WO2012108490A1 - Isoquinoline amide derivative - Google Patents

Isoquinoline amide derivative Download PDF

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WO2012108490A1
WO2012108490A1 PCT/JP2012/052936 JP2012052936W WO2012108490A1 WO 2012108490 A1 WO2012108490 A1 WO 2012108490A1 JP 2012052936 W JP2012052936 W JP 2012052936W WO 2012108490 A1 WO2012108490 A1 WO 2012108490A1
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Prior art keywords
isoquinoline
compound
carboxamide
chloro
trifluorophenyl
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PCT/JP2012/052936
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French (fr)
Japanese (ja)
Inventor
▲はま▼口　渉
陽平 小金丸
竜一 関岡
統 金子
加藤　浩二
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アステラス製薬株式会社
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Publication of WO2012108490A1 publication Critical patent/WO2012108490A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to a pharmaceutical, particularly an isoquinolinamide derivative having a 5-HT 5A receptor modulating action and useful as a therapeutic or prophylactic agent for dementia, schizophrenia and the like.
  • 5-HT 5A receptor which is one of serotonin receptor subtypes, plays an important role in dementia and schizophrenia.
  • 5-HT 5A receptor increases, also, overactive by LSD is a 5-HT 5A receptor knockout mice have been reported to be inhibited (Neuron, 22, 581-591, 1999).
  • 5-HT 5A receptor is highly expressed in human and rodent brains, and in hippocampal CA1 and CA3 pyramidal cells, which are involved in memory, and schizophrenia It has been reported that there is a lot of expression in the frontal cortex (cerebral cortex) that is deeply related to the disease (Molecular Brain Research, 56, 1-8, 1998).
  • 5-HT 5A receptor polymorphism is associated with schizophrenia (Neuroreport 11, 2017-2020, 2000; Mol. Psychiatr. 6, 217-219, 2001; J. Psychiatr. Res. 38, 371-376, 2004).
  • regulating the function of 5-HT 5A receptor leads to improvement of dementia and schizophrenia, and a compound having such a function is desired.
  • a tricyclic compound represented by the following formula (a) binds to a 5-HT 5A receptor and is used for the treatment of dementia, schizophrenia and the like (Patent Document 1).
  • A means a benzene, thiophene, furan, cyclohexene or tetrahydropyridine ring
  • B means a benzene, cyclohexene or tetrahydropyridine ring.
  • This publication relates to tricyclic compounds and is different from the isoquinolinamide derivatives of the present invention.
  • a bicyclic acylguanidine compound represented by the following formula (b) binds to a 5-HT 5A receptor and is used for the treatment of dementia, schizophrenia and the like (Patent Document 2).
  • A is phenyl
  • R 1 , R 2 and R 3 are H, lower alkyl, halogen, etc.
  • R 7 and R 8 are H, lower alkyl, etc.
  • X is O
  • R 9a and R 9b are H, etc.
  • dotted line is bonded or absent
  • m is 0, 1 or 2
  • L 1 and L 2 are bonded, etc.
  • R 4 , R 5 and R 6 are H
  • This publication relates to a compound in which the bicyclic ring group moiety is chroman or benzothiophene and is different from the isoquinolinamide derivative of the present invention.
  • a naphthoylguanidine compound substituted with a cyclic group represented by the following formulas (c) and (d) binds to a 5-HT 5A receptor and is useful for the treatment of dementia, schizophrenia and the like.
  • a naphthoylguanidine compound substituted with a cyclic group represented by the following formulas (c) and (d) binds to a 5-HT 5A receptor and is useful for the treatment of dementia, schizophrenia and the like.
  • A represents various ring groups including phenyl, pyridyl, etc.
  • This publication relates to naphthalene compounds and is different from the isoquinolinamide derivative of the present invention.
  • a quinoline or isoquinoline compound substituted with a cyclic group represented by the following formula (e) binds to 5-HT 5A receptor and is useful for the treatment of dementia, schizophrenia, etc. It is disclosed in Document 7.
  • A represents a cyclic group, and any one of Z 1 , Z 2 , Z 3 , Z 4 and Z 5 is a nitrogen atom and the other is a carbon atom.
  • This publication relates to acylguanidino derivatives and is different from the isoquinolinamide derivatives of the present invention.
  • a tetrahydroisoquinoline compound represented by the following formula (g) has been reported as a 5-HT 1B and 5-HT 1D receptor regulator (Patent Document 6).
  • R 1 represents alkyl, halogen or the like
  • R 2 represents aryl, heterocycle or carboxamide
  • W represents a linking group such as —C (O) — or —C (O) NR a —
  • Ring X means an optionally substituted aryl or an optionally substituted heterocycle (see the publication for details)
  • the compound disclosed in the publication relates to a tetrahydroisoquinoline derivative and is different from the isoquinoline amide derivative of the present invention.
  • isoquinoline derivatives in which a ring group is bonded to the 1-position of the isoquinoline ring and a further ring group is bonded to the 7-position via a bonding group such as an amide group have been known as 5-HT 5A receptor modulators. Not.
  • An object of the present invention is to provide an excellent therapeutic or preventive agent for dementia, schizophrenia and the like based on a 5-HT 5A receptor modulating action.
  • the present inventors have shown that the ring group is bonded to the 1-position of the isoquinoline ring represented by the formula (I) and the amide group is located at the 7-position. It was found that isoquinoline derivatives to which a further ring group or the like is bonded via a linking group have a potent 5-HT 5A receptor modulating action and an excellent pharmacological action based on this, such as dementia and schizophrenia.
  • the present invention was completed by discovering that it is useful as a therapeutic or prophylactic agent.
  • the compound of the formula (I) is an isoquinolinamide derivative characterized in that a ring group is bonded to the 1-position of the isoquinoline ring and a further ring group or the like is bonded to the 7-position via a bonding group such as an amide group. . That is, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • A aryl, heteroaryl or cycloalkyl
  • R 1 ⁇ R 3 different same or mutually, H, halogen, halogeno lower alkyl, -CN, -OH, -OR 0, -O- ( halogeno-lower alkyl), - R 00 -OH, -R 00 - OR 0 , cycloalkyl or lower alkylene
  • R 4 H, halogen, halogeno-lower alkyl, R 0, -CN, -OH, -OR 0, -O- ( halogeno-lower alkyl), - R 00 -OH, -R 00 -OR 0, or cycloalkyl
  • R 5 H or R 0 , L: a single bond, -R 00 -O -, - R 00 -S -, - R 00 -SO 2 -, - R 00 -NH
  • the compound of the formula (I) has an advantage of having a potent 5-HT 5A receptor modulating action and a good pharmacological action based thereon.
  • the pharmaceutical composition of the present invention is used for the treatment or prevention of diseases involving 5-HT 5A receptor, particularly for the treatment or prevention of dementia, schizophrenia, bipolar disorder, attention deficit hyperactivity disorder and mood disorder. Useful.
  • the term “5-HT 5A receptor modulator” refers to a compound that suppresses 5-HT 5A receptor activation by antagonizing an endogenous ligand (5-HT 5A antagonist), and 5- It is a general term for compounds (5-HT 5A agonists) that exert their actions by activating the HT 5A receptor.
  • An embodiment of the “5-HT 5A receptor modulator” is, for example, a 5-HT 5A antagonist.
  • “Lower alkyl” means a linear or branched alkyl group having 1 to 6 carbon atoms (hereinafter abbreviated as C 1-6 ), specifically, methyl, ethyl, n-propyl.
  • Another embodiment is C 1-4 alkyl, and yet another embodiment is methyl, ethyl, or n-propyl.
  • the “lower alkylene” means a divalent substituent formed by removing any hydrogen atom from the lower alkyl.
  • methylene, ethylene, 1,2-propylene, or trimethylene is used.
  • methylene, ethylene, or trimethylene is used.
  • methylene or ethylene is used.
  • Halogen means F, Cl, Br, I.
  • One embodiment is F or Cl.
  • Halogeno lower alkyl means lower alkyl substituted with one or more halogens, such as F or Cl, and in some embodiments is trifluoromethyl or difluoromethyl.
  • the “aryl” is a C 6-14 monocyclic to tricyclic aromatic hydrocarbon ring group, and in one embodiment, phenyl or naphthyl, and in another embodiment, phenyl.
  • Heteroaryl is a 5- to 14-membered ring having 1 to 5 heteroatoms selected from O, N and S as atoms forming the ring, and in another embodiment, a 5- to 10-membered ring.
  • monocyclic to tricyclic and in another embodiment are monocyclic to bicyclic aromatic ring groups, which may be condensed.
  • One embodiment is a 5- to 6-membered monocyclic heteroaryl, such as pyridyl, pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl, thiazolyl, oxadiazolyl and the like.
  • monocyclic nitrogen-containing heteroaryl those having a nitrogen atom as a ring-constituting atom are referred to as “monocyclic nitrogen-containing heteroaryl”.
  • Another embodiment is a 9-10 membered bicyclic heteroaryl, such as quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl and the like.
  • Cycloalkyl is a C 3-10 saturated hydrocarbon ring group, which may be bridged or condensed.
  • cyclopropyl is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl group or the like, and as another aspect, a C 3-6 cycloalkyl group, and as another aspect, C A 3-7 cycloalkyl group, and in yet another embodiment, cyclopropyl or cyclobutyl.
  • the condensed ring is a 5- to 6-membered monocyclic heteroaryl.
  • Heterocycloalkyl is a saturated or partially unsaturated 3- to 14-membered ring group having 1 to 6 heteroatoms as atoms constituting the ring, and is bridged and / or condensed. May be.
  • An embodiment is a monocyclic heterocycloalkyl having 1 to 4 heteroatoms selected from O, N, or S, such as acetylidinyl, pyrrolidyl, piperidyl, piperazyl, pyranyl, morpholyl, thiopyranyl, etc. .
  • the monocyclic thing which has a nitrogen atom as an atom which comprises a ring is set as "monocyclic nitrogen-containing heterocycloalkyl.”
  • Another embodiment is a bicyclic ring group in which a monocyclic heterocycloalkyl having 1 to 4 heteroatoms selected from O, N, or S is condensed with a benzene ring, such as benzopyran- 2-yl, benzopyran-3-niyl and benzopyran-4-yl.
  • a bridged heterocycloalkyl group such as quinuclidyl or 8-azabicyclo [3.2.1] oct-3-yl.
  • “It may be substituted” means unsubstituted or having 1 to 5 substituents. In one embodiment, there are 1 to 2 unsubstituted or substituted groups, in another embodiment, one substituent, and in another embodiment, two substituents. When it has a plurality of substituents, these substituents may be the same or different from each other.
  • substituent in the “optionally substituted lower alkylene” examples include —OH, —OR 0 , —N (R 0 ) 2 , —CO 2 H, —CO 2 R 0 , —CN, phenyl, cyclopropyl, And another group selected from the group consisting of —OH, —N (R 0 ) 2 , —CN, cyclopropyl, and oxo, and Another embodiment is -OH. In one embodiment, it is unsubstituted, in another embodiment, 1 or 2 substituents, in another embodiment, 1 substituent, and in another embodiment, 2 substituents. is there. When there are two substituents, these may be the same or different from each other.
  • heterocycloalkyl, heteroaryl, cycloalkyl, or aryl “optionally substituted, heterocycloalkyl or heteroaryl”, “optionally substituted, respectively” , "Monocyclic nitrogen-containing heterocycloalkyl or monocyclic nitrogen-containing heteroaryl”, “optionally substituted phenyl, piperidyl, imidazolyl or pyridyl”, and "optionally substituted piperidyl” -R 0 , -R 00 -OH, -R 00 -OR 0 , -R 00 -CN, -R 00 -N (R 0 ) 2 , -R 00 -COR 0 , -R 00 -CONH 2 , -COR 0 , -CO 2 H, -CO 2 R 0 , -CONH 2 , -CN, -OH, -OR 0 , -NH 2 , -SR
  • A is aryl, heteroaryl or cycloalkyl;
  • R 1 to R 3 are the same or different from each other, and are H, halogen, halogeno lower alkyl, -O- (lower alkyl), or lower alkyl;
  • R 4 is H, halogen, halogeno lower alkyl, lower alkyl, -O- (lower alkyl), or cycloalkyl;
  • R 5 is H or lower alkyl, L is a single bond, lower alkylene,-(lower alkylene) -O-,-(lower alkylene) -S-,-(lower alkylene) -NH-,-(lower alkylene) -NR 0 -,-(lower alkylene) ) —SO 2 —, cycloalkylene, or optionally substituted lower alkylene
  • B is -OH, -OR 0 , -SR 0 , -N (R 0
  • (B) A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein L is a single bond, cycloalkylene or optionally substituted lower alkylene.
  • L is, -R 00 -O -, - R 00 -S -, - R 00 -NH -, - R 00 -NR 0 - or -R 00 -SO 2 - and is, B is, -R 00 —OR 0 , —CONH 2 or —CO 2 R 0 , or each optionally substituted heterocycloalkyl, heteroaryl, cycloalkyl or aryl, a compound of formula (I) or a pharmaceutically acceptable salt thereof Acceptable salt.
  • this invention includes the following.
  • A is phenyl, pyridyl or C 3-7 cycloalkyl, and in one embodiment, phenyl, in another embodiment, monocyclic nitrogen-containing heteroaryl, and in another embodiment, pyridyl.
  • Yet another embodiment is a compound of formula (I), which is C 3-7 cycloalkyl.
  • R 1 to R 3 are the same or different from each other, and in one embodiment, are halogen or H, in another embodiment, a group selected from F, Cl and H, and in another embodiment, A compound of formula (I) which is F or H.
  • R 4 is halogen, C 1-3 alkyl, —O— (C 1-3 alkyl) or cyclopropyl, and in one embodiment, F or Cl, and in another embodiment, lower alkyl.
  • the compound of formula (I) is methyl or ethyl.
  • the substitution position of R 4 is, in one embodiment, the 4-position of the isoquinoline ring.
  • R 5 is H.
  • the compound of the formula (I), wherein L is a single bond or lower alkylene, and in one embodiment is a single bond, and in another embodiment, is a single bond, methylene, ethylene or trimethylene.
  • B is an optionally substituted heterocycloalkyl or heteroaryl, and in another embodiment, each may be substituted, a monocyclic nitrogen-containing heterocycloalkyl or monocyclic nitrogen-containing In the formula (I), which is heteroaryl, and in yet another embodiment is phenyl, piperidyl, imidazolyl or pyridyl, which may each be substituted, and in another embodiment is optionally substituted piperidyl Compound.
  • B is -R 0 , -R 00 -OH, -R 00 -OR 0 , -R 00 -CN, -R 00 -N (R 0 ) 2 , -COR 0 , -CO 2 R 0 , -CONH 2 , -CN, -OH, -OR 0 , -NH 2 , -SR 0 , halogen, -R 00- (phenyl), halogeno lower alkyl, cycloalkyl, -R 00- (cyclopropyl ), - R 00 - (cyclohexyl), - CO- (cyclopropyl), - R 00 - (morpholyl), - R 00 - (piperidyl), pyrrolidyl, piperidyl, -R 00 - (pyridyl), and pyrimidinyl
  • -R 0 , -R 00 -NH 2, -R 00 Phenyl, piperidyl, quinucidyl, imidazolyl, or pyridyl each optionally substituted with a group selected from -OH and -R 00 -OR 0
  • -R 0 , -R 00 A compound of formula (I) which is piperidyl optionally substituted with a group selected from -CO-NH 2 and -R 00 -OR 0 , and in another embodiment is imidazolyl.
  • the present invention includes compounds in which the embodiments of the substituents shown in the above (1) to (6) and (A) to (C) are arbitrarily combined, for example, the following compounds.
  • A is phenyl, pyridyl or C 3-7 cycloalkyl
  • R 1 to R 3 are the same or different from each other and are selected from F, Cl and H
  • R 4 is halogen, C 1-3 alkyl, —O— (C 1-3 alkyl) or cyclopropyl
  • R 5 is H
  • L is a single bond or lower alkylene
  • B is lower alkyl, —R 00 —NH 2
  • a compound of formula (I) which is a monocyclic nitrogen-containing heterocycloalkyl or monocyclic nitrogen-containing heteroaryl, each optionally substituted with a group selected from -R 00 -OH.
  • A is phenyl
  • R 1 to R 3 are F or H
  • R 4 is F or Cl
  • R 5 is H
  • L is a single bond, methylene, ethylene or trimethylene
  • B is phenyl, piperidyl, imidazolyl, or pyridyl, each optionally substituted with a group selected from lower alkyl, -R 00 -NH 2, -R 00 -OH and -R 00 -OR 0 Compound (I).
  • A is phenyl
  • R 1 to R 3 are F or H
  • R 4 is F or Cl
  • R 5 is H
  • L is a single bond
  • B is phenyl, piperidyl, quinucidyl, imidazolyl, or pyridyl, each optionally substituted with a group selected from lower alkyl, -R 00 -NH 2, -R 00 -OH and -R 00 -OR 0
  • A is phenyl, R 1 to R 3 are F or H, R 4 is Cl or methyl, R 5 is H, L is a single bond, B is lower alkyl, A compound of formula (I) which is piperidyl optionally substituted with a group selected from -R 00 -CO-NH 2 and -R 00 -OR 0 .
  • A is phenyl, R 1 to R 3 are F or H, R 4 is Cl, R 5 is H, and L is ethylene that may be substituted with -OH;
  • the present application includes the following (13) to (26).
  • (13) A pharmaceutical composition comprising the compound of the above formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • (16) The pharmaceutical composition according to the above (13), which is used for prevention or treatment of dementia or schizophrenia.
  • a preventive or therapeutic agent for dementia, schizophrenia, bipolar disorder, or attention deficit / hyperactivity disorder comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a preventive or therapeutic agent for dementia or schizophrenia comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • (19) Use of the compound of the above formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a preventive or therapeutic agent for dementia, schizophrenia, bipolar disorder, or attention deficit hyperactivity disorder .
  • (20) Use of the compound of the above formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a preventive or therapeutic agent for dementia or schizophrenia.
  • the above schizophrenia includes positive symptoms, negative symptoms, cognitive impairment, and mood disorders.
  • the present invention includes pharmaceutically acceptable prodrugs of the compound of formula (I).
  • Pharmaceutically acceptable prodrugs are compounds having groups that can be converted to amino groups, OH, CO 2 H, etc. by solvolysis or under physiological conditions. Examples of groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) and “Development of Pharmaceuticals” (Yodogawa Shoten, 1990), Volume 7, Molecular Design 163-198. Can be mentioned.
  • the compound of the formula (I) may form an acid addition salt or a salt with a base depending on the kind of the substituent, and as long as such a salt is a pharmaceutically acceptable salt, the compound of the present invention is used.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid
  • Acid addition salts with organic acids such as lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid or glutamic acid, sodium, potassium, magnesium, calcium, aluminum, etc.
  • Inorganic bases salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, ammonium salts, and the like.
  • the compound of formula (I) and pharmaceutically acceptable salts thereof include various hydrates, solvates and polymorphic substances.
  • the compounds of formula (I) and pharmaceutically acceptable salts thereof include compounds labeled with various radioactive or non-radioactive isotopes.
  • the compound of the formula (I) and pharmaceutically acceptable salts thereof can be produced by applying various known synthetic methods utilizing characteristics based on the basic skeleton or the type of substituent.
