (A) XYZ is N—CO—NR 3A R 3B , N—COR 4A , CR 5 —CO—NR 3A R 3B or CR 5 —NR 6 —COR 4B ;
  • A is phenyl or pyridyl (the phenyl and the pyridyl may each be substituted with halogen, hydroxyl group, C 1-6 alkyl optionally substituted with 1 to 5 fluorine, and 1 to 5 fluorine; And optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy),
  • B is B-1, B-2, B-3, B-4 or B-5,
  • W is an oxygen atom or a sulfur atom
  • R 1 is a hydrogen atom; halogen; cyano; or halogen, hydroxyl, C 3-10 cycloalkyl optionally substituted with 1 to 5 fluorines, C 1-6 al
  • R 3A , R 3B and R 4A are the same or different and are halogen, hydroxyl group, C 1-6 alkoxy, C 3-10 cycloalkyl and a 4- to 10-membered saturated heterocyclic ring (provided that a carbonyl group is present on the ring).
  • C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of: a group consisting of halogen, hydroxyl, C 1-6 alkoxy and C 1-6 alkyl
  • a C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from: a 4-10 membered saturated heterocycle optionally substituted with C 1-6 alkyl; or (1) R 4A is not a hydrogen atom, (2) R 3A and R 3B are not simultaneously hydrogen atoms, (3) B is B-3, and W is an oxygen atom.
  • X-Y-Z is N-COR
  • R 4A is not C 3 alkyl substituted with 1 to 5 fluorines
  • 1 to 5 R 4B independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy, C 3-10 cycloalkyl and a 4-10 membered saturated heterocyclic ring not substituted with a carbonyl group substituted halogen, hydroxyl, with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy and C 1-6 alkyl; the optionally substituted with a substituent C 1-6 alkyl An optionally substituted C 3-10 cycloalkyl; or a 4-10 membered saturated heterocycle optionally substituted with C 1-6 alkyl; 1 to 5 R 6 independently selected from the group
  • (B) is mentioned as a more preferable aspect.
  • (B) XYZ is N—CO—NR 3A R 3B , N—COR 4A or CR 5 —NR 6 —COR 4B ;
  • A is phenyl or pyridyl (each said phenyl and said pyridyl fluorine, chlorine, from one to five fluorines optionally substituted C 1-6 alkyl, optionally substituted with 1-5 fluorine Optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy),
  • B is B-1, B-2, B-3, B-4 or B-5, W is an oxygen atom or a sulfur atom,
  • R 1 is a hydrogen atom, halogen or cyano
  • R 2A , R 2B , R 2C , R 2D and R 5 are the same or different and are a hydrogen atom or C 1-6 alkyl, wherein R 2A , R 2B , R
  • R 4A is not a hydrogen atom
  • R 3A and R 3B are not simultaneously a hydrogen atom
  • B is B-3, W is an oxygen atom and XYZ is N-COR 4A , R 4A is not methyl and (4) A is unsubstituted phenyl; B is B-4, W is an oxygen atom, XY
  • Z is N-COR 4A is, R 4A is not C 3 alkyl substituted with 1-5 fluorine, R 4B is selected from the group consisting of fluorine, C 1-6 alkoxy, and C 3-10 1 ⁇ 5 amino optionally substituted with a substituent C 1-6 alkyl independently selected from the group consisting
  • (C) is N—CO—NR 3A R 3B or N—COR 4A ;
  • A is substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, chlorine, C 1-6 alkyl optionally substituted with 1 to 3 fluorine and C 1-6 alkoxy Which may be phenyl, B is B-1, B-4 or B-5, W is an oxygen atom,
  • R 1 is a hydrogen atom, chlorine or cyano
  • R 2A , R 2B , R 2C and R 2D are hydrogen atoms,
  • R 3A , R 3B and R 4A are the same or different and are substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, C 1-6 alkoxy and C 1-6 alkyl A C 3-10 cycloalkyl; a 4-10 membered saturated heterocyclic ring; or a hydrogen atom, wherein R 3A and R 3B are not simultaneously a hydrogen
  • the most preferable embodiment includes the following (D).
  • (D) XYZ is N—CO—NR 3A R 3B or N—COR 4A ;
  • A is phenyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine and C 1-6 alkoxy;
  • B is B-1 or B-4, W is an oxygen atom,
  • R 1 is a hydrogen atom or chlorine;
  • R 2A , R 2B , R 2C and R 2D are hydrogen atoms,
  • R 3A and R 4A are the same or different and each is a C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine and C 1-6 alkoxy;
  • a 4-10 membered saturated heterocycle A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3B is a hydrogen atom.
  • the pharmaceutically acceptable salt of the compound represented by the formula (I) means a salt formed by adding a pharmaceutically acceptable acid or base to the compound of the formula (I).
  • a pharmaceutically acceptable acid or base When the compound of the present invention represented by the formula (I) has a basic functional group such as an amino group, it can form salts with various acids.
  • acid addition salts include hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, phosphate, and other inorganic acid salts, oxalate, and malonic acid.
  • Salt maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, trifluoromethane
  • organic acid salts such as sulfonate
  • amino acid salts such as glutamate and aspartate.
  • salts When the compound of the present invention represented by the formula (I) has an acidic functional group such as a carboxyl group, it can form salts with various bases.
  • pharmaceutically acceptable salts include alkali metal salts such as sodium salt or potassium salt, alkaline earth metal salts such as calcium salt, or triethylammonium salt, triethanolammonium salt, pyridinium salt, diisopropylammonium salt. Examples thereof include organic base salts such as salts. These salts can be obtained by a conventional method such as recrystallization after mixing the compound of the present invention represented by the formula (I) with a base.
  • the method for producing 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 to M.
  • Production method A production method of synthetic intermediate
  • synthetic intermediates a6, a8 and a10 of a compound in which B is B-1 can be produced, for example, by the following production method.
  • P X represents a protecting group of amino
  • R X represents a hydrogen atom, alkyl or phenyl
  • R 1X represents halogen
  • R 1Y represents the term 1 R 1 as defined is not halogen
  • the protective group P X Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts al, John Wiley & Sons, Inc. published in 1999), and those described in as a protecting group for amino.
  • Compound a1 can be synthesized by a known method such as a halogenation reaction of imidazole, or can be purchased as a commercial product.
  • Step A-1 This step is a step of obtaining compound a2 by reacting compound a1 with an appropriate boronic acid derivative in the presence of an appropriate transition metal reagent.
  • An example of the transition metal reagent used in this step is copper acetate.
  • Examples of the boronic acid derivative used in this step include boronic acid, boronic acid ester, and boronic acid pinacolate.
  • the solvent used in this step is selected from the solvents exemplified below, but is preferably dichloroethane or methanol.
  • a similar reaction for example, a method described in Journal of Medicinal Chemistry, 2009, 52 (11), 3441-3444 is known and can be synthesized in the same manner.
  • reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C. to 200 ° C., preferably ⁇ 20 ° C. to 150 ° C., more preferably room temperature to 100 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step A-2 This step is a step of obtaining compound a4 by reacting compound a2 obtained in step A-1 with compound a3 in the presence of an appropriate transition metal reagent.
  • the transition metal reagent used in this step include tris (dibenzylideneacetone) dipalladium and tetrakis (triphenylphosphine) palladium.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably DMF or dioxane.
  • a similar reaction for example, a method described in Journal of Organic Chemistry, 2010, 75 (5), 1733-1739 is known and can be synthesized in the same manner.
  • reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C. to 200 ° C., preferably ⁇ 20 ° C. to 150 ° C., more preferably room temperature to 100 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step A-3 This step is a step of obtaining compound a5 by reacting compound a4 obtained in step A-2 with a suitable transition metal reagent in a hydrogen atmosphere.
  • the transition metal reagent used in this step include palladium / carbon and platinum (IV) oxide.
  • the solvent used in this step is selected from the solvents exemplified below, but is preferably methanol or ethanol.
  • a similar reaction for example, a method described in Journal of Medicinal Chemistry, 2012, 55 (1), 115-125, etc. is known and can be synthesized in the same manner. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 20 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C., more preferably room temperature to 60 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step A-4 This step is a protecting group P X of the amino compound a5 prepared in the above Preparation Method A-3, by deprotection, to give compound compound a6.
  • 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-5 This step is a step of obtaining compound a7 by reacting compound a5 obtained in step A-3 with various halogenating agents in a suitable solvent in the presence of a suitable acid.
  • the halogenating agent used in this step is, for example, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably methylene chloride or dichloroethane.
  • the acid used in this step is selected from the acids exemplified below, and preferably trifluoroacetic acid or hydrochloric acid.
  • a similar reaction for example, a method described in Bioorg. Med. Chem.
  • reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C., more preferably room temperature to 70 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step A-6 This step is a step of obtaining compound a8 from compound a7 obtained in step A-5, under the same conditions as in step A-4.
  • Step A-7 This step is a step of obtaining compound a9 by reacting compound a7 obtained in step A-5 with a suitable boronic acid derivative in a suitable solvent in the presence of a suitable transition metal reagent.
  • a suitable transition metal reagent examples include tris (dibenzylideneacetone) dipalladium and tetrakis (triphenylphosphine) palladium.
  • the boronic acid derivative used in this step include boronic acid, boronic acid ester, and boronic acid pinacolate.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably DMF or dioxane. Similar reactions include, for example, Tetrahedron Lett.
  • the reaction temperature varies depending on the type of raw material compound used, reagents and the like, but is usually ⁇ 78 ° C. to 200 ° C., preferably ⁇ 20 ° C. to 180 ° C., more preferably room temperature to 150 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step A-8 This step is a step of obtaining compound a10 from compound a9 obtained in step A-7, under the same conditions as in step A-4.
  • Production method B (Production method of synthetic intermediate) Among the compounds represented by formula (I), a synthetic intermediate b7 of a compound in which B is B-2 and W is an oxygen atom can be produced, for example, by the following production method. (Wherein, A, R 2A, R 2B , R 2C and R 2D are as defined in claim 1, P X denotes a protective group for amino)
  • the protective group P X Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts al, John Wiley & Sons, Inc. published in 1999), and those described in as a protecting group for amino.
  • Compound b1 can be synthesized by a known method such as oxidation of the corresponding alcohol, or can be purchased as a commercial product.
  • Step B-1 This step is a step of obtaining compound b2 by reacting compound b1 with nitromethane in the presence of a suitable base.
  • the base used in this step is selected from the bases exemplified below, and preferably tert-butoxy potassium.
  • the solvent used in this step is selected from the solvents exemplified below, but is preferably a mixed solvent of tetrahydrofuran and tert-butanol.
  • a similar reaction for example, a method described in International Publication No. 2007/41061 pamphlet or the like is known and can be synthesized in the same manner. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C.
  • reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step B-2 This step is a step of obtaining compound b3 by reacting compound b2 obtained in B-1 above in a hydrogen atmosphere using an appropriate transition metal catalyst.
  • the transition metal reagent used in this step include palladium / carbon and platinum (IV) oxide.
  • the solvent used in this step is selected from the solvents exemplified below, but is preferably methanol or ethanol. As similar reactions, for example, the methods described in Bioorganic and Medicinal Chemistry Letters, 2004, 14 (13), 3419-3424, International Publication No. 2006/19768, etc. are known and can be synthesized similarly. .
  • the reaction temperature varies depending on the type of raw material compound used, reagents and the like, but is usually ⁇ 20 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C., more preferably room temperature to 70 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step B-3 In this step, compound b3 obtained in B-2 above is reacted with carboxylic acid b8 or acid chloride b9 in a suitable solvent in the presence or absence of a suitable condensing agent and in the presence of a suitable base.
  • compound b4 is obtained.
  • the condensing agent used in this step include EDCI (including hydrochloride) or HBTU.
  • 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 dimethylformamide, tetrahydrofuran or methylene chloride.
  • reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C., more preferably room temperature to 100 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step B-4 This step is a step of obtaining compound b5 by reacting compound b4 obtained in B-3 with an appropriate oxidizing agent.
  • the oxidizing agent used in this step include a desmartin reagent.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably methylene chloride or DMSO.
  • a similar reaction for example, a method described in International Publication No. 2010/138589 pamphlet is known and can be synthesized in the same manner.
  • reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally -78 ° C to 200 ° C, preferably -20 ° C to 150 ° C, more preferably 0 ° C to 100 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step B-5 This step is a step of obtaining compound b6 by reacting compound b5 obtained in B-4 with an appropriate dehydrating reagent.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably tetrahydrofuran.
  • Examples of the dehydrating reagent used in this step include Burgess reagent.
  • a similar reaction for example, a method described in Synlett, 1999, 10, 1642-1644 is known, and can be synthesized in the same manner. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C. to 200 ° C., preferably ⁇ 20 ° C. to 150 ° C., more preferably 0 ° C. to 100 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step B-6 This step is a step of obtaining the compound b7 from the compound b6 obtained in the step B-5 under the conditions according to the step A-4.
  • c2 which is a synthetic intermediate of a compound in which B is B-2 and W is a sulfur atom can be produced, for example, by the following production method.
  • A, R 2A, R 2B , R 2C and R 2D are as defined in claim 1, P X denotes a protective group for amino
  • the protective group P X Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts al, John Wiley & Sons, Inc. published in 1999), and those described in as a protecting group for amino.
  • Step C-1 This step is a step of obtaining compound c1 by reacting compound b5 obtained in step B-4 with an appropriate thiocarbonylating reagent.
  • the thiocarbonylation reagent used in this step include Lawson's reagent.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably tetrahydrofuran.
  • a similar reaction for example, a method described in US Publication No. 2010/261617, etc. is known, and can be synthesized in the same manner. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C.
  • reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step C-2 In this step, compound c2 is obtained from compound c1 obtained in step C-1 under the same conditions as in step A-4.
  • d4 that is a synthetic intermediate of a compound in which B is B-3 and W is an oxygen atom can be produced, for example, by the following production method.
  • A, R 2A, R 2B , R 2C and R 2D are as defined in claim 1, P X denotes a protective group for amino
  • the protective group P X Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts al, John Wiley & Sons, Inc. published in 1999), and those described in as a protecting group for amino.
  • Compound d1 can be synthesized by a known method such as oxidation of the corresponding alcohol or aldehyde or corresponding ester hydrolysis, or can be purchased as a commercial product.
  • Step D-1 This step is a step in which compound d1 and compound d5 are reacted under the same conditions as in step B-3 to obtain compound d2.
  • Step D-2 This step is a step of obtaining a compound d3 by reacting the compound d2 obtained in the step D-1 with the conditions according to the step B-5.
  • Step D-3 This step is a step of obtaining a compound d4 by reacting the compound d3 obtained in the step D-2 with the conditions according to the step A-4.
  • Production method E (Production method of synthetic intermediate) Among the compounds represented by the formula (I), e2 which is a synthetic intermediate of a compound in which B is B-3 and W is a sulfur atom can be produced by, for example, the following production method. (Wherein, A, R 2A, R 2B , R 2C and R 2D are as defined in claim 1, P X denotes a protective group for amino)
  • the protective group P X Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts al, John Wiley & Sons, Inc. published in 1999), and those described in as a protecting group for amino.
  • Step E-1 This step is a step of obtaining a compound e1 by reacting the compound d2 obtained in the step D-1 with the conditions according to the step C-1.
  • Step E-2 This step is a step of obtaining a compound e2 by reacting the compound e1 obtained in the step E-1 with the conditions according to the step A-4.
  • the protective group P X Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts al, John Wiley & Sons, Inc. published in 1999), and those described in as a protecting group for amino.
  • Compound f1 can be purchased as a commercial product.
  • Compound f4 can be synthesized by known methods such as oxidation of the corresponding alcohol, or can be purchased as a commercial product.
  • Step F-1 compound f2 is obtained by reacting compound f1 with a diazotizing reagent using an appropriate base.
  • the diazotizing reagent used in this step include 4-toluenesulfonyl azide.
  • the base used in this step is selected from the bases exemplified below, and is preferably sodium hydride.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably tetrahydrofuran.
  • the methods described in Bioorganic and Medicinal Chemistry Letters, 2013, 23 (19), 5267-5269, etc. are known, and can be synthesized in the same manner.
  • reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C. to 200 ° C., preferably ⁇ 20 ° C. to 150 ° C., more preferably 0 ° C. to 100 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step F-2 This step is a step of obtaining compound f3 by reacting compound f2 obtained in step F-1 with compound b1 in the presence of a suitable base.
  • the base used in this step is selected from the bases exemplified below, and is preferably potassium carbonate.
  • the solvent used in this step is selected from the solvents exemplified below, but is preferably methanol.
  • a similar reaction for example, a method described in Journal of the American Chemical Society, 2003, 125 (13), 3714-3715 is known and can be synthesized in the same manner.
  • reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally -78 ° C to 200 ° C, preferably -20 ° C to 150 ° C, more preferably 0 ° C to 100 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step F-3 This step is a step of reacting compound f4 and hydroxylamine to obtain compound f5.
  • the solvent used in this step is selected from the solvents exemplified below, but is preferably methanol.
  • a similar reaction for example, a method described in Organic Letters, 2001, 3 (26), 4209-4211, etc. is known and can be synthesized in the same manner. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally -78 ° C to 200 ° C, preferably -20 ° C to 150 ° C, more preferably 0 ° C to 100 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step F-4 This step is a step of reacting the compound f5 obtained in the step F-3 with a chlorinating reagent to obtain the compound f6.
  • chlorinating reagent used in this step include N-chlorosuccinimide.
  • the solvent used in this step is selected from the solvents exemplified below, but is preferably DMF. Similar reactions are described in, for example, Bioorganic and Medicinal Chemistry Letters, 2006, 16 (21), 5576-5579, Journal of Heterocyclic Chemistry, 1996, 33 (6), 1583-1592, and the like. It can be synthesized similarly. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C.
  • reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step F-5 In this step, compound f3 obtained in step F-2 and compound f6 obtained in step F-4 are reacted in the presence of a suitable base to obtain compound f7.
  • the base used in this step is selected from the bases exemplified below, but is preferably triethylamine.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably tetrahydrofuran.
  • the methods described in Journal of Medicinal Chemistry, 2003, 46 (2), 284-302, European Journal of Medicinal Chemistry, 2012, 54, 324-342, and the like are known. can do.
  • reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C. to 200 ° C., preferably ⁇ 20 ° C. to 150 ° C., more preferably 0 ° C. to 100 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step F-6 This step is a step of obtaining compound f8 by reacting compound f7 obtained in step F-5 with the conditions according to step A-4.
  • Production method G (Production method of synthetic intermediate) Among the compounds represented by the formula (I), g5 which is a synthetic intermediate of a compound in which B is B-5 and W is an oxygen atom can be produced, for example, by the following production method. (Wherein, A, R 2A, R 2B , R 2C and R 2D are as defined in claim 1, P X denotes a protective group for amino)
  • the protective group P X Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts al, John Wiley & Sons, Inc. published in 1999), and those described in as a protecting group for amino.
  • Compound f4 can be synthesized by a known method such as oxidation of the corresponding alcohol, or can be purchased as a commercial product.
  • Compound b1 can be synthesized by a known method such as oxidation of the corresponding alcohol, or can be purchased as a commercial product.
  • Step G-1 This step is a step of obtaining compound g1 by reacting compound f4 with compound f2 obtained in Step F-1 under the same conditions as in Step F-2.
  • Step G-2 This step is a step of obtaining compound g2 by reacting compound b1 under the conditions according to the above F-3 step.
  • Step G-3 This step is a step of obtaining compound g3 by reacting compound g2 obtained in the above step G-2 under the same conditions as in the above step F-4.
  • Step G-4 This step is a step of obtaining compound g4 by reacting compound g3 obtained in step G-3 and g1 obtained in step G-1 under the same conditions as in step F-5.
  • Step G-5 This step is a step of obtaining compound g5 by reacting compound g4 obtained in the above step G-4 with the conditions according to the above step A-4.
  • Manufacturing method H Of the compounds represented by the formula (I), the compounds represented by the formulas [H1], [H2] and [H3], wherein B is B-1 and XYZ is N—CO—NR 3A R 3B
  • the compounds to be prepared (hereinafter also referred to as compounds H1, H2, and H3) can be produced, for example, by the following production method. Further, using the same production method, compounds represented by the formulas [H2] and [H3] can be produced using the intermediates a8 and a10 obtained by the intermediate production method A as starting materials. Further, using the same production method, the intermediates B7, c2, d4, e2, f8 and g5 obtained by the above intermediate production methods B, C, D, E, F and G are used as starting materials.
  • XYZ is N-CO-NR 3A R 3B
  • W is an oxygen atom or a sulfur atom.
  • A, R 2A , R 2B , R 2C , R 2D , R 3A and R 3B are as defined in item 1; R Y represents hydrogen, nitro or cyano; and R 1X represents halogen. And R 1Y means a non-halogen among R 1 defined in item 1)
  • Step H-1 This step is a step of obtaining Compound H1 by reacting Compound a6 obtained in Step A-4 with h1 or h2 which is a urea agent in a suitable solvent in the presence of a suitable base.
  • the base used in this step is selected from the bases exemplified below, and is preferably diisopropylethylamine or triethylamine.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably tetrahydrofuran or methylene chloride. Similar reactions include, for example, J. Org. Chem. 1995, 60 (25), 8262-8266, Bioorg. Med. Chem. Lett.
  • reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C. to 200 ° C., preferably ⁇ 20 ° C. to 150 ° C., more preferably 0 ° C. to 100 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step H-2 This step is a step for obtaining compound H2 by reacting compound H1 obtained in step H-1 with various halogenating agents in a suitable solvent in the presence of a suitable acid.
  • the halogenating agent used in this step is preferably N-chlorosuccinimide, N-bromosuccinimide, or N-iodosuccinimide.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably methylene chloride or dichloroethane.
  • the acid used in this step is selected from the acids exemplified below, and preferably trifluoroacetic acid or hydrochloric acid.
  • a similar reaction for example, methods described in Bioorg. Med. Chem. Lett.
  • reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C. to 200 ° C., preferably ⁇ 20 ° C. to 150 ° C., more preferably 0 ° C. to 70 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step H-3 This step is a step of obtaining compound H3 by reacting compound H2 obtained in step H-2 with an appropriate boronic acid derivative in an appropriate solvent in the presence of an appropriate transition metal reagent.
  • the transition metal reagent used in this step include tris (dibenzylideneacetone) dipalladium and tetrakis (triphenylphosphine) palladium.
  • the boronic acid derivative used in this step include boronic acid, boronic acid ester, and boronic acid pinacolate.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably DMF or dioxane. Similar reactions include, for example, Tetrahedron Lett.
  • the reaction temperature varies depending on the type of raw material compound used, reagents and the like, but is usually ⁇ 78 ° C. to 200 ° C., preferably ⁇ 20 ° C. to 180 ° C., more preferably room temperature to 150 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • XYZ is N-COR 4A
  • W is an oxygen atom or a sulfur atom. it can.
  • R 1Y represents a non-halogen of R 1 defined in item 1.
  • R 1X means halogen
  • Step I-1 In this step, compound a6 obtained in step A-4 is reacted with carboxylic acid i1 or acid chloride i2 in the presence of a suitable base in the presence or absence of a suitable condensing agent and in the presence of a suitable base.
  • the condensing agent used in this step is, for example, EDCI (including hydrochloride) or HBTU.
  • the base used in this step is selected from the bases exemplified below, and is preferably diisopropylethylamine or triethylamine.
  • the solvent used in this step is selected from the solvents exemplified below, and preferably dimethylformamide, tetrahydrofuran or methylene chloride.
  • reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C. to 200 ° C., preferably ⁇ 20 ° C. to 150 ° C., more preferably 0 ° C. to 100 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step I-2 This step is a step of obtaining compound I2 by reacting compound I1 obtained in the above step I-1 under the same conditions as in the above step H-2.
  • Step I-3 This step is a step of obtaining compound I3 by reacting compound I2 obtained in the above step I-2 with the conditions according to the above step H-3.
  • Manufacturing method J Of the compounds represented by formula (I), the formulas [J1] [J2] [J3] and [J4] wherein B is B-4 and XYZ is CR 5 —NR 6 —COR 4B (Hereinafter also referred to as compounds J1, J2, J3, and J4) can be produced, for example, by the following production method according to the intermediate production method F. Further, by combining the following production method J and the production methods according to the intermediate production methods A, B, C, D, E and G, XYZ is CR 5 —NR 6 —COR 4B ; Is a corresponding compound group in which is B-1, B-2, B-3 and B-5, and W is an oxygen atom or a sulfur atom.
  • R 1X represents halogen
  • R 1Y represents item 1
  • R 1 which is not halogen among the defined R 1 represents R Z represents a leaving group such as halogen
  • P X represents an amino protecting group
  • the protective group P X Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts al, John Wiley & Sons, Inc. published in 1999), and those described in as a protecting group for amino.
  • Compound j1 can be synthesized by a known method such as oxidation of the corresponding alcohol, or can be purchased as a commercial product.
  • Step J-1 This step is a step wherein compound j2 is obtained by reacting compound j1 under the same conditions as in Step F-2.
  • Step J-2 This step is a step of obtaining compound j3 by reacting compound j2 obtained in step J-1 under the same conditions as in step F-5.
  • Step J-3 This step is a protecting group P X of the amino compound j3 prepared in the above Preparation Method J-2, is deprotected, to give compound compound j4.
  • 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 J-4 In this step, compound j4 obtained in J-3 above is reacted with carboxylic acid j5 or acid chloride j6 in a suitable solvent in the presence or absence of a suitable condensing agent and in the presence of a suitable base.
  • compound J1 is obtained.
  • the condensing agent used in this step include EDCI (including hydrochloride) or HBTU.
  • 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 dimethylformamide, tetrahydrofuran or methylene chloride.
  • reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C., more preferably room temperature to 100 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step J-5 This step is a step of obtaining compound J2 by reacting compound J1 obtained in the above step J-4 under the conditions according to the above step H-2.
  • Step J-6 In this step, compound J2 obtained in step J-5 is reacted under the same conditions as in step H-3 to obtain compound J3.
  • Step J-7 This step is a step of obtaining compound J4 by reacting compound j7 obtained in step J-6 with compound j7 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 sodium hydride or diisopropylamine.
  • the solvent used in this step is selected from the solvents exemplified below and preferably dimethylformamide or tetrahydrofuran.
  • the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 30 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C., more preferably 0 ° C. to 80 ° C.
  • the reaction time is usually about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
  • Manufacturing method K Of the compounds represented by formula (I), the compounds of formula [K1] [K2] [K3] and [K3] wherein B is B-4 and XYZ is CR 5 —NR 6 —CONR 3A R 3B
  • the compound represented by K4] (hereinafter also referred to as compounds K1, K2, K3 and K4) can be produced, for example, by the following production method.
  • XYZ is CR 5 —NR 6 —CONR 3A R 3B by combining the following production method K and production methods according to the above intermediate production methods A, B, C, D, E and G.
  • B is B-1, B-2, B-3 and B-5, and corresponding compounds can be produced wherein W is an oxygen atom or a sulfur atom.
  • R 1X represents halogen
  • R 1Y represents R 1 defined in Item 1 is not halogen
  • R Y represents hydrogen, nitro or cyano
  • R Z represents a leaving group such as halogen
  • Step K-1 This step is a step of obtaining compound K1 by reacting compound j4 obtained in the above step J-3 under the conditions according to the above step H-1.
  • Step K-2 This step is a step of obtaining compound K2 by reacting compound K1 obtained in the above step K-1 under the same conditions as in the above step J-7.
  • Step K-3 This step is a step of obtaining a compound K3 by reacting the compound K2 obtained in the step K-2 with the conditions according to the step H-2.
  • Step K-4 This step is a step of obtaining a compound K4 by reacting the compound K3 obtained in the step K-3 with the conditions according to the step H-3.
  • Manufacturing method M Of the compounds represented by the formula (I), the compounds represented by the formulas [M1] [M2] and [M3], wherein B is B-4 and XYZ is CR 5 —CO—NR 3A R 3B
  • the compounds to be produced (hereinafter also referred to as compounds M1, M2 and M3) can be produced, for example, by the following production method according to the intermediate production method F. Further, by combining the following production method M and the production methods according to the intermediate production methods A, B, C, D, E and G, XYZ is CR 5 —CO—NR 3A R 3B , Corresponding compound groups in which B is B-1, B-2, B-3 and B-5 and W is an oxygen atom or a sulfur atom can be produced.
  • R 1X represents halogen
  • R 1Y represents item 1 R 1 which is not halogen among the defined R 1 represents P Y represents a protecting group for a carboxyl group
  • the protective group P Y Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts al, John Wiley & Sons, Inc. published in 1999), and those described in as a protecting group of a carboxylic acid .
  • Compound m1 can be synthesized by a known method such as oxidation of the corresponding alcohol, or can be purchased as a commercial product.
  • Step M-1 This step is a step of obtaining compound m2 by reacting compound m1 under the same conditions as in Step F-2.
  • Step M-2 This step is a step of obtaining a compound m3 by reacting the compound m2 obtained in the step M-1 with the conditions according to the step F-5.
  • This step is a step of obtaining the compound m4 by deprotecting the protecting group P Y of the carboxylic acid of the compound m3 obtained in the step M-2.
  • 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 M-4 This step is a step of obtaining compound M1 by reacting compound m4 obtained in step M-3 with amine m5 in the presence of a suitable condensing agent and in the presence of a suitable base in a suitable solvent.
  • a suitable condensing agent used in this step include EDCI (including hydrochloride) or HBTU.
  • 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 dimethylformamide, tetrahydrofuran or methylene chloride.
  • reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally ⁇ 78 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C., more preferably room temperature to 100 ° C.
  • the reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
  • Step M-5 In this step, compound M1 obtained in step M-4 is reacted under the same conditions as in step H-2 to obtain compound M2.
  • Step M-6 In this step, compound M2 obtained in step M-5 is reacted under the same conditions as in step H-3 to obtain compound M3.
  • alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate, sodium carbonate and potassium carbonate
  • Alkali carbonates such as sodium hydride, metal hydrides such as sodium hydride and potassium hydride, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metals such as sodium methoxide and sodium t-butoxide Alkoxides, organometallic bases such as butyllithium and lithium diisopropylamide, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo [5.4.0] -7-undecene ( Organic bases such as DBU) That.
  • DMAP 4-dimethylaminopyridine
  • DBU 1,8-diazabicyclo [5.4.0] -7-undecene
  • the solvent used in each of the above steps should be appropriately selected depending on the reaction and the type of raw material compound.
  • alcohols such as methanol, ethanol and isopropanol
  • ketones such as acetone and ethyl methyl ketone.
  • 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), nitriles such as acetonitrile
  • solvents can be used alone There can be used as a mixture of two or more kinds. Depending on the type of reaction, organic bases may be used as a solvent.
  • the compound of the present invention represented by the formula (I) or an intermediate thereof can be separated and purified by methods known to those skilled in the art.
  • separation or purification methods include extraction, distribution, reprecipitation, column chromatography (for example, silica gel column chromatography, ion exchange column chromatography or preparative liquid chromatography) or recrystallization.
  • 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.
  • a spectroscopic method such as nuclear magnetic resonance, infrared absorption, circular dichroism spectrum analysis, And mass spectrometry.
  • the compound of the present invention represented by the formula (I) or a pharmaceutically acceptable salt thereof may have asymmetry or may have a substituent having an asymmetric carbon.
  • optical isomers exist.
  • the compounds of the present invention include mixtures of these isomers and isolated ones, and 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, by using an optically active raw material or performing optical resolution or the like at an appropriate stage of the production process, the optical properties of the compound of the present invention represented by formula (I) or a pharmaceutically acceptable salt thereof Isomers can be obtained.
  • the solvent is an inert solvent (for example, an alcohol solvent such as methanol, ethanol or 2-propanol).
  • 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 thereof), an optically active acid (for example, mandelic acid, N-benzyloxyalanine or monocarboxylic acid such as lactic acid, tartaric acid, dicarboxylic acid such as o-diisopropylidene tartaric acid or malic acid, sulfonic acid such as camphorsulfonic acid or bromocamphorsulfonic acid) Stereomer method can be mentioned.
  • an optically active amine for example, 1-phenylethylamine, quinine, quinidine, cinchonidine, cinchonine or strychnine
  • 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 or 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, hydrocarbon solvents such as toluene, acetonitrile, etc. And a high purity optically active salt can be obtained. 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 or 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, hydrocarbon solvents such as toluene, acetonitrile, etc.
  • an optically resolved salt can be treated with an acid or a base by a conventional method to obtain a free form.
  • an optically active amine for example, 1-phenylethylamine etc.
  • an optically active amine for example, 1-phenylethylamine etc.
  • the compound of the present invention is useful as a therapeutic and / or prophylactic agent for diseases caused by abnormalities in intracellular signal transduction involving acetylcholine.
  • diseases caused by abnormal intracellular signal transduction involving acetylcholine include a neurological disease, a mental disease or an inflammatory disease.
  • neurological diseases, psychiatric diseases or inflammatory diseases include schizophrenia, Alzheimer's disease, Down's syndrome, attention deficit / hyperactivity disorder, or cerebrovascular angiopathy.
  • the compound of the present invention is (1) CIAS (cognitive dysfunction associated with schizophrenia), or (2) schizophrenia, Alzheimer's disease, Down's syndrome, attention deficit / hyperactivity disorder or cerebrovascular angiopathy, Useful for treating and / or preventing cognitive impairment, mild cognitive impairment, memory impairment or learning impairment.
  • CIAS cognitive dysfunction associated with schizophrenia
  • schizophrenia Alzheimer's disease, Down's syndrome, attention deficit / hyperactivity disorder or cerebrovascular angiopathy, Useful for treating and / or preventing cognitive impairment, mild cognitive impairment, memory impairment or learning impairment.
  • the compounds of the present invention are also useful for treating and / or preventing negative and / or positive symptoms associated with schizophrenia.
  • the compound of the present invention can be used in combination with an atypical antipsychotic agent for the purpose of the treatment and / or prevention.
  • the pharmaceutical agent in the case where the compound of the present invention or a pharmaceutically acceptable salt thereof and an atypical antipsychotic drug are used in combination may be a single compounding agent, or simultaneously, separately and continuously. Or multiple formulations administered at regular intervals.
  • 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, coating agents, 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 pharmaceutically acceptable additives.
  • Additives are excipients, disintegrants, binders, fluidizers, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, sweeteners depending on the purpose. Perfumes and the like can be used.
  • the compound of the present invention can be used in combination with an atypical antipsychotic drug.
  • atypical antipsychotics include olanzapine, risperidone, paliperidone, quetiapine, ziprasidone, aripiprazole, asenapine, iloperidone, clozapine, sertindole, blonanserin and lurasidone.
  • Me means a methyl group
  • Et means an ethyl group
  • Ph means a phenyl group
  • Ts means a tosyl group.
  • TFA means trifluoroacetic acid.
  • 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 lines
  • br means broad
  • brs means broad single line
  • brd means broad double line
  • brt means broad triple line
  • J means coupling constant.
  • High-performance liquid chromatographic 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 (min, min). In each actual measurement value, any one of A to H is added as a measurement condition used for the measurement.
  • Reference example 1 4- [5-Chloro-1- (3-fluorophenyl) -1H-imidazol-4-yl] piperidine dihydrochloride a) Preparation of 4-bromo-1- (3-fluorophenyl) -1H-imidazole (compound Q1) 4-Fluoroimidazole (50 g) in methylene chloride solution (1500 mL) at room temperature with 3-fluorophenylboronic acid ( 94.0 g), copper (II) acetate (91.0 g) and pyridine (50 mL) were added, and the mixture was stirred at 30 ° C. for 48 hours.
  • Reference example 2 4- [5-Cyano-1- (3-fluorophenyl) -1H-imidazol-4-yl] piperidine dihydrochloride a) Preparation of tert-butyl 4- [1- (3-fluorophenyl) -5-iodo-1H-imidazol-4-yl] piperidine-1-carboxylate (Compound Q5) Compound Q3 (5.0 g) in acetonitrile N-iodosuccinimide (3.6 g) and trifluoroacetic acid (0.05 mL) were added to the solution (30 mL) at room temperature, and the mixture was stirred at room temperature for 72 hours under light shielding.
  • Reference example 3 4- ⁇ 3- [5- (trifluoromethyl) pyridin-2-yl] -1,2-oxazol-5-yl ⁇ piperidine dihydrochloride a) Preparation of tert-butyl 4-ethiylpiperidine-1-carboxylate (Compound Q7) To a methanol solution (50 mL) of tert-butyl 4-formylpiperidine-1-carboxylate (7.8 g) at 0 ° C. Potassium carbonate (11 g) and dimethyl (acetyldiazomethyl) phosphonate (8.6 g) were added and stirred at 0 ° C. for 2 hours.
