WO2012133509A1 - Novel benzimidazole derivative - Google Patents

Novel benzimidazole derivative Download PDF

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WO2012133509A1
WO2012133509A1 PCT/JP2012/058096 JP2012058096W WO2012133509A1 WO 2012133509 A1 WO2012133509 A1 WO 2012133509A1 JP 2012058096 W JP2012058096 W JP 2012058096W WO 2012133509 A1 WO2012133509 A1 WO 2012133509A1
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group
alkoxy
optionally substituted
alkyl
halogen
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PCT/JP2012/058096
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French (fr)
Japanese (ja)
Inventor
幸博 西尾
慶介 柿口
治 市川
貴士 ▲高▼田
山口　洋輝
嘉人 畳谷
裕介 澤山
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大日本住友製薬株式会社
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Publication of WO2012133509A1 publication Critical patent/WO2012133509A1/en

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    • 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
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    • A61K31/4164—1,3-Diazoles
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • 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
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel benzimidazole derivative which is a modulator of ⁇ 7 nicotinic acetylcholine receptor ( ⁇ 7 nAChR). Due to their pharmacological properties, the compounds of the present invention can be used for diseases related to cholinergic activity of the central nervous system (CNS) and / or peripheral nervous system (PNS), diseases related to smooth muscle contraction, endocrine diseases, diseases related to neurodegeneration, It may be useful for the treatment of diseases such as inflammation or pain and diseases related to withdrawal symptoms caused by addictive drug abuse.
  • CNS central nervous system
  • PNS peripheral nervous system
  • diseases related to smooth muscle contraction endocrine diseases
  • diseases related to neurodegeneration It may be useful for the treatment of diseases such as inflammation or pain and diseases related to withdrawal symptoms caused by addictive drug abuse.
  • ⁇ 7 nicotinic acetylcholine receptor represents a valid molecular target for neuroprotection.
  • neuroprotection can be achieved by developing an active agonist / positive modulator of the receptor (positive allosteric modulator: PAM).
  • PAM positive allosteric modulator
  • ⁇ 7 nicotinic receptor agonists have already been identified and evaluated as potential clues for the development of neuroprotective drugs.
  • the involvement of ⁇ 7 nicotinic acetylcholine receptors in inflammation has also been reported. From the above, the development of a novel modulator of the receptor is expected to be a novel treatment for nervous system diseases, psychiatric diseases and inflammatory diseases.
  • Patent Document 1 a modulator of ⁇ 7 nicotinic acetylcholine receptor ( ⁇ 7 nAChR), but the structure is different from the compound of the present invention (Patent Document 1 and Patent Document 2).
  • An object of the present invention is to provide a novel compound having a potent ⁇ 7 nicotinic acetylcholine receptor ( ⁇ 7 nAChR) regulating action and useful as a novel therapeutic and / or preventive agent for nervous system diseases, mental disorders and inflammatory diseases. Is to provide.
  • ⁇ 7 nAChR potent ⁇ 7 nicotinic acetylcholine receptor
  • a novel compound represented by the following formula (I) has a potent ⁇ 7 nicotinic acetylcholine receptor ( ⁇ 7 nAChR) regulating action, and completed the present invention.
  • ⁇ 7 nAChR potent ⁇ 7 nicotinic acetylcholine receptor
  • a benzimidazole derivative 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.
  • Optionally substituted C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkoxy and —NR 16 R 17 3-10 cycloalkyl; 4-10 membered saturated heterocycle; hydrogen atom; halogen; hydroxyl group; or C 1-6 alkoxy R 10 to R 17 are the same or different and each represents a hydrogen atom or C 1-6 alkyl; n represents 1 or 2] Or a pharmaceutically acceptable salt thereof.
  • A is CR 1D or a nitrogen atom
  • XYZ represents N-CO-NR 4A R 5 , CR 6 -CO-NR 4A R 5 , CR 6 -NR 7 -CONR 4A R 5 , CR 6 -NR 7 -COR 4B , CR 6 -NR 7 -aryl, CR 6 -NR 7 -heteroaryl or CR 6 -CR 8 R 9 -NR 4A R 5 , R 1A , R 1B , R 1C and R 1D are the same or different and are substituted with 1 to 5 substituents selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy and —NR 10 R 11 An optionally substituted C 1-6 alkyl; a C 3-10 optionally substituted with 1 to 5 substituents selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy and —NR 10 R 11 cycloalkyl; halogen
  • A is CR 1D
  • XYZ is N—CO—NR 4A R 5
  • R 1A , R 1C and R 1D are both hydrogen atoms, and one of R 4A and R 5
  • R 1B is fluorine
  • the other of R 4A and R 5 is phenyl, 2-methoxyphenyl, 4-ethoxyphenyl, cyclohexyl, 4-methoxyphenyl, 2-ethoxyphenyl, 4-chloro-3-trifluoro Phenyl, 3-methoxyphenyl, 2-trifluoromethylphenyl, 3-methylphenyl, 2-chlorophenyl, adamantyl, 2-methylphenyl, 2,4-difluorophenyl, 4-ethoxyphenyl, 3-fluorophenyl
  • XYZ represents N—CO—NR 4A R 5 , CR 6 —NR 7 —CONR 4A R 5 , CR 6 —NR 7 —COR 4B , CR 6 —NR 7 —aryl, CR 6 -NR 7 -heteroaryl or CR 6 -CR 8 R 9 -NR 4A R 5 Item 5.
  • XYZ is N—CO—NR 4A R 5 or CR 6 —NR 7 —COR 4B .
  • Item 5 The compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.
  • XYZ is CR 6 —NR 7 —COR 4B .
  • Item 5 The compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.
  • R 4B is substituted with 1 to 5 substituents independently selected from the group consisting of aryl, heteroaryl, hydroxyl group, fluorine, C 1-6 alkoxy and C 3-10 cycloalkyl.
  • C 1-6 alkyl which may be substituted; aryl, heteroaryl, hydroxyl group, fluorine, C 1-6 alkoxy optionally substituted with 1 to 5 fluorines and optionally substituted with 1 to 5 fluorines
  • C 3-10 cycloalkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkyl (the group may form a condensed ring with aryl)
  • a 4- to 10-membered saturated heterocycle optionally substituted with 1 to 5 identical or different C 1-6 alkyls; or halogen, C 1-6 alkoxy and C 1-6 alkyl (the alkoxy and alkyl are 1-5
  • Aryl or heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group
  • R 4B may be substituted with 1 to 5 substituents independently selected from the group consisting of aryl, heteroaryl, fluorine, C 1-6 alkoxy and C 3-10 cycloalkyl.
  • C 1-6 alkyl; aryl, heteroaryl, fluorine, 1-5 fluorine may be substituted with an optionally substituted C 1-6 alkoxy and 1 to 5 fluorine by C 1-6 C 3-10 cycloalkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of alkyl (the group may form a condensed ring with aryl); the same or different A 4- to 10-membered saturated heterocycle optionally substituted with 1 to 5 C 1-6 alkyl; or halogen, C 1-6 alkoxy and C 1-6 alkyl (wherein the alkoxy and alkyl are 1-5 Replaced with one fluorine An aryl or heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of: Item 8.
  • A is CR 1D .
  • Item 10 The compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof.
  • R 2 is a hydrogen atom.
  • Item 11 The compound according to any one of Items 1 to 10, or a pharmaceutically acceptable salt thereof.
  • n is 1.
  • Item 12 The compound according to any one of Items 1 to 11, or a pharmaceutically acceptable salt thereof.
  • R 3A , R 3B , R 3C and R 3D are the same or different and each is a hydrogen atom, a halogen, a hydroxyl group or C 1-6 alkoxy.
  • Item 13 The compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof.
  • R 1A , R 1B , R 1C and R 1D are the same or different and substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group and C 1-6 alkoxy C 1-6 alkyl which may be substituted; C 3-10 cycloalkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group and C 1-6 alkoxy ; halogen, hydroxyl, C 1-6 alkoxy and C 3-6 optionally substituted by one to five substituents independently selected from the group consisting of cycloalkyl C 1-6 alkoxy; hydrogen atom; Independently from the group consisting of hydroxyl group; halogen; halogen, C 1-6 alkyl optionally substituted with 1 to 5 fluorines and C 1-6 alkoxy optionally substituted with 1 to 5 fluorines Selected That 1-5 phenyl optionally substituted with a substituent; a halogen, optionally
  • R 1A , R 1B , R 1C and R 1D are the same or different and substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group and C 1-6 alkoxy C 1-6 alkyl which may be substituted; C 3-7 cycloalkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group and C 1-6 alkoxy ; halogen, hydroxyl, C 1-6 alkoxy and C 3-6 optionally substituted by one to five substituents independently selected from the group consisting of cycloalkyl C 1-6 alkoxy; hydrogen atom; Halogen; 4-7 membered saturated heterocycle; cyano; —COOR 10 ; or —CONR 10 R 11 Item 14.
  • R 4A , R 5 and R 7 are the same or different and are substituted with 1 to 5 substituents independently selected from the group consisting of aryl, halogen, hydroxyl group and C 1-6 alkoxy.
  • R 6 , R 8, and R 9 are the same or different and each represents C 1-6 alkyl, a hydroxyl group, or a hydrogen atom.
  • Item 18 The compound according to any one of Items 1 to 16, or a pharmaceutically acceptable salt thereof.
  • R 4B is substituted with 1 to 5 substituents independently selected from the group consisting of aryl, heteroaryl, hydroxyl group, fluorine, C 1-6 alkoxy and C 3-10 cycloalkyl.
  • C 1-6 alkyl which may be substituted; aryl, heteroaryl, hydroxyl group, fluorine, C 1-6 alkoxy optionally substituted with 1 to 5 fluorines and optionally substituted with 1 to 5 fluorines
  • C 3-10 cycloalkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkyl (the group may form a condensed ring with aryl)
  • a 4- to 10-membered saturated heterocycle optionally substituted with 1 to 5 identical or different C 1-6 alkyls; or halogen, C 1-6 alkoxy and C 1-6 alkyl (the alkoxy and alkyl are 1 An aryl or heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consist
  • R 4A and R 5 are the same or different, and aryl (the group is 1 to 5 Halogen, hydroxyl, optionally substituted with C 1-6 alkyl or C 1-6 alkoxy), heteroaryl (the group consists of halogen, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy) Independently substituted from the group consisting of halogen, hydroxyl, C 1-6 alkoxy, C 3-10 cycloalkyl and —NR 14 R 15 , optionally substituted with 1 to 5 substituents selected from the group C 1-6 alkyl optionally substituted with 1 to 5 selected substituents; aryl (the group is independent of the group consisting of halogen, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy) 1 to 5 selected May be substituted with substituent), heteroaryl (in which, halogen, hydroxyl, 1 to 5 substituents
  • C 3-10 cycloalkyl (the group may form a condensed ring with aryl or heteroaryl); halogen, hydroxyl group, C 1-6 alkoxy and C 1-6 alkyl (the group is Heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of 1 to 5 fluorines), or a hydrogen atom, Item 19.
  • A is CR 1D , R 1A , R 1C and R 1D are both hydrogen atoms, R 1B is a fluorine atom or methyl, and XYZ is N—CO—NR 4A R 5.
  • R 4A and R 5 are the same or different and are aryl (the group is independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy) Optionally substituted with 1 substituent), heteroaryl (wherein the group is independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy) 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy, C 3-10 cycloalkyl and —NR 14 R 15.
  • aryl in an optionally substituted C 1 6 alkyl; aryl (said groups, halogen, optionally substituted with one to five substituents independently selected from the group consisting of hydroxyl and C 1-6 alkoxy), heteroaryl (said group , Optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy), C 3-9 cycloalkyl (including The group may form a condensed ring with aryl or heteroaryl, and is independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy, C 1-6 alkyl and —NR 14 R 15.
  • a 4-10 membered saturated heterocycle optionally substituted with C 1-6 alkyl; halogen, C 1-6 alkoxy and C 1-6 alkyl 1-5 groups 1-5 may be substituted with a substituent aryl independently selected from the group consisting of Tsu may be substituted with hydrogen); halogen, hydroxyl, C 1-6 alkoxy and C 1-6 A heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl (the group may be optionally substituted with 1 to 5 fluorines); or a hydrogen atom Is, Item 21.
  • A is CR 1D, R 1A, R 1C and R 1D are both hydrogen atoms, R 1B is a fluorine atom or a -NR 10 R 11, X-Y -Z is N-CO-
  • R 4A R 5 , R 4A and R 5 are the same or different and are independently selected from the group consisting of aryl (halogen, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy) Independently selected from the group consisting of heteroaryl, halogen, hydroxyl, C 1-6 alkoxy, C 3-10 cycloalkyl and —NR 14 R 15.
  • C 1-6 alkyl optionally substituted with 1 to 5 substituents of C 1-6 alkyl; aryl (wherein the group is selected from the group consisting of halogen, hydroxyl group and C 1-6 alkoxy) Substituted with a group Good), heteroaryl, or hydroxyl, C 1-6 alkoxy, C 1-6 alkyl, -NR 14 R 15 or the same or different one to five good C 3-10 cycloalkyl optionally substituted with halogen (However, unsubstituted cyclohexyl, except said groups, aryl or may form a heteroaryl and fused); C 1-6 saturated heterocyclic ring may 4-10 membered optionally substituted with alkyl; halogen Substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy and C 1-6 alkyl, which group may be substituted with 1 to 5 fluorines Item 22.
  • aryl wherein the group is selected from the group consisting
  • XYZ is CR 6 —NR 7 —COR 4B , n is 1, and the 1- and 4-positions of the cyclohexane ring formed are in a cis relationship.
  • Item 23 The compound according to any one of Items 1 to 22, or a pharmaceutically acceptable salt thereof.
  • R 7 is a hydrogen atom.
  • Item 24 The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 23.
  • XYZ is CR 6 —CR 8 R 9 —NR 4A R 5
  • one of R 4A and R 5 is (1) halogen, C 1-6 alkoxy and C 1-6 alkyl ( The alkoxy and alkyl are aryl or heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of 1 to 5 fluorines)
  • the other is (2) a combination of hydrogen atoms, Item 25.
  • a pharmaceutical composition comprising the compound according to any one of items 1 to 27 or a pharmaceutically acceptable salt thereof.
  • a therapeutic agent for diseases caused by abnormal intracellular signaling involving acetylcholine comprising the compound according to any one of items 1 to 27 or a pharmaceutically acceptable salt thereof as an active ingredient Or a preventive agent.
  • CIAS cognitive impairment associated with schizophrenia
  • Alzheimer's disease Down's syndrome
  • cognitive impairment memory impairment / learning impairment
  • mild cognitive impairment Item 30.
  • An acetylcholine characterized by administering a therapeutically effective amount of the compound according to any one of items 1 to 27 or a pharmaceutically acceptable salt thereof to a patient in need of treatment.
  • the compound of the present invention is useful as a novel therapeutic agent and / or preventive agent for nervous system diseases, psychiatric diseases, and inflammatory diseases (for example, senile dementia, attention deficit disorder, Alzheimer's disease, and schizophrenia).
  • the compound of the present invention is useful for the treatment and / or prevention of nervous system diseases such as schizophrenia and mental disorders as a concomitant drug with drugs classified as atypical antipsychotic drugs.
  • the compounds of the present invention may exist in the form of hydrates and / or solvates, these hydrates and / or solvates are also included in the compounds of the present invention.
  • 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.
  • the compound represented by the general formula (I) includes a deuterium converter obtained by converting any one or two or more 1 H of the compound represented by the general formula (I) to 2 H (D). Is done.
  • a solvate such as a hydrate of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof or an ethanol solvate is also represented by the general formula (I). Included in the compound.
  • Alkyl means a linear or branched saturated hydrocarbon group.
  • C 1-6 alkyl means an alkyl having 1 to 6 carbon atoms. Specific examples thereof include “C 1-6 alkyl” such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the like.
  • Cycloalkyl means a monocyclic or polycyclic saturated hydrocarbon. For example, “C 3-6 cycloalkyl” or “C 3-10 cycloalkyl” means 3 to 6 or 3 to C carbon atoms.
  • cyclic alkyls and those having a partially bridged structure or those formed a condensed ring with aryl or heteroaryl are also included.
  • C 3-6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • C 3-10 cycloalkyl in addition to the above, cycloheptyl, cyclooctyl, adamantyl and the like can be mentioned.
  • Alkoxy means a group in which a linear or branched saturated hydrocarbon group is interposed via an oxygen atom.
  • C 1-6 alkoxy means a group having 1 to 6 carbon atoms. Means alkoxy. Specific examples of “C 1-6 alkoxy” include methoxy, ethoxy, propoxy, isopropoxy, butyloxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like.
  • Halogen means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Among them, preferred is a fluorine atom or a chlorine atom.
  • aryl include phenyl, 1-naphthyl, 2-naphthyl, anthracene and the like. Of these, phenyl is preferable.
  • Heteroaryl is a monocyclic 5- to 7-membered aromatic heterocyclic group or bicyclic ring containing 1 to 4 atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom And an 8- to 11-membered aromatic heterocyclic group or a 3-ring 12- to 16-membered aromatic heterocyclic group.
  • the “4- to 10-membered saturated heterocyclic ring” means 4 to 10 atoms including 1 to 2 atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom. Means a composed heterocycle.
  • azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, tetrahydrofuran, tetrahydropyran and the like can be mentioned.
  • the “4- to 10-membered nitrogen-containing saturated heterocyclic ring” means a saturated heterocyclic ring composed of 4 to 10 atoms containing 1 to 2 nitrogen atoms in addition to carbon atoms.
  • azetidine, pyrrolidine, piperidine, piperazine, homopiperidine and the like can be mentioned.
  • CR 6 -NR 7 -aryl refers to a group in which aryl is substituted on the nitrogen atom of CR 6 -NR 7 . Like the - "aryl CR 6 -NR 7" - it means "CR 6 -NR 7 heteroaryl” etc. was also replaced with the latter group.
  • A is preferably CR 1D .
  • X—Y—Z is preferably N—CO—NR 4A R 5 , CR 6 —NR 7 —CONR 4A R 5 , CR 6 —NR 7 —COR 4B , CR 6 —NR 7 —aryl, CR 6 —NR 7 -heteroaryl or CR 6 -CR 8 R 9 -NR 4A R 5 may be mentioned, more preferably N-CO-NR 4A R 5 , CR 6 -NR 7 -COR 4B , CR 6 -NR 7 -aryl. Or CR 6 -NR 7 -heteroaryl.
  • N—CO—NR 4A R 5 or CR 6 —NR 7 —COR 4B is used.
  • R 1A to R 1D are preferably the same or different and may be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, C 1-6 alkoxy and —NR 10 R 11.
  • C 1-6 alkyl, hydrogen atom, halogen, C 3-10 cycloalkyl, C 1-6 alkoxy, C 3-10 cycloalkoxy, —NR 10 R 11 , cyano, —COOR 10 , —CONR 10 R 11 , —NR 10 COR 11 , —SO 2 NR 10 R 11, or —NR 10 SO 2 R 11 may be mentioned. More preferably, C 1-6 alkyl, hydrogen atom, halogen, C 3-10 which may be substituted with 1 to 5 substituents independently selected from the group consisting of halogen and C 1-6 alkoxy Examples include cycloalkyl, C 1-6 alkoxy or C 3-10 cycloalkoxy.
  • R 2 is preferably C 1-6 alkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group and —NR 12 R 13 , a hydrogen atom, C 1 -6 alkoxy or a 4- to 10-membered saturated heterocyclic ring can be mentioned, and more preferable examples include C 1-6 alkyl, hydrogen atom or C 1-6 alkoxy optionally substituted with 1 to 5 halogens. . Most preferably, a hydrogen atom is mentioned.
  • R 3A , R 3B , R 3C and R 3D are preferably the same or different and may be substituted with 1 to 5 substituents independently selected from the group consisting of halogen and —NR 14 R 15 Good C 1-6 alkyl, a hydrogen atom or halogen is preferable, and C 1-6 alkyl, a hydrogen atom or halogen is more preferable.
  • R 4A preferably as R 5 and R 7, which may be identical or different, halogen, optionally substituted with 1 to 5 substituents selected from the group consisting of hydroxyl and C 1-6 alkoxy C 1- 6 alkyl; C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents selected from the group consisting of halogen, hydroxyl group and C 1-6 alkoxy; 4- to 10-membered saturated heterocycle or hydrogen Atoms, and more preferably, a C 3-10 cycloalkyl which may be substituted with 1 to 5 substituents selected from the group consisting of halogen, hydroxyl group and C 1-6 alkoxy, or a hydrogen atom. It is done.
  • R 4B is preferably substituted with 1 to 5 substituents independently selected from the group consisting of aryl, heteroaryl, hydroxyl group, fluorine, C 1-6 alkoxy and C 3-10 cycloalkyl.
  • C 1-6 alkyl; aryl, heteroaryl, hydroxyl, fluorine, 1-5 fluorine may be substituted with C 1-6 alkoxy and 1 to 5 substituents
  • C 1 be substituted by fluorine C 3-10 cycloalkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of -6 alkyl (the group may form a condensed ring with aryl); Or a 4- to 10-membered saturated heterocycle optionally substituted with 1 to 5 different C 1-6 alkyls; or halogen, C 1-6 alkoxy and C 1-6 alkyl (the alkoxy and alkyl are And aryl or heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of 1 to 5
  • aryl, heteroaryl, hydroxyl, fluorine, C 1-6 alkoxy and C 3-10 cycloalkyl 1 to 5 substituents independently selected from the group consisting of aryl, heteroaryl, hydroxyl, fluorine, C 1-6 alkoxy and C 3-10 cycloalkyl.
  • 1-6 alkyl; aryl, heteroaryl, hydroxyl, fluorine, optionally substituted with 1-5 optionally substituted by fluorine C 1-6 alkoxy and 1 to 5 fluorine C 1-6 C 3-10 cycloalkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of alkyl (which may form a condensed ring with aryl); or the same or Examples thereof include a 4- to 10-membered saturated heterocyclic ring which may be substituted with 1 to 5 different C 1-6 alkyls.
  • fluorine, C 1-6 alkoxy and C 3-10 ⁇ 1 are independently selected from the group consisting of cycloalkyl 5 substituents optionally substituted by C 1-6 alkyl; fluorine, 1 to 1 to 5 selected 5 substituents are fluorine substituted C 1-6 alkoxy and 1 to 5 fluorine independently from the group consisting of C 1-6 alkyl optionally substituted C 3-10 cycloalkyl optionally substituted with one substituent; or a 4-10 membered saturated heterocycle.
  • R 6 , R 8 and R 9 are preferably the same or different and include a hydrogen atom, halogen, hydroxyl group, C 1-6 alkyl or C 1-6 alkoxy, and more preferably a hydrogen atom or halogen.
  • R 10 to R 17 are the same or different and include a hydrogen atom or C 1-6 alkyl, preferably a hydrogen atom.
  • n 1 or 2 is mentioned, Preferably 1 is mentioned.
  • the pharmaceutically acceptable salt of the compound represented by the formula (I) is a pharmaceutically acceptable acid addition of the compound of the formula (I) having a group capable of forming an acid addition salt in the structure.
  • Means salt Specific examples of acid addition salts include hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, phosphate and other inorganic acid salts, oxalate, malonate, maleate Acid, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate And organic acid salts such as glutamic acid salts and aspartic acid salts.
  • compound represented by a formula (I) has acidic functional groups, such as a carboxyl group
  • various bases and salts can be formed.
  • the pharmaceutically acceptable salt in this case include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt, and ammonium salt. These salts can be obtained by a conventional method such as recrystallization after mixing the compound of the present invention represented by formula (I) with a base.
  • the 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 D.
  • a compound represented by the formula A1 in which XYZ is N—CO—NR 4A R 5 (hereinafter also referred to as the compound A1) is, for example, the following production method Can be manufactured.
  • A, R 1A to R 1D , R 2 , R 3A to R 3D , R 4A , R 5 and n are as defined in Item 1, P is an amino-protecting group, and X is halogen. Etc., R means a methyl group or a phenyl group)
  • 2-halonitrobenzene in which A is a compound a1 having CR 1D is, for example, Bioorganic & Medicinal Chemistry Letters 2003, 13 (10), 1725-1728, Tetrahedron 1999, 55 (25), 7725-7738, Synth. Commun. 1998, 28 (23), 4295-4301, etc., or can be synthesized as a commercial product.
  • 2-halonitropyridine in which A is a nitrogen atom compound a1 is, for example, Bioorganic & Medicinal Chemistry Letters 2003, 13 (10), 525-527, J. Heterocyclic Chem. 2000, 37 (5), 1253. -1256, Tetrahedron Lett. 1993, 34 (18), 2937-2940, J. Heterocyclic Chem. 1996, 33 (6), 1815-1821, J. Org. Chem. 1991, 56 (9), 3006-3009, etc. 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 compound a6 in a suitable solvent in the presence of various bases.
  • the base used in this step is selected from the bases exemplified below, and is preferably diisopropylethylamine or potassium carbonate.
  • the solvent used in this step is selected from the solvents exemplified below, and preferably dimethylformamide or tetrahydrofuran.
  • the methods described in Tetrahedron Lett. 1994, 35 (31), 5649-5652, Tetrahedron Lett. 2002, 43 (43), 7707-7710, etc. are known and synthesized in the same manner. Can do.
  • Step A-2 compound a3 can be obtained by reducing compound a2 obtained in step A-1 in the presence or absence of a catalyst.
  • a catalyst formic acid salts such as ammonium formate, hydrazine, zinc, iron, and tin dichloride can be used.
  • the catalyst include those supported on a carrier such as a transition metal such as palladium, nickel, rhodium, cobalt or platinum, a salt thereof, a complex thereof, or a polymer.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably tetrahydrofuran or methanol. Similar reactions include, for example, Org. Lett.
  • Step A-3 Compound a4 in which R 2 is a hydrogen atom can be obtained by reacting compound a3 obtained in step A-2 with trimethoxymethane, triethoxyethane, or formic acid in a suitable solvent.
  • trimethoxymethane triethoxyethane
  • formic acid formic acid
  • the methods described in Tetrahedron Lett. 2006, 47 (30), 5359-5361, International Publication No. 2010/012121, International Publication No. 2010/027500, etc. are known, Can be synthesized.
  • the compound a4 in which R 2 is bonded to the benzimidazole ring with carbon-carbon is obtained by reacting the compound a3 obtained in the above step A-2 with the corresponding carboxylic acid (R 2 CO 2 H) or acid in an appropriate solvent.
  • Step A-4 This step is a step of obtaining a compound a5 by deprotecting the amino-protecting group P of the compound a4 obtained in the step A-3.
  • 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 A1 by reacting compound a5 obtained in step A-4 with compound a7, a8 or a9 in an appropriate solvent in the presence of various bases.
  • the base used in this step is selected from the bases exemplified below, and is preferably diisopropylethylamine or triethylamine.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably tetrahydrofuran or ethanol.
  • Step A-6 This step is a step of introducing a leaving group L into the compound a5 obtained in the above step A-4.
  • a1 is obtained by reacting 1,1′-carbonyldiimidazole or substituted or unsubstituted phenyl chloroformate in an appropriate solvent in the presence of various bases.
  • 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 methylene chloride or dichloroethane. As a similar reaction, for example, it can be synthesized by a method described in International Publication No. 2003/103669 pamphlet.
  • Step A-7 This step is a step of obtaining compound A1 by reacting compound a10 obtained in the above step A-6 with an amine in an appropriate solvent in the presence of various bases.
  • the solvent used in this step is selected from the solvents exemplified below, and is preferably tetrahydrofuran or dimethylformamide. As a similar reaction, for example, it can be synthesized by a method described in International Publication No. 2003/103669 pamphlet.
  • a compound represented by the formula [B1] in which XYZ is CR 6 —CO—NR 4A R 5 (hereinafter also referred to as compound B1) is, for example, It can be produced by the following production method.
  • A, R 1A to R 1D , R 2 , R 3A to R 3D , R 4A , R 5 , R 6 and n are as defined in Item 1, and Rx is a C 1-4 alkyl group.
  • X means a leaving group such as halogen
  • Step B-1 This step is a step of obtaining compound b1 by reacting compound b1 with compound b5 under the conditions according to the above step A-1.
  • Compound b5 can be synthesized, for example, by the method described in International Publication No. 2007/127382 pamphlet, or can be purchased as a commercial product.
  • Step B-2 This step is a step of converting the compound b1 obtained in the step B-1 into the compound b2 under the conditions according to the step A-2.
  • Step B-3 This step is a step of converting the compound b2 obtained in the step B-2 to the compound b3 under the conditions according to the step A-3.
  • Step B-4 This step is a step of converting the ester compound b3 obtained in the step B-3 to the corresponding carboxylic acid compound b4.
  • This step can be carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).
  • Step B-5 This step is a step of obtaining compound B1 by reacting compound b6 obtained in step B-4 with compound b6 in a suitable solvent in the presence of various condensing agents.
  • the condensing agent used in this step is preferably EDCI (including hydrochloride) or HBTU.
  • the solvent used in this step is selected from the solvents exemplified below.
  • a compound represented by the formula [C1] wherein XYZ is CR 6 -CR 8 R 9 -NR 4A R 5 (hereinafter also referred to as the compound C1) Can be produced, for example, by the following production method.
  • A, R 1A to R 1D , R 2 , R 3A to R 3D , R 4A , R 5 , R 6 , R 8 , R 9 and n are as defined in Item 1; , C 1-4 alkyl group)
  • Step C-1 This step is a step of converting the ester compound b3 obtained in the step B-3 to the corresponding aldehyde compound c1 using a reducing agent such as diisobutylaluminum hydride, sodium borohydride or lithium borohydride.
  • a reducing agent such as diisobutylaluminum hydride, sodium borohydride or lithium borohydride.
  • Similar reactions include, for example, Chem. Pharm. Bull. 1993, 41 (5), 882-888, Tetrahedron Lett. 1996, 37 (14), 2467-2470, Chem. Lett. 2007, 36 (7), 886- The methods described in 887, Tetrahedron 2001, 57 (14), 2701-2710 and the like are known and can be synthesized in the same manner.
  • the same conversion can also be performed by converting to an alcohol compound using a reducing agent such as lithium aluminum hydride and then converting to an aldehyde by Swern oxidation or the like.
  • a reducing agent such as lithium aluminum hydride
  • a similar reaction for example, a method described in Bioorg. Med. Chem. Lett. 2001, 11 (16), 2177-2180, Bioorg. Med. Chem. Lett. 1998, 8 (24), 3615-3620, etc. Are known and can be synthesized similarly.
  • Step C-2 the corresponding aldehyde compound C1 is obtained by reductive amination of the compound c2 in the presence of a reducing agent such as NaBH (OAc) 3 or NaBH 3 CN with respect to the aldehyde compound c1 obtained in the step C-1. It is the process of converting into. Similar reactions include, for example, J. Org. Chem. 1996, 61 (11), 3849-3862, J. Org. Chem. 1991, 56 (17), 5192-5196, Carbohydr. Res. 1999, 315 (3- 4), 339-344 and the like are known and can be synthesized in the same manner.
  • a reducing agent such as NaBH (OAc) 3 or NaBH 3 CN
  • XYZ is the formula [D1, D2], which is CR 6 —NR 7 —COR 4B , or the formula, which is CR 6 —NR 7 —CONR 4A R 5
  • the compounds represented by [D3, D4] (hereinafter also referred to as compounds D1, D2, D3, and D4) can be produced, for example, by the following production method.
  • A, R 1A to R 1D , R 2 , R 3A to R 3D , R 4B , R 5 to R 7 and n are as defined in Item 1, P is an amino-protecting group, X means a leaving group such as halogen)
  • Step D-1 This step is a step of obtaining compound d1 by reacting compound d1 with compound d6 under the same conditions as in step A-1.
  • Compound d6 can be synthesized, for example, by the method described in International Publication No. 2010/022159 pamphlet or International Publication No. 2007/08669 pamphlet, or can be purchased as a commercial product.
  • Step D-2 This step is a step of converting the compound d1 obtained in the step D-1 into the compound d2 under the conditions according to the step A-2.
  • Step D-3 This step is a step of converting the compound d2 obtained in the step D-2 to the compound d3 under the conditions according to the step A-3.
  • Step D-4 This step is a step of obtaining the compound d4 by deprotecting the amino-protecting group P of the compound d3 obtained in the step D-3.
  • 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 D-5 This step is a step of obtaining compound D1 by reacting compound d4 obtained in step D-4 with compound d7 or d8 in a suitable solvent in the presence of various condensing agents or bases.