  • an appropriate protecting group a group that can be easily converted into the functional group
  • Examples of such a functional group include an amino group, a hydroxyl group, and a carboxyl group
  • examples of protective groups thereof include, for example, “Greene's Protective Groups in Organic Synthesis (No. 4) by PGM Wuts and Green (TW Greene)”. Edition, 2006) ”, and these may be appropriately selected depending on the reaction conditions.
  • a desired compound can be obtained by introducing the protecting group and carrying out the reaction, and then removing the protecting group as necessary.
  • the prodrug of the compound of the formula (I) introduces a specific group at the stage from the raw material to the intermediate as in the case of the protective group, or further reacts with the obtained compound of the formula (I).
  • the reaction can be carried out by applying a method known by those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.
  • typical production methods of the compound of the formula (I) will be described. Each manufacturing method can also be performed with reference to the reference attached to the said description.
  • the manufacturing method of this invention is not limited to the example shown below.
  • the compound of formula (I) can be produced by reacting compound (II) with compound (III) or a salt thereof. The reaction can be carried out using an equal amount of compound (II) and compound (III) or an excess amount of compound (III).
  • Aromatic hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform, ethers such as diethyl ether, tetrahydrofuran (THF), dioxane or dimethoxyethane (DME), Under cooling in a solvent inert to the reaction such as N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), ethyl acetate, acetonitrile or water, or a mixture thereof.
  • the heating can be performed preferably at -20 ° C to 80 ° C.
  • the reaction is preferably performed in the presence of a condensing agent.
  • a condensing agent N, N'-dicyclohexylcarbodiimide (DCC), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide (WSC), 1,1'-carbonyldiimidazole (CDI) 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), diphenyl phosphate azide (DPPA), phosphorus oxychloride and the like.
  • DCC N, N'-dicyclohexylcarbodiimide
  • WSC 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide
  • CDI 1,1'-carbonyldiimidazole
  • HBTU 1- (1H-benzotriazol-1-yl) -1
  • an additive for example, N-hydroxysuccinimide (HONSu) or 1-hydroxybenzotriazole (HOBt)
  • the condensing agent is used in an equivalent amount or an excess amount relative to the carboxylic acid.
  • organic bases such as base (triethylamine (TEA), diisopropylethylamine (DIPEA), N-methylmorpholine, pyridine or 4- (N, N-dimethylamino) pyridine, or sodium bicarbonate, etc. It may be advantageous to carry out the reaction in the presence of an inorganic base, etc.) in order to allow the reaction to proceed smoothly.
  • Pyridine can also serve as a solvent.
  • the reaction is preferably carried out at room temperature to heating under reflux.
  • X 1 represents a trifluoromethanesulfonyloxy group, a halogen, a methanesulfonyloxy group, or a p-toluenesulfonyloxy group
  • X 2 represents —B (OH) 2 , —B (OY) OW, etc.
  • Compound (II) can be produced by a coupling reaction with compound (IV) and compound (V) and then deprotection of the carboxyl group.
  • X 2 is an active group such as -B (OH) 2 or -B (OY) OW
  • compounds (IV) and (V) are used in an equal amount, or one of them is used in excess, and a mixture thereof is reacted.
  • an inert solvent usually in the presence of a base and a palladium catalyst at room temperature to heating under reflux, usually by stirring for 0.1 hour to 5 days. This reaction is preferably performed in an inert gas atmosphere.
  • the solvent used here are not particularly limited, but include aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols such as methanol and ethanol, DMF, DMSO, and mixed solvents thereof. It is done.
  • inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide and the like are preferable.
  • the palladium catalyst include tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1,1′-bis (diphenylphosphino) ferrocene, and tris (dibenzylideneacetone) dipalladium.
  • the palladium ligand tert-butylphosphine, cyclohexylphosphine, 2-dicyclohexylphosphinobiphenyl derivative and the like can also be used.
  • the compound (V) when X 2 is halogen, the compound (V) is converted into an organolithium compound using n-butyllithium or LDA (lithium diisopropylamide), and then zinc chloride is allowed to act. It can be converted into an organic zinc compound.
  • Compound (II) can be produced by reacting the obtained organic zinc compound with compound (IV) in the presence of a base and a palladium catalyst in a solvent inert to the reaction.
  • a base and a palladium catalyst As the reaction solvent, base, and palladium catalyst used here, the same reaction as in the case where X 2 is an active group such as —B (OH) 2 or —B (OY) OW can be used.
  • the manufacturing method of the compound used as a raw material is described as a manufacture example.
  • the manufacturing method of the compound of a formula (I) is not limited only to the manufacturing method of the specific Example shown below, It can manufacture also by the combination of these manufacturing methods, or a well-known manufacturing method.
  • the concentration [M] means [mol / L], and “rel” means relative configuration.
  • Example 1 4-Chloro-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxylic acid (90 mg), 2- (1-methyl-1H-imidazol-2-yl) ethanamine dihydrochloride (58 mg ), HOBt (40 mg), WSC hydrochloride (56 mg), DIPEA (0.12 mL) and DMF (5 mL) were stirred at room temperature for 4 hours. A saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and a liquid separation operation was performed.
  • Example 2 4-chloro-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxylic acid (80 mg), trans-4-aminocyclohexanol (33 mg), HOBt (38 mg), WSC hydrochloride ( 54 mg) and DMF (2.7 mL) were stirred at room temperature for 3 days. A saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and a liquid separation operation was performed. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure.
  • Example 3 tert-Butyl [trans-3-( ⁇ [4-Chloro-1- (2,4,6-trifluorophenyl) isoquinolin-7-yl] carbonyl ⁇ amino) cyclobutyl] carbamate (500 mg), methanol (5 mL ) And ethyl acetate (5 mL) were added 4M hydrogen chloride / ethyl acetate (1.5 mL), and the mixture was stirred at room temperature for 3 days. Chloroform and saturated sodium bicarbonate water were sequentially added to the reaction solution, and a liquid separation operation was performed. The organic layer was washed and dried, and concentrated under reduced pressure.
  • Example 4 4-chloro-N- [2- (1H-imidazol-2-yl) ethyl] -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide (60 mg), 2-iodopropane (170 mg) and DMF (2 mL) were added with DIPEA (30 mg), stirred at an oil temperature of 90 ° C. for 2 days, and then cooled to room temperature. Ethyl acetate and water were added to the reaction solution to carry out a liquid separation operation. The organic layer was washed successively with water and saturated brine, dried and concentrated under reduced pressure.
  • Example 6 To a methanol solution (1.74 mL) of tert-butyl 4-( ⁇ [4-chloro-1- (2,4-difluorophenyl) isoquinolin-7-yl] carbonyl ⁇ amino) piperidine-1-carboxylate (173 mg) 4M Hydrogen chloride / dioxane (1.3 mL) was added, and the mixture was stirred at room temperature for 1 day. The reaction solution was concentrated under reduced pressure to obtain 4-chloro-1- (2,4-difluorophenyl) -N- (piperidin-4-yl) isoquinoline-7-carboxamide dihydrochloride (80 mg).
  • Example 7 4-Chloro-N- (piperidin-4-yl) -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide dihydrochloride (100 mg), cyclopropanecarbaldehyde (374 mg), acetic acid (0.058 mL) and TEA (0.085 mL) in dichloromethane (8.6 mL) were added sodium triacetoxyborohydride (64 mg), and the mixture was stirred at room temperature for 18 hours. A 1M aqueous sodium hydroxide solution and ethyl acetate were added to the reaction solution to carry out a liquid separation operation.
  • Example 9 4-chloro-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxylic acid (80 mg), tetrahydro-2H-pyran-4-amine (29 mg), HOBt (32 mg), TEA ( To a mixture of 0.1 ml) and DMF (2.7 mL), WSC hydrochloride (68 mg) was added and stirred at room temperature for 20 hours. A 1M aqueous sodium hydroxide solution and ethyl acetate were added to the reaction solution, and a liquid separation operation was performed.
  • Example 10 4-chloro-N- (piperidin-4-yl) -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide dihydrochloride (62 mg), 2,2-difluoroethyl trifluoromethanesulfonate ( A mixture of 54 mg), TEA (0.07 mL) and DMF (6.2 mL) was stirred at 60 ° C. overnight and then cooled to room temperature. A saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and a liquid separation operation was performed.
  • Example 13 4-Chloro-N- (piperidin-4-yl) -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide dihydrochloride (80 mg), TEA (82 mg) and dichloromethane (4 mL ) was added to the mixture and stirred at room temperature overnight. A 1M aqueous sodium hydroxide solution and ethyl acetate were added to the reaction solution, and a liquid separation operation was performed.
  • Example 14 tert-butyl 4-( ⁇ [4-chloro-1- (2,4,6-trifluorophenyl) isoquinolin-7-yl] carbonyl ⁇ amino) piperidine-1-carboxylate (169 mg) and ethyl acetate (10 4M hydrogen chloride / ethyl acetate (10 mL) was added to the mixture, and the mixture was stirred at room temperature for 1 day, and then the reaction mixture was concentrated under reduced pressure. The residue was washed with ethyl acetate to obtain 4-chloro-N- (piperidin-4-yl) -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide dihydrochloride (161 mg) .
  • Example 16 To a mixture of 6-[( ⁇ [4-chloro-1- (2,4,6-trifluorophenyl) isoquinolin-7-yl] carbonyl ⁇ amino) methyl] nicotinic acid (50 mg) and DMF (10 mL) , CDI (25 mg) was added, and the mixture was stirred at room temperature for 1 hr, 28% aqueous ammonia (5 mL) was added, and the mixture was stirred at an oil temperature of 60 ° C. for 16 hr. The reaction solution was cooled to room temperature and concentrated under reduced pressure.
  • Example 17 4-Chloro-N-[(2S) -piperidin-2-ylmethyl] -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide hydrochloride (70 mg), DIPEA (57 mg), iodine A mixture of methyl chloride (28 mg) and ethanol (1 mL) was stirred at 120 ° C. for 30 minutes under microwave irradiation.
  • Example 19 A mixture of 6-nitroimidazo [1,2-a] pyridine (584 mg), methanol (41 mg) and 10% palladium / carbon (905 mg) was stirred at room temperature for 3 hours in a hydrogen gas atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure.
  • Example 20 To a mixture of 4-chloro-1- (2-fluorophenyl) -N- (1H-imidazol-2-ylmethyl) isoquinoline-7-carboxamide (88 mg) and DMF (20 mL) was added 1-chloropyrrolidine-2, 5-dione (34 mg) was added, and the mixture was stirred at room temperature for 1 day. Water and ethyl acetate were added to the reaction liquid, and liquid separation operation was performed.
  • Example 21 Under an argon gas atmosphere, N-[(6-chloropyridin-3-yl) methyl] -1- (2-fluorophenyl-l) -4-methylisoquinoline-7-carboxamide (269 mg), trimethylboroxine (210 mg ), Potassium phosphate (422 mg), toluene (6 mL) and water (0.4 mL), palladium acetate (15 mg) and tricyclohexylphosphine (37 mg) are added, and the oil temperature is 100 ° C. for 1 day. Stir. The reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the mixture was filtered through Celite.
  • Example 22 4-Chloro-1- (2-fluorophenyl) -N- (1H-imidazol-2-ylmethyl) isoquinoline-7-carboxamide (60 mg), 2-bromoethyl methyl ether (24 mg), cesium carbonate (128 mg ) And N-methylpyrrolidone (1 mL) were stirred at 120 ° C. for 15 minutes under microwave irradiation. The reaction solution was ice-cooled, and water and ethyl acetate were added to carry out a liquid separation operation.
  • Example 23 4-chloro-1- (2-fluorophenyl) -N- (1H-imidazol-2-ylmethyl) isoquinoline-7-carboxamide (60 mg), 2-bromoacetamide (24 mg), cesium carbonate (128 mg) and A mixture of DMF (10 mL) was stirred at an oil temperature of 60 ° C. for 15 hours. After the reaction solution was cooled to room temperature, ethyl acetate and water were added to carry out a liquid separation operation. The organic layer was washed successively with water and saturated brine, dried and concentrated under reduced pressure.
  • Example 24 4-chloro-1- (2-fluorophenyl) -N- (1H-imidazol-2-ylmethyl) isoquinoline-7-carboxamide (52 mg), DIPEA (35 mg), 1M oxirane / THF solution (1.4 mL), A mixture of methanol (1 mL) and N-methylpyrrolidone (1 mL) was stirred at 60 ° C. for 30 minutes under microwave irradiation, and further stirred at 150 ° C. for 15 minutes. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction solution to carry out a liquid separation operation. The organic layer was washed successively with water and saturated brine, dried and concentrated under reduced pressure.
  • Example 25 Under an argon gas atmosphere, a mixture of 4-chloro-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxylic acid (60 mg) and dichloromethane (1 mL) was added to oxalyl chloride (25 mg) and DMF (0.01 mL) were added sequentially, and the solution stirred at room temperature for 1.5 hours was added to a mixture of pyrimidine-2-amine (20 mg), TEA (18 mg) and dichloromethane (1 mL) in a separate container with ice. The solution was added dropwise under cooling and stirred at room temperature for 2 hours. Methanol was added to the reaction mixture and the mixture was concentrated under reduced pressure.
  • Example 26 Ethyl-2-[( ⁇ [4-chloro-1- (2,4,6-trifluorophenyl) isoquinolin-7-yl] carbonyl ⁇ amino) methyl] -1,3-thiazole-4-carboxylate (50 mg), ethanol (0.5 mL) and THF (0.5 mL) were added 1M aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at an oil temperature of 50 ° C. for 0.5 hr. The reaction solution was concentrated under reduced pressure, and water and diethyl ether were added to carry out a liquid separation operation. The aqueous layer was weakly acidified with 1M hydrochloric acid, and chloroform was added to carry out a liquid separation operation.
  • Example 27 2-[( ⁇ [4-Chloro-1- (2,4,6-trifluorophenyl) isoquinolin-7-yl] carbonyl ⁇ amino) methyl] -1,3-thiazole-4-carboxylic acid (30 mg) , HOBt (13 mg), WSC hydrochloride (18 mg), and DMF (1.2 mL) were stirred at room temperature for 1 hour, 28% aqueous ammonia (0.04 mL) was added, and the mixture was further stirred at room temperature for 16 hours. . Water and ethyl acetate were added to the reaction liquid, and liquid separation operation was performed. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure.
  • Example 28 Under an argon gas atmosphere, N-[(4-carbamoyl-1,3-thiazol-2-yl) methyl] -4-chloro-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide (10 mg) and pyridine (0.13 mL) were added phosphoryl chloride (2.5 ⁇ L) under ice-cooling and stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction liquid, and liquid separation operation was performed. The organic layer was washed with saturated brine, dried, and concentrated under reduced pressure.
  • Example 29 4-Chloro-N- ⁇ [4- (hydroxymethyl) -1,3-thiazol-2-yl] methyl ⁇ -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide (14 mg) And methanol (720 mL) were added trimethyl orthoformate (640 mg) and sulfuric acid (31 mg), and the mixture was stirred with heating under reflux for 3 hours.
  • Example 30 4-Chloro-N- [2-hydroxy-2- (1-trityl-1H-imidazol-2-yl) ethyl] -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide (120 mg ) And dioxane (3.5 mL), 1M hydrochloric acid (2 mL) was added, and the mixture was stirred with heating at an oil temperature of 60 ° C. for 2 hours and cooled to room temperature. The reaction mixture was neutralized with 1M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure.
  • Example 31 1,2,2,6,6-pentamethylpiperidin-4-amine (4.3 mg) and 4-chloro-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxylic acid (8.4 mg) , DIPEA (19.2 ⁇ l) in DMF (400 ⁇ l), and N-[(dimethylamino) (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methylene] -N -Methylmethananium Hexafluorophosphoric acid (11.4 mg) in DMF (100 ⁇ l) was added and stirred at room temperature overnight.
  • Example 360 4-Chloro-1- (2-fluorophenyl) -N-[(2S) -piperidin-2-ylmethyl] isoquinoline-7-carboxamide monohydrochloride (63 mg) in DMF (2 mL) was added to potassium carbonate ( mg) and methyl iodide (11 ⁇ L) were sequentially added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed successively with saturated brine, dried and concentrated under reduced pressure.
  • Example compounds shown in the table below were produced using the corresponding raw materials in the same manner as in the above examples.
  • the structural formulas, physicochemical data and production methods of the example compounds are shown in the table below.
  • HEK293 cells Human embryonic kidney-derived cell line HEK293 cells (ATCC) are seeded, and the expression plasmid (1 ⁇ g) obtained above is added together with LIPOFECTAMINE 2000 (Invitrogen; 2 ⁇ l). After introducing the gene into HEK293 cells, An expression cell was selected with a certain geneticin (G418 sulfate 500 ⁇ g / ml; Kanto Chemical).
  • Recombinant cells expressing the gene thus produced were D-MEM (Dulbecco's Modified Eagle Medium, Sigma), 10% FCS (Fetal calf serum), 1% Pc./Sm (penicillin / Culturing was performed with streptomycin (Invitrogen) and 500 ⁇ g / ml G418 medium for 3 days.
  • D-MEM Dulbecco's Modified Eagle Medium, Sigma
  • FCS Fetal calf serum
  • Pc./Sm penicillin / Culturing was performed with streptomycin (Invitrogen) and 500 ⁇ g / ml G418 medium for 3 days.
  • the above experimental procedures are described in the instruction manual attached to the genetic manipulation experiment manuals and reagents such as known methods (Sambrook, J. et al, “Molecular Cloning-A Laboratory Manual”, Cold Spring Harabor laboratory, NY, 1989). I followed.
  • Test Example 2 Human 5-HT 5A receptor binding inhibition test (1) were cultured in F500 plates membrane preparation Human 5-HT 5A receptor forced expression HEK293 cells from human 5-HT 5A receptor forced expression HEK293 cells, scraper I've written it. After centrifugation, the precipitate was collected, and incubation buffer (50 mM Tris (HCl) PH7.4, 10 mM MgSO 4 , 0.5 mM EDTA (ethylenediaminetetraacetic acid)) was added. After homogenization, the mixture was further centrifuged, and an incubation buffer was added to the precipitate to suspend well. After repeating this operation, the protein concentration was measured and the membrane preparation was completed.
  • incubation buffer 50 mM Tris (HCl) PH7.4, 10 mM MgSO 4 , 0.5 mM EDTA (ethylenediaminetetraacetic acid)
  • the radioactivity remaining on the GF / C filter plate was measured using a top count.
  • the following table shows the Ki values of some example compounds.
  • Ex indicates an example number, and “-” indicates not evaluated.
  • the compound of formula (I) has 5-HT 5A receptor affinity, and 5-HT 5A receptor than 5-HT 7 receptor which is another 5-HT subtype receptor It has been confirmed that it has excellent subtype selectivity for.
  • Test Example 3 Evaluation of various drugs against a drug that increases mouse momentum (MK-801) (Measurement method of infrared radiation momentum) The improvement effect of the compound of formula (I) on schizophrenia was evaluated by measuring the amount of exercise suppressed under the administration of the compound in a model in which symptoms were induced by MK-801.
  • Animal species Male ICR mouse
  • Operating procedure The animal was removed from the breeding cage, and the test compound was orally administered and placed in the breeding cage. After 30 minutes, the test compound alone was measured for momentum in a measurement cage.