  • Reference example 4 4- ⁇ 5- [5- (trifluoromethyl) pyridin-2-yl] -1,2-oxazol-3-yl ⁇ piperidine dihydrochloride a) Preparation of tert-butyl 4-[(hydroxyimino) methyl] piperidine-1-carboxylate (Compound Q11) Methanol / water solution of tert-butyl 4-formylpiperidine-1-carboxylate (11 g) (80 mL / 80 mL) To the mixture, sodium carbonate (2.7 g) and hydroxylamine hydrochloride (4.3 g) were added at room temperature, and the mixture was stirred at room temperature for 16 hours.
  • Tetrahydrofuran 40 mL was added to the reaction solution, and then a tetrahydrofuran solution (20 mL) of compound Q12 (2.9 g) and triethylamine (5.6 g) was added at room temperature.
  • the reaction solution was heated to 60 ° C. and stirred for 2 hours, and then the solvent was distilled off under reduced pressure.
  • the residue was extracted with ethyl acetate (20 mL) and saturated aqueous sodium hydrogen carbonate (30 mL). The obtained organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Reference Example 8 4- [5- (4-Fluorophenyl) -1,3-thiazol-2-yl] piperidine hydrochloride (Reference Example 8) a) Preparation of tert-butyl 4- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] piperidine-1-carboxylate (Compound Q22) Compound Q19 (2 g) in tetrahydrofuran (50 mL) After adding Lawson's reagent (1.7 g) at room temperature, the mixture was heated to 70 ° C. and stirred for 4 hours.
  • Example 1 4- [5-Chloro-1- (3-fluorophenyl) -1H-imidazol-4-yl] -N- (4,4-difluorocyclohexyl) piperidine-1-carboxamide Phenyl 4,4-difluorocyclohexylcarbamate (272 mg) and triethylamine (0.50 mL) were added to a methylene chloride solution (8 mL) of the compound of Reference Example 1 (198 mg) at room temperature, and the temperature was raised to 38 ° C. Stir for 48 hours. After distilling off the reaction solvent under reduced pressure, the compound of Example 1 (200 mg) was obtained by purification by preparative HPLC.
  • Example 2 ⁇ 4- [5-Chloro-1- (3-fluorophenyl) -1H-imidazol-4-yl] piperidin-1-yl ⁇ (4,4-difluorocyclohexyl) methanone
  • a methylene chloride solution (4 mL) of the compound of Reference Example 1 (198 mg), 4,4-difluorocyclohexanecarboxylic acid (175 mg), HBTU (540 mg) and triethylamine (0.50 mL) were added at room temperature. Stir for 24 hours. After distilling off the reaction solvent under reduced pressure, the compound of Example 2 (100 mg) was obtained by purification by preparative HPLC.
  • Example 3 4- [5-Cyano-1- (3-fluorophenyl) -1H-imidazol-4-yl] -N- (4,4-difluorocyclohexyl) piperidine-1-carboxamide
  • the compound of Example 3 (26 mg) was obtained by the method according to Example 1 using the compound of Reference Example 2 (259 mg).
  • Example 4 N- (Tetrahydro-2H-pyran-4-yl) -4- ⁇ 3- [5- (trifluoromethyl) pyridin-2-yl] -1,2-oxazol-5-yl ⁇ piperidine-1-carboxamide
  • the compound of Example 4 (90 mg) was obtained by the method according to Example 1 using the compound of Reference Example 3 (327 mg).
  • Example 5 N- (Tetrahydro-2H-pyran-4-yl) -4- ⁇ 5- [5- (trifluoromethyl) pyridin-2-yl] -1,2-oxazol-3-yl ⁇ piperidine-1-carboxamide
  • the compound of Example 5 (85 mg) was obtained by the method according to Example 1 using the compound of Reference Example 4 (247 mg).
  • Example 6 N- (4,4-difluorocyclohexyl) -4- [2- (4-fluorophenyl) -1,3-oxazol-5-yl] piperidine-1-carboxamide
  • the compound of Example 6 (38 mg) was obtained by the method according to Example 1 using the compound of Reference Example 5 (290 mg).
  • Example 7 N- (4,4-difluorocyclohexyl) -4- [5- (4-fluorophenyl) -1,3-oxazol-2-yl] piperidine-1-carboxamide
  • the compound of Example 7 (200 mg) was obtained by the method according to Example 1 using the compound of Reference Example 6 (300 mg).
  • Example 8 N- (4,4-difluorocyclohexyl) -4- [2- (4-fluorophenyl) -1,3-thiazol-5-yl] piperidine-1-carboxamide
  • the compound of Example 8 (35 mg) was obtained by the method according to Example 1 using the compound of Reference Example 7 (120 mg).
  • Example 9 N- (4,4-difluorocyclohexyl) -4- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] piperidine-1-carboxamide Triethylamine (0.46 mL) was added to a solution of the compound of Reference Example 8 (340 mg) and phenyl 4,4-diphenylcyclohexanecarbamate (434 mg) in acetonitrile (5 mL) at room temperature, and the temperature was raised to 55 ° C. Stir for hours.
  • Example 10 4- [4-Chloro-5- (4-fluorophenyl) -1,3-thiazol-2-yl] -N- (4,4-difluorocyclohexyl) piperidine-1-carboxamide N-chlorosuccinimide (38 mg) and trifluoroacetic acid (0.05 mL) were added to an acetonitrile solution (5 mL) of the compound of Example 9 (100 mg) at room temperature, and then the mixture was heated to 55 ° C. and stirred for 4 hours. did. A saturated sodium bicarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate, and the organic layer was washed with water and saturated brine.
  • Examples 11 to 39 The compounds shown in Table 1 were obtained by the method according to Example 1 or 3 using the corresponding raw material compounds.
  • Examples 40-50 The compounds shown in Table 2 were obtained by the method according to Example 2 using the corresponding raw material compounds.
  • Examples 51-91 The compounds shown in Table 3 were obtained by the method according to Example 4 using the corresponding starting compounds.
  • Examples 92-98 The compounds shown in Table 4 were obtained by the method according to Reference Example 3 and Example 2 using the corresponding starting compounds.
  • Examples 101-142 The compounds shown in Table 6 were obtained by the method according to Example 5 using the corresponding starting compounds.
  • Examples 143-148 The compounds shown in Table 7 were obtained by the method according to Reference Example 4 and Example 2 using the corresponding starting compounds.
  • Example 149 The compounds shown in Table 8 were obtained by the method according to Example 6 using the corresponding starting compounds.
  • Examples 150-151 The compounds shown in Table 9 were obtained by the method according to Reference Example 5 and Example 2 using the corresponding starting compounds.
  • Examples 152-154 The compounds shown in Table 10 were obtained by the method according to Example 7 using the corresponding starting compounds.
  • Examples 155 to 156 The compounds shown in Table 11 were obtained by the method according to Reference Example 6 and Example 2 using the corresponding starting compounds.
  • Examples 157 to 159 The compounds shown in Table 12 were obtained by the method according to Example 8 using the corresponding starting compounds.
  • Examples 160-161 The compounds shown in Table 13 were obtained by the method according to Reference Example 7 and Example 2 using the corresponding starting compounds.
  • Examples 162-163 The compounds shown in Table 14 were obtained by the method according to Examples 9 and 10 using the corresponding starting compounds.
  • Examples 164 to 165 The compounds shown in Table 15 were obtained by the method according to Reference Example 8 and Example 2 using the corresponding starting compounds.
  • Examples 166-175 The compounds shown in Table 16 were obtained by the method according to Example 6 using the corresponding starting compounds.
  • Examples 176-184 The compounds shown in Table 17 were obtained by the method according to Reference Example 5 and Example 2 using the corresponding starting compounds.
  • Examples 185-191 The compounds shown in Table 18 were obtained by the method according to Example 7 using the corresponding starting compounds.
  • Example 192 The compounds shown in Table 19 were obtained by the method according to Reference Example 6 and Example 2 using the corresponding starting compounds.
  • Examples 193-198 The compounds shown in Table 20 were obtained by the method according to Example 8 using the corresponding starting compounds.
  • Examples 199-210 The compounds shown in Table 21 were obtained by the method according to Reference Example 7 and Example 2 using the corresponding starting compounds.
  • Examples 211-214 The compounds shown in Table 22 were obtained by the method according to Examples 9 and 10 using the corresponding starting compounds.
  • Examples 215 to 219 The compounds shown in Table 23 were obtained by the method according to Reference Example 8 and Example 2 using the corresponding starting compounds.
  • 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. No. CCL-82.2, ATCC, USA) were used as host cells.
  • Introduction of pcDNA3.1Zeo vector into which the nucleotide sequence encoding the protein of GenBank BAC81731 was inserted, and introduction of pcDNA3.1 vector into which the human ⁇ 7 nAChR gene was inserted (cat. No.
  • V790-20, invitrogen, Carlsbad, CA, USA Thus, aequorin and human ⁇ 7 nAChR stably expressing cells were obtained.
  • Zeocin catalog. No. R25001, invitrogen, Carlsbad, CA, USA
  • Geneticin catalog. No. 10131-027, invitrogen, Carlsbad, CA, USA
  • Medium includes 2.5% fetal bovine serum (cat. No. 2917354, ICN Biomedicals, Inc, USA), 15% inactivated horse serum (cat. No. 26050-088, invitrogen, Carlsbad, CA, USA), 1 ⁇ g / ML Geneticin, F-10 Nutrient Mixture (Ham) medium (cat. No.
  • 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 mmol / L HEPES / 0.2% BSA (cat. No. A3803, Sigma, St. Louis, MO, USA) and 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. The luminescence signal (center wavelength: 465 nm) was measured for 138 seconds after the addition of ACh to calculate RLU (Max-Min), and the ratio of RLU (Max-Min) between the control well and the test compound added well was defined as PAM activity. . Data of ⁇ 7 PAM activity of representative compounds is shown in Table 24, Table 25 and Table 26.
  • Test Example 2 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. As a result, the compounds of Examples 1, 45, 51, 79 and 124 showed a significant memory enhancing action at 3 or 10 mg / kg (oral).
  • mORT mouse novel object recognition test
  • the compound represented by the formula (I), or a pharmaceutically acceptable salt thereof has a strong ⁇ 7 nicotinic acetylcholine receptor ( ⁇ 7hnAChR) 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 It is useful for treatment and / or prevention of diseases and the like.

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Abstract

The present invention provides a compound that has a strong α7 nicotinic acetylcholine receptor (α7 nAChR)-regulating effect and is useful as a therapeutic drug for diseases associated with cholinergicity of the central nervous system (CNS) and/or peripheral nervous system (PNS), diseases associated with smooth muscle contraction, endocrine diseases, diseases associated with neurodegeneration, etc. Provided is a compound of formula (I) or a pharmaceutically acceptable salt of said compound [In the formula, X-Y-Z represents N-CO-NR3AR3B or the like, A represents an optionally substituted phenyl or the like, B represents optionally substituted imidazole or the like, R2A, R2B, R2C, and R2D may be the same or different and represent hydrogen atoms or the like, and R3A and R3B may be the same or different and represent optionally substituted C3-10 cycloalkyls or the like].

Description

５員環ヘテロアリール誘導体5-membered heteroaryl 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５員環ヘテロアリ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 5-membered heteroaryl derivative that 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。これらの報告により、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に結びつくことが想定される。 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 reports suggest that nicotine serves to mediate neuroprotective effects and have been recalled for direct involvement of receptors including the α7 subtype. 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, it is assumed that the development of novel modulators of the receptor will lead to novel treatments 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）のアゴニスト及び正のモジュレーター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、特許文献２、特許文献３、特許文献４、特許文献５及び特許文献６）。 So far, there are disclosures regarding agonists and positive modulators of α7 nicotinic acetylcholine receptor (α7 nAChR), but the structure is different from the compounds of the present invention (Patent Document 1, Patent Document 2, Patent Document 3, Patent Document) 4, Patent Document 5 and Patent Document 6).
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 国際公開第２０１２／１３３５０９号パンフレットInternational Publication No. 2012/133509 Pamphlet 国際公開第２０１２／１７６７６３号パンフレットInternational Publication No. 2012/176863 Brochure 国際公開第２０１３／１５４１０９号パンフレットInternational Publication No. 2013/154109 Pamphlet 国際公開第２０１４／０３８６２３号パンフレットInternational Publication No. 2014/038623 Pamphlet
　本発明が解決しようとする課題は、強力なα７ニコチン性アセチルコリン受容体（α７ ｎＡＣｈＲ）の正のモジュレーター作用を有し、神経系疾患、精神疾患及び炎症性疾患の新規な治療剤として有用な新規化合物を提供することにある。 The problem to be solved by the present invention is a novel having a positive modulator action of a potent α7 nicotinic acetylcholine receptor (α7 nAChR) and useful as a novel therapeutic agent for nervous system diseases, mental diseases and inflammatory diseases. It is to provide a compound.
　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）の正のモジュレーター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５員環ヘテロアリール化合物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 positive modulator action of a potent α7 nicotinic acetylcholine receptor (α7 nAChR). Was completed. According to the present invention, a 5-membered heteroaryl compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as “the compound of the present invention”) is provided. .
［項１］式（Ｉ）：
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000004
 ［式中、
　Ｘ－Ｙ－Ｚは、Ｎ－ＣＯ－ＮＲ３ＡＲ３Ｂ、Ｎ－ＣＯＲ４Ａ、ＣＲ５－ＣＯ－ＮＲ３ＡＲ３Ｂ、ＣＲ５－ＮＲ６－ＣＯＲ４Ｂ又はＣＲ５－ＮＲ６－ＣＯＮＲ３ＡＲ３Ｂを表し、
　Ａは、フェニル又はピリジル（該フェニル及び該ピリジルは、それぞれハロゲン、水酸基、１から５個のフッ素で置換されていてもよいＣ１－６アルキル、１から５個のフッ素で置換されていてもよいＣ１－６アルコキシ及びシアノ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）を表し、
　Ｂは、Ｂ－１、Ｂ－２、Ｂ－３、Ｂ－４又はＢ－５を表し、
　式（Ｉ）の化合物におけるａおよびｂは、Ｂに結合する２つの結合手が、Ｂ－１からＢ－５における２つの結合手のいずれに該当する結合かを示す記号であり、
　Ｗは、酸素原子又は硫黄原子を表し、
　Ｒ１は、水素原子；ハロゲン；シアノ；Ｃ１－６アルキル（該アルキルは、ハロゲン、水酸基、１から５個のフッ素で置換されていてもよいＣ３－１０シクロアルキル、１から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４～１０員の飽和複素環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）；又はハロゲン、水酸基、Ｃ１－６アルキル及び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シクロアルキルを表し、
　Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ、Ｒ２Ｄ及びＲ５は、同一又は異なって、水素原子；フッ素；水酸基；１から５個のフッ素で置換されていてもよいＣ１－６アルコキシ；又は１から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、Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ、Ｒ２Ｄ及びＲ５のいずれかの２つが１から５個のフッ素で置換されていてもよいＣ１－６アルキルのとき、２個のアルキルが一緒になって該アルキルが結合している環と別の環を形成していてもよく、
　Ｒ３Ａ、Ｒ３Ｂ、Ｒ４Ａ、Ｒ４Ｂ及びＲ６は、同一又は異なって、ハロゲン、水酸基、Ｃ１－６アルコキシ、Ｃ３－１０シクロアルキル及び４～１０員の飽和複素環（ただし、環上にカルボニル基を有しない）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Ｃ１－６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Ｃ３－１０シクロアルキル；Ｃ１－６アルキルで置換されていてもよい４～１０員の飽和複素環；又は水素原子を表し、ここにおいて、（１）Ｒ４Ａ及びＲ４Ｂは水素原子ではなく、（２）Ｒ３Ａ及びＲ３Ｂは同時に水素原子ではなく、（３）ＢがＢ－３であり、Ｗが酸素原子であり、Ｘ－Ｙ－ＺがＮ－ＣＯＲ４Ａであるときは、Ｒ４Ａはメチルではなく、（４）Ａが無置換のフェニルであり、ＢがＢ－４であり、Ｗが酸素原子であり、Ｘ－Ｙ－ＺがＮ－ＣＯＲ４Ａであるときは、Ｒ４Ａは１～５個のフッ素で置換されたＣ３アルキルではなく、かつ（５）Ｒ３Ａ及びＲ３Ｂが共にＣ１－６アルキルのとき、それらが結合する窒素原子と一緒になって、フッ素、Ｃ１－６アルキル及び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４～１０員の含窒素飽和複素環を形成していてもよい]
で表される化合物又はその製薬学的に許容される塩。 [Item 1] Formula (I):
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000004
 [Where:
XYZ represents N-CO-NR 3A R 3B , N-COR 4A , CR 5 -CO-NR 3A R 3B , CR 5 -NR 6 -COR 4B or CR 5 -NR 6 -CONR 3A R 3B Represents
A is phenyl or pyridyl (said phenyl and said pyridyl, halogen, respectively, hydroxyl, 1 to 5 fluorine optionally substituted by C 1-6 alkyl, optionally substituted with 1-5 fluorine And optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy and cyano,
B represents B-1, B-2, B-3, B-4 or B-5,
A and b in the compound of the formula (I) are symbols indicating which of the two bonds in B-1 to B-5 the two bonds that bind to B correspond to;
W represents an oxygen atom or a sulfur atom,
R 1 is a hydrogen atom; halogen; cyano; C 1-6 alkyl (wherein the alkyl is halogen, hydroxyl, C 3-10 cycloalkyl optionally substituted with 1 to 5 fluorines, 1 to 5 Halogen optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy optionally substituted with fluorine and a 4- to 10-membered saturated heterocyclic ring; or halogen Represents a C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of hydroxyl, C 1-6 alkyl and C 1-6 alkoxy,
R 2A , R 2B , R 2C , R 2D and R 5 are the same or different and represent a hydrogen atom; fluorine; a hydroxyl group; C 1-6 alkoxy optionally substituted with 1 to 5 fluorines; Represents C 1-6 alkyl optionally substituted with 5 fluorines, wherein two of R 2A , R 2B , R 2C , R 2D and R 5 are substituted with 1 to 5 fluorines In the case of C 1-6 alkyl which may be substituted , two alkyls may be combined to form another ring with the ring to which the alkyl is bonded,
R 3A , R 3B , R 4A , R 4B and R 6 are the same or different and are halogen, hydroxyl group, C 1-6 alkoxy, C 3-10 cycloalkyl and a 4- to 10-membered saturated heterocyclic ring (provided that the ring C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of (having no carbonyl group above); halogen, hydroxyl, C 1-6 alkoxy and C 1 C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of -6 alkyl; 4 to 10 members optionally substituted with C 1-6 alkyl Or a hydrogen atom, wherein (1) R 4A and R 4B are not hydrogen atoms, (2) R 3A and R 3B are not simultaneously hydrogen atoms, and (3) B is B— 3 and W is an oxygen atom When XYZ is N—COR 4A , R 4A is not methyl, (4) A is unsubstituted phenyl, B is B-4, and W is an oxygen atom. , XYZ is N—COR 4A , R 4A is not C 3 alkyl substituted with 1 to 5 fluorines, and (5) R 3A and R 3B are both C 1-6 When alkyl, together with the nitrogen atom to which they are attached, is substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, C 1-6 alkyl and C 1-6 alkoxy. It may form a 4- to 10-membered nitrogen-containing saturated heterocyclic ring.
Or a pharmaceutically acceptable salt thereof.
［項２］Ｒ３Ａ、Ｒ３Ｂ、Ｒ４Ａ、Ｒ４Ｂ及びＲ６が、同一又は異なって、フッ素、Ｃ１－６アルコキシ、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Ｃ１－６アルキル；フッ素、Ｃ１－６アルコキシ及びＣ１－６アルキルからなる群から独立して選択される１～５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；又は水素原子であり、ここにおいて、（１）Ｒ４Ａ及びＲ４Ｂは水素原子ではなく、（２）Ｒ３Ａ及びＲ３Ｂは同時に水素原子ではなく、（３）ＢがＢ－３であり、Ｗが酸素原子であり、Ｘ－Ｙ－ＺがＮ－ＣＯＲ４Ａであるときは、Ｒ４Ａはメチルではなく、（４）Ａが無置換のフェニルであり、ＢがＢ－４であり、Ｗが酸素原子であり、Ｘ－Ｙ－ＺがＮ－ＣＯＲ４Ａであるときは、Ｒ４Ａは１～５個のフッ素で置換されたＣ３アルキルではない、
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] R 3A , R 3B , R 4A , R 4B and R 6 are the same or different and are independently selected from the group consisting of fluorine, C 1-6 alkoxy, and C 3-10 cycloalkyl. C 1-6 alkyl optionally substituted with 1-5 substituents; 1-5 substituents independently selected from the group consisting of fluorine, C 1-6 alkoxy and C 1-6 alkyl in an optionally substituted C 3-10 cycloalkyl; saturated heterocyclic 4-10 membered; a or a hydrogen atom, wherein, (1) R 4A and R 4B are not hydrogen atom, (2) R 3A and R 3B are not simultaneously hydrogen atoms; (3) when B is B-3, W is an oxygen atom, and XYZ is N-COR 4A , R 4A is not methyl (4) A is unsubstituted phenyl and B is B- In it, W is an oxygen atom, when X-Y-Z is N-COR 4A is, R 4A is not a C 3 alkyl substituted with 1-5 fluorine,
Item 12. The compound according to Item 1 or a pharmaceutically acceptable salt thereof.
［項３］Ｒ３Ａ、Ｒ３Ｂ及びＲ４Ａが、同一又は異なって、フッ素、Ｃ１－６アルコキシ及びＣ１－６アルキルからなる群から独立して選択される１～５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；又は水素原子であり、ここにおいて、Ｒ３Ａ及びＲ３Ｂは同時に水素原子ではなく、Ｒ４Ａは水素原子ではない、
項１又は２に記載の化合物又はその製薬学的に許容される塩。 [Claim 3] R 3A , R 3B and R 4A are the same or different and are each 1 to 5 substituents independently selected from the group consisting of fluorine, C 1-6 alkoxy and C 1-6 alkyl An optionally substituted C 3-10 cycloalkyl; a 4-10 membered saturated heterocycle; or a hydrogen atom, wherein R 3A and R 3B are not simultaneously a hydrogen atom and R 4A is not a hydrogen atom ,
Item 3. The compound according to Item 1 or 2, or a pharmaceutically acceptable salt thereof.
［項４］Ｒ４Ｂが、フッ素、Ｃ１－６アルコキシ、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Ｃ１－６アルキルである、
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。 [Claim 4] R 4B is good fluorine, C 1-6 alkoxy, and C 3-10 optionally substituted with one to five substituents independently selected from the group consisting of cycloalkyl C 1- 6 alkyl,
Item 4. The compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof.
［項５］Ａが、フェニル又はピリジル（該フェニル及び該ピリジルは、それぞれフッ素、１から５個のフッ素で置換されていてもよいＣ１－６アルキル及び１から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）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。 [Item 5] A is phenyl or pyridyl (the phenyl and the pyridyl are each substituted with fluorine, C 1-6 alkyl optionally substituted with 1 to 5 fluorine, and 1 to 5 fluorine. And optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy).
Item 5. The compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.
［項６］Ａが、フェニル（該フェニルは、それぞれフッ素、１から５個のフッ素で置換されていてもよいＣ１－６アルキル及び１から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）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。 [Item 6] A is phenyl (the phenyl is each fluorine, C 1-6 alkyl optionally substituted with 1 to 5 fluorines, and C 1 optionally substituted with 1 to 5 fluorines) Optionally substituted with 1 to 5 substituents independently selected from the group consisting of -6 alkoxy.)
Item 5. The compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.
［項７］Ａが、ピリジル（該ピリジルは、それぞれフッ素、１から５個のフッ素で置換されていてもよいＣ１－６アルキル及び１から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）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。 [Item 7] A is pyridyl (the pyridyl is each fluorine, C 1-6 alkyl optionally substituted with 1 to 5 fluorines, and C 1 optionally substituted with 1 to 5 fluorines) Optionally substituted with 1 to 5 substituents independently selected from the group consisting of -6 alkoxy.)
Item 5. The compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.
［項８］Ｒ１が、水素原子；ハロゲン；シアノ；Ｃ１－６アルキル；又はＣ３－１０シクロアルキルである、
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。 [Item 8] R 1 is a hydrogen atom; halogen; cyano; C 1-6 alkyl; or C 3-10 cycloalkyl.
Item 8. The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof.
［項９］Ｒ１が、水素原子、塩素又はシアノである、
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。 [Item 9] R 1 is a hydrogen atom, chlorine or cyano.
Item 8. The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof.
［項１０］Ｒ１が、水素原子である、
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。 [Item 10] R 1 is a hydrogen atom.
Item 8. The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof.
［項１１］Ｒ１が、塩素である、
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。 [Item 11] R 1 is chlorine.
Item 8. The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof.
［項１２］Wが、酸素原子である、
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。 [Item 12] W is an oxygen atom.
Item 12. The compound according to any one of Items 1 to 11 or a pharmaceutically acceptable salt thereof.
［項１３］Wが、硫黄原子である、
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。 [Item 13] W is a sulfur atom.
Item 12. The compound according to any one of Items 1 to 11 or a pharmaceutically acceptable salt thereof.
［項１４］Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ、Ｒ２Ｄ及びＲ５が、同一又は異なって、水素原子、又はＣ１－６アルキルであり、ここにおいて、Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ、Ｒ２Ｄ及びＲ５のいずれかの２つがＣ１－６アルキルのとき、２個のアルキルが一緒になって該アルキルが結合している環と別の環を形成していてもよい、
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 2A , R 2B , R 2C , R 2D and R 5 are the same or different and are a hydrogen atom or C 1-6 alkyl, wherein R 2A , R 2B , R 2C , R When any two of 2D and R 5 are C 1-6 alkyl, the two alkyls may be combined together to form another ring with the ring to which the alkyl is attached,
Item 14. The compound according to any one of Items 1 to 13, or a pharmaceutically acceptable salt thereof.
［項１５］Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ、Ｒ２Ｄ及びＲ５が、すべて水素原子である、
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 15] R 2A , R 2B , R 2C , R 2D and R 5 are all hydrogen atoms.
Item 14. The compound according to any one of Items 1 to 13, or a pharmaceutically acceptable salt thereof.
［項１６］Ｒ６が、フッ素、Ｃ１－６アルコキシ、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Ｃ１－６アルキル；又は水素原子である、
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。 [Claim 16] R 6 is optionally fluorine, C 1-6 alkoxy, and C 3-10 optionally substituted with one to five substituents independently selected from the group consisting of cycloalkyl C 1- 6 alkyl; or a hydrogen atom,
Item 16. The compound according to any one of Items 1 to 15, or a pharmaceutically acceptable salt thereof.
［項１７］Ｒ６が、水素原子である、
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。 [Section 17] R 6 is a hydrogen atom.
Item 16. The compound according to any one of Items 1 to 15, or a pharmaceutically acceptable salt thereof.
［項１８］Ｒ３Ｂが、水素原子であり、Ｒ３Ａ及びＲ４Ａが、同一又は異なって、フッ素、Ｃ１－６アルコキシ及びＣ１－６アルキルからなる群から独立して選択される１～５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；又は４～１０員の飽和複素環である、
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] R 3B is a hydrogen atom, and R 3A and R 4A are the same or different and are independently selected from the group consisting of fluorine, C 1-6 alkoxy and C 1-6 alkyl A C 3-10 cycloalkyl optionally substituted with 5 substituents; or a 4-10 membered saturated heterocycle,
Item 18. The compound according to any one of Items 1 to 17, or a pharmaceutically acceptable salt thereof.
［項１９］Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ３ＡＲ３Ｂ又はＮ－ＣＯＲ４Ａである、
項１～１８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 19] XYZ is N—CO—NR 3A R 3B or N—COR 4A .
Item 19. The compound according to any one of Items 1 to 18, or a pharmaceutically acceptable salt thereof.
［項２０］Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ３ＡＲ３Ｂである、
項１～１８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 20] XYZ is N—CO—NR 3A R 3B .
Item 19. The compound according to any one of Items 1 to 18, or a pharmaceutically acceptable salt thereof.
［項２１］Ｘ－Ｙ－Ｚが、Ｎ－ＣＯＲ４Ａである、
項１～１８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 21] XYZ is N-COR 4A .
Item 19. The compound according to any one of Items 1 to 18, or a pharmaceutically acceptable salt thereof.
［項２２］Ｘ－Ｙ－Ｚが、ＣＲ５－ＣＯ－ＮＲ３ＡＲ３Ｂである、
項１～１８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 22] XYZ is CR 5 —CO—NR 3A R 3B .
Item 19. The compound according to any one of Items 1 to 18, or a pharmaceutically acceptable salt thereof.
［項２３］Ｘ－Ｙ－Ｚが、ＣＲ５－ＮＲ６－ＣＯＲ４Ｂである、
項１～１８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 23] XYZ is CR 5 —NR 6 —COR 4B .
Item 19. The compound according to any one of Items 1 to 18, or a pharmaceutically acceptable salt thereof.
［項２４］Ｂが、Ｂ－１である、
項１～２３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 24] B is B-1.
Item 24. The compound according to any one of Items 1 to 23 or a pharmaceutically acceptable salt thereof.
［項２５］Ｂが、Ｂ－２である、
項１～２３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 25] B is B-2.
Item 24. The compound according to any one of Items 1 to 23 or a pharmaceutically acceptable salt thereof.
［項２６］Ｂが、Ｂ－３である、
項１～２３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。 [Section 26] B is B-3.
Item 24. The compound according to any one of Items 1 to 23 or a pharmaceutically acceptable salt thereof.
［項２７］Ｂが、Ｂ－４である、
項１～２３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。 [Section 27] B is B-4.
Item 24. The compound according to any one of Items 1 to 23 or a pharmaceutically acceptable salt thereof.
［項２８］Ｂが、Ｂ－５である、
項１～２３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 28] B is B-5.
Item 24. The compound according to any one of Items 1 to 23 or a pharmaceutically acceptable salt thereof.
［項２９］以下の化合物から選択される、項１に記載の化合物又はその製薬学的に許容される塩：
４－[５－クロロ－１－（３－フルオロフェニル）－１Ｈ－イミダゾール－４－イル]－Ｎ－（４，４－ジフルオロシクロヘキシル）ピペリジン－１－カルボキサミド（実施例１）、
｛４－[５－クロロ－１－（４－フルオロフェニル）－１Ｈ－イミダゾール－４－イル]ピペリジン－１－イル｝（４，４－ジフルオロシクロヘキシル）メタノン（実施例４５）、
Ｎ－シクロヘキシル－４－[３－（４－フルオロフェニル）－１，２－オキサゾール－５－イル]ピペリジン－１－カルボキサミド（実施例５１）、
Ｎ－（４，４－ジフルオロシクロヘキシル）－４－[３－（２，５－ジフルオロフェニル）－１，２－オキサゾール－５－イル]ピペリジン－１－カルボキサミド（実施例７７）、
４－[４－クロロ－３－（４－フルオロフェニル）－１，２－オキサゾール－５－イル]－Ｎ－（テトラヒドロ－２Ｈ－ピラン－４－イル）ピペリジン－１－カルボキサミド（実施例７９）、
４－[４－クロロ－５－（４－フルオロフェニル）－１，２－オキサゾール－３－イル]－Ｎ－（テトラヒドロ－２Ｈ－ピラン－４－イル）ピペリジン－１－カルボキサミド（実施例１２４）、
４－[４－クロロ－５－（３，４－ジフルオロフェニル）－１，２－オキサゾール－３－イル]－Ｎ－（テトラヒドロ－２Ｈ－ピラン－４－イル）ピペリジン－１－カルボキサミド（実施例１３４）、及び
４－[５－（４－クロロフェニル）－１，３－オキサゾール－２－イル]－Ｎ－（テトラヒドロ－２Ｈ－ピラン－４－イル）ピペリジン－１－カルボキサミド（実施例１８９）。 [Item 29] The compound according to item 1 or a pharmaceutically acceptable salt thereof selected from the following compounds:
4- [5-Chloro-1- (3-fluorophenyl) -1H-imidazol-4-yl] -N- (4,4-difluorocyclohexyl) piperidine-1-carboxamide (Example 1),
{4- [5-Chloro-1- (4-fluorophenyl) -1H-imidazol-4-yl] piperidin-1-yl} (4,4-difluorocyclohexyl) methanone (Example 45),
N-cyclohexyl-4- [3- (4-fluorophenyl) -1,2-oxazol-5-yl] piperidine-1-carboxamide (Example 51),
N- (4,4-difluorocyclohexyl) -4- [3- (2,5-difluorophenyl) -1,2-oxazol-5-yl] piperidine-1-carboxamide (Example 77),
4- [4-Chloro-3- (4-fluorophenyl) -1,2-oxazol-5-yl] -N- (tetrahydro-2H-pyran-4-yl) piperidine-1-carboxamide (Example 79) ,
4- [4-Chloro-5- (4-fluorophenyl) -1,2-oxazol-3-yl] -N- (tetrahydro-2H-pyran-4-yl) piperidine-1-carboxamide (Example 124) ,
4- [4-Chloro-5- (3,4-difluorophenyl) -1,2-oxazol-3-yl] -N- (tetrahydro-2H-pyran-4-yl) piperidine-1-carboxamide (Examples) 134), and 4- [5- (4-Chlorophenyl) -1,3-oxazol-2-yl] -N- (tetrahydro-2H-pyran-4-yl) piperidine-1-carboxamide (Example 189).
［項３０］項１～２９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 30] A pharmaceutical composition comprising the compound according to any one of items 1 to 29 or a pharmaceutically acceptable salt thereof.
［項３１］項１～２９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及び／又は予防剤。 [Item 31] Treatment of a disease caused by an abnormality in intracellular signal transduction involving acetylcholine, comprising the compound according to any one of items 1 to 29 or a pharmaceutically acceptable salt thereof as an active ingredient Agent and / or preventive agent.
［項３２］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、神経疾患、精神疾患又は炎症性疾患である、項３１に記載の治療剤及び／又は予防剤。 [Item 32] The therapeutic and / or prophylactic agent according to item 31, wherein the disease caused by abnormality in intracellular signal transduction involving acetylcholine is a neurological disease, a mental disease or an inflammatory disease.
［項３２］神経疾患、精神疾患又は炎症性疾患が、統合失調症、アルツハイマー病、ダウン症、注意欠陥・多動性障害又は脳血管アンギオパチーである、項３２に記載の治療剤及び／又は予防剤。 [Item 32] The therapeutic and / or prophylactic agent according to item 32, wherein the neurological disease, mental disease or inflammatory disease is schizophrenia, Alzheimer's disease, Down's syndrome, attention deficit / hyperactivity disorder or cerebrovascular angiopathy. .
［項３３］ＣＩＡＳ（統合失調症に伴う認知機能障害）、或いは、統合失調症、アルツハイマー病、ダウン症、注意欠陥・多動性障害又は脳血管アンギオパチーにおける、認知障害、軽度認知障害、記憶障害又は学習障害を治療及び／又は予防するための、項３０に記載の医薬組成物。 [Claim 33] CIAS (cognitive impairment associated with schizophrenia) or cognitive impairment, mild cognitive impairment, memory impairment in schizophrenia, Alzheimer's disease, Down's syndrome, attention deficit / hyperactivity disorder or cerebrovascular angiopathy or Item 31. A pharmaceutical composition according to Item 30, for treating and / or preventing learning disorders.
［項３４］項１～２９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、非定型抗精神病薬から選択される少なくとも１種以上の薬剤とを含有する医薬。 [Item 34] A pharmaceutical comprising the compound according to any one of items 1 to 29 or a pharmaceutically acceptable salt thereof and at least one drug selected from atypical antipsychotics .
［項３５］治療が必要な患者に、治療上の有効量の項１～２９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を治療及び／又は予防するための方法。 [Item 35] Acetylcholine characterized by administering a therapeutically effective amount of the compound according to any one of Items 1 to 29 or a pharmaceutically acceptable salt thereof to a patient in need of treatment. A method for treating and / or preventing a disease caused by an abnormality in intracellular signal transduction associated with a cell.
［項３６］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及び／又は予防剤を製造するための、項１～２９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の使用。 [Item 36] The compound according to any one of items 1 to 29 or a pharmacological agent thereof for producing a therapeutic and / or prophylactic agent for a disease caused by an abnormality in intracellular signal transduction involving acetylcholine Use of acceptable salts.
［項３７］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及び／又は予防に使用するための、項１～２９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を含有する医薬組成物。 [Item 37] The compound according to any one of items 1 to 29 or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of a disease caused by an abnormality in intracellular signal transduction involving acetylcholine The pharmaceutical composition containing the salt made.