  • the condensing agent used in this step is preferably EDCI (including hydrochloride) or HBTU.
  • the base used 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 or tetrahydrofuran.
  • Step D-6 This step is a step of converting the compound d4 obtained in the step D-4 to the compound d5.
  • R 7 is alkyl or cycloalkyl
  • Compound d5 can be synthesized. Similar transformations include, for example, Chem. Commun. 2004, 353-359, J. Comb. Chem. 2006, 8 (6), 834-840, J. Org. Chem. 1994, 59 (7), 1771-1778 , J. Org. Chem. 1995, 60 (10), 2989-2999, Bioorg. Med.
  • Step D-7 This step is a step of converting the compound d5 obtained in the step D-6 to the compound D2 by reacting the compound d7 or d8 under the conditions according to the step D-5.
  • R 1A to R 1D , R 2 , R 3A to R 3D , R 4A , R 5 to R 7 and n are as defined in Item 1;
  • X is a leaving group such as halogen;
  • R means a methyl group or a phenyl group
  • Step D-8 This step is a step of converting the compound d4 obtained in the step D-4 to the compound D3 under the conditions according to the step A-5.
  • Step D-9 This step is a step of converting the compound d5 obtained in the step D-6 to the compound D4 under the conditions according to the step A-5.
  • 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 methyl ketone
  • Halogenated hydrocarbons such as methylene and chloroform
  • ethers such as tetrahydrofuran (THF) and dioxane
  • aromatic hydrocarbons such as toluene and benzene
  • aliphatic hydrocarbons such as hexane and heptane
  • ethyl acetate Esters such as propyl acetate
  • amides such as N, N-dimethylformamide (DMF), N-methyl-2-pyrrolidone
  • sulfoxides such as dimethyl sulfoxide (DMSO)
  • nitriles such as acetonitrile.
  • 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.
  • extraction, distribution, reprecipitation, column chromatography (for example, silica gel column chromatography, ion exchange column chromatography or preparative liquid chromatography) or recrystallization may be mentioned.
  • the recrystallization solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as benzene and toluene, acetone and the like.
  • Ketone solvents such as dichloromethane or chloroform
  • hydrocarbon solvents such as hexane
  • aprotic solvents such as dimethylformamide or acetonitrile
  • water or a mixed solvent thereof.
  • the methods described in Experimental Chemistry Course (The Chemical Society of Japan, Maruzen) vol. 1 can be used.
  • the molecular structure of the compound of the present invention is determined by referring to the structure derived from each raw material compound, spectroscopic techniques such as nuclear magnetic resonance, infrared absorption, and circular two-spectrum spectroscopy, and mass. It can be easily done by analytical methods.
  • the compounds of the present invention represented by the formula (I) or pharmaceutically acceptable salts thereof may have asymmetry or may have a substituent having an asymmetric carbon.
  • Has optical isomers The compounds of the present invention include mixtures of these isomers and isolated ones, which can be produced according to ordinary methods. Examples of the production method include a method using a raw material having an asymmetric point, or a method of introducing asymmetry at an intermediate stage. For example, in the case of optical isomers, optical isomers can be obtained by using optically active raw materials or by performing optical resolution at an appropriate stage of the production process.
  • the optical resolution method for example, when the compound represented by the formula (I) or an intermediate thereof has a basic functional group, it 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, or sulfonic acid such as camphorsulfonic acid or bromocamphorsulfonic acid
  • camphorsulfonic acid or bromocamphorsulfonic acid camphorsulfonic acid or bromocamphorsul
  • Stereomer method can be mentioned.
  • an optically active amine for example, 1-phenylethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine, etc.
  • the optical resolution can also be carried out by forming a salt using an organic amine).
  • the temperature for forming the salt 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.
  • a high-purity optically active salt can be obtained.
  • the optically resolved salt can be treated with an acid or base by a conventional method to obtain a free form.
  • an optical resolution is achieved by forming an amide using a chemically active amine (eg, 1-phenylethylamine). Can also be performed.
  • the compound of the present invention can be a novel therapeutic agent and / or preventive agent for nervous system diseases, psychiatric diseases, and inflammatory diseases (for example, senile dementia, attention deficit disorder, Alzheimer's disease, and schizophrenia).
  • the administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration, and the daily dose varies depending on the type of compound, administration method, patient symptom / age and the like.
  • oral administration usually about 0.01 to 1000 mg, more preferably about 0.1 to 500 mg per kg body weight of a human or mammal can be administered in 1 to several divided doses.
  • parenteral administration such as intravenous injection, usually, for example, about 0.01 mg to 300 mg, more preferably about 1 mg to 100 mg per kg body weight of a human or mammal can be administered.
  • Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, injections, suppositories, eye drops, ointments, coatings, patches, inhalants and the like.
  • These preparations can be prepared according to a conventional method. In the case of a liquid preparation, it may be dissolved or suspended in water, an appropriate aqueous solution or other appropriate medium at the time of use. Tablets and granules may be coated by a known method. In addition, these formulations may contain other therapeutically valuable ingredients.
  • the compound of the present invention can be used in combination with drugs classified as atypical antipsychotic drugs.
  • atypical antipsychotics include olanzapine, risperidone, paliperidone, quetiapine, ziprasidone, aripiprazole, asenapine, iloperidone, clozapine, sertindole, blonanserin and lurasidone.
  • LCMS measurement conditions 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, measurement conditions used for the measurement are denoted by A to G.
  • Reference example 3 cis-4- (5-Methyl-1H-benzimidazol-1-yl) cyclohexanecarbaldehyde Lithium aluminum hydride (1.5 g) was added to a THF solution (20 ml) of C2 (8.2 g) obtained by the same method as in Reference Example 2 under ice cooling. The resulting suspension was stirred overnight at room temperature and then quenched with saturated aqueous ammonium chloride and then filtered through celite. THF was removed from the solution after filtration, and the mixture was extracted twice with chloroform and washed with saturated brine. The chloroform layer was dried over sodium sulfate and concentrated under reduced pressure to obtain a solid (3.5 g).
  • Example 1 N-cyclohexyl-4- (5-fluoro-1H-benzimidazol-1-yl) piperidine-1-carboxamide Reference Example 1 (300 mg) was dissolved in formic acid (10 ml), and the resulting solution was stirred at 60 ° C. for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with 2% methanol-containing chloroform. The obtained organic layer was dried over sodium sulfate and evaporated under reduced pressure.
  • Example 2 cis-N-cyclohexyl-4- (5-methyl-1H-benzimidazol-1-yl) cyclohexanecarboxamide Triethylamine (150 mg) and cyclohexylamine (150 mg) were added to a suspension of THF (3 ml) in Reference Example 2 (110 mg), EDCI hydrochloride (152 mg) and HOBt (110 mg). Stir overnight. After THF was removed under reduced pressure, ethyl acetate was added, and the mixture was washed with a saturated aqueous ammonium chloride solution and saturated brine.
  • Example 3 trans-N-cyclohexyl-4- (5-methyl-1H-benzimidazol-1-yl) cyclohexanecarboxamide
  • trans-4- (5-methyl-1H-benzoimidazol-1-yl) cyclohexanecarboxylic acid formate (60 mg) obtained by the same method as in Reference Example 2.
  • Example 3 was synthesized (42 mg).
  • Example 4 4-chloro-N- ⁇ [cis-4- (5-methyl-1H-benzimidazol-1-yl) cyclohexyl] methyl ⁇ aniline 4-Chloroaniline (30 mg) and acetic acid (0.1 ml) were added to the methanol solution of Reference Example 3 (0.2 ml, 1.0 M) and stirred for 1 hour, and then NaBH 3 CN (15 mg) was added at room temperature. Stir overnight. A saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with chloroform, and washed with saturated brine. The obtained chloroform solution was dried over sodium sulfate and concentrated.
  • Example 5 N- [cis-4- (5-methyl-1H-benzimidazol-1-yl) cyclohexyl] cyclohexanecarboxamide Triethylamine (37.8 ⁇ l), HOAt (13.5 mg) and EDCI hydrochloride (17.3 mg) were added to a DMF solution (1.0 ml) of Reference Example 4 (20 mg), and after stirring at room temperature for 1 hour, cyclohexanecarboxylic acid ( 13 ⁇ l) was added and stirred overnight at room temperature. After THF was removed under reduced pressure, ethyl acetate was added, and the mixture was washed with a saturated aqueous ammonium chloride solution and saturated brine.
  • Example 6 to 79 (Example 1 analogs) The corresponding starting materials were used and reacted in the same manner as in Example 1 to obtain the compounds shown in Table 1.
  • Example 80 to 91 (Example 2 analogs) The corresponding starting materials were used and reacted in the same manner as in Example 2 to obtain the compounds shown in Table 2.
  • Example 414 trans-4- (5-Methyl-1H-benzimidazol-1-yl) cyclohexanamine dihydrochloride was prepared in the same manner as in Reference Example 4 using tert-butyl (trans-4-aminocyclohexyl) carbamate.
  • the compounds shown in Table 5 were obtained by synthesizing and subjecting the corresponding carboxylic acid to the same reaction and treatment as in Example 5.
  • the following compounds are envisaged. These include various amines (cis-4- [5- (cyclopropoxy) -1H-benzoimidazol-1-yl] cyclohexaneamine, cis-4- [5- (cyclobutoxy) -1H-benzimidazole-1- Yl] cyclohexanamine or cis-4- [5- (difluoromethoxy) -1H-benzimidazol-1-yl] cyclohexanamine) and the corresponding carboxylic acid, the same reaction and treatment as in Example 5. Can be synthesized.
  • the various amines can be synthesized by alkylating 4-fluoro-3-nitrophenol and reacting and treating the resulting 4-alkoxy-1-fluoro-2-nitrobenzene in the same manner as in Reference Example 4.
  • As a similar reaction of the above cyclopropylation for example, it is synthesized in the same manner by the method described in International Publication No. 2011/079102, Pamphlet of International Publication No. 2010/105179, Pamphlet of International Publication No. 2008/101939, etc. can do.
  • Test Examples The pharmacological test results of the representative compounds of the present invention are shown below, and the pharmacological actions of the compounds are described. However, the present invention is not limited to these test examples.
  • Test Example 1 PAM activity evaluation using human ⁇ 7 nACh receptor stable expression cells
  • Human ⁇ 7 nAChR stable expression cells Human ⁇ 7 nAChR stable expression cells were prepared and subjected to culture. Specifically, rat pituitary-derived GH4C1 cells (cat # CCL-82.2, ATCC, USA) were used as host cells.
  • Aequorin by introducing pcDNA3.1Zeo vector into which the nucleotide sequence encoding the protein of GenBank BAC81731 was inserted and pcDNA3.1 vector (cat # V790-20, invitrogen, Carlsbad, CA, USA) into which the human ⁇ 7 nAChR gene was inserted And human ⁇ 7 nAChR stably expressing cells were obtained.
  • Zeocin catalog # R25001, invitrogen, Carlsbad, CA, USA
  • Geneticin catalog # 10131-027, invitrogen, Carlsbad, CA, USA
  • the medium includes 2.5% fetal bovine serum (cat # 2917354, ICN Biomedicals, Inc, USA), 15% inactivated horse serum (cat # 26050-088, invitrogen, Carlsbad, CA, USA), 1 ⁇ g / mL Geneticin, Collagen Type 1 using F-10 Nutrient Mixture (Ham) medium (cat # 11550-043, invitrogen, Carlsbad, CA, USA) containing 5 ⁇ g / mL Puromycin (cat # 14861-84, invitrogen, Carlsbad, CA, USA) Culturing was performed in a coat dish (cat # 4030-010, iwaki, Tokyo, Japan).
  • the medium was changed every 2-3 days, and cells were collected by TrypLE Express (cat # 45604-021, invitrogen, Carlsbad, CA, USA) treatment every 7 days and subcultured. Seven days after passage, cells were collected by TrypLE Express treatment in a state of about 80% confluence, and Hanks (cat # 14065-056, invitrogen, Carlsbad, CA, USA) / 20 mM Hepes (cat # 15630-080, invitrogen , Carlsbad, CA, USA) Suspended in a reaction medium consisting of Buffer (pH 7.4), F-10 Nutrient Mixture (Ham), 0.1 mg / mL Geneticin to 20000 cells / 25 ⁇ L / well, and a 384-well plate ( cat # 781090, Greiner, Germany).
  • Viviren (cat # E649X, Promega, Madison, WI, USA) was added to a final concentration of 4 ⁇ M (15 ⁇ L / well), and the mixture was allowed to stand for 4 hours at room temperature in the dark after centrifugation.
  • test compound A DMSO solution having a concentration 1000 times the final concentration was prepared as a test compound, and this solution was added to Hanks / 20 mM HEPES / 0.2% BSA (cat # A3803, Sigma, St. Louis, MO, USA). The final concentration was adjusted to 6 times the final concentration.
  • PAM activity evaluation FDSS7000 (Hamamatsu Photonics) was used for the detection of the luminescent signal by ⁇ 7 nAChR stimulation. Test compounds were added to the plates to which cells and luminescent substrate had been added, and ACh at a concentration indicative of EC 20 was added alone after 150 seconds. The luminescence signal (center wavelength: 465 nm) was measured for 138 seconds after 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. . Table 7 shows data of ⁇ 7 PAM activity of representative compounds.
  • the compound of the present invention had ⁇ 7 nAChR PAM activity in the PAM activity evaluation test.
  • Examples 2, 5, 6, 9, 20, 36, 54, 103, 106, 108, 137, 150, 157, 159, 168, 172, 174, 180, 181, 202, 212, 217, 221, 222, 224, 244, 245, 247, 280, 282, 283 showed stronger PAM activity.
  • Example 3 Evaluation of improvement of cognitive impairment using rat Y-shaped maze test (hereinafter referred to as Y-maze test)
  • Y-maze test In a Y-shaped maze test using 280-300 g Slc: Wistar rats (male, SLC), memory impairment was caused by subcutaneous administration of 0.6 mg / kg Scopolamine HBr (cat # S0929, Sigma Aldrich, Japan)
  • the compound of the present invention is pretreated and the memory impairment improving action is evaluated.
  • Example 9 and Example 192 a significant memory impairment improving action was confirmed at 3 or 10 mg / kg (oral), respectively.
  • the derivative 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 Useful for treatment of diseases and the like.
  • ⁇ 7hnAChR central nervous system
  • PNS peripheral nervous system

Abstract

A therapeutic agent for diseases associated with the cholinergic properties of the central nervous system (CNS) and/or the peripheral nervous system (PNS), diseases associated with the contraction of smooth muscles, endocrine diseases, diseases associated with nerve degeneration and the like, which comprises a compound represented by formula (I) [wherein A represents CR1D or a nitrogen atom; X-Y-Z represents N-CO-NR4AR5 or the like; R1A, R1B, R1C and R1D may be the same as or different from one another and independently represent a C1-6 alkyl group which may be substituted, or the like; R2 represents a hydrogen atom or the like; R4A, R4B, R5 and R7 may be the same as or different from one another and independently represent a C3-10 cycloalkyl group which may be substituted, or the like; R6, R8 and R9 may be the same as or different from one another and independently represent a hydrogen atom or the like; R10 to R17 may be the same as or different from one another and independently represent a hydrogen atom or the like; and n represents 1 or 2] or a pharmaceutically acceptable salt thereof and has a potent α7 nicotinic acetylcholine receptor (α7 nAChR) modulating activity.

Description

新規ベンズイミダゾール誘導体New benzimidazole 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ベンズイミダゾール誘導体に関する。それらの薬理学的特性から、本発明の化合物は、中枢神経系（ＣＮＳ）及び／又は末梢神経系（ＰＮＳ）のコリン作動性に関する疾患、平滑筋収縮に関する疾患、内分泌疾患、神経変性に関する疾患、炎症又は痛み等の疾患及び常習性の薬物乱用から引き起こされる禁断症状に関する疾患等の治療に有用であり得る。 The present invention relates to a novel benzimidazole derivative which is a modulator of α7 nicotinic acetylcholine receptor (α7 nAChR). Due to their pharmacological properties, the compounds of the present invention can be used for diseases related to cholinergic activity of the central nervous system (CNS) and / or peripheral nervous system (PNS), diseases related to smooth muscle contraction, endocrine diseases, diseases related to neurodegeneration, It may be useful for the treatment of diseases such as inflammation or pain and diseases related to withdrawal symptoms caused by addictive drug abuse.
　近年、ニコチンの潜在的な神経保護効果が示されており、興奮毒性傷害、栄養欠乏、虚血、外傷、アミロイドベータ（Ａβ）媒介神経細胞死およびタンパク質凝集媒介神経変性を伴う動物および培養細胞の様々な神経変性モデルが提唱されている。ニコチンが神経保護効果を呈する多くの例において、α７サブタイプ含有ニコチン性アセチルコリン受容体が活性化されていることが明らかになっている。これらは、ニコチンが神経保護効果を媒介するために役立つことが示唆され、α７サブタイプを含む受容体の直接的関与が想起されてきた。これらデータから、α７ニコチン性アセチルコリン受容体が、神経保護として妥当な分子標的の代表であることが示唆される。つまり、該受容体の活性なアゴニスト／正のモジュレーター（ポジティブアロステリックモジュレーター：ＰＡＭ）を開発することにより、神経保護が達成され得る。実際に、α７ニコチン性受容体アゴニストはすでに同定され、神経保護薬の開発のために可能性ある手がかりとして評価されている。また、近年α７ニコチン性アセチルコリン受容体の炎症への関与も、報告されている。以上のことから、該受容体の新規モジュレーターの開発は、神経系疾患、精神疾患及び炎症性疾患の新規な治療が想定される。 In recent years, the potential neuroprotective effects of nicotine have been shown, in animals and cultured cells with excitotoxic injury, nutrient deprivation, ischemia, trauma, amyloid beta (Aβ) mediated neuronal cell death and protein aggregation mediated neurodegeneration Various neurodegenerative models have been proposed. In many instances where nicotine exhibits a neuroprotective effect, it has been shown that the α7 subtype-containing nicotinic acetylcholine receptor is activated. These have been suggested that nicotine helps to mediate neuroprotective effects, and direct involvement of receptors including the α7 subtype has been recalled. These data suggest that the α7 nicotinic acetylcholine receptor represents a valid molecular target for neuroprotection. Thus, neuroprotection can be achieved by developing an active agonist / positive modulator of the receptor (positive allosteric modulator: PAM). In fact, α7 nicotinic receptor agonists have already been identified and evaluated as potential clues for the development of neuroprotective drugs. In recent years, the involvement of α7 nicotinic acetylcholine receptors in inflammation has also been reported. From the above, the development of a novel modulator of the receptor is expected to be a novel treatment for nervous system diseases, psychiatric diseases and inflammatory diseases.
　これまでに、α７ニコチン性アセチルコリン受容体（α７ ｎＡＣｈＲ）の調節物質に関する開示はあるが、本願発明の化合物とは構造が異なる（特許文献１及び特許文献２）。 So far, there has been disclosure regarding a modulator of α7 nicotinic acetylcholine receptor (α7 nAChR), but the structure is different from the compound of the present invention (Patent Document 1 and Patent Document 2).
国際公開第２００３／０９３２５０号パンフレットInternational Publication No. 2003/093250 Pamphlet 国際公開第２００６／１３８５１０号パンフレットInternational Publication No. 2006/138510 Pamphlet
　本発明の課題は、強力なα７ニコチン性アセチルコリン受容体（α７ ｎＡＣｈＲ）の調節作用を有し、神経系疾患、精神疾患及び炎症性疾患の新規な治療剤及び／又は予防剤として有用な新規化合物を提供することにある。 An object of the present invention is to provide a novel compound having a potent α7 nicotinic acetylcholine receptor (α7 nAChR) regulating action and useful as a novel therapeutic and / or preventive agent for nervous system diseases, mental disorders and inflammatory diseases. Is to provide.
　本発明者らは、鋭意研究を行った結果、下記式（Ｉ）で表される新規化合物が強力なα７ニコチン性アセチルコリン受容体（α７ ｎＡＣｈＲ）の調節作用を有することを見出し、本発明を完成させた。本発明によれば、下記式（Ｉ）で表されるベンズイミダゾール誘導体又はその製薬学的に許容される塩（以下、「本発明の化合物」と称することもある）が提供される。 As a result of intensive studies, the present inventors have found that a novel compound represented by the following formula (I) has a potent α7 nicotinic acetylcholine receptor (α7 nAChR) regulating action, and completed the present invention. I let you. According to the present invention, a benzimidazole derivative 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］下記式（Ｉ）：
Figure JPOXMLDOC01-appb-C000002
 ［式中、
　Ａは、ＣＲ１Ｄ又は窒素原子を表し、
　Ｘ－Ｙ－Ｚは、Ｎ－ＣＯ－ＮＲ４ＡＲ５、ＣＲ６－ＣＯ－ＮＲ４ＡＲ５、ＣＲ６－ＮＲ７－ＣＯＮＲ４ＡＲ５、ＣＲ６－ＮＲ７－ＣＯＲ４Ｂ、ＣＲ６－ＮＲ７－アリール、ＣＲ６－ＮＲ７－ヘテロアリール又はＣＲ６－ＣＲ８Ｒ９－ＮＲ４ＡＲ５を表し、
　Ｒ１Ａ、Ｒ１Ｂ、Ｒ１Ｃ及びＲ１Ｄは、同一又は異なって、ハロゲン、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１０Ｒ１１からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；ハロゲン、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１０Ｒ１１からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルキル；ハロゲン、水酸基、Ｃ１－６アルコキシ、Ｃ３－６シクロアルキル及び－ＮＲ１０Ｒ１１からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルコキシ（但し、Ｒ１Ｂが－ＮＲ１０Ｒ１１で置換された該基を除く）；水素原子；水酸基；ハロゲン；ハロゲン、１～５個のフッ素で置換されていてもよいＣ１－６アルキル及び１～５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フェニル；ハロゲン、１～５個のフッ素で置換されていてもよいＣ１－６アルキル及び１～５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ヘテロアリール；ハロゲン、１～５個のフッ素で置換されていてもよいＣ１－６アルキル及び１～５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Ｃ３－１０シクロアルコキシ；４～１０員の飽和複素環；ニトロ；－ＮＲ１０Ｒ１１；シアノ；－ＣＯＯＲ１０；－ＣＯＮＲ１０Ｒ１１；－ＮＲ１０ＣＯＲ１１；－ＳＯ２ＮＲ１０Ｒ１１；又は－ＮＲ１０ＳＯ２Ｒ１１を表し、ここにおいて、（１）Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ４ＡＲ５のとき、Ｒ１Ａ、Ｒ１Ｂ、Ｒ１Ｃ及びＲ１Ｄは、少なくとも１つは、水素原子以外の基であり（但し、Ｒ１Ａ、Ｒ１Ｃ及びＲ１Ｄが共に水素原子であり、Ｒ４Ａがベンジルであり、Ｒ５が水素原子であるとき、Ｒ１Ｂがフッ素原子ではない）、又は、（２）ＡがＣＲ１Ｄであり、Ｘ－Ｙ－ＺがＣＲ６－ＣＯ－ＮＲ４ＡＲ５であり、Ｒ４Ａが１－（２－フルオロフェニル）－ピラゾ－３－イルであり、Ｒ５が水素原子であるとき、Ｒ１Ａ、Ｒ１Ｂ、Ｒ１Ｃ及びＲ１Ｄのうち、少なくとも１つは、水素原子以外の基であり、
　Ｒ２は、ハロゲン、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１２Ｒ１３からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；ハロゲン、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１２Ｒ１３からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルキル；水素原子；Ｃ１－６アルコキシで置換されていてもよいアリール；又は４～１０員の飽和複素環を表し、
　Ｒ３Ａ、Ｒ３Ｂ、Ｒ３Ｃ及びＲ３Ｄは、同一又は異なって、ハロゲン、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１４Ｒ１５からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；水素原子；ハロゲン；水酸基；又はＣ１－６アルコキシを表し、
　Ｒ４Ａ、Ｒ５及びＲ７は、同一又は異なって、アリール（該基は、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）、ヘテロアリール、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－ＮＲ１４Ｒ１５からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；アリール（該基は、ハロゲン、水酸基及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよい）、ヘテロアリール、又は、同一又は異なる１～５個のハロゲン、水酸基、Ｃ１－６アルコキシ、Ｃ１－６アルキル又は－ＮＲ１４Ｒ１５で置換されていてもよいＣ３－１０シクロアルキル（該基は、アリール又はヘテロアリールと縮環を形成してもよい）；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；ハロゲン、Ｃ１－６アルコキシ及びＣ１－６アルキル（該基は、１～５個のフッ素で置換されていてもよい）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アリール；ヘテロアリール；又は水素原子を表し、ここにおいて、Ｒ４Ａ及びＲ５は一緒になって４～１０員の含窒素飽和複素環（但し、該環は、（１）モルフォリンではなく、（２）水酸基で置換されていてもよい）を形成していてもよく、
　Ｒ４Ｂは、アリール、ヘテロアリール（該アリール及び該ヘテロアリールは、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）、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－ＮＲ１４Ｒ１５からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；アリール、ヘテロアリール（該アリール及び該ヘテロアリールは、ハロゲン、水酸基及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよい）、ハロゲン、水酸基、１～５個のフッ素で置換されていてもよいＣ１－６アルコキシ、１～５個のフッ素で置換されていてもよいＣ１－６アルキル及び－ＮＲ１４Ｒ１５からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルキル（該基は、アリール又はヘテロアリールと縮環を形成してもよい）；同一又は異なる１～５個の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；ハロゲン、Ｃ１－６アルコキシ及びＣ１－６アルキル（該アルコキシ及びアルキルは、１～５個のフッ素で置換されていてもよい）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アリール又はヘテロアリールを表し、
　Ｒ６、Ｒ８及びＲ９は、同一又は異なって、ハロゲン、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１６Ｒ１７からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；ハロゲン、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１６Ｒ１７からなる群から独立して選択される１～５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；水素原子；ハロゲン；水酸基；又はＣ１－６アルコキシを表し、
　Ｒ１０～Ｒ１７は、同一又は異なって、水素原子又はＣ１－６アルキルを表し、
　ｎは、１又は２を表す］
で表される化合物又はその製薬学的に許容される塩。 [Item 1] The following formula (I):
Figure JPOXMLDOC01-appb-C000002
 [Where:
A represents CR 1D or a nitrogen atom,
XYZ represents N—CO—NR 4A R 5 , CR 6 —CO—NR 4A R 5 , CR 6 —NR 7 —CONR 4A R 5 , CR 6 —NR 7 —COR 4B , CR 6 —NR 7 -aryl, CR 6 -NR 7 -heteroaryl or CR 6 -CR 8 R 9 -NR 4A R 5
R 1A , R 1B , R 1C and R 1D are the same or different and are 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy and —NR 10 R 11 C 1-6 alkyl which may be substituted with: 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy and —NR 10 R 11 C 3-10 cycloalkyl; substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkoxy, C 3-6 cycloalkyl and —NR 10 R 11 C 1-6 alkoxy (excluding the group wherein R 1B is substituted with —NR 10 R 11 ); hydrogen atom; hydroxyl group; halogen; halogen; substituted with 1 to 5 fluorine atoms Even There C 1-6 alkyl and 1 to 5 fluorine with 1-5 phenyl which may be substituted with a substituent selected independently from the group consisting of which may be optionally C 1-6 alkoxy-substituted ; halogen, is selected from 1-5 fluorine independently from the group consisting of which may be C 1-6 alkyl and 1 to 5 fluorine optionally substituted by a C 1-6 alkoxy-substituted Heteroaryl optionally substituted with 1 to 5 substituents; halogen, C 1-6 alkyl optionally substituted with 1 to 5 fluorines and optionally substituted with 1 to 5 fluorines C 3-10 cycloalkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of good C 1-6 alkoxy; 4-10 membered saturated heterocycle; nitro; 10 R 11 ; Cyano; —COOR 10; -CONR 10 R 11; -NR 10 COR 11; -SO 2 NR 10 R 11; represents or -NR 10 SO 2 R 11, wherein the (1) X-Y-Z , N-CO- When NR 4A R 5 , at least one of R 1A , R 1B , R 1C and R 1D is a group other than a hydrogen atom (provided that R 1A , R 1C and R 1D are both hydrogen atoms, When R 4A is benzyl and R 5 is a hydrogen atom, R 1B is not a fluorine atom) or (2) A is CR 1D and XYZ is CR 6 —CO—NR 4A When R 5 , R 4A is 1- (2-fluorophenyl) -pyrazo-3-yl, and R 5 is a hydrogen atom, at least one of R 1A , R 1B , R 1C and R 1D Is a group other than a hydrogen atom,
R 2 represents C 1-6 alkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy and —NR 12 R 13 ; halogen A C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of: hydroxyl group, C 1-6 alkoxy and —NR 12 R 13 ; a hydrogen atom; C 1 An aryl optionally substituted with -6 alkoxy; or a 4-10 membered saturated heterocycle,
R 3A , R 3B , R 3C and R 3D are the same or different and are 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy and —NR 14 R 15 C 1-6 alkyl optionally substituted by: hydrogen atom; halogen; hydroxyl group; or C 1-6 alkoxy,
R 4A , R 5 and R 7 are the same or different and are aryl (the group is 1 to 5 independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy) 1 to 5 independently selected from the group consisting of heteroaryl, halogen, hydroxyl, C 1-6 alkoxy, C 3-10 cycloalkyl and —NR 14 R 15 C 1-6 alkyl optionally substituted with 1 substituent; aryl (the group is 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group and C 1-6 alkoxy) Optionally substituted), heteroaryl, or C 1-6 optionally substituted with 1 to 5 halogens, hydroxyl, C 1-6 alkoxy, C 1-6 alkyl or —NR 14 R 15 3- 10 cycloalkyl (the group may form a condensed ring with aryl or heteroaryl); a 4-10 membered saturated heterocycle optionally substituted with C 1-6 alkyl; halogen, C 1-6 Optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkoxy and C 1-6 alkyl (which group may be substituted with 1 to 5 fluorines) Represents aryl; heteroaryl; or a hydrogen atom, wherein R 4A and R 5 are taken together to form a 4- to 10-membered nitrogen-containing saturated heterocycle (provided that the ring is not (1) morpholine, 2) may be substituted with a hydroxyl group),
R 4B is aryl, heteroaryl (wherein the aryl and the heteroaryl are 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy; Optionally substituted), substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkoxy, C 3-10 cycloalkyl and —NR 14 R 15 Optionally substituted C 1-6 alkyl; aryl, heteroaryl (wherein the aryl and the heteroaryl are 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group and C 1-6 alkoxy) optionally substituted), halogen, hydroxyl, 1-5 fluorine optionally substituted C 1-6 alkoxy, optionally substituted with 1-5 fluorine C -6 alkyl and -NR 14 R 15 optionally C 3-10 cycloalkyl (in which optionally substituted with one to five substituents independently selected from the group consisting of an aryl or heteroaryl condensed A 4 to 10-membered saturated heterocycle optionally substituted with 1 to 5 C 1-6 alkyl which may be the same or different; halogen, C 1-6 alkoxy and C 1-6 Aryl or heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl (wherein the alkoxy and alkyl may be optionally substituted with 1 to 5 fluorines) Represents
R 6 , R 8 and R 9 are the same or different and are substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy and —NR 16 R 17. Optionally substituted C 1-6 alkyl; optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkoxy and —NR 16 R 17 3-10 cycloalkyl; 4-10 membered saturated heterocycle; hydrogen atom; halogen; hydroxyl group; or C 1-6 alkoxy
R 10 to R 17 are the same or different and each represents a hydrogen atom or C 1-6 alkyl;
n represents 1 or 2]
Or a pharmaceutically acceptable salt thereof.