  • the compounds of Examples 32, 39, 42, 62, 63, 85, 106 and 158 caused MK-801-induced overactivity by 1.0 mg / kg, 0.1 mg / kg, 0.3 mg / kg, respectively.
  • the dose was significantly suppressed at 0.3 mg / kg, 0.3 mg / kg, 0.3 mg / kg, 0.03 mg / kg and 0.3 mg / kg. From this, it was confirmed that the compound of Formula (I) has an improvement effect with respect to the increase in exercise amount (overactivity) which is a symptom of schizophrenia.
  • a mouse was placed in one end of a maze (Y-maze) arm with the same length of arm in three directions, and allowed to explore freely for 8 minutes, and the number of entries into the arm during this period was counted. Moreover, the case where it entered into three different arms continuously was made into the spontaneous alternation behavior (Spontaneous alternation behavior), and the ratio with respect to the total number of entries of this behavior number was computed as the spontaneous alternation rate (Alternation rate) by the following formula
  • Spontaneous turnover rate (%) number of spontaneous turnover actions / (total number of entries -2) x 100 (3)
  • Data analysis When a significant difference (Student T test) was found between the normal group and the control group in the spontaneous alternation rate (%), it was judged that learning disability was established by scopolamine administration. The presence or absence of the learning disorder effect of the test compound was determined by conducting a Dunnett test of the test compound administration group with respect to the control group. In each test, p ⁇ 0.10 was a trend, and p ⁇ 0.05 was a significant difference.
  • the compound of the formula (I) suppressed spontaneous alternation behavior of mice induced by scopolamine.
  • the compounds of Examples 39, 62, 63, 85 and 106 show that scopolamine-induced spontaneous alternation behavior was 0.03 mg / kg, 0.03 mg / kg, 0.3 mg / kg, 1.0 mg / kg and 0.01 mg, respectively. It was significantly suppressed at a dose of / kg. Thus, it was confirmed that the compound of formula (I) has an effect on cognitive impairment in dementia and schizophrenia.
  • Test Example 5 Improving effect on disorder of PCP-induced prepulse inhibition (PPI) in rats
  • the ameliorating effect of the compound of formula (I) on schizophrenia is evaluated by a known PCP-induced prepulse inhibition disorder model as a disease state model. be able to. Specifically, the method described in “Neuropsychopharmacology, 1989; 2: 61-66, Mansbach, RS and Geyer, MA” and Brain Research (1998; 781: 227-235) is followed.
  • Test Example 6 Evaluation of Drugs in Water Maze Learning Disorders of Aged Rats The improvement effect of the compound of formula (I) on dementia can be evaluated by a known water maze learning disorder model as a disease state model. Specifically, the method described in “J Pharmacol Exp Ther, 1996; 279: 1157-73, Yamazaki M. et al.” Is followed.
  • Test Example 7 Evaluation of Drug in Forced swimming Test of DBA / 2 Mice
  • the improvement effect of the compound of formula (I) on depression can be evaluated by a known forced swimming test as an evaluation model. Specifically, the method described in “Behav Brain Res. 2005; 156 (1): 153-162, Ducottet C. et al.)” Is followed.
  • Test Example 8 Phototoxic effect evaluation test [Day 1]: Cell culture (96-well plate) 1) Remove BALB / 3T3 from the culture flask and count the number of cells. 2) Adjust the cell concentration to 0.7 ⁇ 10 5 cells / ml and spread 100 ⁇ l / well in a 96-well plate. Add 100 ⁇ l of PBS to each side of the hole that does not cover cells. 3) Incubate in a CO2 incubator for 2 days. [Day 2]: Addition of compound and UV irradiation (non-irradiation) 1) The minimum weight of the test compound is 0.8 mg.
  • MPE is a value indicating a mean photo effect, that is, an average light effect.
  • MPE can be calculated according to Equation 2 in the following document. ATLA (2002), 30, 415-432
  • Test Example 9 Solubility test 1 mL of Japanese Pharmacopoeia disintegration test solution 2 was accurately added to 13 ⁇ L of a 10 mM DMSO solution of a test substance prepared in advance, and shaken at 25 ° C. for 20 hours to obtain a sample stock solution. Next, a sample stock solution of 200 ⁇ L was filtered and moistened in advance, a sample stock solution of 200 ⁇ ⁇ ochL was newly added and filtered, and the resulting solution was used as a sample solution.
  • the inhibitory activity with respect to the CYP1A2 metabolic enzyme was evaluated about some compounds of Formula (I).
  • the CYP1A2 metabolic enzyme inhibitory activities of the compounds of Examples 15, 32, 39, 42, 58, 62, 63, 91, 106 and 158 all have an IC 50 value of 20 ⁇ M or more and do not inhibit the metabolic enzyme. It was confirmed to be a compound.
  • the compound of formula (I) of the present invention is used for the treatment or prevention of diseases involving 5-HT 5A , particularly dementia, schizophrenia (positive symptoms, negative symptoms, cognitive impairment). , Including symptoms such as mood disorder), bipolar disorder, attention deficit / hyperactivity disorder, and mood disorder (anxiety disorder, depressive disorder).
  • Formulations containing one or more of the compounds of formula (I) or salts thereof as active ingredients are generally used methods using pharmaceutical carriers, excipients and the like that are usually used in the art Can be prepared. Administration is orally by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intra-articular, intravenous, intramuscular, suppositories, eye drops, ophthalmic ointments, transdermal solutions, Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.
  • solid composition for oral administration tablets, powders, granules and the like are used.
  • one or more active ingredients are combined with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone. And / or mixed with magnesium aluminate metasilicate.
  • the composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, a stabilizer, and a solubilizing agent according to a conventional method. .
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or contains ethanol.
  • the liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances and preservatives in addition to the inert diluent.
  • Injections for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of the aqueous solvent include distilled water for injection or physiological saline.
  • water-insoluble solvents examples include propylene glycol, polyethylene glycol or vegetable oils such as olive oil, alcohols such as ethanol, or polysorbate 80 (a pharmacopeia name).
  • Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
  • External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like.
  • ointment bases include commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like.
  • ointments or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, etc. Can be mentioned.
  • Transmucosal agents such as inhalants and nasal agents are used in solid, liquid or semi-solid form and can be produced according to conventionally known methods.
  • known excipients, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added.
  • an appropriate device for inhalation or insufflation can be used.
  • a known device such as a metered dose inhalation device or a nebulizer
  • the compound is administered alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. be able to.
  • the dry powder inhaler or the like may be for single or multiple administration, and a dry powder or a powder-containing capsule can be used. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable gas such as a suitable propellant such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.
  • a suitable gas such as a suitable propellant such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.
  • the appropriate daily dose is about 0.0001 to 100 mg / kg, preferably 0.0001 to 10 mg / kg, more preferably 0.0001 to 1 mg / kg per body weight.
  • Administer in 4 to 4 divided doses When administered intravenously, the appropriate daily dosage is about 0.00001 to 1 mg / kg per body weight, and is administered once a day or divided into multiple times.
  • an external preparation or transmucosal agent As an external preparation or transmucosal agent, about 0.0001 to 10 mg / kg per body weight is administered once to several times a day. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like. The content of the active ingredient in the preparation is 0.0001 to 50%, more preferably 0.001 to 50%.
  • the compound of the formula (I) can be used in combination with various therapeutic agents or preventive agents for diseases for which the compound of the formula (I) is considered to be effective.
  • the combination may be administered simultaneously, separately separately, or at desired time intervals.
  • the simultaneous administration preparation may be a combination drug or may be separately formulated.
  • the compound of the formula (I) has an advantage of having a potent 5-HT 5A receptor modulating action and a good pharmacological action based thereon.
  • the pharmaceutical composition of the present invention is used for the treatment or prevention of diseases involving 5-HT 5A receptor, particularly for the treatment or prevention of dementia, schizophrenia, bipolar disorder, attention deficit hyperactivity disorder and mood disorder. Useful.

Abstract

[Problem] To provide an excellent therapeutic or prophylactic agent for dementia, schizophrenia, and the like, which is based on a serotonin 5-HT5A receptor-modulating action. [Solution] The present invention was realized by discovering that an isoquinoline derivative, wherein a ring group is bonded to position 1 of the isoquinoline ring and a ring group or the like is further bonded to position 7 of the isoquinoline ring via a linking group having an amide group, has a potent 5-HT5A receptor-modulating action and an excellent pharmacological action based on that action, and by finding that the derivative is effective as a prophylactic or therapeutic agent for dementia, schizophrenia, and the like.

Description

イソキノリンアミド誘導体Isoquinolinamide derivatives
　本発明は、医薬、殊に5-HT5A受容体調節作用を有し、認知症、統合失調症等の治療又は予防剤として有用なイソキノリンアミド誘導体に関する。 The present invention relates to a pharmaceutical, particularly an isoquinolinamide derivative having a 5-HT 5A receptor modulating action and useful as a therapeutic or prophylactic agent for dementia, schizophrenia and the like.
　近年、セロトニン受容体サブタイプの一つである5-HT5A受容体が、認知症及び統合失調症に重要な役割を果たしていることが示唆されている。例えば、5-HT5A受容体のノックアウトマウスで新規の探索行動が増加することが、また、LSDによる過活動が5-HT5A受容体ノックアウトマウスでは抑制されることが報告されている（Neuron, 22, 581-591, 1999）。遺伝子発現解析の結果から、5-HT5A受容体は、ヒト、げっ歯類の脳で高発現し、脳内では記憶と関わっている海馬のCA1,CA3の錐体細胞で、また、統合失調症とかかわりが深い前頭葉（大脳皮質）で発現が多いことが報告されている（Molecular Brain Research, 56, 1-8, 1998）。更に、5-HT5A受容体の遺伝子多型が統合失調症と関係があることが報告されている（Neuroreport 11, 2017-2020, 2000; Mol. Psychiatr. 6, 217-219, 2001; J. Psychiatr. Res. 38, 371-376, 2004）。このように、5-HT5A受容体の機能を調節すれば認知症及び統合失調症の改善につながることが示唆されており、そのような機能を有する化合物が望まれている。 In recent years, it has been suggested that 5-HT 5A receptor, which is one of serotonin receptor subtypes, plays an important role in dementia and schizophrenia. For example, it is a new exploratory behavior in knockout mice 5-HT 5A receptor increases, also, overactive by LSD is a 5-HT 5A receptor knockout mice have been reported to be inhibited (Neuron, 22, 581-591, 1999). From the results of gene expression analysis, 5-HT 5A receptor is highly expressed in human and rodent brains, and in hippocampal CA1 and CA3 pyramidal cells, which are involved in memory, and schizophrenia It has been reported that there is a lot of expression in the frontal cortex (cerebral cortex) that is deeply related to the disease (Molecular Brain Research, 56, 1-8, 1998). Furthermore, it has been reported that 5-HT 5A receptor polymorphism is associated with schizophrenia (Neuroreport 11, 2017-2020, 2000; Mol. Psychiatr. 6, 217-219, 2001; J. Psychiatr. Res. 38, 371-376, 2004). Thus, it has been suggested that regulating the function of 5-HT 5A receptor leads to improvement of dementia and schizophrenia, and a compound having such a function is desired.
　これまでに、5-HT5A受容体に親和性を有する化合物がいくつか報告されている。
　例えば、下記式(a)で示される三環式化合物が、5-HT5A受容体に結合し、認知症、統合失調症等の治療に用いられることが報告されている（特許文献１）。
Figure JPOXMLDOC01-appb-C000002
 （式中、Aはベンゼン、チオフェン、フラン、シクロへキセン又はテトラヒドロピリジンン環を意味し、Bはベンゼン、シクロへキセン又はテトラヒドロピリジン環を意味する。詳細は当該公報を参照。）
　当該公報は三環式化合物に関し、本発明のイソキノリンアミド誘導体とは異なる。 So far, several compounds having affinity for the 5-HT 5A receptor have been reported.
For example, it has been reported that a tricyclic compound represented by the following formula (a) binds to a 5-HT 5A receptor and is used for the treatment of dementia, schizophrenia and the like (Patent Document 1).
Figure JPOXMLDOC01-appb-C000002
 (In the formula, A means a benzene, thiophene, furan, cyclohexene or tetrahydropyridine ring, and B means a benzene, cyclohexene or tetrahydropyridine ring. For details, see the publication.)
This publication relates to tricyclic compounds and is different from the isoquinolinamide derivatives of the present invention.
　また、下記式(b)で示される二環式アシルグアニジン化合物が、5-HT5A受容体に結合し、認知症、統合失調症等の治療に用いられることが報告されている（特許文献２）。
Figure JPOXMLDOC01-appb-C000003
 （式中、Aはフェニル等を、R1、R2及びR3はH、低級アルキル、ハロゲン等を、R7及びR8はH、低級アルキル等を、XはO、SまたはCR9aR9bを、R9a及びR9bはH等を、点線は結合または不存在を、mは0、1または2を、L1及びL2は結合等を、R4、R5及びR6はH等を、各々示す。詳細は当該公報を参照。）
　当該公報は、二環式環基部分がクロマン又はベンゾチオフェンである化合物に関し、本発明のイソキノリンアミド誘導体とは異なる。 Further, it has been reported that a bicyclic acylguanidine compound represented by the following formula (b) binds to a 5-HT 5A receptor and is used for the treatment of dementia, schizophrenia and the like (Patent Document 2). ).
Figure JPOXMLDOC01-appb-C000003
 (Wherein A is phenyl, R 1 , R 2 and R 3 are H, lower alkyl, halogen, etc., R 7 and R 8 are H, lower alkyl, etc., X is O, S or CR 9a R 9b , R 9a and R 9b are H, etc., dotted line is bonded or absent, m is 0, 1 or 2, L 1 and L 2 are bonded, etc., R 4 , R 5 and R 6 are H (Refer to the publication for details.)
This publication relates to a compound in which the bicyclic ring group moiety is chroman or benzothiophene and is different from the isoquinolinamide derivative of the present invention.
　また、下記式(c)及び(d)で示される、環基で置換されたナフトイルグアニジン化合物が、5-HT5A受容体に結合し、認知症、統合失調症等の治療に有用であることが、それぞれ特許文献３及び特許文献４に開示されている。
Figure JPOXMLDOC01-appb-C000004
 （Aはフェニル、ピリジル等をはじめ種々の環基を示す。詳細は当該公報を参照。）
　当該公報はナフタレン化合物に関するものであり、本発明のイソキノリンアミド誘導体とは異なる。 In addition, a naphthoylguanidine compound substituted with a cyclic group represented by the following formulas (c) and (d) binds to a 5-HT 5A receptor and is useful for the treatment of dementia, schizophrenia and the like. Are disclosed in Patent Document 3 and Patent Document 4, respectively.
Figure JPOXMLDOC01-appb-C000004
 (A represents various ring groups including phenyl, pyridyl, etc. For details, see the publication.)
This publication relates to naphthalene compounds and is different from the isoquinolinamide derivative of the present invention.
また、下記式(e)で示される、環基で置換されたキノリン又はイソキノリン化合物が、5-HT5A受容体に結合し、認知症、統合失調症等の治療に有用であることが、特許文献７に開示されている。
Figure JPOXMLDOC01-appb-C000005
 （式中、Aは環基を示し、Z1, Z2, Z3, Z4 及びZ5の何れか一つが窒素原子であり、他が炭素原子である。詳細は当該公報を参照。）
当該公報はアシルグアニジノ誘導体に関するものであり、本発明のイソキノリンアミド誘導体とは異なる。 In addition, a quinoline or isoquinoline compound substituted with a cyclic group represented by the following formula (e) binds to 5-HT 5A receptor and is useful for the treatment of dementia, schizophrenia, etc. It is disclosed in Document 7.
Figure JPOXMLDOC01-appb-C000005
 (In the formula, A represents a cyclic group, and any one of Z 1 , Z 2 , Z 3 , Z 4 and Z 5 is a nitrogen atom and the other is a carbon atom. For details, refer to the publication.)
This publication relates to acylguanidino derivatives and is different from the isoquinolinamide derivatives of the present invention.
　また、下記式(f)で示されるナフトイルアニジン化合物が、Na+/H+交換抑制剤として、不整脈、狭心症等の治療に用いられることが報告されている（特許文献５）。
Figure JPOXMLDOC01-appb-C000006
 （式中、R1、R3～R8はO、アミド等の結合基を介した種々の置換基、或いはH、アルキル等を意味する。詳細は当該公報を参照。） Further, it has been reported that a naphthoylanidin compound represented by the following formula (f) is used as a Na + / H + exchange inhibitor for the treatment of arrhythmia, angina, etc. (Patent Document 5).
Figure JPOXMLDOC01-appb-C000006
 (In the formula, R1, R3 to R8 mean various substituents through bonding groups such as O and amide, or H, alkyl, etc. For details, refer to the publication.)
　また、下記式(ｇ)で示されるテトラヒドロイソキノリン化合物が、5-HT1B及び5-HT1D受容体調整剤として報告されている（特許文献６）。
Figure JPOXMLDOC01-appb-C000007
 　（式中、R1はアルキル、ハロゲン等を意味し、R2はアリール、ヘテロ環又はカルボキサミドを意味し、Wは-C(O)-、-C(O)NRa-等の連結基を意味し、環Xは置換されていてもよいアリール又は置換されていてもよいヘテロ環を意味する。詳細は当該公報を参照）
　当該公報に開示される化合物は、テトラヒドロイソキノリン誘導体に関し、本発明のイソキノリンアミド誘導体とは異なる。 Further, a tetrahydroisoquinoline compound represented by the following formula (g) has been reported as a 5-HT 1B and 5-HT 1D receptor regulator (Patent Document 6).
Figure JPOXMLDOC01-appb-C000007
 (Wherein R 1 represents alkyl, halogen or the like, R 2 represents aryl, heterocycle or carboxamide, W represents a linking group such as —C (O) — or —C (O) NR a —). Ring X means an optionally substituted aryl or an optionally substituted heterocycle (see the publication for details)
The compound disclosed in the publication relates to a tetrahydroisoquinoline derivative and is different from the isoquinoline amide derivative of the present invention.
　現在までに、5-HT5A受容体調節剤として、イソキノリン環の１位に環基が結合し、７位にアミド基等の結合基を介して更なる環基が結合したイソキノリン誘導体は知られていない。 To date, isoquinoline derivatives in which a ring group is bonded to the 1-position of the isoquinoline ring and a further ring group is bonded to the 7-position via a bonding group such as an amide group have been known as 5-HT 5A receptor modulators. Not.
国際公開第2008/096791号パンフレットInternational Publication No. 2008/096791 Pamphlet 国際公開第2009/022633号パンフレットInternational Publication No. 2009/022633 Pamphlet 国際公開第2010/090304号パンフレットInternational Publication No. 2010/090304 Pamphlet 国際公開第2010/090305号パンフレットInternational Publication No. 2010/090305 Pamphlet EP810206EP810206 国際公開第2003/037887号パンフレットInternational Publication No. 2003/037887 Pamphlet 国際公開第2011/016504号パンフレットInternational Publication No. 2011/016504 Pamphlet
　本発明の課題は、5-HT5A受容体調節作用に基づく、認知症、統合失調症等の優れた治療又は予防剤を提供することにある。 An object of the present invention is to provide an excellent therapeutic or preventive agent for dementia, schizophrenia and the like based on a 5-HT 5A receptor modulating action.