　本発明の化合物は、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及び／又は予防剤として有用である。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としては、神経疾患、精神疾患又は炎症性疾患が挙げられる。神経疾患、精神疾患又は炎症性疾患の具体例としては、統合失調症、アルツハイマー病、ダウン症、注意欠陥・多動性障害又は脳血管アンギオパチーが挙げられる。また、本発明の化合物は、（１）ＣＩＡＳ（統合失調症に伴う認知機能障害）、或いは、（２）統合失調症、アルツハイマー病、ダウン症、注意欠陥・多動性障害又は脳血管アンギオパチーにおける、認知障害、軽度認知障害、記憶障害又は学習障害を治療及び／又は予防するために有用である。　 The compound of the present invention is useful as a therapeutic and / or prophylactic agent for diseases caused by abnormalities in intracellular signal transduction involving acetylcholine. Examples of the disease caused by abnormal intracellular signal transduction involving acetylcholine include a neurological disease, a mental disease or an inflammatory disease. Specific examples of neurological diseases, psychiatric diseases or inflammatory diseases include schizophrenia, Alzheimer's disease, Down's syndrome, attention deficit / hyperactivity disorder, or cerebrovascular angiopathy. In addition, the compound of the present invention is (1) CIAS (cognitive dysfunction associated with schizophrenia), or (2) schizophrenia, Alzheimer's disease, Down's syndrome, attention deficit / hyperactivity disorder or cerebrovascular angiopathy, Useful for treating and / or preventing cognitive impairment, mild cognitive impairment, memory impairment or learning impairment. *
　さらに、本発明の化合物は、前記治療及び／又は予防の目的で、非定型抗精神病薬と併用して用いることもできる。 Furthermore, the compound of the present invention can be used in combination with an atypical antipsychotic agent for the purpose of the treatment and / or prevention.
　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、式（Ｉ）で表される化合物又はその製薬学的に許容される塩の水和物及び／又は溶媒和物もまた本発明の化合物に包含される。 Since the compound of the present invention may exist in the form of a hydrate and / or a solvate, a hydrate of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and / or Alternatively, solvates are also encompassed by the compounds of the present invention.
　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。 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.
　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。 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.
　結晶として得られる一般式（Ｉ）で表される化合物及びその製薬学的に許容される塩には、結晶多形が存在する場合があり、本発明の化合物には、あらゆる結晶形のものが含まれる。 Crystalline polymorphisms may exist in the compound represented by the general formula (I) obtained as crystals and pharmaceutically acceptable salts thereof, and the compounds of the present invention may be in any crystalline form. included.
　つぎに、本明細書における用語について以下に説明する。 Next, terms used in this specification will be described below.
　「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」又は「Ｃ１－６アルキル」とは炭素原子数が１～４又は１～６のアルキルを意味する。「Ｃ１－６アルキル」の中で好ましくは、「Ｃ１－４アルキル」が挙げられる。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、前記に加えて、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る。 “Alkyl” means a linear or branched saturated hydrocarbon group. For example, “C 1-4 alkyl” or “C 1-6 alkyl” has 1 to 4 carbon atoms or Means 1-6 alkyl. Among “C 1-6 alkyl”, “C 1-4 alkyl” is preferable. 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, pentyl, isopentyl, neopentyl, hexyl and the like can be mentioned.
　「シクロアルキル」とは、単環又は多環式飽和炭化水素からなる基を意味し、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等が挙げられる。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、アダマンチル等が挙げられる。 “Cycloalkyl” means a group consisting of monocyclic or polycyclic saturated hydrocarbons. For example, “C 3-10 cycloalkyl” means a cyclic alkyl having 3 to 10 carbon atoms. The thing of the structure of bridge | crosslinking is mentioned. Specific examples thereof include “C 3-10 cycloalkyl” such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl and the like.
　「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と結合している基であって、当該酸素原子を介して他の部分に結合する基を意味し、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。 “Alkoxy” means a group in which a linear or branched saturated hydrocarbon group is bonded to an oxygen atom, and is bonded to another moiety via the oxygen atom. “C 1-6 alkoxy” means alkoxy having 1 to 6 carbon atoms. Specific examples of “C 1-6 alkoxy” include methoxy, ethoxy, propoxy, isopropoxy, butyloxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like.
　「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。 “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.
　「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飽和複素環を意味し、好ましくは、単環の４～１０員の飽和複素環を意味する。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、オキセタン等が挙げられる。好ましい４～１０員の飽和複素環としては、テトラヒドロフラン、テトラヒドロピラン、オキセタンが挙げられる。さらに好ましくは、テトラヒドロピランである。 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. Means a saturated heterocyclic ring, preferably a monocyclic 4- to 10-membered saturated heterocyclic ring. Examples thereof include azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, tetrahydrofuran, tetrahydropyran, oxetane and the like. Preferred 4- to 10-membered saturated heterocycles include tetrahydrofuran, tetrahydropyran, and oxetane. More preferred is tetrahydropyran.
　「４～１０員の含窒素飽和複素環」とは、炭素原子以外に１～２個の窒素原子及び、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０～２個の原子を含む４～１０個の原子で構成される飽和複素環を意味する。例えば、アゼチジン、ピロリジン、ピペリジン、ピペラジン、ホモピペリジン等が挙げられる。好ましい４～１０員の含窒素飽和複素環としては、炭素原子以外に１個の窒素原子を含む４～１０個の原子で構成される飽和複素環が挙げられる。例えば、アゼチジン、ピロリジン、ピペリジン等が挙げられる。 The “4- to 10-membered nitrogen-containing saturated heterocycle” means 0 to 2 atoms independently selected from the group consisting of 1 to 2 nitrogen atoms, oxygen atoms and sulfur atoms in addition to carbon atoms. A saturated heterocyclic ring composed of 4 to 10 atoms is included. For example, azetidine, pyrrolidine, piperidine, piperazine, homopiperidine and the like can be mentioned. Preferred examples of the 4 to 10-membered nitrogen-containing saturated heterocyclic ring include saturated heterocyclic rings composed of 4 to 10 atoms containing one nitrogen atom in addition to the carbon atom. For example, azetidine, pyrrolidine, piperidine and the like can be mentioned.
　式（Ｉ）で表される本発明の化合物の中でも、Ａ、Ｂ、Ｗ、Ｘ－Ｙ－Ｚ、Ｒ１、Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ、Ｒ２Ｄ、Ｒ３Ａ、Ｒ３Ｂ、Ｒ４Ａ、Ｒ４Ｂ、Ｒ５及びＲ６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, B, W, XYZ, R 1 , R 2A , R 2B , R 2C , R 2D , R 3A , R 3B , R 4A , R 4B , R 5 and R 6 are preferably as follows, but the technical scope of the present invention is not limited to the scope of the compounds listed below.
　Ｘ－Ｙ－Ｚとして好ましくは、Ｎ－ＣＯ－ＮＲ３ＡＲ３Ｂ、Ｎ－ＣＯＲ４Ａ、ＣＲ５－ＣＯ－ＮＲ３ＡＲ３Ｂ又はＣＲ５－ＮＲ６－ＣＯＲ４Ｂが挙げられる。
　より好ましくは、Ｎ－ＣＯ－ＮＲ３ＡＲ３Ｂ、Ｎ－ＣＯＲ４Ａ又はＣＲ５－ＮＲ６－ＣＯＲ４Ｂが挙げられる。
　さらに好ましくは、Ｎ－ＣＯ－ＮＲ３ＡＲ３Ｂ又はＮ－ＣＯＲ４Ａが挙げられる。 X—Y—Z is preferably N—CO—NR 3A R 3B , N—COR 4A , CR 5 —CO—NR 3A R 3B or CR 5 —NR 6 —COR 4B .
More preferably, N—CO—NR 3A R 3B , N—COR 4A or CR 5 —NR 6 —COR 4B may be mentioned.
More preferred is N—CO—NR 3A R 3B or N—COR 4A .
　Ａとして好ましくは、フェニル又はピリジル（該フェニル及び該ピリジルは、それぞれハロゲン、水酸基、１から５個のフッ素で置換されていてもよいＣ１－６アルキル、及び１から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）が挙げられる。
　より好ましくは、フェニル又はピリジル（該フェニル及び該ピリジルは、それぞれフッ素、塩素、１から５個のフッ素で置換されていてもよいＣ１－６アルキル、及び１から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）が挙げられる。
　さらに好ましくは、フッ素、塩素、１～３個のフッ素で置換されていてもよいＣ１－６アルキル及び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フェニルが挙げられる。
　もっとも好ましくは、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フェニルが挙げられる。 A is preferably phenyl or pyridyl (the phenyl and pyridyl are each substituted with halogen, hydroxyl, C 1-6 alkyl optionally substituted with 1 to 5 fluorine, and 1 to 5 fluorine. And optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy.
More preferably, phenyl or pyridyl (the phenyl and the pyridyl are each substituted with fluorine, chlorine, C 1-6 alkyl optionally substituted with 1 to 5 fluorine, and 1 to 5 fluorine. And optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy.
More preferably, it is 1 to 5 substituents independently selected from the group consisting of fluorine, chlorine, C 1-6 alkyl optionally substituted with 1 to 3 fluorine and C 1-6 alkoxy. Examples include optionally substituted phenyl.
Most preferably, mention may be made of phenyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine and C 1-6 alkoxy.
　Ｂとして好ましくは、Ｂ－１、Ｂ－２、Ｂ－３、Ｂ－４又はＢ－５が挙げられる。より好ましくは、Ｂ－１、Ｂ－４又はＢ－５が挙げられる。さらに好ましくは、Ｂ－１又はＢ－４が挙げられる。 B is preferably B-1, B-2, B-3, B-4 or B-5. More preferred is B-1, B-4 or B-5. More preferred is B-1 or B-4.
　Ｗとして好ましくは、酸素原子又は硫黄原子が挙げられる。より好ましくは、酸素原子が挙げられる。 W is preferably an oxygen atom or a sulfur atom. More preferably, an oxygen atom is mentioned.
　Ｒ１として好ましくは、水素原子；ハロゲン；シアノ；又はハロゲン、水酸基、１から５個のフッ素で置換されていてもよいＣ３－１０シクロアルキル、Ｃ１－６アルコキシ及び４～１０員の飽和複素環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アルキルが挙げられる。より好ましくは、水素原子、ハロゲン又はシアノが挙げられる。さらに好ましくは、水素原子、塩素又はシアノが挙げられる。もっとも好ましくは、水素原子又は塩素が挙げられる。 R 1 is preferably a hydrogen atom; halogen; cyano; or halogen, hydroxyl, C 3-10 cycloalkyl optionally substituted with 1 to 5 fluorines, C 1-6 alkoxy, and 4 to 10 membered saturation And C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of heterocycles. More preferably, a hydrogen atom, halogen, or cyano is mentioned. More preferably, a hydrogen atom, chlorine, or cyano is mentioned. Most preferably, a hydrogen atom or chlorine is mentioned.
　Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ、Ｒ２Ｄ及びＲ５として好ましくは、同一又は異なって、水素原子、フッ素、水酸基又はＣ１－６アルキルが挙げられる。ここにおいて、Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ、Ｒ２Ｄ及びＲ５のいずれかの２つが１から５個のフッ素で置換されていてもよいＣ１－６アルキルのとき、２個のアルキルが一緒になって該アルキルが結合している環と別の環を形成していてもよい。
　Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ、Ｒ２Ｄ及びＲ５としてより好ましくは、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る。ここにおいて、Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ、Ｒ２Ｄ及びＲ５のいずれかの２つが、Ｃ１－６アルキルのとき、２個のアルキルが一緒になって該アルキルが結合している環と別の環を形成していてもよい。
　Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ、Ｒ２Ｄ及びＲ５としてさらに好ましくは、水素原子が挙げられる。 R 2A , R 2B , R 2C , R 2D and R 5 are preferably the same or different and include a hydrogen atom, fluorine, a hydroxyl group or C 1-6 alkyl. Here, when any two of R 2A , R 2B , R 2C , R 2D and R 5 are C 1-6 alkyl optionally substituted with 1 to 5 fluorines, the two alkyls together To form a ring different from the ring to which the alkyl is bonded.
R 2A , R 2B , R 2C , R 2D and R 5 are more preferably the same or different and include a hydrogen atom or C 1-6 alkyl. Here, when any two of R 2A , R 2B , R 2C , R 2D and R 5 are C 1-6 alkyl, the two alkyls are joined together to form a ring to which the alkyl is bonded Another ring may be formed.
R 2A , R 2B , R 2C , R 2D and R 5 are more preferably a hydrogen atom.
　Ｒ３Ａ、Ｒ３Ｂ及びＲ４Ａとして好ましくは、同一又は異なって、ハロゲン、水酸基、Ｃ１－６アルコキシ、Ｃ３－１０シクロアルキル及び４～１０員の飽和複素環（ただし、環上にカルボニル基を有しない）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Ｃ１－６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Ｃ３－１０シクロアルキル；Ｃ１－６アルキルで置換されていてもよい４～１０員の飽和複素環；又は水素原子が挙げられ、ここにおいて、（１）Ｒ４Ａは水素原子ではなく、（２）Ｒ３Ａ及びＲ３Ｂは同時に水素原子ではなく、（３）ＢがＢ－３であり、Ｗが酸素原子であり、Ｘ－Ｙ－ＺがＮ－ＣＯＲ４Ａであるときは、Ｒ４Ａはメチルではなく、（４）Ａが無置換のフェニルであり、ＢがＢ－４であり、Ｗが酸素原子であり、Ｘ－Ｙ－ＺがＮ－ＣＯＲ４Ａであるときは、Ｒ４Ａは１～５個のフッ素で置換されたＣ３アルキルではない。
　Ｒ３Ａ、Ｒ３Ｂ及びＲ４Ａとしてより好ましくは、同一又は異なって、フッ素、Ｃ１－６アルコキシ、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Ｃ１－６アルキル；フッ素、Ｃ１－６アルコキシ及びＣ１－６アルキルからなる群から独立して選択される１～５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；又は水素原子が挙げられ、ここにおいて、（１）Ｒ４Ａは水素原子ではなく、（２）Ｒ３Ａ及びＲ３Ｂは同時に水素原子ではなく、（３）ＢがＢ－３であり、Ｗが酸素原子であり、Ｘ－Ｙ－ＺがＮ－ＣＯＲ４Ａであるときは、Ｒ４Ａはメチルではなく、（４）Ａが無置換のフェニルであり、ＢがＢ－４であり、Ｗが酸素原子であり、Ｘ－Ｙ－ＺがＮ－ＣＯＲ４Ａであるときは、Ｒ４Ａは１～５個のフッ素で置換されたＣ３アルキルではない。
　Ｒ３Ａ、Ｒ３Ｂ及びＲ４Ａとしてさらに好ましくは、同一又は異なって、フッ素、Ｃ１－６アルコキシ及びＣ１－６アルキルからなる群から独立して選択される１～５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；又は水素原子が挙げられ、ここにおいて、Ｒ３Ａ及びＲ３Ｂは同時に水素原子ではなく、Ｒ４Ａは水素原子ではない。
　Ｒ３Ａ及びＲ４Ａとしてもっとも好ましくは、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Ｃ３－１０シクロアルキル又は４～１０員の飽和複素環が挙げられる。
　Ｒ３Ｂとしてもっとも好ましくは、水素原子が挙げられる。
　なお、本明細書において、「Ｒ４Ａは１～５個のフッ素で置換されたＣ３アルキルではない」とは、「Ｒ４Ａは１～５個のフッ素で置換され、当該フッ素以外の他の置換基で置換されていないＣ３アルキルではない」ことを意味する。 R 3A , R 3B and R 4A are preferably the same or different and are halogen, hydroxyl group, C 1-6 alkoxy, C 3-10 cycloalkyl and a 4- to 10-membered saturated heterocyclic ring (provided that a carbonyl group is present on the ring). C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of: a halogen, a hydroxyl group, C 1-6 alkoxy and C 1-6 alkyl C 3-10 cycloalkyl optionally substituted with 1-5 substituents independently selected from the group consisting of: 4-10 membered saturated heterocycle optionally substituted with C 1-6 alkyl Or a hydrogen atom, wherein (1) R 4A is not a hydrogen atom, (2) R 3A and R 3B are not simultaneously a hydrogen atom, (3) B is B-3, and W is An oxygen atom, X- When -Z is N-COR 4A is, R 4A is not methyl, (4) A a is unsubstituted phenyl, B is B-4, W is an oxygen atom, X-Y- When Z is N—COR 4A , R 4A is not C 3 alkyl substituted with 1 to 5 fluorines.
More preferably, R 3A , R 3B and R 4A are the same or different and are 1 to 5 substituents independently selected from the group consisting of fluorine, C 1-6 alkoxy and C 3-10 cycloalkyl C 1-6 alkyl optionally substituted with 1-6 alkyls independently selected from the group consisting of fluorine, C 1-6 alkoxy and C 1-6 alkyl C 3-10 cycloalkyl; a 4-10 membered saturated heterocycle; or a hydrogen atom, where (1) R 4A is not a hydrogen atom and (2) R 3A and R 3B are simultaneously a hydrogen atom And (3) when B is B-3, W is an oxygen atom, and XYZ is N—COR 4A , R 4A is not methyl and (4) A is unsubstituted Phenyl, B is B-4, W is An atom, X-Y-Z is and when is N-COR 4A, R 4A is not C 3 alkyl substituted with 1-5 fluorine.
More preferably, R 3A , R 3B and R 4A are the same or different and substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, C 1-6 alkoxy and C 1-6 alkyl A C 3-10 cycloalkyl which may be substituted ; a 4 to 10 membered saturated heterocyclic ring; or a hydrogen atom, wherein R 3A and R 3B are not simultaneously a hydrogen atom and R 4A is not a hydrogen atom .
Most preferably the R 3A and R 4A, the same or different, fluorine and C 1-6 optionally substituted with 1-5 substituents independently selected from the group consisting of alkoxy C 3-10 Examples include cycloalkyl or a 4- to 10-membered saturated heterocyclic ring.
Most preferably, R 3B includes a hydrogen atom.
In the present specification, “R 4A is not C 3 alkyl substituted with 1 to 5 fluorines” means that “R 4A is substituted with 1 to 5 fluorines, It is not C 3 alkyl not substituted with a substituent ”.
　Ｒ４Ｂとして好ましくは、ハロゲン、水酸基、Ｃ１－６アルコキシ、Ｃ３－１０シクロアルキル及びカルボニル基で置換されていない４～１０員の飽和複素環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Ｃ１－６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Ｃ３－１０シクロアルキル；Ｃ１－６アルキルで置換されていてもよい４～１０員の飽和複素環が挙げられる。
　より好ましくは、フッ素、Ｃ１－６アルコキシ、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Ｃ１－６アルキル；フッ素、Ｃ１－６アルコキシ及びＣ１－６アルキルからなる群から独立して選択される１～５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；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、フッ素、Ｃ１－６アルコキシ、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Ｃ１－６アルキルが挙げられる。
　もっとも好ましくは、１～５個のフッ素で置換されていてもよいＣ１－６アルキルが挙げられる。 R 4B is preferably selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy, C 3-10 cycloalkyl and a 4-10 membered saturated heterocyclic ring not substituted with a carbonyl group. C 1-6 alkyl optionally substituted with 5 substituents; 1-5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy and C 1-6 alkyl C 3-10 cycloalkyl which may be substituted with a 4-10 membered saturated heterocyclic ring which may be substituted with C 1-6 alkyl.
More preferably fluorine, C 1-6 alkoxy, and C 3-10 1 ~ 5 amino optionally substituted with a substituent C 1-6 alkyl independently selected from the group consisting of cycloalkyl; fluorine C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy and C 1-6 alkyl; or 4-10 membered saturation Heterocycles are mentioned.
More preferable examples include C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, C 1-6 alkoxy, and C 3-10 cycloalkyl. It is done.
Most preferred is C 1-6 alkyl optionally substituted with 1 to 5 fluorines.
　Ｒ６として好ましくは、ハロゲン、水酸基、Ｃ１－６アルコキシ、Ｃ３－１０シクロアルキル及びカルボニル基で置換されていない４～１０員の飽和複素環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Ｃ１－６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Ｃ３－１０シクロアルキル；Ｃ１－６アルキルで置換されていてもよい４～１０員の飽和複素環；又は水素原子が挙げられる。
　より好ましくは、フッ素、Ｃ１－６アルコキシ、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Ｃ１－６アルキル；フッ素、Ｃ１－６アルコキシ及びＣ１－６アルキルからなる群から独立して選択される１～５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；又は水素原子が挙げられる。
　さらに好ましくは、フッ素、Ｃ１－６アルコキシ、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Ｃ１－６アルキル；又は水素原子が挙げられる。
　もっとも好ましくは、水素原子が挙げられる。 R 6 is preferably selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy, C 3-10 cycloalkyl and a 4-10 membered saturated heterocyclic ring not substituted with a carbonyl group. C 1-6 alkyl optionally substituted with 5 substituents; 1-5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy and C 1-6 alkyl A C 3-10 cycloalkyl which may be substituted with a 4 to 10-membered saturated heterocyclic ring which may be substituted with a C 1-6 alkyl; or a hydrogen atom.
More preferably fluorine, C 1-6 alkoxy, and C 3-10 1 ~ 5 amino optionally substituted with a substituent C 1-6 alkyl independently selected from the group consisting of cycloalkyl; fluorine C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy and C 1-6 alkyl; A ring; or a hydrogen atom.
More preferably, fluorine, C 1-6 alkoxy, and C 3-10 1 ~ 5 amino C 1-6 alkyl optionally substituted with a substituent selected independently from the group consisting of cycloalkyl; or A hydrogen atom is mentioned.
Most preferably, a hydrogen atom is mentioned.
　式（Ｉ）で表される化合物のうちで、好ましい化合物としては、以下のような化合物またはその製薬学的に許容される塩が挙げられる。 Among the compounds represented by the formula (I), preferred compounds include the following compounds or pharmaceutically acceptable salts thereof.
好ましい態様としては、以下の（Ａ）が挙げられる。
（Ａ）　
　Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ３ＡＲ３Ｂ、Ｎ－ＣＯＲ４Ａ、ＣＲ５－ＣＯ－ＮＲ３ＡＲ３Ｂ又はＣＲ５－ＮＲ６－ＣＯＲ４Ｂであり、
　Ａが、フェニル又はピリジル（該フェニル及び該ピリジルはそれぞれハロゲン、水酸基、１から５個のフッ素で置換されていてもよいＣ１－６アルキル、及び１から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）であり、
　Ｂが、Ｂ－１、Ｂ－２、Ｂ－３、Ｂ－４又はＢ－５であり、
　Ｗが、酸素原子又は硫黄原子であり、
　Ｒ１が、水素原子；ハロゲン；シアノ；又はハロゲン、水酸基、１から５個のフッ素で置換されていてもよいＣ３－１０シクロアルキル、Ｃ１－６アルコキシ及び４～１０員の飽和複素環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アルキルであり、
　Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ、Ｒ２Ｄ及びＲ５が、同一又は異なって、水素原子、フッ素、水酸基又はＣ１－６アルキルであり、ここにおいて、Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ、Ｒ２Ｄ及びＲ５のいずれかの２つが１から５個のフッ素で置換されていてもよいＣ１－６アルキルのとき、２個のアルキルが一緒になって該アルキルが結合している環と別の環を形成していてもよく、
　Ｒ３Ａ、Ｒ３Ｂ及びＲ４Ａが、同一又は異なって、ハロゲン、水酸基、Ｃ１－６アルコキシ、Ｃ３－１０シクロアルキル及び４～１０員の飽和複素環（ただし、環上にカルボニル基を有しない）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Ｃ１－６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Ｃ３－１０シクロアルキル；Ｃ１－６アルキルで置換されていてもよい４～１０員の飽和複素環；又は水素原子であり、ここにおいて、（１）Ｒ４Ａは水素原子ではなく、（２）Ｒ３Ａ及びＲ３Ｂは同時に水素原子ではなく、（３）ＢがＢ－３であり、Ｗが酸素原子であり、Ｘ－Ｙ－ＺがＮ－ＣＯＲ４Ａであるときは、Ｒ４Ａはメチルではなく、（４）Ａが無置換のフェニルであり、ＢがＢ－４であり、Ｗが酸素原子であり、Ｘ－Ｙ－ＺがＮ－ＣＯＲ４Ａであるときは、Ｒ４Ａは１～５個のフッ素で置換されたＣ３アルキルではなく、
　Ｒ４Ｂが、ハロゲン、水酸基、Ｃ１－６アルコキシ、Ｃ３－１０シクロアルキル及びカルボニル基で置換されていない４～１０員の飽和複素環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Ｃ１－６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Ｃ３－１０シクロアルキル；又はＣ１－６アルキルで置換されていてもよい４～１０員の飽和複素環であり、
　Ｒ６が、ハロゲン、水酸基、Ｃ１－６アルコキシ、Ｃ３－１０シクロアルキル及びカルボニル基で置換されていない４～１０員の飽和複素環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Ｃ１－６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Ｃ３－１０シクロアルキル；Ｃ１－６アルキルで置換されていてもよい４～１０員の飽和複素環；又は水素原子である、
式（Ｉ）の化合物又はその製薬学的に許容される塩。 The following (A) is mentioned as a preferable aspect.
(A)
XYZ is N—CO—NR 3A R 3B , N—COR 4A , CR 5 —CO—NR 3A R 3B or CR 5 —NR 6 —COR 4B ;
A is phenyl or pyridyl (the phenyl and the pyridyl may each be substituted with halogen, hydroxyl group, C 1-6 alkyl optionally substituted with 1 to 5 fluorine, and 1 to 5 fluorine; And optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy),
B is B-1, B-2, B-3, B-4 or B-5,
W is an oxygen atom or a sulfur atom,
R 1 is a hydrogen atom; halogen; cyano; or halogen, hydroxyl, C 3-10 cycloalkyl optionally substituted with 1 to 5 fluorines, C 1-6 alkoxy, and a 4- to 10-membered saturated heterocyclic ring C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of:
R 2A , R 2B , R 2C , R 2D and R 5 are the same or different and are a hydrogen atom, fluorine, hydroxyl group or C 1-6 alkyl, wherein R 2A , R 2B , R 2C , R 2D And any two of R 5 are C 1-6 alkyl optionally substituted with 1 to 5 fluorines, and the two alkyls together are different from the ring to which the alkyl is bonded. May form a ring,
R 3A , R 3B and R 4A are the same or different and are halogen, hydroxyl group, C 1-6 alkoxy, C 3-10 cycloalkyl and a 4- to 10-membered saturated heterocyclic ring (provided that a carbonyl group is present on the ring). C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of: a group consisting of halogen, hydroxyl, C 1-6 alkoxy and C 1-6 alkyl A C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from: a 4-10 membered saturated heterocycle optionally substituted with C 1-6 alkyl; or (1) R 4A is not a hydrogen atom, (2) R 3A and R 3B are not simultaneously hydrogen atoms, (3) B is B-3, and W is an oxygen atom. There, X-Y-Z is N-COR When an A is, R 4A is not methyl, (4) A a is unsubstituted phenyl, B is B-4, W is an oxygen atom, X-Y-Z is N-COR 4A When R 4A is not C 3 alkyl substituted with 1 to 5 fluorines,
1 to 5 R 4B independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy, C 3-10 cycloalkyl and a 4-10 membered saturated heterocyclic ring not substituted with a carbonyl group substituted halogen, hydroxyl, with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy and C 1-6 alkyl; the optionally substituted with a substituent C 1-6 alkyl An optionally substituted C 3-10 cycloalkyl; or a 4-10 membered saturated heterocycle optionally substituted with C 1-6 alkyl;
1 to 5 R 6 independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy, C 3-10 cycloalkyl and a 4-10 membered saturated heterocyclic ring not substituted with a carbonyl group substituted halogen, hydroxyl, with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy and C 1-6 alkyl; the optionally substituted with a substituent C 1-6 alkyl A C 3-10 cycloalkyl which may be substituted; a 4-10 membered saturated heterocyclic ring optionally substituted with C 1-6 alkyl; or a hydrogen atom,
A compound of formula (I) or a pharmaceutically acceptable salt thereof.
　より好ましい態様としては、以下の（Ｂ）が挙げられる。
（Ｂ）
　Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ３ＡＲ３Ｂ、Ｎ－ＣＯＲ４Ａ又はＣＲ５－ＮＲ６－ＣＯＲ４Ｂであり、
　Ａが、フェニル又はピリジル（該フェニル及び該ピリジルはそれぞれフッ素、塩素、１から５個のフッ素で置換されていてもよいＣ１－６アルキル、１から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）であり、
　Ｂが、Ｂ－１、Ｂ－２、Ｂ－３、Ｂ－４又はＢ－５であり、
　Ｗが、酸素原子又は硫黄原子であり、
　Ｒ１が、水素原子、ハロゲン又はシアノであり、
　Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ、Ｒ２Ｄ及びＲ５が、同一又は異なって、水素原子、又はＣ１－６アルキルであり、ここにおいて、Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ、Ｒ２Ｄ及びＲ５のいずれかの２つがＣ１－６アルキルのとき、２個のアルキルが一緒になって該アルキルが結合している環と別の環を形成していてもよく、
　Ｒ３Ａ、Ｒ３Ｂ及びＲ４Ａが、同一又は異なって、フッ素、Ｃ１－６アルコキシ、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Ｃ１－６アルキル；フッ素、Ｃ１－６アルコキシ及びＣ１－６アルキルからなる群から独立して選択される１～５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；又は水素原子であり、ここにおいて、（１）Ｒ４Ａは水素原子ではなく、（２）Ｒ３Ａ及びＲ３Ｂは同時に水素原子ではなく、（３）ＢがＢ－３であり、Ｗが酸素原子であり、Ｘ－Ｙ－ＺがＮ－ＣＯＲ４Ａであるときは、Ｒ４Ａはメチルではなく、（４）Ａが無置換のフェニルであり、ＢがＢ－４であり、Ｗが酸素原子であり、Ｘ－Ｙ－ＺがＮ－ＣＯＲ４Ａであるときは、Ｒ４Ａは１～５個のフッ素で置換されたＣ３アルキルではなく、
　Ｒ４Ｂが、フッ素、Ｃ１－６アルコキシ、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Ｃ１－６アルキル；フッ素、Ｃ１－６アルコキシ及びＣ１－６アルキルからなる群から独立して選択される１～５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；又は４～１０員の飽和複素環であり、
　Ｒ６が、フッ素、Ｃ１－６アルコキシ、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Ｃ１－６アルキル；フッ素、Ｃ１－６アルコキシ及びＣ１－６アルキルからなる群から独立して選択される１～５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；又は水素原子である、
式（Ｉ）の化合物又はその製薬学的に許容される塩。 The following (B) is mentioned as a more preferable aspect.
(B)
XYZ is N—CO—NR 3A R 3B , N—COR 4A or CR 5 —NR 6 —COR 4B ;
A is phenyl or pyridyl (each said phenyl and said pyridyl fluorine, chlorine, from one to five fluorines optionally substituted C 1-6 alkyl, optionally substituted with 1-5 fluorine Optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy),
B is B-1, B-2, B-3, B-4 or B-5,
W is an oxygen atom or a sulfur atom,
R 1 is a hydrogen atom, halogen or cyano,
R 2A , R 2B , R 2C , R 2D and R 5 are the same or different and are a hydrogen atom or C 1-6 alkyl, wherein R 2A , R 2B , R 2C , R 2D and R 5 Any two of the above are C 1-6 alkyl, the two alkyls may be combined to form a ring with the ring to which the alkyl is attached;
R 3A , R 3B and R 4A are the same or different and are substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, C 1-6 alkoxy, and C 3-10 cycloalkyl. which may be C 1-6 alkyl; fluorine, C 1-6 alkoxy and C 1-6 independently from the group consisting of alkyl optionally substituted with 1 to 5 substituents selected C 3- 10 cycloalkyl; 4 to 10 membered saturated heterocycle; or a hydrogen atom, wherein (1) R 4A is not a hydrogen atom, and (2) R 3A and R 3B are not simultaneously a hydrogen atom, (3 ) When B is B-3, W is an oxygen atom and XYZ is N-COR 4A , R 4A is not methyl and (4) A is unsubstituted phenyl; B is B-4, W is an oxygen atom, XY When Z is N-COR 4A is, R 4A is not C 3 alkyl substituted with 1-5 fluorine,
R 4B is selected from the group consisting of fluorine, C 1-6 alkoxy, and C 3-10 1 ~ 5 amino optionally substituted with a substituent C 1-6 alkyl independently selected from the group consisting of cycloalkyl; fluorine C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy and C 1-6 alkyl; or 4-10 membered saturation A heterocycle,
R 6 is fluorine, C 1-6 alkoxy, and C 3-10 1 ~ 5 amino optionally substituted with a substituent C 1-6 alkyl independently selected from the group consisting of cycloalkyl; fluorine C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy and C 1-6 alkyl; A ring; or a hydrogen atom,
A compound of formula (I) or a pharmaceutically acceptable salt thereof.
　さらに好ましい態様としては、以下の（Ｃ）が挙げられる。
（Ｃ）
　Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ３ＡＲ３Ｂ又はＮ－ＣＯＲ４Ａであり、
　Ａが、フッ素、塩素、１～３個のフッ素で置換されていてもよいＣ１－６アルキル及び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フェニルであり、
　Ｂが、Ｂ－１、Ｂ－４又はＢ－５であり、
　Ｗが、酸素原子であり、
　Ｒ１が、水素原子、塩素又はシアノであり、
　Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ及びＲ２Ｄが、水素原子であり、
　Ｒ３Ａ、Ｒ３Ｂ及びＲ４Ａが、同一又は異なって、フッ素、Ｃ１－６アルコキシ及びＣ１－６アルキルからなる群から独立して選択される１～５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；又は水素原子であり、ここにおいて、Ｒ３Ａ及びＲ３Ｂは同時に水素原子ではなく、Ｒ４Ａは水素原子ではない、
式（Ｉ）の化合物又はその製薬学的に許容される塩。 The following (C) is mentioned as a more preferable aspect.
(C)
XYZ is N—CO—NR 3A R 3B or N—COR 4A ;
A is substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, chlorine, C 1-6 alkyl optionally substituted with 1 to 3 fluorine and C 1-6 alkoxy Which may be phenyl,
B is B-1, B-4 or B-5,
W is an oxygen atom,
R 1 is a hydrogen atom, chlorine or cyano,
R 2A , R 2B , R 2C and R 2D are hydrogen atoms,
R 3A , R 3B and R 4A are the same or different and are substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, C 1-6 alkoxy and C 1-6 alkyl A C 3-10 cycloalkyl; a 4-10 membered saturated heterocyclic ring; or a hydrogen atom, wherein R 3A and R 3B are not simultaneously a hydrogen atom, and R 4A is not a hydrogen atom,
A compound of formula (I) or a pharmaceutically acceptable salt thereof.
　もっとも好ましい態様としては、以下の（Ｄ）が挙げられる。
（Ｄ）
　Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ３ＡＲ３Ｂ又はＮ－ＣＯＲ４Ａであり、
　Ａが、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フェニルであり、
　Ｂが、Ｂ－１又はＢ－４であり、
　Ｗが、酸素原子であり、
　Ｒ１が、水素原子又は塩素であり、
　Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ及びＲ２Ｄが、水素原子であり、
　Ｒ３Ａ及びＲ４Ａが、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Ｃ３－１０シクロアルキル又は４～１０員の飽和複素環であり、
　Ｒ３Ｂが、水素原子である、式（Ｉ）の化合物又はその製薬学的に許容される塩。 The most preferable embodiment includes the following (D).
(D)
XYZ is N—CO—NR 3A R 3B or N—COR 4A ;
A is phenyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine and C 1-6 alkoxy;
B is B-1 or B-4,
W is an oxygen atom,
R 1 is a hydrogen atom or chlorine;
R 2A , R 2B , R 2C and R 2D are hydrogen atoms,
R 3A and R 4A are the same or different and each is a C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine and C 1-6 alkoxy; A 4-10 membered saturated heterocycle,
A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 3B is a hydrogen atom.
　式（Ｉ）で表される化合物の製薬学的に許容される塩とは、式（Ｉ）の化合物に製薬学的に許容される酸又は塩基を加えて形成された塩を意味する。
　式（Ｉ）で表される本発明の化合物がアミノ基などの塩基性官能基を有する場合、各種の酸と塩を形成しうる。このような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。これらの塩は、式（Ｉ）で表される本発明の化合物を酸と混合した後、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) means a salt formed by adding a pharmaceutically acceptable acid or base to the compound of the formula (I).
When the compound of the present invention represented by the formula (I) has a basic functional group such as an amino group, it can form salts with various acids. Specific examples of such acid addition salts include hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, phosphate, and other inorganic acid salts, oxalate, and malonic acid. Salt, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, trifluoromethane Examples thereof include organic acid salts such as sulfonate, and amino acid salts such as glutamate and aspartate. These salts can be obtained by a conventional method such as recrystallization after mixing the compound of the present invention represented by the formula (I) with an acid.