［項２］Ａが、ＣＲ１Ｄ又は窒素原子であり、
　Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ４ＡＲ５、ＣＲ６－ＣＯ－ＮＲ４ＡＲ５、ＣＲ６－ＮＲ７－ＣＯＮＲ４ＡＲ５、ＣＲ６－ＮＲ７－ＣＯＲ４Ｂ、ＣＲ６－ＮＲ７－アリール、ＣＲ６－ＮＲ７－ヘテロアリール又はＣＲ６－ＣＲ８Ｒ９－ＮＲ４ＡＲ５であり、
　Ｒ１Ａ、Ｒ１Ｂ、Ｒ１Ｃ及びＲ１Ｄが、同一又は異なって、ハロゲン、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１０Ｒ１１からなる群から選択される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－ＮＲ１０Ｒ１１からなる群から選択される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；ハロゲン、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１０Ｒ１１からなる群から選択される１～５個の置換基で置換されていてもよいＣ１－６アルコキシ(但し、Ｒ１Ｂが－ＮＲ１０Ｒ１１で置換された該基を除く)；水素原子；水酸基；ハロゲン；アリール；ヘテロアリール；４～１０員の飽和複素環；ニトロ；－ＮＲ１０Ｒ１１；シアノ；－ＣＯＯＲ１０；－ＣＯＮＲ１０Ｒ１１；－ＮＲ１０ＣＯＲ１１；－ＳＯ２ＮＲ１０Ｒ１１；又は－ＮＲ１０ＳＯ２Ｒ１１であり、ここにおいて、（１）Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ４ＡＲ５のとき、Ｒ１Ａ、Ｒ１Ｂ、Ｒ１Ｃ及びＲ１Ｄは、少なくとも１つは、水素原子以外の基であり（但し、Ｒ４Ａが、ベンジルであり、Ｒ５が、水素原子であるとき、Ｒ１Ａ、Ｒ１Ｃ及びＲ１Ｄが共に水素原子であって、Ｒ１Ｂがフッ素原子ではなく）、又は、（２）Ａが、ＣＲ１Ｄであり、Ｘ－Ｙ－Ｚが、ＣＲ６－ＣＯ－ＮＲ４ＡＲ５であり、Ｒ４Ａが、１－（２－フルオロフェニル）－ピラゾ－３－イルであり、Ｒ５が、水素原子であるとき、Ｒ１Ａ、Ｒ１Ｂ、Ｒ１Ｃ及びＲ１Ｄのうち、少なくとも１つは、水素原子以外の基であり、
　Ｒ２が、ハロゲン、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１２Ｒ１３からなる群から選択される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－ＮＲ１２Ｒ１３からなる群から選択される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；水素原子；Ｃ１－６アルコキシで置換されていてもよいアリール；又は４～１０員の飽和複素環であり、
　Ｒ３Ａ、Ｒ３Ｂ、Ｒ３Ｃ及びＲ３Ｄが、同一又は異なって、ハロゲン、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１４Ｒ１５からなる群から選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；水素原子；ハロゲン；水酸基；又はＣ１－６アルコキシであり、
　Ｒ４Ａ、Ｒ５及びＲ７が、同一又は異なって、アリール（該基は、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選択される１～５個の置換基で置換されていてもよい）、ヘテロアリール（該基は、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選択される１～５個の置換基で置換されていてもよい）、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－ＮＲ１４Ｒ１５からなる群から選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；アリール（該基は、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選択される１～５個の置換基で置換されていてもよい）、ヘテロアリール（該基は、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選択される１～５個の置換基で置換されていてもよい）、１～５個のハロゲン、水酸基、Ｃ１－６アルコキシ、Ｃ１－６アルキル又は－ＮＲ１４Ｒ１５で置換されていてもよいＣ３－１０シクロアルキル（該基は、アリール又はヘテロアリールと縮環を形成してもよい）；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；ハロゲン、水酸基、Ｃ１－６アルコキシ及びＣ１－６アルキル（該基は、１～５個のフッ素で置換されていてもよい）からなる群から選択される１～５個の置換基で置換されていてもよいアリール；ハロゲン、水酸基、Ｃ１－６アルコキシ及びＣ１－６アルキル（該基は、１～５個のフッ素で置換されていてもよい）からなる群から選択される１～５個の置換基で置換されていてもよいヘテロアリール；又は水素原子であり、ここにおいて、Ｒ４Ａ及びＲ５は一緒になって４～１０員の含窒素飽和複素環（該環は、水酸基で置換されていてもよい）を形成していてもよく、
　Ｒ４Ｂが、アリール（該基は、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選択される１～５個の置換基で置換されていてもよい）、ヘテロアリール（該基は、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選択される１～５個の置換基で置換されていてもよい）、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－ＮＲ１４Ｒ１５からなる群から選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；アリール（該基は、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選択される１～５個の置換基で置換されていてもよい）、ヘテロアリール（該基は、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選択される１～５個の置換基で置換されていてもよい）、ハロゲン、水酸基、Ｃ１－６アルコキシ、Ｃ１－６アルキル及び－ＮＲ１４Ｒ１５からなる群から選択される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（該基は、アリール又はヘテロアリールと縮環を形成してもよい）；１～５個の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；ハロゲン、水酸基、Ｃ１－６アルコキシ及びＣ１－６アルキル（該基は、１～５個のフッ素で置換されていてもよい）からなる群から選択される１～５個の置換基で置換されていてもよいアリール；又はハロゲン、水酸基、Ｃ１－６アルコキシ及びＣ１－６アルキル（該基は、１～５個のフッ素で置換されていてもよい）からなる群から選択される１～５個の置換基で置換されていてもよいヘテロアリールであり、
　Ｒ６、Ｒ８及びＲ９が、同一又は異なって、ハロゲン、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１６Ｒ１７からなる群から選択される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－ＮＲ１６Ｒ１７からなる群から選択される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；水素原子；ハロゲン；水酸基；又はＣ１－６アルコキシであり、
　Ｒ１０～Ｒ１７が、同一又は異なって、水素原子又はＣ１－６アルキルであり、
　ｎは、１又は２である、
項１に記載の化合物又はその製薬学的に許容される塩。 [Claim 2] A is CR 1D or a nitrogen atom,
XYZ represents N-CO-NR 4A R 5 , CR 6 -CO-NR 4A R 5 , CR 6 -NR 7 -CONR 4A R 5 , CR 6 -NR 7 -COR 4B , CR 6 -NR 7 -aryl, CR 6 -NR 7 -heteroaryl or CR 6 -CR 8 R 9 -NR 4A R 5 ,
R 1A , R 1B , R 1C and R 1D are the same or different and are substituted with 1 to 5 substituents selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy and —NR 10 R 11 An optionally substituted C 1-6 alkyl; a C 3-10 optionally substituted with 1 to 5 substituents selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy and —NR 10 R 11 cycloalkyl; halogen, hydroxyl, C 1-6 alkoxy and -NR 10 1 ~ is selected from the group consisting of R 11 5 amino optionally substituted with a substituent C 1-6 alkoxy (wherein, R 1B is -NR 10 R 11 is excluded); hydrogen atom; hydroxyl group; halogen; aryl; heteroaryl; 4- to 10-membered saturated heterocycle; nitro; -NR 10 R 11 ; cyano; 10; -CONR 10 R 11; -NR 10 COR 11; -SO 2 NR 10 R 11; a or -NR 10 SO 2 R 11, wherein the (1) X-Y-Z , N-CO- When NR 4A R 5 , at least one of R 1A , R 1B , R 1C and R 1D is a group other than a hydrogen atom (provided that R 4A is benzyl, R 5 is a hydrogen atom, In some cases, R 1A , R 1C and R 1D are all hydrogen atoms and R 1B is not a fluorine atom) or (2) A is CR 1D and XYZ is CR 6 When —CO—NR 4A R 5 , R 4A is 1- (2-fluorophenyl) -pyrazo-3-yl, and R 5 is a hydrogen atom, R 1A , R 1B , R 1C and of R 1D, at least one, other than a hydrogen atom Is a group,
R 2 is halogen, hydroxyl, C 1-6 alkoxy and -NR 12 R 13 may be substituted with 1 to 5 substituents selected from the group consisting of C 1-6 alkyl; halogen, hydroxyl, C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents selected from the group consisting of C 1-6 alkoxy and —NR 12 R 13 ; hydrogen atom; substituted with C 1-6 alkoxy Optionally aryl; or a 4-10 membered saturated heterocycle;
R 3A , R 3B , R 3C and R 3D are the same or different and are substituted with 1 to 5 substituents selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy and —NR 14 R 15 An optionally substituted C 1-6 alkyl; a hydrogen atom; a halogen; a hydroxyl group; or a C 1-6 alkoxy;
R 4A , R 5 and R 7 are the same or different and are aryl (the group is 1 to 5 substituents selected from the group consisting of halogen, hydroxyl group, C 1-6 alkyl and C 1-6 alkoxy) Optionally substituted with 1 to 5 substituents selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy may also be), halogen, hydroxyl, C 1-6 alkoxy, optionally C 3-10 optionally substituted with 1 to 5 substituents selected from the group consisting of cycloalkyl and -NR 14 R 15 C 1- 6 alkyl; aryl (the group may be substituted with 1 to 5 substituents selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy), heteroaryl ( The group is Optionally substituted with 1 to 5 substituents selected from the group consisting of Rogen, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy), 1-5 halogens, hydroxyl, C 1-1 6 alkoxy, C 1-6 alkyl or -NR 14 R 15 which may C 3-10 also be cycloalkyl substituted with (said group may form a condensed ring with the aryl or heteroaryl); C 1- 4-10 membered saturated heterocycle optionally substituted with 6 alkyl; halogen, hydroxyl, C 1-6 alkoxy and C 1-6 alkyl (the group may be substituted with 1-5 fluorines) Aryl optionally substituted with 1 to 5 substituents selected from the group consisting of: halogen, hydroxyl, C 1-6 alkoxy and C 1-6 alkyl (wherein the group is 1-5 May be substituted with fluorine) A heteroaryl optionally substituted with 1 to 5 substituents selected from the group consisting of: or a hydrogen atom, wherein R 4A and R 5 together are a 4 to 10 membered nitrogen-containing A saturated heterocyclic ring (which may be substituted with a hydroxyl group),
R 4B is aryl (the group may be substituted with 1 to 5 substituents selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy), heteroaryl (said group, halogen, hydroxyl, optionally substituted with 1 to 5 substituents selected from the group consisting of C 1-6 alkyl and C 1-6 alkoxy), halogen, hydroxyl, C 1- 6 alkoxy, C 3-10 cycloalkyl and -NR 14 1 ~ 5 amino C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of R 15; aryl (said groups, halogen, hydroxyl, optionally substituted with 1 to 5 substituents selected from the group consisting of C 1-6 alkyl and C 1-6 alkoxy), heteroaryl (in which, halogen, hydroxyl, C 1- 6 alkyl It may be substituted with 1 to 5 substituents selected from the group consisting of finely C 1-6 alkoxy), halogen, hydroxyl, C 1-6 alkoxy, C 1-6 alkyl and -NR 14 R 15 C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents selected from the group consisting of (the group may form a condensed ring with aryl or heteroaryl); 1 to 5 pieces of C 1-6 saturated heterocyclic ring may 4-10 membered optionally substituted with alkyl; halogen, hydroxyl, C 1-6 alkoxy and C 1-6 alkyl (said groups, one to five fluorines Aryl optionally substituted with 1 to 5 substituents selected from the group consisting of optionally substituted); or halogen, hydroxyl, C 1-6 alkoxy and C 1-6 alkyl (the group is 1-5 substituted with fluorine A heteroaryl optionally substituted with 1 to 5 substituents selected from the group consisting of:
R 6 , R 8 and R 9 may be the same or different and substituted with 1 to 5 substituents selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy and —NR 16 R 17 Preferred C 1-6 alkyl; C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents selected from the group consisting of halogen, hydroxyl, C 1-6 alkoxy and —NR 16 R 17 ; A 4- to 10-membered saturated heterocyclic ring; a hydrogen atom; a halogen; a hydroxyl group; or C 1-6 alkoxy,
R 10 to R 17 are the same or different and each represents a hydrogen atom or C 1-6 alkyl;
n is 1 or 2.
Item 12. The compound according to Item 1 or a pharmaceutically acceptable salt thereof.
［項３］ＡがＣＲ１Ｄであり、Ｘ－Ｙ－ＺがＮ－ＣＯ－ＮＲ４ＡＲ５であり、Ｒ１Ａ、Ｒ１Ｃ及びＲ１Ｄが共に水素原子であり、Ｒ４Ａ及びＲ５の一方が水素原子であるとき、以下のＲ１Ｂ並びにＲ４Ａ及びＲ５のもう一方の組み合わせの化合物群を除く、
項１又は項２に記載の化合物又はその製薬学的に許容される塩：
　Ｒ１Ｂが、フッ素であり、Ｒ４Ａ及びＲ５のもう一方が、フェニル、２－メトキシフェニル、４－エトキシフェニル、シクロヘキシル、４－メトキシフェニル、２－エトキシフェニル、４－クロロ－３－トリフルオロフェニル、３－メトキシフェニル、２－トリフルオロメチルフェニル、３－メチルフェニル、２－クロロフェニル、アダマンチル、２－メチルフェニル、２，４－ジフルオロフェニル、４－エトキシフェニル、３－フルオロフェニル及び４－メチルフェニルからなる群から選択される基である化合物、
　Ｒ１Ｂが、ジメチルアミノカルボニルであり、Ｒ４Ａ及びＲ５のもう一方が、４－エトキシフェニル、３，４－ジフルオロフェニル及び４－メチルベンジルからなる群から選択される基である化合物、
　Ｒ１Ｂが、メチルであり、Ｒ４Ａ及びＲ５のもう一方が、２，６－ジメチルフェニル、アダマンチル及び２－フルオロフェニルからなる群から選択される基である化合物、
　Ｒ１Ｂが、トリフルオロメチルであり、Ｒ４Ａ及びＲ５のもう一方が、２－フルオロフェニル、４－メトキシフェニル及びフェニルからなる群から選択される基である化合物。 [Item 3] A is CR 1D , XYZ is N—CO—NR 4A R 5 , R 1A , R 1C and R 1D are both hydrogen atoms, and one of R 4A and R 5 When is a hydrogen atom, the following R 1B and the compound group of the other combination of R 4A and R 5 are excluded,
Item 1 or Item 2 or a pharmaceutically acceptable salt thereof:
R 1B is fluorine, and the other of R 4A and R 5 is phenyl, 2-methoxyphenyl, 4-ethoxyphenyl, cyclohexyl, 4-methoxyphenyl, 2-ethoxyphenyl, 4-chloro-3-trifluoro Phenyl, 3-methoxyphenyl, 2-trifluoromethylphenyl, 3-methylphenyl, 2-chlorophenyl, adamantyl, 2-methylphenyl, 2,4-difluorophenyl, 4-ethoxyphenyl, 3-fluorophenyl and 4-methyl A compound which is a group selected from the group consisting of phenyl,
A compound wherein R 1B is dimethylaminocarbonyl and the other of R 4A and R 5 is a group selected from the group consisting of 4-ethoxyphenyl, 3,4-difluorophenyl and 4-methylbenzyl;
A compound wherein R 1B is methyl and the other of R 4A and R 5 is a group selected from the group consisting of 2,6-dimethylphenyl, adamantyl and 2-fluorophenyl;
A compound wherein R 1B is trifluoromethyl and the other of R 4A and R 5 is a group selected from the group consisting of 2-fluorophenyl, 4-methoxyphenyl and phenyl.
［項４］
　Ａが窒素原子であるとき、Ｒ１Ｂ及びＲ１Ｃの一方が置換されていてもよいフェニルであり、もう一方が水素原子の組み合わせでない、
項１又は項２に記載の化合物又はその製薬学的に許容される塩。 [Claim 4]
When A is a nitrogen atom, one of R 1B and R 1C is optionally substituted phenyl, and the other is not a combination of hydrogen atoms,
Item 3. The compound according to Item 1 or Item 2, or a pharmaceutically acceptable salt thereof.
［項５］Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ４ＡＲ５、ＣＲ６－ＮＲ７－ＣＯＮＲ４ＡＲ５、ＣＲ６－ＮＲ７－ＣＯＲ４Ｂ、ＣＲ６－ＮＲ７－アリール、ＣＲ６－ＮＲ７－ヘテロアリール又はＣＲ６－ＣＲ８Ｒ９－ＮＲ４ＡＲ５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] XYZ represents N—CO—NR 4A R 5 , CR 6 —NR 7 —CONR 4A R 5 , CR 6 —NR 7 —COR 4B , CR 6 —NR 7 —aryl, CR 6 -NR 7 -heteroaryl or CR 6 -CR 8 R 9 -NR 4A R 5
Item 5. The compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.
［項６］Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ４ＡＲ５又はＣＲ６－ＮＲ７－ＣＯＲ４Ｂ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] XYZ is N—CO—NR 4A R 5 or CR 6 —NR 7 —COR 4B .
Item 5. The compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.
［項７］Ｘ－Ｙ－Ｚが、ＣＲ６－ＮＲ７－ＣＯＲ４Ｂ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。 [Section 7] XYZ is CR 6 —NR 7 —COR 4B .
Item 5. The compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.
［項８］Ｒ４Ｂが、アリール、ヘテロアリール、水酸基、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；アリール、ヘテロアリール、水酸基、フッ素、１～５個のフッ素で置換されていてもよいＣ１－６アルコキシ及び１～５個のフッ素で置換されていてもよい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（該基はアリールと縮環を形成してもよく）；同一又は異なる１～５個の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；又はハロゲン、Ｃ１－６アルコキシ及びＣ１－６アルキル（該アルコキシ及びアルキルは、１～５個のフッ素で置換されていてもよい）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アリール又はヘテロアリールである、
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 4B is substituted with 1 to 5 substituents independently selected from the group consisting of aryl, heteroaryl, hydroxyl group, fluorine, C 1-6 alkoxy and C 3-10 cycloalkyl. C 1-6 alkyl which may be substituted; aryl, heteroaryl, hydroxyl group, fluorine, C 1-6 alkoxy optionally substituted with 1 to 5 fluorines and optionally substituted with 1 to 5 fluorines C 3-10 cycloalkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkyl (the group may form a condensed ring with aryl) A 4- to 10-membered saturated heterocycle optionally substituted with 1 to 5 identical or different C 1-6 alkyls; or halogen, C 1-6 alkoxy and C 1-6 alkyl (the alkoxy and alkyl are 1-5 Aryl or heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of
Item 8. The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof.
［項９］Ｒ４Ｂが、アリール、ヘテロアリール、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；アリール、ヘテロアリール、フッ素、１～５個のフッ素で置換されていてもよいＣ１－６アルコキシ及び１～５個のフッ素で置換されていてもよい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（該基はアリールと縮環を形成しても良く）；同一又は異なる１～５個の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；又はハロゲン、Ｃ１－６アルコキシ及びＣ１－６アルキル（該アルコキシ及びアルキルは、１～５個のフッ素で置換されていてもよい）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アリール又はヘテロアリールである、
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 9] R 4B may be substituted with 1 to 5 substituents independently selected from the group consisting of aryl, heteroaryl, fluorine, C 1-6 alkoxy and C 3-10 cycloalkyl. C 1-6 alkyl; aryl, heteroaryl, fluorine, 1-5 fluorine may be substituted with an optionally substituted C 1-6 alkoxy and 1 to 5 fluorine by C 1-6 C 3-10 cycloalkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of alkyl (the group may form a condensed ring with aryl); the same or different A 4- to 10-membered saturated heterocycle optionally substituted with 1 to 5 C 1-6 alkyl; or halogen, C 1-6 alkoxy and C 1-6 alkyl (wherein the alkoxy and alkyl are 1-5 Replaced with one fluorine An aryl or heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of:
Item 8. The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof.
［項１０］Ａが、ＣＲ１Ｄである、
項１～９のいずれか一項に記載の化合物又はその製薬学的に許容される塩。 [Item 10] A is CR 1D .
Item 10. The compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof.
［項１１］Ｒ２が、水素原子である、
項１～１０のいずれか一項に記載の化合物又はその製薬学的に許容される塩。 [Item 11] R 2 is a hydrogen atom.
Item 11. The compound according to any one of Items 1 to 10, or a pharmaceutically acceptable salt thereof.
［項１２］ｎが、１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] n is 1.
Item 12. The compound according to any one of Items 1 to 11, or a pharmaceutically acceptable salt thereof.
［項１３］Ｒ３Ａ、Ｒ３Ｂ、Ｒ３Ｃ及びＲ３Ｄが、同一又は異なって、水素原子、ハロゲン、水酸基又はＣ１－６アルコキシである、
項１～１２のいずれか一項に記載の化合物又はその製薬学的に許容される塩。 [Item 13] R 3A , R 3B , R 3C and R 3D are the same or different and each is a hydrogen atom, a halogen, a hydroxyl group or C 1-6 alkoxy.
Item 13. The compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof.
［項１４］Ｒ１Ａ、Ｒ１Ｂ、Ｒ１Ｃ及びＲ１Ｄが、同一又は異なって、ハロゲン、水酸基及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；ハロゲン、水酸基及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルキル；ハロゲン、水酸基、Ｃ１－６アルコキシ及びＣ３－６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アルコキシ；水素原子；水酸基；ハロゲン；ハロゲン、１～５個のフッ素で置換されていてもよいＣ１－６アルキル及び１～５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フェニル；ハロゲン、１～５個のフッ素で置換されていてもよいＣ１－６アルキル及び１～５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ヘテロアリール；ハロゲン、１～５個のフッ素で置換されていてもよいＣ１－６アルキル及び１～５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Ｃ３－１０シクロアルコキシ；４～１０員の飽和複素環；－ＮＲ１０Ｒ１１；シアノ；－ＣＯＯＲ１０；又は－ＣＯＮＲ１０Ｒ１１である、
項１～１３のいずれか一項に記載の化合物又はその製薬学的に許容される塩。 [Item 14] R 1A , R 1B , R 1C and R 1D are the same or different and substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group and C 1-6 alkoxy C 1-6 alkyl which may be substituted; C 3-10 cycloalkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group and C 1-6 alkoxy ; halogen, hydroxyl, C 1-6 alkoxy and C 3-6 optionally substituted by one to five substituents independently selected from the group consisting of cycloalkyl C 1-6 alkoxy; hydrogen atom; Independently from the group consisting of hydroxyl group; halogen; halogen, C 1-6 alkyl optionally substituted with 1 to 5 fluorines and C 1-6 alkoxy optionally substituted with 1 to 5 fluorines Selected That 1-5 phenyl optionally substituted with a substituent; a halogen, optionally substituted with one to five fluorines optionally substituted C 1-6 alkyl and 1 to 5 fluorine A heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of good C 1-6 alkoxy; halogen, C 1 optionally substituted with 1 to 5 fluorines C 3-10 optionally substituted with 1-5 substituents independently selected from the group consisting of -6 alkyl and C 1-6 alkoxy optionally substituted with 1-5 fluorines Cycloalkoxy; 4-10 membered saturated heterocycle; —NR 10 R 11 ; cyano; —COOR 10 ; or —CONR 10 R 11 ,
Item 14. The compound according to any one of Items 1 to 13, or a pharmaceutically acceptable salt thereof.
［項１５］Ｒ１Ａ、Ｒ１Ｂ、Ｒ１Ｃ及びＲ１Ｄが、同一又は異なって、ハロゲン、水酸基及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；ハロゲン、水酸基及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－７シクロアルキル；ハロゲン、水酸基、Ｃ１－６アルコキシ及びＣ３－６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アルコキシ；水素原子；ハロゲン；４～７員の飽和複素環；シアノ；－ＣＯＯＲ１０；又は－ＣＯＮＲ１０Ｒ１１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 1A , R 1B , R 1C and R 1D are the same or different and substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group and C 1-6 alkoxy C 1-6 alkyl which may be substituted; C 3-7 cycloalkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group and C 1-6 alkoxy ; halogen, hydroxyl, C 1-6 alkoxy and C 3-6 optionally substituted by one to five substituents independently selected from the group consisting of cycloalkyl C 1-6 alkoxy; hydrogen atom; Halogen; 4-7 membered saturated heterocycle; cyano; —COOR 10 ; or —CONR 10 R 11
Item 14. The compound according to any one of Items 1 to 13, or a pharmaceutically acceptable salt thereof.
［項１６］Ｒ４Ａ、Ｒ５及びＲ７が、同一又は異なって、アリール、ハロゲン、水酸基及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；ハロゲン、水酸基及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－９シクロアルキル；ハロゲン、Ｃ１－６アルコキシ及びＣ１－６アルキル（該基は、１～５個のフッ素で置換されていてもよい）からなる群から選択される１～５個の置換基で置換されていてもよいアリール；ヘテロアリール；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。 [Item 16] R 4A , R 5 and R 7 are the same or different and are substituted with 1 to 5 substituents independently selected from the group consisting of aryl, halogen, hydroxyl group and C 1-6 alkoxy. An optionally substituted C 1-6 alkyl; a C 3-9 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group and C 1-6 alkoxy; Substituted with 1 to 5 substituents selected from the group consisting of halogen, C 1-6 alkoxy and C 1-6 alkyl, which group may be substituted with 1 to 5 fluorines Optionally aryl; heteroaryl; 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、Ｒ８及びＲ９が、同一又は異なって、Ｃ１－６アルキル、水酸基又は水素原子である、
項１～１６のいずれか一項に記載の化合物又はその製薬学的に許容される塩。 [Item 17] R 6 , R 8, and R 9 are the same or different and each represents C 1-6 alkyl, a hydroxyl group, or a hydrogen atom.
Item 18. The compound according to any one of Items 1 to 16, or a pharmaceutically acceptable salt thereof.
［項１８］Ｒ４Ｂが、アリール、ヘテロアリール、水酸基、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；アリール、ヘテロアリール、水酸基、フッ素、１～５個のフッ素で置換されていてもよいＣ１－６アルコキシ及び１～５個のフッ素で置換されていてもよい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（該基はアリールと縮環を形成しても良く）；同一または異なる１～５個の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；又はハロゲン、Ｃ１－６アルコキシ及びＣ１－６アルキル（該アルコキシ及びアルキルは、１～５個のフッ素で置換されていてもよい）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アリール又はヘテロアリールである、
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 4B is substituted with 1 to 5 substituents independently selected from the group consisting of aryl, heteroaryl, hydroxyl group, fluorine, C 1-6 alkoxy and C 3-10 cycloalkyl. C 1-6 alkyl which may be substituted; aryl, heteroaryl, hydroxyl group, fluorine, C 1-6 alkoxy optionally substituted with 1 to 5 fluorines and optionally substituted with 1 to 5 fluorines C 3-10 cycloalkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkyl (the group may form a condensed ring with aryl) A 4- to 10-membered saturated heterocycle optionally substituted with 1 to 5 identical or different C 1-6 alkyls; or halogen, C 1-6 alkoxy and C 1-6 alkyl (the alkoxy and alkyl are 1 An aryl or heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of
Item 18. The compound according to any one of Items 1 to 17, or a pharmaceutically acceptable salt thereof.
［項１９］ＡがＣＲ１Ｄであり、Ｘ－Ｙ－ＺがＮ－ＣＯ－ＮＲ４ＡＲ５であるとき、Ｒ４Ａ及びＲ５が、同一又は異なって、アリール（該基は、１～５個のハロゲン、水酸基、Ｃ１－６アルキル又はＣ１－６アルコキシで置換されていてもよい）、ヘテロアリール（該基は、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選択される１～５個の置換基で置換されていてもよい）、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－ＮＲ１４Ｒ１５からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；アリール（該基は、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）、ヘテロアリール（該基は、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）、ハロゲン、水酸基、Ｃ１－６アルコキシ、Ｃ１－６アルキル及び－ＮＲ１４Ｒ１５からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルキル（該基は、アリール又はヘテロアリールと縮環を形成してもよい）；ハロゲン、水酸基、Ｃ１－６アルコキシ及びＣ１－６アルキル（該基は、１～５個のフッ素で置換されていてもよい）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ヘテロアリール；又は水素原子である、
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] When A is CR 1D and XYZ is N—CO—NR 4A R 5 , R 4A and R 5 are the same or different, and aryl (the group is 1 to 5 Halogen, hydroxyl, optionally substituted with C 1-6 alkyl or C 1-6 alkoxy), heteroaryl (the group consists of halogen, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy) Independently substituted from the group consisting of halogen, hydroxyl, C 1-6 alkoxy, C 3-10 cycloalkyl and —NR 14 R 15 , optionally substituted with 1 to 5 substituents selected from the group C 1-6 alkyl optionally substituted with 1 to 5 selected substituents; aryl (the group is independent of the group consisting of halogen, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy) 1 to 5 selected May be substituted with substituent), heteroaryl (in which, halogen, hydroxyl, 1 to 5 substituents independently selected from the group consisting of C 1-6 alkyl and C 1-6 alkoxy Substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy, C 1-6 alkyl, and —NR 14 R 15. C 3-10 cycloalkyl (the group may form a condensed ring with aryl or heteroaryl); halogen, hydroxyl group, C 1-6 alkoxy and C 1-6 alkyl (the group is Heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of 1 to 5 fluorines), or a hydrogen atom,
Item 19. The compound according to any one of Items 1 to 18, or a pharmaceutically acceptable salt thereof.
［項２０］Ｒ４Ａ及びＲ５が、一緒になって４～１０員の含窒素飽和複素環を形成し該環を構築する窒素原子以外のヘテロ原子が存在するとき、該へテロ原子が１～２個の窒素原子及び／又は１個の硫黄原子である、
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。 [Item 20] When R 4A and R 5 together form a 4- to 10-membered nitrogen-containing saturated heterocyclic ring and there are heteroatoms other than the nitrogen atom constituting the ring, the heteroatom is 1 ~ 2 nitrogen atoms and / or 1 sulfur atom,
Item 20. The compound according to any one of Items 1 to 19 or a pharmaceutically acceptable salt thereof.
［項２１］ＡがＣＲ１Ｄであり、Ｒ１Ａ、Ｒ１Ｃ及びＲ１Ｄが共に水素原子であり、Ｒ１Ｂがフッ素原子又はメチルであり、Ｘ－Ｙ－ＺがＮ－ＣＯ－ＮＲ４ＡＲ５であるとき、Ｒ４Ａ及びＲ５が、同一又は異なって、アリール（該基は、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）、ヘテロアリール（該基は、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）、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－ＮＲ１４Ｒ１５からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；アリール（該基は、ハロゲン、水酸基及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよい）、ヘテロアリール（該基は、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）、Ｃ３－９シクロアルキル（該基は、アリール又はヘテロアリールと縮環を形成してもよく、ハロゲン、水酸基、Ｃ１－６アルコキシ、Ｃ１－６アルキル及び－ＮＲ１４Ｒ１５からなる群から独立して選択される１～５個の置換基で置換されていてもよい）；Ｃ１－６アルキルで置換されていてもよい４～１０員の飽和複素環；ハロゲン、Ｃ１－６アルコキシ及びＣ１－６アルキル（該基は、１～５個のフッ素で置換されていてもよい）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アリール；ハロゲン、水酸基、Ｃ１－６アルコキシ及びＣ１－６アルキル（該基は、１～５個のフッ素で置換されていてもよい）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ヘテロアリール；又は水素原子である、
項１～２０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] A is CR 1D , R 1A , R 1C and R 1D are both hydrogen atoms, R 1B is a fluorine atom or methyl, and XYZ is N—CO—NR 4A R 5. When R 4A and R 5 are the same or different and are aryl (the group is independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy) Optionally substituted with 1 substituent), heteroaryl (wherein the group is independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy) 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy, C 3-10 cycloalkyl and —NR 14 R 15. in an optionally substituted C 1 6 alkyl; aryl (said groups, halogen, optionally substituted with one to five substituents independently selected from the group consisting of hydroxyl and C 1-6 alkoxy), heteroaryl (said group , Optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy), C 3-9 cycloalkyl (including The group may form a condensed ring with aryl or heteroaryl, and is independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy, C 1-6 alkyl and —NR 14 R 15. Optionally substituted with 5 substituents); a 4-10 membered saturated heterocycle optionally substituted with C 1-6 alkyl; halogen, C 1-6 alkoxy and C 1-6 alkyl 1-5 groups 1-5 may be substituted with a substituent aryl independently selected from the group consisting of Tsu may be substituted with hydrogen); halogen, hydroxyl, C 1-6 alkoxy and C 1-6 A heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl (the group may be optionally substituted with 1 to 5 fluorines); or a hydrogen atom Is,
Item 21. The compound according to any one of Items 1 to 20, or a pharmaceutically acceptable salt thereof.