　本発明者等は、5-HT5A受容体調節作用を有する化合物につき鋭意検討した結果、式（I）で示される、イソキノリン環の１位に環基が結合し、７位にアミド基を有する結合基を介して更なる環基等が結合したイソキノリン誘導体が、強力な5-HT5A受容体調節作用と、これに基づく優れた薬理作用を有することを見い出し、認知症、統合失調症等の治療又は予防剤として有用であることを知見して本発明を完成した。
　式（I）の化合物は、イソキノリン環の１位に環基が結合し、７位にアミド基等の結合基を介して更なる環基等が結合することを特徴とするイソキノリンアミド誘導体である。
　即ち、本発明は、式（I）の化合物又はその製薬学的に許容される塩に関する。 As a result of intensive studies on compounds having a 5-HT 5A receptor-modulating activity, the present inventors have shown that the ring group is bonded to the 1-position of the isoquinoline ring represented by the formula (I) and the amide group is located at the 7-position. It was found that isoquinoline derivatives to which a further ring group or the like is bonded via a linking group have a potent 5-HT 5A receptor modulating action and an excellent pharmacological action based on this, such as dementia and schizophrenia. The present invention was completed by discovering that it is useful as a therapeutic or prophylactic agent.
The compound of the formula (I) is an isoquinolinamide derivative characterized in that a ring group is bonded to the 1-position of the isoquinoline ring and a further ring group or the like is bonded to the 7-position via a bonding group such as an amide group. .
That is, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Figure JPOXMLDOC01-appb-C000008
 （式中の記号は以下の意味を示す。
A：アリール、ヘテロアリール又はシクロアルキル、
R1～R3：それぞれ同一又は互いに異なって、H、ハロゲン、ハロゲノ低級アルキル、-CN、-OH、-OR0、-O-(ハロゲノ低級アルキル)、-R00-OH、-R00-OR0、シクロアルキル又は低級アルキレン、
R4：H、ハロゲン、ハロゲノ低級アルキル、R0、-CN、-OH、-OR0、-O-(ハロゲノ低級アルキル)、-R00-OH、-R00-OR0、又はシクロアルキル、
R5：H又はR0、
L：単結合、-R00-O-、-R00-S-、-R00-SO2-、-R00-NH-、-R00-NR0-、シクロアルキレン、又は置換されていてもよい低級アルキレン、
B：-OH、-OR0、-SR0、-N(R0)2、-R00-OR0、-CONH2、又は-CO2R0、或いはそれぞれ置換されていてもよい、ヘテロシクロアルキル、ヘテロアリール、シクロアルキル、又はアリール、
R0：低級アルキル、
R00：低級アルキレン。）
Figure JPOXMLDOC01-appb-C000008
 (The symbols in the formula have the following meanings.
A: aryl, heteroaryl or cycloalkyl,
R 1 ~ R 3: different same or mutually, H, halogen, halogeno lower alkyl, -CN, -OH, -OR 0, -O- ( halogeno-lower alkyl), - R 00 -OH, -R 00 - OR 0 , cycloalkyl or lower alkylene,
R 4: H, halogen, halogeno-lower alkyl, R 0, -CN, -OH, -OR 0, -O- ( halogeno-lower alkyl), - R 00 -OH, -R 00 -OR 0, or cycloalkyl,
R 5 : H or R 0 ,
L: a single bond, -R 00 -O -, - R 00 -S -, - R 00 -SO 2 -, - R 00 -NH -, - R 00 -NR 0 -, cycloalkylene, or substituted May be lower alkylene,
B: -OH, -OR 0 , -SR 0 , -N (R 0 ) 2 , -R 00 -OR 0 , -CONH 2 , or -CO 2 R 0 , or heterocyclo, each of which may be substituted, Alkyl, heteroaryl, cycloalkyl, or aryl,
R 0 : lower alkyl,
R 00 : lower alkylene. )
　式（I）の化合物は、強力な5-HT5A受容体調節作用と、これに基づく良好な薬理作用を有するという利点がある。本発明の医薬組成物は、5-HT5A受容体の関与する疾患の治療又は予防、特に、認知症、統合失調症、双極性障害、注意欠陥多動性障害及び気分障害の治療又は予防に有用である。 The compound of the formula (I) has an advantage of having a potent 5-HT 5A receptor modulating action and a good pharmacological action based thereon. The pharmaceutical composition of the present invention is used for the treatment or prevention of diseases involving 5-HT 5A receptor, particularly for the treatment or prevention of dementia, schizophrenia, bipolar disorder, attention deficit hyperactivity disorder and mood disorder. Useful.
　以下、本発明について詳述する。
　本明細書中、「5-HT5A受容体調節剤」とは、内在性リガンドに拮抗することにより5-HT5A受容体活性化を抑制する化合物（5-HT5A拮抗剤）、並びに5-HT5A受容体の活性化により作用を発現する化合物（5-HT5A作動剤）の総称である。「5-HT5A受容体調節剤」のある態様としては、例えば5-HT5A拮抗剤である。
　「低級アルキル」とは、直鎖または分枝状の、炭素数が１から６（以後、C1-6と略す）のアルキル基を意味し、具体的には、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、sec-ブチル、tert-ブチル、n-ペンチル、n-ヘキシル基等である。別の態様としては、C1-4アルキルであり、さらに別の態様としては、メチル、エチル、又はn-プロピルである。
　「低級アルキレン」とは、上記低級アルキルから任意の水素原子を除去して形成される二価基の置換基を意味する。ある態様としてはメチレン、エチレン、1,2-プロピレン、又はトリメチレンであり、別の態様としてはメチレン、エチレン又はトリメチレンであり、また別の態様としてはメチレン又はエチレンである。
　「ハロゲン」とは、F、Cl、Br、Iを意味する。ある態様としてはF又はClである。
　「ハロゲノ低級アルキル」とは、１以上のハロゲン、例えばF又はClで置換された低級アルキルを意味し、ある態様としては、トリフルオロメチル又はジフルオロメチルである。
　「アリール」とは、C6-14の単環乃至三環式芳香族炭化水素環基であり、ある態様としてはフェニル又はナフチルであり、別の態様としてはフェニルである。
　「ヘテロアリール」とは、環を形成する原子として、O、N、及びSから選択されるヘテロ原子を１～５個有する、５～１４員環の、別の態様としては５～１０員環の、単環～三環式、別の態様としては単環～二環式芳香族性環基であり、縮合していてもよい。ある態様としては、５～６員環の単環式ヘテロアリールであり、例えば、ピリジル、ピリミジニル、ピリダジニル、ピロリル、イミダゾリル、チアゾリル、オキサジアゾリル等である。これらのうち、環を構成する原子として窒素原子を有するものを「単環式含窒素ヘテロアリール」とする。また別の態様としては９～１０員環の二環式ヘテロアリールであり、例えば、キノリル、イソキノリル、ベンゾイミダゾリル、ベンゾオキサゾリル、ベンゾチアゾリル等である。
　「シクロアルキル」とは、C3-10の飽和炭化水素環基であり、架橋又は縮合を有していてもよい。具体的には、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、アダマンチル基等であり、別の態様としては、C3-6シクロアルキル基であり、更に別の態様としては、C3-7シクロアルキル基であり、更に別の態様としては、シクロプロピル又はシクロブチルである。また、縮合する環としては５～６員環性の単環式ヘテロアリールである。
　「ヘテロシクロアルキル」とは、環を構成する原子として１～６個のヘテロ原子を有する、飽和又は一部不飽和の３～１４員環の環基であり、架橋及び/又は縮環していてもよい。ある態様としては、O、N、又はSから選択されるヘテロ原子を１～４個有する単環式ヘテロシクロアルキルであり、例えば、アセチジニル、ピロリジル、ピペリジル、ピペラジル、ピラニル、モルホリル、チオピラニル等である。これらのうち、環を構成する原子として窒素原子を有する単環式のものを「単環式含窒素ヘテロシクロアルキル」とする。また、別の態様としては、O、N、又はSから選択されるヘテロ原子を１～４個有する単環式ヘテロシクロアルキルがベンゼン環と縮合した二環式環基であり、例えば、ベンゾピラン-2-イル、ベンゾピラン-3-ニイル、ベンゾピラン-4-イルである。また、更に別の態様としては、架橋したヘテロシクロアルキル基であり、例えばキヌクリジル又は8-アザビシクロ［3.2.1］オクト-3-イルである。 Hereinafter, the present invention will be described in detail.
In the present specification, the term “5-HT 5A receptor modulator” refers to a compound that suppresses 5-HT 5A receptor activation by antagonizing an endogenous ligand (5-HT 5A antagonist), and 5- It is a general term for compounds (5-HT 5A agonists) that exert their actions by activating the HT 5A receptor. An embodiment of the “5-HT 5A receptor modulator” is, for example, a 5-HT 5A antagonist.
“Lower alkyl” means a linear or branched alkyl group having 1 to 6 carbon atoms (hereinafter abbreviated as C 1-6 ), specifically, methyl, ethyl, n-propyl. Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl group and the like. Another embodiment is C 1-4 alkyl, and yet another embodiment is methyl, ethyl, or n-propyl.
The “lower alkylene” means a divalent substituent formed by removing any hydrogen atom from the lower alkyl. In one embodiment, methylene, ethylene, 1,2-propylene, or trimethylene is used. In another embodiment, methylene, ethylene, or trimethylene is used. In another embodiment, methylene or ethylene is used.
“Halogen” means F, Cl, Br, I. One embodiment is F or Cl.
“Halogeno lower alkyl” means lower alkyl substituted with one or more halogens, such as F or Cl, and in some embodiments is trifluoromethyl or difluoromethyl.
The “aryl” is a C 6-14 monocyclic to tricyclic aromatic hydrocarbon ring group, and in one embodiment, phenyl or naphthyl, and in another embodiment, phenyl.
“Heteroaryl” is a 5- to 14-membered ring having 1 to 5 heteroatoms selected from O, N and S as atoms forming the ring, and in another embodiment, a 5- to 10-membered ring. These are monocyclic to tricyclic, and in another embodiment are monocyclic to bicyclic aromatic ring groups, which may be condensed. One embodiment is a 5- to 6-membered monocyclic heteroaryl, such as pyridyl, pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl, thiazolyl, oxadiazolyl and the like. Among these, those having a nitrogen atom as a ring-constituting atom are referred to as “monocyclic nitrogen-containing heteroaryl”. Another embodiment is a 9-10 membered bicyclic heteroaryl, such as quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl and the like.
“Cycloalkyl” is a C 3-10 saturated hydrocarbon ring group, which may be bridged or condensed. Specifically, it is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl group or the like, and as another aspect, a C 3-6 cycloalkyl group, and as another aspect, C A 3-7 cycloalkyl group, and in yet another embodiment, cyclopropyl or cyclobutyl. The condensed ring is a 5- to 6-membered monocyclic heteroaryl.
“Heterocycloalkyl” is a saturated or partially unsaturated 3- to 14-membered ring group having 1 to 6 heteroatoms as atoms constituting the ring, and is bridged and / or condensed. May be. An embodiment is a monocyclic heterocycloalkyl having 1 to 4 heteroatoms selected from O, N, or S, such as acetylidinyl, pyrrolidyl, piperidyl, piperazyl, pyranyl, morpholyl, thiopyranyl, etc. . Among these, the monocyclic thing which has a nitrogen atom as an atom which comprises a ring is set as "monocyclic nitrogen-containing heterocycloalkyl." Another embodiment is a bicyclic ring group in which a monocyclic heterocycloalkyl having 1 to 4 heteroatoms selected from O, N, or S is condensed with a benzene ring, such as benzopyran- 2-yl, benzopyran-3-niyl and benzopyran-4-yl. Yet another embodiment is a bridged heterocycloalkyl group such as quinuclidyl or 8-azabicyclo [3.2.1] oct-3-yl.
　「置換されていてもよい」とは、無置換、若しくは置換基を１～５個有していることを意味する。ある態様としては無置換又は置換基が１～２個であり、別の態様としては置換基が１個であり、また別の態様としては置換基が２個である。複数の置換基を有する場合、それらの置換基は同一であっても、互いに異なっていてもよい。 “It may be substituted” means unsubstituted or having 1 to 5 substituents. In one embodiment, there are 1 to 2 unsubstituted or substituted groups, in another embodiment, one substituent, and in another embodiment, two substituents. When it has a plurality of substituents, these substituents may be the same or different from each other.
　「置換されていてもよい低級アルキレン」における置換基としては、-OH、-OR0、-N(R0)2、-CO2H、-CO2R0、-CN、フェニル、シクロプロピル、及びオキソからなる群より選択される基であり、別の態様としては、-OH、-N(R0)2、-CN、シクロプロピル、及びオキソからなる群より選択される基であり、また別の態様としては-OHである。ある態様としては、無置換であり、別の態様としては置換基は１又は２個であり、別の態様としては置換基は１個であり、また別の態様としては置換基は２個である。置換基が２個の場合、これらは互いに同一又は異なってもよい。 Examples of the substituent in the “optionally substituted lower alkylene” include —OH, —OR 0 , —N (R 0 ) 2 , —CO 2 H, —CO 2 R 0 , —CN, phenyl, cyclopropyl, And another group selected from the group consisting of —OH, —N (R 0 ) 2 , —CN, cyclopropyl, and oxo, and Another embodiment is -OH. In one embodiment, it is unsubstituted, in another embodiment, 1 or 2 substituents, in another embodiment, 1 substituent, and in another embodiment, 2 substituents. is there. When there are two substituents, these may be the same or different from each other.
　また、「それぞれ置換されていてもよい、ヘテロシクロアルキル、ヘテロアリール、シクロアルキル、又はアリール」、「それぞれ置換されていてもよい、ヘテロシクロアルキル又はヘテロアリール」、「それぞれ置換されていてもよい、単環式含窒素ヘテロシクロアルキル又は単環式含窒素ヘテロアリール」、「それぞれ置換されていてもよい、フェニル、ピペリジル、イミダゾリル又はピリジル」、及び「置換されていてもよいピペリジル」における置換基としては、-R0、-R00-OH、-R00-OR0、-R00-CN、-R00-N(R0)2、-R00-COR0、-R00-CONH2、-COR0、-CO2H、-CO2R0、-CONH2、-CN、-OH、-OR0、-NH2、-SR0、ハロゲン、-R00-(フェニル)、ハロゲノ低級アルキル、C3-6シクロアルキル、-R00-(C3-6シクロアルキル)、-CO-(C3-6シクロアルキル)、-R00-(モルホリル)、テトラヒドロフリル、-R00-(ピペリジル)、ピロリジル、ピペリジル、-R00-(ピリジル)及びピリミジニルからなる群より選択される基である。ある態様としては、１～２個の置換基であり、別の態様としては１個の置換基であり、また別の態様としては２個の置換基である。置換基が２個の場合、これらは互いに同一又は異なってもよい。 Further, “optionally substituted heterocycloalkyl, heteroaryl, cycloalkyl, or aryl”, “optionally substituted, heterocycloalkyl or heteroaryl”, “optionally substituted, respectively” , "Monocyclic nitrogen-containing heterocycloalkyl or monocyclic nitrogen-containing heteroaryl", "optionally substituted phenyl, piperidyl, imidazolyl or pyridyl", and "optionally substituted piperidyl" -R 0 , -R 00 -OH, -R 00 -OR 0 , -R 00 -CN, -R 00 -N (R 0 ) 2 , -R 00 -COR 0 , -R 00 -CONH 2 , -COR 0 , -CO 2 H, -CO 2 R 0 , -CONH 2 , -CN, -OH, -OR 0 , -NH 2 , -SR 0 , halogen, -R 00- (phenyl), halogeno lower Alkyl, C 3-6 cycloalkyl, -R 00- (C 3-6 cycloalkyl), -CO- (C 3-6 cycloalkyl), -R 00- It is a group selected from the group consisting of (morpholyl), tetrahydrofuryl, -R 00- (piperidyl), pyrrolidyl, piperidyl, -R 00- (pyridyl) and pyrimidinyl. In one embodiment, there are 1 to 2 substituents, in another embodiment, 1 substituent, and in another embodiment, 2 substituents. When there are two substituents, these may be the same or different from each other.
　本発明は以下を包含する。
（Ａ）Aが、アリール、ヘテロアリール又はシクロアルキルであり、
R1～R3が、それぞれ同一又は互いに異なって、H、ハロゲン、ハロゲノ低級アルキル、-O-(低級アルキル)、又は低級アルキルであり、
R4が、H、ハロゲン、ハロゲノ低級アルキル、低級アルキル、-O-(低級アルキル)、又はシクロアルキルであり、
R5が、H、又は低級アルキルであり、
Lが、単結合、低級アルキレン、-(低級アルキレン)-O-、-(低級アルキレン)-S-、-(低級アルキレン)-NH-、-(低級アルキレン)-NR0-、-(低級アルキレン)-SO2-、シクロアルキレン、又は置換されていてもよい低級アルキレンであり、
Bが、-OH、-OR0、-SR0、-N(R0)2、-R00-OR0、-CONH2、又は-CO2R0、或いはそれぞれ置換されていてもよい、ヘテロシクロアルキル、ヘテロアリール、シクロアルキル、又はアリール、
である、式（I）の化合物又はその製薬学的に許容される塩。
（Ｂ）Lが、単結合、シクロアルキレン又は置換されていてもよい低級アルキレンである、式（I）の化合物又はその製薬学的に許容される塩。
（Ｃ）Lが、-R00-O-、-R00-S-、-R00-NH-、-R00-NR0-又は-R00-SO2-であり、Bが、-R00-OR0、-CONH2又は-CO2R0、或いはそれぞれ置換されていてもよい、ヘテロシクロアルキル、ヘテロアリール、シクロアルキル又はアリールである、式（I）の化合物又はその製薬学的に許容される塩。 The present invention includes the following.
(A) A is aryl, heteroaryl or cycloalkyl;
R 1 to R 3 are the same or different from each other, and are H, halogen, halogeno lower alkyl, -O- (lower alkyl), or lower alkyl;
R 4 is H, halogen, halogeno lower alkyl, lower alkyl, -O- (lower alkyl), or cycloalkyl;
R 5 is H or lower alkyl,
L is a single bond, lower alkylene,-(lower alkylene) -O-,-(lower alkylene) -S-,-(lower alkylene) -NH-,-(lower alkylene) -NR 0 -,-(lower alkylene) ) —SO 2 —, cycloalkylene, or optionally substituted lower alkylene,
B is -OH, -OR 0 , -SR 0 , -N (R 0 ) 2 , -R 00 -OR 0 , -CONH 2 , or -CO 2 R 0 , or each optionally substituted hetero Cycloalkyl, heteroaryl, cycloalkyl, or aryl,
A compound of formula (I) or a pharmaceutically acceptable salt thereof.
(B) A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein L is a single bond, cycloalkylene or optionally substituted lower alkylene.
(C) L is, -R 00 -O -, - R 00 -S -, - R 00 -NH -, - R 00 -NR 0 - or -R 00 -SO 2 - and is, B is, -R 00 —OR 0 , —CONH 2 or —CO 2 R 0 , or each optionally substituted heterocycloalkyl, heteroaryl, cycloalkyl or aryl, a compound of formula (I) or a pharmaceutically acceptable salt thereof Acceptable salt.