　式（Ｉ）で表される本発明の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。この場合の製薬学的に許容される塩としては、ナトリウム塩もしくはカリウム塩などのアルカリ金属塩、カルシウム塩などのアルカリ土類金属塩、又はトリエチルアンモニウム塩、トリエタノールアンモニウム塩、ピリジニウム塩、ジイソプロピルアンモニウム塩等の有機塩基塩等などが挙げられる。これらの塩は、式（Ｉ）で表される本発明の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。 When the compound of the present invention represented by the formula (I) has an acidic functional group such as a carboxyl group, it can form salts with various bases. In this case, pharmaceutically acceptable salts include alkali metal salts such as sodium salt or potassium salt, alkaline earth metal salts such as calcium salt, or triethylammonium salt, triethanolammonium salt, pyridinium salt, diisopropylammonium salt. Examples thereof include organic base salts such as salts. These salts can be obtained by a conventional method such as recrystallization after mixing the compound of the present invention represented by the 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－、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、ｄ６－ＤＭＳＯ：重ジメチルスルホキシド、ＨＥＰＥＳ：Ｎ－２－ヒドロキシエチルピペラジン－Ｎ’－２－エタンスルホン酸、ＢＳＡ：ｂｏｖｉｎｅ　ｓｅｒｕｍ　ａｌｂｕｍｉｎ、牛血清アルブミン、ＦＤＳＳ：Ｆｕｎｃｔｉｏｎａｌ　Ｄｒｕｇ　Ｓｃｒｅｅｎｉｎｇ　Ｓｙｓｔｅｍ、ＡＣｈ：アセチルコリン、ＰＡＭ：ポジティブアロステリックモジュレーター、ｎＡＣｈＲ：ニコチン性アセチルコリン受容体、ＥＣ２０：２０％効果濃度、ＲＬＵ：Ｒｅｌａｔｉｖｅ　Ｌｉｇｈｔ　Ｕｎｉｔ、Ｂｏｃ：ｔｅｒｔ－ブトキシカルボニル、ＥＤＣＩ：１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド、ＨＯＢｔ：１－ヒドロキシベンゾトリアゾール、ＨＢＴＵ：２－（１Ｈ－７－ベンゾトリアゾール－１－イル）－１，１，３，３－テトラメチルウロニウムヘキサフルオロリン酸塩。 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-, THF: tetrahydrofuran, DMF: N, N-dimethylformamide, DMSO: dimethyl sulfoxide, d 6 -DMSO: heavy dimethyl sulfoxide, HEPES: N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid, BSA: bovine serum albumin, bovine serum albumin, FDSS: Functional Drug Screening System, ACh: acetylcholine, PAM: positive Allosteric modulator, nAChR: nicotinic acetylcholine receptor, EC20: 20% effective concentration, RLU: Relative Light Unit, Boc: tert-butoxycarbonyl, DCI: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, HOBt: 1-hydroxybenzotriazole, HBTU: 2- (1H-7-benzotriazol-1-yl) -1,1,3,3- Tetramethyluronium hexafluorophosphate.
　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Ａ～Ｍにより製造することができる。 The method for producing 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 to M.
製造法Ａ（合成中間体の製法）
　式（Ｉ）で表される化合物のうち、ＢがＢ－１である化合物の合成中間体ａ６、ａ８及びａ１０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-C000005
 （式中、Ａ、Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ及びＲ２Ｄは項１に定義されるとおりであり、ＰＸはアミノの保護基を表し、ＲＸは水素原子、アルキル又はフェニルを表し、ここにおいてＲＸがアルキルのとき、２個の当該アルキルが一緒になって４～１０員の含酸素飽和複素環を形成していてもよく、Ｒ１Xはハロゲンを表し、Ｒ１Ｙは項１に定義されるＲ１のうちハロゲンではないものを意味する） Production method A (production method of synthetic intermediate)
Among the compounds represented by the formula (I), synthetic intermediates a6, a8 and a10 of a compound in which B is B-1 can be produced, for example, by the following production method.
Figure JPOXMLDOC01-appb-C000005
 (Wherein, A, R 2A, R 2B , R 2C and R 2D are as defined in claim 1, P X represents a protecting group of amino, R X represents a hydrogen atom, alkyl or phenyl, In this case, when R X is alkyl, the two alkyls together may form a 4- to 10-membered oxygen-containing saturated heterocyclic ring, R 1X represents halogen, R 1Y represents the term 1 R 1 as defined is not halogen)
　保護基ＰＸとしては、Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年) にアミノの保護基として記載されているものが挙げられる。 The protective group P X, Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts al, John Wiley & Sons, Inc. published in 1999), and those described in as a protecting group for amino.
　化合物ａ１はイミダゾールのハロゲン化反応などの既知の方法により合成できるか、又は市販品として購入できる。 Compound a1 can be synthesized by a known method such as a halogenation reaction of imidazole, or can be purchased as a commercial product.
［Ａ－１工程］
　本工程は化合物ａ１に、適当な遷移金属試薬の存在下、適当なボロン酸誘導体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遷移金属試薬は、例えば酢酸銅が挙げられる。本工程において使用されるボロン酸誘導体は、例えばボロン酸、ボロン酸エステル、ボロン酸ピナコラートが挙げられる。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、好ましくはジクロロエタン又はメタノールである。類似反応として、例えば、Journal of Medicinal Chemistry, 2009, 52(11), 3441－3444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。反応温度は、用いられる原料化合物の種類、試薬等により異なるが、通常、－７８℃～２００℃、好ましくは－２０℃～１５０℃であり、より好ましくは室温～１００℃である。反応時間は通常５分～７２時間程度であり、好ましくは３０分～４８時間、さらに好ましくは１時間～２４時間である。 [Step A-1]
This step is a step of obtaining compound a2 by reacting compound a1 with an appropriate boronic acid derivative in the presence of an appropriate transition metal reagent. An example of the transition metal reagent used in this step is copper acetate. Examples of the boronic acid derivative used in this step include boronic acid, boronic acid ester, and boronic acid pinacolate. The solvent used in this step is selected from the solvents exemplified below, but is preferably dichloroethane or methanol. As a similar reaction, for example, a method described in Journal of Medicinal Chemistry, 2009, 52 (11), 3441-3444 is known and can be synthesized in the same manner. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally −78 ° C. to 200 ° C., preferably −20 ° C. to 150 ° C., more preferably room temperature to 100 ° C. The reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
［Ａ－２工程］
　本工程は上記Ａ－１工程で得られた化合物ａ２と化合物ａ３を、適当な遷移金属試薬の存在下で反応させることにより、化合物ａ４を得る工程である。本工程において使用される遷移金属試薬は、例えばトリス（ジベンジリデンアセトン）ジパラジウムやテトラキス（トリフェニルフォスフィン）パラジウムが挙げられる。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ＤＭＦ又はジオキサンである。類似反応として、例えば、Journal of Organic Chemistry, 2010, 75(5), 1733-1739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。反応温度は、用いられる原料化合物の種類、試薬等により異なるが、通常、－７８℃～２００℃、好ましくは－２０℃～１５０℃であり、より好ましくは室温～１００℃である。反応時間は通常５分～７２時間程度であり、好ましくは３０分～４８時間、さらに好ましくは１時間～２４時間である。 [Step A-2]
This step is a step of obtaining compound a4 by reacting compound a2 obtained in step A-1 with compound a3 in the presence of an appropriate transition metal reagent. Examples of the transition metal reagent used in this step include tris (dibenzylideneacetone) dipalladium and tetrakis (triphenylphosphine) palladium. The solvent used in this step is selected from the solvents exemplified below, and is preferably DMF or dioxane. As a similar reaction, for example, a method described in Journal of Organic Chemistry, 2010, 75 (5), 1733-1739 is known and can be synthesized in the same manner. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally −78 ° C. to 200 ° C., preferably −20 ° C. to 150 ° C., more preferably room temperature to 100 ° C. The reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
［Ａ－３工程］
　本工程は上記Ａ－２工程で得られた化合物ａ４を、適当な遷移金属試薬を用いて水素雰囲気下で反応させることにより化合物ａ５を得る工程である。本工程において使用される遷移金属試薬は、例えばパラジウム/炭素や酸化プラチナ（IV）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、好ましくはメタノール又はエタノールである。類似反応として、例えば、Journal of Medicinal Chemistry, 2012, 55(1), 115-125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。反応温度は、用いられる原料化合物の種類、試薬等により異なるが、通常、－２０℃～１５０℃、好ましくは０℃～１００℃であり、より好ましくは室温～６０℃である。反応時間は通常５分～７２時間程度であり、好ましくは３０分～４８時間、さらに好ましくは１時間～２４時間である。 [Step A-3]
This step is a step of obtaining compound a5 by reacting compound a4 obtained in step A-2 with a suitable transition metal reagent in a hydrogen atmosphere. Examples of the transition metal reagent used in this step include palladium / carbon and platinum (IV) oxide. The solvent used in this step is selected from the solvents exemplified below, but is preferably methanol or ethanol. As a similar reaction, for example, a method described in Journal of Medicinal Chemistry, 2012, 55 (1), 115-125, etc. is known and can be synthesized in the same manner. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally −20 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C., more preferably room temperature to 60 ° C. The reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
［Ａ－４工程］
　本工程は上記製造法Ａ－３で得られた化合物ａ５のアミノの保護基ＰＸ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-4]
This step is a protecting group P X of the amino compound a5 prepared in the above Preparation Method A-3, by deprotection, to give compound compound a6. 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－５工程］
　本工程は上記Ａ－３工程で得られた化合物ａ５に、適当な溶媒中、適当な酸の存在下で、種々のハロゲン化剤を反応させることにより、化合物ａ７を得る工程である。本工程において使用されるハロゲン化剤は、例えばＮ－クロロスクシンイミド、Ｎ－ブロモスクシンイミド、Ｎ－ヨードスクシンイミドである。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、好ましくは塩化メチレン又はジクロロエタンである。本工程において使用される酸は、後記に例示する酸等から選択されるが、好ましくはトリフルオロ酢酸又は塩酸である。類似反応として、例えば、Bioorg. Med. Chem. Lett. 2008, 18(5), 1702-1707、J. Org. Chem. 2002, 67(17), 5913-5918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。反応温度は、用いられる原料化合物の種類、試薬等により異なるが、通常、－７８℃～２００℃、好ましくは０℃～１００℃であり、より好ましくは室温～７０℃である。反応時間は通常５分～７２時間程度であり、好ましくは３０分～４８時間、さらに好ましくは１時間～２４時間である。 [Step A-5]
This step is a step of obtaining compound a7 by reacting compound a5 obtained in step A-3 with various halogenating agents in a suitable solvent in the presence of a suitable acid. The halogenating agent used in this step is, for example, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide. The solvent used in this step is selected from the solvents exemplified below, and is preferably methylene chloride or dichloroethane. The acid used in this step is selected from the acids exemplified below, and preferably trifluoroacetic acid or hydrochloric acid. As a similar reaction, for example, a method described in Bioorg. Med. Chem. Lett. 2008, 18 (5), 1702-1707, J. Org. Chem. 2002, 67 (17), 5913-5918, etc. is known. And can be synthesized similarly. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally −78 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C., more preferably room temperature to 70 ° C. The reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
［Ａ－６工程］
　本工程は上記Ａ－５工程で得られた化合物ａ７に、上記Ａ－４工程に準じた条件で、化合物ａ８を得る工程である。 [Step A-6]
This step is a step of obtaining compound a8 from compound a7 obtained in step A-5, under the same conditions as in step A-4.
［Ａ－７工程］
　本工程は上記Ａ－５工程で得られた化合物ａ７に、適当な溶媒中、適当な遷移金属試薬の存在下、適当なボロン酸誘導体と反応させることにより、化合物ａ９を得る工程である。本工程において使用される遷移金属試薬は、例えばトリス（ジベンジリデンアセトン）ジパラジウムやテトラキス（トリフェニルフォスフィン）パラジウムが挙げられる。本工程において使用されるボロン酸誘導体は、例えばボロン酸、ボロン酸エステル、ボロン酸ピナコラートが挙げられる。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ＤＭＦ又はジオキサンである。類似反応として、例えば、Tetrahedron Lett. 2003, 44(7), 1379-1382、J. Med. Chem. 2009, 52(14), 4370-4379、Bioorg. Med. Chem. Lett. 2012, 20(9), 3009-3015、J. Org. Chem. 2002, 67(10), 3365-3373、Tetrahedron Lett. 2007, 48(13), 2339-2343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。反応温度は、用いられる原料化合物の種類、試薬等により異なるが、通常、－７８℃～２００℃、好ましくは－２０℃～１８０℃であり、より好ましくは室温～１５０℃である。反応時間は通常５分～７２時間程度であり、好ましくは３０分～４８時間、さらに好ましくは１時間～２４時間である。 [Step A-7]
This step is a step of obtaining compound a9 by reacting compound a7 obtained in step A-5 with a suitable boronic acid derivative in a suitable solvent in the presence of a suitable transition metal reagent. Examples of the transition metal reagent used in this step include tris (dibenzylideneacetone) dipalladium and tetrakis (triphenylphosphine) palladium. Examples of the boronic acid derivative used in this step include boronic acid, boronic acid ester, and boronic acid pinacolate. The solvent used in this step is selected from the solvents exemplified below, and is preferably DMF or dioxane. Similar reactions include, for example, Tetrahedron Lett. 2003, 44 (7), 1379-1382, J. Med. Chem. 2009, 52 (14), 4370-4379, Bioorg. Med. Chem. Lett. 2012, 20 (9 ), 3009-3015, J. Org. Chem. 2002, 67 (10), 3365-3373, Tetrahedron Lett. 2007, 48 (13), 2339-2343, etc. Can be synthesized. The reaction temperature varies depending on the type of raw material compound used, reagents and the like, but is usually −78 ° C. to 200 ° C., preferably −20 ° C. to 180 ° C., more preferably room temperature to 150 ° C. The reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
［Ａ－８工程］
　本工程は上記Ａ－７工程で得られた化合物ａ９に、上記Ａ－４工程に準じた条件で、化合物ａ１０を得る工程である。 [Step A-8]
This step is a step of obtaining compound a10 from compound a9 obtained in step A-7, under the same conditions as in step A-4.
製造法Ｂ（合成中間体の製法）
　式（Ｉ）で表される化合物のうち、ＢがＢ－２であり、Ｗが酸素原子である化合物の合成中間体ｂ７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-C000006
 （式中、Ａ、Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ及びＲ２Ｄは項１に定義されるとおりであり、ＰＸはアミノの保護基を意味する） Production method B (Production method of synthetic intermediate)
Among the compounds represented by formula (I), a synthetic intermediate b7 of a compound in which B is B-2 and W is an oxygen atom can be produced, for example, by the following production method.
Figure JPOXMLDOC01-appb-C000006
 (Wherein, A, R 2A, R 2B , R 2C and R 2D are as defined in claim 1, P X denotes a protective group for amino)
　保護基ＰＸとしては、Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年) にアミノの保護基として記載されているものが挙げられる。 The protective group P X, Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts al, John Wiley & Sons, Inc. published in 1999), and those described in as a protecting group for amino.
　化合物ｂ１は対応するアルコールの酸化などの既知の方法により合成できるか、又は市販品として購入できる。 Compound b1 can be synthesized by a known method such as oxidation of the corresponding alcohol, or can be purchased as a commercial product.
［Ｂ－１工程］
　本工程は化合物ｂ１に、適当な塩基存在下でニトロメタンを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ｔｅｒｔ-ブトキシカリウムである。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とｔｅｒｔ-ブタノールの混合溶媒である。類似反応として、例えば、国際公開第２００７/４１０６１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。反応温度は、用いられる原料化合物の種類、試薬等により異なるが、通常、－７８℃～２００℃、好ましくは－２０℃～１５０℃であり、より好ましくは０℃～１００℃である。反応時間は通常５分～７２時間程度であり、好ましくは３０分～４８時間、さらに好ましくは１時間～２４時間である。 [Step B-1]
This step is a step of obtaining compound b2 by reacting compound b1 with nitromethane in the presence of a suitable base. The base used in this step is selected from the bases exemplified below, and preferably tert-butoxy potassium. The solvent used in this step is selected from the solvents exemplified below, but is preferably a mixed solvent of tetrahydrofuran and tert-butanol. As a similar reaction, for example, a method described in International Publication No. 2007/41061 pamphlet or the like is known and can be synthesized in the same manner. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally −78 ° C. to 200 ° C., preferably −20 ° C. to 150 ° C., more preferably 0 ° C. to 100 ° C. The reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
［Ｂ－２工程］
　本工程は上記Ｂ－１で得られた化合物ｂ２を、適当な遷移金属触媒を用いて水素雰囲気下で反応させることにより、化合物ｂ３を得る工程である。本工程において使用される遷移金属試薬は、例えばパラジウム/炭素や酸化プラチナ（IV）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、好ましくはメタノール又はエタノールである。類似反応として、例えば、Ｂｉｏｏｒｇａｎｉｃ ａｎｄ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ Ｌｅｔｔｅｒｓ, ２００４, １４（１３）, ３４１９－３４２４、国際公開第２００６／１９７６８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。反応温度は、用いられる原料化合物の種類、試薬等により異なるが、通常、－２０℃～２００℃、好ましくは０℃～１００℃であり、より好ましくは室温～７０℃である。反応時間は通常５分～７２時間程度であり、好ましくは３０分～４８時間、さらに好ましくは１時間～２４時間である。 [Step B-2]
This step is a step of obtaining compound b3 by reacting compound b2 obtained in B-1 above in a hydrogen atmosphere using an appropriate transition metal catalyst. Examples of the transition metal reagent used in this step include palladium / carbon and platinum (IV) oxide. The solvent used in this step is selected from the solvents exemplified below, but is preferably methanol or ethanol. As similar reactions, for example, the methods described in Bioorganic and Medicinal Chemistry Letters, 2004, 14 (13), 3419-3424, International Publication No. 2006/19768, etc. are known and can be synthesized similarly. . The reaction temperature varies depending on the type of raw material compound used, reagents and the like, but is usually −20 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C., more preferably room temperature to 70 ° C. The reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
［Ｂ－３工程］
　本工程は上記Ｂ－２で得られた化合物ｂ３に、適当な縮合剤存在下又は非存在下、適当な塩基存在下、適当な溶媒中でカルボン酸ｂ８又は酸クロライドｂ９と反応させることにより、化合物ｂ４を得る工程である。本工程において使用される縮合剤は、例えばＥＤＣＩ（塩酸塩を含む）又はＨＢＴＵが挙げられる。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、好ましくはジメチルホルムアミド、テトラヒドロフラン又は塩化メチレンが挙げられる。反応温度は、用いられる原料化合物の種類、試薬等により異なるが、通常、－７８℃～２００℃、好ましくは０℃～１５０℃であり、より好ましくは室温～１００℃である。反応時間は通常５分～７２時間程度であり、好ましくは３０分～４８時間、さらに好ましくは１時間～２４時間である。 [Step B-3]
In this step, compound b3 obtained in B-2 above is reacted with carboxylic acid b8 or acid chloride b9 in a suitable solvent in the presence or absence of a suitable condensing agent and in the presence of a suitable base. In this step, compound b4 is obtained. Examples of the condensing agent used in this step include EDCI (including hydrochloride) or HBTU. 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 dimethylformamide, tetrahydrofuran or methylene chloride. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally −78 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C., more preferably room temperature to 100 ° C. The reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
［Ｂ－４工程］
　本工程は上記Ｂ－３で得られた化合物ｂ４を、適当な酸化剤と反応させることにより、化合物ｂ５を得る工程である。本工程において使用される酸化剤は、例えばデスマーチン試薬が挙げられる。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、好ましくは塩化メチレン又はＤＭＳＯである。類似反応として、例えば、国際公開第２０１０／１３８５８９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。反応温度は、用いられる原料化合物の種類、試薬等により異なるが、通常、－７８℃～２００℃、好ましくは－２０℃～１５０℃であり、より好ましくは０℃～１００℃である。反応時間は通常５分～７２時間程度であり、好ましくは３０分～４８時間、さらに好ましくは１時間～２４時間である。 [Step B-4]
This step is a step of obtaining compound b5 by reacting compound b4 obtained in B-3 with an appropriate oxidizing agent. Examples of the oxidizing agent used in this step include a desmartin reagent. The solvent used in this step is selected from the solvents exemplified below, and is preferably methylene chloride or DMSO. As a similar reaction, for example, a method described in International Publication No. 2010/138589 pamphlet is known and can be synthesized in the same manner. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally -78 ° C to 200 ° C, preferably -20 ° C to 150 ° C, more preferably 0 ° C to 100 ° C. The reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
［Ｂ－５工程］
　本工程は上記Ｂ－４で得られた化合物ｂ５を、適当な脱水化試薬と反応させることにより、化合物ｂ６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である。本工程において使用される脱水化試薬は、例えばバージェス試薬が挙げられる。類似反応として、例えば、Ｓｙｎｌｅｔｔ, １９９９, １０, １６４２－１６４４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。反応温度は、用いられる原料化合物の種類、試薬等により異なるが、通常、－７８℃～２００℃、好ましくは－２０℃～１５０℃であり、より好ましくは０℃～１００℃である。反応時間は通常５分～７２時間程度であり、好ましくは３０分～４８時間、さらに好ましくは１時間～２４時間である。 [Step B-5]
This step is a step of obtaining compound b6 by reacting compound b5 obtained in B-4 with an appropriate dehydrating reagent. The solvent used in this step is selected from the solvents exemplified below, and is preferably tetrahydrofuran. Examples of the dehydrating reagent used in this step include Burgess reagent. As a similar reaction, for example, a method described in Synlett, 1999, 10, 1642-1644 is known, and can be synthesized in the same manner. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally −78 ° C. to 200 ° C., preferably −20 ° C. to 150 ° C., more preferably 0 ° C. to 100 ° C. The reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
［Ｂ－６工程］
　本工程は上記Ｂ－５工程で得られた化合物ｂ６に、上記Ａ－４工程に準じた条件で、化合物ｂ７を得る工程である。 [Step B-6]
This step is a step of obtaining the compound b7 from the compound b6 obtained in the step B-5 under the conditions according to the step A-4.
製造法Ｃ（合成中間体の製法）
　式（Ｉ）で表される化合物のうち、ＢがＢ－２であり、Ｗが硫黄原子である化合物の合成中間体となるｃ２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、Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ及びＲ２Ｄは項１に定義されるとおりであり、ＰＸはアミノの保護基を意味する） Production Method C (Production of synthetic intermediate)
Among the compounds represented by the formula (I), c2 which is a synthetic intermediate of a compound in which B is B-2 and W is a sulfur atom can be produced, for example, by the following production method.
Figure JPOXMLDOC01-appb-C000007
 (Wherein, A, R 2A, R 2B , R 2C and R 2D are as defined in claim 1, P X denotes a protective group for amino)
　保護基ＰＸとしては、Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年) にアミノの保護基として記載されているものが挙げられる。 The protective group P X, Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts al, John Wiley & Sons, Inc. published in 1999), and those described in as a protecting group for amino.
［Ｃ－１工程］
　本工程は上記Ｂ－４工程で得られた化合物ｂ５に、適当なチオカルボニル化試薬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チオカルボニル化試薬は、例えばローソンズ試薬が挙げられる。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である。類似反応として、例えば、米国公開第２０１０／２６１６９７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。反応温度は、用いられる原料化合物の種類、試薬等により異なるが、通常、－７８℃～２００℃、好ましくは－２０℃～１５０℃であり、より好ましくは０℃～１００℃である。反応時間は通常５分～７２時間程度であり、好ましくは３０分～４８時間、さらに好ましくは１時間～２４時間である。 [Step C-1]
This step is a step of obtaining compound c1 by reacting compound b5 obtained in step B-4 with an appropriate thiocarbonylating reagent. Examples of the thiocarbonylation reagent used in this step include Lawson's reagent. The solvent used in this step is selected from the solvents exemplified below, and is preferably tetrahydrofuran. As a similar reaction, for example, a method described in US Publication No. 2010/261617, etc. is known, and can be synthesized in the same manner. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally −78 ° C. to 200 ° C., preferably −20 ° C. to 150 ° C., more preferably 0 ° C. to 100 ° C. The reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
［Ｃ－２工程］
　本工程は上記Ｃ－１工程で得られた化合物ｃ１に、上記Ａ－４工程に準じた条件で、化合物ｃ２を得る工程である。 [Step C-2]
In this step, compound c2 is obtained from compound c1 obtained in step C-1 under the same conditions as in step A-4.
製造法Ｄ（合成中間体の製法）
　式（Ｉ）で表される化合物のうち、ＢがＢ－３であり、Ｗが酸素原子である化合物の合成中間体となるｄ４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、Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ及びＲ２Ｄは項１に定義されるとおりであり、ＰＸはアミノの保護基を意味する） Production Method D (Production Method of Synthetic Intermediate)
Among the compounds represented by the formula (I), d4 that is a synthetic intermediate of a compound in which B is B-3 and W is an oxygen atom can be produced, for example, by the following production method.
Figure JPOXMLDOC01-appb-C000008
 (Wherein, A, R 2A, R 2B , R 2C and R 2D are as defined in claim 1, P X denotes a protective group for amino)
　保護基ＰＸとしては、Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年) にアミノの保護基として記載されているものが挙げられる。 The protective group P X, Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts al, John Wiley & Sons, Inc. published in 1999), and those described in as a protecting group for amino.
　化合物ｄ１は対応するアルコール又はアルデヒドの酸化や対応するエステル加水分解などの既知の方法により合成できるか、又は市販品として購入できる。 Compound d1 can be synthesized by a known method such as oxidation of the corresponding alcohol or aldehyde or corresponding ester hydrolysis, or can be purchased as a commercial product.
［Ｄ－１工程］
　本工程は化合物ｄ１と化合物ｄ５を、上記Ｂ－３工程に準じた条件で反応させて、化合物ｄ２を得る工程である。 [Step D-1]
This step is a step in which compound d1 and compound d5 are reacted under the same conditions as in step B-3 to obtain compound d2.
［Ｄ－２工程］
　本工程は上記Ｄ－１工程で得られた化合物ｄ２を、上記Ｂ－５工程に準じた条件で反応させて、化合物ｄ３を得る工程である。 [Step D-2]
This step is a step of obtaining a compound d3 by reacting the compound d2 obtained in the step D-1 with the conditions according to the step B-5.
［Ｄ－３工程］
　本工程は上記Ｄ－２工程で得られた化合物ｄ３を、上記Ａ－４工程に準じた条件で反応させて、化合物ｄ４を得る工程である。 [Step D-3]
This step is a step of obtaining a compound d4 by reacting the compound d3 obtained in the step D-2 with the conditions according to the step A-4.
製造法Ｅ（合成中間体の製法）
　式（Ｉ）で表される化合物のうち、ＢがＢ－３であり、Ｗが硫黄原子である化合物の合成中間体となるｅ２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、Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ及びＲ２Ｄは項１に定義されるとおりであり、ＰＸはアミノの保護基を意味する） Production method E (Production method of synthetic intermediate)
Among the compounds represented by the formula (I), e2 which is a synthetic intermediate of a compound in which B is B-3 and W is a sulfur atom can be produced by, for example, the following production method.
Figure JPOXMLDOC01-appb-C000009
 (Wherein, A, R 2A, R 2B , R 2C and R 2D are as defined in claim 1, P X denotes a protective group for amino)
　保護基ＰＸとしては、Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年) にアミノの保護基として記載されているものが挙げられる。 The protective group P X, Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts al, John Wiley & Sons, Inc. published in 1999), and those described in as a protecting group for amino.
［Ｅ－１工程］
　本工程は上記Ｄ－１工程で得られた化合物ｄ２を、上記Ｃ－１工程に準じた条件で反応させて、化合物ｅ1得る工程である。 [Step E-1]
This step is a step of obtaining a compound e1 by reacting the compound d2 obtained in the step D-1 with the conditions according to the step C-1.
［Ｅ－2工程］
　本工程は上記Ｅ－１工程で得られた化合物ｅ1を、上記Ａ－４工程に準じた条件で反応させて、化合物ｅ２得る工程である。 [Step E-2]
This step is a step of obtaining a compound e2 by reacting the compound e1 obtained in the step E-1 with the conditions according to the step A-4.
製造法Ｆ（合成中間体の製法）
　式（Ｉ）で表される化合物のうち、ＢがＢ－４であり、Ｗが酸素原子である化合物の合成中間体となるｆ８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-C000010
 （式中、Ａ、Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ及びＲ２Ｄは項１に定義されるとおりであり、ＰＸはアミノの保護基を意味する） Production Method F (Production of synthetic intermediate)
Of the compounds represented by formula (I), f8, which is a synthetic intermediate of a compound in which B is B-4 and W is an oxygen atom, can be produced, for example, by the following production method.
Figure JPOXMLDOC01-appb-C000010
 (Wherein, A, R 2A, R 2B , R 2C and R 2D are as defined in claim 1, P X denotes a protective group for amino)
　保護基ＰＸとしては、Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年) にアミノの保護基として記載されているものが挙げられる。 The protective group P X, Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts al, John Wiley & Sons, Inc. published in 1999), and those described in as a protecting group for amino.
　化合物ｆ１は市販品として購入できる。化合物ｆ４は、対応するアルコールの酸化などの既知の方法により合成できるか、又は市販品として購入できる。 Compound f1 can be purchased as a commercial product. Compound f4 can be synthesized by known methods such as oxidation of the corresponding alcohol, or can be purchased as a commercial product.
［Ｆ－１工程］
　本工程は化合物ｆ１と適当な塩基を用いて、ジアゾ化試薬と反応させることにより、化合物ｆ２を得る工程である。本工程において使用されるジアゾ化試薬は、例えば４－トルエンスルフォニルアジドが挙げられる。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である。類似反応として、例えば、Ｂｉｏｏｒｇａｎｉｃ ａｎｄ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ Ｌｅｔｔｅｒｓ, ２０１３, ２３（１９）, ５２６７－５２６９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。反応温度は、用いられる原料化合物の種類、試薬等により異なるが、通常、－７８℃～２００℃、好ましくは－２０℃～１５０℃であり、より好ましくは０℃～１００℃である。反応時間は通常５分～７２時間程度であり、好ましくは３０分～４８時間、さらに好ましくは１時間～２４時間である。 [Step F-1]
In this step, compound f2 is obtained by reacting compound f1 with a diazotizing reagent using an appropriate base. Examples of the diazotizing reagent used in this step include 4-toluenesulfonyl azide. The base used in this step is selected from the bases exemplified below, and is preferably sodium hydride. The solvent used in this step is selected from the solvents exemplified below, and is preferably tetrahydrofuran. As a similar reaction, for example, the methods described in Bioorganic and Medicinal Chemistry Letters, 2013, 23 (19), 5267-5269, etc. are known, and can be synthesized in the same manner. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally −78 ° C. to 200 ° C., preferably −20 ° C. to 150 ° C., more preferably 0 ° C. to 100 ° C. The reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
［Ｆ－２工程］
　本工程は上記Ｆ－１工程で得られる化合物ｆ２と化合物ｂ１を、適当な塩基存在下で反応させることにより、化合物ｆ３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、好ましくは炭酸カリウムである。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、好ましくはメタノールである。類似反応として、例えば、Ｊｏｕｒｎａｌ ｏｆ ｔｈｅ Ａｍｅｒｉｃａｎ Ｃｈｅｍｉｃａｌ Ｓｏｃｉｅｔｙ，　２００３，　１２５（１３）, ３７１４－３７１５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。反応温度は、用いられる原料化合物の種類、試薬等により異なるが、通常、－７８℃～２００℃、好ましくは－２０℃～１５０℃であり、より好ましくは０℃～１００℃である。反応時間は通常５分～７２時間程度であり、好ましくは３０分～４８時間、さらに好ましくは１時間～２４時間である。 [Step F-2]
This step is a step of obtaining compound f3 by reacting compound f2 obtained in step F-1 with compound b1 in the presence of a suitable base. The base used in this step is selected from the bases exemplified below, and is preferably potassium carbonate. The solvent used in this step is selected from the solvents exemplified below, but is preferably methanol. As a similar reaction, for example, a method described in Journal of the American Chemical Society, 2003, 125 (13), 3714-3715 is known and can be synthesized in the same manner. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally -78 ° C to 200 ° C, preferably -20 ° C to 150 ° C, more preferably 0 ° C to 100 ° C. The reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
［Ｆ－３工程］
　本工程は化合物ｆ４とヒドロキシルアミンを反応させて、化合物ｆ５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、好ましくはメタノールである。類似反応として、例えば、Ｏｒｇａｎｉｃ Ｌｅｔｔｅｒｓ,　２００１， ３(２６)， ４２０９－４２１１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。反応温度は、用いられる原料化合物の種類、試薬等により異なるが、通常、－７８℃～２００℃、好ましくは－２０℃～１５０℃であり、より好ましくは０℃～１００℃である。反応時間は通常５分～７２時間程度であり、好ましくは３０分～４８時間、さらに好ましくは１時間～２４時間である。 [Step F-3]
This step is a step of reacting compound f4 and hydroxylamine to obtain compound f5. The solvent used in this step is selected from the solvents exemplified below, but is preferably methanol. As a similar reaction, for example, a method described in Organic Letters, 2001, 3 (26), 4209-4211, etc. is known and can be synthesized in the same manner. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally -78 ° C to 200 ° C, preferably -20 ° C to 150 ° C, more preferably 0 ° C to 100 ° C. The reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
［Ｆ－４工程］
　本工程は上記Ｆ－３工程で得られる化合物ｆ５とクロロ化試薬を反応させて、化合物ｆ６を得る工程である。本工程において使用されるクロロ化試薬は、例えばＮ－クロロスクシンイミドが挙げられる。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ＤＭＦである。類似反応として、例えば、Ｂｉｏｏｒｇａｎｉｃ ａｎｄ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ Ｌｅｔｔｅｒｓ，　２００６, １６（２１）, ５５７６－５５７９、Ｊｏｕｒｎａｌ ｏｆ Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍｉｓｔｒｙ,　１９９６， ３３(６)， １５８３－１５９２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。反応温度は、用いられる原料化合物の種類、試薬等により異なるが、通常、－７８℃～２００℃、好ましくは－２０℃～１５０℃であり、より好ましくは０℃～１００℃である。反応時間は通常５分～７２時間程度であり、好ましくは３０分～４８時間、さらに好ましくは１時間～２４時間である。 [Step F-4]
This step is a step of reacting the compound f5 obtained in the step F-3 with a chlorinating reagent to obtain the compound f6. Examples of the chlorinating reagent used in this step include N-chlorosuccinimide. The solvent used in this step is selected from the solvents exemplified below, but is preferably DMF. Similar reactions are described in, for example, Bioorganic and Medicinal Chemistry Letters, 2006, 16 (21), 5576-5579, Journal of Heterocyclic Chemistry, 1996, 33 (6), 1583-1592, and the like. It can be synthesized similarly. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally −78 ° C. to 200 ° C., preferably −20 ° C. to 150 ° C., more preferably 0 ° C. to 100 ° C. The reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
［Ｆ－５工程］
　本工程は上記Ｆ－２工程で得られる化合物ｆ３と上記Ｆ－４工程で得られる化合物ｆ６を、適当な塩基存在下で反応させて、化合物ｆ７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、好ましくはトリエチルアミンである。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である。類似反応として、例えば、Ｊｏｕｒｎａｌ ｏｆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ,　２００３， ４６(２)， ２８４－３０２、Ｅｕｒｏｐｅａｎ Ｊｏｕｒｎａｌ ｏｆ Ｍｅｄｉｃｉｎａｌ Ｃｈｅｍｉｓｔｒｙ,　２０１２， ５４， ３２４－３４２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。反応温度は、用いられる原料化合物の種類、試薬等により異なるが、通常、－７８℃～２００℃、好ましくは－２０℃～１５０℃であり、より好ましくは０℃～１００℃である。反応時間は通常５分～７２時間程度であり、好ましくは３０分～４８時間、さらに好ましくは１時間～２４時間である。 [Step F-5]
In this step, compound f3 obtained in step F-2 and compound f6 obtained in step F-4 are reacted in the presence of a suitable base to obtain compound f7. The base used in this step is selected from the bases exemplified below, but is preferably triethylamine. The solvent used in this step is selected from the solvents exemplified below, and is preferably tetrahydrofuran. As similar reactions, for example, the methods described in Journal of Medicinal Chemistry, 2003, 46 (2), 284-302, European Journal of Medicinal Chemistry, 2012, 54, 324-342, and the like are known. can do. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally −78 ° C. to 200 ° C., preferably −20 ° C. to 150 ° C., more preferably 0 ° C. to 100 ° C. The reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
［Ｆ－６工程］
　本工程は上記Ｆ－５工程で得られた化合物ｆ７を、上記Ａ－４工程に準じた条件で反応させて、化合物ｆ８を得る工程である。 [Step F-6]
This step is a step of obtaining compound f8 by reacting compound f7 obtained in step F-5 with the conditions according to step A-4.
製造法Ｇ（合成中間体の製法）
　式（Ｉ）で表される化合物のうち、ＢがＢ－５であり、Ｗが酸素原子である化合物の合成中間体となるｇ５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-C000011
 （式中、Ａ、Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ及びＲ２Ｄは項１に定義されるとおりであり、ＰＸはアミノの保護基を意味する） Production method G (Production method of synthetic intermediate)
Among the compounds represented by the formula (I), g5 which is a synthetic intermediate of a compound in which B is B-5 and W is an oxygen atom can be produced, for example, by the following production method.