［項２２］ＡがＣＲ１Ｄであり、Ｒ１Ａ、Ｒ１Ｃ及びＲ１Ｄが共に水素原子であり、Ｒ１Ｂがフッ素原子又は－ＮＲ１０Ｒ１１であり、Ｘ－Ｙ－ＺがＮ－ＣＯ－ＮＲ４ＡＲ５であるとき、Ｒ４Ａ及びＲ５が、同一又は異なって、アリール（該基は、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）、ヘテロアリール、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－ＮＲ１４Ｒ１５からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；アリール（該基は、ハロゲン、水酸基及びＣ１－６アルコキシからなる群から選択される１～５個の置換基で置換されていてもよい）、ヘテロアリール、又は、水酸基、Ｃ１－６アルコキシ、Ｃ１－６アルキル、－ＮＲ１４Ｒ１５又は同一又は異なる１～５個のハロゲンで置換されていてもよいＣ３－１０シクロアルキル（但し、無置換シクロヘキシルは除き、該基は、アリール又はヘテロアリールと縮環を形成してもよい）；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；ハロゲン、Ｃ１－６アルコキシ及びＣ１－６アルキル（該基は、１～５個のフッ素で置換されていてもよい）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アリール；ヘテロアリール；又は水素原子である、項１～２１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 22] A is CR 1D, R 1A, R 1C and R 1D are both hydrogen atoms, R 1B is a fluorine atom or a -NR 10 R 11, X-Y -Z is N-CO- When NR 4A R 5 , R 4A and R 5 are the same or different and are independently selected from the group consisting of aryl (halogen, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy) Independently selected from the group consisting of heteroaryl, halogen, hydroxyl, C 1-6 alkoxy, C 3-10 cycloalkyl and —NR 14 R 15. Optionally substituted with 1 to 5 substituents of C 1-6 alkyl; aryl (wherein the group is selected from the group consisting of halogen, hydroxyl group and C 1-6 alkoxy) Substituted with a group Good), heteroaryl, or hydroxyl, C 1-6 alkoxy, C 1-6 alkyl, -NR 14 R 15 or the same or different one to five good C 3-10 cycloalkyl optionally substituted with halogen (However, unsubstituted cyclohexyl, except said groups, aryl or may form a heteroaryl and fused); C 1-6 saturated heterocyclic ring may 4-10 membered optionally substituted with alkyl; halogen Substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy and C 1-6 alkyl, which group may be substituted with 1 to 5 fluorines Item 22. The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 21, which is aryl optionally substituted; heteroaryl; or hydrogen atom.
［項２３］Ｘ－Ｙ－ＺがＣＲ６－ＮＲ７－ＣＯＲ４Ｂであり、ｎが１であり、形成されるシクロヘキサン環の１位と４位の立体がシスの関係である、
項１～２２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 6 —NR 7 —COR 4B , n is 1, and the 1- and 4-positions of the cyclohexane ring formed are in a cis relationship.
Item 23. The compound according to any one of Items 1 to 22, or a pharmaceutically acceptable salt thereof.
［項２４］Ｒ７が、水素原子である、
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 24] R 7 is a hydrogen atom.
Item 24. The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 23.
［項２５］Ｘ－Ｙ－ＺがＣＲ６－ＣＲ８Ｒ９－ＮＲ４ＡＲ５であり、Ｒ４Ａ及びＲ５の一方が（１）ハロゲン、Ｃ１－６アルコキシ及びＣ１－６アルキル（該アルコキシ及びアルキルは、１～５個のフッ素で置換されていてもよい）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アリール又はヘテロアリールであり、もう一方が（２）水素原子の組み合わせである、
項１～２４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 25] XYZ is CR 6 —CR 8 R 9 —NR 4A R 5 , and one of R 4A and R 5 is (1) halogen, C 1-6 alkoxy and C 1-6 alkyl ( The alkoxy and alkyl are aryl or heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of 1 to 5 fluorines) The other is (2) a combination of hydrogen atoms,
Item 25. The compound according to any one of Items 1 to 24 or a pharmaceutically acceptable salt thereof.
［項２６］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：
２，２－ジメチル－Ｎ－｛ｃｉｓ－４－［６－（トリフルオロメチル）－１Ｈ－ベンゾイミダゾール－１－イル］シクロヘキシル｝プロパンアミド（実施例１９２）、
Ｎ－［ｃｉｓ－４－（５－ブロモ－１Ｈ－ベンゾイミダゾール－１－イル）シクロヘキシル］－２，２－ジメチルプロパンアミド（実施例２０２）、
Ｎ－｛ｃｉｓ－４－［５－（トリフルオロメチル）－１Ｈ－ベンゾイミダゾール－１－イル］シクロヘキシル｝シクロブタンカルボキサミド（実施例１５０）、
２－フルオロ－２－メチル－Ｎ－｛ｃｉｓ－４－［５－（トリフルオロメチル）－１Ｈ－ベンゾイミダゾール－１－イル］シクロヘキシル｝プロパンアミド（実施例１６５）、
１－（トリフルオロメチル）－Ｎ－｛ｃｉｓ－４－［５－（トリフルオロメチル）－１Ｈ－ベンゾイミダゾール－１－イル］シクロヘキシル｝シクロプロパンカルボキサミド（実施例２２０）、
２，２－ジメチル－Ｎ－｛ｃｉｓ－４－［６－（トリフルオロメチル）－３Ｈ－イミダゾ［４，５－ｂ］ピリジン－３－イル］シクロヘキシル｝プロパンアミド（実施例２３９）、
２－フルオロ－２－メチル－Ｎ－｛ｃｉｓ－４－［５－（トリフルオロメトシキ）－１Ｈ－ベンゾイミダゾール－１－イル］シクロヘキシル｝プロパンアミド（実施例２３８）、
Ｎ－｛ｃｉｓ－４－［５－（トリフルオロメチル）－１Ｈ－ベンゾイミダゾール－１－イル］シクロヘキシル｝シクロペンタンカルボキサミド（実施例２３６）、
Ｎ－［ｃｉｓ－４－（６－ブロモ－３Ｈ－イミダゾ［４，５－ｂ］ピリジン－３－イル）シクロヘキシル］－２－フルオロ－２－メチルプロパンアミド（実施例２２５）、
２，２－ジメチル－Ｎ－｛ｃｉｓ－４－［５－（トリフルオロメトシキ）－１Ｈ－ベンゾイミダゾール－１－イル］シクロヘキシル｝プロパンアミド（実施例２２８）、及び、
Ｎ－［ｃｉｓ－４－（６－ブロモ－３Ｈ－イミダゾ［４，５－ｂ］ピリジン－３－イル）シクロヘキシル］－２，２－ジメチルプロパンアミド（実施例２１１）。 [Item 26] The compound according to item 1 or a pharmaceutically acceptable salt thereof selected from the following compounds:
2,2-dimethyl-N- {cis-4- [6- (trifluoromethyl) -1H-benzimidazol-1-yl] cyclohexyl} propanamide (Example 192),
N- [cis-4- (5-bromo-1H-benzimidazol-1-yl) cyclohexyl] -2,2-dimethylpropanamide (Example 202),
N- {cis-4- [5- (trifluoromethyl) -1H-benzimidazol-1-yl] cyclohexyl} cyclobutanecarboxamide (Example 150),
2-fluoro-2-methyl-N- {cis-4- [5- (trifluoromethyl) -1H-benzimidazol-1-yl] cyclohexyl} propanamide (Example 165),
1- (trifluoromethyl) -N- {cis-4- [5- (trifluoromethyl) -1H-benzimidazol-1-yl] cyclohexyl} cyclopropanecarboxamide (Example 220),
2,2-dimethyl-N- {cis-4- [6- (trifluoromethyl) -3H-imidazo [4,5-b] pyridin-3-yl] cyclohexyl} propanamide (Example 239),
2-fluoro-2-methyl-N- {cis-4- [5- (trifluoromethoxy) -1H-benzimidazol-1-yl] cyclohexyl} propanamide (Example 238),
N- {cis-4- [5- (trifluoromethyl) -1H-benzimidazol-1-yl] cyclohexyl} cyclopentanecarboxamide (Example 236),
N- [cis-4- (6-Bromo-3H-imidazo [4,5-b] pyridin-3-yl) cyclohexyl] -2-fluoro-2-methylpropanamide (Example 225),
2,2-dimethyl-N- {cis-4- [5- (trifluoromethoxy) -1H-benzimidazol-1-yl] cyclohexyl} propanamide (Example 228), and
N- [cis-4- (6-Bromo-3H-imidazo [4,5-b] pyridin-3-yl) cyclohexyl] -2,2-dimethylpropanamide (Example 211).
［項２７］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：
２，２－ジメチル－Ｎ－｛ｃｉｓ－４－［６－（トリフルオロメチル）－１Ｈ－ベンゾイミダゾール－１－イル］シクロヘキシル｝プロパンアミド（実施例１９２）、
Ｎ－［ｃｉｓ－４－（５－ブロモ－１Ｈ－ベンゾイミダゾール－１－イル）シクロヘキシル］－２，２－ジメチルプロパンアミド（実施例２０２）、
Ｎ－｛ｃｉｓ－４－［５－（トリフルオロメチル）－１Ｈ－ベンゾイミダゾール－１－イル］シクロヘキシル｝シクロブタンカルボキサミド（実施例１５０）、
２－フルオロ－２－メチル－Ｎ－｛ｃｉｓ－４－［５－（トリフルオロメチル）－１Ｈ－ベンゾイミダゾール－１－イル］シクロヘキシル｝プロパンアミド（実施例１６５）、及び、
１－（トリフルオロメチル）－Ｎ－｛ｃｉｓ－４－［５－（トリフルオロメチル）－１Ｈ－ベンゾイミダゾール－１－イル］シクロヘキシル｝シクロプロパンカルボキサミド（実施例２２０）。 [Item 27] The compound according to item 1 or a pharmaceutically acceptable salt thereof selected from the following compounds:
2,2-dimethyl-N- {cis-4- [6- (trifluoromethyl) -1H-benzimidazol-1-yl] cyclohexyl} propanamide (Example 192),
N- [cis-4- (5-bromo-1H-benzimidazol-1-yl) cyclohexyl] -2,2-dimethylpropanamide (Example 202),
N- {cis-4- [5- (trifluoromethyl) -1H-benzimidazol-1-yl] cyclohexyl} cyclobutanecarboxamide (Example 150),
2-fluoro-2-methyl-N- {cis-4- [5- (trifluoromethyl) -1H-benzimidazol-1-yl] cyclohexyl} propanamide (Example 165), and
1- (Trifluoromethyl) -N- {cis-4- [5- (trifluoromethyl) -1H-benzimidazol-1-yl] cyclohexyl} cyclopropanecarboxamide (Example 220).
［項２８］項１～２７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 28] A pharmaceutical composition comprising the compound according to any one of items 1 to 27 or a pharmaceutically acceptable salt thereof.
［項２９］項１～２７のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩を有効成分とするアセチルコリンが関与する細胞内シグナル伝達の異常に起因する疾患の治療剤又は予防剤。 [Item 29] A therapeutic agent for diseases caused by abnormal intracellular signaling involving acetylcholine, comprising the compound according to any one of items 1 to 27 or a pharmaceutically acceptable salt thereof as an active ingredient Or a preventive agent.
［項３０］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、ＣＩＡＳ（統合失調症に伴う認知機能障害）、アルツハイマー病、ダウン症、認知障害、記憶障害・学習障害、軽度認知障害、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２９に記載の治療剤又は予防剤。 [Section 30] Diseases caused by abnormal intracellular signaling involving acetylcholine include CIAS (cognitive impairment associated with schizophrenia), Alzheimer's disease, Down's syndrome, cognitive impairment, memory impairment / learning impairment, mild cognitive impairment, Item 30. The therapeutic or prophylactic agent according to Item 29, which is attention deficit / hyperactivity disorder or cerebrovascular angiopathy.
［項３１］項１～２７のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩と、非定型抗精神病薬に分類される薬剤から選択される少なくとも１種以上の薬剤とを組み合わせてなる医薬。 [Item 31] At least one or more drugs selected from the compound according to any one of Items 1 to 27 or a pharmaceutically acceptable salt thereof and a drug classified as an atypical antipsychotic drug A medicine that combines
［項３２］治療が必要な患者に、治療上の有効量の項１～２７のいずれか１項に記載の化合物又はその製薬学的に許容される塩を投与することを特徴とするアセチルコリンが関与する細胞内シグナル伝達の異常に起因する疾患の治療または予防方法。 [Item 32] An acetylcholine characterized by administering a therapeutically effective amount of the compound according to any one of items 1 to 27 or a pharmaceutically acceptable salt thereof to a patient in need of treatment. A method for treating or preventing a disease caused by abnormality of intracellular signaling involved.
［項３３］アセチルコリンが関与する細胞内シグナル伝達の異常に起因する疾患の治療剤又は予防剤を製造するための項１～２７のいずれか１項に記載の化合物又はその製薬学的に許容される塩の使用。 [Item 33] The compound according to any one of items 1 to 27 or a pharmaceutically acceptable salt thereof for producing a therapeutic or prophylactic agent for a disease caused by an abnormality in intracellular signal transduction involving acetylcholine. Use of salt.
［項３４］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または予防に使用する、項１～２７のいずれか１項に記載の化合物又はその製薬学的に許容される塩を含む医薬組成物。 [Item 34] The compound according to any one of items 1 to 27 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease caused by an abnormality in intracellular signal transduction involving acetylcholine. A pharmaceutical composition comprising.
　本発明化合物は神経系疾患、精神疾患、および炎症性疾患（例えば老人性認知症、注意力欠陥障害、アルツハイマー病、および統合失調症）の新規な治療剤及び／又は予防剤として有用である。また、本発明化合物は、非定型抗精神病薬に分類される薬剤との併用剤として、統合失調症などの神経系疾患、精神疾患の治療及び／又は予防に有用である。 The compound of the present invention is useful as a novel therapeutic agent and / or preventive agent for nervous system diseases, psychiatric diseases, and inflammatory diseases (for example, senile dementia, attention deficit disorder, Alzheimer's disease, and schizophrenia). In addition, the compound of the present invention is useful for the treatment and / or prevention of nervous system diseases such as schizophrenia and mental disorders as a concomitant drug with drugs classified as atypical antipsychotic drugs.
　本発明の化合物は、水和物及び／又は溶媒和物の形で存在することもあるので、これらの水和物及び／又は溶媒和物もまた本発明の化合物に包含される。 Since the compounds of the present invention may exist in the form of hydrates and / or solvates, these hydrates and / or solvates are also included in the compounds of the present invention.
　式（Ｉ）の化合物は、１個又は場合によりそれ以上の不斉炭素原子を有する場合があり、また幾何異性や軸性キラリティを生じることがあるので、数種の立体異性体として存在することがある。本発明においては、これらの立体異性体、それらの混合物及びラセミ体は本発明の式（Ｉ）で表される化合物に包含される。
　また、一般式（Ｉ）で表される化合物のいずれか１つまたは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。
　また、本発明には、式（Ｉ）で表される化合物またはその製剤学的に許容される塩の水和物、エタノール溶媒和物等の溶媒和物も一般式（Ｉ）で表される化合物に包含される。 The compound of formula (I) may have one or more asymmetric carbon atoms and may cause geometric isomerism and axial chirality, and therefore exist as several stereoisomers. There is. In the present invention, these stereoisomers, mixtures thereof and racemates are included in the compound represented by the formula (I) of the present invention.
In addition, the compound represented by the general formula (I) includes a deuterium converter obtained by converting any one or two or more 1 H of the compound represented by the general formula (I) to 2 H (D). Is done.
In the present invention, a solvate such as a hydrate of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof or an ethanol solvate is also represented by the general formula (I). Included in the compound.
　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、「Ｃ１－６アルキル」とは炭素原子数が１～６のアルキルを意味する。その具体例として、「Ｃ１－６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、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。
　「シクロアルキル」とは、単環又は多環式飽和炭化水素を意味し、例えば「Ｃ３－６シクロアルキル」又は「Ｃ３－１０シクロアルキル」とは炭素原子数が３～６又は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又はアリール若しくはヘテロアリールと縮環を形成したものも含まれる。その具体例として、「Ｃ３－６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、シクロへキシル等が挙げられる。「Ｃ３－１０シクロアルキル」の場合には、前記に加え、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。
　「アルコキシ」とは、直鎖状又は分枝鎖状の飽和炭化水素基が酸素原子を介している基を意味し、例えば、「Ｃ１－６アルコキシ」とは炭素原子数が１～６のアルコキシを意味する。その具体例として、「Ｃ１－６アルコキシ」の場合には、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブチルオキシ、ペンチルオキシ、イソペンチルオキシ、ネオペンチルオキシ、ヘキシルオキシ等が挙げられる。 “Alkyl” means a linear or branched saturated hydrocarbon group. For example, “C 1-6 alkyl” means an alkyl having 1 to 6 carbon atoms. Specific examples thereof include “C 1-6 alkyl” such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the like.
“Cycloalkyl” means a monocyclic or polycyclic saturated hydrocarbon. For example, “C 3-6 cycloalkyl” or “C 3-10 cycloalkyl” means 3 to 6 or 3 to C carbon atoms. It means 10 cyclic alkyls, and those having a partially bridged structure or those formed a condensed ring with aryl or heteroaryl are also included. Specific examples of “C 3-6 cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. In the case of “C 3-10 cycloalkyl”, in addition to the above, cycloheptyl, cyclooctyl, adamantyl and the like can be mentioned.
“Alkoxy” means a group in which a linear or branched saturated hydrocarbon group is interposed via an oxygen atom. For example, “C 1-6 alkoxy” means a group having 1 to 6 carbon atoms. Means alkoxy. Specific examples of “C 1-6 alkoxy” include methoxy, ethoxy, propoxy, isopropoxy, butyloxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like.
　「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、フッ素原子または塩素原子である。
　「アリール」としては、具体的にはフェニル、１－ナフチル、２－ナフチル、アントラセン等が挙げられる。中でも好ましくは、フェニルが挙げられる。
　「ヘテロアリール」としては、窒素原子、酸素原子及び硫黄原子からなる群から独立して選ばれる１から４個の原子を含む、単環の５～７員環の芳香族複素環基、２環の８～１１員の芳香族複素環基又は３環の１２～１６員の芳香族複素環基が挙げられる。具体的にはピリジル、ピリダジニル、イソチアゾリル、ピロリル、フリル、チエニル、チアゾリル、イミダゾリル、ピリミジニル、チアジアゾリル、ピラゾリル、オキサゾリル、イソオキサゾリル、ピラジニル、トリアジニル、トリアゾリル、イミダゾリジニル、オキサジアゾリル、トリアゾリル、テトラゾリル、インドリル、インダゾリル、クロメニル、キノリル、イソキノリル、ベンゾフラニル、ベンゾチエニル、ベンゾオキサゾリル、ベンゾチアゾリル、ベンズイソオキサゾリル、ベンズイソチアゾリル、ベンゾトリアゾリル、ベンズイミダゾリル、チオキサンテン、６，１１－ジヒドロジベンゾ［Ｂ，Ｅ］チエピニル等が挙げられる。好ましいヘテロアリールとしては、ピリジル、ピリミジニル、キノリル、及びイソキノリルが挙げられる。 “Halogen” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Among them, preferred is a fluorine atom or a chlorine atom.
Specific examples of “aryl” include phenyl, 1-naphthyl, 2-naphthyl, anthracene and the like. Of these, phenyl is preferable.
“Heteroaryl” is a monocyclic 5- to 7-membered aromatic heterocyclic group or bicyclic ring containing 1 to 4 atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom And an 8- to 11-membered aromatic heterocyclic group or a 3-ring 12- to 16-membered aromatic heterocyclic group. Specifically, pyridyl, pyridazinyl, isothiazolyl, pyrrolyl, furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, triazinyl, triazolyl, imidazolidinyl, oxadiazolyl, triazolyl, tetrazolyl, indolyl, indolyl, indolyl, indryl Quinolyl, isoquinolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzotriazolyl, benzimidazolyl, thioxanthene, 6,11-dihydrodibenzo [B, E] thiepinyl Etc. Preferred heteroaryls include pyridyl, pyrimidinyl, quinolyl, and isoquinolyl.
　「４～１０員の飽和複素環」とは、炭素原子以外に窒素原子、酸素原子及び硫黄原子からなる群から独立して選択される１～２個の原子を含む４～１０個の原子で構成される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等が挙げられる。
　「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。 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 composed heterocycle. For example, azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, tetrahydrofuran, tetrahydropyran and the like can be mentioned.
The “4- to 10-membered nitrogen-containing saturated heterocyclic ring” means a saturated heterocyclic ring composed of 4 to 10 atoms containing 1 to 2 nitrogen atoms in addition to carbon atoms. For example, azetidine, pyrrolidine, piperidine, piperazine, homopiperidine and the like can be mentioned.
　「ＣＲ６－ＮＲ７－アリール」とは、ＣＲ６－ＮＲ７の窒素原子にアリールが置換した基を意味する。「ＣＲ６－ＮＲ７－アリール」と同様に、「ＣＲ６－ＮＲ７－ヘテロアリール」等も後者に置換した基を意味する。 “CR 6 -NR 7 -aryl” refers to a group in which aryl is substituted on the nitrogen atom of CR 6 -NR 7 . Like the - "aryl CR 6 -NR 7" - it means "CR 6 -NR 7 heteroaryl" etc. was also replaced with the latter group.
　式（Ｉ）で表される本発明の化合物の中でも、Ａ、Ｘ－Ｙ－Ｚ、Ｒ１Ａ～Ｒ１Ｄ、Ｒ２、Ｒ３Ａ～Ｒ３Ｄ、Ｒ４Ａ、Ｒ４Ｂ、Ｒ５～Ｒ１７及びｎで、好ましいものは以下のとおりであるが、本発明の技術的範囲は下記に挙げる化合物の範囲に限定されるものではない。 Among the compounds of the present invention represented by the formula (I), A, XYZ, R 1A to R 1D , R 2 , R 3A to R 3D , R 4A , R 4B , R 5 to R 17 and Preferred examples of n are as follows, but the technical scope of the present invention is not limited to the following compounds.
　Ａとして好ましくは、ＣＲ１Ｄが挙げられる。
　Ｘ－Ｙ－Ｚとして好ましくは、Ｎ－ＣＯ－ＮＲ４ＡＲ５、ＣＲ６－ＮＲ７－ＣＯＮＲ４ＡＲ５、ＣＲ６－ＮＲ７－ＣＯＲ４Ｂ、ＣＲ６－ＮＲ７－アリール、ＣＲ６－ＮＲ７－ヘテロアリール又はＣＲ６－ＣＲ８Ｒ９－ＮＲ４ＡＲ５が挙げられ、より好ましくは、Ｎ－ＣＯ－ＮＲ４ＡＲ５、ＣＲ６－ＮＲ７－ＣＯＲ４Ｂ、ＣＲ６－ＮＲ７－アリール又はＣＲ６－ＮＲ７－ヘテロアリールが挙げられる。さらに好ましくは、Ｎ－ＣＯ－ＮＲ４ＡＲ５又はＣＲ６－ＮＲ７－ＣＯＲ４Ｂが挙げられる。最も好ましくは、ＣＲ６－ＮＲ７－ＣＯＲ４Ｂが挙げられる。
　Ｒ１Ａ～Ｒ１Ｄとして好ましくは、同一又は異なって、ハロゲン、Ｃ１－６アルコキシ及び－ＮＲ１０Ｒ１１からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル、水素原子、ハロゲン、Ｃ３－１０シクロアルキル、Ｃ１－６アルコキシ、Ｃ３－１０シクロアルコキシ、－ＮＲ１０Ｒ１１、シアノ、－ＣＯＯＲ１０、－ＣＯＮＲ１０Ｒ１１、－ＮＲ１０ＣＯＲ１１、－ＳＯ２ＮＲ１０Ｒ１１又は－ＮＲ１０ＳＯ２Ｒ１１が挙げられる。より好ましくは、ハロゲン及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル、水素原子、ハロゲン、Ｃ３－１０シクロアルキル、Ｃ１－６アルコキシ又はＣ３－１０シクロアルコキシが挙げられる。 A is preferably CR 1D .
X—Y—Z is preferably N—CO—NR 4A R 5 , CR 6 —NR 7 —CONR 4A R 5 , CR 6 —NR 7 —COR 4B , CR 6 —NR 7 —aryl, CR 6 —NR 7 -heteroaryl or CR 6 -CR 8 R 9 -NR 4A R 5 may be mentioned, more preferably N-CO-NR 4A R 5 , CR 6 -NR 7 -COR 4B , CR 6 -NR 7 -aryl. Or CR 6 -NR 7 -heteroaryl. More preferred is N—CO—NR 4A R 5 or CR 6 —NR 7 —COR 4B . Most preferably, CR 6 —NR 7 —COR 4B is used.
R 1A to R 1D are preferably the same or different and may be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, C 1-6 alkoxy and —NR 10 R 11. Good C 1-6 alkyl, hydrogen atom, halogen, C 3-10 cycloalkyl, C 1-6 alkoxy, C 3-10 cycloalkoxy, —NR 10 R 11 , cyano, —COOR 10 , —CONR 10 R 11 , —NR 10 COR 11 , —SO 2 NR 10 R 11, or —NR 10 SO 2 R 11 may be mentioned. More preferably, C 1-6 alkyl, hydrogen atom, halogen, C 3-10 which may be substituted with 1 to 5 substituents independently selected from the group consisting of halogen and C 1-6 alkoxy Examples include cycloalkyl, C 1-6 alkoxy or C 3-10 cycloalkoxy.
　Ｒ２として好ましくは、ハロゲン、水酸基及び－ＮＲ１２Ｒ１３からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル、水素原子、Ｃ１－６アルコキシ又は４～１０員の飽和複素環が挙げられ、より好ましくは、１～５個のハロゲンで置換されていてもよいＣ１－６アルキル、水素原子又はＣ１－６アルコキシが挙げられる。最も好ましくは、水素原子が挙げられる。
　Ｒ３Ａ、Ｒ３Ｂ、Ｒ３Ｃ及びＲ３Ｄとして好ましくは、同一又は異なって、ハロゲン及び－ＮＲ１４Ｒ１５からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル、水素原子又はハロゲンが挙げられ、より好ましくは、Ｃ１－６アルキル、水素原子又はハロゲンが挙げられる。 R 2 is preferably C 1-6 alkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group and —NR 12 R 13 , a hydrogen atom, C 1 -6 alkoxy or a 4- to 10-membered saturated heterocyclic ring can be mentioned, and more preferable examples include C 1-6 alkyl, hydrogen atom or C 1-6 alkoxy optionally substituted with 1 to 5 halogens. . Most preferably, a hydrogen atom is mentioned.
R 3A , R 3B , R 3C and R 3D are preferably the same or different and may be substituted with 1 to 5 substituents independently selected from the group consisting of halogen and —NR 14 R 15 Good C 1-6 alkyl, a hydrogen atom or halogen is preferable, and C 1-6 alkyl, a hydrogen atom or halogen is more preferable.
　Ｒ４Ａ、Ｒ５及びＲ７として好ましくは、同一又は異なって、ハロゲン、水酸基及びＣ１－６アルコキシからなる群から選択される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、水酸基及びＣ１－６アルコキシからなる群から選択される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、より好ましくは、ハロゲン、水酸基及びＣ１－６アルコキシからなる群から選択される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水素原子が挙げられる。
　Ｒ４Ｂとして好ましくは、アリール、ヘテロアリール、水酸基、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；アリール、ヘテロアリール、水酸基、フッ素、１～５個のフッ素で置換されていてもよいＣ１－６アルコキシ及び１～５個のフッ素で置換されていてもよい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（該基はアリールと縮環を形成してもよく）；同一又は異なる１～５個の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；又はハロゲン、Ｃ１－６アルコキシ及びＣ１－６アルキル（該アルコキシ及びアルキルは、１～５個のフッ素で置換されていてもよい）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アリール又はヘテロアリールが挙げられる。より好ましくは、アリール、ヘテロアリール、水酸基、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；アリール、ヘテロアリール、水酸基、フッ素、１～５個のフッ素で置換されていてもよいＣ１－６アルコキシ及び１～５個のフッ素で置換されていてもよい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（該基はアリールと縮環を形成してもよく）；又は同一又は異なる１～５個の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。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；フッ素、１～５個のフッ素で置換されていてもよいＣ１－６アルコキシ及び１～５個のフッ素で置換されていてもよい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。
　Ｒ６、Ｒ８及びＲ９として好ましくは、同一又は異なって、水素原子、ハロゲン、水酸基、Ｃ１－６アルキル又はＣ１－６アルコキシが挙げられ、より好ましくは、水素原子、ハロゲンが挙げられる。
　Ｒ１０～Ｒ１７としては、同一又は異なって、水素原子又はＣ１－６アルキルが挙げられ、好ましくは、水素原子が挙げられる。
　ｎとしては、１又は２が挙げられ、好ましくは、１が挙げられる。 R 4A, preferably as R 5 and R 7, which may be identical or different, halogen, optionally substituted with 1 to 5 substituents selected from the group consisting of hydroxyl and C 1-6 alkoxy C 1- 6 alkyl; C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents selected from the group consisting of halogen, hydroxyl group and C 1-6 alkoxy; 4- to 10-membered saturated heterocycle or hydrogen Atoms, and more preferably, a C 3-10 cycloalkyl which may be substituted with 1 to 5 substituents selected from the group consisting of halogen, hydroxyl group and C 1-6 alkoxy, or a hydrogen atom. It is done.
R 4B is preferably substituted with 1 to 5 substituents independently selected from the group consisting of aryl, heteroaryl, hydroxyl group, fluorine, C 1-6 alkoxy and C 3-10 cycloalkyl. C 1-6 alkyl; aryl, heteroaryl, hydroxyl, fluorine, 1-5 fluorine may be substituted with C 1-6 alkoxy and 1 to 5 substituents C 1 be substituted by fluorine C 3-10 cycloalkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of -6 alkyl (the group may form a condensed ring with aryl); Or a 4- to 10-membered saturated heterocycle optionally substituted with 1 to 5 different C 1-6 alkyls; or halogen, C 1-6 alkoxy and C 1-6 alkyl (the alkoxy and alkyl are And aryl or heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of 1 to 5 fluorines). More preferably, it may be substituted with 1 to 5 substituents independently selected from the group consisting of aryl, heteroaryl, hydroxyl, fluorine, C 1-6 alkoxy and C 3-10 cycloalkyl. 1-6 alkyl; aryl, heteroaryl, hydroxyl, fluorine, optionally substituted with 1-5 optionally substituted by fluorine C 1-6 alkoxy and 1 to 5 fluorine C 1-6 C 3-10 cycloalkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of alkyl (which may form a condensed ring with aryl); or the same or Examples thereof include a 4- to 10-membered saturated heterocyclic ring which may be substituted with 1 to 5 different C 1-6 alkyls. More preferably, fluorine, C 1-6 alkoxy and C 3-10 ~ 1 are independently selected from the group consisting of cycloalkyl 5 substituents optionally substituted by C 1-6 alkyl; fluorine, 1 to 1 to 5 selected 5 substituents are fluorine substituted C 1-6 alkoxy and 1 to 5 fluorine independently from the group consisting of C 1-6 alkyl optionally substituted C 3-10 cycloalkyl optionally substituted with one substituent; or a 4-10 membered saturated heterocycle.
R 6 , R 8 and R 9 are preferably the same or different and include a hydrogen atom, halogen, hydroxyl group, C 1-6 alkyl or C 1-6 alkoxy, and more preferably a hydrogen atom or halogen. .
R 10 to R 17 are the same or different and include a hydrogen atom or C 1-6 alkyl, preferably a hydrogen atom.
As n, 1 or 2 is mentioned, Preferably 1 is mentioned.
　式（Ｉ）で表される化合物の製薬学的に許容される塩とは、構造中に酸付加塩を形成しうる基を有する式（Ｉ）の化合物の製薬学的に許容される酸付加塩を意味する。酸付加塩の具体例としては、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硫酸塩、過塩素酸塩、リン酸塩等の無機酸塩、シュウ酸塩、マロン酸塩、マレイン酸塩、フマル酸塩、乳酸塩、リンゴ酸塩、クエン酸塩、酒石酸塩、安息香酸塩、トリフルオロ酢酸塩、酢酸塩、メタンスルホン酸塩、ｐ－トルエンスルホン酸塩、トリフルオロメタンスルホン酸塩等の有機酸塩、又はグルタミン酸塩、アスパラギン酸塩等のアミノ酸塩が挙げられる。
　式（Ｉ）で表される本発明化合物がカルボキシル基などの酸性官能基を有する場合、各種の塩基と塩を形成しうる。この場合の薬学的に許容される塩としては、ナトリウム塩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、またはアンモニウム塩などが挙げられる。これらの塩は、式（Ｉ）で表される本発明化合物を塩基と混合した後、再結晶などの常法により得ることができる。 The pharmaceutically acceptable salt of the compound represented by the formula (I) is a pharmaceutically acceptable acid addition of the compound of the formula (I) having a group capable of forming an acid addition salt in the structure. Means salt. Specific examples of acid addition salts include hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, phosphate and other inorganic acid salts, oxalate, malonate, maleate Acid, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate And organic acid salts such as glutamic acid salts and aspartic acid salts.