　また本発明は以下を包含する。
（１）Aが、フェニル、ピリジル又はC3-7シクロアルキルであり、ある態様としてはフェニルであり、別の態様としては単環式含窒素ヘテロアリールであり、更に別の態様としてはピリジルであり、また更に別の態様としてはC3-7シクロアルキルである、式（I）の化合物。
（２）R1～R3がそれぞれ同一又は互いに異なって、ある態様としてはハロゲン又はHであり、別の態様としてはF、Cl及びHから選択される基であり、また別の態様としてはF又はHである、式（I）の化合物。
（３）R4が、ハロゲン、C1-3アルキル、-O-(C1-3アルキル)又はシクロプロピルであり、ある態様としてはF又はClであり、別の態様としては低級アルキルであり、更に別の態様としてはメチル又はエチルである、式（I）の化合物。ここでR4の置換位置は、ある態様としてはイソキノリン環の4位である。
（４）R5が、Hである、式（I）の化合物。
（５）Lが、単結合又は低級アルキレンであり、ある態様としては単結合であり、また別の態様としては、単結合、メチレン、エチレン又はトリメチレンである、式（I）の化合物。また別の態様としては、Lが、-OHで置換されていてもよいエチレンである、式（I）の化合物。
（６）Bが、それぞれ置換されていてもよい、ヘテロシクロアルキル又はヘテロアリールであり、別の態様としてはそれぞれ置換されていてもよい、単環式含窒素ヘテロシクロアルキル又は単環式含窒素ヘテロアリールであり、更に別の態様としてはそれぞれ置換されていてもよい、フェニル、ピペリジル、イミダゾリル又はピリジルであり、更に別の態様としては置換されていてもよいピペリジルである、式（I）の化合物。また別の態様としては、Bが、-R0、-R00-OH、-R00-OR0、-R00-CN、-R00-N(R0)2、-COR0、-CO2R0、-CONH2、-CN、-OH、-OR0、-NH2、-SR0、ハロゲン、-R00-(フェニル)、ハロゲノ低級アルキル、シクロアルキル、-R00-(シクロプロピル)、-R00-(シクロヘキシル)、-CO-(シクロプロピル)、-R00-(モルホリル)、-R00-(ピペリジル)、ピロリジル、ピペリジル、-R00-(ピリジル)、及びピリミジニルからなる群より選択される基でそれぞれ置換されていてもよい、単環式含窒素ヘテロシクロアルキル又は単環式含窒素ヘテロアリールであり、また別の態様としては、Bが、-R0、-R00-OH、-R00-OR0、-R00-CN、-R00-N(R0)2、-R00-COR0、-R00-CONH2、-COR0、-CO2H、-CO2R0、-CONH2、-CN、-OH、-OR0、-NH2、-SR0、ハロゲン、-R00-(フェニル)、ハロゲノ低級アルキル、C3-6シクロアルキル、-R00-(C3-6シクロアルキル)、-CO-(C3-6シクロアルキル)、-R00-(モルホリル)、テトラヒドロフリル、-R00-(ピペリジル)、ピロリジル、ピペリジル、-R00-(ピリジル)及びピリミジニルからなる群より選択される基でそれぞれ置換されていてもよい、単環式含窒素ヘテロシクロアルキル又は単環式含窒素ヘテロアリールであり、また別の態様としては、Bが、-R0、-R00-NH2及び-R00-OHから選択される基でそれぞれ置換されていてもよい、単環式含窒素ヘテロシクロアルキル又は単環式含窒素ヘテロアリールであり、別の態様としては、-R0、-R00-NH2、-R00-OH及び-R00-OR0から選択される基でそれぞれ置換されていてもよい、フェニル、ピペリジル、イミダゾリル、又はピリジルであり、また別の態様としては、-R0、-R00-NH2、-R00-OH及び-R00-OR0から選択される基でそれぞれ置換されていてもよい、フェニル、ピペリジル、キヌクリジル、イミダゾリル、又はピリジルであり、また別の態様としては、-R0、-R00-CO-NH2及び-R00-OR0から選択される基でそれぞれ置換されていてもよいピペリジルであり、また別の態様としてはイミダゾリルである、式(I)の化合物。 Moreover, this invention includes the following.
(1) A is phenyl, pyridyl or C 3-7 cycloalkyl, and in one embodiment, phenyl, in another embodiment, monocyclic nitrogen-containing heteroaryl, and in another embodiment, pyridyl. And yet another embodiment is a compound of formula (I), which is C 3-7 cycloalkyl.
(2) R 1 to R 3 are the same or different from each other, and in one embodiment, are halogen or H, in another embodiment, a group selected from F, Cl and H, and in another embodiment, A compound of formula (I) which is F or H.
(3) R 4 is halogen, C 1-3 alkyl, —O— (C 1-3 alkyl) or cyclopropyl, and in one embodiment, F or Cl, and in another embodiment, lower alkyl. In yet another embodiment, the compound of formula (I) is methyl or ethyl. Here, the substitution position of R 4 is, in one embodiment, the 4-position of the isoquinoline ring.
(4) The compound of formula (I), wherein R 5 is H.
(5) The compound of the formula (I), wherein L is a single bond or lower alkylene, and in one embodiment is a single bond, and in another embodiment, is a single bond, methylene, ethylene or trimethylene. In another embodiment, the compound of formula (I), wherein L is ethylene optionally substituted with -OH.
(6) B is an optionally substituted heterocycloalkyl or heteroaryl, and in another embodiment, each may be substituted, a monocyclic nitrogen-containing heterocycloalkyl or monocyclic nitrogen-containing In the formula (I), which is heteroaryl, and in yet another embodiment is phenyl, piperidyl, imidazolyl or pyridyl, which may each be substituted, and in another embodiment is optionally substituted piperidyl Compound. In another embodiment, B is -R 0 , -R 00 -OH, -R 00 -OR 0 , -R 00 -CN, -R 00 -N (R 0 ) 2 , -COR 0 , -CO 2 R 0 , -CONH 2 , -CN, -OH, -OR 0 , -NH 2 , -SR 0 , halogen, -R 00- (phenyl), halogeno lower alkyl, cycloalkyl, -R 00- (cyclopropyl ), - R 00 - (cyclohexyl), - CO- (cyclopropyl), - R 00 - (morpholyl), - R 00 - (piperidyl), pyrrolidyl, piperidyl, -R 00 - (pyridyl), and pyrimidinyl A monocyclic nitrogen-containing heterocycloalkyl or monocyclic nitrogen-containing heteroaryl, each optionally substituted with a group selected from the group, and in another embodiment, B is -R 0 , -R 00 -OH, -R 00 -OR 0 , -R 00 -CN, -R 00 -N (R 0 ) 2 , -R 00 -COR 0 , -R 00 -CONH 2 , -COR 0 , -CO 2 H , -CO 2 R 0 , -CONH 2 , -CN, -OH, -OR 0 , -NH 2 , -SR 0 , halogen, -R 00- (phenyl), halogeno lower alkyl, C 3 -6 cycloalkyl, -R 00 - (C 3-6 cycloalkyl), - CO- (C 3-6 cycloalkyl), - R 00 - (morpholyl), tetrahydrofuryl, -R 00 - (piperidyl), pyrrolidyl A monocyclic nitrogen-containing heterocycloalkyl or a monocyclic nitrogen-containing heteroaryl, each of which may be substituted with a group selected from the group consisting of, piperidyl, -R 00- (pyridyl) and pyrimidinyl; In an embodiment of the present invention, B is a monocyclic nitrogen-containing heterocycloalkyl or monocyclic, each of which may be substituted with a group selected from -R 0 , -R 00 -NH 2 and -R 00 -OH Nitrogen-containing heteroaryl, and in another embodiment, each may be substituted with a group selected from -R 0 , -R 00 -NH 2, -R 00 -OH and -R 00 -OR 0 , Phenyl, piperidyl, imidazolyl, or pyridyl. In another embodiment, -R 0 , -R 00 -NH 2, -R 00 Phenyl, piperidyl, quinucidyl, imidazolyl, or pyridyl each optionally substituted with a group selected from -OH and -R 00 -OR 0 , and in another embodiment, -R 0 , -R 00 A compound of formula (I) which is piperidyl optionally substituted with a group selected from -CO-NH 2 and -R 00 -OR 0 , and in another embodiment is imidazolyl.
　また、本発明は上記（１）～（６）及び（Ａ）～（Ｃ）に示す置換基の態様を任意に組み合わせた化合物をも包含し、例えば、以下の化合物を包含する。
（７）Aがフェニル、ピリジル又はC3-7シクロアルキルであり、R1～R3が、それぞれ同一又は互いに異なってF、Cl及びHから選択される基であり、R4がハロゲン、C1-3アルキル、-O-(C1-3アルキル)又はシクロプロピルであり、R5がHであり、Lが単結合又は低級アルキレンであり、Bが低級アルキル、-R00-NH2及び-R00-OHから選択される基でそれぞれ置換されていてもよい、単環式含窒素ヘテロシクロアルキル又は単環式含窒素ヘテロアリールである、式（I）の化合物。
（８）Aがフェニルであり、R1～R3がF又はHであり、R4がF又はClであり、R5がHであり、Lが単結合、メチレン、エチレン又はトリメチレンであり、Bが低級アルキル、-R00-NH2、-R00-OH及び-R00-OR0から選択される基でそれぞれ置換されていてもよい、フェニル、ピペリジル、イミダゾリル、又はピリジルである、式（I）の化合物。
（９）Aがフェニルであり、R1～R3がF又はHであり、R4がF又はClであり、R5がHであり、Lが単結合、メチレン、エチレン又はトリメチレンであり、Bが低級アルキル、-R00-NH2、-R00-OH及び-R00-OR0から選択される基でそれぞれ置換されていてもよい、フェニル、ピペリジル、キヌクリジル、イミダゾリル、又はピリジルである、式（I）の化合物。
（１０）Aがフェニルであり、R1～R3がF又はHであり、R4がCl又はメチルであり、R5がHであり、Lが単結合であり、Bが、低級アルキル、-R00-CO-NH2及び-R00-OR0から選択される基でそれぞれ置換されていてもよいピペリジルである、式（I）の化合物。
（１１）Aがフェニルであり、R1～R3がF又はHであり、R4がClであり、R5がHであり、Lが-OHで置換されていてもよいエチレンであり、Bがイミダゾリルである、式（I）の化合物。
（１２）以下の化合物群から選択される化合物、又はその製薬学的に許容される塩。
4-クロロ-N-(1-メチルピペリジン-4-イル)-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド、
N-[1-(2-アミノ-2-オキソエチル)ピペリジン-4-イル]-4-クロロ-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド、
4-クロロ-N-(1-プロピルピペリジン-4-イル)-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド、
4-メチル-N-(1-メチルピペリジン-4-イル)-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド、
4-クロロ-1-(2,6-ジフルオロフェニル)-N-(1-イソプロピルピペリジン-4-イル)イソキノリン-7-カルボキサミド、
4-クロロ-N-(1-エチルピペリジン-4-イル)-1-(2-フルオロフェニル)イソキノリン-7-カルボキサミド、
4-クロロ-1-(2-フルオロフェニル)-N-(1-メチルピペリジン-4-イル)イソキノリン-7-カルボキサミド、
4-メチル-N-(1-プロピルピペリジン-4-イル)-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド、
4-クロロ-N-(1-メチルピペリジン-4-イル)-1-フェニルイソキノリン-7-カルボキサミド
N-[1-(2-アミノ-2-オキソエチル)ピペリジン-4-イル]-4-メチル-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド、
4-クロロ-1-(2,4-ジフルオロフェニル)-N-(1-メチルピペリジン-4-イル)-イソキノリン-7-カルボキサミド、
4-クロロ-N-[1-(2-メトキシエチル)ピペリジン-4-イル]-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド、
4-クロロ-N-[2-(1H-イミダゾール-2-イル)エチル]-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド、及び
4-クロロ-N-[2-ヒドロキシ-2-(1H-イミダゾール-2-イル)エチル]-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド。 In addition, the present invention includes compounds in which the embodiments of the substituents shown in the above (1) to (6) and (A) to (C) are arbitrarily combined, for example, the following compounds.
(7) A is phenyl, pyridyl or C 3-7 cycloalkyl, R 1 to R 3 are the same or different from each other and are selected from F, Cl and H, R 4 is halogen, C 1-3 alkyl, —O— (C 1-3 alkyl) or cyclopropyl, R 5 is H, L is a single bond or lower alkylene, B is lower alkyl, —R 00 —NH 2 and A compound of formula (I) which is a monocyclic nitrogen-containing heterocycloalkyl or monocyclic nitrogen-containing heteroaryl, each optionally substituted with a group selected from -R 00 -OH.
(8) A is phenyl, R 1 to R 3 are F or H, R 4 is F or Cl, R 5 is H, L is a single bond, methylene, ethylene or trimethylene, B is phenyl, piperidyl, imidazolyl, or pyridyl, each optionally substituted with a group selected from lower alkyl, -R 00 -NH 2, -R 00 -OH and -R 00 -OR 0 Compound (I).
(9) A is phenyl, R 1 to R 3 are F or H, R 4 is F or Cl, R 5 is H, L is a single bond, methylene, ethylene or trimethylene, B is phenyl, piperidyl, quinucidyl, imidazolyl, or pyridyl, each optionally substituted with a group selected from lower alkyl, -R 00 -NH 2, -R 00 -OH and -R 00 -OR 0 A compound of formula (I).
(10) A is phenyl, R 1 to R 3 are F or H, R 4 is Cl or methyl, R 5 is H, L is a single bond, B is lower alkyl, A compound of formula (I) which is piperidyl optionally substituted with a group selected from -R 00 -CO-NH 2 and -R 00 -OR 0 .
(11) A is phenyl, R 1 to R 3 are F or H, R 4 is Cl, R 5 is H, and L is ethylene that may be substituted with -OH; A compound of formula (I) wherein B is imidazolyl.
(12) A compound selected from the following compound group, or a pharmaceutically acceptable salt thereof.
4-chloro-N- (1-methylpiperidin-4-yl) -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide,
N- [1- (2-amino-2-oxoethyl) piperidin-4-yl] -4-chloro-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide,
4-chloro-N- (1-propylpiperidin-4-yl) -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide,
4-methyl-N- (1-methylpiperidin-4-yl) -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide,
4-chloro-1- (2,6-difluorophenyl) -N- (1-isopropylpiperidin-4-yl) isoquinoline-7-carboxamide,
4-chloro-N- (1-ethylpiperidin-4-yl) -1- (2-fluorophenyl) isoquinoline-7-carboxamide,
4-chloro-1- (2-fluorophenyl) -N- (1-methylpiperidin-4-yl) isoquinoline-7-carboxamide,
4-methyl-N- (1-propylpiperidin-4-yl) -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide,
4-Chloro-N- (1-methylpiperidin-4-yl) -1-phenylisoquinoline-7-carboxamide
N- [1- (2-amino-2-oxoethyl) piperidin-4-yl] -4-methyl-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide,
4-chloro-1- (2,4-difluorophenyl) -N- (1-methylpiperidin-4-yl) -isoquinoline-7-carboxamide,
4-chloro-N- [1- (2-methoxyethyl) piperidin-4-yl] -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide,
4-chloro-N- [2- (1H-imidazol-2-yl) ethyl] -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide, and
4-Chloro-N- [2-hydroxy-2- (1H-imidazol-2-yl) ethyl] -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide.
　また更に、本願は以下の（１３）～（２６）をも包含する。
（１３）前記式(I)の化合物又はその製薬学的に許容される塩及び製薬学的に許容される賦形剤を含有する医薬組成物。
（１４）5-HT5A受容体調節剤である、上記（１３）の医薬組成物。
（１５）認知症、統合失調症、双極性障害、又は注意欠陥多動性障害の治療又は予防用である上記（１３）の医薬組成物。
（１６）認知症又は統合失調症の予防又は治療用である上記（１３）の医薬組成物。
（１７）前記式（I）の化合物又はその製薬学的に許容される塩を有効成分とする、認知症、統合失調症、双極性障害、又は注意欠陥多動性障害の予防又は治療剤。
（１８）前記式（I）の化合物又はその製薬学的に許容される塩を有効成分とする、認知症又は統合失調症の予防又は治療剤。
（１９）認知症、統合失調症、双極性障害、又は注意欠陥多動性障害の予防又は治療剤の製造のための前記式（I）の化合物又はその製薬学的に許容される塩の使用。
（２０）認知症又は統合失調症の予防又は治療剤の製造のための前記式（I）の化合物又はその製薬学的に許容される塩の使用。
（２１）認知症、統合失調症、双極性障害、又は注意欠陥多動性障害の予防又は治療のための前記式（I）の化合物又はその製薬学的に許容される塩の使用。
（２２）認知症又は統合失調症の予防又は治療のための前記式（I）の化合物又はその製薬学的に許容される塩の使用。
（２３）認知症、統合失調症、双極性障害、又は注意欠陥多動性障害の予防又は治療のための前記式（I）の化合物又はその製薬学的に許容される塩。
（２４）認知症又は統合失調症の予防又は治療のための前記式（I）の化合物又はその製薬学的に許容される塩。
（２５）前記式(I)の化合物又はのその製薬学的に許容される塩の治療有効量を哺乳動物に投与することからなる、認知症、統合失調症、双極性障害、注意欠陥多動性障害の予防又は治療方法。
（２６）前記式(I)の化合物又はその製薬学的に許容される塩の治療有効量を哺乳動物に投与することからなる、認知症又は統合失調症の予防又は治療方法。 Furthermore, the present application includes the following (13) to (26).
(13) A pharmaceutical composition comprising the compound of the above formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
(14) The pharmaceutical composition according to the above (13), which is a 5-HT 5A receptor modulator.
(15) The pharmaceutical composition according to the above (13), which is used for treatment or prevention of dementia, schizophrenia, bipolar disorder, or attention deficit hyperactivity disorder.
(16) The pharmaceutical composition according to the above (13), which is used for prevention or treatment of dementia or schizophrenia.
(17) A preventive or therapeutic agent for dementia, schizophrenia, bipolar disorder, or attention deficit / hyperactivity disorder, comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
(18) A preventive or therapeutic agent for dementia or schizophrenia comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
(19) Use of the compound of the above formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a preventive or therapeutic agent for dementia, schizophrenia, bipolar disorder, or attention deficit hyperactivity disorder .
(20) Use of the compound of the above formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a preventive or therapeutic agent for dementia or schizophrenia.
(21) Use of the compound of the above formula (I) or a pharmaceutically acceptable salt thereof for the prevention or treatment of dementia, schizophrenia, bipolar disorder, or attention deficit hyperactivity disorder.
(22) Use of the compound of the above formula (I) or a pharmaceutically acceptable salt thereof for the prevention or treatment of dementia or schizophrenia.
(23) The compound of the above formula (I) or a pharmaceutically acceptable salt thereof for the prevention or treatment of dementia, schizophrenia, bipolar disorder, or attention deficit hyperactivity disorder.
(24) The compound of the above formula (I) or a pharmaceutically acceptable salt thereof for the prevention or treatment of dementia or schizophrenia.
(25) Dementia, schizophrenia, bipolar disorder, attention deficit hyperactivity comprising administering to a mammal a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof. How to prevent or treat sexual disorders.
(26) A method for preventing or treating dementia or schizophrenia, comprising administering to a mammal a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
　上記の統合失調症には陽性症状、陰性症状、認知障害、及び気分障害が含まれる。 The above schizophrenia includes positive symptoms, negative symptoms, cognitive impairment, and mood disorders.