Figure JPOXMLDOC01-appb-C000011
 (Wherein, A, R 2A, R 2B , R 2C and R 2D are as defined in claim 1, P X denotes a protective group for amino)
　保護基ＰＸとしては、Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年) にアミノの保護基として記載されているものが挙げられる。 The protective group P X, Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts al, John Wiley & Sons, Inc. published in 1999), and those described in as a protecting group for amino.
　化合物ｆ４は、対応するアルコールの酸化などの既知の方法により合成できるか、又は市販品として購入できる。 Compound f4 can be synthesized by a known method such as oxidation of the corresponding alcohol, or can be purchased as a commercial product.
　化合物ｂ１は対応するアルコールの酸化などの既知の方法により合成できるか、又は市販品として購入できる。 Compound b1 can be synthesized by a known method such as oxidation of the corresponding alcohol, or can be purchased as a commercial product.
［Ｇ－１工程］
　本工程は化合物ｆ４と上記Ｆ－１工程で得られる化合物ｆ２を、上記Ｆ－２工程に準じた条件で反応させて、化合物ｇ１を得る工程である。 [Step G-1]
This step is a step of obtaining compound g1 by reacting compound f4 with compound f2 obtained in Step F-1 under the same conditions as in Step F-2.
［Ｇ－２工程］
　本工程は化合物ｂ１を、上記Ｆ－３工程に準じた条件で反応させて、化合物ｇ２を得る工程である。 [Step G-2]
This step is a step of obtaining compound g2 by reacting compound b1 under the conditions according to the above F-3 step.
［Ｇ－３工程］
　本工程は上記Ｇ－２工程で得られる化合物ｇ２を、上記Ｆ－４工程に準じた条件で反応させて、化合物ｇ３を得る工程である。 [Step G-3]
This step is a step of obtaining compound g3 by reacting compound g2 obtained in the above step G-2 under the same conditions as in the above step F-4.
［Ｇ－４工程］
　本工程は上記Ｇ－３工程で得られる化合物ｇ３と上記Ｇ－１工程で得られるｇ１を、上記工程Ｆ－５に準じた条件で反応させて、化合物ｇ４を得る工程である。 [Step G-4]
This step is a step of obtaining compound g4 by reacting compound g3 obtained in step G-3 and g1 obtained in step G-1 under the same conditions as in step F-5.
［Ｇ－５工程］
　本工程は上記Ｇ－４工程で得られる化合物ｇ４を、上記Ａ－４工程に準じた条件で反応させて、化合物ｇ５を得る工程である。 [Step G-5]
This step is a step of obtaining compound g5 by reacting compound g4 obtained in the above step G-4 with the conditions according to the above step A-4.
製造法Ｈ
　式（Ｉ）で表される化合物のうち、ＢがＢ－１であり、Ｘ－Ｙ－ＺがＮ－ＣＯ－ＮＲ３ＡＲ３Ｂである式［Ｈ１］、［Ｈ２］及び［Ｈ３］で表される化合物（以下、化合物Ｈ１、Ｈ２、Ｈ３とも称する）は、例えば下記の製法により製造することができる。また、同様の製造法を用いて、上記中間体製造法Ａで得られる中間体ａ８及びａ１０を出発原料として式［Ｈ２］及び［Ｈ３］で表される化合物を製造することができる。さらに、同様の製造法を用いて、上記中間体製造法Ｂ、Ｃ、Ｄ、Ｅ、Ｆ及びＧで得られる中間体ｂ７、ｃ２、ｄ４、ｅ２、ｆ８及びｇ５を出発物質として、ＢがＢ－２、Ｂ－３、Ｂ－４及びＢ－５であり、Ｘ－Ｙ－ＺがＮ－ＣＯ－ＮＲ３ＡＲ３Ｂであり、Ｗが酸素原子又は硫黄原子で表される対応の化合物群を製造することができる。
Figure JPOXMLDOC01-appb-C000012
 （式中、Ａ、Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ、Ｒ２Ｄ、Ｒ３Ａ及びＲ３Ｂは項１に定義されるとおりであり、ＲＹは水素、ニトロ又はシアノを表し、Ｒ１Ｘはハロゲンを表し、Ｒ１Ｙは項１に定義されるＲ１のうちハロゲンではないものを意味する） Manufacturing method H
Of the compounds represented by the formula (I), the compounds represented by the formulas [H1], [H2] and [H3], wherein B is B-1 and XYZ is N—CO—NR 3A R 3B The compounds to be prepared (hereinafter also referred to as compounds H1, H2, and H3) can be produced, for example, by the following production method. Further, using the same production method, compounds represented by the formulas [H2] and [H3] can be produced using the intermediates a8 and a10 obtained by the intermediate production method A as starting materials. Further, using the same production method, the intermediates B7, c2, d4, e2, f8 and g5 obtained by the above intermediate production methods B, C, D, E, F and G are used as starting materials. -2, B-3, B-4 and B-5, XYZ is N-CO-NR 3A R 3B , and W is an oxygen atom or a sulfur atom. Can be manufactured.
Figure JPOXMLDOC01-appb-C000012
 (In the formula, A, R 2A , R 2B , R 2C , R 2D , R 3A and R 3B are as defined in item 1; R Y represents hydrogen, nitro or cyano; and R 1X represents halogen. And R 1Y means a non-halogen among R 1 defined in item 1)
［Ｈ－１工程］
　本工程は上記Ａ－４工程で得られた化合物ａ６に、適当な塩基存在下、適当な溶媒中、ウレア化剤であるｈ１又はｈ２を反応させることにより、化合物Ｈ１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塩化メチレンである。類似反応として、例えば、Ｊ. Ｏｒｇ. Ｃｈｅｍ. １９９５, ６０（２５）, ８２６２－８２６６、Ｂｉｏｏｒｇ. Ｍｅｄ. Ｃｈｅｍ. Ｌｅｔｔ. ２００４, １４（３）, ７２７－７７９、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ. ２００１, ４２（８）, １４４５－１４４７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。反応温度は、用いられる原料化合物の種類、試薬等により異なるが、通常、－７８℃～２００℃、好ましくは－２０℃～１５０℃であり、より好ましくは０℃～１００℃である。反応時間は通常５分～７２時間程度であり、好ましくは３０分～４８時間、さらに好ましくは１時間～２４時間である。 [Step H-1]
This step is a step of obtaining Compound H1 by reacting Compound a6 obtained in Step A-4 with h1 or h2 which is a urea agent in a suitable solvent in the presence of a suitable base. The base used in this step is selected from the bases exemplified below, and is preferably diisopropylethylamine or triethylamine. The solvent used in this step is selected from the solvents exemplified below, and is preferably tetrahydrofuran or methylene chloride. Similar reactions include, for example, J. Org. Chem. 1995, 60 (25), 8262-8266, Bioorg. Med. Chem. Lett. 2004, 14 (3), 727-779, Tetrahedron Lett. 2001, 42 (8 ), 1445-1447, etc. are known and can be synthesized in the same manner. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally −78 ° C. to 200 ° C., preferably −20 ° C. to 150 ° C., more preferably 0 ° C. to 100 ° C. The reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
［Ｈ－２工程］
　本工程は上記Ｈ－１工程で得られた化合物Ｈ１に、適当な溶媒中、適当な酸の存在下で、種々のハロゲン化剤を反応させることにより、化合物Ｈ２を得る工程である。本工程において使用されるハロゲン化剤は、好ましくはＮ－クロロスクシンイミド、Ｎ－ブロモスクシンイミド、Ｎ－ヨードスクシンイミドである。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、好ましくは塩化メチレン又はジクロロエタンである。本工程において使用される酸は、後記に例示する酸等から選択されるが、好ましくはトリフルオロ酢酸又は塩酸である。類似反応として、例えば、Ｂｉｏｏｒｇ. Ｍｅｄ. Ｃｈｅｍ. Ｌｅｔｔ. ２００８, １８（５）, １７０２－１７０７、Ｊ. Ｏｒｇ. Ｃｈｅｍ. ２００２, ６７（１７）, ５９１３－５９１８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。反応温度は、用いられる原料化合物の種類、試薬等により異なるが、通常、－７８℃～２００℃、好ましくは－２０℃～１５０℃であり、より好ましくは０℃～７０℃である。反応時間は通常５分～７２時間程度であり、好ましくは３０分～４８時間、さらに好ましくは１時間～２４時間である。 [Step H-2]
This step is a step for obtaining compound H2 by reacting compound H1 obtained in step H-1 with various halogenating agents in a suitable solvent in the presence of a suitable acid. The halogenating agent used in this step is preferably N-chlorosuccinimide, N-bromosuccinimide, or N-iodosuccinimide. The solvent used in this step is selected from the solvents exemplified below, and is preferably methylene chloride or dichloroethane. The acid used in this step is selected from the acids exemplified below, and preferably trifluoroacetic acid or hydrochloric acid. As a similar reaction, for example, methods described in Bioorg. Med. Chem. Lett. 2008, 18 (5), 1702-1707, J. Org. Chem. 2002, 67 (17), 5913-5918 and the like are known. And can be synthesized similarly. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally −78 ° C. to 200 ° C., preferably −20 ° C. to 150 ° C., more preferably 0 ° C. to 70 ° C. The reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
［Ｈ－３工程］
　本工程は上記Ｈ－２工程で得られた化合物Ｈ２に、適当な溶媒中、適当な遷移金属試薬の存在下で、適当なボロン酸誘導体と反応させることにより、化合物Ｈ３を得る工程である。本工程において使用される遷移金属試薬は、例えばトリス（ジベンジリデンアセトン）ジパラジウムやテトラキス（トリフェニルフォスフィン）パラジウムが挙げられる。本工程において使用されるボロン酸誘導体は、例えばボロン酸、ボロン酸エステル、ボロン酸ピナコラートが挙げられる。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ＤＭＦ又はジオキサンである。類似反応として、例えば、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ. ２００３, ４４（７）, １３７９－１３８２、Ｊ. Ｍｅｄ. Ｃｈｅｍ. ２００９, ５２（１４）, ４３７０－４３７９、Ｂｉｏｏｒｇ. Ｍｅｄ. Ｃｈｅｍ. Ｌｅｔｔ. ２０１２, ２０（９）, ３００９－３０１５、Ｊ. Ｏｒｇ. Ｃｈｅｍ. ２００２, ６７（１０）, ３３６５－３３７３、Ｔｅｔｒａｈｅｄｒｏｎ Ｌｅｔｔ. ２００７, ４８（１３）, ２３３９－２３４３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。反応温度は、用いられる原料化合物の種類、試薬等により異なるが、通常、－７８℃～２００℃、好ましくは－２０℃～１８０℃であり、より好ましくは室温～１５０℃である。反応時間は通常５分～７２時間程度であり、好ましくは３０分～４８時間、さらに好ましくは１時間～２４時間である。 [Step H-3]
This step is a step of obtaining compound H3 by reacting compound H2 obtained in step H-2 with an appropriate boronic acid derivative in an appropriate solvent in the presence of an appropriate transition metal reagent. Examples of the transition metal reagent used in this step include tris (dibenzylideneacetone) dipalladium and tetrakis (triphenylphosphine) palladium. Examples of the boronic acid derivative used in this step include boronic acid, boronic acid ester, and boronic acid pinacolate. The solvent used in this step is selected from the solvents exemplified below, and is preferably DMF or dioxane. Similar reactions include, for example, Tetrahedron Lett. 2003, 44 (7), 1379-1382, J. Med. Chem. 2009, 52 (14), 4370-4379, Bioorg. Med. Chem. Lett. 2012, 20 (9 ), 3009-3015, J. Org. Chem. 2002, 67 (10), 3365-3373, Tetrahedron Lett. 2007, 48 (13), 2339-2343, and the like. Can be synthesized. The reaction temperature varies depending on the type of raw material compound used, reagents and the like, but is usually −78 ° C. to 200 ° C., preferably −20 ° C. to 180 ° C., more preferably room temperature to 150 ° C. The reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
製造法Ｉ
　式（Ｉ）で表される化合物のうち、ＢがＢ－１であり、Ｘ－Ｙ－ＺがＮ－ＣＯＲ４Ａである式［Ｉ１］［Ｉ２］[Ｉ３]で表される化合物（以下、化合物Ｉ１、Ｉ２、Ｉ３とも称する）は、例えば下記の製法により製造することができる。
　また、同様の製造法を用いて、上記中間体製造法Ａで得られる中間体ａ８及びａ１０を出発原料として式［Ｉ２］及び［Ｉ３］で表される化合物を製造することができる。
　さらに、同様の製造法を用いて、上記中間体製造法Ｂ、Ｃ、Ｄ、Ｅ、Ｆ及びＧで得られる中間体ｂ７、ｃ２、ｄ４、ｅ２、ｆ８及びｇ５を出発物質として、ＢがＢ－２、Ｂ－３、Ｂ－４及びＢ－５であり、Ｘ－Ｙ－ＺがＮ－ＣＯＲ４Ａであり、Ｗが酸素原子又は硫黄原子で表される対応の化合物群を製造することができる。
Figure JPOXMLDOC01-appb-C000013
 （式中、Ａ、Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ、Ｒ２Ｄ及びＲ４Ａは項１に定義されるとおりであり、Ｒ１Ｙは項１に定義されるＲ１のうちハロゲンではないものを表し、Ｒ１Ｘはハロゲンを意味する） Manufacturing method I
Of the compounds represented by the formula (I), compounds represented by the formula [I1] [I2] [I3] wherein B is B-1 and XYZ is N—COR 4A (hereinafter, Compounds I1, I2, and I3) can be produced, for example, by the following production method.
Further, using the same production method, compounds represented by the formulas [I2] and [I3] can be produced using the intermediates a8 and a10 obtained by the intermediate production method A as starting materials.
Further, using the same production method, the intermediates B7, c2, d4, e2, f8 and g5 obtained by the above intermediate production methods B, C, D, E, F and G are used as starting materials. -2, B-3, B-4, and B-5, XYZ is N-COR 4A , and W is an oxygen atom or a sulfur atom. it can.
Figure JPOXMLDOC01-appb-C000013
 (In the formula, A, R 2A , R 2B , R 2C , R 2D and R 4A are as defined in item 1, and R 1Y represents a non-halogen of R 1 defined in item 1. , R 1X means halogen)
［Ｉ－１工程］
　本工程は上記Ａ－４工程で得られた化合物ａ６に、適当な縮合剤存在下または非存在下、適当な塩基存在下、適当な溶媒中で、カルボン酸ｉ１又は酸クロライドｉ２と反応させることにより、化合物Ｉ１を得る工程である。本工程において使用される縮合剤は、例えばＥＤＣＩ（塩酸塩を含む）又はＨＢＴＵ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、好ましくはジメチルホルムアミド、テトラヒドロフラン又は塩化メチレンである。反応温度は、用いられる原料化合物の種類、試薬等により異なるが、通常、－７８℃～２００℃、好ましくは－２０℃～１５０℃であり、より好ましくは０℃～１００℃である。反応時間は通常５分～７２時間程度であり、好ましくは３０分～４８時間、さらに好ましくは１時間～２４時間である。 [Step I-1]
In this step, compound a6 obtained in step A-4 is reacted with carboxylic acid i1 or acid chloride i2 in the presence of a suitable base in the presence or absence of a suitable condensing agent and in the presence of a suitable base. To obtain compound I1. The condensing agent used in this step is, for example, EDCI (including hydrochloride) or HBTU. The base used in this step is selected from the bases exemplified below, and is preferably diisopropylethylamine or triethylamine. The solvent used in this step is selected from the solvents exemplified below, and preferably dimethylformamide, tetrahydrofuran or methylene chloride. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally −78 ° C. to 200 ° C., preferably −20 ° C. to 150 ° C., more preferably 0 ° C. to 100 ° C. The reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
［Ｉ－２工程］
　本工程は上記Ｉ－１工程で得られる化合物Ｉ１を、上記Ｈ－２工程に準じた条件で反応させて、化合物Ｉ２を得る工程である。 [Step I-2]
This step is a step of obtaining compound I2 by reacting compound I1 obtained in the above step I-1 under the same conditions as in the above step H-2.
［Ｉ－３工程］
　本工程は上記Ｉ－２工程で得られる化合物Ｉ２を、上記Ｈ－３工程に準じた条件で反応させて、化合物Ｉ３を得る工程である。 [Step I-3]
This step is a step of obtaining compound I3 by reacting compound I2 obtained in the above step I-2 with the conditions according to the above step H-3.
製造法Ｊ
　式（Ｉ）で表される化合物のうち、ＢがＢ－４であり、Ｘ－Ｙ－ＺがＣＲ５－ＮＲ６－ＣＯＲ４Ｂである式［Ｊ１］［Ｊ２］[Ｊ３]及び[Ｊ４]で表される化合物（以下、化合物Ｊ１、Ｊ２、Ｊ３及びＪ４とも称する）は、例えば上記中間体製造方法Ｆに準じた下記の製法により製造することができる。
　また、下記製造法Ｊと上記中間体製造法Ａ、Ｂ、Ｃ、Ｄ、Ｅ及びＧに準じた製法を組み合わせることにより、Ｘ－Ｙ－ＺがＣＲ５－ＮＲ６－ＣＯＲ４Ｂであり、ＢがＢ－１、Ｂ－２、Ｂ－３及びＢ－５であり、Ｗが酸素原子又は硫黄原子で表される対応の化合物群を製造することができる。
Figure JPOXMLDOC01-appb-C000014
 （式中、Ａ、Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ、Ｒ２Ｄ、Ｒ４Ｂ、Ｒ５及びＲ６は項１に定義されるとおりであり、Ｒ１Ｘはハロゲンを表し、Ｒ１Ｙは項１に定義されるＲ１のうちハロゲンではないものを表し、ＲＺはハロゲン等の脱離基を表し、ＰＸはアミノの保護基を意味する） Manufacturing method J
Of the compounds represented by formula (I), the formulas [J1] [J2] [J3] and [J4] wherein B is B-4 and XYZ is CR 5 —NR 6 —COR 4B (Hereinafter also referred to as compounds J1, J2, J3, and J4) can be produced, for example, by the following production method according to the intermediate production method F.
Further, by combining the following production method J and the production methods according to the intermediate production methods A, B, C, D, E and G, XYZ is CR 5 —NR 6 —COR 4B ; Is a corresponding compound group in which is B-1, B-2, B-3 and B-5, and W is an oxygen atom or a sulfur atom.
Figure JPOXMLDOC01-appb-C000014
 (In the formula, A, R 2A , R 2B , R 2C , R 2D , R 4B , R 5 and R 6 are as defined in item 1; R 1X represents halogen; R 1Y represents item 1; R 1 which is not halogen among the defined R 1 represents R Z represents a leaving group such as halogen, and P X represents an amino protecting group)
　保護基ＰＸとしては、Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年) にアミノの保護基として記載されているものが挙げられる。 The protective group P X, Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts al, John Wiley & Sons, Inc. published in 1999), and those described in as a protecting group for amino.
　化合物ｊ１は、対応するアルコールの酸化などの既知の方法により合成できるか、又は市販品として購入できる。 Compound j1 can be synthesized by a known method such as oxidation of the corresponding alcohol, or can be purchased as a commercial product.
［Ｊ－１工程］
　本工程は化合物ｊ１を、上記Ｆ－２工程に準じた条件で反応させて、化合物ｊ２を得る工程である。 [Step J-1]
This step is a step wherein compound j2 is obtained by reacting compound j1 under the same conditions as in Step F-2.
［Ｊ－２工程］
　本工程は上記Ｊ－１工程で得られる化合物ｊ２を、上記Ｆ－５工程に準じた条件で反応させて、化合物ｊ３を得る工程である。 [Step J-2]
This step is a step of obtaining compound j3 by reacting compound j2 obtained in step J-1 under the same conditions as in step F-5.
［Ｊ－３工程］
　本工程は上記製造法Ｊ－２で得られた化合物ｊ３のアミノの保護基ＰＸを、脱保護することにより、化合物ｊ４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 J-3]
This step is a protecting group P X of the amino compound j3 prepared in the above Preparation Method J-2, is deprotected, to give compound compound j4. 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).
［Ｊ－４工程］
　本工程は上記Ｊ－３で得られた化合物ｊ４に、適当な縮合剤存在下又は非存在下、適当な塩基存在下、適当な溶媒中でカルボン酸ｊ５又は酸クロライドｊ６と反応させることにより、化合物Ｊ１を得る工程である。本工程において使用される縮合剤は、例えばＥＤＣＩ（塩酸塩を含む）又はＨＢＴＵが挙げられる。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、好ましくはジメチルホルムアミド、テトラヒドロフラン又は塩化メチレンが挙げられる。反応温度は、用いられる原料化合物の種類、試薬等により異なるが、通常、－７８℃～２００℃、好ましくは０℃～１５０℃であり、より好ましくは室温～１００℃である。反応時間は通常５分～７２時間程度であり、好ましくは３０分～４８時間、さらに好ましくは１時間～２４時間である。 [Step J-4]
In this step, compound j4 obtained in J-3 above is reacted with carboxylic acid j5 or acid chloride j6 in a suitable solvent in the presence or absence of a suitable condensing agent and in the presence of a suitable base. In this step, compound J1 is obtained. Examples of the condensing agent used in this step include EDCI (including hydrochloride) or HBTU. 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 dimethylformamide, tetrahydrofuran or methylene chloride. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally −78 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C., more preferably room temperature to 100 ° C. The reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
［Ｊ－５工程］
　本工程は上記Ｊ－４工程で得られる化合物Ｊ１を、上記Ｈ－２工程に準じた条件で反応させて、化合物Ｊ２を得る工程である。 [Step J-5]
This step is a step of obtaining compound J2 by reacting compound J1 obtained in the above step J-4 under the conditions according to the above step H-2.
［Ｊ－６工程］
　本工程は上記Ｊ－５工程で得られる化合物Ｊ２を、上記Ｈ－３工程に準じた条件で反応させて、化合物Ｊ３を得る工程である。 [Step J-6]
In this step, compound J2 obtained in step J-5 is reacted under the same conditions as in step H-3 to obtain compound J3.
［Ｊ－７工程］
　本工程は上記Ｊ－６工程で得られた化合物Ｊ３に、種々の塩基存在下、適当な溶媒中、化合物ｊ７を反応させることにより、化合物Ｊ４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又はジイソプロピ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。反応温度は、用いられる原料化合物の種類、試薬等により異なるが、通常、－３０℃～２００℃、好ましくは０℃～１５０℃であり、より好ましくは０℃～８０℃である。反応時間は通常１時間～４８時間程度であり、好ましくは１～２４時間、さらに好ましくは１～１６時間である。 [Step J-7]
This step is a step of obtaining compound J4 by reacting compound j7 obtained in step J-6 with compound j7 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 sodium hydride or diisopropylamine. The solvent used in this step is selected from the solvents exemplified below and preferably dimethylformamide or tetrahydrofuran. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally −30 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C., more preferably 0 ° C. to 80 ° C. The reaction time is usually about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
製造法Ｋ
　式（Ｉ）で表される化合物のうち、ＢがＢ－４であり、Ｘ－Ｙ－ＺがＣＲ５－ＮＲ６－ＣＯＮＲ３ＡＲ３Ｂである式［Ｋ１］［Ｋ２］[Ｋ３]及び[Ｋ４]で表される化合物（以下、化合物Ｋ１、Ｋ２、Ｋ３及びＫ４とも称する）は、例えば下記の製法により製造することができる。
　また、下記製造法Ｋ及び上記中間体製造法Ａ、Ｂ、Ｃ、Ｄ、Ｅ及びＧに準じた製法を組み合わせることにより、Ｘ－Ｙ－ＺがＣＲ５－ＮＲ６－ＣＯＮＲ３ＡＲ３Ｂであり、ＢがＢ－１、Ｂ－２、Ｂ－３及びＢ－５であり、Ｗが酸素原子又は硫黄原子で表される対応の化合物群を製造することができる。
Figure JPOXMLDOC01-appb-C000015
 （式中、Ａ、Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ、Ｒ２Ｄ、Ｒ３Ａ、Ｒ３Ｂ、Ｒ５及びＲ６は項１に定義されるとおりであり、Ｒ１Ｘはハロゲンを表し、Ｒ１Ｙは項１に定義されるＲ１のうちハロゲンではないものを表し、ＲＹは水素、ニトロ又はシアノを表し、ＲＺはハロゲン等の脱離基を意味する） Manufacturing method K
Of the compounds represented by formula (I), the compounds of formula [K1] [K2] [K3] and [K3] wherein B is B-4 and XYZ is CR 5 —NR 6 —CONR 3A R 3B The compound represented by K4] (hereinafter also referred to as compounds K1, K2, K3 and K4) can be produced, for example, by the following production method.
Further, XYZ is CR 5 —NR 6 —CONR 3A R 3B by combining the following production method K and production methods according to the above intermediate production methods A, B, C, D, E and G. , B is B-1, B-2, B-3 and B-5, and corresponding compounds can be produced wherein W is an oxygen atom or a sulfur atom.
Figure JPOXMLDOC01-appb-C000015
 (In the formula, A, R 2A , R 2B , R 2C , R 2D , R 3A , R 3B , R 5 and R 6 are as defined in Item 1, R 1X represents halogen, and R 1Y represents R 1 defined in Item 1 is not halogen, R Y represents hydrogen, nitro or cyano, and R Z represents a leaving group such as halogen)
［Ｋ－１工程］
　本工程は上記Ｊ－３工程で得られる化合物ｊ４を、上記Ｈ－１工程に準じた条件で反応させて、化合物Ｋ１を得る工程である。 [Step K-1]
This step is a step of obtaining compound K1 by reacting compound j4 obtained in the above step J-3 under the conditions according to the above step H-1.
［Ｋ－２工程］
　本工程は上記Ｋ－１工程で得られる化合物Ｋ１を、上記Ｊ－７工程に準じた条件で反応させて、化合物Ｋ２を得る工程である。 [Step K-2]
This step is a step of obtaining compound K2 by reacting compound K1 obtained in the above step K-1 under the same conditions as in the above step J-7.
［Ｋ－３工程］
　本工程は上記Ｋ－２工程で得られる化合物Ｋ２を、上記Ｈ－２工程に準じた条件で反応させて、化合物Ｋ３を得る工程である。 [Step K-3]
This step is a step of obtaining a compound K3 by reacting the compound K2 obtained in the step K-2 with the conditions according to the step H-2.
［Ｋ－４工程］
　本工程は上記Ｋ－３工程で得られる化合物Ｋ３を、上記Ｈ－３工程に準じた条件で反応させて、化合物Ｋ４を得る工程である。 [Step K-4]
This step is a step of obtaining a compound K4 by reacting the compound K3 obtained in the step K-3 with the conditions according to the step H-3.
製造法Ｍ
　式（Ｉ）で表される化合物のうち、ＢがＢ－４であり、Ｘ－Ｙ－ＺがＣＲ５－ＣＯ－ＮＲ３ＡＲ３Ｂである式［Ｍ１］［Ｍ２］及び[Ｍ３]で表される化合物（以下、化合物Ｍ１、Ｍ２及びＭ３とも称する）は、例えば上記中間体製造方法Ｆに準じた下記の製法により製造することができる。
　また、下記製造法Ｍと上記中間体製造法Ａ、Ｂ、Ｃ、Ｄ、Ｅ及びＧに準じた製法を組み合わせることにより、Ｘ－Ｙ－ＺがＣＲ５－ＣＯ－ＮＲ３ＡＲ３Ｂであり、ＢがＢ－１、Ｂ－２、Ｂ－３及びＢ－５であり、Ｗが酸素原子又は硫黄原子で表される対応の化合物群を製造することができる。
Figure JPOXMLDOC01-appb-C000016
 （式中、Ａ、Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ、Ｒ２Ｄ、Ｒ３Ａ、Ｒ３Ｂ及びＲ５は項１に定義されるとおりであり、Ｒ１Ｘはハロゲンを表し、Ｒ１Ｙは項１に定義されるＲ１のうちハロゲンではないものを表し、ＰＹはカルボキシル基の保護基を意味する） Manufacturing method M
Of the compounds represented by the formula (I), the compounds represented by the formulas [M1] [M2] and [M3], wherein B is B-4 and XYZ is CR 5 —CO—NR 3A R 3B The compounds to be produced (hereinafter also referred to as compounds M1, M2 and M3) can be produced, for example, by the following production method according to the intermediate production method F.
Further, by combining the following production method M and the production methods according to the intermediate production methods A, B, C, D, E and G, XYZ is CR 5 —CO—NR 3A R 3B , Corresponding compound groups in which B is B-1, B-2, B-3 and B-5 and W is an oxygen atom or a sulfur atom can be produced.
Figure JPOXMLDOC01-appb-C000016
 (In the formula, A, R 2A , R 2B , R 2C , R 2D , R 3A , R 3B and R 5 are as defined in item 1, R 1X represents halogen, and R 1Y represents item 1 R 1 which is not halogen among the defined R 1 represents P Y represents a protecting group for a carboxyl group)
　保護基ＰＹとしては、Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年) にカルボン酸の保護基として記載されているものが挙げられる。 The protective group P Y, Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts al, John Wiley & Sons, Inc. published in 1999), and those described in as a protecting group of a carboxylic acid .
　化合物ｍ１は、対応するアルコールの酸化などの既知の方法により合成できるか、又は市販品として購入できる。 Compound m1 can be synthesized by a known method such as oxidation of the corresponding alcohol, or can be purchased as a commercial product.
［Ｍ－１工程］
　本工程は化合物ｍ１を、上記Ｆ－２工程に準じた条件で反応させて、化合物ｍ２を得る工程である。 [Step M-1]
This step is a step of obtaining compound m2 by reacting compound m1 under the same conditions as in Step F-2.
［Ｍ－２工程］
　本工程は上記Ｍ－１工程で得られる化合物ｍ２を、上記Ｆ－５工程に準じた条件で反応させて、化合物ｍ３を得る工程である。 [Step M-2]
This step is a step of obtaining a compound m3 by reacting the compound m2 obtained in the step M-1 with the conditions according to the step F-5.
［Ｍ－３工程］
　本工程は上記Ｍ－２工程で得られた化合物ｍ３のカルボン酸の保護基ＰＹを、脱保護することにより、化合物ｍ４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。 [M-3 process]
This step is a step of obtaining the compound m4 by deprotecting the protecting group P Y of the carboxylic acid of the compound m3 obtained in the step M-2. 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).
［Ｍ－４工程］
　本工程は上記Ｍ－３工程で得られた化合物ｍ４に、適当な縮合剤存在下、適当な塩基存在下、適当な溶媒中でアミンｍ５と反応させることにより、化合物Ｍ１を得る工程である。本工程において使用される縮合剤は、例えばＥＤＣＩ（塩酸塩を含む）又はＨＢＴＵが挙げられる。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、好ましくはジメチルホルムアミド、テトラヒドロフラン又は塩化メチレンが挙げられる。反応温度は、用いられる原料化合物の種類、試薬等により異なるが、通常、－７８℃～２００℃、好ましくは０℃～１５０℃であり、より好ましくは室温～１００℃である。反応時間は通常５分～７２時間程度であり、好ましくは３０分～４８時間、さらに好ましくは１時間～２４時間である。 [Step M-4]
This step is a step of obtaining compound M1 by reacting compound m4 obtained in step M-3 with amine m5 in the presence of a suitable condensing agent and in the presence of a suitable base in a suitable solvent. Examples of the condensing agent used in this step include EDCI (including hydrochloride) or HBTU. 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 dimethylformamide, tetrahydrofuran or methylene chloride. While the reaction temperature varies depending on the type of raw material compound used, reagents and the like, it is generally −78 ° C. to 200 ° C., preferably 0 ° C. to 150 ° C., more preferably room temperature to 100 ° C. The reaction time is usually about 5 minutes to 72 hours, preferably 30 minutes to 48 hours, more preferably 1 hour to 24 hours.
［Ｍ－５工程］
　本工程は上記Ｍ－４工程で得られる化合物Ｍ１を、上記Ｈ－２工程に準じた条件で反応させて、化合物Ｍ２を得る工程である。 [Step M-5]
In this step, compound M1 obtained in step M-4 is reacted under the same conditions as in step H-2 to obtain compound M2.
［Ｍ－６工程］
　本工程は上記Ｍ－５工程で得られる化合物Ｍ２を、上記Ｈ－３工程に準じた条件で反応させて、化合物Ｍ３を得る工程である。 [Step M-6]
In this step, compound M2 obtained in step M-5 is reacted under the same conditions as in step H-3 to obtain compound M3.
　上記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 of the above steps should be selected in a timely manner depending on the reaction and the type of raw material compound. For example, alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate, sodium carbonate and potassium carbonate Alkali carbonates such as sodium hydride, metal hydrides such as sodium hydride and potassium hydride, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metals such as sodium methoxide and sodium t-butoxide Alkoxides, organometallic bases such as butyllithium and lithium diisopropylamide, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo [5.4.0] -7-undecene ( Organic bases such as DBU) That.
　上記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宜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、エチル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あるいは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 of the above steps should be appropriately selected depending on the reaction and the type of raw material compound. For example, alcohols such as methanol, ethanol and isopropanol, and ketones such as acetone and ethyl methyl ketone. 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), nitriles such as acetonitrile These solvents can be used alone There can be used as a mixture of two or more kinds. Depending on the type of reaction, organic bases may be used as a solvent.
　式（Ｉ）で表される本発明の化合物又はその中間体は、当業者に公知の方法で分離、精製することができる。そのような分離または精製方法としては、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も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、エタノールもしくは２－プロパノールなどのアルコール系溶媒、ジエチルエーテルなどのエーテル系溶媒、酢酸エチルなどのエステル系溶媒、ベンゼンもしくはトルエンなどの芳香族炭化水素系溶媒、アセトンなどのケトン系溶媒、ジクロロメタンもしくはクロロホルムなどのハロゲン系溶媒、ヘキサンなどの炭化水素系溶媒、ジメチルホルムアミドもしくはアセトニトリルなどの非プロトン系溶媒、水、又はこれら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。また、本発明の化合物の分子構造の決定は、それぞれの原料化合物に由来する構造を参照して、核磁気共鳴法、赤外吸収法、円二色性スペクトル分析法などの分光学的手法、及び質量分析法により容易に行える。 The compound of the present invention represented by the formula (I) or an intermediate thereof can be separated and purified by methods known to those skilled in the art. Examples of such separation or purification methods 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. A ketone solvent, a halogen solvent such as dichloromethane or chloroform, a hydrocarbon solvent such as hexane, an aprotic solvent such as dimethylformamide or acetonitrile, water, or a mixed solvent thereof. As other purification methods, the methods described in Experimental Chemistry Course (The Chemical Society of Japan, Maruzen) vol. 1 can be used. Further, the molecular structure of the compound of the present invention is determined by referring to the structure derived from each raw material compound, a spectroscopic method such as nuclear magnetic resonance, infrared absorption, circular dichroism spectrum analysis, And mass spectrometry.
　式（Ｉ）で表される本発明の化合物またはそれらの製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。本発明の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、式（Ｉ）で表される本発明の化合物またはそれらの製薬学的に許容される塩の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、エタノールもしくは２－プロパノールなどのアルコール系溶媒、ジエチルエーテルなどのエーテル系溶媒、酢酸エチルなどのエステル系溶媒、トルエンなどの炭化水素系溶媒、アセトニトリルなどの非プロトン系溶媒、又はこれらの混合溶媒）、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もしくは乳酸などのモノカルボン酸、酒石酸、ｏ－ジイソプロピリデン酒石酸もしくはリンゴ酸などのジカルボン酸、カンファースルフォン酸もしくはブロモカンファースルホン酸などのスルホン酸）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）で表される本発明の化合物の中間体が、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、シンコニンもしくはストリキニーネなどの有機アミン）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 asymmetry or may have a substituent having an asymmetric carbon. In that case, optical isomers exist. The compounds of the present invention include mixtures of these isomers and isolated ones, and 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, by using an optically active raw material or performing optical resolution or the like at an appropriate stage of the production process, the optical properties of the compound of the present invention represented by formula (I) or a pharmaceutically acceptable salt thereof Isomers can be obtained. As the optical resolution method, for example, when the compound represented by the formula (I) or an intermediate thereof has a basic functional group, the solvent is an inert solvent (for example, an alcohol solvent such as methanol, ethanol or 2-propanol). 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 thereof), an optically active acid (for example, mandelic acid, N-benzyloxyalanine or monocarboxylic acid such as lactic acid, tartaric acid, dicarboxylic acid such as o-diisopropylidene tartaric acid or malic acid, sulfonic acid such as camphorsulfonic acid or bromocamphorsulfonic acid) Stereomer method can be mentioned. 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 or strychnine) 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、エタノールもしくは２－プロパノールなどのアルコール系溶媒、ジエチルエーテルなどのエーテル系溶媒、酢酸エチルなどのエステル系溶媒、トルエンなどの炭化水素系溶媒、アセトニトリルなどの非プロトン系溶媒、又はこれらの混合溶媒）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 or 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, hydrocarbon solvents such as toluene, acetonitrile, etc. And a high purity optically active salt can be obtained. 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.