When this invention compound represented by a formula (I) has acidic functional groups, such as a carboxyl group, various bases and salts can be formed. Examples of the pharmaceutically acceptable salt in this case include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt, and ammonium salt. These salts can be obtained by a conventional method such as recrystallization after mixing the compound of the present invention represented by formula (I) with a base.
　なお、本明細書において記載の簡略化のために、次に挙げる略号を用いることもある。o－：ｏｒｔｈｏ－、ｍ－：ｍｅｔａ－、ｐ－：ｐａｒａ－、ｔ－：ｔｅｒｔ－、ｓ－：ｓｅｃ－、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、ＰＡＭ：ポジティブアロステリックモジュレーター、ＨＥＰＥＳ：Ｎ－２－ヒドロキンエチルピペラジン－Ｎ’－２－エタンスルホン酸、ＢＳＡ：ｂｏｖｉｎｅ　ｓｅｒｕｍ　ａｌｂｕｍｉｎ、牛血清アルブミン、ＦＤＳＳ：Ｆｕｎｃｔｉｏｎａｌ　Ｄｒｕｇ　Ｓｃｒｅｅｎｉｎｇ　Ｓｙｓｔｅｍ、Ｂｏｃ：ｔｅｒｔ－ブトキシカルボニル、ＣＢｚ：ベンジルオキシカルボニル、ｃ－Ｈｅｘ：シクロヘキシル、Ｎｓ：２-ニトロベンゼンスルホニル、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燐酸塩、ＤＭＡＰ：４－ジメチルアミノピリジン Note that the following abbreviations may be used to simplify the description in this specification. o-: ortho-, m-: meta-, p-: para-, t-: tert-, s-: sec-, THF: tetrahydrofuran, DMF: N, N-dimethylformamide, DMSO: dimethyl sulfoxide, d 6 -DMSO: deuterated dimethyl sulfoxide, PAM: positive allosteric modulator, HEPES: N-2-hydroquinethylpiperazine-N'-2-ethanesulfonic acid, BSA: bovine serum albumin, bovine serum albumin, FDSS: Functional Drug Screening System, Boc: tert-butoxycarbonyl, CBz: benzyloxycarbonyl, c-Hex: cyclohexyl, Ns: 2-nitrobenzenesulfonyl, EDCI: 1-ethyl-3- (3-dimethylamino Nopropyl) carbodiimide, HOBt: 1-hydroxybenzotriazole, HBTU: 2- (1H-7-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate, DMAP: 4- Dimethylaminopyridine
　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～Ｄ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 D.
製造法Ａ
　式（Ｉ）で表される化合物のうち、Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ４ＡＲ５である式Ａ１で表される化合物（以下、化合物Ａ１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。
Figure JPOXMLDOC01-appb-C000003
 （式中、Ａ、Ｒ１Ａ～Ｒ１Ｄ、Ｒ２、Ｒ３Ａ～Ｒ３Ｄ、Ｒ４Ａ、Ｒ５及びｎは項１に定義されるとおりであり、Ｐはアミノ基の保護基、Ｘはハロゲン等の脱離基、Ｒはメチル基又はフェニル基を意味する） Manufacturing method A
Of the compounds represented by the formula (I), a compound represented by the formula A1 in which XYZ is N—CO—NR 4A R 5 (hereinafter also referred to as the compound A1) is, for example, the following production method Can be manufactured.
Figure JPOXMLDOC01-appb-C000003
 (In the formula, A, R 1A to R 1D , R 2 , R 3A to R 3D , R 4A , R 5 and n are as defined in Item 1, P is an amino-protecting group, and X is halogen. Etc., R means a methyl group or a phenyl group)
　ＡがＣＲ１Ｄの化合物ａ１である２－ハロニトロベンゼンは、例えば、Bioorganic & Medicinal Chemistry Letters 2003, 13(10), 1725-1728、Tetrahedron 1999, 55(25), 7725-7738、Synth. Commun. 1998, 28(23), 4295-4301などに記載されている方法により合成できるか、または市販品として購入できる。
　Ａが窒素原子の化合物ａ１である２－ハロニトロピリジンは、例えば、Bioorganic & Medicinal Chemistry Letters 2003, 13(10), 525-527、J. Heterocyclic Chem. 2000, 37(5), 1253-1256、Tetrahedron Lett. 1993, 34(18), 2937-2940、J. Heterocyclic Chem. 1996, 33(6), 1815-1821、J. Org. Chem. 1991, 56(9), 3006-3009などに記載されている方法により合成できるか、または市販品として購入できる。 2-halonitrobenzene in which A is a compound a1 having CR 1D is, for example, Bioorganic & Medicinal Chemistry Letters 2003, 13 (10), 1725-1728, Tetrahedron 1999, 55 (25), 7725-7738, Synth. Commun. 1998, 28 (23), 4295-4301, etc., or can be synthesized as a commercial product.
2-halonitropyridine in which A is a nitrogen atom compound a1 is, for example, Bioorganic & Medicinal Chemistry Letters 2003, 13 (10), 525-527, J. Heterocyclic Chem. 2000, 37 (5), 1253. -1256, Tetrahedron Lett. 1993, 34 (18), 2937-2940, J. Heterocyclic Chem. 1996, 33 (6), 1815-1821, J. Org. Chem. 1991, 56 (9), 3006-3009, etc. Or can be purchased as a commercial product.
［Ａ－１工程］
　本工程は化合物ａ１に、種々の塩基存在下、適当な溶媒中、化合物ａ６を反応させることにより、化合物ａ２を得る工程である。本工程において使用される塩基は、後記に例示する塩基等から選択されるが、好ましくはジイソプロピルエチルアミン又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、好ましくはジメチルホルムアミド又はテトラヒドロフランである。類似反応として、例えば、Tetrahedron Lett. 1994, 35(31), 5649-5652、Tetrahedron Lett. 2002, 43(43), 7707-7710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。 [Step A-1]
This step is a step of obtaining compound a2 by reacting compound a1 with compound a6 in a suitable solvent in the presence of various bases. The base used in this step is selected from the bases exemplified below, and is preferably diisopropylethylamine or potassium carbonate. The solvent used in this step is selected from the solvents exemplified below, and preferably dimethylformamide or tetrahydrofuran. As a similar reaction, for example, the methods described in Tetrahedron Lett. 1994, 35 (31), 5649-5652, Tetrahedron Lett. 2002, 43 (43), 7707-7710, etc. are known and synthesized in the same manner. Can do.
［Ａ－２工程］
　本工程は上記Ａ－１工程で得られた化合物ａ２を触媒存在下又は非存在化で還元し化合物ａ３を得ることができる。還元剤としては水素、蟻酸アンモニウムなどの蟻酸の塩、ヒドラジン、亜鉛、鉄、２塩化スズを用いることができる。触媒としては、パラジウム、ニッケル、ロジウム、コバルトもしくは白金などの遷移金属やその塩、その錯体、ポリマーなどの担体に担持させたものを挙げることができる。本工程において使用される溶媒は、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メタノールである。類似反応として、例えば、Org. Lett. 2005, 7(8), 1549-1552、Tetrahedron Lett. 2006, 47(6), 969-972、Tetrahedron Lett. 2010, 51(10), 1380-1382、Synth. Commun. 2010, 40(5), 661-665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。 [Step A-2]
In this step, compound a3 can be obtained by reducing compound a2 obtained in step A-1 in the presence or absence of a catalyst. As the reducing agent, hydrogen, formic acid salts such as ammonium formate, hydrazine, zinc, iron, and tin dichloride can be used. Examples of the catalyst include those supported on a carrier such as a transition metal such as palladium, nickel, rhodium, cobalt or platinum, a salt thereof, a complex thereof, or a polymer. The solvent used in this step is selected from the solvents exemplified below, and is preferably tetrahydrofuran or methanol. Similar reactions include, for example, Org. Lett. 2005, 7 (8), 1549-1552, Tetrahedron Lett. 2006, 47 (6), 969-972, Tetrahedron Lett. 2010, 51 (10), 1380-1382, Synth. Commun. 2010, 40 (5), 661-665 and the like are known and can be synthesized in the same manner.
［Ａ－３工程］
　Ｒ２が水素原子である化合物ａ４は、上記Ａ－２工程で得られた化合物ａ３に、適当な溶媒中、トリメトキシメタン又はトリエトキシエタン又は蟻酸を反応させることにより得ることができる。類似反応として、例えば、Tetrahedron Lett. 2006, 47(30), 5359-5361、国際公開第2010/012121号パンフレット、国際公開第2010/027500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。
　Ｒ２がベンズイミダゾール環と炭素－炭素で結合している化合物ａ４は、上記Ａ－２工程で得られた化合物ａ３に、適当な溶媒中、対応するカルボン酸（Ｒ２ＣＯ２Ｈ）あるいは酸塩化物（Ｒ２ＣＯＣｌ）を反応させることにより得ることができる。類似反応として、例えば、Chemistry and Biodiversity 2008, 714-728、Bioorganic & Medicinal Chemistry Letters 2007, 17(23), 6633-6637、国際公開第2008/108958号パンフレット、米国公開特許公報US2008/0249101などに記載されている方法により合成することもできる。本工程において使用される溶媒は、後記に例示する溶媒等から選択される。 [Step A-3]
Compound a4 in which R 2 is a hydrogen atom can be obtained by reacting compound a3 obtained in step A-2 with trimethoxymethane, triethoxyethane, or formic acid in a suitable solvent. As similar reactions, for example, the methods described in Tetrahedron Lett. 2006, 47 (30), 5359-5361, International Publication No. 2010/012121, International Publication No. 2010/027500, etc. are known, Can be synthesized.
The compound a4 in which R 2 is bonded to the benzimidazole ring with carbon-carbon is obtained by reacting the compound a3 obtained in the above step A-2 with the corresponding carboxylic acid (R 2 CO 2 H) or acid in an appropriate solvent. It can be obtained by reacting chloride (R 2 COCl). As a similar reaction, for example, Chemistry and Biodiversity 2008, 714-728, Bioorganic & Medicinal Chemistry Letters 2007, 17 (23), 6633-6637, International Publication No. 2008/108958 Pamphlet, U.S. Published Patent Publication US2008 / 0249101 It can also be synthesized by the method described in the above. The solvent used in this step is selected from the solvents exemplified below.
［Ａ－４工程］
　本工程は上記Ａ－３工程で得られた化合物ａ４のアミノ基の保護基Ｐを、脱保護することにより、化合物ａ５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 step of obtaining a compound a5 by deprotecting the amino-protecting group P of the compound a4 obtained in the step A-3. 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－４工程で得られた化合物ａ５に、種々の塩基存在下、適当な溶媒中、化合物ａ７又はａ８又はａ９を反応させることにより、化合物Ａ１を得る工程である。本工程において使用される塩基は、後記に例示する塩基等から選択されるが、好ましくはジイソプロピルエチルアミン又はトリエチルアミンである。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エタノールある。類似反応として、例えば、Tetrahedron Lett.1998, 39(21), 3609-3612、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。
Figure JPOXMLDOC01-appb-C000004
 （式中、Ａ、Ｒ１Ａ～Ｒ１Ｄ、Ｒ２、Ｒ３Ａ～Ｒ３Ｄ、Ｒ４Ａ、Ｒ５及びｎは項１に定義されるとおりであり、Ｌは脱離基を意味する） [Step A-5]
This step is a step of obtaining compound A1 by reacting compound a5 obtained in step A-4 with compound a7, a8 or a9 in an appropriate solvent in the presence of various bases. The base used in this step is selected from the bases exemplified below, and is preferably diisopropylethylamine or triethylamine. The solvent used in this step is selected from the solvents exemplified below, and is preferably tetrahydrofuran or ethanol. As a similar reaction, for example, Tetrahedron Lett. 1998, 39 (21), 3609-3612, 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.
Figure JPOXMLDOC01-appb-C000004
 (In the formula, A, R 1A to R 1D , R 2 , R 3A to R 3D , R 4A , R 5 and n are as defined in Item 1 and L means a leaving group)
［Ａ－６工程]
　本工程は上記Ａ－４工程で得られた化合物ａ５に脱離基Ｌを導入する工程である。種々の塩基存在下、適当な溶媒中、１，１’－カルボニルジイミダゾール又は置換されたあるいは無置換のフェニルクロロホルメートを反応させることにａ１０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、好ましくは塩化メチレン又はジクロロエタンある。類似反応として、例えば、国際公開第2003/103669号パンフレットに記載されている方法により合成することもできる。 [Step A-6]
This step is a step of introducing a leaving group L into the compound a5 obtained in the above step A-4. In this step, a1 is obtained by reacting 1,1′-carbonyldiimidazole or substituted or unsubstituted phenyl chloroformate in an appropriate solvent in the presence of various bases. 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 methylene chloride or dichloroethane. As a similar reaction, for example, it can be synthesized by a method described in International Publication No. 2003/103669 pamphlet.
［Ａ－７工程］
　本工程は上記Ａ－６工程で得られた化合物ａ１０に、種々の塩基存在下、適当な溶媒中、アミンを反応させることにより、化合物Ａ１を得る工程である。本工程において使用される溶媒は、後記に例示する溶媒等から選択されが、好ましくはテトラヒドロフラン又はジメチルホルムアミドである。類似反応として、例えば、国際公開第2003/103669号パンフレットに記載されている方法により合成することもできる。 [Step A-7]
This step is a step of obtaining compound A1 by reacting compound a10 obtained in the above step A-6 with an amine in an appropriate solvent in the presence of various bases. The solvent used in this step is selected from the solvents exemplified below, and is preferably tetrahydrofuran or dimethylformamide. As a similar reaction, for example, it can be synthesized by a method described in International Publication No. 2003/103669 pamphlet.
製造法Ｂ
　式（Ｉ）で表される化合物のうち、Ｘ－Ｙ－Ｚが、ＣＲ６－ＣＯ－ＮＲ４ＡＲ５である式［Ｂ１］で表される化合物（以下、化合物Ｂ１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。
Figure JPOXMLDOC01-appb-C000005
 （式中、Ａ、Ｒ１Ａ～Ｒ１Ｄ、Ｒ２、Ｒ３Ａ～Ｒ３Ｄ、Ｒ４Ａ、Ｒ５、Ｒ６及びｎは項１に定義されるとおりであり、ＲｘはＣ１－４アルキル基、Ｘはハロゲン等の脱離基を意味する） Manufacturing method B
Of the compounds represented by the formula (I), a compound represented by the formula [B1] in which XYZ is CR 6 —CO—NR 4A R 5 (hereinafter also referred to as compound B1) is, for example, It can be produced by the following production method.
Figure JPOXMLDOC01-appb-C000005
 (In the formula, A, R 1A to R 1D , R 2 , R 3A to R 3D , R 4A , R 5 , R 6 and n are as defined in Item 1, and Rx is a C 1-4 alkyl group. , X means a leaving group such as halogen)
［Ｂ－１工程］
　本工程は化合物ａ１に、上記Ａ－１工程に準じた条件で、化合物ｂ５を反応させることにより、化合物ｂ１を得る工程である。化合物ｂ５は例えば、国際公開第2007/127382号パンフレットに記載されている方法により合成できるか、または市販品として購入できる。 [Step B-1]
This step is a step of obtaining compound b1 by reacting compound b1 with compound b5 under the conditions according to the above step A-1. Compound b5 can be synthesized, for example, by the method described in International Publication No. 2007/127382 pamphlet, or can be purchased as a commercial product.
［Ｂ－２工程］
　本工程は上記Ｂ－１工程で得られた化合物ｂ１を、上記Ａ－２工程に準じた条件で化合物ｂ２へ変換する工程である。 [Step B-2]
This step is a step of converting the compound b1 obtained in the step B-1 into the compound b2 under the conditions according to the step A-2.
［Ｂ－３工程］
　本工程は上記Ｂ－２工程で得られた化合物ｂ２を、上記Ａ－３工程に準じた条件で化合物ｂ３へ変換する工程である。 [Step B-3]
This step is a step of converting the compound b2 obtained in the step B-2 to the compound b3 under the conditions according to the step A-3.
［Ｂ－４工程］
　本工程は上記Ｂ－３工程で得られたエステル化合物ｂ３を、対応するカルボン酸化合物ｂ４に変換する工程である。本工程はProtective Groups in Organic Synthesis（Theodora W. Greene, Peter G. M. Wuts著、John Wiley & Sons, Inc.発行、1999年）に記載されている方法等に準じて行うことができる。 [Step B-4]
This step is a step of converting the ester compound b3 obtained in the step B-3 to the corresponding carboxylic acid compound b4. This step can be carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).
［Ｂ－５工程］
　本工程は上記Ｂ－４工程で得られた化合物ｂ４に、種々の縮合剤存在下、適当な溶媒中、化合物ｂ６を反応させることにより、化合物Ｂ１を得る工程である。本工程において使用される縮合剤は、好ましくは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溶媒は、後記に例示する溶媒等から選択される。 [Step B-5]
This step is a step of obtaining compound B1 by reacting compound b6 obtained in step B-4 with compound b6 in a suitable solvent in the presence of various condensing agents. The condensing agent used in this step is preferably EDCI (including hydrochloride) or HBTU. The solvent used in this step is selected from the solvents exemplified below.
製造法Ｃ
　式（Ｉ）で表される化合物のうち、Ｘ－Ｙ－Ｚが、ＣＲ６－ＣＲ８Ｒ９－ＮＲ４ＡＲ５である式［Ｃ１］で表される化合物（以下、化合物Ｃ１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。
Figure JPOXMLDOC01-appb-C000006
 （式中、Ａ、Ｒ１Ａ～Ｒ１Ｄ、Ｒ２、Ｒ３Ａ～Ｒ３Ｄ、Ｒ４Ａ、Ｒ５、Ｒ６、Ｒ８、Ｒ９及びｎは項１に定義されるとおりであり、Ｒｘは、Ｃ１－４アルキル基を意味する） Manufacturing method C
Of the compounds represented by the formula (I), a compound represented by the formula [C1] wherein XYZ is CR 6 -CR 8 R 9 -NR 4A R 5 (hereinafter also referred to as the compound C1) Can be produced, for example, by the following production method.
Figure JPOXMLDOC01-appb-C000006
 (In the formula, A, R 1A to R 1D , R 2 , R 3A to R 3D , R 4A , R 5 , R 6 , R 8 , R 9 and n are as defined in Item 1; , C 1-4 alkyl group)
［Ｃ－１工程］
　本工程は上記Ｂ－３工程で得られたエステル化合物ｂ３をジイソブチルアルミニウムヒドリド又は水素化ホウ素ナトリウム又は水素化ホウ素リチウム等の還元剤を用いて、対応するアルデヒド化合物ｃ１に変換する工程である。類似反応として、例えば、Chem. Pharm. Bull. 1993, 41(5), 882-888、Tetrahedron Lett.1996, 37(14), 2467-2470、Chem. Lett. 2007, 36(7), 886-887、Tetrahedron 2001, 57(14), 2701-2710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。また、同様の変換は水素化リチウムアルミニムなどの還元剤を用いてアルコール化合物に変換した後、Ｓｗｅｒｎ酸化などによりアルデヒドに変換することでも可能である。類似反応として、例えば、Bioorg. Med. Chem. Lett. 2001, 11(16), 2177-2180、Bioorg. Med. Chem. Lett. 1998, 8(24), 3615-3620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。 [Step C-1]
This step is a step of converting the ester compound b3 obtained in the step B-3 to the corresponding aldehyde compound c1 using a reducing agent such as diisobutylaluminum hydride, sodium borohydride or lithium borohydride. Similar reactions include, for example, Chem. Pharm. Bull. 1993, 41 (5), 882-888, Tetrahedron Lett. 1996, 37 (14), 2467-2470, Chem. Lett. 2007, 36 (7), 886- The methods described in 887, Tetrahedron 2001, 57 (14), 2701-2710 and the like are known and can be synthesized in the same manner. The same conversion can also be performed by converting to an alcohol compound using a reducing agent such as lithium aluminum hydride and then converting to an aldehyde by Swern oxidation or the like. As a similar reaction, for example, a method described in Bioorg. Med. Chem. Lett. 2001, 11 (16), 2177-2180, Bioorg. Med. Chem. Lett. 1998, 8 (24), 3615-3620, etc. Are known and can be synthesized similarly.
［Ｃ－２工程］
　本工程は上記Ｃ－１工程で得られたアルデヒド化合物ｃ１に対し、ＮａＢＨ（ＯＡｃ）３又はＮａＢＨ３ＣＮ等の還元剤存在下、化合物ｃ２を還元的アミノ化することにより、対応するアミン化合物Ｃ１に変換する工程である。類似反応として、例えば、J. Org. Chem. 1996, 61(11), 3849-3862、J. Org. Chem. 1991, 56(17), 5192-5196、Carbohydr. Res. 1999, 315(3-4), 339-344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。 [Step C-2]
In this step, the corresponding aldehyde compound C1 is obtained by reductive amination of the compound c2 in the presence of a reducing agent such as NaBH (OAc) 3 or NaBH 3 CN with respect to the aldehyde compound c1 obtained in the step C-1. It is the process of converting into. Similar reactions include, for example, J. Org. Chem. 1996, 61 (11), 3849-3862, J. Org. Chem. 1991, 56 (17), 5192-5196, Carbohydr. Res. 1999, 315 (3- 4), 339-344 and the like are known and can be synthesized in the same manner.
製造法Ｄ
　式（Ｉ）で表される化合物のうち、Ｘ－Ｙ－Ｚが、ＣＲ６－ＮＲ７－ＣＯＲ４Ｂである式［Ｄ１、Ｄ２］又は、ＣＲ６－ＮＲ７－ＣＯＮＲ４ＡＲ５である式［Ｄ３、Ｄ４］で表される化合物（以下、化合物Ｄ１、Ｄ２、Ｄ３、Ｄ４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。
Figure JPOXMLDOC01-appb-C000007
 （式中、Ａ、Ｒ１Ａ～Ｒ１Ｄ、Ｒ２、Ｒ３Ａ～Ｒ３Ｄ、Ｒ４Ｂ、Ｒ５～Ｒ７及びｎは項１に定義されるとおりであり、Ｐはアミノ基の保護基、Ｘはハロゲン等の脱離基を意味する） Manufacturing method D
Of the compounds represented by formula (I), XYZ is the formula [D1, D2], which is CR 6 —NR 7 —COR 4B , or the formula, which is CR 6 —NR 7 —CONR 4A R 5 The compounds represented by [D3, D4] (hereinafter also referred to as compounds D1, D2, D3, and D4) can be produced, for example, by the following production method.
Figure JPOXMLDOC01-appb-C000007
 (In the formula, A, R 1A to R 1D , R 2 , R 3A to R 3D , R 4B , R 5 to R 7 and n are as defined in Item 1, P is an amino-protecting group, X means a leaving group such as halogen)
［Ｄ－１工程］
　本工程は化合物ａ１に、上記Ａ－１工程に準じた条件で、化合物ｄ６を反応させることにより、化合物ｄ１を得る工程である。化合物ｄ６は例えば、国際公開第2010/022159号パンフレット又は国際公開第2007/08669号パンフレットに記載されている方法により合成できるか、または市販品として購入できる。 [Step D-1]
This step is a step of obtaining compound d1 by reacting compound d1 with compound d6 under the same conditions as in step A-1. Compound d6 can be synthesized, for example, by the method described in International Publication No. 2010/022159 pamphlet or International Publication No. 2007/08669 pamphlet, or can be purchased as a commercial product.
［Ｄ－２工程］
　本工程は上記Ｄ－１工程で得られた化合物ｄ１を、上記Ａ－２工程に準じた条件で化合物ｄ２へ変換する工程である。 [Step D-2]
This step is a step of converting the compound d1 obtained in the step D-1 into the compound d2 under the conditions according to the step A-2.
［Ｄ－３工程］
　本工程は上記Ｄ－２工程で得られた化合物ｄ２を、上記Ａ－３工程に準じた条件で化合物ｄ３へ変換する工程である。 [Step D-3]
This step is a step of converting the compound d2 obtained in the step D-2 to the compound d3 under the conditions according to the step A-3.
［Ｄ－４工程］
　本工程は上記Ｄ－３工程で得られた化合物ｄ３のアミノ基の保護基Ｐを、脱保護することにより、化合物ｄ４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 D-4]
This step is a step of obtaining the compound d4 by deprotecting the amino-protecting group P of the compound d3 obtained in the step D-3. 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).
［Ｄ－５工程］
　本工程は上記Ｄ－４工程で得られた化合物ｄ４に、種々の縮合剤又は塩基存在下、適当な溶媒中、化合物ｄ７又はｄ８を反応させることにより、化合物Ｄ１を得る工程である。本工程において使用される縮合剤は、好ましくはＥＤＣＩ（塩酸塩を含む）又はＨＢＴＵである。また使用される塩基は、後記に例示する塩基等から選択されるが、好ましくはジイソプロピルエチルアミン又はトリエチルアミンである。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又はテトラヒドロフランある。 [Step D-5]
This step is a step of obtaining compound D1 by reacting compound d4 obtained in step D-4 with compound d7 or d8 in a suitable solvent in the presence of various condensing agents or bases. The condensing agent used in this step is preferably EDCI (including hydrochloride) or HBTU. The base used 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 or tetrahydrofuran.
［Ｄ－６工程］
　本工程は上記Ｄ－４工程で得られた化合物ｄ４を化合物ｄ５へ変換する工程である。Ｒ７がアルキル又はシクロアルキルの場合、化合物ｄ４を対応するＮｓアミド又はトリフルオロアセタミドに誘導し、種々の塩基存在下、適当な溶媒中、化合物ｄ８を反応させ、脱保護を行うことにより、化合物ｄ５が合成できる。類似の変換として、例えば、Chem. Commun. 2004, 353-359、J. Comb. Chem. 2006, 8(6), 834-840、J. Org. Chem. 1994, 59(7), 1771-1778、J. Org. Chem. 1995, 60(10), 2989-2999、Bioorg. Med. Chem. Lett. 2005, 15(5), 1467-1470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。また、同様の変換は上記Ｃ－２工程に準じた条件で対応するケトン又はアルデヒドと反応させることでも可能である。Ｒ７がアリール又はヘテロアリールの場合、化合物ｄ４にパラジウム錯体やヨウ化銅などの触媒や塩基の存在又は非存在下、適当な溶媒中、化合物ｄ８を反応させることにより、化合物ｄ５が合成できる。類似反応として、例えば、J. Am. Chem. Soc. 1996, 118(30), 7217-7218、J. Org. Chem. 2004, 69(9), 3173-3180、Coordination Chemistry Reviews 2004, 248, 2337-2364、Eur. J. Org. Chem. 2010, 19, 3621-3630、Angew. Chem. Int. Ed. 2005, 44(9), 1371、Synth. Commun. 2004, 34(5), 759-766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。 [Step D-6]
This step is a step of converting the compound d4 obtained in the step D-4 to the compound d5. When R 7 is alkyl or cycloalkyl, by deriving compound d4 to the corresponding Ns amide or trifluoroacetamide, reacting compound d8 in a suitable solvent in the presence of various bases, and deprotecting, Compound d5 can be synthesized. Similar transformations include, for example, Chem. Commun. 2004, 353-359, J. Comb. Chem. 2006, 8 (6), 834-840, J. Org. Chem. 1994, 59 (7), 1771-1778 , J. Org. Chem. 1995, 60 (10), 2989-2999, Bioorg. Med. Chem. Lett. 2005, 15 (5), 1467-1470, etc. are known, and similarly Can be synthesized. The same conversion can also be performed by reacting with the corresponding ketone or aldehyde under the conditions in accordance with the above step C-2. When R 7 is aryl or heteroaryl, compound d5 can be synthesized by reacting compound d4 with compound d8 in a suitable solvent in the presence or absence of a catalyst such as palladium complex or copper iodide or a base. Similar reactions include, for example, J. Am. Chem. Soc. 1996, 118 (30), 7217-7218, J. Org. Chem. 2004, 69 (9), 3173-3180, Coordination Chemistry Reviews 2004, 248, 2337. -2364, Eur. J. Org. Chem. 2010, 19, 3621-3630, Angew. Chem. Int. Ed. 2005, 44 (9), 1371, Synth. Commun. 2004, 34 (5), 759-766 Are known, and can be synthesized in the same manner.
［Ｄ－７工程］
　本工程は上記Ｄ－６工程で得られた化合物ｄ５を、上記Ｄ－５工程に準じた条件で化合物ｄ７又はｄ８を反応させることにより、化合物Ｄ２へ変換する工程である。 [Step D-7]
This step is a step of converting the compound d5 obtained in the step D-6 to the compound D2 by reacting the compound d7 or d8 under the conditions according to the step D-5.
Figure JPOXMLDOC01-appb-C000008
 （式中、Ａ、Ｒ１Ａ～Ｒ１Ｄ、Ｒ２、Ｒ３Ａ～Ｒ３Ｄ、Ｒ４Ａ、Ｒ５～Ｒ７及びｎは項１に定義されるとおりであ、Ｘはハロゲン等の脱離基、Ｒはメチル基又はフェニル基を意味する）
Figure JPOXMLDOC01-appb-C000008
 (In the formula, A, R 1A to R 1D , R 2 , R 3A to R 3D , R 4A , R 5 to R 7 and n are as defined in Item 1; X is a leaving group such as halogen; , R means a methyl group or a phenyl group)
［Ｄ－８工程］
　本工程は上記Ｄ－４工程で得られた化合物ｄ４を、上記Ａ－５工程に準じた条件で化合物Ｄ３へ変換する工程である。 [Step D-8]
This step is a step of converting the compound d4 obtained in the step D-4 to the compound D3 under the conditions according to the step A-5.
［Ｄ－９工程］
　本工程は上記Ｄ－６工程で得られた化合物ｄ５を、上記Ａ－５工程に準じた条件で化合物Ｄ４へ変換する工程である。 [Step D-9]
This step is a step of converting the compound d5 obtained in the step D-6 to the compound D4 under the conditions according to the step A-5.
　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、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, ketones such as acetone and methyl ketone, Halogenated hydrocarbons such as methylene and chloroform, ethers such as tetrahydrofuran (THF) and dioxane, aromatic hydrocarbons such as toluene and benzene, aliphatic hydrocarbons such as hexane and heptane, ethyl acetate Esters such as propyl acetate, amides such as N, N-dimethylformamide (DMF), N-methyl-2-pyrrolidone, sulfoxides such as dimethyl sulfoxide (DMSO), and nitriles such as acetonitrile. These solvents can be used alone or It can be used as a mixture or more. Depending on the type of reaction, organic bases may be used as a solvent.
　式（Ｉ）で表される本発明化合物またはその中間体は、当業者に公知の方法で分離、精製することができる。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）また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、また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、円二光スペクトル分析法などの分光学的手法、およ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. For example, extraction, distribution, reprecipitation, column chromatography (for example, silica gel column chromatography, ion exchange column chromatography or preparative liquid chromatography) or recrystallization may be mentioned. Examples of the recrystallization solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as benzene and toluene, acetone and the like. Ketone solvents, halogen solvents such as dichloromethane or chloroform, hydrocarbon solvents such as hexane, aprotic solvents 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. In addition, the molecular structure of the compound of the present invention is determined by referring to the structure derived from each raw material compound, spectroscopic techniques such as nuclear magnetic resonance, infrared absorption, and circular two-spectrum spectroscopy, and mass. It can be easily done by analytical methods.
　式（Ｉ）で表される本発明化合物またそれらの薬学的に許容される塩には、不斉が生じる場合または不斉炭素を有する置換基を有する場合があり、そのような化合物にあっては光学異性体が存在する。本発明化合物にはこれらの各異性体の混合物や単離されたものも含まれ、通常の方法に従って製造することができる。製造方法としては例えば、不斉点を有する原料を用いる方法か、または途中の段階で不斉を導入する方法が挙げられる。例えば、光学異性体の場合、光学活性な原料を用いるか、製造工程の適当な段階で光学分割などを行うことで、光学異性体を得ることができる。光学分割法としては例えば、式（Ｉ）で表される化合物またはその中間体が、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、また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 compounds of the present invention represented by the formula (I) or pharmaceutically acceptable salts thereof may have asymmetry or may have a substituent having an asymmetric carbon. Has optical isomers. The compounds of the present invention include mixtures of these isomers and isolated ones, which can be produced according to ordinary methods. Examples of the production method include a method using a raw material having an asymmetric point, or a method of introducing asymmetry at an intermediate stage. For example, in the case of optical isomers, optical isomers can be obtained by using optically active raw materials or by performing optical resolution at an appropriate stage of the production process. As the optical resolution method, for example, when the compound represented by the formula (I) or an intermediate thereof has a basic functional group, it 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, or sulfonic acid such as camphorsulfonic acid or bromocamphorsulfonic acid) to form a salt. 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, strychnine, etc.) The optical resolution can also be carried out by forming a salt using an organic amine).