　式（I）の化合物には、置換基の種類によっては他の互変異性体や配座異性体、又は光学異性体が存在する場合もある。本明細書中、それら異性体の一形態のみで記載することがあるが、本発明はこれらの異性体も包含し、異性体の分離したもの、或いは混合物も包含する。 In the compound of the formula (I), other tautomers, conformers, or optical isomers may exist depending on the type of substituent. In the present specification, only one form of these isomers may be described, but the present invention also includes these isomers, and also includes separated isomers or mixtures thereof.
　更に、本発明には、式（I）の化合物の製薬学的に許容されるプロドラッグも含まれる。製薬学的に許容されるプロドラッグとは、加溶媒分解によりまたは生理学的条件下でアミノ基、OH、CO2H等に変換できる基を有する化合物である。プロドラッグを形成する基としては、例えば、Prog. Med., 5, 2157-2161 (1985)や「医薬品の開発」（廣川書店、1990年）第７巻　分子設計163-198に記載の基が挙げられる。 Furthermore, the present invention includes pharmaceutically acceptable prodrugs of the compound of formula (I). Pharmaceutically acceptable prodrugs are compounds having groups that can be converted to amino groups, OH, CO 2 H, etc. by solvolysis or under physiological conditions. Examples of groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) and “Development of Pharmaceuticals” (Yodogawa Shoten, 1990), Volume 7, Molecular Design 163-198. Can be mentioned.
　また、式（I）の化合物は、酸付加塩、又は置換基の種類によっては塩基との塩を形成する場合もあり、かかる塩が製薬学的に許容され得る塩である限りにおいて本発明に包含される。具体的には、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸等の無機酸や、ギ酸、酢酸、プロピオン酸、シュウ酸、マロン酸、コハク酸、フマル酸、マレイン酸、乳酸、リンゴ酸、酒石酸、クエン酸、メタンスルホン酸、エタンスルホン酸、p-トルエンスルホン酸、アスパラギン酸、又はグルタミン酸等の有機酸との酸付加塩、ナトリウム、カリウム、マグネシウム、カルシウム、アルミニウム等の無機塩基、メチルアミン、エチルアミン、エタノールアミン、リシン、オルニチン等の有機塩基との塩やアンモニウム塩等が挙げられる。
　更に、式（I）の化合物及びその製薬学的に許容される塩には、各種の水和物や溶媒和物及び結晶多形の物質が包含される。また式（I）の化合物及びその製薬学的に許容される塩には、種々の放射性又は非放射性同位体でラベルされた化合物も包含される。 Further, the compound of the formula (I) may form an acid addition salt or a salt with a base depending on the kind of the substituent, and as long as such a salt is a pharmaceutically acceptable salt, the compound of the present invention is used. Is included. Specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid Acid addition salts with organic acids such as lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid or glutamic acid, sodium, potassium, magnesium, calcium, aluminum, etc. Inorganic bases, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, ammonium salts, and the like.
Further, the compound of formula (I) and pharmaceutically acceptable salts thereof include various hydrates, solvates and polymorphic substances. In addition, the compounds of formula (I) and pharmaceutically acceptable salts thereof include compounds labeled with various radioactive or non-radioactive isotopes.
（製造法）
　式（I）の化合物及びその製薬学的に許容される塩は、その基本骨格或いは置換基の種類に基づく特徴を利用し、種々の公知の合成法を適用して製造することができる。その際、官能基の種類によっては、当該官能基を原料乃至中間体の段階で適当な保護基（容易に当該官能基に転化可能な基）に置き換えておくことが製造技術上効果的な場合がある。このような官能基としては例えばアミノ基、水酸基、カルボキシル基等であり、それらの保護基としては例えば、ウッツ(P. G. M. Wuts)及びグリーン(T. W. Greene)著、「Greene's Protective Groups in Organic Synthesis (第4版、2006年)」に記載の保護基等を挙げることができ、これらを反応条件に応じて適宜選択して用いればよい。このような方法では、当該保護基を導入して反応を行った後、必要に応じて保護基を除去することにより、所望の化合物を得ることができる。
　また、式（I）の化合物のプロドラッグは上記保護基と同様、原料から中間体へ到る段階で特定の基を導入、或いは得られた式（I）の化合物を用いてさらに反応を行うことで製造できる。反応は通常のエステル化、アミド化、脱水等、当業者により公知の方法を適用することにより行うことができる。
　以下、式（I）の化合物の代表的な製造法を説明する。各製法は、当該説明に付した参考文献を参照して行うこともできる。なお、本発明の製造法は以下に示した例には限定されない。 (Production method)
The compound of the formula (I) and pharmaceutically acceptable salts thereof can be produced by applying various known synthetic methods utilizing characteristics based on the basic skeleton or the type of substituent. In this case, depending on the type of functional group, it is effective in terms of production technology to replace the functional group with an appropriate protecting group (a group that can be easily converted into the functional group) at the raw material or intermediate stage. There is. Examples of such a functional group include an amino group, a hydroxyl group, and a carboxyl group, and examples of protective groups thereof include, for example, “Greene's Protective Groups in Organic Synthesis (No. 4) by PGM Wuts and Green (TW Greene)”. Edition, 2006) ”, and these may be appropriately selected depending on the reaction conditions. In such a method, a desired compound can be obtained by introducing the protecting group and carrying out the reaction, and then removing the protecting group as necessary.
Moreover, the prodrug of the compound of the formula (I) introduces a specific group at the stage from the raw material to the intermediate as in the case of the protective group, or further reacts with the obtained compound of the formula (I). Can be manufactured. The reaction can be carried out by applying a method known by those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.
Hereinafter, typical production methods of the compound of the formula (I) will be described. Each manufacturing method can also be performed with reference to the reference attached to the said description. In addition, the manufacturing method of this invention is not limited to the example shown below.
Figure JPOXMLDOC01-appb-C000009
 （式中、Xは-OH又は脱離基を示す。）
　式（I）の化合物は、化合物(II)と化合物(III)又はその塩とを反応させることにより製造することができる。
　反応は化合物(II)と化合物(III)とを等量、若しくは化合物(III)を過剰量用いて行うことができる。ベンゼン、トルエン若しくはキシレン等の芳香族炭化水素類、ジクロロメタン、1,2-ジクロロエタン若しくはクロロホルム等のハロゲン化炭化水素類、ジエチルエーテル、テトラヒドロフラン（THF）、ジオキサン若しくはジメトキシエタン（DME）等のエーテル類、N,N-ジメチルホルムアミド（DMF）、ジメチルスルホキシド（DMSO）、N-メチルピロリドン（NMP）、酢酸エチル、アセトニトリルまたは水等の反応に不活性な溶媒中、或いはそれらの混合物中で、冷却下～加熱下、好ましくは、-20℃～80℃で行うことができる。
　化合物(II)として、Xが-OHであるカルボン酸を用いる場合には、縮合剤の存在下で反応を行うことが好ましい。この場合の縮合剤としては、N,N'-ジシクロヘキシルカルボジイミド（DCC）、1-[3-(ジメチルアミノ)プロピル]-3-エチルカルボジイミド（WSC）、1,1'-カルボニルジイミダゾール（CDI）、2-(1H-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 ヘキサフルオロホスファート（HBTU）、ジフェニルリン酸アジド（DPPA）、オキシ塩化リン等が挙げられる。場合によっては、更に添加剤（例えば、N-ヒドロキシスクシンイミド（HONSu）又は1-ヒドロキシベンゾトリアゾール（HOBt）等）を用いることが好ましい。通常、縮合剤はカルボン酸に対して等量若しくは過剰量用いる。
　化合物(II)として、Xが脱離基であるカルボン酸の反応性誘導体を用いる場合には、酸ハロゲン化物（酸クロリド又は酸ブロミド等）、酸無水物（クロロ炭酸フェニル、p-トルエンスルホン酸、又はイソ吉草酸等との反応で得られる混合酸無水物、或いは対称酸無水物）、活性エステル（ニトロ基もしくはフッ素原子等の電子吸引基で置換していてもよいフェノール、1-ヒドロキシベンゾトリアゾール(HOBt)、HONSu等を用いて調製できるエステル）等が挙げられ、何れもカルボン酸より当業者に自明な反応を用いて製造することができる。反応性誘導体の種類によっては、塩基（トリエチルアミン(TEA)、ジイソプロピルエチルアミン（DIPEA）、N-メチルモルホリン、ピリジン若しくは4-(N,N-ジメチルアミノ)ピリジン等の有機塩基類、又は炭酸水素ナトリウム等の無機塩基等）の存在下に反応させるのが、反応を円滑に進行させる上で有利な場合がある。ピリジンは溶媒を兼ねることもできる。尚、反応性誘導体として低級アルキルエステルを用いる場合には、反応を室温下～加熱還流下で行うことが好ましい。
Figure JPOXMLDOC01-appb-C000009
 (In the formula, X represents —OH or a leaving group.)
The compound of formula (I) can be produced by reacting compound (II) with compound (III) or a salt thereof.
The reaction can be carried out using an equal amount of compound (II) and compound (III) or an excess amount of compound (III). Aromatic hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane or chloroform, ethers such as diethyl ether, tetrahydrofuran (THF), dioxane or dimethoxyethane (DME), Under cooling in a solvent inert to the reaction such as N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), ethyl acetate, acetonitrile or water, or a mixture thereof. The heating can be performed preferably at -20 ° C to 80 ° C.
When a carboxylic acid in which X is —OH is used as compound (II), the reaction is preferably performed in the presence of a condensing agent. In this case, N, N'-dicyclohexylcarbodiimide (DCC), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide (WSC), 1,1'-carbonyldiimidazole (CDI) 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), diphenyl phosphate azide (DPPA), phosphorus oxychloride and the like. In some cases, it is preferable to use an additive (for example, N-hydroxysuccinimide (HONSu) or 1-hydroxybenzotriazole (HOBt)). Usually, the condensing agent is used in an equivalent amount or an excess amount relative to the carboxylic acid.
When a reactive derivative of carboxylic acid in which X is a leaving group is used as compound (II), acid halide (acid chloride or acid bromide, etc.), acid anhydride (phenyl chlorocarbonate, p-toluenesulfonic acid) Or a mixed acid anhydride obtained by reaction with isovaleric acid or the like, or a symmetric acid anhydride), an active ester (phenol optionally substituted with an electron-withdrawing group such as a nitro group or a fluorine atom, 1-hydroxybenzo Triazoles (HOBt), esters that can be prepared using HONSu, etc.) and the like. Depending on the type of reactive derivative, organic bases such as base (triethylamine (TEA), diisopropylethylamine (DIPEA), N-methylmorpholine, pyridine or 4- (N, N-dimethylamino) pyridine, or sodium bicarbonate, etc. It may be advantageous to carry out the reaction in the presence of an inorganic base, etc.) in order to allow the reaction to proceed smoothly. Pyridine can also serve as a solvent. In the case where a lower alkyl ester is used as the reactive derivative, the reaction is preferably carried out at room temperature to heating under reflux.
（原料製法）
Figure JPOXMLDOC01-appb-C000010
 （式中、X1はトリフルオロメタンスルホニルオキシ基、ハロゲン、メタンスルホニルオキシ基、又はｐ－トルエンスルホニルオキシ基等を示し、X2は、-B(OH)2、-B(OY)OW等の活性基、或いはハロゲンを示す。ここで、Y及びWは同一又は互いに異なって低級アルキル、又は、Y及びWが一体となって低級アルキレンを示す。）
　化合物（II）は、化合物(IV)及び化合物(V)とのカップリング反応、次いでカルボキシル基の脱保護により製造することができる。X2が-B(OH)2、-B(OY)OW等の活性基である場合は、化合物(IV)と(V)を等量、或いは一方を過剰に用い、これらの混合物を、反応に不活性な溶媒中、塩基及びパラジウム触媒の存在下、室温～加熱還流下で、通常0.1時間～5日間撹拌することによって行なわれる。本反応は不活性ガス雰囲気下で行うことが好ましい。ここで用いられる溶媒の例としては、特に限定はされないが、芳香族炭化水素類、エーテル類、ハロゲン化炭化水素類、メタノール、エタノール等のアルコール類、DMF、DMSO、及びこれらの混合溶媒が挙げられる。塩基としては、炭酸ナトリウム、炭酸カリウム、水酸化ナトリウム等の無機塩基が好ましい。パラジウム触媒としては、テトラキス（トリフェニルホスフィン）パラジウム、ジクロロビス（トリフェニルホスフィン）パラジウム、塩化パラジウム-1,1'-ビス（ジフェニルホスフィノ）フェロセン、トリス（ジベンジリデンアセトン）ジパラジウム等が挙げられる。パラジウムリガンドとして、tert-ブチルホスフィン、シクロヘキシルホスフィン、2-ジシクロヘキシルホスフィノビフェニル誘導体等も用いることができる。
　他方で、X2がハロゲンである場合は、n-ブチルリチウム又はLDA（リチウムジイソプロピルアミド）等を用いて、化合物(V)を有機リチウム化合物へと変換後、塩化亜鉛を作用させることより、系中で有機亜鉛化合物へと変換することができる。得られた有機亜鉛化合物を、反応に不活性な溶媒中、塩基及びパラジウム触媒の存在下、化合物(IV)と反応させることより、化合物(II)を製造することができる。ここで用いる反応溶媒、塩基、及びパラジウム触媒は、上記X2が-B(OH)2、-B(OY)OW等の活性基である場合の反応と同様のものを用いることができる。また、塩化亜鉛の代わりに、塩化ジルコニウム、塩化アルミニウム等を用いることもできる。
　カップリング反応は、以下の文献を参照して実施することができる。
〔文献〕
A. de Meijere及びF. Diederich編、「Metal-Catalyzed Cross-Coupling Reactions」、第2版、VCH Publishers Inc.、2004年
日本化学会編「実験化学講座(第5版)」13巻(2005年)(丸善) (Raw material manufacturing method)
Figure JPOXMLDOC01-appb-C000010
 (In the formula, X 1 represents a trifluoromethanesulfonyloxy group, a halogen, a methanesulfonyloxy group, or a p-toluenesulfonyloxy group, and X 2 represents —B (OH) 2 , —B (OY) OW, etc. Represents an active group or halogen, wherein Y and W are the same or different from each other and represent lower alkyl, or Y and W together represent lower alkylene.
Compound (II) can be produced by a coupling reaction with compound (IV) and compound (V) and then deprotection of the carboxyl group. When X 2 is an active group such as -B (OH) 2 or -B (OY) OW, compounds (IV) and (V) are used in an equal amount, or one of them is used in excess, and a mixture thereof is reacted. In an inert solvent, usually in the presence of a base and a palladium catalyst at room temperature to heating under reflux, usually by stirring for 0.1 hour to 5 days. This reaction is preferably performed in an inert gas atmosphere. Examples of the solvent used here are not particularly limited, but include aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols such as methanol and ethanol, DMF, DMSO, and mixed solvents thereof. It is done. As the base, inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide and the like are preferable. Examples of the palladium catalyst include tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1,1′-bis (diphenylphosphino) ferrocene, and tris (dibenzylideneacetone) dipalladium. As the palladium ligand, tert-butylphosphine, cyclohexylphosphine, 2-dicyclohexylphosphinobiphenyl derivative and the like can also be used.
On the other hand, when X 2 is halogen, the compound (V) is converted into an organolithium compound using n-butyllithium or LDA (lithium diisopropylamide), and then zinc chloride is allowed to act. It can be converted into an organic zinc compound. Compound (II) can be produced by reacting the obtained organic zinc compound with compound (IV) in the presence of a base and a palladium catalyst in a solvent inert to the reaction. As the reaction solvent, base, and palladium catalyst used here, the same reaction as in the case where X 2 is an active group such as —B (OH) 2 or —B (OY) OW can be used. Further, zirconium chloride, aluminum chloride or the like can be used instead of zinc chloride.
The coupling reaction can be carried out with reference to the following documents.
[Reference]
A. de Meijere and F. Diederich, "Metal-Catalyzed Cross-Coupling Reactions", 2nd edition, VCH Publishers Inc., 2004, Chemical Society of Japan "Experimental Chemistry Course (5th edition)", Volume 13 (2005) (Maruzen)
　以下、式(I)の化合物の製造法を実施例として記載する。また原料として用いた化合物の製法を製造例として記載する。なお、式(I)の化合物の製造法は、以下に示される具体的実施例の製法のみに限定されるものではなく、これらの製造法の組み合わせ、或いは公知の製法によっても製造しうる。また、濃度［M］は、［mol/L］を意味し、「rel」は相対配置を意味する。 Hereinafter, production methods of the compound of formula (I) will be described as examples. Moreover, the manufacturing method of the compound used as a raw material is described as a manufacture example. In addition, the manufacturing method of the compound of a formula (I) is not limited only to the manufacturing method of the specific Example shown below, It can manufacture also by the combination of these manufacturing methods, or a well-known manufacturing method. The concentration [M] means [mol / L], and “rel” means relative configuration.
製造例１
　4-クロロ-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボン酸(337 mg)、tert-ブチル (トランス-3-アミノシクロブチル)カルバメート(186 mg)、HOBt(148 mg)、WSC塩酸塩(219 mg)及びDMF(10 mL)の混合物を、室温で4時間攪拌した。反応液に飽和重曹水及び酢酸エチルを加え、分液操作を行った。有機層を飽和食塩水で洗浄後、乾燥して減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/酢酸エチル）で精製し、tert-ブチル [トランス-3-({[4-クロロ-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-イル]カルボニル}アミノ)シクロブチル]カルバメート (500 mg)を得た。
製造例２
　メチル 4-クロロ-1-{[(トリフルオロメチル)スルホニル]オキシ}イソキノリン-7-カルボキシラート(500 mg)、テトラキス(トリフェニルホスフィン)パラジウム(156 mg)及びTHF(10 mL)の混合物に、シクロペンチル亜鉛ブロミド(8.1 mL; 0.5M THF溶液)を加え、3時間加熱還流した。室温まで冷却後、反応液に水及び酢酸エチルを加え、分液操作を行った。有機層を飽和重曹水で洗浄後、乾燥して減圧下濃縮した。残渣ををシリカゲルカラムクロマトグラフィー（ヘキサン/クロロホルム）で精製し、メチル 4-クロロ-1-シクロペンチルイソキノリン-7-カルボキシラート(140 mg)を得た。
製造例３
　メチル 4-クロロ-1-シクロペンチルイソキノリン-7-カルボキシラート(140 mg)、メタノール(5 mL)及びTHF(5 mL)の混合物に、1M水酸化ナトリウム水溶液(2.5 mL)を加え、室温で2時間攪拌した。反応液に1M塩酸(2.5 mL)を加え、更に水及びクロロホルムを加えて分液操作を行った。有機層を乾燥して減圧下濃縮し、4-クロロ-1-シクロペンチルイソキノリン-7-カルボン酸(116 mg)を得た。 Production Example 1
4-chloro-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxylic acid (337 mg), tert-butyl (trans-3-aminocyclobutyl) carbamate (186 mg), HOBt (148 mg ), WSC hydrochloride (219 mg) and DMF (10 mL) were stirred at room temperature for 4 hours. A saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and a liquid separation operation was performed. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / ethyl acetate) and tert-butyl [trans-3-({[4-chloro-1- (2,4,6-trifluorophenyl) isoquinolin-7-yl] Carbonyl} amino) cyclobutyl] carbamate (500 mg) was obtained.