　あるいは式（Ｉ）で表される本発明の化合物の中間体が、カルボキシル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など）を用いてアミドを形成させることにより、光学分割を行うこともできる。 Alternatively, when the intermediate of the compound of the present invention represented by the formula (I) has a carboxyl group, an optically active amine (for example, 1-phenylethylamine etc.) is used to form an amide. Division can also be performed.
　本発明の化合物は、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及び／又は予防剤として有用である。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としては、神経疾患、精神疾患又は炎症性疾患が挙げられる。神経疾患、精神疾患又は炎症性疾患の具体例としては、統合失調症、アルツハイマー病、ダウン症、注意欠陥・多動性障害又は脳血管アンギオパチーが挙げられる。また、本発明の化合物は、（１）ＣＩＡＳ（統合失調症に伴う認知機能障害）、或いは、（２）統合失調症、アルツハイマー病、ダウン症、注意欠陥・多動性障害又は脳血管アンギオパチーにおける、認知障害、軽度認知障害、記憶障害又は学習障害を治療及び／又は予防するために有用である。また、本発明の化合物は、統合失調症に伴う陰性症状及び／又は陽性症状を治療及び／又は予防するために有用である。 The compound of the present invention is useful as a therapeutic and / or prophylactic agent for diseases caused by abnormalities in intracellular signal transduction involving acetylcholine. Examples of the disease caused by abnormal intracellular signal transduction involving acetylcholine include a neurological disease, a mental disease or an inflammatory disease. Specific examples of neurological diseases, psychiatric diseases or inflammatory diseases include schizophrenia, Alzheimer's disease, Down's syndrome, attention deficit / hyperactivity disorder, or cerebrovascular angiopathy. In addition, the compound of the present invention is (1) CIAS (cognitive dysfunction associated with schizophrenia), or (2) schizophrenia, Alzheimer's disease, Down's syndrome, attention deficit / hyperactivity disorder or cerebrovascular angiopathy, Useful for treating and / or preventing cognitive impairment, mild cognitive impairment, memory impairment or learning impairment. The compounds of the present invention are also useful for treating and / or preventing negative and / or positive symptoms associated with schizophrenia.
　さらに、本発明の化合物は、前記治療及び／又は予防の目的で、非定型抗精神病薬と併用して用いることもできる。本発明の化合物又はその製薬学的に許容される塩と、非定型抗精神病薬とを併用する場合における医薬は、単一の配合剤であってもよく、あるいは、同時に、別々に、連続してまたは一定間隔を空けて投与される複数製剤であってもよい。 Furthermore, the compound of the present invention can be used in combination with an atypical antipsychotic agent for the purpose of the treatment and / or prevention. The pharmaceutical agent in the case where the compound of the present invention or a pharmaceutically acceptable salt thereof and an atypical antipsychotic drug are used in combination may be a single compounding agent, or simultaneously, separately and continuously. Or multiple formulations administered at regular intervals.
　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 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.
　剤形としては、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、これらの製剤は製薬学的に許容される添加剤を含有してもよい。添加剤は、目的に応じて、賦形剤、崩壊剤、結合剤、流動化剤、滑沢剤、コーティング剤、溶解剤、溶解補助剤、増粘剤、分散剤、安定化剤、甘味剤、香料等を用いることができる。 Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, injections, suppositories, eye drops, ointments, coating agents, 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 pharmaceutically acceptable additives. Additives are excipients, disintegrants, binders, fluidizers, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, sweeteners depending on the purpose. Perfumes and the like can be used.
　本発明の化合物は、非定型抗精神病薬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 an atypical antipsychotic drug. 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はメチル基、Ｅｔはエチル基、Ｐｈはフェニル基、Ｔｓはトシル基を意味する。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、ｂｒｄは幅広い二重線、ｂｒｔは幅広い三重線及び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 a methyl group, Et means an ethyl group, Ph means a phenyl group, and Ts means a tosyl group. 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 lines, br means broad, brs means broad single line, brd means broad double line, brt means broad triple line, and J means 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、ｍｉｎ）で示す。なお、各実測値においては、測定に用いた測定条件としてＡ～Ｈのいずれかを付記する。 High-performance liquid chromatographic 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 (min, min). In each actual measurement value, any one of A to H is added as a measurement condition used for the measurement.
測定条件Ａ 
検出機器：Waters ACQUITY UPLC
ｃｏｌｕｍｎ：ACQUITY UPLC BEH C18 1.7μm 2.1×50 mm column
Ｓｏｌｖｅｎｔ：Ａ液：0.05% HCOOH／H2O、Ｂ液：CH3CN
Ｇｒａｄｉｅｎｔ Ｃｏｎｄｉｔｉｏｎ：
　　0.0-1.3分；Ａ／Ｂ＝90：10～1：99（linear gradient）
　　1.35-1.5分；Ａ／Ｂ＝1:99
　　1.5-2分；Ａ／Ｂ＝90：10
Ｆｌｏｗ Ｒａｔｅ：0.75 mL／min.
ＵＶ：220 nm, 254 nm
カラム温度：50℃ Measurement condition A
Detection equipment: Waters ACQUITY UPLC
column: ACQUITY UPLC BEH C18 1.7μm 2.1 × 50 mm column
Solvent: Liquid A: 0.05% HCOOH / H 2 O, Liquid B: CH 3 CN
Gradient Condition:
0.0-1.3 min; A / B = 90: 10 to 1:99 (linear gradient)
1.35-1.5 minutes; A / B = 1: 99
1.5-2 minutes; A / B = 90: 10
Flow Rate: 0.75 mL / min.
UV: 220 nm, 254 nm
Column temperature: 50 ° C
測定条件Ｂ
検出機器：Shimadzu LCMS-2020
Ｃｏｌｕｍｎ：Phenomenex Kinetex  1.7μm C18 2.1 mm×50 mm
Ｓｏｌｖｅｎｔ：Ａ液：MeCN, Ｂ液 : 0.05% TFA/H2O
Ｇｒａｄｉｅｎｔ ｃｏｎｄｉｔｉｏｎ：
   0 min: Ａ／Ｂ＝ 10:90
   0-1.70 min: Ａ／Ｂ= 10:90-99:1 （linear gradient）
   1.71-1.90 min: Ａ／Ｂ＝99:1
   1.91-3.00 min: Ａ／Ｂ＝10:90
Ｆｌｏｗ Ｒａｔｅ：0.5 mL/min.
UＶ：220 nm
カラム温度：40℃ Measurement condition B
Detection equipment: Shimadzu LCMS-2020
Column: Phenomenex Kinetex 1.7μm C18 2.1 mm x 50 mm
Solvent: A solution: MeCN, B solution: 0.05% TFA / H 2 O
Gradient condition:
0 min: A / B = 10: 90
0-1.70 min: A / B = 10: 90-99: 1 (linear gradient)
1.71-1.90 min: A / B = 99: 1
1.91-3.00 min: A / B = 10: 90
Flow Rate: 0.5 mL / min.
UV: 220 nm
Column temperature: 40 ° C
測定条件Ｃ
検出機器：Shimadzu LC:20A, MS:2010
Ｃｏｌｕｍｎ：Xtimate  3μm C18 2.1 mm×30 mm
Ｓｏｌｖｅｎｔ：Ａ液：1.5mL/4L TFA/H2O, Ｂ液 : 0.75mL/4L TFA/MeCN
Ｇｒａｄｉｅｎｔ ｃｏｎｄｉｔｉｏｎ：
   0 min: Ａ／Ｂ＝ 90:10
   0-2.2 min: Ａ／Ｂ= 90:10-20:80 （linear gradient）
   2.21-2.5 min: Ａ／Ｂ＝20:80
Ｆｌｏｗ Ｒａｔｅ：0.8 mL/min.
UＶ：220 nm
カラム温度：50℃ Measurement condition C
Detection equipment: Shimadzu LC: 20A, MS: 2010
Column: Xtimate 3μm C18 2.1 mm x 30 mm
Solvent: Liquid A: 1.5mL / 4L TFA / H 2 O, Liquid B: 0.75mL / 4L TFA / MeCN
Gradient condition:
0 min: A / B = 90:10
0-2.2 min: A / B = 90: 10-20: 80 (linear gradient)
2.21-2.5 min: 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：Shimadzu LC:20A, MS:2010
Ｃｏｌｕｍｎ：Xtimate  3μm C18 2.1 mm×30 mm
Ｓｏｌｖｅｎｔ：Ａ液：1.5mL/4L TFA/H2O, Ｂ液 : 0.75mL/4L TFA/MeCN
Ｇｒａｄｉｅｎｔ ｃｏｎｄｉｔｉｏｎ：
   0 min: Ａ／Ｂ＝ 70:30
   0-2.2 min: Ａ／Ｂ= 70:30-10:90 （linear gradient）
   2.21-2.5 min: Ａ／Ｂ＝10:90
Ｆｌｏｗ Ｒａｔｅ：0.8 mL/min.
UＶ：220 nm
カラム温度：50℃ Measurement condition D
Detection equipment: Shimadzu LC: 20A, MS: 2010
Column: Xtimate 3μm C18 2.1 mm x 30 mm
Solvent: Liquid A: 1.5mL / 4L TFA / H 2 O, Liquid B: 0.75mL / 4L TFA / MeCN
Gradient condition:
0 min: A / B = 70:30
0-2.2 min: A / B = 70: 30-10: 90 (linear gradient)
2.21-2.5 min: A / B = 10: 90
Flow Rate: 0.8 mL / min.
UV: 220 nm
Column temperature: 50 ° C
測定条件E
検出機器：Shimadzu LC:20A, MS:2010
Ｃｏｌｕｍｎ：Xtimate  3μm C18 2.1 mm×30 mm
Ｓｏｌｖｅｎｔ：Ａ液：1.5mL/4L TFA/H2O, Ｂ液 : 0.75mL/4L TFA/MeCN
Ｇｒａｄｉｅｎｔ ｃｏｎｄｉｔｉｏｎ：
   0 min: Ａ／Ｂ＝ 100:0
   0-2.2 min: Ａ／Ｂ= 100:0-40:60 （linear gradient）
   2.21-2.5 min: Ａ／Ｂ＝40:60
Ｆｌｏｗ Ｒａｔｅ：0.8 mL/min.
UＶ：220 nm
カラム温度：50℃ Measurement condition E
Detection equipment: Shimadzu LC: 20A, MS: 2010
Column: Xtimate 3μm C18 2.1 mm x 30 mm
Solvent: Liquid A: 1.5mL / 4L TFA / H 2 O, Liquid B: 0.75mL / 4L TFA / MeCN
Gradient condition:
0 min: A / B = 100: 0
0-2.2 min: A / B = 100: 0-40: 60 (linear gradient)
2.21-2.5 min: A / B = 40: 60
Flow Rate: 0.8 mL / min.
UV: 220 nm
Column temperature: 50 ° C
測定条件F
検出機器：Agilent LC:1200, MS:6110
Ｃｏｌｕｍｎ：Xbrige  RP-18.5μm 2.1 mm×50 mm
Ｓｏｌｖｅｎｔ：Ａ液：0.5mL/1L NH3・H2O/H2O, Ｂ液 : MeCN
Ｇｒａｄｉｅｎｔ ｃｏｎｄｉｔｉｏｎ：
   0 min: Ａ／Ｂ＝ 10:90
   0-2.0 min: Ａ／Ｂ= 10:90-20:80 （linear gradient）
   2.01-2.5 min: Ａ／Ｂ＝20:80
Ｆｌｏｗ Ｒａｔｅ：1.0 mL/min.
UＶ：220 nm
カラム温度：30℃ Measurement condition F
Detection equipment: Agilent LC: 1200, MS: 6110
Column: Xbrige RP-18.5μm 2.1 mm x 50 mm
Solvent: A solution: 0.5mL / 1L NH3 · H2O / H 2 O, B solution: MeCN
Gradient condition:
0 min: A / B = 10: 90
0-2.0 min: A / B = 10: 90-20: 80 (linear gradient)
2.01-2.5 min: A / B = 20: 80
Flow Rate: 1.0 mL / min.
UV: 220 nm
Column temperature: 30 ° C
測定条件G
検出機器：Agilent LC:1200, MS:6110
Ｃｏｌｕｍｎ：Durashell  3.0μm C18 2.1 mm×30 mm
Ｓｏｌｖｅｎｔ：Ａ液：1.5mL/4L TFA/H2O, Ｂ液 : 0.75mL/4L TFA/MeCN
Ｇｒａｄｉｅｎｔ ｃｏｎｄｉｔｉｏｎ：
   0 min: Ａ／Ｂ＝ 10:90
   0-2.2 min: Ａ／Ｂ= 10:90-20:80 （linear gradient）
   2.21-2.5 min: Ａ／Ｂ＝20:80
Ｆｌｏｗ Ｒａｔｅ：0.8 mL/min.
UＶ：220 nm
カラム温度：50℃ Measurement condition G
Detection equipment: Agilent LC: 1200, MS: 6110
Column: Durashell 3.0μm C18 2.1 mm x 30 mm
Solvent: Liquid A: 1.5mL / 4L TFA / H 2 O, Liquid B: 0.75mL / 4L TFA / MeCN
Gradient condition:
0 min: A / B = 10: 90
0-2.2 min: A / B = 10: 90-20: 80 (linear gradient)
2.21-2.5 min: A / B = 20: 80
Flow Rate: 0.8 mL / min.
UV: 220 nm
Column temperature: 50 ° C
測定条件H
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-5, 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 H
Detection equipment: Agilent 1100 series for API series (Applied Biosystems)
HPLC: API 150EX LC / MS system (Applied Biosystems)
Column: YMC CombiScreen Hydrosphere C18 (S-5, 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: 25-1: 99 (linear gradient)
Flow rate: 3.5 mL / min UV: 254 nm
参考例１
４－[５－クロロ－１－（３－フルオロフェニル）－１Ｈ－イミダゾール－４－イル]ピペリジン・２塩酸塩
Figure JPOXMLDOC01-appb-C000017
 ａ）４－ブロモ－１－（３－フルオロフェニル）－１Ｈ－イミダゾール（化合物Ｑ１）の製造
　４－ブロモイミダゾール (５０ｇ)の塩化メチレン溶液（１５００ｍＬ）に、室温にて３－フルオロフェニルボロン酸（９４．０ｇ）、酢酸銅(II)(９１．０ｇ）及びピリジン（５０ｍＬ）を加えた後に、３０℃にて４８時間撹拌した。反応溶液をセライト濾過した後に、得られたろ液の溶媒を減圧留去した。シリカゲルカラムクロマトグラフィーにて精製することで、化合物Ｑ１（３５ｇ）を得た。
1H-NMR (400 MHz, CDCl3)： δ7.75 (s, 1H), 7.50-7.47 (m, 1H), 7.29 (s, 1H), 7.21-7.11 (m, 3H). Reference example 1
4- [5-Chloro-1- (3-fluorophenyl) -1H-imidazol-4-yl] piperidine dihydrochloride
Figure JPOXMLDOC01-appb-C000017
 a) Preparation of 4-bromo-1- (3-fluorophenyl) -1H-imidazole (compound Q1) 4-Fluoroimidazole (50 g) in methylene chloride solution (1500 mL) at room temperature with 3-fluorophenylboronic acid ( 94.0 g), copper (II) acetate (91.0 g) and pyridine (50 mL) were added, and the mixture was stirred at 30 ° C. for 48 hours. The reaction solution was filtered through Celite, and then the solvent of the obtained filtrate was distilled off under reduced pressure. Purification by silica gel column chromatography gave Compound Q1 (35 g).
1 H-NMR (400 MHz, CDCl3): δ 7.75 (s, 1H), 7.50-7.47 (m, 1H), 7.29 (s, 1H), 7.21-7.11 (m, 3H).
ｂ）ｔｅｒｔ-ブチル　４－[１－（３－フルオロフェニル）－１Ｈ－イミダゾール－４－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Ｑ２）の製造
　化合物Ｑ１（５０ｇ）のＤＭＦ（３５０ｍＬ）及び水（３５ｍＬ）の混合溶液に、室温にてｔｅｒｔ-ブチル　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）－３，６－ジヒドロピリジン－１（２Ｈ）－カルボキシレート（５７．０ｇ）、[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（５．６ｇ）及び炭酸カリウム（６４．０ｇ）を加えた後に、窒素雰囲気下、１００℃にて２４時間撹拌した。反応溶液をセライト濾過した。得られたろ液を酢酸エチルで抽出、硫酸ナトリウムで乾燥後、溶媒を減圧留去した。シリカゲルカラムクロマトグラフィーで精製することにより、化合物Ｑ２（３２ｇ）を取得した。
1H-NMR (400 MHz, DMSO-d6)： δ8.31 (s, 1H), 7.82 (s, 1H), 7.66-7.62 (m, 1H), 7.54-7.52 (m, 2H), 7.18-7.16 (m, 1H), 6.32 (brs, 1H), 3.98 (brs, 2H), 3.52-3.49 (m, 2H), 2.39 (brs, 2H), 1.05 (s, 9H). b) Preparation of tert-butyl 4- [1- (3-fluorophenyl) -1H-imidazol-4-yl] -3,6-dihydropyridine-1 (2H) -carboxylate (compound Q2) Compound Q1 (50 g) Tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3, was added to a mixed solution of DMF (350 mL) and water (35 mL) at room temperature. After adding 6-dihydropyridine-1 (2H) -carboxylate (57.0 g), [1,1′-bis (diphenylphosphino) ferrocene] palladium dichloride (5.6 g) and potassium carbonate (64.0 g). The mixture was stirred at 100 ° C. for 24 hours under a nitrogen atmosphere. The reaction solution was filtered through celite. The obtained filtrate was extracted with ethyl acetate and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. Compound Q2 (32 g) was obtained by purification by silica gel column chromatography.
1 H-NMR (400 MHz, DMSO-d6): δ8.31 (s, 1H), 7.82 (s, 1H), 7.66-7.62 (m, 1H), 7.54-7.52 (m, 2H), 7.18-7.16 (m, 1H), 6.32 (brs, 1H), 3.98 (brs, 2H), 3.52-3.49 (m, 2H), 2.39 (brs, 2H), 1.05 (s, 9H).
ｃ）ｔｅｒｔ-ブチル　４－[１－（３－フルオロフェニル）－１Ｈ－イミダゾール－４－イル]ピペリジン－１－カルボキシレート（化合物Ｑ３）の製造
　化合物Ｑ２（３２．０ｇ）のメタノール溶液（２００ｍＬ）に、室温にて含水の１０% パラジウムカーボン（５．０ｇ）を加えた後に、２気圧の水素雰囲気下、３０℃で２４時間撹拌した。反応液をセライト濾過した。得られたろ液の溶媒を減圧留去することで、化合物Ｑ３（３３ｇ）を粗生成物として取得した。
1H-NMR (400 MHz, CDCl3)： δ7.80 (s, 1H), 7.64-7.44 (m, 1H), 7.20-7.18 (m, 1H), 7.13-7.10 (m, 2H), 6.99 (s, 1H), 4.20 (brs, 2H), 2.91-2.78 (m, 3H), 2.07-2.03 (m, 2H), 1.63-1.55 (m, 2H), 1.49 (s, 9H). c) Preparation of tert-butyl 4- [1- (3-fluorophenyl) -1H-imidazol-4-yl] piperidine-1-carboxylate (Compound Q3) Compound Q2 (32.0 g) in methanol (200 mL) After adding 10% palladium carbon (5.0 g) containing water at room temperature, the mixture was stirred at 30 ° C. for 24 hours under a hydrogen atmosphere of 2 atm. The reaction solution was filtered through celite. The solvent of the obtained filtrate was distilled off under reduced pressure to obtain Compound Q3 (33 g) as a crude product.
1 H-NMR (400 MHz, CDCl3): δ7.80 (s, 1H), 7.64-7.44 (m, 1H), 7.20-7.18 (m, 1H), 7.13-7.10 (m, 2H), 6.99 (s , 1H), 4.20 (brs, 2H), 2.91-2.78 (m, 3H), 2.07-2.03 (m, 2H), 1.63-1.55 (m, 2H), 1.49 (s, 9H).
ｄ）ｔｅｒｔ-ブチル　４－[５－クロロ－１－（３－フルオロフェニル）－１Ｈ－イミダゾール－４－イル]ピペリジン－１－カルボキシレート（化合物Ｑ４）の製造
　化合物Ｑ３（５．１ｇ）のアセトニトリル溶液（１０ｍＬ）に、室温にてＮ－クロロスクシンイミド（２．２ｇ）及びトリフルオロ酢酸（０．０５ｍＬ）を加えた後に、３０℃にて４８時間撹拌した。反応液に水を加えた後に、酢酸エチルで抽出、水と飽和食塩水で洗浄した。得られた有機層を硫酸ナトリウムで乾燥後、溶媒を減圧留去した。シリカゲルカラムクロマトグラフィーで精製することにより、化合物Ｑ４（４．０ｇ）を取得した。
1H-NMR (400 MHz, CDCl3)： δ7.60 (s, 1H), 7.51-7.47 (m, 1H), 7.20-7.13 (m, 3H), 4.25 (brs, 2H), 2.88-2.81 (m, 3H), 1.89-1.83 (m, 4H), 1.49 (s, 9H). d) Preparation of tert-butyl 4- [5-chloro-1- (3-fluorophenyl) -1H-imidazol-4-yl] piperidine-1-carboxylate (Compound Q4) Acetonitrile of Compound Q3 (5.1 g) N-chlorosuccinimide (2.2 g) and trifluoroacetic acid (0.05 mL) were added to the solution (10 mL) at room temperature, and the mixture was stirred at 30 ° C. for 48 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate and washed with water and saturated brine. The obtained organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Compound Q4 (4.0 g) was obtained by purification by silica gel column chromatography.
1 H-NMR (400 MHz, CDCl3): δ7.60 (s, 1H), 7.51-7.47 (m, 1H), 7.20-7.13 (m, 3H), 4.25 (brs, 2H), 2.88-2.81 (m , 3H), 1.89-1.83 (m, 4H), 1.49 (s, 9H).
ｅ）４－[５－クロロ－１－（３－フルオロフェニル）－１Ｈ－イミダゾール－４－イル]ピペリジン・２塩酸塩（参考例１）の製造
　化合物Ｑ４(３．０ｇ)のジオキサン溶液（５ｍＬ）に、室温にて４規定の塩化水素/ジオキサン溶液（１０ｍＬ）を加えた後に、室温にて３時間撹拌した。反応溶媒を減圧留去して、参考例１の化合物（４．６ｇ）を取得した。 e) Preparation of 4- [5-chloro-1- (3-fluorophenyl) -1H-imidazol-4-yl] piperidine dihydrochloride (Reference Example 1) Compound Q4 (3.0 g) in dioxane (5 mL) ), 4N hydrogen chloride / dioxane solution (10 mL) was added at room temperature, and the mixture was stirred at room temperature for 3 hours. The reaction solvent was distilled off under reduced pressure to obtain the compound of Reference Example 1 (4.6 g).
参考例２
４－[５－シアノ－１－（３－フルオロフェニル）－１Ｈ－イミダゾール－４－イル]ピペリジン・２塩酸塩
Figure JPOXMLDOC01-appb-C000018
 ａ）ｔｅｒｔ-ブチル　４－[１－（３－フルオロフェニル）－５－ヨード－１Ｈ－イミダゾール－４－イル]ピペリジン－１－カルボキシレート（化合物Ｑ５）の製造
　化合物Ｑ３（５．０ｇ） のアセトニトリル溶液（３０ｍＬ）に、室温にてＮ－ヨードスクシンイミド（３．６ｇ）及びトリフルオロ酢酸（０．０５mL）を加えた後に、室温で遮光下７２時間攪拌した。反応液にチオ硫酸ナトリウム水溶液を加えた後に、酢酸エチルで抽出、飽和食塩水で洗浄した。得られた有機層を硫酸ナトリウムで乾燥後、溶媒を減圧留去した。シリカゲルカラムクロマトグラフィーで精製することにより、化合物Ｑ５（４．３ｇ）を取得した。
1H-NMR (400 MHz, CDCl3)： δ7.78 (s, 1H), 7.49-7.48 (m, 1H), 7.21-7.08 (m, 3H), 4.24 (brs, 2H), 2.84-2.75 (m, 3H), 1.88-1.75 (m, 4H), 1.48 (s, 9H). Reference example 2
4- [5-Cyano-1- (3-fluorophenyl) -1H-imidazol-4-yl] piperidine dihydrochloride
Figure JPOXMLDOC01-appb-C000018
 a) Preparation of tert-butyl 4- [1- (3-fluorophenyl) -5-iodo-1H-imidazol-4-yl] piperidine-1-carboxylate (Compound Q5) Compound Q3 (5.0 g) in acetonitrile N-iodosuccinimide (3.6 g) and trifluoroacetic acid (0.05 mL) were added to the solution (30 mL) at room temperature, and the mixture was stirred at room temperature for 72 hours under light shielding. A sodium thiosulfate aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate and washing with saturated brine. The obtained organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Compound Q5 (4.3 g) was obtained by purification by silica gel column chromatography.
1 H-NMR (400 MHz, CDCl3): δ7.78 (s, 1H), 7.49-7.48 (m, 1H), 7.21-7.08 (m, 3H), 4.24 (brs, 2H), 2.84-2.75 (m , 3H), 1.88-1.75 (m, 4H), 1.48 (s, 9H).
ｂ）ｔｅｒｔ-ブチル　４－[５－シアノ－１－（３－フルオロフェニル）－１Ｈ－イミダゾール－４－イル]ピペリジン－１－カルボキシレート（化合物Ｑ６）の製造
　化合物Ｑ５（４．３ｇ）のジメチルホルムアミド（３０ｍＬ）溶液に、室温にてシアン化銅（２．６ｇ）を加えて、１２０℃で１８時間加熱攪拌した。反応液をセライト濾過した後に、得られたろ液の溶媒を減圧留去した。シリカゲルカラムクロマトグラフィーで精製することにより、化合物Ｑ６（１．２ｇ）を取得した。
1H-NMR (400 MHz, CDCl3)： δ7.79 (s, 1H), 7.57-7.55 (m, 1H), 7.30-7.21 (m, 3H), 4.27 (brs, 2H), 3.08-3.04 (m, 1H), 2.87 (brs, 2H), 1.97-1.86 (m, 4H), 1.48 (s, 9H). b) Preparation of tert-butyl 4- [5-cyano-1- (3-fluorophenyl) -1H-imidazol-4-yl] piperidine-1-carboxylate (Compound Q6) Dimethyl of Compound Q5 (4.3 g) Copper cyanide (2.6 g) was added to a formamide (30 mL) solution at room temperature, and the mixture was heated with stirring at 120 ° C. for 18 hours. After the reaction solution was filtered through Celite, the solvent of the obtained filtrate was distilled off under reduced pressure. Compound Q6 (1.2 g) was obtained by purification by silica gel column chromatography.
1 H-NMR (400 MHz, CDCl3): δ 7.79 (s, 1H), 7.57-7.55 (m, 1H), 7.30-7.21 (m, 3H), 4.27 (brs, 2H), 3.08-3.04 (m , 1H), 2.87 (brs, 2H), 1.97-1.86 (m, 4H), 1.48 (s, 9H).
ｃ）４－[５－シアノ－１－（３－フルオロフェニル）－１Ｈ－イミダゾール－４－イル]ピペリジン・２塩酸塩（参考例２）の製造
　化合物Ｑ６（１．２ｇ）を用いて、参考例１の工程ｅ）に準ずる方法により参考例２の化合物（１．１ｇ）を取得した。 c) Preparation of 4- [5-cyano-1- (3-fluorophenyl) -1H-imidazol-4-yl] piperidine dihydrochloride (Reference Example 2) Compound Q6 (1.2 g) was used as a reference. The compound of Reference Example 2 (1.1 g) was obtained by the method according to Step e) of Example 1.
参考例３
４－｛３－[５－（トリフルオロメチル）ピリジン－２－イル]－１，２－オキサゾール－５－イル｝ピペリジン・２塩酸塩
Figure JPOXMLDOC01-appb-C000019
 ａ）ｔｅｒｔ-ブチル　４－エチイルピペリジン－１－カルボキシレート（化合物Ｑ７）の製造
　ｔｅｒｔ-ブチル　４－ホルミルピペリジン－１－カルボキシレート（７．８ｇ）のメタノール溶液（５０ｍＬ）に、０℃にて炭酸カリウム（１１ｇ）及びジメチル（アセチルジアゾメチル）ホスホネート（８．６ｇ）を加えて、０℃で２時間攪拌した。反応液に飽和塩化アンモニウム水溶液（５０ｍＬ）を加えた後に、溶媒を減圧留去し、酢酸エチルで抽出した。得られた有機層を硫酸ナトリウムで乾燥、溶媒を減圧留去した後に、シリカゲルカラムクロマトグラフィーで精製することにより、化合物Ｑ７（３．７ｇ）を取得した。
1H-NMR (400 MHz, CDCl3)： δ3.71-3.68 (m, 2H), 3.21-3.15 (m, 2H), 2.63-2.53 (m, 1H), 2.10-2.11 (m, 1H), 1.80-1.75 (m, 2H), 1.60-1.55 (m, 2H). Reference example 3
4- {3- [5- (trifluoromethyl) pyridin-2-yl] -1,2-oxazol-5-yl} piperidine dihydrochloride
Figure JPOXMLDOC01-appb-C000019
 a) Preparation of tert-butyl 4-ethiylpiperidine-1-carboxylate (Compound Q7) To a methanol solution (50 mL) of tert-butyl 4-formylpiperidine-1-carboxylate (7.8 g) at 0 ° C. Potassium carbonate (11 g) and dimethyl (acetyldiazomethyl) phosphonate (8.6 g) were added and stirred at 0 ° C. for 2 hours. Saturated aqueous ammonium chloride solution (50 mL) was added to the reaction mixture, and the solvent was evaporated under reduced pressure and extracted with ethyl acetate. The obtained organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound Q7 (3.7 g).
1 H-NMR (400 MHz, CDCl3): δ3.71-3.68 (m, 2H), 3.21-3.15 (m, 2H), 2.63-2.53 (m, 1H), 2.10-2.11 (m, 1H), 1.80 -1.75 (m, 2H), 1.60-1.55 (m, 2H).
ｂ）Ｎ－ヒドロキシ－１－[５－（トリフルオロメチル）ピリジン－２－イル]メタンイミン（化合物Ｑ８）の製造
　５－（トリフルオロメチル）ピリジン－２－カルバアルデヒド（２．０ｇ）のメタノール溶液（６０ｍＬ）に、０℃にてトリエチルアミン（１０ｍＬ）及びヒドロキシルアミンの塩酸塩（３．０ｇ）を加えた後に、室温まで昇温して１６時間攪拌した。反応液を減圧留去した後に、酢酸エチル（２０ｍＬ）で抽出、飽和炭酸水素ナトリウム水溶液（３０ｍＬ）で洗浄した。得られた有機層を硫酸ナトリウムで乾燥後、溶媒を減圧留去した。シリカゲルクロマトグラフィー (石油エーテル/酢酸エチル = ９０／１０)で精製することにより、化合物Ｑ８（０．９ｇ）を取得した。
1H-NMR (400 MHz, DMSO-d6)： δ12.10 (s, 1H), 8.97 (s, 1H), 8.22 (d, J=8.4Hz, 1H), 8.17 (s, 1H), 7.98 (d, J=8.4Hz, 1H). b) Preparation of N-hydroxy-1- [5- (trifluoromethyl) pyridin-2-yl] methanimine (Compound Q8) 5- (Trifluoromethyl) pyridine-2-carbaldehyde (2.0 g) in methanol (60 mL), triethylamine (10 mL) and hydroxylamine hydrochloride (3.0 g) were added at 0 ° C., and then the mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was evaporated under reduced pressure, extracted with ethyl acetate (20 mL), and washed with saturated aqueous sodium hydrogen carbonate solution (30 mL). The obtained organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Purification by silica gel chromatography (petroleum ether / ethyl acetate = 90/10) gave Compound Q8 (0.9 g).
1 H-NMR (400 MHz, DMSO-d6): δ12.10 (s, 1H), 8.97 (s, 1H), 8.22 (d, J = 8.4Hz, 1H), 8.17 (s, 1H), 7.98 ( d, J = 8.4Hz, 1H).
ｃ）Ｎ－ヒドロキシ－５－（トリフルオロメチル）ピリジン－２－カルボキシイミドイル　クロライド（化合物Ｑ９）の製造
　化合物Ｑ８（０．９ｇ）のＤＭＦ溶液（７ｍＬ）に、０℃にてＮ－クロロスクシンイミド（７７０ｍｇ）を加えた後に、室温まで昇温して１６時間撹拌した。反応液に水（２５ｍＬ）を加えた後に、酢酸エチル（１５ｍＬ）で抽出、水（５０ｍＬ）で洗浄した。得られた有機層を硫酸ナトリウムで乾燥後、溶媒を減圧留去することにより、化合物Ｑ９（９３０ｍｇ）を取得した。
1H-NMR (400 MHz, DMSO-d6)： δ13.07 (s, 1H), 9.08 (s, 1H), 8.31-8.29 (m, 1H), 8.10-8.08 (m, 1H). c) Preparation of N-hydroxy-5- (trifluoromethyl) pyridine-2-carboximidoyl chloride (Compound Q9) N-chlorosuccinimide at 0 ° C. in DMF solution (7 mL) of Compound Q8 (0.9 g) (770 mg) was added, and the mixture was warmed to room temperature and stirred for 16 hours. Water (25 mL) was added to the reaction solution, followed by extraction with ethyl acetate (15 mL) and washing with water (50 mL). The obtained organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to obtain Compound Q9 (930 mg).
1 H-NMR (400 MHz, DMSO-d6): δ13.07 (s, 1H), 9.08 (s, 1H), 8.31-8.29 (m, 1H), 8.10-8.08 (m, 1H).
ｄ）ｔｅｒｔ-ブチル　４－｛３－[５－（トリフルオロメチル）ピリジン－２－イル]－１，２－オキサゾール－５－イル｝ピペリジン－１－カルボキシレート（化合物Ｑ１０）の製造
　化合物Ｑ９（９３０ｍｇ）及び化合物Ｑ７（６９０ｍｇ）のテトラヒドロフラン溶液（１０ｍＬ）に、室温にてトリエチルアミン（１．７ｍＬ）のテトラヒドロフラン溶液（５ｍＬ）を加えた後に、６０℃まで昇温して２時間撹拌した。反応液を減圧留去した後に、飽和炭酸水素ナトリウム水溶液（１０ｍＬ）を加えて、酢酸エチル（５ｍＬ）で抽出した。得られた有機層を硫酸ナトリウムで乾燥後、溶媒を減圧留去した。シリカゲルクロマトグラフィー (石油エーテル/酢酸エチル = ９０／１０)で精製することにより、化合物Ｑ１０（５００ｍｇ）を取得した。
1H-NMR (400 MHz, CDCl3)： δ8.93 (s, 1H), 8.23-8.20 (m, 1H), 8.05-8.03 (m, 1H), 6.70 (s, 1H), 4.18 (brs, 2H), 3.05-2.90 (m, 3H), 2.11-2.08 (m, 2H), 1.74-1.70 (m, 2H), 1.48 (s, 9H). d) Preparation of tert-butyl 4- {3- [5- (trifluoromethyl) pyridin-2-yl] -1,2-oxazol-5-yl} piperidine-1-carboxylate (Compound Q10) Compound Q9 ( To a tetrahydrofuran solution (10 mL) of 930 mg) and compound Q7 (690 mg) was added a tetrahydrofuran solution (5 mL) of triethylamine (1.7 mL) at room temperature, and then the mixture was heated to 60 ° C. and stirred for 2 hours. The reaction mixture was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (10 mL) was added, and the mixture was extracted with ethyl acetate (5 mL). The obtained organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Purification by silica gel chromatography (petroleum ether / ethyl acetate = 90/10) gave Compound Q10 (500 mg).
1 H-NMR (400 MHz, CDCl3): δ8.93 (s, 1H), 8.23-8.20 (m, 1H), 8.05-8.03 (m, 1H), 6.70 (s, 1H), 4.18 (brs, 2H ), 3.05-2.90 (m, 3H), 2.11-2.08 (m, 2H), 1.74-1.70 (m, 2H), 1.48 (s, 9H).
ｅ）４－｛３－[５－（トリフルオロメチル）ピリジン－２－イル]－１，２－オキサゾール－５－イル｝ピペリジン・２塩酸塩（参考例３）の製造
　化合物Ｑ１０（５００ｍｇ）を用いて、参考例１の工程ｅ）に準ずる方法により参考例３の化合物（３６０ｍｇ）を取得した。 e) Preparation of 4- {3- [5- (trifluoromethyl) pyridin-2-yl] -1,2-oxazol-5-yl} piperidine dihydrochloride (Reference Example 3) Compound Q10 (500 mg) And the compound of Reference Example 3 (360 mg) was obtained by the method according to Step e) of Reference Example 1.