　塩を形成させる温度としては、室温から溶媒の沸点までの範囲から選択される。光学純度を向上させるためには、一旦、溶媒の沸点付近まで温度を上げることが望ましい。析出した塩を濾取する際、必要に応じて冷却し、収率を向上させることができる。光学活性な酸また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、また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または塩基で処理し、フリー体として得ることもできる。
　あるいは式（Ｉ）で表される本発明化合物の中間体が、カルボキシル基を有する場合には、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。 The temperature for forming the salt 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, the optically resolved salt can be treated with an acid or base by a conventional method to obtain a free form.
Alternatively, when the intermediate of the compound of the present invention represented by the formula (I) has a carboxyl group, an optical resolution is achieved by forming an amide using a chemically active amine (eg, 1-phenylethylamine). Can also be performed.
　本発明の化合物は、神経系疾患、精神疾患、および炎症性疾患（例えば老人性認知症、注意力欠陥障害、アルツハイマー病、および統合失調症）の新規な治療剤及び／又は予防剤となり得る。本発明の化合物の投与経路としては、経口投与、非経口投与又は直腸内投与のいずれでもよく、その一日投与量は、化合物の種類、投与方法、患者の症状・年齢等により異なる。例えば、経口投与の場合は、通常、ヒト又は哺乳動物１ｋｇ体重当たり約０．０１～１０００ｍｇ、更に好ましくは約０．１～５００ｍｇを１～数回に分けて投与することができる。静注等の非経口投与の場合は、通常、例えば、ヒト又は哺乳動物１ｋｇ体重当たり約０．０１ｍｇ～３００ｍｇ、更に好ましくは約１ｍｇ～１００ｍｇを投与することができる。 The compound of the present invention can be a novel therapeutic agent and / or preventive agent for nervous system diseases, psychiatric diseases, and inflammatory diseases (for example, senile dementia, attention deficit disorder, Alzheimer's disease, and schizophrenia). The administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration, and the daily dose varies depending on the type of compound, administration method, patient symptom / age and the like. For example, in the case of oral administration, usually about 0.01 to 1000 mg, more preferably about 0.1 to 500 mg per kg body weight of a human or mammal can be administered in 1 to several divided doses. In the case of parenteral administration such as intravenous injection, usually, for example, about 0.01 mg to 300 mg, more preferably about 1 mg to 100 mg per kg body weight of a human or mammal can be administered.
　剤型としては、錠剤、カプセル剤、顆粒剤、散剤、シロップ剤、懸濁剤、注射剤、坐剤、点眼剤、軟膏剤、塗布剤、貼付剤、吸入剤等が挙げられる。これらの製剤は常法に従って調製することができる。なお、液体製剤にあっては、用時、水、適当な水溶液又は他の適当な媒体に溶解又は懸濁する形であってもよい。また、錠剤及び顆粒剤は周知の方法でコーティングしてもよい。更に、これらの製剤は治療上価値ある他の成分を含有してもよい。 Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, injections, suppositories, eye drops, ointments, coatings, patches, inhalants and the like. These preparations can be prepared according to a conventional method. In the case of a liquid preparation, it may be dissolved or suspended in water, an appropriate aqueous solution or other appropriate medium at the time of use. Tablets and granules may be coated by a known method. In addition, these formulations may contain other therapeutically valuable ingredients.
　本発明の化合物は、非定型抗精神病薬に分類される薬剤と併用することができる。非定型抗精神病薬としては、例えば、オランザピン、リスペリドン、パリペリドン、ケチアピン、ジプラシドン、アリピプラゾール、アセナピン、イロペリドン、クロザピン、セルティンドール、ブロナンセリン及びルラシドンが挙げられる。 The compound of the present invention can be used in combination with drugs classified as atypical antipsychotic drugs. Examples of atypical antipsychotics include olanzapine, risperidone, paliperidone, quetiapine, ziprasidone, aripiprazole, asenapine, iloperidone, clozapine, sertindole, blonanserin and lurasidone.
　以下に参考例、実施例及び試験例を挙げて本発明を更に具体的に説明するが、これらは本発明を限定するものではない。なお、化合物の同定は元素分析値、マス・スペクトル、高速液体クロマト質量分析計；ＬＣＭＳ、ＩＲスペクトル、ＮＭＲスペクトル、高速液体クロマトグラフィー（ＨＰＬＣ）等により行った。 Hereinafter, the present invention will be described more specifically with reference to reference examples, examples and test examples, but these examples do not limit the present invention. The compound was identified by elemental analysis, mass spectrum, high performance liquid chromatography / mass spectrometer; LCMS, IR spectrum, NMR spectrum, high performance liquid chromatography (HPLC) and the like.
　明細書の記載を簡略化するために参考例、実施例及び実施例中の表において以下に示すような略号を用いることもある。置換基として用いられる略号としては、Ｍｅはメチル基、Ｐｈはフェニル基を意味する。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 an abbreviation used as a substituent, Me means a methyl group and Ph means a phenyl 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をＡ～Ｇで付記する。
測定条件Ａ
検出機器：Perkin-Elmer Sciex API 150EX Massspectrometer (40 eV)
ＨＰＬＣ：Shimadzu LC 10ATVP
Ｃｏｌｕｍｎ：Shiseido CAPCELL PAK C18 ACR (S-5μm, 4.6 mm×50 mm)
Ｓｏｌｖｅｎｔ：Ａ液：0.035 % TFA／MeOH、Ｂ液：0.05 % TFA／H2O
Ｇｒａｄｉｅｎｔ Ｃｏｎｄｉｔｉｏｎ：
　　0.0-0.5分；Ａ／Ｂ＝10：90
　　0.5-5.9分；Ａ／Ｂ＝10：90～99：1（linear gradient）
　　5.9-6.4分；Ａ／Ｂ＝99：1
Ｆｌｏｗ ｒａｔｅ：2.8 mL/分
ＵＶ：220 nm
カラム温度：40℃ High-performance liquid chromatograph / mass spectrometer: LCMS measurement conditions 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, measurement conditions used for the measurement are denoted by A to G.
Measurement condition A
Detector: Perkin-Elmer Sciex API 150EX Massspectrometer (40 eV)
HPLC: Shimadzu LC 10ATVP
Column: Shiseido CAPCELL PAK C18 ACR (S-5μm, 4.6 mm x 50 mm)
Solvent: Liquid A: 0.035% TFA / MeOH, Liquid B: 0.05% TFA / H 2 O
Gradient Condition:
0.0-0.5 min; A / B = 10: 90
0.5-5.9 min; A / B = 10: 90 to 99: 1 (linear gradient)
5.9-6.4 minutes; A / B = 99: 1
Flow rate: 2.8 mL / min UV: 220 nm
Column temperature: 40 ° C
測定条件Ｂ
検出機器：Perkin-Elmer Sciex API 150EX Massspectrometer (40 eV)
ＨＰＬＣ：Shimadzu LC 10ATVP
Ｃｏｌｕｍｎ：Shiseido CAPCELL PAK C18 ACR (S-5μm, 4.6 mm×50 mm)
Ｓｏｌｖｅｎｔ：Ａ液：0.035 % TFA／CH3CN、Ｂ液：0.05 % TFA／H2O
Ｇｒａｄｉｅｎｔ Ｃｏｎｄｉｔｉｏｎ：
　　0.0-0.5分；Ａ／Ｂ＝1：99
　　0.5-4.8分；Ａ／Ｂ＝1：99～99：1（linear gradient）
　　4.8-5.0分；Ａ／Ｂ＝99：1
Ｆｌｏｗ ｒａｔｅ：3.5 mL／分
ＵＶ：220 nm
カラム温度：40℃ Measurement condition B
Detector: Perkin-Elmer Sciex API 150EX Massspectrometer (40 eV)
HPLC: Shimadzu LC 10ATVP
Column: Shiseido CAPCELL PAK C18 ACR (S-5μm, 4.6 mm x 50 mm)
Solvent: Liquid A: 0.035% TFA / CH 3 CN, Liquid B: 0.05% TFA / H 2 O
Gradient Condition:
0.0-0.5 min; A / B = 1: 99
0.5-4.8 min; A / B = 1: 99 to 99: 1 (linear gradient)
4.8-5.0 min; A / B = 99: 1
Flow rate: 3.5 mL / min UV: 220 nm
Column temperature: 40 ° C
測定条件Ｃ
検出機器：ＡＰＩシリーズ用Agilent 1100シリーズ (applied Biosystems社製)
ＨＰＬＣ：API 150EX LC/MS system (applied Biosystems社製)
Ｃｏｌｕｍｎ：YMC CombiScreen Hydrosphere C18 (S-5μM, 12 nm, 4.6×50 mm)
Ｓｏｌｖｅｎｔ：Ａ液：0.05 % TFA／H2O、Ｂ液：0.05 % TFA/MeOH
Ｇｒａｄｉｅｎｔ Ｃｏｎｄｉｔｉｏｎ：
　　0.0-6.0分；Ａ／Ｂ＝90：10～1：99（linear gradient）
Ｆｌｏｗ ｒａｔｅ：３．５ mL／分
ＵＶ：254、220 nm Measurement condition C
Detection equipment: Agilent 1100 series for API series (Applied Biosystems)
HPLC: API 150EX LC / MS system (Applied Biosystems)
Column: YMC CombiScreen Hydrosphere C18 (S-5μM, 12 nm, 4.6 × 50 mm)
Solvent: Liquid A: 0.05% TFA / H 2 O, Liquid B: 0.05% TFA / MeOH
Gradient Condition:
0.0-6.0 min; A / B = 90: 10 to 1:99 (linear gradient)
Flow rate: 3.5 mL / min UV: 254, 220 nm
測定条件Ｄ
検出機器：ＡＰＩシリーズ用Agilent 1100シリーズ (applied Biosystems社製)
ＨＰＬＣ：API 150EX LC/MS system (applied Biosystems社製)
Ｃｏｌｕｍｎ：YMC CombiScreen Hydrosphere C18 (S-5μM, 12 nm, 4.6×50 mm)
Ｓｏｌｖｅｎｔ：Ａ液：0.05 % TFA／H2O、Ｂ液：0.05 % TFA/MeOH
Ｇｒａｄｉｅｎｔ Ｃｏｎｄｉｔｉｏｎ：
　　0.0-6.0分；Ａ／Ｂ＝75：25～1：99（linear gradient）
Ｆｌｏｗ ｒａｔｅ：3.5 mL／分
ＵＶ：254 nm Measurement condition D
Detection equipment: Agilent 1100 series for API series (Applied Biosystems)
HPLC: API 150EX LC / MS system (Applied Biosystems)
Column: YMC CombiScreen Hydrosphere C18 (S-5μM, 12 nm, 4.6 × 50 mm)
Solvent: Liquid A: 0.05% TFA / H 2 O, Liquid B: 0.05% TFA / MeOH
Gradient Condition:
0.0-6.0 min; A / B = 75: 25 to 1:99 (linear gradient)
Flow rate: 3.5 mL / min UV: 254 nm
測定条件Ｅ
検出機器：Agilent 6110 single quadrupole mass spectrometer, and Agilent G1315C diode array detector Agilent G1367C injector
ＨＰＬＣ：Agilent G1367C injector, an Agilent G1322A binary pump, an Agilent G1316B column oven
Ｃｏｌｕｍｎ：Agilent TC-C18, 2.1 x 50 mm, 5 mm
Ｓｏｌｖｅｎｔ：Ａ液：0.038 % TFA／H2O、Ｂ液：0.019 % TFA／CH3CN
Ｇｒａｄｉｅｎｔ Ｃｏｎｄｉｔｉｏｎ：
　　0.0分；Ａ／Ｂ＝90：10
　　0.0-1.35分；Ａ／Ｂ＝90：10～20：80（linear gradient）
　　1.35-2.25分；Ａ／Ｂ＝20：80
　　2.25-2.26分；Ａ／Ｂ＝90：10
　　2.26-3.00分；Ａ／Ｂ＝90：10
Ｆｌｏｗ ｒａｔｅ：0.8 mL／分
ＵＶ：220 nm
カラム温度：50℃ Measurement condition E
Detector: Agilent 6110 single quadrupole mass spectrometer, and Agilent G1315C diode array detector Agilent G1367C injector
HPLC: Agilent G1367C injector, an Agilent G1322A binary pump, an Agilent G1316B column oven
Column: Agilent TC-C18, 2.1 x 50 mm, 5 mm
Solvent: Liquid A: 0.038% TFA / H 2 O, Liquid B: 0.019% TFA / CH 3 CN
Gradient Condition:
0.0 min; A / B = 90: 10
0.0-1.35 minutes; A / B = 90: 10-20: 80 (linear gradient)
1.35-2.25 minutes; A / B = 20: 80
2.25-2.26 min; A / B = 90: 10
2.26-3.00 min; A / B = 90: 10
Flow rate: 0.8 mL / min UV: 220 nm
Column temperature: 50 ° C
測定条件Ｆ
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／分
ＵＶ：220 nm, 254 nm
カラム温度：50℃ Measurement condition F
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: 10-1: 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Ｇ
検出機器：Shimadzu LCMS-2010EV
Ｃｏｌｕｍｎ：Ximate C18 3.0μm 2.1 mm×30 mm
Ｓｏｌｖｅｎｔ：Ａ液：0.019 %TFA/H2O, Ｂ液:0.038 % TFA/CH3CN
Ｇｒａｄｉｅｎｔ ｃｏｎｄｉｔｉｏｎ：
   0 min: Ａ／Ｂ＝ 90:10
   0-1.35 min: Ａ／Ｂ＝20:80
   1.35-2.25 min: Ａ／Ｂ＝20:80
   2.25-2.26 min: Ａ／Ｂ＝90:10
   2.26-3.00 min: Ａ／Ｂ＝90:10
Ｆｌｏｗ Ｒａｔｅ：0.8 ml/min.
UＶ：220 nm
カラム温度：50℃ Measurement condition G
Detection equipment: Shimadzu LCMS-2010EV
Column: Ximate C18 3.0μm 2.1 mm x 30 mm
Solvent: Liquid A: 0.019% TFA / H 2 O, Liquid B: 0.038% TFA / CH 3 CN
Gradient condition:
0 min: A / B = 90:10
0-1.35 min: A / B = 20: 80
1.35-2.25 min: A / B = 20: 80
2.25-2.26 min: A / B = 90: 10
2.26-3.00 min: A / B = 90: 10
Flow Rate: 0.8 ml / min.
UV: 220 nm
Column temperature: 50 ° C
参考例１
ｔｅｒｔ－ブチル ４－（２－アミノ－４－フルオロフェニルアミノ）ピペリジン－１－カルボキシラート
Figure JPOXMLDOC01-appb-C000009
 Reference example 1
tert-Butyl 4- (2-amino-4-fluorophenylamino) piperidine-1-carboxylate
Figure JPOXMLDOC01-appb-C000009
ａ）ｔｅｒｔ－ブチル ４－（４－フルオロ－２－ニトロフェニルアミノ）ピペリジン－１－カルボキシラート（化合物Ａ２）の製造
　１，４－ジフルオロ－２－ニトロベンゼン（1.59 g）のＤＭＦ溶液（10 ml）にｔｅｒｔ－ブチル ４－アミノピペリジン－１－カルボキシラート（2.00 g）を加え、次いで、炭酸カリウム（1.60 g）を加えて、８０℃で７時間加熱攪拌した。反応終了後、酢酸エチル－水で分液抽出し、有機層を硫酸ナトリウムで乾燥後、減圧留去した。得られた残査を短いシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル＝３:１）で粗製することにより化合物Ａ２（2.1 g）を取得し、そのまま次反応を行った。 a) Preparation of tert-butyl 4- (4-fluoro-2-nitrophenylamino) piperidine-1-carboxylate (Compound A2) 1,4-Difluoro-2-nitrobenzene (1.59 g) in DMF (10 ml) To the mixture was added tert-butyl 4-aminopiperidine-1-carboxylate (2.00 g), potassium carbonate (1.60 g) was added, and the mixture was heated with stirring at 80 ° C. for 7 hr. After completion of the reaction, the mixture was extracted with ethyl acetate-water, and the organic layer was dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was crudely purified by short silica gel column chromatography (elution solvent; hexane: ethyl acetate = 3: 1) to obtain compound A2 (2.1 g), and the next reaction was carried out as it was.
ｂ）ｔｅｒｔ－ブチル ４－（２－アミノ－４－フルオロフェニルアミノ）ピペリジン－１－カルボキシラート（参考例１）の製造
　化合物Ａ２（2.1 g）のメタノール/酢酸エチル溶液（20/5 ml）にパラジウム－カーボン（20 mg）を加え、室温で４時間、水素接触還元した。反応終了後、濾過し、ろ液を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル＝１:１）で精製することで、参考例１を濃紫色結晶として得た（1.7 g）。
1H-NMR (400 MHz, CDCl3): 1.30-1.40 (2H, m), 1.46 (9H, s), 1.97 (2H, d, J = 7.1 Hz), 2.89 (2H, t, J = 12 Hz), 3.26 (1H, m), 3.68 (1H, brs), 4.03 (2H, brs), 6.40-6.50 (2H, m), 6.61-6.68 (1H, m)． b) Preparation of tert-butyl 4- (2-amino-4-fluorophenylamino) piperidine-1-carboxylate (Reference Example 1) Compound A2 (2.1 g) in methanol / ethyl acetate solution (20/5 ml) Palladium-carbon (20 mg) was added, and hydrogen reduction was performed at room temperature for 4 hours. After completion of the reaction, the mixture was filtered, the filtrate was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 1: 1) to give Reference Example 1 as dark purple crystals. As (1.7 g).
1 H-NMR (400 MHz, CDCl 3 ): 1.30-1.40 (2H, m), 1.46 (9H, s), 1.97 (2H, d, J = 7.1 Hz), 2.89 (2H, t, J = 12 Hz ), 3.26 (1H, m), 3.68 (1H, brs), 4.03 (2H, brs), 6.40-6.50 (2H, m), 6.61-6.68 (1H, m).
参考例２
ｃｉｓ－４－（５－メチル－１Ｈ－ベンゾイミダゾール－１－イル）シクロへキサンカルボン酸 蟻酸塩
Figure JPOXMLDOC01-appb-C000010
 Reference example 2
cis-4- (5-Methyl-1H-benzimidazol-1-yl) cyclohexanecarboxylic acid formate
Figure JPOXMLDOC01-appb-C000010
ａ）ｔｅｒｔ－ブチル ｃｉｓ－４－［（４－メチル－２－ニトロフェニル）アミノ］シクロへキサンカルボキシラート（化合物Ｂ２）の製造
　４－フルオロ－３－ニトロトルエン（1.07 g）のＤＭＦ溶液 (10 ml)にｔｅｒｔ－ブチル ｃｉｓ－４－アミノシクロへキサンカルボキシラートを加え、次いで、炭酸カリウム（1.0 g）を加えて８０℃下、５時間加熱攪拌した。反応終了後、酢酸エチル－水で分液抽出し、有機層を飽和塩化アンモニウム水溶液、飽和食塩水を用いて順に洗浄し、硫酸ナトリウムで乾燥後、減圧留去した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル＝３:１）で粗製することによりＢ２を赤色の油状物質として得た（1.10 g）。 a) Preparation of tert-butyl cis-4-[(4-methyl-2-nitrophenyl) amino] cyclohexanecarboxylate (Compound B2) 4-Fluoro-3-nitrotoluene (1.07 g) in DMF (10 ml ) Was added tert-butyl cis-4-aminocyclohexanecarboxylate, potassium carbonate (1.0 g) was added, and the mixture was heated with stirring at 80 ° C. for 5 hours. After completion of the reaction, the mixture was extracted with ethyl acetate-water, and the organic layer was washed successively with a saturated aqueous ammonium chloride solution and saturated brine, dried over sodium sulfate, and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 3: 1) to obtain B2 as a red oily substance (1.10 g).
ｂ）ｃｉｓ－４－（５－メチル－１Ｈ－ベンゾイミダゾール－１－イル）シクロへキサンカルボン酸 蟻酸塩（参考例２）の製造
　上記の実験で得られた化合物Ｂ２（1.10 g）のメタノール－酢酸エチル混合溶液（50 ml/15 ml）に、５０％ ｗｅｔパラジウム－カーボン（50 mg）を加え、室温下で４時間、水素接触還元した。反応終了後、セライト濾過し、ろ液を減圧留去した。
　得られた残渣に蟻酸（5 ml）を加え、６０℃で、3時間攪拌した。反応終了後、蟻酸を減圧留去し、更に、トルエン（20 ml）とメタノール（5 ml）で共沸して完全に蟻酸を留去することによって参考例２を蟻酸塩として得た（630 mg）。
1H-NMR (400 MHz, DMSO-d６)：1.68-1.78 (2H, m), 1.90-2.00 (4H, m), 2.14-2.20 (2H, m), 2.40 (3H, s), 2.68-2.72 (1H, m), 3.31-3.34 (1H, m), 4.33-4.41 (1H, m), 7.05 (1H, dd, J = 8.3, 1.4 Hz), 7.41-7.46 (2H, m), 8.18 (1H, s)． b) Preparation of cis-4- (5-methyl-1H-benzimidazol-1-yl) cyclohexanecarboxylic acid formate (Reference Example 2) Compound B2 (1.10 g) obtained in the above experiment with methanol 50% wet palladium-carbon (50 mg) was added to an ethyl acetate mixed solution (50 ml / 15 ml), and hydrogen reduction was carried out at room temperature for 4 hours. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was distilled off under reduced pressure.
Formic acid (5 ml) was added to the resulting residue, and the mixture was stirred at 60 ° C. for 3 hours. After completion of the reaction, formic acid was distilled off under reduced pressure, and further, formic acid was distilled off azeotropically with toluene (20 ml) and methanol (5 ml) to obtain Reference Example 2 as formate (630 mg). ).
1 H-NMR (400 MHz, DMSO-d 6 ): 1.68-1.78 (2H, m), 1.90-2.00 (4H, m), 2.14-2.20 (2H, m), 2.40 (3H, s), 2.68- 2.72 (1H, m), 3.31-3.34 (1H, m), 4.33-4.41 (1H, m), 7.05 (1H, dd, J = 8.3, 1.4 Hz), 7.41-7.46 (2H, m), 8.18 ( 1H, s).
参考例３
ｃｉｓ－４－（５－メチル－１Ｈ－ベンゾイミダゾール－１－イル）シクロへキサンカルバルデヒド（参考例３）
Figure JPOXMLDOC01-appb-C000011
 　参考例２と同様の方法で得られたＣ２（8.2 g）のＴＨＦ溶液（20 ml）に、氷冷下で水素化リチウムアルミニム（1.5 g）を加えた。得られた懸濁溶液を一晩、室温で撹拌した後に、飽和塩化アンモニウム水溶液でクエンチした後にセライトろ過を行った。ろ過後の溶液からＴＨＦを除いた後にクロロホルムで２回抽出し、飽和食塩水で洗浄した。クロロホルム層を硫酸ナトリウムで乾燥後、減圧濃縮すると固体が得られた（3.5 g）。得られた残渣（860 mg）をトルエン／ＴＨＦ溶液（5/20 ml）に溶かした。ＤＭＳＯ（0.33 ml）のトルエン溶液（5 ml）にオキサリルクロライド（0.31 ml）を－７８℃で加えて、１０分間撹拌して得られた溶液に、上記で調整した溶液を加えた。得られた溶液を－７８℃で１時間撹拌した後に、トリエチルアミン（2.0 ml）を加えて室温まで戻した。減圧下で濃縮した後に、得られた残渣に酢酸エチルを加えて、飽和塩化アンモニウム水溶液と飽和食塩水で洗浄し、硫酸ナトリウムで乾燥し、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（展開溶媒 クロロホルム:メタノール＝10/1）で精製することで参考例３を得た（500 mg）。
1H-NMR (400 MHz, CDCl3)：1.48-1.61 (2H, m), 1.70-1.98 (2H, m), 2.10-2.50 (5H, m), 2.48 (3H, s), 4.13-4.27 (1H, m), 7.13 (1H, d, J = 8.2 Hz), 7.21-7.32 (1H, m), 7.60 (1H, s), 7.98 (1H, s), 9.72 (1H, s). Reference example 3
cis-4- (5-Methyl-1H-benzimidazol-1-yl) cyclohexanecarbaldehyde (Reference Example 3)
Figure JPOXMLDOC01-appb-C000011
 Lithium aluminum hydride (1.5 g) was added to a THF solution (20 ml) of C2 (8.2 g) obtained by the same method as in Reference Example 2 under ice cooling. The resulting suspension was stirred overnight at room temperature and then quenched with saturated aqueous ammonium chloride and then filtered through celite. THF was removed from the solution after filtration, and the mixture was extracted twice with chloroform and washed with saturated brine. The chloroform layer was dried over sodium sulfate and concentrated under reduced pressure to obtain a solid (3.5 g). The obtained residue (860 mg) was dissolved in a toluene / THF solution (5/20 ml). Oxalyl chloride (0.31 ml) was added to a toluene solution (5 ml) of DMSO (0.33 ml) at −78 ° C., and the solution prepared above was added to the solution obtained by stirring for 10 minutes. The resulting solution was stirred at −78 ° C. for 1 hour, and then triethylamine (2.0 ml) was added to return to room temperature. After concentrating under reduced pressure, ethyl acetate was added to the resulting residue, washed with saturated aqueous ammonium chloride and saturated brine, dried over sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (developing solvent: chloroform: methanol = 10/1) to give Reference Example 3 (500 mg).
1 H-NMR (400 MHz, CDCl 3 ): 1.48-1.61 (2H, m), 1.70-1.98 (2H, m), 2.10-2.50 (5H, m), 2.48 (3H, s), 4.13-4.27 ( 1H, m), 7.13 (1H, d, J = 8.2 Hz), 7.21-7.32 (1H, m), 7.60 (1H, s), 7.98 (1H, s), 9.72 (1H, s).
参考例４
ｃｉｓ－４－（５－メチル－１Ｈ－ベンゾイミダゾール－１－イル）シクロへキサンアミン ２塩酸塩
Figure JPOXMLDOC01-appb-C000012
 Reference example 4
cis-4- (5-Methyl-1H-benzimidazol-1-yl) cyclohexaneamine dihydrochloride
Figure JPOXMLDOC01-appb-C000012
ａ）ベンジル ｛ｃｉｓ－４－［（４－メチル－２－ニトロフェニル）アミノ］シクロへキシル｝カルバマート（化合物Ｄ５）の製造
　１－フルオロ－４－メチル－２－ニトロベンゼン（1.55 g）のジメチルホルムアミド溶液（10 ml）にベンジル （ｃｉｓ－４－アミノシクロへキシル）カルバメート（2.48g）を加え、次いで、炭酸カリウム（1.72 g）を加えて８０℃下、５時間加熱攪拌した。反応終了後、酢酸エチル－水で分液抽出し、有機層を飽和塩化アンモニウム水溶液、飽和食塩水を用いて順に洗浄し、硫酸ナトリウムで乾燥後、減圧留去した。得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；ヘキサン：酢酸エチル＝３:１）で精製することにより化合物Ｄ５を 赤色油状物質として得た（1.84 g）。 a) Preparation of benzyl {cis-4-[(4-methyl-2-nitrophenyl) amino] cyclohexyl} carbamate (compound D5) 1-Fluoro-4-methyl-2-nitrobenzene (1.55 g) in dimethylformamide To the solution (10 ml) was added benzyl (cis-4-aminocyclohexyl) carbamate (2.48 g), then potassium carbonate (1.72 g) was added, and the mixture was heated with stirring at 80 ° C. for 5 hours. After completion of the reaction, the mixture was extracted with ethyl acetate-water, and the organic layer was washed successively with a saturated aqueous ammonium chloride solution and saturated brine, dried over sodium sulfate, and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 3: 1) to give Compound D5 as a red oil (1.84 g).
ｂ）ベンジル ｛ｃｉｓ－４－［（２－アミノ－４－メチルフェニル）アミノ］シクロへキシル｝カルバメート（化合物Ｄ６）の製造
　化合物Ｄ５（1.84 g）のメタノール－酢酸エチル混合溶液（5 ml/10 ml）に、５０％ ｗｅｔパラジウム－カーボン（50 mg）を加え、室温下で４時間、水素接触還元した。反応終了後、セライト濾過し、ろ液を減圧留去した、得られた残査をシリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：メタノール＝１０:１）で精製することにより化合物Ｄ６を濃紫色結晶として得た（1.52 g）。 b) Preparation of benzyl {cis-4-[(2-amino-4-methylphenyl) amino] cyclohexyl} carbamate (Compound D6) Compound D5 (1.84 g) in methanol-ethyl acetate mixed solution (5 ml / 10 ml) was added 50% wet palladium-carbon (50 mg) and subjected to hydrogen reduction at room temperature for 4 hours. After completion of the reaction, the reaction mixture was filtered through Celite, and the filtrate was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent; chloroform: methanol = 10: 1) to give Compound D6 as dark purple crystals. Obtained (1.52 g).
ｃ）ｃｉｓ－４－（５－メチル－１Ｈ－ベンゾイミダゾール－１－イル）シクロへキサンアミン ２塩酸塩（参考例４）の製造
化合物Ｄ６（1.52 g）に蟻酸（5 ml）を加え、６０℃で、３時間攪拌した。反応終了後、蟻酸を減圧留去し、更に、トルエン（20 ml）とメタノール（5 ml）で４回共沸して完全に蟻酸を留去した。次に残渣のメタノール溶液（5 ml）に、４Ｎ塩酸－メタノール溶液（10 ml）を加えた後、溶媒を留去した。更にトルエン（20 ml）で３回共沸して参考例４を得た（1.12 g）。
1H-NMR (400 MHz, DMSO-d6)： 1.83-2.08 (6H, m), 2.48 (3H, s), 3.30-3.60 (3H, m), 4.81-4.87 (1H, m), 7.46 (1H, d, J = 8.6 Hz), 7.67 (1H, s), 8.06 (1H, d, J = 8.6 Hz), 8.50-8.60 (3H, brs), 9.96 (1H, s)． c) Preparation of cis-4- (5-methyl-1H-benzimidazol-1-yl) cyclohexaneamine dihydrochloride (Reference Example 4) Formic acid (5 ml) was added to compound D6 (1.52 g), and And stirred for 3 hours. After completion of the reaction, formic acid was distilled off under reduced pressure, and then formic acid was completely distilled off by azeotropic distillation four times with toluene (20 ml) and methanol (5 ml). Next, 4N hydrochloric acid-methanol solution (10 ml) was added to a methanol solution (5 ml) of the residue, and then the solvent was distilled off. Further, azeotropic distillation with toluene (20 ml) was performed three times to obtain Reference Example 4 (1.12 g).
1 H-NMR (400 MHz, DMSO-d 6 ): 1.83-2.08 (6H, m), 2.48 (3H, s), 3.30-3.60 (3H, m), 4.81-4.87 (1H, m), 7.46 ( 1H, d, J = 8.6 Hz), 7.67 (1H, s), 8.06 (1H, d, J = 8.6 Hz), 8.50-8.60 (3H, brs), 9.96 (1H, s).
参考例５
２－ニトロ－４－トリフルオロメトキシフェニル トリフルオロスルホナート
Figure JPOXMLDOC01-appb-C000013
 　４－トリフルオロメトキシフェノール（1.0 g）の酢酸溶液（6 ml）に、氷冷下濃硝酸（0.51 g）の酢酸溶液（2.5 ml）を滴下した。滴下後、室温まで戻し３時間攪拌した。反応混合物を氷水にゆっくり注ぎ、トルエンで３回抽出した。有機相を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥し、濃縮した。残渣をピリジン（5 ml）に溶解し、触媒量のＤＭＡＰを加え、トリフルオロメタンスルホン酸無水物（1 ml）を０℃で滴下した。０℃で１時間、室温で２時間攪拌した後、減圧下濃縮した。水を加え、酢酸エチルで３回抽出し、有機相を５％硫酸水素カリウム水溶液、飽和食塩水で洗浄した。硫酸ナトリウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、参考例５（1.53g）を得た。
1H-NMR (300 MHz, CDCl3)：7.54(1H, d, J= 9.2 Hz), 7.59-7.63(1H, m), 8.04(1H, d, J= 2.8 Hz).  Reference Example 5
2-Nitro-4-trifluoromethoxyphenyl trifluorosulfonate
Figure JPOXMLDOC01-appb-C000013
 To an acetic acid solution (6 ml) of 4-trifluoromethoxyphenol (1.0 g), an acetic acid solution (2.5 ml) of concentrated nitric acid (0.51 g) was added dropwise under ice cooling. After dropping, the mixture was returned to room temperature and stirred for 3 hours. The reaction mixture was slowly poured into ice water and extracted three times with toluene. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in pyridine (5 ml), a catalytic amount of DMAP was added, and trifluoromethanesulfonic anhydride (1 ml) was added dropwise at 0 ° C. The mixture was stirred at 0 ° C. for 1 hour and at room temperature for 2 hours, and then concentrated under reduced pressure. Water was added, and the mixture was extracted 3 times with ethyl acetate. The organic phase was washed with 5% aqueous potassium hydrogen sulfate solution and saturated brine. After drying over sodium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain Reference Example 5 (1.53 g).