Production Example 2
To a mixture of methyl 4-chloro-1-{[(trifluoromethyl) sulfonyl] oxy} isoquinoline-7-carboxylate (500 mg), tetrakis (triphenylphosphine) palladium (156 mg) and THF (10 mL), Cyclopentyl zinc bromide (8.1 mL; 0.5 M THF solution) was added, and the mixture was heated to reflux for 3 hours. Water and ethyl acetate were added to the reaction liquid after cooling to room temperature, and liquid separation operation was performed. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / chloroform) to obtain methyl 4-chloro-1-cyclopentylisoquinoline-7-carboxylate (140 mg).
Production Example 3
To a mixture of methyl 4-chloro-1-cyclopentylisoquinoline-7-carboxylate (140 mg), methanol (5 mL) and THF (5 mL), 1M aqueous sodium hydroxide solution (2.5 mL) was added and stirred at room temperature for 2 hours. Stir. 1M hydrochloric acid (2.5 mL) was added to the reaction solution, and water and chloroform were further added to carry out a liquid separation operation. The organic layer was dried and concentrated under reduced pressure to obtain 4-chloro-1-cyclopentylisoquinoline-7-carboxylic acid (116 mg).
製造例４
　5,6-ジヒドロ-7H-シクロペンタ[c]ピリジン-7-オン(135 mg)、O-メチルヒドロキシルアンモニウムクロリド(169 mg)及びメタノール(2.7 mL)の混合物にDIPEA(0.28 mL)を加え、油温70℃で3時間攪拌後、室温に冷却した。反応液に水及びクロロホルムを加えて分液操作を行った。有機層を乾燥して減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール）で精製し、N-メトキシ-5,6-ジヒドロ-7H-シクロペンタ[c]ピリジン-7-イミン(118 mg)を得た。
製造例５
　N-メトキシ-5,6-ジヒドロ-7H-シクロペンタ[c]ピリジン-7-イミン(118 mg)、メタノール(5 mL)、トリフルオロ酢酸(0.5 mL)及び10%Pd/C(25 mg)の混合物を、水素ガス雰囲気下、室温で5.5時間攪拌し、セライトろ過した。ろ液に28%アンモニア水(1 mL)を加え、減圧下濃縮し、残渣をNHシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール）にて精製し、6,7-ジヒドロ-5H-シクロペンタ[c]ピリジン-7-アミン(53 mg)を得た。
製造例６
　rel-(2R,3R)-1-ベンジル-2-メチルピロリジン-3-アミン(10 g)、TEA(16 g)及びTHF(866 mL)の混合物にジ‐tert‐ブチルジカルボナート(12 g)を加え室温で1日間攪拌した。反応液に1M水酸化ナトリウム水溶液(50 mL)及び酢酸エチルを加え分液操作を行った。有機層を水で洗浄して減圧下濃縮し、tert-ブチル rel-[(2R,3R)-1-ベンジル-2-メチルピロリジン-3-イル]カルバメート(15 g)を得た。 Production Example 4
Add DIPEA (0.28 mL) to a mixture of 5,6-dihydro-7H-cyclopenta [c] pyridin-7-one (135 mg), O-methylhydroxylammonium chloride (169 mg) and methanol (2.7 mL) The mixture was stirred at a temperature of 70 ° C. for 3 hours and then cooled to room temperature. Water and chloroform were added to the reaction solution to carry out a liquid separation operation. The organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain N-methoxy-5,6-dihydro-7H-cyclopenta [c] pyridine-7-imine (118 mg).
Production Example 5
N-methoxy-5,6-dihydro-7H-cyclopenta [c] pyridine-7-imine (118 mg), methanol (5 mL), trifluoroacetic acid (0.5 mL) and 10% Pd / C (25 mg) The mixture was stirred at room temperature under a hydrogen gas atmosphere for 5.5 hours and filtered through celite. 28% aqueous ammonia (1 mL) was added to the filtrate, and the mixture was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (chloroform / methanol), and 6,7-dihydro-5H-cyclopenta [c] pyridine- 7-amine (53 mg) was obtained.
Production Example 6
Di-tert-butyl dicarbonate (12 g) was added to a mixture of rel- (2R, 3R) -1-benzyl-2-methylpyrrolidin-3-amine (10 g), TEA (16 g) and THF (866 mL). ) Was added and stirred at room temperature for 1 day. A 1M aqueous sodium hydroxide solution (50 mL) and ethyl acetate were added to the reaction solution to carry out a liquid separation operation. The organic layer was washed with water and concentrated under reduced pressure to obtain tert-butyl rel-[(2R, 3R) -1-benzyl-2-methylpyrrolidin-3-yl] carbamate (15 g).
製造例７
　tert-ブチル rel-[(2R,3R)-1-ベンジル-2-メチルピロリジン-3-イル]カルバメート(16 g)、メタノール(50 mL)及び水(5 mL)の混合物に10%Pd/C(1.0 g)及びギ酸アンモニウム(35 g)を加え、加熱還流下7時間攪拌した。反応液を室温に冷却し、反応液をセライトろ過して、ろ液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール)で精製し、tert-ブチル rel-[(2R,3R)-2-メチルピロリジン-3-イル]カルバメート(6.5 g)を得た。
製造例８
　tert-ブチル rel-[(2R,3R)-2-メチルピロリジン-3-イル]カルバメート(500 mg)、37%ホルムアルデヒド水溶液(2.0 g)、酢酸(224 mg)、及びジクロロエタン(43 mL)の混合物に、トリアセトキシ水素化ホウ素ナトリウム(794 mg)を加え、室温で1日攪拌した。反応液に1M水酸化ナトリウム水溶液(10 mL)及び酢酸エチルを加えて分液操作を行った。有機層を減圧下濃縮し、tert-ブチル rel-[(2R,3R)-1,2-ジメチルピロリジン-3-イル]カルバメート(370 mg)を得た。
製造例９
　tert-ブチル rel-[(2R,3R)-1,2-ジメチルピロリジン-3-イル]カルバメート(359 mg)及びエタノール(5 mL)の混合物に、4M 塩化水素/酢酸エチル(5 mL)を加え、室温で3日間攪拌した。反応液を減圧下濃縮し、rel-(2S,3S)-1,2-ジメチルピロリジン-3-アミン 二塩酸塩(313 mg)を得た。 Production Example 7
To a mixture of tert-butyl rel-[(2R, 3R) -1-benzyl-2-methylpyrrolidin-3-yl] carbamate (16 g), methanol (50 mL) and water (5 mL) 10% Pd / C (1.0 g) and ammonium formate (35 g) were added, and the mixture was stirred for 7 hours with heating under reflux. The reaction solution was cooled to room temperature, the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) to obtain tert-butyl rel-[(2R, 3R) -2-methylpyrrolidin-3-yl] carbamate (6.5 g).
Production Example 8
A mixture of tert-butyl rel-[(2R, 3R) -2-methylpyrrolidin-3-yl] carbamate (500 mg), 37% aqueous formaldehyde (2.0 g), acetic acid (224 mg), and dichloroethane (43 mL) Was added with sodium triacetoxyborohydride (794 mg) and stirred at room temperature for 1 day. A 1M aqueous sodium hydroxide solution (10 mL) and ethyl acetate were added to the reaction solution to carry out a liquid separation operation. The organic layer was concentrated under reduced pressure to obtain tert-butyl rel-[(2R, 3R) -1,2-dimethylpyrrolidin-3-yl] carbamate (370 mg).
Production Example 9
Add 4M hydrogen chloride / ethyl acetate (5 mL) to a mixture of tert-butyl rel-[(2R, 3R) -1,2-dimethylpyrrolidin-3-yl] carbamate (359 mg) and ethanol (5 mL). And stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure to obtain rel- (2S, 3S) -1,2-dimethylpyrrolidin-3-amine dihydrochloride (313 mg).
製造例１０
　イミダゾ[1,2-a]ピリジン-7-アミン(200 mg)及びエタノール(2 mL)の混合物に、10%Pd/C(50%含水、179 mg)を加え、3気圧の水素ガス雰囲気下、室温で10時間攪拌した。反応液をセライトろ過して、ろ液を減圧下濃縮し、5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-7-アミン(200 mg)を得た。
製造例１１
　アルゴンガス雰囲気下、メチル 4-ブロモ-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキシラート(232 mg)、シクロプロピルボロン酸(150 mg)、リン酸三カリウム(372 mg)、トルエン(20 mL)及び水(1 mL)の混合物に、テトラキストリフェニルホスフィンパラジウム(135 mg)を加え、油温100℃で1日間攪拌した。反応液を室温まで放冷後、酢酸エチル及び水を加えて分液操作を行った。有機層を乾燥後、減圧下濃縮して、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン/酢酸エチル）で精製し、メチル 4-シクロプロピル-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキシラート(206 mg)を得た。
製造例１２
　3-(1,3-ベンソチアゾール-2-イル)-N-{[4-クロロ-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-イル]カルボニル}アラニン(40mg)、HOBt(15mg)、WSC塩酸塩(21 mg)、及びDMF(2 mL)の混合物を室温で0.5時間攪拌後、28%アンモニア水(0.05 mL)を加え、室温で更に16時間攪拌した。反応液に水及び酢酸エチルを加え、分液操作を行った。有機層を飽和食塩水で洗浄後、乾燥して、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール=10:0-9:1）で精製し、N-[1-アミノ-3-(1,3-ベンゾチアゾール-2-イル)-1-オキソプロパン-2-イル]-4-クロロ-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド(12 mg)を得た。 Production Example 10
To a mixture of imidazo [1,2-a] pyridin-7-amine (200 mg) and ethanol (2 mL), 10% Pd / C (50% water content, 179 mg) was added, and the atmosphere was 3 atmospheres of hydrogen gas. And stirred at room temperature for 10 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain 5,6,7,8-tetrahydroimidazo [1,2-a] pyridin-7-amine (200 mg).
Production Example 11
Under an argon gas atmosphere, methyl 4-bromo-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxylate (232 mg), cyclopropylboronic acid (150 mg), tripotassium phosphate (372 mg) ), Toluene (20 mL) and water (1 mL) were added tetrakistriphenylphosphine palladium (135 mg), and the mixture was stirred at an oil temperature of 100 ° C. for 1 day. The reaction solution was allowed to cool to room temperature, and ethyl acetate and water were added to carry out a liquid separation operation. The organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) and methyl 4-cyclopropyl-1- (2,4,6-trifluorophenyl) isoquinoline-7. -Carboxylate (206 mg) was obtained.
Production Example 12
3- (1,3-Benzothiazol-2-yl) -N-{[4-chloro-1- (2,4,6-trifluorophenyl) isoquinolin-7-yl] carbonyl} alanine (40 mg), A mixture of HOBt (15 mg), WSC hydrochloride (21 mg), and DMF (2 mL) was stirred at room temperature for 0.5 hour, 28% aqueous ammonia (0.05 mL) was added, and the mixture was further stirred at room temperature for 16 hours. Water and ethyl acetate were added to the reaction liquid, and liquid separation operation was performed. The organic layer was washed with saturated brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 10: 0-9: 1), and N- [1-amino-3- (1,3-benzothiazol-2-yl) -1-oxopropane- 2-yl] -4-chloro-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide (12 mg) was obtained.
製造例１３
　アルゴンガス雰囲気下、1-トリチル-1H-イミダゾール-2-カルバルデヒド(280 mg)及びジクロロメタン(2 mL)の混合物に、トリメチルシリルシアニド(250 mg)、及びヨウ化亜鉛(40 mg)を加え、室温で3時間攪拌した。反応液に飽和重層水及びジクロロメタンを加え、分液操作を行った。有機層を飽和食塩水で洗浄後、乾燥して減圧下濃縮し、[(トリメチルシリル)オキシ](1-トリチル-1H-イミダゾール-2-イル)アセトニトリル(300 mg)を得た。
製造例１４
　アルゴンガス雰囲気下、氷冷下でTHF(9 mL)に水素化リチウムアルミニウム(96 mg)を加え、[(トリメチルシリル)オキシ](1-トリチル-1H-イミダゾール-2-イル)アセトニトリル(370 mg)のTHF(9 mL)溶液をゆっくり滴下した後、室温で3時間攪拌した。反応液に硫酸ナトリウム十水和物を加え、室温で5時間攪拌後、酢酸エチルを加えて更に0.5時間攪拌した。不溶物をセライトでろ過して、ろ液を減圧下濃縮し、2-アミノ-1-(1-トリチル-1H-イミダゾール-2-イル)エタノール(270 mg)を得た。
製造例１５
　rel-2,2,2-トリフルオロ-N-[(3R,4S)-3-フルオロ-1-メチルピペリジン-4-イル]アセトアミド(160 mg)及びメタノール(1 mL)の混合物に2M水酸化ナトリウム水溶液(1.4 mL)を加え、室温で1時間攪拌後、減圧下濃縮した。残渣にジクロロメタン及び水を加え、分液操作を行った。有機層を乾燥して、減圧下濃縮し、rel-(3R,4S)-3-フルオロ-1-メチルピペリジン-4-アミン(92 mg)を得た。 Production Example 13
Under an argon gas atmosphere, trimethylsilyl cyanide (250 mg) and zinc iodide (40 mg) were added to a mixture of 1-trityl-1H-imidazole-2-carbaldehyde (280 mg) and dichloromethane (2 mL). Stir at room temperature for 3 hours. Saturated multistory water and dichloromethane were added to the reaction liquid, and liquid separation operation was performed. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure to give [(trimethylsilyl) oxy] (1-trityl-1H-imidazol-2-yl) acetonitrile (300 mg).
Production Example 14
Add lithium aluminum hydride (96 mg) to THF (9 mL) under argon gas atmosphere and ice cooling, and add [(trimethylsilyl) oxy] (1-trityl-1H-imidazol-2-yl) acetonitrile (370 mg) Of THF (9 mL) was slowly added dropwise, followed by stirring at room temperature for 3 hours. Sodium sulfate decahydrate was added to the reaction mixture, and the mixture was stirred at room temperature for 5 hr. Ethyl acetate was added, and the mixture was further stirred for 0.5 hr. The insoluble material was filtered through celite, and the filtrate was concentrated under reduced pressure to give 2-amino-1- (1-trityl-1H-imidazol-2-yl) ethanol (270 mg).
Production Example 15
2M hydroxylation to a mixture of rel-2,2,2-trifluoro-N-[(3R, 4S) -3-fluoro-1-methylpiperidin-4-yl] acetamide (160 mg) and methanol (1 mL) Aqueous sodium solution (1.4 mL) was added, and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. Dichloromethane and water were added to the residue, and a liquid separation operation was performed. The organic layer was dried and concentrated under reduced pressure to obtain rel- (3R, 4S) -3-fluoro-1-methylpiperidin-4-amine (92 mg).
製造例１６
　rel-2,2,2-トリフルオロ-N-[(3S,4R)-3-フルオロピペリジン-4-イル]アセトアミド トリフルオロ酢酸塩(240 mg)、炭酸カリウム(303 mg)及びDMF(2.5 mL)の混合物に、氷冷下、ヨードメタン(106 mg)を加え、室温で2時間攪拌した。反応液に酢酸エチル及び水を加え、分液操作を行った。有機層を水及び飽和食塩水で順次洗浄後、乾燥して減圧下濃縮し、rel-2,2,2-トリフルオロ-N-[(3R,4S)-3-フルオロ-1-メチルピペリジン-4-イル]アセトアミド(166 mg)を得た。
製造例１７
　tert-ブチル rel(3R,4S)-3-フルオロ-4-[(トリフルオロアセチル)アミノ]ピペリジン-1-カルボキシラート(1.00 g)及びジクロロメタン(10 mL)の混合物に、トリフルオロ酢酸(3 mL)を加え、室温で一終夜攪拌した。反応液を減圧下濃縮し、残渣にジイソプロピルエーテルを加え、生じた固体をろ取し、rel-2,2,2-トリフルオロ-N-[(3S,4R)-3-フルオロピリジン-4-イル]アセトアミド トリフルオロ酢酸塩(1.01 g)を得た。
製造例１８
　tert-ブチル rel(3R,4S)-4-アミノ-3-フルオロピペリジン-1-カルボキシラート(21 g)、ジクロロメタン(210 mL)及びTEA(54 mL)の混合物に、氷冷下、トリフルオロ酢酸無水物(30 mL)のジクロロメタン(42 mL)溶液を、内温10℃以下に保ちながら1時間かけて滴下し、室温で1時間攪拌した。反応液に氷を加え室温まで昇温後、分液操作を行った。有機層を飽和食塩水で洗浄後、乾燥して減圧下濃縮した。残渣にヘキサン及び酢酸エチルを加え、生じた固体をろ取し、tert-ブチル rel-(3R,4S)-3-フルオロ-4-[(トリフルオロアセチル)アミノ]ピペリジン-1-カルボキシラート(16.9 g)を得た。 Production Example 16
rel-2,2,2-trifluoro-N-[(3S, 4R) -3-fluoropiperidin-4-yl] acetamide trifluoroacetate (240 mg), potassium carbonate (303 mg) and DMF (2.5 mL ) Was added with iodomethane (106 mg) under ice-cooling and stirred at room temperature for 2 hours. Ethyl acetate and water were added to the reaction solution, and a liquid separation operation was performed. The organic layer was washed successively with water and saturated brine, dried and concentrated under reduced pressure to give rel-2,2,2-trifluoro-N-[(3R, 4S) -3-fluoro-1-methylpiperidine- 4-yl] acetamide (166 mg) was obtained.
Production Example 17
To a mixture of tert-butyl rel (3R, 4S) -3-fluoro-4-[(trifluoroacetyl) amino] piperidine-1-carboxylate (1.00 g) and dichloromethane (10 mL) was added trifluoroacetic acid (3 mL ) And stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, diisopropyl ether was added to the residue, the resulting solid was collected by filtration, and rel-2,2,2-trifluoro-N-[(3S, 4R) -3-fluoropyridine-4- [Il] acetamide trifluoroacetate (1.01 g) was obtained.
Production Example 18
To a mixture of tert-butyl rel (3R, 4S) -4-amino-3-fluoropiperidine-1-carboxylate (21 g), dichloromethane (210 mL) and TEA (54 mL) was added trifluoroacetic acid under ice-cooling. A solution of anhydride (30 mL) in dichloromethane (42 mL) was added dropwise over 1 hour while maintaining the internal temperature at 10 ° C. or lower, and the mixture was stirred at room temperature for 1 hour. Ice was added to the reaction solution, and the temperature was raised to room temperature, followed by liquid separation operation. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure. Hexane and ethyl acetate were added to the residue, and the resulting solid was collected by filtration, and tert-butyl rel- (3R, 4S) -3-fluoro-4-[(trifluoroacetyl) amino] piperidine-1-carboxylate (16.9 g) was obtained.