参考例４
４－｛５－[５－（トリフルオロメチル）ピリジン－２－イル]－１，２－オキサゾール－３－イル｝ピペリジン・２塩酸塩
Figure JPOXMLDOC01-appb-C000020
 ａ）ｔｅｒｔ-ブチル　４－[（ヒドロキシイミノ）メチル]ピペリジン－１－カルボキシレート（化合物Ｑ１１）の製造
　ｔｅｒｔ-ブチル　４－ホルミルピペリジン－１－カルボキシレート（１１ｇ） のメタノール／水溶液（８０ｍＬ／８０ｍＬ）に、室温にて炭酸ナトリウム（２．７ｇ）及びとヒドロキシルアミンの塩酸塩（４．３ｇ）を加えて、室温で１６時間撹拌した。反応液を減圧留去した後に、塩化メチレン（５０ｍL)で抽出した。得られた有機層を硫酸ナトリウムで乾燥後、溶媒を減圧留去することにより、化合物Ｑ１１（８．５ｇ)を取得した。
1H-NMR (400 MHz, CDCl3)： δ7.40 (brs, 1H), 7.34 (d, J=5.6Hz, 1H), 4.08 (brs, 2H), 2.82-2.77 (m, 2H), 2.41-2.34 (m, 1H), 1.77-1.75 (m, 2H), 1.49-1.42 (m, 11H). Reference example 4
4- {5- [5- (trifluoromethyl) pyridin-2-yl] -1,2-oxazol-3-yl} piperidine dihydrochloride
Figure JPOXMLDOC01-appb-C000020
 a) Preparation of tert-butyl 4-[(hydroxyimino) methyl] piperidine-1-carboxylate (Compound Q11) Methanol / water solution of tert-butyl 4-formylpiperidine-1-carboxylate (11 g) (80 mL / 80 mL) To the mixture, sodium carbonate (2.7 g) and hydroxylamine hydrochloride (4.3 g) were added at room temperature, and the mixture was stirred at room temperature for 16 hours. The reaction solution was distilled off under reduced pressure and then extracted with methylene chloride (50 mL). The obtained organic layer was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain Compound Q11 (8.5 g).
1 H-NMR (400 MHz, CDCl3): δ7.40 (brs, 1H), 7.34 (d, J = 5.6Hz, 1H), 4.08 (brs, 2H), 2.82-2.77 (m, 2H), 2.41- 2.34 (m, 1H), 1.77-1.75 (m, 2H), 1.49-1.42 (m, 11H).
ｂ）ｔｅｒｔ-ブチル　４－[クロロ（ヒドロキシイミノ）メチル]ピペリジン－１－カルボキシレート（化合物Ｑ１２）の製造
　化合物Ｑ１１（８．５ｇ）のＤＭＦ溶液（７ｍＬ）に、０℃にてＮ－クロロスクシンイミド（６．０ｇ）を加えた後に、室温まで昇温して４時間撹拌した。反応液に水（５０ｍＬ）を加えて後に、析出した固体をろ取することで、化合物Ｑ１２（２．９ｇ）を取得した。
1H-NMR (400 MHz, CDCl3)： δ8.87 (s, 1H), 4.14 (brs, 2H), 2.82-2.78 (m, 2H), 2.61-2.55 (m, 1H), 1.94-1.91 (m, 2H), 1.66-1.62 (m, 2H), 1.46 (s, 9H). b) Preparation of tert-butyl 4- [chloro (hydroxyimino) methyl] piperidine-1-carboxylate (compound Q12) N-chlorosuccinimide in a DMF solution (7 mL) of compound Q11 (8.5 g) at 0 ° C (6.0 g) was added, and the mixture was warmed to room temperature and stirred for 4 hours. After adding water (50 mL) to the reaction solution, the precipitated solid was collected by filtration to obtain Compound Q12 (2.9 g).
1 H-NMR (400 MHz, CDCl3): δ8.87 (s, 1H), 4.14 (brs, 2H), 2.82-2.78 (m, 2H), 2.61-2.55 (m, 1H), 1.94-1.91 (m , 2H), 1.66-1.62 (m, 2H), 1.46 (s, 9H).
ｃ）ｔｅｒｔ-ブチル　４－｛５－[５－（トリフルオロメチル）ピリジン－２－イル]－１，２－オキサゾール－３－イル｝ピペリジン－１－カルボキシレート（化合物Ｑ１３）の製造
　５－（トリフルオロメチル）ピリジン－２－カルバルデヒド（１．０ ｇ）のメタノール溶液（１０ｍＬ）に、０℃にてジメチル（アセチルジアゾメチル）ホスホネート（１．１ｇ）及び炭酸カリウム（１．６ｇ）を加えた後に、室温まで昇温して窒素雰囲気下で１６時間撹拌した。反応液にテトラヒドロフラン（４０ｍＬ）を加えた後に、室温にて化合物Ｑ１２（２．９ｇ）及びトリエチルアミン（５．６ｇ）のテトラヒドロフラン溶液（２０ｍＬ）を加えた。反応液を６０℃に昇温して２時間撹拌した後に、溶媒を減圧留去した。残渣に酢酸エチル（２０ｍＬ）及び飽和炭酸水素ナトリウム水溶液（３０ｍＬ）を加えて抽出した。得られた有機層を硫酸ナトリウムで乾燥後、溶媒を減圧留去。シリカゲルクロマトグラフィー (石油エーテル/酢酸エチル = ９０／１０)で精製することにより、化合物Ｑ１３（２７０ｍｇ）を取得した。
1H-NMR (400 MHz, CDCl3)： δ8.92 (s, 1H), 8.08-8.00 (m, 2H), 6.91 (s, 1H), 4.20 (brs, 2H), 3.04-2.89 (m, 3H), 2.02-1.99 (m, 2H), 1.77-1.67 (m, 2H), 1.48 (s, 9H). c) Preparation of tert-butyl 4- {5- [5- (trifluoromethyl) pyridin-2-yl] -1,2-oxazol-3-yl} piperidine-1-carboxylate (Compound Q13) 5- ( Dimethyl (acetyldiazomethyl) phosphonate (1.1 g) and potassium carbonate (1.6 g) were added to a methanol solution (10 mL) of trifluoromethyl) pyridine-2-carbaldehyde (1.0 g) at 0 ° C. Then, the temperature was raised to room temperature and stirred for 16 hours under a nitrogen atmosphere. Tetrahydrofuran (40 mL) was added to the reaction solution, and then a tetrahydrofuran solution (20 mL) of compound Q12 (2.9 g) and triethylamine (5.6 g) was added at room temperature. The reaction solution was heated to 60 ° C. and stirred for 2 hours, and then the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate (20 mL) and saturated aqueous sodium hydrogen carbonate (30 mL). The obtained organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 90/10) to obtain Compound Q13 (270 mg).
1 H-NMR (400 MHz, CDCl3): δ8.92 (s, 1H), 8.08-8.00 (m, 2H), 6.91 (s, 1H), 4.20 (brs, 2H), 3.04-2.89 (m, 3H ), 2.02-1.99 (m, 2H), 1.77-1.67 (m, 2H), 1.48 (s, 9H).
ｄ）４－｛５－[５－（トリフルオロメチル）ピリジン－２－イル]－１，２－オキサゾール－３－イル｝ピペリジン・２塩酸塩（参考例４）の製造
　化合物Ｑ１３（２７０ｍｇ）を用いて、参考例１の工程ｅ）に準ずる方法により参考例４の化合物（２１０ｍｇ）を取得した。 d) Preparation of 4- {5- [5- (trifluoromethyl) pyridin-2-yl] -1,2-oxazol-3-yl} piperidine dihydrochloride (Reference Example 4) Compound Q13 (270 mg) And the compound of Reference Example 4 (210 mg) was obtained by the method according to Step e) of Reference Example 1.
参考例５
４－[２－（４－フルオロフェニル）－１，３－オキサゾール－５－イル]ピペリジン・塩酸塩
Figure JPOXMLDOC01-appb-C000021
 ａ）ｔｅｒｔ-ブチル　４－（１－ヒドロキシ－２－ニトロエチル）ピペリジン－１－カルボキシレート（化合物Ｑ１４）の製造
　ｔｅｒｔ-ブチル　４－ホルミルピペリジン－１－カルボキシレート（５．０ｇ）のテトラヒドロフラン／ｔｅｒｔ-ブタノール溶液（４０ｍＬ／４０ｍＬ）に、室温にてｔｅｒｔ-ブトキシカリウム（２．６３ｇ）及びニトロメタン（２．５１ｍＬ）を加えた後に、室温で２時間撹拌した。反応液に室温にて酢酸（１．６ｍＬ）加えた後に、酢酸エチル（２００ｍＬ）を加えて抽出、飽和食塩水で洗浄をおこなった。得られた有機層を硫酸ナトリウムで乾燥後、溶媒を減圧留去することで、化合物Ｑ１４（６．８ｇ）を取得した。
1H-NMR (400 MHz, CDCl3)： δ4.47-4.40 (m, 1H), 4.18-4.12 (m, 3H), 2.70-2.63 (m, 2H), 2.07-2.04 (m, 1H), 1.61-1.57 (m, 2H), 1.44 (s, 9H), 1.30-1.25 (m, 4H). Reference Example 5
4- [2- (4-Fluorophenyl) -1,3-oxazol-5-yl] piperidine hydrochloride
Figure JPOXMLDOC01-appb-C000021
 a) Preparation of tert-butyl 4- (1-hydroxy-2-nitroethyl) piperidine-1-carboxylate (compound Q14) tert-butyl 4-formylpiperidine-1-carboxylate (5.0 g) in tetrahydrofuran / tert- To a butanol solution (40 mL / 40 mL) were added tert-butoxypotassium (2.63 g) and nitromethane (2.51 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. Acetic acid (1.6 mL) was added to the reaction solution at room temperature, followed by extraction with ethyl acetate (200 mL) and washing with saturated brine. The obtained organic layer was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain Compound Q14 (6.8 g).
1 H-NMR (400 MHz, CDCl3): δ4.47-4.40 (m, 1H), 4.18-4.12 (m, 3H), 2.70-2.63 (m, 2H), 2.07-2.04 (m, 1H), 1.61 -1.57 (m, 2H), 1.44 (s, 9H), 1.30-1.25 (m, 4H).
ｂ）ｔｅｒｔ-ブチル　４－（２－アミノ－１－ヒドロキシエチル）ピペリジン－１－カルボキシレート（化合物Ｑ１５）の製造
　化合物Ｑ１４（６．８ｇ）のメタノール溶液（６５ｍＬ）に、室温にて１０％パラジウムカーボン（０．６８ｇ）を加えた後に、水素雰囲気下で２時間撹拌した。反応液をセライト濾過した後に、ろ液の溶媒を減圧留去することで、化合物Ｑ１５（６．０ｇ）を取得した。
1H-NMR (400 MHz, CDCl3)： δ4.13 (brs, 2H), 3.36 (brs, 1H), 2.93 (brs, 5H), 2.65 (brs, 2H), 1.84-1.81 (m, 1H), 1.60-1.54 (m, 2H), 1.45 (s, 9H), 1.27-1.16 (m, 2H). b) Preparation of tert-butyl 4- (2-amino-1-hydroxyethyl) piperidine-1-carboxylate (Compound Q15) To a methanol solution (65 mL) of Compound Q14 (6.8 g) at room temperature with 10% palladium After adding carbon (0.68 g), the mixture was stirred for 2 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and then the solvent of the filtrate was distilled off under reduced pressure to obtain Compound Q15 (6.0 g).
1 H-NMR (400 MHz, CDCl3): δ4.13 (brs, 2H), 3.36 (brs, 1H), 2.93 (brs, 5H), 2.65 (brs, 2H), 1.84-1.81 (m, 1H), 1.60-1.54 (m, 2H), 1.45 (s, 9H), 1.27-1.16 (m, 2H).
ｃ）ｔｅｒｔ-ブチル　４－｛２－[（４－フルオロベンゾイル）アミノ]－１－ヒドロキシエチル｝ピペリジン－１－カルボキシレート（化合物Ｑ１６）の製造
　化合物Ｑ１５（６．０ｇ）のＤＭＦ溶液（５０ｍＬ）に、室温にて４－フルオロ安息香酸（２．５ｇ）、ＥＤＣＩ（４．４ｇ）、ＨＯＢｔ（３．１ｇ）及びトリエチルアミン（３．５ｇ）を加えた後に、室温にて１８時間撹拌した。反応液に酢酸エチル（３００ｍＬ）を加えた後に、１ｍｏｌ／Ｌの塩酸水溶液（２００ｍＬ）、水（２００ｍＬ）及び、１ｍｏｌ／Ｌの炭酸水素ナトリウム水溶液（２００ｍＬ）で洗浄した。得られた有機層を硫酸ナトリウムで乾燥後、溶媒を減圧留去した。シリカゲルカラムクロマトグラフィー（石油エーテル／酢酸エチル ＝ ２／１）で精製することにより、化合物Ｑ１６（３．８ｇ）を取得した。
1H-NMR (400 MHz, CDCl3)： δ7.81-7.78 (m, 2H), 7.13-7.09 (m, 2H), 6.67-6.66 (m, 1H), 4.14-4.09 (m, 1H), 3.73-3.68 (m, 1H), 3.57 (brs, 1H), 3.41-3.35 (m, 1H), 2.93 (brs, 2H), 2.67 (brs, 2H), 1.68-1.65 (m, 1H), 1.56-1.24 (m, 13H). c) Preparation of tert-butyl 4- {2-[(4-fluorobenzoyl) amino] -1-hydroxyethyl} piperidine-1-carboxylate (Compound Q16) Compound D15 (6.0 g) in DMF (50 mL) 4-fluorobenzoic acid (2.5 g), EDCI (4.4 g), HOBt (3.1 g) and triethylamine (3.5 g) were added thereto at room temperature, followed by stirring at room temperature for 18 hours. Ethyl acetate (300 mL) was added to the reaction solution, and then washed with a 1 mol / L hydrochloric acid aqueous solution (200 mL), water (200 mL), and a 1 mol / L sodium hydrogen carbonate aqueous solution (200 mL). The obtained organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 2/1) gave Compound Q16 (3.8 g).
1 H-NMR (400 MHz, CDCl3): δ7.81-7.78 (m, 2H), 7.13-7.09 (m, 2H), 6.67-6.66 (m, 1H), 4.14-4.09 (m, 1H), 3.73 -3.68 (m, 1H), 3.57 (brs, 1H), 3.41-3.35 (m, 1H), 2.93 (brs, 2H), 2.67 (brs, 2H), 1.68-1.65 (m, 1H), 1.56-1.24 (m, 13H).
ｄ）ｔｅｒｔ-ブチル　４－[Ｎ－（４－フルオロベンゾイル）グリシル]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（３．３ｇ）の塩化メチレン溶液（４０ｍＬ）に、氷冷下にてデスマーチン試薬（７．６ｇ）を加えた後に、室温まで昇温して４時間撹拌した。反応液に塩化メチレン（６０ｍＬ）を加えて抽出した後に、飽和炭酸水素ナトリウム水溶液（８０ｍＬ）及び水（１００ｍＬ）で洗浄をおこなった。得られた有機層を硫酸ナトリウムで乾燥後、溶媒を減圧留去した。シリカゲルカラムクロマトグラフィー(石油エーテル/酢酸エチル = ２／１)で精製することにより、化合物Ｑ１７（２．１ｇ）を取得した。
1H-NMR (400 MHz, CDCl3)： δ7.85-7.81 (m, 2H), 7.14-7.10 (m, 2H), 6.91 (brs, 1H), 4.40-4.39 (m, 2H), 4.14-4.09 (m, 2H), 2.84-2.78 (m, 2H), 2.62-2.61 (m, 1H), 1.89-1.86 (m, 2H), 1.65-1.60 (m, 2H), 1.46 (s, 9H). d) Preparation of tert-butyl 4- [N- (4-fluorobenzoyl) glycyl] piperidine-1-carboxylate (Compound Q17) To a solution of Compound Q16 (3.3 g) in methylene chloride (40 mL) under ice-cooling After adding Dess-Martin reagent (7.6 g), the mixture was warmed to room temperature and stirred for 4 hours. The reaction solution was extracted with methylene chloride (60 mL), and then washed with a saturated aqueous sodium hydrogen carbonate solution (80 mL) and water (100 mL). The obtained organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 2/1) gave Compound Q17 (2.1 g).
1 H-NMR (400 MHz, CDCl3): δ7.85-7.81 (m, 2H), 7.14-7.10 (m, 2H), 6.91 (brs, 1H), 4.40-4.39 (m, 2H), 4.14-4.09 (m, 2H), 2.84-2.78 (m, 2H), 2.62-2.61 (m, 1H), 1.89-1.86 (m, 2H), 1.65-1.60 (m, 2H), 1.46 (s, 9H).
ｅ）ｔｅｒｔ-ブチル　４－[２－（４－フルオロフェニル）－１，３－オキサゾール－５－イル]ピペリジン－１－カルボキシレート（化合物Ｑ１８）の製造
　化合物Ｑ１７（１．２ｇ）のテトラヒドロフラン溶液（１３ｍＬ）に、室温にてバージェス試薬（１．６ｇ）を加えた後に、７０℃まで昇温して１２時間撹拌した。反応液を室温まで冷却した後に、酢酸エチル（５０ｍＬ）を加えた。有機層を飽和炭酸水素ナトリウム水溶液（３０ｍＬ）及び水（４０ｍＬ）で洗浄した。得られた有機層を硫酸ナトリウムで乾燥後、溶媒を減圧留去した。シリカゲルカラムクロマトグラフィー(石油エーテル/酢酸エチル = ２／１)で精製することにより、化合物Ｑ１８（０．９ｇ）を取得した。
1H-NMR (400 MHz, CDCl3)： δ8.00-7.97 (m, 2H), 7.16-7.11 (m, 2H), 6.83 (s, 1H), 4.17 (brs, 2H), 2.93-2.88 (m, 3H), 2.05-2.01 (m, 2H), 1.68-1.64 (m, 2H), 1.48 (s, 9H). e) Preparation of tert-butyl 4- [2- (4-fluorophenyl) -1,3-oxazol-5-yl] piperidine-1-carboxylate (Compound Q18) Compound Q17 (1.2 g) in tetrahydrofuran solution ( 13 mL) was added Burgess reagent (1.6 g) at room temperature, and then the mixture was heated to 70 ° C. and stirred for 12 hours. After cooling the reaction solution to room temperature, ethyl acetate (50 mL) was added. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (30 mL) and water (40 mL). The obtained organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 2/1) gave Compound Q18 (0.9 g).
1 H-NMR (400 MHz, CDCl3): δ8.00-7.97 (m, 2H), 7.16-7.11 (m, 2H), 6.83 (s, 1H), 4.17 (brs, 2H), 2.93-2.88 (m , 3H), 2.05-2.01 (m, 2H), 1.68-1.64 (m, 2H), 1.48 (s, 9H).
ｆ）４－[２－（４－フルオロフェニル）－１，３－オキサゾール－５－イル]ピペリジン・塩酸塩（参考例５）の製造
　化合物Ｑ１８（５００ｍｇ）を用いて、参考例１の工程ｅ）に準ずる方法により参考例５の化合物（５８０ｍｇ）を取得した。 f) Preparation of 4- [2- (4-fluorophenyl) -1,3-oxazol-5-yl] piperidine hydrochloride (Reference Example 5) Step e of Reference Example 1 using Compound Q18 (500 mg) ) To obtain the compound of Reference Example 5 (580 mg).
参考例６
４－[５－（４－フルオロフェニル）－１，３－オキサゾール－２－イル]ピペリジン・塩酸塩
Figure JPOXMLDOC01-appb-C000022
 ａ）ｔｅｒｔ-ブチル　４－{[２－（４－フルオロフェニル）－２－オキソエチル]カルバモイル}ピペリジン－１－カルボキシレート（化合物Ｑ１９）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（８．０ｇ）及び２－アミノ－１－（４－フルオロフェニル）エタノン（７．０ｇ）のピリジン溶液（１６０ｍＬ）に、１０℃にてＥＤＣＩ（１３．３ｇ）を加えた後に、１０℃にて３時間撹拌した。反応液に水（１．５Ｌ）を加えて５分間撹拌した後に、析出した固体をろ取した。得られた固体を減圧乾燥することで、化合物Ｑ１９（１１ｇ）得た。
1H-NMR (400 MHz, CDCl3)： δ8.03-7.99 (m, 2H), 7.20-7.16 (m, 2H), 6.60 (brs, 1H), 4.73-4.72 (m, 2H), 4.16 (brs, 2H), 2.80-2.75 (m, 2H), 2.40-2.36 (m, 1H), 1.88-1.85 (m, 2H), 1.72-1.66 (m, 2H), 1.46 (s, 9H). Reference Example 6
4- [5- (4-Fluorophenyl) -1,3-oxazol-2-yl] piperidine hydrochloride
Figure JPOXMLDOC01-appb-C000022
 a) Preparation of tert-butyl 4-{[2- (4-fluorophenyl) -2-oxoethyl] carbamoyl} piperidine-1-carboxylate (Compound Q19) 1- (tert-Butoxycarbonyl) piperidine-4-carboxylic acid EDCI (13.3 g) was added at 10 ° C. to a pyridine solution (160 mL) of (8.0 g) and 2-amino-1- (4-fluorophenyl) ethanone (7.0 g). And stirred for 3 hours. Water (1.5 L) was added to the reaction solution and stirred for 5 minutes, and then the precipitated solid was collected by filtration. The obtained solid was dried under reduced pressure to obtain Compound Q19 (11 g).
1 H-NMR (400 MHz, CDCl3): δ8.03-7.99 (m, 2H), 7.20-7.16 (m, 2H), 6.60 (brs, 1H), 4.73-4.72 (m, 2H), 4.16 (brs) , 2H), 2.80-2.75 (m, 2H), 2.40-2.36 (m, 1H), 1.88-1.85 (m, 2H), 1.72-1.66 (m, 2H), 1.46 (s, 9H).
ｂ）ｔｅｒｔ-ブチル　４－[５－（４－フルオロフェニル）－１，３－オキサゾール－２－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（３．０ｇ）のテトラヒドロフラン溶液（３３ｍＬ）に、室温にてバージェス試薬（１．６ｇ）を加えた後に、６５℃まで昇温して１４時間撹拌した。反応液を減圧留去した後に、酢酸エチル（８０ｍＬ）を加え、飽和炭酸水素ナトリウム水溶液（４０ｍＬ）及び、飽和食塩水（４０ｍＬ）で洗浄した。得られた有機層を硫酸ナトリウムで乾燥後、溶媒を減圧留去した。シリカゲルカラムクロマトグラフィー(石油エーテル/酢酸エチル = １００／１から３／１)で精製することにより、化合物Ｑ２０（２．２ｇ）を取得した。
1H-NMR (400 MHz, CDCl3)： δ7.59-7.56 (m, 2H), 7.17 (s, 1H), 7.13-7.08 (m, 2H), 4.12 (brs, 2H), 3.04-2.95 (m, 3H), 2.10-2.06 (m, 2H), 1.85-1.81 (m, 2H), 1.47 (s, 9H). b) Preparation of tert-butyl 4- [5- (4-fluorophenyl) -1,3-oxazol-2-yl] piperidine-1-carboxylate (Compound Q20) Compound Q19 (3.0 g) in tetrahydrofuran solution ( (33 mL), Burgess reagent (1.6 g) was added at room temperature, and the mixture was heated to 65 ° C. and stirred for 14 hours. The reaction solution was evaporated under reduced pressure, ethyl acetate (80 mL) was added, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution (40 mL) and saturated brine (40 mL). The obtained organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 100/1 to 3/1) gave Compound Q20 (2.2 g).
1 H-NMR (400 MHz, CDCl3): δ7.59-7.56 (m, 2H), 7.17 (s, 1H), 7.13-7.08 (m, 2H), 4.12 (brs, 2H), 3.04-2.95 (m , 3H), 2.10-2.06 (m, 2H), 1.85-1.81 (m, 2H), 1.47 (s, 9H).
ｃ）４－[５－（４－フルオロフェニル）－１，３－オキサゾール－２－イル]ピペリジン・塩酸塩（参考例６）の製造
　化合物Ｑ２０（８００ｍｇ）を用いて、参考例１の工程ｅ）に準ずる方法により参考例６の化合物（７００ｍｇ）を取得した。 c) Preparation of 4- [5- (4-fluorophenyl) -1,3-oxazol-2-yl] piperidine hydrochloride (Reference Example 6) Step e of Reference Example 1 using Compound Q20 (800 mg) ) To obtain the compound of Reference Example 6 (700 mg).
参考例７
４－[２－（４－フルオロフェニル）－１，３－チアゾール－５－イル]ピペリジン・塩酸塩
Figure JPOXMLDOC01-appb-C000023
 a) ｔｅｒｔ-ブチル　４－[２－（４－フルオロフェニル）－１，３－チアゾール－５－イル]ピペリジン－１－カルボキシレート（化合物Ｑ２１）
　化合物Ｑ１７（１．３ｇ）のテトラヒドロフラン溶液（５０ｍＬ）に、室温にてローソン試薬（１．７ｇ）を加えた後に、７０℃まで昇温して１２時間撹拌した。反応液を室温まで冷却した後に、酢酸エチル（２００ｍＬ）を加えて抽出後、有機層を水（１００ｍＬ）で洗浄した。得られた有機層を硫酸ナトリウムで乾燥後、溶媒を減圧留去した。シリカゲルカラムクロマトグラフィー(石油エーテル/酢酸エチル = ２／１)で精製することにより、化合物Ｑ２１（６５０ｍｇ）を取得した。
1H-NMR (400 MHz, CDCl3)： δ7.92-7.88 (m, 2H), 7.56 (s, 1H), 7.16-7.12 (m, 2H), 4.24 (brs, 2H), 3.08-3.02 (m, 1H), 2.91-2.85 (m, 2H), 2.06-2.02 (m, 2H), 1.73-1.63 (m, 2H), 1.50 (s, 9H). Reference Example 7
4- [2- (4-Fluorophenyl) -1,3-thiazol-5-yl] piperidine hydrochloride
Figure JPOXMLDOC01-appb-C000023
 a) tert-butyl 4- [2- (4-fluorophenyl) -1,3-thiazol-5-yl] piperidine-1-carboxylate (compound Q21)
To a tetrahydrofuran solution (50 mL) of compound Q17 (1.3 g), Lawesson's reagent (1.7 g) was added at room temperature, and then the mixture was heated to 70 ° C. and stirred for 12 hours. The reaction solution was cooled to room temperature, extracted with ethyl acetate (200 mL), and the organic layer was washed with water (100 mL). The obtained organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 2/1) gave Compound Q21 (650 mg).
1 H-NMR (400 MHz, CDCl3): δ7.92-7.88 (m, 2H), 7.56 (s, 1H), 7.16-7.12 (m, 2H), 4.24 (brs, 2H), 3.08-3.02 (m , 1H), 2.91-2.85 (m, 2H), 2.06-2.02 (m, 2H), 1.73-1.63 (m, 2H), 1.50 (s, 9H).
ｂ)　４－[２－（４－フルオロフェニル）－１，３－チアゾール－５－イル]ピペリジン・塩酸塩（参考例７）
　化合物Ｑ２１（６００ｍｇ）を用いて、参考例１の工程ｅ）に準ずる方法により参考例７の化合物（６００ｍｇ）を取得した。 b) 4- [2- (4-Fluorophenyl) -1,3-thiazol-5-yl] piperidine hydrochloride (Reference Example 7)
The compound (600 mg) of Reference Example 7 was obtained by the method according to Step e) of Reference Example 1 using Compound Q21 (600 mg).
参考例８
４－[５－（４－フルオロフェニル）－１，３－チアゾール－２－イル]ピペリジン・塩酸塩（参考例８）
Figure JPOXMLDOC01-appb-C000024
 ａ）ｔｅｒｔ-ブチル　４－[５－（４－フルオロフェニル）－１，３－チアゾール－２－イル]ピペリジン－１－カルボキシレート（化合物Ｑ２２）の製造
　化合物Ｑ１９（２ｇ）のテトラヒドロフラン溶液（５０ｍＬ）に、室温にてローソン試薬（１．７ｇ）を加えた後に、７０℃まで昇温して４時間撹拌した。反応液を減圧留去した後に、塩化メチレン（１００ｍＬ）を加え、飽和炭酸水素ナトリウム水溶液（３０ｍＬ）で洗浄した。得られた有機層を硫酸ナトリウムで乾燥後、溶媒を減圧留去した。シリカゲルカラムクロマトグラフィー(石油エーテル/酢酸エチル = ９０／１０から５０／５０)で精製することにより、化合物Ｑ２２（１．３ｇ）を取得した。
1H-NMR (400 MHz, CDCl3)： δ7.76 (s, 1H), 7.51-7.48 (m, 2H), 7.11-7.09 (m, 2H), 4.21 (brs, 2H), 3.15-3.10 (m, 1H), 2.93-2.90 (m, 2H), 2.14-2.05 (m, 2H), 1.78-1.74 (m, 2H), 1.48 (s, 9H). Reference Example 8
4- [5- (4-Fluorophenyl) -1,3-thiazol-2-yl] piperidine hydrochloride (Reference Example 8)
Figure JPOXMLDOC01-appb-C000024
 a) Preparation of tert-butyl 4- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] piperidine-1-carboxylate (Compound Q22) Compound Q19 (2 g) in tetrahydrofuran (50 mL) After adding Lawson's reagent (1.7 g) at room temperature, the mixture was heated to 70 ° C. and stirred for 4 hours. The reaction solution was evaporated under reduced pressure, methylene chloride (100 mL) was added, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution (30 mL). The obtained organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 90/10 to 50/50) gave Compound Q22 (1.3 g).
1 H-NMR (400 MHz, CDCl3): δ7.76 (s, 1H), 7.51-7.48 (m, 2H), 7.11-7.09 (m, 2H), 4.21 (brs, 2H), 3.15-3.10 (m , 1H), 2.93-2.90 (m, 2H), 2.14-2.05 (m, 2H), 1.78-1.74 (m, 2H), 1.48 (s, 9H).
ｂ）４－[５－（４－フルオロフェニル）－１，３－チアゾール－２－イル]ピペリジン・塩酸塩（参考例８）の製造
　化合物Ｑ２２（８４０ｍｇ）を用いて、参考例１の工程ｅ）に準ずる方法により参考例８の化合物（６８０ｍｇ）を取得した。 b) Preparation of 4- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] piperidine hydrochloride (Reference Example 8) Step e of Reference Example 1 using Compound Q22 (840 mg) ) To obtain the compound of Reference Example 8 (680 mg).
実施例１
４－[５－クロロ－１－（３－フルオロフェニル）－１Ｈ－イミダゾール－４－イル]－Ｎ－（４，４－ジフルオロシクロヘキシル）ピペリジン－１－カルボキサミド
Figure JPOXMLDOC01-appb-C000025
 　参考例１の化合物（１９８ｍｇ）の塩化メチレン溶液（８ｍＬ）に、室温にてフェニル ４，４－ジフルオロシクロヘキシルカルバメート（２７２ｍｇ）及びトリエチルアミン（０．５０ｍＬ）を加えた後に、３８℃まで昇温して４８時間撹拌した。反応溶媒を減圧留去した後に、分取ＨＰＬＣで精製することにより、実施例１の化合物（２００ｍｇ）を取得した。
1H-NMR (400 MHz, CDCl3)： δ7.60 (s, 1H), 7.52-7.45 (m, 1H), 7.21-7.13 (m, 3H), 4.33-4.31 (m, 1H), 4.08-4.04 (m, 2H), 3.84-3.83 (m, 1H), 2.98-2.86 (m, 3H), 2.09-1.88 (m, 10H), 1.55-1.45 (m, 2H).
LCMS　; [M+H]+ / Rt (min)　: 測定条件　（４４１ / １．９４ ： Ｆ） Example 1
4- [5-Chloro-1- (3-fluorophenyl) -1H-imidazol-4-yl] -N- (4,4-difluorocyclohexyl) piperidine-1-carboxamide
Figure JPOXMLDOC01-appb-C000025
 Phenyl 4,4-difluorocyclohexylcarbamate (272 mg) and triethylamine (0.50 mL) were added to a methylene chloride solution (8 mL) of the compound of Reference Example 1 (198 mg) at room temperature, and the temperature was raised to 38 ° C. Stir for 48 hours. After distilling off the reaction solvent under reduced pressure, the compound of Example 1 (200 mg) was obtained by purification by preparative HPLC.
1 H-NMR (400 MHz, CDCl3): δ7.60 (s, 1H), 7.52-7.45 (m, 1H), 7.21-7.13 (m, 3H), 4.33-4.31 (m, 1H), 4.08-4.04 (m, 2H), 3.84-3.83 (m, 1H), 2.98-2.86 (m, 3H), 2.09-1.88 (m, 10H), 1.55-1.45 (m, 2H).
LCMS; [M + H] + / Rt (min): Measurement conditions (441 / 1.94: F)
実施例２
｛４－[５－クロロ－１－（３－フルオロフェニル）－１Ｈ－イミダゾール－４－イル]ピペリジン－１－イル｝（４，４－ジフルオロシクロヘキシル）メタノン
Figure JPOXMLDOC01-appb-C000026
 　参考例１の化合物（１９８ｍｇ）の塩化メチレン溶液（４ｍＬ）に、室温にて４，４－ジフルオロシクロヘキサンカルボン酸（１７５ｍｇ）、ＨＢＴＵ（５４０ｍｇ）及びトリエチルアミン（０．５０ｍＬ）を加えた後に、室温で２４時間撹拌した。反応溶媒を減圧留去した後に、分取ＨＰＬＣで精製することにより、実施例２の化合物（１００ｍｇ）を取得した。
1H-NMR (400 MHz, CDCl3)： δ7.61 (s, 1H), 7.52-7.49 (m, 1H), 7.22-7.14 (m, 3H), 4.78-4.75 (m, 1H), 4.05-4.02 (m, 1H), 3.24-3.20 (m, 1H), 3.00-2.95 (m, 1H), 2.73-2.64 (m, 2H), 2.25-2.22 (m, 2H), 1.95-1.78 (m, 10H).
LCMS　; [M+H]+ / Rt (min)　: 測定条件　（４２６ / １．９６ ： Ｆ） Example 2
{4- [5-Chloro-1- (3-fluorophenyl) -1H-imidazol-4-yl] piperidin-1-yl} (4,4-difluorocyclohexyl) methanone
Figure JPOXMLDOC01-appb-C000026
 To a methylene chloride solution (4 mL) of the compound of Reference Example 1 (198 mg), 4,4-difluorocyclohexanecarboxylic acid (175 mg), HBTU (540 mg) and triethylamine (0.50 mL) were added at room temperature. Stir for 24 hours. After distilling off the reaction solvent under reduced pressure, the compound of Example 2 (100 mg) was obtained by purification by preparative HPLC.
1 H-NMR (400 MHz, CDCl3): δ7.61 (s, 1H), 7.52-7.49 (m, 1H), 7.22-7.14 (m, 3H), 4.78-4.75 (m, 1H), 4.05-4.02 (m, 1H), 3.24-3.20 (m, 1H), 3.00-2.95 (m, 1H), 2.73-2.64 (m, 2H), 2.25-2.22 (m, 2H), 1.95-1.78 (m, 10H) .
LCMS; [M + H] + / Rt (min): Measurement conditions (426 / 1.96: F)
実施例３
４－[５－シアノ－１－（３－フルオロフェニル）－１Ｈ－イミダゾール－４－イル]－Ｎ－（４，４－ジフルオロシクロヘキシル）ピペリジン－１－カルボキサミド
Figure JPOXMLDOC01-appb-C000027
 　参考例２の化合物（２５９ｍｇ）を用いて、実施例１に準ずる方法により、実施例３の化合物（２６ｍｇ）を取得した。
LCMS　; [M+H]+ / Rt (min)　: 測定条件　（４３２ / ２．０１ ： Ｃ） Example 3
4- [5-Cyano-1- (3-fluorophenyl) -1H-imidazol-4-yl] -N- (4,4-difluorocyclohexyl) piperidine-1-carboxamide
Figure JPOXMLDOC01-appb-C000027
 The compound of Example 3 (26 mg) was obtained by the method according to Example 1 using the compound of Reference Example 2 (259 mg).