1 H-NMR (300 MHz, CDCl 3 ): 7.54 (1H, d, J = 9.2 Hz), 7.59-7.63 (1H, m), 8.04 (1H, d, J = 2.8 Hz).
参考例６
ｃｉｓ－４－［５－（トリフルオロメトキシ）－１Ｈ－ベンゾイミダゾール－１－イル］シクロへキサンアミン 塩酸塩
Figure JPOXMLDOC01-appb-C000014
 ａ）ｔｅｒｔ－ブチル （ｃｉｓ－４－｛［２－ニトロ－４－（トリフルオロメトキシ）フェニル］アミノ｝シクロへキシル）カルバメート（化合物Ｄ７）の製造
　参考例５（500 mg）をＤＭＦ（5 ml）に溶解し、ジイソプロピルエチルアミン（0.48ml）とｔｅｒｔ－ブチル （ｃｉｓ－４－アミノシクロへキシル）カルバメート（300 mg）を加えた。反応混合物を８０℃で２．５時間攪拌した。室温に冷却後、飽和食塩水を加え、酢酸エチルで３回抽出した。有機相を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィーで精製し、オレンジ色の固体Ｄ７（390 mg）を得た。
1H-NMR (300 MHz, CDCl3)：1.45 (9H, d, J= 2.7 Hz), 1.51-1.65(2H, m), 1.66-1.74(1H, m), 1.74-1.90(5H, m), 3.55-3.78(3H, m), 4.57(1H, brs), 6.87(1H, d, J= 9.3 Hz), 7.32(1H, dd, J= 9.4 Hz, 2.8 Hz), 8.08(1H, d, J= 2.9 Hz), 8.31(1H, d, J= 6.8 Hz). Reference Example 6
cis-4- [5- (Trifluoromethoxy) -1H-benzimidazol-1-yl] cyclohexanamine hydrochloride
Figure JPOXMLDOC01-appb-C000014
 a) Preparation of tert-butyl (cis-4-{[2-nitro-4- (trifluoromethoxy) phenyl] amino} cyclohexyl) carbamate (Compound D7) Reference Example 5 (500 mg) was treated with DMF (5 ml And diisopropylethylamine (0.48 ml) and tert-butyl (cis-4-aminocyclohexyl) carbamate (300 mg) were added. The reaction mixture was stirred at 80 ° C. for 2.5 hours. After cooling to room temperature, saturated brine was added, and the mixture was extracted 3 times with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain an orange solid D7 (390 mg).
1 H-NMR (300 MHz, CDCl 3 ): 1.45 (9H, d, J = 2.7 Hz), 1.51-1.65 (2H, m), 1.66-1.74 (1H, m), 1.74-1.90 (5H, m) , 3.55-3.78 (3H, m), 4.57 (1H, brs), 6.87 (1H, d, J = 9.3 Hz), 7.32 (1H, dd, J = 9.4 Hz, 2.8 Hz), 8.08 (1H, d, J = 2.9 Hz), 8.31 (1H, d, J = 6.8 Hz).
ｂ）ｃｉｓ－４－［５－（トリフルオロメトキシ）－１Ｈ－ベンゾイミダゾール－１－イル］シクロへキサンアミン 塩酸塩（参考例６）の製造
　Ｄ７（390 mg）をＥｔＯＨ（3 ml）に懸濁させ、水（0.3ml）、鉄粉（280 mg）と塩化アンモニウム（58.8 mg）を加えた。反応混合物を９０℃で４時間攪拌した。不溶物をろ過で除き、ろ液を濃縮後、残渣をオルトギ酸トリメチル（2 ml）に懸濁した。触媒量のｐ－トルエンスルホン酸１水和物を加え、室温で１時間攪拌した。減圧濃縮後、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝1：2）で精製し、白色の固体（250 mg）を得た。得られた固体をクロロホルム（2 ml）／メタノール（1 ml）に溶解し、４Ｎ塩酸／ジオキサン（0.63 ml）を加え、数時間攪拌した。減圧濃縮することで参考例６（250 mg）を得た。
1H-NMR (400 MHz, DMSO-d6):1.85-1.92(2H, m), 1.98-2.00(4H, m), 2.38-2.46(2H, m), 3.49(1H, brs), 4.72-4.77(1H, m), 7.51(1H, d, J= 8.8 Hz), 7.83(1H, s), 8.13(1H, d, J= 9.2 Hz), 8.37(3H, brs), 9.47(1H, brs). b) Preparation of cis-4- [5- (trifluoromethoxy) -1H-benzimidazol-1-yl] cyclohexanamine hydrochloride (Reference Example 6) D7 (390 mg) was suspended in EtOH (3 ml) Water (0.3 ml), iron powder (280 mg) and ammonium chloride (58.8 mg) were added. The reaction mixture was stirred at 90 ° C. for 4 hours. Insoluble materials were removed by filtration, and the filtrate was concentrated. The residue was suspended in trimethyl orthoformate (2 ml). A catalytic amount of p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to obtain a white solid (250 mg). The obtained solid was dissolved in chloroform (2 ml) / methanol (1 ml), 4N hydrochloric acid / dioxane (0.63 ml) was added, and the mixture was stirred for several hours. Reference Example 6 (250 mg) was obtained by concentration under reduced pressure.
1 H-NMR (400 MHz, DMSO-d 6 ): 1.85-1.92 (2H, m), 1.98-2.00 (4H, m), 2.38-2.46 (2H, m), 3.49 (1H, brs), 4.72- 4.77 (1H, m), 7.51 (1H, d, J = 8.8 Hz), 7.83 (1H, s), 8.13 (1H, d, J = 9.2 Hz), 8.37 (3H, brs), 9.47 (1H, brs ).
参考例７
ｔｅｒｔ－ブチル ［ｃｉｓ－４－（５－シクロプロピル－１Ｈ－ベンゾイミダゾール－１－イル）シクロへキシル］カルバメート
Figure JPOXMLDOC01-appb-C000015
 　参考例６と同様の方法で得られたｔｅｒｔ－ブチル ［ｃｉｓ－４－（５－ブロモ－１Ｈ－ベンゾイミダゾール－１－イル）シクロへキシル］カルバメート（200 mg）の１，４-ジオキサン－水混合溶液（2.0 ml/0.50 ml）に炭酸セシウム（413 mg）、［１，１’－ビス(ジフェニルホスフィノ)フェロセン］パラジウム(II)ジクロリド（37 mg）、シクロプロピルボロン酸（87 mg）を加えて１００℃下、２時間撹拌した。反応終了後そのまま反応溶液を減圧留去し、得られた残渣をアミノシリカゲルクロマトグラフィー（溶出溶媒:クロロホルム：メタノール = 1:1）で精製することで参考例７を得た (88 mg)。
1H-NMR (300 MHz, CDCl3)：0.71 (2H, m), 0.95 (2H, m), 1.46 (9H, s), 1.70-2.15 (8H, m), 3.90 (1H, m), 4.21 (1H, m), 4.72 (1H, m), 7.06 (1H, dd, J = 9, 2 Hz), 7.26 (1H, d, J = 9 Hz), 7.48 (1H, d, J = 2Hz), 7.97 (1H, s). Reference Example 7
tert-Butyl [cis-4- (5-cyclopropyl-1H-benzimidazol-1-yl) cyclohexyl] carbamate
Figure JPOXMLDOC01-appb-C000015
 Tert-Butyl [cis-4- (5-bromo-1H-benzoimidazol-1-yl) cyclohexyl] carbamate (200 mg) obtained in the same manner as in Reference Example 6 in 1,4-dioxane-water Add cesium carbonate (413 mg), [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (37 mg), and cyclopropylboronic acid (87 mg) to the mixed solution (2.0 ml / 0.50 ml). In addition, the mixture was stirred at 100 ° C for 2 hours. After completion of the reaction, the reaction solution was distilled off under reduced pressure, and the resulting residue was purified by amino silica gel chromatography (elution solvent: chloroform: methanol = 1: 1) to obtain Reference Example 7 (88 mg).
1 H-NMR (300 MHz, CDCl 3 ): 0.71 (2H, m), 0.95 (2H, m), 1.46 (9H, s), 1.70-2.15 (8H, m), 3.90 (1H, m), 4.21 (1H, m), 4.72 (1H, m), 7.06 (1H, dd, J = 9, 2 Hz), 7.26 (1H, d, J = 9 Hz), 7.48 (1H, d, J = 2Hz), 7.97 (1H, s).
実施例１
Ｎ－シクロへキシル－４－（５－フルオロ－１Ｈ－ベンゾイミダゾール－１－イル）ピペリジン－１－カルボキサミド
Figure JPOXMLDOC01-appb-C000016
 　参考例１（300 mg）を蟻酸（10 ml）に溶かし、得られた溶液を６０℃で、３時間攪拌した。反応終了後、溶媒を減圧留去して得られた残査に飽和炭酸水素ナトリウム水溶液を加え、２％メタノール含有クロロホルムで３回抽出した。得られた有機層を硫酸ナトリウムで乾燥後、減圧留去した。得られた残渣をアミンシリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：メタノール＝10:1）で精製し、得られたアモルファス（130 mg）をテトラヒドロフラン（2 ml）に溶かし、シクロヘキシルイソシアナート（0.08 ml）を加え、濃縮した。生じた残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒；クロロホルム：メタノール＝10:1）で精製することにより実施例１をアモルファスとして得た（220 mg）。
1H-NMR (400 MHz, CDCl3)： 1.07-1.20 (3H, m), 1.30-1.43 (2H, m), 1.59-1.78 (3H, m), 1.90-2.11 (4H, m), 2.17-2.22 (2H, m), 2.98 (2Hm t, J = 13 Hz), 3.66 (1H, m), 4.17 (2H, d, J = 12 Hz), 4.30-4.42 (2H, m), 7.09 (1H, td, J = 9, 2.4 Hz), 7.32-7.38 (1H, m), 7.49 (1H, dd, J = 12, 2.4 Hz), 8.07 (1H, s)．  Example 1
N-cyclohexyl-4- (5-fluoro-1H-benzimidazol-1-yl) piperidine-1-carboxamide
Figure JPOXMLDOC01-appb-C000016
 Reference Example 1 (300 mg) was dissolved in formic acid (10 ml), and the resulting solution was stirred at 60 ° C. for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted 3 times with 2% methanol-containing chloroform. The obtained organic layer was dried over sodium sulfate and evaporated under reduced pressure. The obtained residue was purified by amine silica gel column chromatography (elution solvent; chloroform: methanol = 10: 1), and the resulting amorphous (130 mg) was dissolved in tetrahydrofuran (2 ml), and cyclohexyl isocyanate (0.08 ml). And concentrated. The resulting residue was purified by silica gel column chromatography (elution solvent; chloroform: methanol = 10: 1) to give Example 1 as an amorphous substance (220 mg).
1 H-NMR (400 MHz, CDCl 3 ): 1.07-1.20 (3H, m), 1.30-1.43 (2H, m), 1.59-1.78 (3H, m), 1.90-2.11 (4H, m), 2.17- 2.22 (2H, m), 2.98 (2Hm t, J = 13 Hz), 3.66 (1H, m), 4.17 (2H, d, J = 12 Hz), 4.30-4.42 (2H, m), 7.09 (1H, td, J = 9, 2.4 Hz), 7.32-7.38 (1H, m), 7.49 (1H, dd, J = 12, 2.4 Hz), 8.07 (1H, s).
実施例２
ｃｉｓ－Ｎ－シクロへキシル－４－（５－メチル－１Ｈ－ベンゾイミダゾール－１－イル）シクロへキサンカルボキサミド
Figure JPOXMLDOC01-appb-C000017
 　参考例２（110 mg）、ＥＤＣＩ塩酸塩（152 mg）とＨＯＢｔ（110 mg）のＴＨＦ懸濁溶液（3 ml）にトリエチルアミン（150 mg）とシクロヘキシルアミン（150 mg）を加えて、室温で一晩撹拌した。ＴＨＦを減圧下で除いた後に、酢酸エチルを加えて、飽和塩化アンモニウム水溶液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した後に、濃縮し、得られた残渣をシリカゲルクロマトグラフィー（溶出溶媒:クロロホルム：メタノール＝10:1）で精製することで実施例２を得た（102 mg）。
1H-NMR (400 MHz, CDCl3)：1.08-1.21 (3H, m), 1.32-1.43 (2H, m), 1.59-1.83 (5H, m), 1.90-2.05 (4H, m), 2.11-2.20 (2H, m), 2.32-2.50 (3H, m), 2.47 (3H, s), 3.79-3.85 (1H, m), 4.19-4.27 (1H, m), 4.42 (1H, d, J = 7.2 Hz), 7.11 (1H, dd, J = 8.2, 1.2 Hz), 7.35 (1H, d, J = 8.3 Hz), 7.59 (1H, s), 8.00 (1H, s). Example 2
cis-N-cyclohexyl-4- (5-methyl-1H-benzimidazol-1-yl) cyclohexanecarboxamide
Figure JPOXMLDOC01-appb-C000017
 Triethylamine (150 mg) and cyclohexylamine (150 mg) were added to a suspension of THF (3 ml) in Reference Example 2 (110 mg), EDCI hydrochloride (152 mg) and HOBt (110 mg). Stir overnight. After THF was removed under reduced pressure, ethyl acetate was added, and the mixture was washed with a saturated aqueous ammonium chloride solution and saturated brine. The obtained organic layer was dried over sodium sulfate and concentrated, and the obtained residue was purified by silica gel chromatography (elution solvent: chloroform: methanol = 10: 1) to give Example 2 (102 mg). ).
1 H-NMR (400 MHz, CDCl 3 ): 1.08-1.21 (3H, m), 1.32-1.43 (2H, m), 1.59-1.83 (5H, m), 1.90-2.05 (4H, m), 2.11- 2.20 (2H, m), 2.32-2.50 (3H, m), 2.47 (3H, s), 3.79-3.85 (1H, m), 4.19-4.27 (1H, m), 4.42 (1H, d, J = 7.2 Hz), 7.11 (1H, dd, J = 8.2, 1.2 Hz), 7.35 (1H, d, J = 8.3 Hz), 7.59 (1H, s), 8.00 (1H, s).
実施例３
ｔｒａｎｓ－Ｎ－シクロへキシル－４－（５－メチル－１Ｈ－ベンゾイミダゾール－１－イル）シクロへキサンカルボキサミド
Figure JPOXMLDOC01-appb-C000018
 　参考例２と同様の方法で得られたｔｒａｎｓ－４－（５－メチル－１Ｈ－ベンゾイミダゾール－１－イル）シクロへキサンカルボン酸 蟻酸塩（60 mg）を用いて実施例２と同様にして実施例３を合成した（42 mg）。
1H-NMR (400 MHz, CDCl3)：1.08-1.21 (3H, m), 1.32-1.43 (2H, m), 1.59-2.00 (7H, m), 2.11-2.35 (7H, m), 2.48 (3H, s), 3.77-3.83 (1H, m), 4.19-4.27 (1H, m), 5.38 (1H, d, J = 8.0 Hz), 7.13 (1H, d, J = 8.2 Hz), 7.30 (1H, d, J = 8.3 Hz), 7.60 (1H, s), 8.05 (1H, s). Example 3
trans-N-cyclohexyl-4- (5-methyl-1H-benzimidazol-1-yl) cyclohexanecarboxamide
Figure JPOXMLDOC01-appb-C000018
 In the same manner as in Example 2 using trans-4- (5-methyl-1H-benzoimidazol-1-yl) cyclohexanecarboxylic acid formate (60 mg) obtained by the same method as in Reference Example 2. Example 3 was synthesized (42 mg).
1 H-NMR (400 MHz, CDCl 3 ): 1.08-1.21 (3H, m), 1.32-1.43 (2H, m), 1.59-2.00 (7H, m), 2.11-2.35 (7H, m), 2.48 ( 3H, s), 3.77-3.83 (1H, m), 4.19-4.27 (1H, m), 5.38 (1H, d, J = 8.0 Hz), 7.13 (1H, d, J = 8.2 Hz), 7.30 (1H , d, J = 8.3 Hz), 7.60 (1H, s), 8.05 (1H, s).
実施例４
４－クロロ－Ｎ－｛［ｃｉｓ－４－（５－メチル－１Ｈ－ベンゾイミダゾール－１－イル）シクロへキシル］メチル｝アニリン
Figure JPOXMLDOC01-appb-C000019
 　参考例３のメタノール溶液（0.2 ml，1.0 M）に４－クロロアニリン（30 mg）と酢酸（0.1 ml）を加えて、一時間撹拌した後に、ＮａＢＨ３ＣＮ（15 mg）を加えて室温で一晩撹拌した。反応溶液に飽和塩化アンモニウム水溶液を加え、クロロホルムで抽出し、飽和食塩水で洗浄した。得られたクロロホルム溶液を硫酸ナトリウムで乾燥後、濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（展開溶媒 クロロホルム:メタノール＝10 :1）で洗浄し、実施例４を得た（20 mg）。
1H-NMR (400 MHz, CDCl3)：1.20-1.34 (2H, m), 1.70-1.90 (3H, m), 2.00-2.10 (2H, m), 2.21-2.30 (2H, m), 2.48 (3H, s), 3.04 (2H, d, J = 6.6 Hz), 4.13-4.27 (1H, m), 6.53 (2H, d, J = 12 Hz), 7.10-7.15 (3H, m), 7.29 (1H, d, J = 8.3 Hz), 7.59 (1H, s), 7.94 (1H, s). Example 4
4-chloro-N-{[cis-4- (5-methyl-1H-benzimidazol-1-yl) cyclohexyl] methyl} aniline
Figure JPOXMLDOC01-appb-C000019
 4-Chloroaniline (30 mg) and acetic acid (0.1 ml) were added to the methanol solution of Reference Example 3 (0.2 ml, 1.0 M) and stirred for 1 hour, and then NaBH 3 CN (15 mg) was added at room temperature. Stir overnight. A saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with chloroform, and washed with saturated brine. The obtained chloroform solution was dried over sodium sulfate and concentrated. The obtained residue was washed with silica gel column chromatography (developing solvent: chloroform: methanol = 10: 1) to obtain Example 4 (20 mg).
1 H-NMR (400 MHz, CDCl 3 ): 1.20-1.34 (2H, m), 1.70-1.90 (3H, m), 2.00-2.10 (2H, m), 2.21-2.30 (2H, m), 2.48 ( 3H, s), 3.04 (2H, d, J = 6.6 Hz), 4.13-4.27 (1H, m), 6.53 (2H, d, J = 12 Hz), 7.10-7.15 (3H, m), 7.29 (1H , d, J = 8.3 Hz), 7.59 (1H, s), 7.94 (1H, s).
実施例５
Ｎ－［ｃｉｓ－４－（５－メチル－１Ｈ－ベンゾイミダゾール－１－イル）シクロへキシル］シクロへキサンカルボキサミド
Figure JPOXMLDOC01-appb-C000020
 　参考例４（20 mg）のＤＭＦ溶液（1.0 ml）にトリエチルアミン（37.8μl）、ＨＯＡｔ（13.5 mg）とＥＤＣＩ塩酸塩（17.3 mg）を加えて、室温で一時間撹拌した後に、シクロヘキサンカルボン酸（13 μl）を加えて、室温で一晩撹拌した。ＴＨＦを減圧下で除いた後に、酢酸エチルを加えて、飽和塩化アンモニウム水溶液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した後に、濃縮し、得られた残渣をアミノシリカゲルクロマトグラフィー（溶出溶媒:クロロホルム：メタノール＝30:1）で精製することで実施例５を得た（18 mg）。
1H-NMR (400 MHz, CDCl3)：1.18-1.21 (3H, m), 1.40-1.51 (2H, m), 1.72-1.90 (6H, m), 1.90-2.20 (8H, m), 2.47 (3H, s), 4.19-4.31 (2H, m), 6.16 (1H, brs), 7.12 (1H, dd, J = 8.3, 1.2 Hz), 7.27 (1H, d, J = 8.3 Hz), 7.57 (1H, s), 7.96 (1H, s). Example 5
N- [cis-4- (5-methyl-1H-benzimidazol-1-yl) cyclohexyl] cyclohexanecarboxamide
Figure JPOXMLDOC01-appb-C000020
 Triethylamine (37.8 μl), HOAt (13.5 mg) and EDCI hydrochloride (17.3 mg) were added to a DMF solution (1.0 ml) of Reference Example 4 (20 mg), and after stirring at room temperature for 1 hour, cyclohexanecarboxylic acid ( 13 μl) was added and stirred overnight at room temperature. After THF was removed under reduced pressure, ethyl acetate was added, and the mixture was washed with a saturated aqueous ammonium chloride solution and saturated brine. The obtained organic layer was dried over sodium sulfate and concentrated, and the resulting residue was purified by amino silica gel chromatography (elution solvent: chloroform: methanol = 30: 1) to give Example 5 (18). mg).
1 H-NMR (400 MHz, CDCl 3 ): 1.18-1.21 (3H, m), 1.40-1.51 (2H, m), 1.72-1.90 (6H, m), 1.90-2.20 (8H, m), 2.47 ( 3H, s), 4.19-4.31 (2H, m), 6.16 (1H, brs), 7.12 (1H, dd, J = 8.3, 1.2 Hz), 7.27 (1H, d, J = 8.3 Hz), 7.57 (1H , s), 7.96 (1H, s).
実施例６～７９（実施例１類似化合物）
　対応する原料化合物を用いて実施例１と同様に反応・処理し、表１に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000024
 Examples 6 to 79 (Example 1 analogs)
The corresponding starting materials were used and reacted in the same manner as in Example 1 to obtain the compounds shown in Table 1.
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000024
実施例８０～９１（実施例２類似化合物）
　対応する原料化合物を用いて実施例２と同様に反応・処理し、表２に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000025
 Examples 80 to 91 (Example 2 analogs)
The corresponding starting materials were used and reacted in the same manner as in Example 2 to obtain the compounds shown in Table 2.
Figure JPOXMLDOC01-appb-T000025
実施例９２～９８（実施例４類似化合物）
　対応する原料化合物を用いて実施例４と同様に反応・処理し、表３に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000026
 Examples 92 to 98 (Example 4 analogs)
The corresponding starting materials were used and reacted and treated in the same manner as in Example 4 to obtain the compounds shown in Table 3.
Figure JPOXMLDOC01-appb-T000026
実施例９９～４１３（実施例５類似化合物）
　対応する原料化合物を用いて実施例５と同様に反応・処理し、表４に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000045
 Examples 99 to 413 (Example 5 analogs)
Reaction and treatment were performed in the same manner as in Example 5 using the corresponding starting compounds, and the compounds shown in Table 4 were obtained.
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000045
実施例４１４
　ｔｅｒｔ－ブチル（ｔｒａｎｓ－４－アミノシクロへキシル）カルバマートを用いて参考例４と同様の方法でｔｒａｎｓ－４－（５－メチル－１Ｈ－ベンゾイミダゾール－１－イル）シクロへキサンアミン ２塩酸塩を合成し、これと対応するカルボン酸に実施例５と同様の反応・処理を施して表５に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000046
 Example 414
trans-4- (5-Methyl-1H-benzimidazol-1-yl) cyclohexanamine dihydrochloride was prepared in the same manner as in Reference Example 4 using tert-butyl (trans-4-aminocyclohexyl) carbamate. The compounds shown in Table 5 were obtained by synthesizing and subjecting the corresponding carboxylic acid to the same reaction and treatment as in Example 5.
Figure JPOXMLDOC01-appb-T000046
実施例４１５および４１６
　対応する原料化合物を用いて実施例１と同様に反応・処理し、表６に示す化合物を得た。
Figure JPOXMLDOC01-appb-T000047
 Examples 415 and 416
The corresponding starting materials were used and reacted and treated in the same manner as in Example 1 to obtain the compounds shown in Table 6.
Figure JPOXMLDOC01-appb-T000047
　以上の実施例の他に以下に示す化合物が想定される。
Figure JPOXMLDOC01-appb-C000048
 　これらは、各種アミン（ｃｉｓ－４－［５－（シクロプロポキシ）－１Ｈ－ベンゾイミダゾール－１－イル］シクロへキサンアミン、ｃｉｓ－４－［５－（シクロブトキシ）－１Ｈ－ベンゾイミダゾール－１－イル］シクロへキサンアミン又はｃｉｓ－４－［５－（ジフルオロメトキシ）－１Ｈ－ベンゾイミダゾール－１－イル］シクロへキサンアミン）と対応するカルボン酸を用いて実施例５と同様に反応・処理することで合成できる。また、上記の各種アミンは４－フルオロ－３－ニトロフェノールをアルキル化し、得られる４－アルコキシ－１－フルオロ－２－ニトロベンゼンを参考例４と同様に反応・処理することで合成できる。上記のシクロプロピル化の類似反応として、例えば、国際公開第2011/079102号パンフレット、国際公開第2010/105179号パンフレット、国際公開第2008/101939号パンフレットなどに記載されている方法で、同様に合成することができる。また、上記のシクロブチル化の類似反応として、例えば、国際公開第2011/0065691号パンフレット、国際公開第2011/023812号パンフレット、国際公開第2010/030954号パンフレットなどに記載されている方法で、同様に合成することができる。さらに、ジフルオロメチル化の類似反応として、例えば、J. Med. Chem. 2009, 52(23), 7653-7668、Tetrahedron 2009, 65, 5278-5283などに記載されている方法で、同様に合成することができる。 In addition to the above examples, the following compounds are envisaged.
Figure JPOXMLDOC01-appb-C000048
 These include various amines (cis-4- [5- (cyclopropoxy) -1H-benzoimidazol-1-yl] cyclohexaneamine, cis-4- [5- (cyclobutoxy) -1H-benzimidazole-1- Yl] cyclohexanamine or cis-4- [5- (difluoromethoxy) -1H-benzimidazol-1-yl] cyclohexanamine) and the corresponding carboxylic acid, the same reaction and treatment as in Example 5. Can be synthesized. The various amines can be synthesized by alkylating 4-fluoro-3-nitrophenol and reacting and treating the resulting 4-alkoxy-1-fluoro-2-nitrobenzene in the same manner as in Reference Example 4. As a similar reaction of the above cyclopropylation, for example, it is synthesized in the same manner by the method described in International Publication No. 2011/079102, Pamphlet of International Publication No. 2010/105179, Pamphlet of International Publication No. 2008/101939, etc. can do. Further, as a similar reaction of the above cyclobutylation, for example, the method described in International Publication No. 2011/0065691, Pamphlet of International Publication No. 2011/023812, Pamphlet of International Publication No. 2010/030954, etc. Can be synthesized. Furthermore, as a similar reaction of difluoromethylation, for example, it is synthesized in the same manner by the method described in J. Med. Chem. 2009, 52 (23), 7653-7668, Tetrahedron 2009, 65, 5278-5283, etc. be able to.
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、本発明にこれらの試験例に限定されるものではない。 Test Examples The pharmacological test results of the representative compounds of the present invention are shown below, and the pharmacological actions of the compounds are described. However, the present invention is not limited to these test examples.
試験例１．ヒトα７ ｎＡＣｈ受容体安定発現細胞を用いたＰＡＭ活性評価
（１）ヒトα７ ｎＡＣｈＲ安定発現細胞
　ヒトα７ ｎＡＣｈＲ安定発現細胞を作製し、培養に供した。具体的には、宿主細胞としてラット下垂体由来ＧＨ４Ｃ１細胞（cat#CCL-82.2, ATCC, USA）を用いた。GenBank BAC81731の蛋白をコードする塩基配列を挿入したpcDNA3.1Zeoベクターの導入、およびヒトα７ ｎＡＣｈＲ遺伝子を挿入したpcDNA3.1ベクター（cat#V790-20, invitrogen, Carlsbad，CA，USA）の導入によりエクオリンおよびヒトα７ ｎＡＣｈＲ安定発現細胞を得た。選別にはそれぞれZeocin（cat#R25001, invitrogen, Carlsbad，CA，USA）およびGeneticin（cat#10131-027, invitrogen, Carlsbad，CA，USA）を用いた。
　培地には２．５％ウシ胎児血清（cat#2917354, ICN Biomedicals, Inc, USA）、１５％非働化ウマ血清（cat#26050-088, invitrogen, Carlsbad，CA，USA）、１μｇ／ｍＬ Geneticin、５μｇ／ｍＬ Puromycin（cat#14861-84, invitrogen, Carlsbad，CA，USA）を含むF-10 Nutrient Mixture（Ham）培地（cat#11550-043, invitrogen, Carlsbad，CA，USA）を用い、コラーゲンType1コートディッシュ（cat#4030-010, iwaki, Tokyo, Japan）にて培養を行った。培養中、２－３日毎に培地交換を行い、７日毎にTrypLE Express（cat# 45604-021, invitrogen, Carlsbad，CA，USA）処理にて細胞を回収し、継代培養を行った。
　継代から7日後、約８０％コンフルエントな状態でTrypLE Express処理にて細胞を回収し、Hanks（cat#14065-056, invitrogen, Carlsbad，CA，USA）／２０ｍＭ Hepes（cat#15630-080, invitrogen, Carlsbad，CA，USA）Buffer（pH 7.4）、F-10 Nutrient Mixture（Ham）、０．１mg／ｍＬ Geneticinからなる反応培地にて20000 cells/25μL/wellとなるように懸濁し、３８４ｗｅｌｌプレート（cat#781090, Greiner,Germany）に播種した。
播種翌日、Viviren（cat#E649X, Promega, Madison，WI，USA）を終濃度４μＭとなるように添加し（15μL/well）、遠心後４時間室温、遮光下で静置した。 Test Example 1 PAM activity evaluation using human α7 nACh receptor stable expression cells (1) Human α7 nAChR stable expression cells Human α7 nAChR stable expression cells were prepared and subjected to culture. Specifically, rat pituitary-derived GH4C1 cells (cat # CCL-82.2, ATCC, USA) were used as host cells. Aequorin by introducing pcDNA3.1Zeo vector into which the nucleotide sequence encoding the protein of GenBank BAC81731 was inserted and pcDNA3.1 vector (cat # V790-20, invitrogen, Carlsbad, CA, USA) into which the human α7 nAChR gene was inserted And human α7 nAChR stably expressing cells were obtained. For selection, Zeocin (cat # R25001, invitrogen, Carlsbad, CA, USA) and Geneticin (cat # 10131-027, invitrogen, Carlsbad, CA, USA) were used.
The medium includes 2.5% fetal bovine serum (cat # 2917354, ICN Biomedicals, Inc, USA), 15% inactivated horse serum (cat # 26050-088, invitrogen, Carlsbad, CA, USA), 1 μg / mL Geneticin, Collagen Type 1 using F-10 Nutrient Mixture (Ham) medium (cat # 11550-043, invitrogen, Carlsbad, CA, USA) containing 5 μg / mL Puromycin (cat # 14861-84, invitrogen, Carlsbad, CA, USA) Culturing was performed in a coat dish (cat # 4030-010, iwaki, Tokyo, Japan). During the culture, the medium was changed every 2-3 days, and cells were collected by TrypLE Express (cat # 45604-021, invitrogen, Carlsbad, CA, USA) treatment every 7 days and subcultured.
Seven days after passage, cells were collected by TrypLE Express treatment in a state of about 80% confluence, and Hanks (cat # 14065-056, invitrogen, Carlsbad, CA, USA) / 20 mM Hepes (cat # 15630-080, invitrogen , Carlsbad, CA, USA) Suspended in a reaction medium consisting of Buffer (pH 7.4), F-10 Nutrient Mixture (Ham), 0.1 mg / mL Geneticin to 20000 cells / 25 μL / well, and a 384-well plate ( cat # 781090, Greiner, Germany).
On the day after seeding, Viviren (cat # E649X, Promega, Madison, WI, USA) was added to a final concentration of 4 μM (15 μL / well), and the mixture was allowed to stand for 4 hours at room temperature in the dark after centrifugation.
（２）試験化合物の調製
　試験化合物は最終濃度の1000倍濃度のＤＭＳＯ溶液を作製し、この溶液をHanks／20 mM HEPES／0.2% BSA（cat#A3803, Sigma，St.Louis, MO, USA）にて最終濃度の６倍濃度に調製した。 (2) Preparation of test compound A DMSO solution having a concentration 1000 times the final concentration was prepared as a test compound, and this solution was added to Hanks / 20 mM HEPES / 0.2% BSA (cat # A3803, Sigma, St. Louis, MO, USA). The final concentration was adjusted to 6 times the final concentration.
（３）ＰＡＭ活性評価
　α７ ｎＡＣｈＲ刺激による発光シグナルの検出にはFDSS7000（浜松ホトニクス）を用いた。細胞およ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７に示す。 (3) PAM activity evaluation FDSS7000 (Hamamatsu Photonics) was used for the detection of the luminescent signal by α7 nAChR stimulation. Test compounds were added to the plates to which cells and luminescent substrate had been added, and ACh at a concentration indicative of EC 20 was added alone after 150 seconds. The luminescence signal (center wavelength: 465 nm) was measured for 138 seconds after 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. .
Table 7 shows data of α7 PAM activity of representative compounds.
Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000050
Figure JPOXMLDOC01-appb-T000050
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000053
Figure JPOXMLDOC01-appb-T000053
　表７に示すように、本発明の化合物はＰＡＭ活性評価試験においてα７ ｎＡＣｈＲのＰＡＭ活性を有した。特に、実施例２、５、６、９、２０、３６、５４、１０３、１０６、１０８、１３７、１５０、１５７、１５９、１６８、１７２，１７４、１８０、１８１、２０２、２１２、２１７、２２１、２２２、２２４、２４４、２４５、２４７、２８０、２８２、２８３は、より強いＰＡＭ活性を示した。 As shown in Table 7, the compound of the present invention had α7 nAChR PAM activity in the PAM activity evaluation test. In particular, Examples 2, 5, 6, 9, 20, 36, 54, 103, 106, 108, 137, 150, 157, 159, 168, 172, 174, 180, 181, 202, 212, 217, 221, 222, 224, 244, 245, 247, 280, 282, 283 showed stronger PAM activity.
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）
　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９及び実施例１９２は、ともに１０ｍｇ／ｋｇ（経口）において有意な記憶増強作用が確認された。 Test Example 2 Evaluation of cognitive function using mouse novel object recognition test (hereinafter referred to as mORT)
In a novel object recognition test using 25-30 g Slc: ddY mice (male, SLC Japan), memory decline for known objects is dependent on the interval time between the first trial (training) and the second trial (test) If a second trial is made 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, in both Example 9 and Example 192, a significant memory enhancing action was confirmed at 10 mg / kg (oral).
試験例３．ラットＹ字型迷路試験を用いた認知障害の改善評価（以下、Ｙ－ｍａzｅ試験とする）
２８０－３００ｇのＳｌｃ：Ｗｉｓｔａｒラット（雄性、日本エスエルシー）を用いたＹ字型迷路試験において、０．６ｍｇ／ｋｇのＳｃｏｐｏｌａｍｉｎｅ ＨＢｒ（cat#S0929, Sigma Aldrich, Japan）皮下投与により記憶障害が惹起され、自発交替行動率の低下が認められる。そこで本発明化合物を前処置し、記憶障害改善作用を評価する。その結果、実施例９及び実施例１９２は、それぞれ３又は１０ｍｇ／ｋｇ（経口）において有意な記憶障害改善作用が確認された。 Test Example 3 Evaluation of improvement of cognitive impairment using rat Y-shaped maze test (hereinafter referred to as Y-maze test)
In a Y-shaped maze test using 280-300 g Slc: Wistar rats (male, SLC), memory impairment was caused by subcutaneous administration of 0.6 mg / kg Scopolamine HBr (cat # S0929, Sigma Aldrich, Japan) In addition, a decrease in the spontaneous alternation behavior rate is observed. Therefore, the compound of the present invention is pretreated and the memory impairment improving action is evaluated. As a result, in Example 9 and Example 192, a significant memory impairment improving action was confirmed at 3 or 10 mg / kg (oral), respectively.
　以上で説明したように、式（Ｉ）で表される誘導体、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に有用である。 As described above, the derivative 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 Useful for treatment of diseases and the like.

Claims (24)

  1. 　式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000001
     ［式中、
    　Ａは、ＣＲ１Ｄ又は窒素原子を表し、
    　Ｘ－Ｙ－Ｚは、Ｎ－ＣＯ－ＮＲ４ＡＲ５、ＣＲ６－ＣＯ－ＮＲ４ＡＲ５、ＣＲ６－ＮＲ７－ＣＯＮＲ４ＡＲ５、ＣＲ６－ＮＲ７－ＣＯＲ４Ｂ、ＣＲ６－ＮＲ７－アリール、ＣＲ６－ＮＲ７－ヘテロアリール又はＣＲ６－ＣＲ８Ｒ９－ＮＲ４ＡＲ５を表し、
    　Ｒ１Ａ、Ｒ１Ｂ、Ｒ１Ｃ及びＲ１Ｄは、同一又は異なって、ハロゲン、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１０Ｒ１１からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；ハロゲン、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１０Ｒ１１からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルキル；ハロゲン、水酸基、Ｃ１－６アルコキシ、Ｃ３－６シクロアルキル及び－ＮＲ１０Ｒ１１からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルコキシ（但し、Ｒ１Ｂが－ＮＲ１０Ｒ１１で置換された該基を除く）；水素原子；水酸基；ハロゲン；ハロゲン、１～５個のフッ素で置換されていてもよいＣ１－６アルキル及び１～５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フェニル；ハロゲン、１～５個のフッ素で置換されていてもよいＣ１－６アルキル及び１～５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ヘテロアリール；ハロゲン、１～５個のフッ素で置換されていてもよいＣ１－６アルキル及び１～５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Ｃ３－１０シクロアルコキシ；４～１０員の飽和複素環；ニトロ；－ＮＲ１０Ｒ１１；シアノ；－ＣＯＯＲ１０；－ＣＯＮＲ１０Ｒ１１；－ＮＲ１０ＣＯＲ１１；－ＳＯ２ＮＲ１０Ｒ１１；又は－ＮＲ１０ＳＯ２Ｒ１１を表し、ここにおいて、（１）Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ４ＡＲ５のとき、Ｒ１Ａ、Ｒ１Ｂ、Ｒ１Ｃ及びＲ１Ｄは、少なくとも１つは、水素原子以外の基であり（但し、Ｒ１Ａ、Ｒ１Ｃ及びＲ１Ｄが共に水素原子であり、Ｒ４Ａがベンジルであり、Ｒ５が水素原子であるとき、Ｒ１Ｂがフッ素原子ではない）、又は、（２）ＡがＣＲ１Ｄであり、Ｘ－Ｙ－ＺがＣＲ６－ＣＯ－ＮＲ４ＡＲ５であり、Ｒ４Ａが１－（２－フルオロフェニル）－ピラゾ－３－イルであり、Ｒ５が水素原子であるとき、Ｒ１Ａ、Ｒ１Ｂ、Ｒ１Ｃ及びＲ１Ｄのうち、少なくとも１つは、水素原子以外の基であり、
    　Ｒ２は、ハロゲン、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１２Ｒ１３からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；ハロゲン、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１２Ｒ１３からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルキル；水素原子；Ｃ１－６アルコキシで置換されていてもよいアリール；又は４～１０員の飽和複素環を表し、
    　Ｒ３Ａ、Ｒ３Ｂ、Ｒ３Ｃ及びＲ３Ｄは、同一又は異なって、ハロゲン、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１４Ｒ１５からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；水素原子；ハロゲン；水酸基；又はＣ１－６アルコキシを表し、
    　Ｒ４Ａ、Ｒ５及びＲ７は、同一又は異なって、アリール（該基は、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）、ヘテロアリール、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－ＮＲ１４Ｒ１５からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；アリール（該基は、ハロゲン、水酸基及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよい）、ヘテロアリール、又は、同一又は異なる１～５個のハロゲン、水酸基、Ｃ１－６アルコキシ、Ｃ１－６アルキル又は－ＮＲ１４Ｒ１５で置換されていてもよいＣ３－１０シクロアルキル（該基は、アリール又はヘテロアリールと縮環を形成してもよい）；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；ハロゲン、Ｃ１－６アルコキシ及びＣ１－６アルキル（該基は、１～５個のフッ素で置換されていてもよい）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アリール；ヘテロアリール；又は水素原子を表し、ここにおいて、Ｒ４Ａ及びＲ５は一緒になって４～１０員の含窒素飽和複素環（但し、該環は、（１）モルフォリンではなく、（２）水酸基で置換されていてもよい）を形成していてもよく、
    　Ｒ４Ｂは、アリール、ヘテロアリール（該アリール及び該ヘテロアリールは、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）、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－ＮＲ１４Ｒ１５からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；アリール、ヘテロアリール（該アリール及び該ヘテロアリールは、ハロゲン、水酸基及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよい）、ハロゲン、水酸基、１～５個のフッ素で置換されていてもよいＣ１－６アルコキシ、１～５個のフッ素で置換されていてもよいＣ１－６アルキル及び－ＮＲ１４Ｒ１５からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルキル（該基は、アリール又はヘテロアリールと縮環を形成してもよい）；同一又は異なる１～５個の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；ハロゲン、Ｃ１－６アルコキシ及びＣ１－６アルキル（該アルコキシ及びアルキルは、１～５個のフッ素で置換されていてもよい）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アリール又はヘテロアリールを表し、
    　Ｒ６、Ｒ８及びＲ９は、同一又は異なって、ハロゲン、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１６Ｒ１７からなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；ハロゲン、水酸基、Ｃ１－６アルコキシ及び－ＮＲ１６Ｒ１７からなる群から独立して選択される１～５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；水素原子；ハロゲン；水酸基；又はＣ１－６アルコキシを表し、
    　Ｒ１０～Ｒ１７は、同一又は異なって、水素原子又はＣ１－６アルキルを表し、
    　ｎは、１又は２を表す］
    で表される化合物又はその製薬学的に許容される塩。     Formula (I):
    Figure JPOXMLDOC01-appb-C000001
     [Where:
    A represents CR 1D or a nitrogen atom,
    XYZ represents N—CO—NR 4A R 5 , CR 6 —CO—NR 4A R 5 , CR 6 —NR 7 —CONR 4A R 5 , CR 6 —NR 7 —COR 4B , CR 6 —NR 7 -aryl, CR 6 -NR 7 -heteroaryl or CR 6 -CR 8 R 9 -NR 4A R 5
    R 1A , R 1B , R 1C and R 1D are the same or different and are 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy and —NR 10 R 11 C 1-6 alkyl which may be substituted with: 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy and —NR 10 R 11 C 3-10 cycloalkyl; substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkoxy, C 3-6 cycloalkyl and —NR 10 R 11 C 1-6 alkoxy (excluding the group wherein R 1B is substituted with —NR 10 R 11 ); hydrogen atom; hydroxyl group; halogen; halogen; substituted with 1 to 5 fluorine atoms Even There C 1-6 alkyl and 1 to 5 fluorine with 1-5 phenyl which may be substituted with a substituent selected independently from the group consisting of which may be optionally C 1-6 alkoxy-substituted ; halogen, is selected from 1-5 fluorine independently from the group consisting of which may be C 1-6 alkyl and 1 to 5 fluorine optionally substituted by a C 1-6 alkoxy-substituted Heteroaryl optionally substituted with 1 to 5 substituents; halogen, C 1-6 alkyl optionally substituted with 1 to 5 fluorines and optionally substituted with 1 to 5 fluorines C 3-10 cycloalkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of good C 1-6 alkoxy; 4-10 membered saturated heterocycle; nitro; 10 R 11 ; Cyano; —COOR 10; -CONR 10 R 11; -NR 10 COR 11; -SO 2 NR 10 R 11; represents or -NR 10 SO 2 R 11, wherein the (1) X-Y-Z , N-CO- When NR 4A R 5 , at least one of R 1A , R 1B , R 1C and R 1D is a group other than a hydrogen atom (provided that R 1A , R 1C and R 1D are both hydrogen atoms, When R 4A is benzyl and R 5 is a hydrogen atom, R 1B is not a fluorine atom) or (2) A is CR 1D and XYZ is CR 6 —CO—NR 4A When R 5 , R 4A is 1- (2-fluorophenyl) -pyrazo-3-yl, and R 5 is a hydrogen atom, at least one of R 1A , R 1B , R 1C and R 1D Is a group other than a hydrogen atom,
    R 2 represents C 1-6 alkyl which may be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy and —NR 12 R 13 ; halogen A C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of: hydroxyl group, C 1-6 alkoxy and —NR 12 R 13 ; a hydrogen atom; C 1 An aryl optionally substituted with -6 alkoxy; or a 4-10 membered saturated heterocycle,
    R 3A , R 3B , R 3C and R 3D are the same or different and are 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy and —NR 14 R 15 C 1-6 alkyl optionally substituted by: hydrogen atom; halogen; hydroxyl group; or C 1-6 alkoxy,
    R 4A , R 5 and R 7 are the same or different and are aryl (the group is 1 to 5 independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy) 1 to 5 independently selected from the group consisting of heteroaryl, halogen, hydroxyl, C 1-6 alkoxy, C 3-10 cycloalkyl and —NR 14 R 15 C 1-6 alkyl optionally substituted with 1 substituent; aryl (the group is 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group and C 1-6 alkoxy) Optionally substituted), heteroaryl, or C 1-6 optionally substituted with 1 to 5 halogens, hydroxyl, C 1-6 alkoxy, C 1-6 alkyl or —NR 14 R 15 3- 10 cycloalkyl (the group may form a condensed ring with aryl or heteroaryl); a 4-10 membered saturated heterocycle optionally substituted with C 1-6 alkyl; halogen, C 1-6 Optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkoxy and C 1-6 alkyl (which group may be substituted with 1 to 5 fluorines) Represents aryl; heteroaryl; or a hydrogen atom, wherein R 4A and R 5 are taken together to form a 4- to 10-membered nitrogen-containing saturated heterocycle (provided that the ring is not (1) morpholine, 2) may be substituted with a hydroxyl group),
    R 4B is aryl, heteroaryl (wherein the aryl and the heteroaryl are 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl and C 1-6 alkoxy; Optionally substituted), substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkoxy, C 3-10 cycloalkyl and —NR 14 R 15 Optionally substituted C 1-6 alkyl; aryl, heteroaryl (wherein the aryl and the heteroaryl are 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group and C 1-6 alkoxy) optionally substituted), halogen, hydroxyl, 1-5 fluorine optionally substituted C 1-6 alkoxy, optionally substituted with 1-5 fluorine C -6 alkyl and -NR 14 R 15 optionally C 3-10 cycloalkyl (in which optionally substituted with one to five substituents independently selected from the group consisting of an aryl or heteroaryl condensed A 4 to 10-membered saturated heterocycle optionally substituted with 1 to 5 C 1-6 alkyl which may be the same or different; halogen, C 1-6 alkoxy and C 1-6 Aryl or heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl (wherein the alkoxy and alkyl may be optionally substituted with 1 to 5 fluorines) Represents
    R 6 , R 8 and R 9 are the same or different and are substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group, C 1-6 alkoxy and —NR 16 R 17. Optionally substituted C 1-6 alkyl; optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl, C 1-6 alkoxy and —NR 16 R 17 3-10 cycloalkyl; 4-10 membered saturated heterocycle; hydrogen atom; halogen; hydroxyl group; or C 1-6 alkoxy
    R 10 to R 17 are the same or different and each represents a hydrogen atom or C 1-6 alkyl;
    n represents 1 or 2]
    Or a pharmaceutically acceptable salt thereof.
  2. 　ＡがＣＲ１Ｄであり、Ｘ－Ｙ－ＺがＮ－ＣＯ－ＮＲ４ＡＲ５であり、Ｒ１Ａ、Ｒ１Ｃ及びＲ１Ｄが共に水素原子であり、Ｒ４Ａ及びＲ５の一方が水素原子であるとき、以下のＲ１Ｂ並びにＲ４Ａ及びＲ５のもう一方の組み合わせの化合物群を除く、
    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：
    　Ｒ１Ｂが、フッ素であり、Ｒ４Ａ及びＲ５のもう一方が、フェニル、２－メトキシフェニル、４－エトキシフェニル、シクロヘキシル、４－メトキシフェニル、２－エトキシフェニル、４－クロロ－３－トリフルオロフェニル、３－メトキシフェニル、２－トリフルオロメチルフェニル、３－メチルフェニル、２－クロロフェニル、アダマンチル、２－メチルフェニル、２，４－ジフルオロフェニル、４－エトキシフェニル、３－フルオロフェニル及び４－メチルフェニルからなる群から選択される基である化合物、
    　Ｒ１Ｂが、ジメチルアミノカルボニルであり、Ｒ４Ａ及びＲ５のもう一方が、４－エトキシフェニル、３，４－ジフルオロフェニル及び４－メチルベンジルからなる群から選択される基である化合物、
    　Ｒ１Ｂが、メチルであり、Ｒ４Ａ及びＲ５のもう一方が、２，６－ジメチルフェニル、アダマンチル及び２－フルオロフェニルからなる群から選択される基である化合物、
    　Ｒ１Ｂが、トリフルオロメチルであり、Ｒ４Ａ及びＲ５のもう一方が、２－フルオロフェニル、４－メトキシフェニル及びフェニルからなる群から選択される基である化合物。     A is CR 1D , XYZ is N—CO—NR 4A R 5 , R 1A , R 1C and R 1D are both hydrogen atoms, and one of R 4A and R 5 is a hydrogen atom When the compound group of the other combination of the following R 1B and R 4A and R 5 is excluded,
    The compound according to claim 1 or a pharmaceutically acceptable salt thereof:
    R 1B is fluorine, and the other of R 4A and R 5 is phenyl, 2-methoxyphenyl, 4-ethoxyphenyl, cyclohexyl, 4-methoxyphenyl, 2-ethoxyphenyl, 4-chloro-3-trifluoro Phenyl, 3-methoxyphenyl, 2-trifluoromethylphenyl, 3-methylphenyl, 2-chlorophenyl, adamantyl, 2-methylphenyl, 2,4-difluorophenyl, 4-ethoxyphenyl, 3-fluorophenyl and 4-methyl A compound which is a group selected from the group consisting of phenyl,
    A compound wherein R 1B is dimethylaminocarbonyl and the other of R 4A and R 5 is a group selected from the group consisting of 4-ethoxyphenyl, 3,4-difluorophenyl and 4-methylbenzyl;
    A compound wherein R 1B is methyl and the other of R 4A and R 5 is a group selected from the group consisting of 2,6-dimethylphenyl, adamantyl and 2-fluorophenyl;
    A compound wherein R 1B is trifluoromethyl and the other of R 4A and R 5 is a group selected from the group consisting of 2-fluorophenyl, 4-methoxyphenyl and phenyl.
  3. 　Ａが窒素原子であるとき、Ｒ１Ｂ及びＲ１Ｃの一方が置換されていてもよいフェニルであり、もう一方が水素原子の組み合わせでない、
    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。     When A is a nitrogen atom, one of R 1B and R 1C is optionally substituted phenyl, and the other is not a combination of hydrogen atoms,
    The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
  4. 　Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ４ＡＲ５、ＣＲ６－ＮＲ７－ＣＯＮＲ４ＡＲ５、ＣＲ６－ＮＲ７－ＣＯＲ４Ｂ、ＣＲ６－ＮＲ７－アリール、ＣＲ６－ＮＲ７－ヘテロアリール又はＣＲ６－ＣＲ８Ｒ９－ＮＲ４ＡＲ５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。     X—Y—Z represents N—CO—NR 4 A R 5 , CR 6 —NR 7 —CONR 4 A R 5 , CR 6 —NR 7 —COR 4B , CR 6 —NR 7 —aryl, CR 6 —NR 7 —. Is heteroaryl or CR 6 -CR 8 R 9 -NR 4A R 5 ,
    The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.
  5. 　Ｘ－Ｙ－Ｚが、Ｎ－ＣＯ－ＮＲ４ＡＲ５又はＣＲ６－ＮＲ７－ＣＯＲ４Ｂ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。     XYZ is N—CO—NR 4A R 5 or CR 6 —NR 7 —COR 4B ;
    Item 4. The compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof.
  6. 　Ｘ－Ｙ－Ｚが、ＣＲ６－ＮＲ７－ＣＯＲ４Ｂ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。     XYZ is CR 6 —NR 7 —COR 4B ;
    The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.
  7. 　Ｒ４Ｂが、アリール、ヘテロアリール、水酸基、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；アリール、ヘテロアリール、水酸基、フッ素、１～５個のフッ素で置換されていてもよいＣ１－６アルコキシ及び１～５個のフッ素で置換されていてもよい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（該基はアリールと縮環を形成してもよく）；同一又は異なる１～５個の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；又はハロゲン、Ｃ１－６アルコキシ及びＣ１－６アルキル（該アルコキシ及びアルキルは、１～５個のフッ素で置換されていてもよい）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アリール又はヘテロアリールである、
    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。     R 4B may be substituted with 1 to 5 substituents independently selected from the group consisting of aryl, heteroaryl, hydroxyl group, fluorine, C 1-6 alkoxy and C 3-10 cycloalkyl. 1-6 alkyl; aryl, heteroaryl, hydroxyl, fluorine, optionally substituted with 1-5 optionally substituted by fluorine C 1-6 alkoxy and 1 to 5 fluorine C 1-6 C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl (the groups may form a condensed ring with aryl); the same or different A 4- to 10-membered saturated heterocycle optionally substituted with 1 to 5 C 1-6 alkyl; or halogen, C 1-6 alkoxy and C 1-6 alkyl (wherein the alkoxy and alkyl are 1-5 Pieces of foot An aryl or heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of:
    The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.
  8. 　Ｒ４Ｂが、アリール、ヘテロアリール、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；アリール、ヘテロアリール、フッ素、１～５個のフッ素で置換されていてもよいＣ１－６アルコキシ及び１～５個のフッ素で置換されていてもよい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（該基はアリールと縮環を形成しても良く）；同一又は異なる１～５個の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；又はハロゲン、Ｃ１－６アルコキシ及びＣ１－６アルキル（該アルコキシ及びアルキルは、１～５個のフッ素で置換されていてもよい）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アリール又はヘテロアリールである、
    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。     R 4B is aryl, heteroaryl, fluorine, optionally substituted with one to five substituents independently selected from the group consisting of C 1-6 alkoxy and C 3-10 cycloalkyl C 1- 6 alkyl; aryl, heteroaryl, fluorine, 1-5 fluorine may be substituted with C 1-6 alkoxy and 1 to 5 C 1-6 alkyl optionally substituted by fluorine C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from (the group may form a condensed ring with aryl); 1 to 5 identical or different 4-10 membered saturated heterocycle optionally substituted by C 1-6 alkyl; or halogen, C 1-6 alkoxy and C 1-6 alkyl (wherein the alkoxy and alkyl are 1-5 fluorines) Has been replaced An aryl or heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of:
    The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.
  9. 　Ａが、ＣＲ１Ｄ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。     A is CR 1D ,
    The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.
  10. 　Ｒ２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 2 is a hydrogen atom,
    The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.
  11. 　ｎが、１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。     n is 1.
    The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.
  12. 　Ｒ３Ａ、Ｒ３Ｂ、Ｒ３Ｃ及びＲ３Ｄが、同一又は異なって、水素原子、ハロゲン、水酸基又はＣ１－６アルコキシである、
    請求項１～１１のいずれか一項に記載の化合物又はその製薬学的に許容される塩。     R 3A , R 3B , R 3C and R 3D are the same or different and each is a hydrogen atom, a halogen, a hydroxyl group or C 1-6 alkoxy.
    The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.
  13. 　Ｒ１Ａ、Ｒ１Ｂ、Ｒ１Ｃ及びＲ１Ｄが、同一又は異なって、ハロゲン、水酸基及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；ハロゲン、水酸基及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－１０シクロアルキル；ハロゲン、水酸基、Ｃ１－６アルコキシ及びＣ３－６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アルコキシ；水素原子；水酸基；ハロゲン；ハロゲン、１～５個のフッ素で置換されていてもよいＣ１－６アルキル及び１～５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フェニル；ハロゲン、１～５個のフッ素で置換されていてもよいＣ１－６アルキル及び１～５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ヘテロアリール；ハロゲン、１～５個のフッ素で置換されていてもよいＣ１－６アルキル及び１～５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Ｃ３－１０シクロアルコキシ；４～１０員の飽和複素環；－ＮＲ１０Ｒ１１；シアノ；－ＣＯＯＲ１０；又は－ＣＯＮＲ１０Ｒ１１である、
    請求項１～１２のいずれか一項に記載の化合物又はその製薬学的に許容される塩。     R 1A , R 1B , R 1C and R 1D may be the same or different and substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group and C 1-6 alkoxy Good C 1-6 alkyl; C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl and C 1-6 alkoxy; halogen, hydroxyl , C 1-6 alkoxy and C 3-6 optionally substituted by one to five substituents independently selected from the group consisting of cycloalkyl C 1-6 alkoxy; hydrogen atom; a hydroxyl group; halogen; halogen, is selected from 1-5 fluorine independently from the group consisting of which may be C 1-6 alkyl and 1 to 5 fluorine optionally substituted by a C 1-6 alkoxy-substituted 1 ~ 5 Phenyl which may be substituted with a substituent; a halogen, 1 to may five fluorine in substituted with which may be C 1-6 alkyl and 1 to 5 fluorine-substituted C 1-6 Heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkoxy; halogen, C 1-6 alkyl optionally substituted with 1-5 fluorine and 1 C 3-10 cycloalkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of C 1-6 alkoxy optionally substituted with 5 fluorines; 10-membered saturated heterocycle; —NR 10 R 11 ; cyano; —COOR 10 ; or —CONR 10 R 11 .
    The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.
  14. 　Ｒ１Ａ、Ｒ１Ｂ、Ｒ１Ｃ及びＲ１Ｄが、同一又は異なって、ハロゲン、水酸基及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；ハロゲン、水酸基及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－７シクロアルキル；ハロゲン、水酸基、Ｃ１－６アルコキシ及びＣ３－６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アルコキシ；水素原子；ハロゲン；４～７員の飽和複素環；シアノ；－ＣＯＯＲ１０；又は－ＣＯＮＲ１０Ｒ１１である、
    請求項１～１２のいずれか一項に記載の化合物又はその製薬学的に許容される塩。     R 1A , R 1B , R 1C and R 1D may be the same or different and substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl group and C 1-6 alkoxy Preferred C 1-6 alkyl; C 3-7 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl and C 1-6 alkoxy; halogen, hydroxyl , C 1-6 alkoxy and C 3-6 optionally substituted by one to five substituents independently selected from the group consisting of cycloalkyl C 1-6 alkoxy; hydrogen atom; a halogen; 4 - 7-membered saturated heterocycle; cyano; —COOR 10 ; or —CONR 10 R 11
    The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.
  15. 　Ｒ４Ａ、Ｒ５及びＲ７が、同一又は異なって、アリール、ハロゲン、水酸基及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ１－６アルキル；ハロゲン、水酸基及びＣ１－６アルコキシからなる群から独立して選択される１～５個の置換基で置換されていてもよいＣ３－９シクロアルキル；ハロゲン、Ｃ１－６アルコキシ及びＣ１－６アルキル（該基は、１～５個のフッ素で置換されていてもよい）からなる群から選択される１～５個の置換基で置換されていてもよいアリール；ヘテロアリール；又は水素原子である、
    請求項１～１４のいずれか一項に記載の化合物又はその製薬学的に許容される塩。     R 4A , R 5 and R 7 are the same or different and may be substituted with 1 to 5 substituents independently selected from the group consisting of aryl, halogen, hydroxyl group and C 1-6 alkoxy. C 1-6 alkyl; C 3-9 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen, hydroxyl and C 1-6 alkoxy; halogen, C 1 Aryl optionally substituted with 1 to 5 substituents selected from the group consisting of -6 alkoxy and C 1-6 alkyl, which group may be substituted with 1 to 5 fluorines Heteroaryl; or a hydrogen atom,
    The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.
  16. 　Ｒ６、Ｒ８及びＲ９が、同一又は異なって、Ｃ１－６アルキル、水酸基又は水素原子である、
    請求項１～１５のいずれか一項に記載の化合物又はその製薬学的に許容される塩。     R 6 , R 8 and R 9 are the same or different and are C 1-6 alkyl, a hydroxyl group or a hydrogen atom,
    The compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.
  17. 　Ｒ４Ｂが、アリール、ヘテロアリール、水酸基、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；アリール、ヘテロアリール、水酸基、フッ素、１～５個のフッ素で置換されていてもよいＣ１－６アルコキシ及び１～５個のフッ素で置換されていてもよい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（該基はアリールと縮環を形成しても良く）；同一または異なる１～５個の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；又はハロゲン、Ｃ１－６アルコキシ及びＣ１－６アルキル（該アルコキシ及びアルキルは、１～５個のフッ素で置換されていてもよい）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アリール又はヘテロアリールである、
    請求項１～１６のいずれか一項に記載の化合物又はその製薬学的に許容される塩。     R 4B may be substituted with 1 to 5 substituents independently selected from the group consisting of aryl, heteroaryl, hydroxyl group, fluorine, C 1-6 alkoxy and C 3-10 cycloalkyl. 1-6 alkyl; aryl, heteroaryl, hydroxyl, fluorine, optionally substituted with 1-5 optionally substituted by fluorine C 1-6 alkoxy and 1 to 5 fluorine C 1-6 C 3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl (the groups may form a condensed ring with aryl); the same or different A 4- to 10-membered saturated heterocycle optionally substituted with 1 to 5 C 1-6 alkyl; or halogen, C 1-6 alkoxy and C 1-6 alkyl (wherein the alkoxy and alkyl are 1-5 Pieces Aryl or heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of (optionally substituted with nitrogen),
    The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof.
  18. 　請求項１～１７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 17 or a pharmaceutically acceptable salt thereof.
  19. 　請求項１～１７のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩を有効成分とするアセチルコリンが関与する細胞内シグナル伝達の異常に起因する疾患の治療剤又は予防剤。 A therapeutic or preventive 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 17 or a pharmaceutically acceptable salt thereof as an active ingredient .
  20. 　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、ＣＩＡＳ（統合失調症に伴う認知機能障害）、アルツハイマー病、ダウン症、認知障害、記憶障害・学習障害、軽度認知障害、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１９に記載の治療剤又は予防剤。     Diseases caused by abnormal intracellular signaling involving acetylcholine include CIAS (cognitive impairment associated with schizophrenia), Alzheimer's disease, Down's syndrome, cognitive impairment, memory impairment / learning impairment, mild cognitive impairment, attention deficit / many Dyskinetic or cerebrovascular angiopathy,
    The therapeutic agent or preventive agent of Claim 19.
  21. 　請求項１～１７のいずれか一項に記載の化合物又はそれらの製薬学的に許容される塩と、非定型抗精神病薬に分類される薬剤から選択される少なくとも１種以上の薬剤とを組み合わせてなる医薬。 A combination of the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof and at least one drug selected from drugs classified as atypical antipsychotic drugs The medicine which becomes.
  22. 　治療が必要な患者に、治療上の有効量の請求項１～１７のいずれか１項に記載の化合物又はその製薬学的に許容される塩を投与することを特徴とするアセチルコリンが関与する細胞内シグナル伝達の異常に起因する疾患の治療または予防方法。 A cell in which acetylcholine is involved, characterized in that a therapeutically effective amount of the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof is administered to a patient in need of treatment A method for treating or preventing a disease caused by abnormal signal transduction.
  23. 　アセチルコリンが関与する細胞内シグナル伝達の異常に起因する疾患の治療剤又は予防剤を製造するための請求項１～１７のいずれか１項に記載の化合物又はその製薬学的に許容される塩の使用。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, for producing a therapeutic or prophylactic agent for a disease caused by an abnormality in intracellular signal transduction involving acetylcholine. use.
  24. 　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または予防に使用する、項１～１７のいずれか１項に記載の化合物又はその製薬学的に許容される塩を含む医薬組成物。 Item 18. A pharmaceutical composition comprising the compound according to any one of Items 1 to 17 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease caused by an abnormality in intracellular signal transduction involving acetylcholine. .
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