LCMS; [M + H] + / Rt (min): Measurement conditions (432 / 2.01: C)
実施例４
Ｎ－（テトラヒドロ－２Ｈ－ピラン－４－イル）－４－{３－[５－（トリフルオロメチル）ピリジン－２－イル]－１，２－オキサゾール－５－イル}ピペリジン－１－カルボキサミド
Figure JPOXMLDOC01-appb-C000028
 　参考例３の化合物（３２７ｍｇ）を用いて、実施例１に準ずる方法により、実施例４の化合物（９０ｍｇ）を取得した。
LCMS　; [M+H]+ / Rt (min)　: 測定条件　（４２５ / １．６８ ： Ｆ） Example 4
N- (Tetrahydro-2H-pyran-4-yl) -4- {3- [5- (trifluoromethyl) pyridin-2-yl] -1,2-oxazol-5-yl} piperidine-1-carboxamide
Figure JPOXMLDOC01-appb-C000028
 The compound of Example 4 (90 mg) was obtained by the method according to Example 1 using the compound of Reference Example 3 (327 mg).
LCMS; [M + H] + / Rt (min): Measurement conditions (425 / 1.68: F)
実施例５
Ｎ－（テトラヒドロ－２Ｈ－ピラン－４－イル）－４－{５－[５－（トリフルオロメチル）ピリジン－２－イル]－１，２－オキサゾール－３－イル}ピペリジン－１－カルボキサミド
Figure JPOXMLDOC01-appb-C000029
 　参考例４の化合物（２４７ｍｇ）を用いて、実施例１に準ずる方法により、実施例５の化合物（８５ｍｇ）を取得した。
LCMS　; [M+H]+ / Rt (min)　: 測定条件　（４２５ / １．８５ ： Ｃ） Example 5
N- (Tetrahydro-2H-pyran-4-yl) -4- {5- [5- (trifluoromethyl) pyridin-2-yl] -1,2-oxazol-3-yl} piperidine-1-carboxamide
Figure JPOXMLDOC01-appb-C000029
 The compound of Example 5 (85 mg) was obtained by the method according to Example 1 using the compound of Reference Example 4 (247 mg).
LCMS; [M + H] + / Rt (min): Measurement conditions (425 / 1.85: C)
実施例６
Ｎ－（４，４－ジフルオロシクロヘキシル）－４－[２－（４－フルオロフェニル）－１，３－オキサゾール－５－イル]ピペリジン－１－カルボキサミド
Figure JPOXMLDOC01-appb-C000030
 　参考例５の化合物（２９０ｍｇ）を用いて、実施例１に準ずる方法により、実施例６の化合物（３８ｍｇ）を取得した。
LCMS　; [M+H]+ / Rt (min)　: 測定条件　（４０８ / ２．５３ ： Ｃ） Example 6
N- (4,4-difluorocyclohexyl) -4- [2- (4-fluorophenyl) -1,3-oxazol-5-yl] piperidine-1-carboxamide
Figure JPOXMLDOC01-appb-C000030
 The compound of Example 6 (38 mg) was obtained by the method according to Example 1 using the compound of Reference Example 5 (290 mg).
LCMS; [M + H] + / Rt (min): Measurement conditions (408 / 2.53: C)
実施例７
Ｎ－（４，４－ジフルオロシクロヘキシル）－４－[５－（４－フルオロフェニル）－１，３－オキサゾール－２－イル]ピペリジン－１－カルボキサミド
Figure JPOXMLDOC01-appb-C000031
 　参考例６の化合物（３００ｍｇ）を用いて、実施例１に準ずる方法により、実施例７の化合物（２００ｍｇ）を取得した。
LCMS　; [M+H]+ / Rt (min)　: 測定条件　（４０８ / ２．０４ ： Ｃ） Example 7
N- (4,4-difluorocyclohexyl) -4- [5- (4-fluorophenyl) -1,3-oxazol-2-yl] piperidine-1-carboxamide
Figure JPOXMLDOC01-appb-C000031
 The compound of Example 7 (200 mg) was obtained by the method according to Example 1 using the compound of Reference Example 6 (300 mg).
LCMS; [M + H] + / Rt (min): Measurement conditions (408 / 2.04: C)
実施例８
Ｎ－（４，４－ジフルオロシクロヘキシル）－４－[２－（４－フルオロフェニル）－１，３－チアゾール－５－イル]ピペリジン－１－カルボキサミド
Figure JPOXMLDOC01-appb-C000032
 　参考例７の化合物（１２０ｍｇ）を用いて、実施例１に準ずる方法により、実施例８の化合物（３５ｍｇ）を取得した。
LCMS　; [M+H]+ / Rt (min)　: 測定条件　（４２４ / ２．６５ ： Ｃ） Example 8
N- (4,4-difluorocyclohexyl) -4- [2- (4-fluorophenyl) -1,3-thiazol-5-yl] piperidine-1-carboxamide
Figure JPOXMLDOC01-appb-C000032
 The compound of Example 8 (35 mg) was obtained by the method according to Example 1 using the compound of Reference Example 7 (120 mg).
LCMS; [M + H] + / Rt (min): Measurement conditions (424 / 2.65: C)
実施例９
Ｎ－（４，４－ジフルオロシクロヘキシル）－４－[５－（４－フルオロフェニル）－１，３－チアゾール－２－イル]ピペリジン－１－カルボキサミド
Figure JPOXMLDOC01-appb-C000033
 　参考例８の化合物（３４０ｍｇ）及びフェニル 4,4-ジフェニルシクロヘキサンカルバメート（４３４ｍｇ）のアセトニトリル溶液（５ｍＬ）に、室温にてトリエチルアミン（０．４６ｍＬ）を加えた後に、５５℃まで昇温して４時間撹拌した。反応溶媒を減圧留去した後に、シリカゲルカラムクロマトグラフィー(酢酸エチル/メタノール = １００／０から９２／８)で精製することにより、実施例９の化合物（５７ｍｇ）を取得した。
1H-NMR (400 MHz, CDCl3)： δ7.76 (s, 1H), 7.50-7.47 (m, 2H), 7.11-7.07 (m, 2H), 4.37-4.30 (m, 1H), 4.05-3.98 (m, 2H), 3.80-3.73 (m, 1H), 3.18-3.10 (m, 1H), 3.00-2.93 (m, 2H), 2.20-2.05 (m, 6H), 1.93-1.75 (m, 4H), 1.53-1.40 (m, 2H).
LCMS　; [M+H]+ / Rt (min)　: 測定条件　（４２４ / １．１０ ： Ｃ） Example 9
N- (4,4-difluorocyclohexyl) -4- [5- (4-fluorophenyl) -1,3-thiazol-2-yl] piperidine-1-carboxamide
Figure JPOXMLDOC01-appb-C000033
 Triethylamine (0.46 mL) was added to a solution of the compound of Reference Example 8 (340 mg) and phenyl 4,4-diphenylcyclohexanecarbamate (434 mg) in acetonitrile (5 mL) at room temperature, and the temperature was raised to 55 ° C. Stir for hours. After distilling off the reaction solvent under reduced pressure, the compound of Example 9 (57 mg) was obtained by purification by silica gel column chromatography (ethyl acetate / methanol = 100/0 to 92/8).
1 H-NMR (400 MHz, CDCl3): δ7.76 (s, 1H), 7.50-7.47 (m, 2H), 7.11-7.07 (m, 2H), 4.37-4.30 (m, 1H), 4.05-3.98 (m, 2H), 3.80-3.73 (m, 1H), 3.18-3.10 (m, 1H), 3.00-2.93 (m, 2H), 2.20-2.05 (m, 6H), 1.93-1.75 (m, 4H) , 1.53-1.40 (m, 2H).
LCMS; [M + H] + / Rt (min): Measurement conditions (424 / 1.10: C)
実施例１０
４－[４－クロロ－５－（４－フルオロフェニル）－１，３－チアゾール－２－イル]－Ｎ－（４，４－ジフルオロシクロヘキシル）ピペリジン－１－カルボキサミド
Figure JPOXMLDOC01-appb-C000034
 　実施例９の化合物（１００ｍｇ）のアセトニトリル溶液（５ｍＬ）に、室温にてＮ-クロロスクシンイミド（３８ｍｇ）及びトリフルオロ酢酸（０．０５ｍＬ）を加えた後に、５５℃まで昇温して４時間撹拌した。反応液に飽和炭酸水素ナトリウム溶液を加えた後に、酢酸エチルで抽出し、有機層を水及び飽和食塩水で洗浄した。得られた有機層を硫酸ナトリウムで乾燥、溶媒を減圧留去した後に、分取ＨＰＬＣで精製することにより、実施例１０の化合物（６４ｍｇ）を取得した。
1H-NMR (400 MHz, CDCl3)： δ7.61-7.57 (m, 2H), 7.16-7.11 (m, 2H), 4.30-4.28 (m, 1H), 4.05-4.01 (m, 2H), 3.78-3.73 (m, 1H), 3.16-3.08 (m, 1H), 2.99-2.92 (m, 2H), 2.17-2.02 (m, 6H), 1.83-1.75 (m, 4H), 1.51-1.42 (m, 2H).
LCMS　; [M+H]+ / Rt (min)　: 測定条件　（４５８ / １．４５ ： Ｃ） Example 10
4- [4-Chloro-5- (4-fluorophenyl) -1,3-thiazol-2-yl] -N- (4,4-difluorocyclohexyl) piperidine-1-carboxamide
Figure JPOXMLDOC01-appb-C000034
 N-chlorosuccinimide (38 mg) and trifluoroacetic acid (0.05 mL) were added to an acetonitrile solution (5 mL) of the compound of Example 9 (100 mg) at room temperature, and then the mixture was heated to 55 ° C. and stirred for 4 hours. did. A saturated sodium bicarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate, and the organic layer was washed with water and saturated brine. The obtained organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by preparative HPLC to obtain the compound of Example 10 (64 mg).
1 H-NMR (400 MHz, CDCl3): δ7.61-7.57 (m, 2H), 7.16-7.11 (m, 2H), 4.30-4.28 (m, 1H), 4.05-4.01 (m, 2H), 3.78 -3.73 (m, 1H), 3.16-3.08 (m, 1H), 2.99-2.92 (m, 2H), 2.17-2.02 (m, 6H), 1.83-1.75 (m, 4H), 1.51-1.42 (m, 2H).
LCMS; [M + H] + / Rt (min): Measurement conditions (458 / 1.45: C)
実施例１１～３９
　対応する原料化合物を用いて、実施例１又は３に準ずる方法により、表１に示す化合物を得た。

























Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000037
 Examples 11 to 39
The compounds shown in Table 1 were obtained by the method according to Example 1 or 3 using the corresponding raw material compounds.

























Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000037
実施例４０～５０
　対応する原料化合物を用いて、実施例２に準ずる方法により、表２に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000038
 Examples 40-50
The compounds shown in Table 2 were obtained by the method according to Example 2 using the corresponding raw material compounds.
Figure JPOXMLDOC01-appb-T000038
実施例５１～９１
　対応する原料化合物を用いて、実施例４に準ずる方法により、表３に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000042
 Examples 51-91
The compounds shown in Table 3 were obtained by the method according to Example 4 using the corresponding starting compounds.
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000042
実施例９２～９８
　対応する原料化合物を用いて、参考例３及び実施例２に準ずる方法により、表４に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000043
 Examples 92-98
The compounds shown in Table 4 were obtained by the method according to Reference Example 3 and Example 2 using the corresponding starting compounds.
Figure JPOXMLDOC01-appb-T000043
実施例９９～１００
　対応する原料化合物を用いて、参考例３及び実施例２に準ずる方法により、表５に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000044
 Examples 99-100
The compounds shown in Table 5 were obtained by the method according to Reference Example 3 and Example 2 using the corresponding starting compounds.
Figure JPOXMLDOC01-appb-T000044
実施例１０１～１４２
　対応する原料化合物を用いて、実施例５に準ずる方法により、表６に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000048
 Examples 101-142
The compounds shown in Table 6 were obtained by the method according to Example 5 using the corresponding starting compounds.
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000048
実施例１４３～１４８
　対応する原料化合物を用いて、参考例４及び実施例２に準ずる方法により、表７に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000049
 Examples 143-148
The compounds shown in Table 7 were obtained by the method according to Reference Example 4 and Example 2 using the corresponding starting compounds.
Figure JPOXMLDOC01-appb-T000049
実施例１４９
　対応する原料化合物を用いて、実施例６に準ずる方法により、表８に示す化合物を得た。

Figure JPOXMLDOC01-appb-T000050
 Example 149
The compounds shown in Table 8 were obtained by the method according to Example 6 using the corresponding starting compounds.

Figure JPOXMLDOC01-appb-T000050
実施例１５０～１５１
　対応する原料化合物を用いて、参考例５及び実施例２に準ずる方法により、表９に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000051
 Examples 150-151
The compounds shown in Table 9 were obtained by the method according to Reference Example 5 and Example 2 using the corresponding starting compounds.
Figure JPOXMLDOC01-appb-T000051
実施例１５２～１５４
　対応する原料化合物を用いて、実施例７に準ずる方法により、表１０に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000052
 Examples 152-154
The compounds shown in Table 10 were obtained by the method according to Example 7 using the corresponding starting compounds.
Figure JPOXMLDOC01-appb-T000052
実施例１５５～１５６
　対応する原料化合物を用いて、参考例６及び実施例２に準ずる方法により、表１１に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000053
 Examples 155 to 156
The compounds shown in Table 11 were obtained by the method according to Reference Example 6 and Example 2 using the corresponding starting compounds.
Figure JPOXMLDOC01-appb-T000053
実施例１５７～１５９
　対応する原料化合物を用いて、実施例８に準ずる方法により、表１２に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000054
 Examples 157 to 159
The compounds shown in Table 12 were obtained by the method according to Example 8 using the corresponding starting compounds.
Figure JPOXMLDOC01-appb-T000054
実施例１６０～１６１
　対応する原料化合物を用いて、参考例７及び実施例２に準ずる方法により、表１３に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000055
 Examples 160-161
The compounds shown in Table 13 were obtained by the method according to Reference Example 7 and Example 2 using the corresponding starting compounds.
Figure JPOXMLDOC01-appb-T000055
実施例１６２～１６３
　対応する原料化合物を用いて、実施例９及び１０に準ずる方法により、表１４に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000056
 Examples 162-163
The compounds shown in Table 14 were obtained by the method according to Examples 9 and 10 using the corresponding starting compounds.
Figure JPOXMLDOC01-appb-T000056
実施例１６４～１６５
　対応する原料化合物を用いて、参考例８及び実施例２に準ずる方法により、表１５に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000057
 Examples 164 to 165
The compounds shown in Table 15 were obtained by the method according to Reference Example 8 and Example 2 using the corresponding starting compounds.
Figure JPOXMLDOC01-appb-T000057
実施例１６６～１７５
　対応する原料化合物を用いて、実施例６に準ずる方法により、表１６に示す化合物を得た。

Figure JPOXMLDOC01-appb-T000058
 Examples 166-175
The compounds shown in Table 16 were obtained by the method according to Example 6 using the corresponding starting compounds.

Figure JPOXMLDOC01-appb-T000058
実施例１７６～１８４
　対応する原料化合物を用いて、参考例５及び実施例２に準ずる方法により、表１７に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000059
 Examples 176-184
The compounds shown in Table 17 were obtained by the method according to Reference Example 5 and Example 2 using the corresponding starting compounds.
Figure JPOXMLDOC01-appb-T000059
実施例１８５～１９１
　対応する原料化合物を用いて、実施例７に準ずる方法により、表１８に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000060
 Examples 185-191
The compounds shown in Table 18 were obtained by the method according to Example 7 using the corresponding starting compounds.
Figure JPOXMLDOC01-appb-T000060
実施例１９２
　対応する原料化合物を用いて、参考例６及び実施例２に準ずる方法により、表１９に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000061
 Example 192
The compounds shown in Table 19 were obtained by the method according to Reference Example 6 and Example 2 using the corresponding starting compounds.
Figure JPOXMLDOC01-appb-T000061
実施例１９３～１９８
　対応する原料化合物を用いて、実施例８に準ずる方法により、表２０に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000062
 Examples 193-198
The compounds shown in Table 20 were obtained by the method according to Example 8 using the corresponding starting compounds.
Figure JPOXMLDOC01-appb-T000062
実施例１９９～２１０
　対応する原料化合物を用いて、参考例７及び実施例２に準ずる方法により、表２１に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000063
Figure JPOXMLDOC01-appb-T000064
 Examples 199-210
The compounds shown in Table 21 were obtained by the method according to Reference Example 7 and Example 2 using the corresponding starting compounds.
Figure JPOXMLDOC01-appb-T000063
Figure JPOXMLDOC01-appb-T000064
実施例２１１～２１４
　対応する原料化合物を用いて、実施例９及び１０に準ずる方法により、表２２に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000065
 Examples 211-214
The compounds shown in Table 22 were obtained by the method according to Examples 9 and 10 using the corresponding starting compounds.
Figure JPOXMLDOC01-appb-T000065
実施例２１５～２１９
　対応する原料化合物を用いて、参考例８及び実施例２に準ずる方法により、表２３に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000066
 Examples 215 to 219
The compounds shown in Table 23 were obtained by the method according to Reference Example 8 and Example 2 using the corresponding starting compounds.
Figure JPOXMLDOC01-appb-T000066
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. no. 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、及びヒトα７ ｎＡＣｈＲ遺伝子を挿入したpcDNA3.1ベクター（cat. no. V790-20, invitrogen, Carlsbad，CA，USA）の導入によりエクオリン及びヒトα７ ｎＡＣｈＲ安定発現細胞を得た。選別にはそれぞれZeocin （cat. no. R25001, invitrogen, Carlsbad，CA，USA）及びGeneticin（cat. no. 10131-027, invitrogen, Carlsbad，CA，USA）を用いた。
　培地には２．５％ウシ胎児血清（cat. no. 2917354, ICN Biomedicals, Inc, USA）、１５％非働化ウマ血清（cat. no. 26050-088, invitrogen, Carlsbad，CA，USA）、１μｇ／ｍＬ Geneticin、５μｇ／ｍＬ Puromycin（cat. no. 14861-84, invitrogen, Carlsbad，CA，USA）を含むF-10 Nutrient Mixture（Ham）培地（cat. no. 11550-043, invitrogen, Carlsbad，CA，USA）を用い、コラーゲンType1コートディッシュ（cat. no. 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. no. 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. no. 14065-056, invitrogen, Carlsbad，CA，USA）／２０ｍｍｏｌ／Ｌ Hepes（cat. no. 15630-080, invitrogen, Carlsbad，CA，USA） Buffer （pH7.4）、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、384 wellプレート（cat. no. 781090, Greiner,Germany）に播種した。
　播種翌日、Viviren（cat. no. E649X, Promega, Madison，WI，USA）を終濃度４μｍｏｌ／Ｌ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. No. CCL-82.2, ATCC, USA) were used as host cells. Introduction of pcDNA3.1Zeo vector into which the nucleotide sequence encoding the protein of GenBank BAC81731 was inserted, and introduction of pcDNA3.1 vector into which the human α7 nAChR gene was inserted (cat. No. V790-20, invitrogen, Carlsbad, CA, USA) Thus, aequorin and human α7 nAChR stably expressing cells were obtained. For selection, Zeocin (cat. No. R25001, invitrogen, Carlsbad, CA, USA) and Geneticin (cat. No. 10131-027, invitrogen, Carlsbad, CA, USA) were used.
Medium includes 2.5% fetal bovine serum (cat. No. 2917354, ICN Biomedicals, Inc, USA), 15% inactivated horse serum (cat. No. 26050-088, invitrogen, Carlsbad, CA, USA), 1 μg / ML Geneticin, F-10 Nutrient Mixture (Ham) medium (cat. No. 11550-043, invitrogen, Carlsbad, CA) containing 5 μg / mL Puromycin (cat. No. 14861-84, invitrogen, Carlsbad, CA, USA) , USA) and cultured in a collagen Type 1 coat dish (cat. No. 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. No. 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. No. 14065-056, invitrogen, Carlsbad, CA, USA) / 20 mmol / L Hepes (cat. No 15630-080, invitrogen, Carlsbad, CA, USA) To reach 20000 cells / 25μL / well in a reaction medium consisting of Buffer (pH7.4), F-10 Nutrient Mixture (Ham), and 0.1mg / mL Geneticin And seeded on 384 well plates (cat. No. 781090, Greiner, Germany).
The day after sowing, Viviren (cat. No. E649X, Promega, Madison, Wis., USA) was added to a final concentration of 4 μmol / L (15 μL / well), and the mixture was allowed to stand at room temperature for 4 hours after light centrifugation at room temperature.
（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 mmol/L HEPES／0.2% BSA（cat. no. A3803, Sigma，St.Louis, MO, USA）にて最終濃度の６倍濃度に調整した。 (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 mmol / L HEPES / 0.2% BSA (cat. No. A3803, Sigma, St. Louis, MO, USA) and 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２４、表２５及び表２６に示す。
Figure JPOXMLDOC01-appb-T000067
Figure JPOXMLDOC01-appb-T000068
Figure JPOXMLDOC01-appb-T000069
 (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. The luminescence signal (center wavelength: 465 nm) was measured for 138 seconds after the addition of ACh to calculate RLU (Max-Min), and the ratio of RLU (Max-Min) between the control well and the test compound added well was defined as PAM activity. .
Data of α7 PAM activity of representative compounds is shown in Table 24, Table 25 and Table 26.
Figure JPOXMLDOC01-appb-T000067
Figure JPOXMLDOC01-appb-T000068
Figure JPOXMLDOC01-appb-T000069
試験例２．マウス新奇物体認識試験を用いた認知機能評価(以下、ｍＯＲＴという）
　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、第二試行における記憶増強作用を評価した。その結果、実施例１、４５、５１、７９及び１２４の化合物は、３または１０ｍｇ／ｋｇ（経口）において有意な記憶増強作用を示した。

 Test Example 2 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. As a result, the compounds of Examples 1, 45, 51, 79 and 124 showed a significant memory enhancing action at 3 or 10 mg / kg (oral).

　以上で説明したように、式（Ｉ）で表される化合物、また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及び／又は予防に有用である。 As described above, the compound represented by the formula (I), or a pharmaceutically acceptable salt thereof, has a strong α7 nicotinic acetylcholine receptor (α7ｈnAChR) 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 It is useful for treatment and / or prevention of diseases and the like.

Claims (28)

  1. 　式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000001
    Figure JPOXMLDOC01-appb-C000002
     ［式中、　
    　Ｘ－Ｙ－Ｚは、Ｎ－ＣＯ－ＮＲ３ＡＲ３Ｂ、Ｎ－ＣＯＲ４Ａ、ＣＲ５－ＣＯ－ＮＲ３ＡＲ３Ｂ、ＣＲ５－ＮＲ６－ＣＯＲ４Ｂ又はＣＲ５－ＮＲ６－ＣＯＮＲ３ＡＲ３Ｂを表し、
    　Ａは、フェニル又はピリジル（該フェニル及び該ピリジルは、それぞれハロゲン、水酸基、１から５個のフッ素で置換されていてもよいＣ１－６アルキル、１から５個のフッ素で置換されていてもよいＣ１－６アルコキシ及びシアノ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）を表し、
    　Ｂは、Ｂ－１、Ｂ－２、Ｂ－３、Ｂ－４又はＢ－５を表し、
    　式（Ｉ）の化合物におけるａおよびｂは、Ｂに結合する２つの結合手が、Ｂ－１からＢ－５における２つの結合手のいずれに該当する結合かを示す記号であり、
    　Ｗは、酸素原子又は硫黄原子を表し、
    　Ｒ１は、水素原子；ハロゲン；シアノ；Ｃ１－６アルキル（該アルキルは、ハロゲン、水酸基、１から５個のフッ素で置換されていてもよいＣ３－１０シクロアルキル、１から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４～１０員の飽和複素環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）；又はハロゲン、水酸基、Ｃ１－６アルキル及び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シクロアルキルを表し、
    　Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ、Ｒ２Ｄ及びＲ５は、同一又は異なって、水素原子；フッ素；水酸基；１から５個のフッ素で置換されていてもよいＣ１－６アルコキシ；又は１から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、Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ、Ｒ２Ｄ及びＲ５のいずれかの２つが１から５個のフッ素で置換されていてもよいＣ１－６アルキルのとき、２個のアルキルが一緒になって該アルキルが結合している環とは別の環を形成していてもよく、
    　Ｒ３Ａ、Ｒ３Ｂ、Ｒ４Ａ、Ｒ４Ｂ及びＲ６は、同一又は異なって、ハロゲン、水酸基、Ｃ１－６アルコキシ、Ｃ３－１０シクロアルキル及び４～１０員の飽和複素環（ただし、環上にカルボニル基を有しない）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Ｃ１－６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Ｃ３－１０シクロアルキル；Ｃ１－６アルキルで置換されていてもよい４～１０員の飽和複素環；又は水素原子を表し、ここにおいて、（１）Ｒ４Ａ及びＲ４Ｂは水素原子ではなく、（２）Ｒ３Ａ及びＲ３Ｂは同時に水素原子ではなく、（３）ＢがＢ－３であり、Ｗが酸素原子であり、Ｘ－Ｙ－ＺがＮ－ＣＯＲ４Ａであるときは、Ｒ４Ａはメチルではなく、（４）Ａが無置換のフェニルであり、ＢがＢ－４であり、Ｗが酸素原子であり、Ｘ－Ｙ－ＺがＮ－ＣＯＲ４Ａであるときは、Ｒ４Ａは１～５個のフッ素で置換されたＣ３アルキルではなく、かつ（５）Ｒ３Ａ及びＲ３Ｂが共にＣ１－６アルキルのとき、それらが結合する窒素原子と一緒になって、フッ素、Ｃ１－６アルキル及び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４～１０員の含窒素飽和複素環を形成していてもよい]
    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
    Figure JPOXMLDOC01-appb-C000002
     [Where:
    XYZ represents N-CO-NR 3A R 3B , N-COR 4A , CR 5 -CO-NR 3A R 3B , CR 5 -NR 6 -COR 4B or CR 5 -NR 6 -CONR 3A R 3B Represents
    A is phenyl or pyridyl (said phenyl and said pyridyl, halogen, respectively, hydroxyl, 1 to 5 fluorine optionally substituted by C 1-6 alkyl, optionally substituted with 1-5 fluorine And optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy and cyano,
    B represents B-1, B-2, B-3, B-4 or B-5,
    A and b in the compound of the formula (I) are symbols indicating which of the two bonds in B-1 to B-5 the two bonds that bind to B correspond to;
    W represents an oxygen atom or a sulfur atom,
    R 1 is a hydrogen atom; halogen; cyano; C 1-6 alkyl (wherein the alkyl is halogen, hydroxyl, C 3-10 cycloalkyl optionally substituted with 1 to 5 fluorines, 1 to 5 Halogen optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy optionally substituted with fluorine and a 4- to 10-membered saturated heterocyclic ring; or halogen Represents a C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of hydroxyl, C 1-6 alkyl and C 1-6 alkoxy,
    R 2A , R 2B , R 2C , R 2D and R 5 are the same or different and represent a hydrogen atom; fluorine; a hydroxyl group; C 1-6 alkoxy optionally substituted with 1 to 5 fluorines; Represents C 1-6 alkyl optionally substituted with 5 fluorines, wherein two of R 2A , R 2B , R 2C , R 2D and R 5 are substituted with 1 to 5 fluorines In the case of C 1-6 alkyl, which may be substituted , two alkyls may be combined to form a ring different from the ring to which the alkyl is bonded;
    R 3A , R 3B , R 4A , R 4B and R 6 are the same or different and are halogen, hydroxyl group, C 1-6 alkoxy, C 3-10 cycloalkyl and a 4- to 10-membered saturated heterocyclic ring (provided that the ring C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of (having no carbonyl group above); halogen, hydroxyl, C 1-6 alkoxy and C 1 C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of -6 alkyl; 4 to 10 members optionally substituted with C 1-6 alkyl Or a hydrogen atom, wherein (1) R 4A and R 4B are not hydrogen atoms, (2) R 3A and R 3B are not simultaneously hydrogen atoms, and (3) B is B— 3 and W is an oxygen atom When XYZ is N—COR 4A , R 4A is not methyl, (4) A is unsubstituted phenyl, B is B-4, and W is an oxygen atom. , XYZ is N—COR 4A , R 4A is not C 3 alkyl substituted with 1 to 5 fluorines, and (5) R 3A and R 3B are both C 1-6 When alkyl, together with the nitrogen atom to which they are attached, is substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, C 1-6 alkyl and C 1-6 alkoxy. It may form a 4- to 10-membered nitrogen-containing saturated heterocyclic ring.
    Or a pharmaceutically acceptable salt thereof.
  2. 　Ｒ３Ａ、Ｒ３Ｂ、Ｒ４Ａ、Ｒ４Ｂ及びＲ６が、同一又は異なって、フッ素、Ｃ１－６アルコキシ、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Ｃ１－６アルキル；フッ素、Ｃ１－６アルコキシ及びＣ１－６アルキルからなる群から独立して選択される１～５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；又は水素原子であり、ここにおいて、（１）Ｒ４Ａ及びＲ４Ｂは水素原子ではなく、（２）Ｒ３Ａ及びＲ３Ｂは同時に水素原子ではなく、（３）ＢがＢ－３であり、Ｗが酸素原子であり、Ｘ－Ｙ－ＺがＮ－ＣＯＲ４Ａであるときは、Ｒ４Ａはメチルではなく、（４）Ａが無置換のフェニルであり、ＢがＢ－４であり、Ｗが酸素原子であり、Ｘ－Ｙ－ＺがＮ－ＣＯＲ４Ａであるときは、Ｒ４Ａは１～５個のフッ素で置換されたＣ３アルキルではない、
    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。     1 to 5 R 3A , R 3B , R 4A , R 4B and R 6 are the same or different and are independently selected from the group consisting of fluorine, C 1-6 alkoxy, and C 3-10 cycloalkyl of which may be substituted with a substituent C 1-6 alkyl; fluorine, optionally substituted with one to five substituents independently selected from the group consisting of C 1-6 alkoxy and C 1-6 alkyl An optionally substituted C 3-10 cycloalkyl; a 4-10 membered saturated heterocycle; or a hydrogen atom, wherein (1) R 4A and R 4B are not hydrogen atoms, but (2) R 3A and R 3B Are not hydrogen atoms at the same time, (3) when B is B-3, W is an oxygen atom, and XYZ is N—COR 4A , R 4A is not methyl and (4) A is unsubstituted phenyl, B is B-4 W is an oxygen atom, when X-Y-Z is N-COR 4A is, R 4A is not a C 3 alkyl substituted with 1-5 fluorine,
    The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
  3. 　Ｒ３Ａ、Ｒ３Ｂ及びＲ４Ａが、同一又は異なって、フッ素、Ｃ１－６アルコキシ及びＣ１－６アルキルからなる群から独立して選択される１～５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；又は水素原子であり、ここにおいて、Ｒ３Ａ及びＲ３Ｂは同時に水素原子ではなく、Ｒ４Ａは水素原子ではない、
    請求項１又は２に記載の化合物又はその製薬学的に許容される塩。     R 3A , R 3B and R 4A are the same or different and are substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, C 1-6 alkoxy and C 1-6 alkyl A C 3-10 cycloalkyl; a 4-10 membered saturated heterocyclic ring; or a hydrogen atom, wherein R 3A and R 3B are not simultaneously a hydrogen atom, and R 4A is not a hydrogen atom,
    The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.
  4. 　Ｒ４Ｂが、フッ素、Ｃ１－６アルコキシ、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Ｃ１－６アルキルである、
    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 4B is selected from the group consisting of fluorine, is C 1-6 alkoxy, and C 3-10 optionally substituted with 1 to 5 substituents selected independently from the group consisting of cycloalkyl C 1-6 alkyl ,
    The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.
  5. 　Ａが、フェニル又はピリジル（該フェニル及び該ピリジルは、それぞれフッ素、１から５個のフッ素で置換されていてもよいＣ１－６アルキル及び１から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）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 phenyl or pyridyl (the phenyl and the pyridyl are each fluorine, C 1-6 alkyl optionally substituted with 1 to 5 fluorines, and C optionally substituted with 1 to 5 fluorines) Which may be substituted with 1 to 5 substituents independently selected from the group consisting of 1-6 alkoxy).
    The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.
  6. 　Ｒ１が、水素原子；ハロゲン；シアノ；Ｃ１－６アルキル；又はＣ３－１０シクロアルキルである、
    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。     R 1 is a hydrogen atom; halogen; cyano; C 1-6 alkyl; or C 3-10 cycloalkyl.
    The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.
  7. 　Wが酸素原子である、
    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。     W is an oxygen atom,
    The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.
  8. 　Wが硫黄原子である、
    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。     W is a sulfur atom,
    The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.
  9. 　Ｒ２Ａ、Ｒ２Ｂ、Ｒ２Ｃ、Ｒ２Ｄ及びＲ５が、すべて水素原子である、
    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 2A , R 2B , R 2C , R 2D and R 5 are all hydrogen atoms,
    The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.
  10. 　Ｒ６が、水素原子である、
    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。     R 6 is a hydrogen atom,
    The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.
  11. 　Ｒ３Ｂが、水素原子であり、Ｒ３Ａ及びＲ４Ａが、同一又は異なって、フッ素、Ｃ１－６アルコキシ及びＣ１－６アルキルからなる群から独立して選択される１～５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；又は４～１０員の飽和複素環である、
    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。     1 to 5 substituents in which R 3B is a hydrogen atom, and R 3A and R 4A are the same or different and are independently selected from the group consisting of fluorine, C 1-6 alkoxy and C 1-6 alkyl A C 3-10 cycloalkyl optionally substituted with a group; or a 4-10 membered saturated heterocycle,
    The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.
  12. 　Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ３ＡＲ３Ｂ又はＮ－ＣＯＲ４Ａ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。     XYZ is N—CO—NR 3A R 3B or N—COR 4A ;
    The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.
  13. 　Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ３ＡＲ３Ｂ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。     XYZ is N—CO—NR 3A R 3B ;
    The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.
  14. 　Ｘ－Ｙ－Ｚが、Ｎ－ＣＯＲ４Ａ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。     XYZ is N-COR 4A ;
    The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.
  15. 　Ｂが、Ｂ－１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。     B is B-1.
    The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.
  16. 　Ｂが、Ｂ－２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。     B is B-2,
    The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.
  17. 　Ｂが、Ｂ－３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。     B is B-3,
    The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.
  18. 　Ｂが、Ｂ－４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。     B is B-4,
    The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.
  19. 　Ｂが、Ｂ－５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。     B is B-5,
    The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.
  20. 　請求項１～１９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 19 or a pharmaceutically acceptable salt thereof.
  21. 　請求項１～１９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及び／又は予防剤。 A therapeutic 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 19 or a pharmaceutically acceptable salt thereof as an active ingredient, and / or Or a preventive agent.
  22. 　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、神経疾患、精神疾患又は炎症性疾患である、請求項２１に記載の治療剤及び／又は予防剤。 The therapeutic and / or prophylactic agent according to claim 21, wherein the disease caused by abnormality in intracellular signal transduction involving acetylcholine is a neurological disease, a mental disease or an inflammatory disease.
  23. 　神経疾患、精神疾患又は炎症性疾患が、統合失調症、アルツハイマー病、ダウン症、注意欠陥・多動性障害又は脳血管アンギオパチーである、請求項２２に記載の治療剤及び／又は予防剤。 The therapeutic agent and / or preventive agent according to claim 22, wherein the neurological disease, psychiatric disease or inflammatory disease is schizophrenia, Alzheimer's disease, Down's syndrome, attention deficit / hyperactivity disorder or cerebrovascular angiopathy.
  24. 　ＣＩＡＳ（統合失調症に伴う認知機能障害）、或いは、統合失調症、アルツハイマー病、ダウン症、注意欠陥・多動性障害又は脳血管アンギオパチーにおける、認知障害、軽度認知障害、記憶障害又は学習障害を治療及び／又は予防するための、請求項２０に記載の医薬組成物。 Treat cognitive impairment, mild cognitive impairment, memory impairment or learning impairment in CIAS (cognitive impairment associated with schizophrenia) or schizophrenia, Alzheimer's disease, Down's syndrome, attention deficit / hyperactivity disorder or cerebrovascular angiopathy 21. A pharmaceutical composition according to claim 20, for and / or prevention.
  25. 　請求項１～１９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、非定型抗精神病薬から選択される少なくとも１種以上の薬剤とを含有する医薬。 A medicament comprising the compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, and at least one drug selected from atypical antipsychotic drugs.
  26. 　治療が必要な患者に、治療上の有効量の請求項１～１９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を治療及び／又は予防するための方法。 Involves acetylcholine, characterized in that a patient in need of treatment is administered a therapeutically effective amount of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof. A method for treating and / or preventing a disease caused by abnormal intracellular signaling.
  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及び／又は予防剤を製造するための、請求項１～１９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の使用。 The compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic and / or prophylactic agent for a disease caused by abnormal intracellular signaling involving acetylcholine. Use of salt.
  28. 　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に使用するための、請求項１～１９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を含む医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof for use in the treatment of a disease caused by abnormal intracellular signaling involving acetylcholine. object.
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