製造例１９
　1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボン酸 メチル(228 mg)、1M水酸化ナトリウム水溶液(4 mL)、THF(3 mL)及びエタノール(3 mL)の混合物を室温で24時間攪拌した。反応混合物を1M塩酸で中和し、析出物をろ取することにより、1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボン酸 塩酸塩（200 mg）を得た。
製造例２０
　アルゴンガス雰囲気下、4-ブロモ-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボン酸メチル(160 mg)、トリメチルボロキシン(117 mg)、テトラキス(トリフェニルホスフィン)パラジウム(23 mg)、2M炭酸ナトリウム水溶液(1 mL)及び1,4-ジオキサン(5 mL)の混合物を油温100℃で4時間攪拌した。反応混合物を室温に戻し、酢酸エチルで希釈後、不溶物をセライトでろ別し、母液を酢酸エチルで抽出した。有機層を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、4-メチル-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボン酸(95 mg)を得た。 Production Example 19
A mixture of methyl 1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxylate (228 mg), 1M aqueous sodium hydroxide solution (4 mL), THF (3 mL) and ethanol (3 mL) at room temperature For 24 hours. The reaction mixture was neutralized with 1M hydrochloric acid, and the precipitate was collected by filtration to obtain 1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxylic acid hydrochloride (200 mg).
Production Example 20
Under an argon gas atmosphere, methyl 4-bromo-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxylate (160 mg), trimethylboroxine (117 mg), tetrakis (triphenylphosphine) palladium ( 23 mg), a 2M aqueous sodium carbonate solution (1 mL) and 1,4-dioxane (5 mL) were stirred at an oil temperature of 100 ° C. for 4 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, insoluble material was filtered off through celite, and the mother liquor was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 4-methyl-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxylic acid. (95 mg) was obtained.
製造例２１
　アルゴンガス雰囲気下、1-{[(トリフルオロメチル)スルホニル]オキシ}イソキノリン-7-カルボン酸 メチル(250 mg)、2,4,6-トリフルオロフェニルホウ酸(184 mg)、テトラキス(トリフェニルホスフィン)パラジウム(22 mg)、トリエチルアミン(189 mg)及び1,4-ジオキサン(15 mL)の混合物を油温95℃で18時間攪拌した。反応混合物を室温に戻し、水及び酢酸エチルを加え分液操作を行った。有機層を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル）で精製し、1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボン酸 メチル(228 mg)を得た。
製造例２２
　4-クロロ-1-ヒドロキシイソキノリン-7-カルボン酸 メチル(117 mg)のジクロロメタン(12 mL)溶液に、ピリジン(47 mg)、及びトリフルオロメタンスルホン酸無水物(153 mg)を順次加え、室温で16時間攪拌した。反応液に水及び酢酸エチルを加え、分液操作を行った。有機層を飽和塩化ナトリウム水溶液で洗浄して、無水硫酸ナトリウムで乾燥し、溶媒を減圧下留去した。残渣をシリカゲルカラムクロマトグラフィー(ヘキサン：酢酸エチル=100:0～80:20)で精製し、4-クロロ-1-{[(トリフルオロメチル)スルホニル]オキシ}イソキノリン-7-カルボン酸 メチルを(150 mg)を得た。 Production Example 21
Under an argon gas atmosphere, methyl 1-{[(trifluoromethyl) sulfonyl] oxy} isoquinoline-7-carboxylate (250 mg), 2,4,6-trifluorophenylboric acid (184 mg), tetrakis (triphenyl A mixture of phosphine) palladium (22 mg), triethylamine (189 mg) and 1,4-dioxane (15 mL) was stirred at an oil temperature of 95 ° C. for 18 hours. The reaction mixture was returned to room temperature, water and ethyl acetate were added, and liquid separation operation was performed. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain methyl 1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxylate (228 mg). It was.
Production Example 22
To a solution of methyl 4-chloro-1-hydroxyisoquinoline-7-carboxylate (117 mg) in dichloromethane (12 mL), sequentially add pyridine (47 mg) and trifluoromethanesulfonic anhydride (153 mg) at room temperature. Stir for 16 hours. Water and ethyl acetate were added to the reaction liquid, and liquid separation operation was performed. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0 to 80:20), and methyl 4-chloro-1-{[(trifluoromethyl) sulfonyl] oxy} isoquinoline-7-carboxylate ( 150 mg) was obtained.
　上記製造例の方法と同様にして後記表に示す製造例化合物をそれぞれ対応する原料を使用して製造した。また、製造例化合物の構造式、物理化学的データ及び製造法を後記表に示す。 In the same manner as in the above production examples, the production example compounds shown in the table below were produced using the corresponding raw materials. The structural formulas, physicochemical data and production methods of the production example compounds are shown in the table below.
実施例１
　4-クロロ-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボン酸(90 mg)、2-(1-メチル-1H-イミダゾール-2-イル)エタンアミン 二塩酸塩(58 mg)、HOBt(40 mg)、WSC塩酸塩(56 mg)、DIPEA(0.12 mL)及びDMF(5 mL)の混合物を、室温で4時間攪拌した。反応液に飽和重曹水及び酢酸エチルを加え、分液操作を行った。有機層を飽和食塩水で洗浄後、乾燥して減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール=10:0-9:1）で精製した。精製物に酢酸エチル及び4M塩化水素/酢酸エチルを加え、生じた固体をろ取し、4-クロロ-N-[2-(1-メチル-1H-イミダゾール-2-イル)エチル]-1-(2,4,6-トリフルオロフェニル）イソキノリン-7-カルボキサミド 二塩酸塩(127 mg)を得た。
実施例２
　4-クロロ-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボン酸(80 mg)、トランス-4-アミノシクロヘキサノール(33 mg)、HOBt(38 mg)、WSC塩酸塩(54 mg)及びDMF(2.7 mL)の混合物を、室温で3日間攪拌した。反応液に飽和重曹水及び酢酸エチルを加え、分液操作を行った。有機層を飽和食塩水で洗浄後、乾燥して減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール=10:0-9:1）で精製し、4-クロロ-N-(トランス-4-ヒドロキシシクロヘキシル)-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド(100 mg)を得た。
実施例３
　tert-ブチル [トランス-3-({[4-クロロ-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-イル]カルボニル}アミノ)シクロブチル]カルバメート(500 mg)、メタノール(5 mL)及び酢酸エチル(5 mL)の混合物に、4M塩化水素/酢酸エチル(1.5 mL)を加え、室温で3日間攪拌した。反応液にクロロホルム及び飽和重曹水を順次加え、分液操作を行った。有機層を洗浄して乾燥し、減圧下濃縮した。残渣をNHシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール=10:0-9:1）で精製し、N-(トランス-3-アミノシクロブチル)-4-クロロ-1-（2,4,6-トリフルオロフェニル）イソキノリン-7-カルボキサミド(300 mg)を得た。 Example 1
4-Chloro-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxylic acid (90 mg), 2- (1-methyl-1H-imidazol-2-yl) ethanamine dihydrochloride (58 mg ), HOBt (40 mg), WSC hydrochloride (56 mg), DIPEA (0.12 mL) and DMF (5 mL) were stirred at room temperature for 4 hours. A saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and a liquid separation operation was performed. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 10: 0-9: 1). Ethyl acetate and 4M hydrogen chloride / ethyl acetate were added to the purified product, and the resulting solid was collected by filtration, and 4-chloro-N- [2- (1-methyl-1H-imidazol-2-yl) ethyl] -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide dihydrochloride (127 mg) was obtained.
Example 2
4-chloro-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxylic acid (80 mg), trans-4-aminocyclohexanol (33 mg), HOBt (38 mg), WSC hydrochloride ( 54 mg) and DMF (2.7 mL) were stirred at room temperature for 3 days. A saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and a liquid separation operation was performed. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 10: 0-9: 1), and 4-chloro-N- (trans- 4-Hydroxycyclohexyl) -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide (100 mg) was obtained.
Example 3
tert-Butyl [trans-3-({[4-Chloro-1- (2,4,6-trifluorophenyl) isoquinolin-7-yl] carbonyl} amino) cyclobutyl] carbamate (500 mg), methanol (5 mL ) And ethyl acetate (5 mL) were added 4M hydrogen chloride / ethyl acetate (1.5 mL), and the mixture was stirred at room temperature for 3 days. Chloroform and saturated sodium bicarbonate water were sequentially added to the reaction solution, and a liquid separation operation was performed. The organic layer was washed and dried, and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (chloroform / methanol = 10: 0-9: 1), and N- (trans-3-aminocyclobutyl) -4-chloro-1- (2,4,6-tri Fluorophenyl) isoquinoline-7-carboxamide (300 mg) was obtained.
実施例４
　4-クロロ-N-[2-(1H-イミダゾール-2-イル)エチル]-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド(60 mg)、2-ヨードプロパン(170 mg)及びDMF(2 mL)の混合物に、DIPEA(30 mg)を加え、油温90℃で2日間攪拌後、室温に冷却した。反応液に酢酸エチル及び水を加えて分液操作を行った。有機層を水及び飽和食塩水で順次洗浄し、乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール=10:0-9:1）で精製し、4-クロロ-N-[2-(1-イソプロピル-1H-イミダゾール-2-イル)エチル]-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド(15 mg)を得た。
実施例５
　4-クロロ-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボン酸(60 mg)、トランス-4-アミノ-1-ベンジル-3-ヒドロキシメチル ピペリジン(44 mg)、HOBt(26 mg)、WSC塩酸塩(38 mg)及びDMF(3 mL)の混合物を、室温で3日間攪拌した。反応液に飽和重曹水及び酢酸エチルを加え、分液操作を行った。有機層を飽和食塩水で洗浄後、乾燥して減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール=10:0-9:1）で精製した。精製物にエタノール及びフマル酸を加え、生じた固体をろ取し、rel-N-[(3R,4R)-1-ベンジル-3-(ヒドロキシメチル)ピペリジン-4-イル]-4-クロロ-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド ヘミフマル酸塩(79 mg)を得た。
実施例６
　tert-ブチル 4-({[4-クロロ-1-(2,4-ジフルオロフェニル)イソキノリン-7-イル]カルボニル}アミノ)ピペリジン-1-カルボキシレート(173 mg)のメタノール溶液(1.74 mL)に4M塩化水素/ジオキサン(1.3 mL)を加え室温で一日攪拌した。反応液を減圧下濃縮し、4-クロロ-1-(2,4-ジフルオロフェニル)-N-(ピペリジン-4-イル)イソキノリン-7-カルボキサミド 二塩酸塩(80 mg)を得た。 Example 4
4-chloro-N- [2- (1H-imidazol-2-yl) ethyl] -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide (60 mg), 2-iodopropane (170 mg) and DMF (2 mL) were added with DIPEA (30 mg), stirred at an oil temperature of 90 ° C. for 2 days, and then cooled to room temperature. Ethyl acetate and water were added to the reaction solution to carry out a liquid separation operation. The organic layer was washed successively with water and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 10: 0-9: 1) to give 4-chloro-N- [2- (1-isopropyl-1H-imidazol-2-yl) ethyl] -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide (15 mg) was obtained.
Example 5
4-chloro-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxylic acid (60 mg), trans-4-amino-1-benzyl-3-hydroxymethylpiperidine (44 mg), HOBt ( 26 mg), WSC hydrochloride (38 mg) and DMF (3 mL) were stirred at room temperature for 3 days. A saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and a liquid separation operation was performed. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 10: 0-9: 1). Ethanol and fumaric acid were added to the purified product, and the resulting solid was collected by filtration, and rel-N-[(3R, 4R) -1-benzyl-3- (hydroxymethyl) piperidin-4-yl] -4-chloro- 1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide hemifumarate (79 mg) was obtained.
Example 6
To a methanol solution (1.74 mL) of tert-butyl 4-({[4-chloro-1- (2,4-difluorophenyl) isoquinolin-7-yl] carbonyl} amino) piperidine-1-carboxylate (173 mg) 4M Hydrogen chloride / dioxane (1.3 mL) was added, and the mixture was stirred at room temperature for 1 day. The reaction solution was concentrated under reduced pressure to obtain 4-chloro-1- (2,4-difluorophenyl) -N- (piperidin-4-yl) isoquinoline-7-carboxamide dihydrochloride (80 mg).
実施例７
　4-クロロ-N-(ピペリジン-4-イル)-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド 二塩酸塩(100 mg)、シクロプロパンカルボアルデヒド(374 mg)、酢酸(0.058 mL)、及びTEA (0.085 mL)のジクロロメタン溶液(8.6 mL)に、トリアセトキシ水素化ホウ素ナトリウム(64 mg)を加え、室温で18時間攪拌した。反応液に1M水酸化ナトリウム水溶液及び酢酸エチルを加えて分液操作を行った。有機層を減圧下濃縮して、残渣をシリカゲルクロマトグラフィー(クロロホルム/メタノール=100:0-85:15)で精製した。精製物に酢酸エチル及び4M塩化水素/酢酸エチルを加え、減圧下濃縮し、4-クロロ-N-[1-(シクロプロピルメチル)ピペリジン-4-イル]-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド 塩酸塩(52 mg)を得た。
実施例８
　4-クロロ-N-(ピペリジン-4-イル)-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド 二塩酸塩(100 mg)、ジクロロメタン(1 mL)、及びメタノール(0.5 mL)の混合物に、1,4-ジオキサン-2,5-ジオール(49 mg)、トリアセトキシ水素化ホウ素ナトリウム(129 mg)を加え、室温で一終夜攪拌した。反応液に水及び酢酸エチルを加え分液操作を行った。有機層を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー(クロロホルム：メタノール=100:0-90:10)で精製した。精製物に酢酸エチル及び4M塩化水素/酢酸エチルを加え、減圧下濃縮し、4-クロロ-N-[1-(2-ヒドロキシエチル)ピペリジン-4-イル]-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド 塩酸塩(45 mg)を得た。
実施例９
　4-クロロ-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボン酸(80 mg)、テトラヒドロ-2H-ピラン-4-アミン(29 mg)、HOBt(32 mg)、TEA(0.1 ml)及びDMF(2.7 mL)の混合物に、WSC塩酸塩(68 mg)を加え、室温で20時間攪拌した。反応液に1M水酸化ナトリウム水溶液及び酢酸エチルを加え、分液操作を行った。有機層を水で洗浄後、乾燥して減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー(クロロホルム/メタノール=100:0-90:10)で精製した。精製物にエタノール及び50%臭化水素酸を加え、減圧下濃縮し、4-クロロ-N-(テトラヒドロ-2H-ピラン-4-イル)-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド 塩酸塩(15 mg)を得た。 Example 7
4-Chloro-N- (piperidin-4-yl) -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide dihydrochloride (100 mg), cyclopropanecarbaldehyde (374 mg), acetic acid (0.058 mL) and TEA (0.085 mL) in dichloromethane (8.6 mL) were added sodium triacetoxyborohydride (64 mg), and the mixture was stirred at room temperature for 18 hours. A 1M aqueous sodium hydroxide solution and ethyl acetate were added to the reaction solution to carry out a liquid separation operation. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform / methanol = 100: 0-85: 15). Ethyl acetate and 4M hydrogen chloride / ethyl acetate were added to the purified product, concentrated under reduced pressure, and 4-chloro-N- [1- (cyclopropylmethyl) piperidin-4-yl] -1- (2,4,6- Trifluorophenyl) isoquinoline-7-carboxamide hydrochloride (52 mg) was obtained.
Example 8
4-Chloro-N- (piperidin-4-yl) -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide dihydrochloride (100 mg), dichloromethane (1 mL), and methanol (0.5 1,4-dioxane-2,5-diol (49 mg) and sodium triacetoxyborohydride (129 mg) were added to the mixture, and the mixture was stirred overnight at room temperature. Water and ethyl acetate were added to the reaction solution to carry out a liquid separation operation. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0-90: 10). Ethyl acetate and 4M hydrogen chloride / ethyl acetate were added to the purified product, concentrated under reduced pressure, and 4-chloro-N- [1- (2-hydroxyethyl) piperidin-4-yl] -1- (2,4,6 -Trifluorophenyl) isoquinoline-7-carboxamide hydrochloride (45 mg) was obtained.
Example 9
4-chloro-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxylic acid (80 mg), tetrahydro-2H-pyran-4-amine (29 mg), HOBt (32 mg), TEA ( To a mixture of 0.1 ml) and DMF (2.7 mL), WSC hydrochloride (68 mg) was added and stirred at room temperature for 20 hours. A 1M aqueous sodium hydroxide solution and ethyl acetate were added to the reaction solution, and a liquid separation operation was performed. The organic layer was washed with water, dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 100: 0-90: 10). Ethanol and 50% hydrobromic acid were added to the purified product, concentrated under reduced pressure, and 4-chloro-N- (tetrahydro-2H-pyran-4-yl)-(2,4,6-trifluorophenyl) isoquinoline- 7-carboxamide hydrochloride (15 mg) was obtained.
実施例１０
　4-クロロ-N-(ピペリジン-4-イル)-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド 二塩酸塩(62 mg)、2,2-ジフルオロエチル トリフルオロメタンスルホネート(54 mg)、TEA(0.07 mL)及びDMF(6.2 mL)の混合物を60℃で一終夜攪拌後、室温に冷却した。反応液に飽和重曹水及び酢酸エチルを加え、分液操作を行った。有機層を飽和食塩水で洗浄後、乾燥して減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー(クロロホルム/メタノール=100:0-85:15)で精製した。精製物にエタノール及び4M塩化水素/ジオキサンを加え、減圧下濃縮し、4-クロロ-N-[1-(2,2-ジフルオロエチル)ピペリジン-4-イル]-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド 塩酸塩(42 mg)を得た。
実施例１１
　4-クロロ-N-(ピペリジン-4-イル)-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド 二塩酸塩(60 mg)、TEA(49 mg)及びDMF(3 mL)の混合物にブロモアセトニトリル(32 mg)を加え室温で一終夜攪拌した。反応液に1M水酸化ナトリウム水溶液及び酢酸エチルを加え、分液操作を行った。有機層を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー(クロロホルム/メタノール=100:0-85:15)で精製した。精製物に酢酸エチル及び4M塩化水素/酢酸エチルを加え、減圧下濃縮し、4-クロロ-N-[1-(シアノメチル)ピペリジン-4-イル]-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド 塩酸塩(51 mg)を得た。
実施例１２
　4-クロロ-N-(ピペリジン-4-イル)-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド 二塩酸塩(60 mg)、及びTEA(0.05 mL)のエタノール溶液(4.8 mL)に、(S)-(-)-プロピレン オキシド(0.09 mL)を加え、室温で18時間攪拌した。反応液に飽和重曹水及び酢酸エチルを加え、分液操作を行った。有機層を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー(クロロホルム/メタノール=100:0-85:15)で精製した。精製物に酢酸エチル及び4M塩化水素/酢酸エチルを加え、生じた固体をろ取し、4-クロロ-N-{1-[(2S)-2-ヒドロキシプロピル]ピペリジン-4-イル}-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド 塩酸塩(14 mg)を得た。 Example 10
4-chloro-N- (piperidin-4-yl) -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide dihydrochloride (62 mg), 2,2-difluoroethyl trifluoromethanesulfonate ( A mixture of 54 mg), TEA (0.07 mL) and DMF (6.2 mL) was stirred at 60 ° C. overnight and then cooled to room temperature. A saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and a liquid separation operation was performed. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 100: 0-85: 15). Ethanol and 4M hydrogen chloride / dioxane were added to the purified product, concentrated under reduced pressure, and 4-chloro-N- [1- (2,2-difluoroethyl) piperidin-4-yl] -1- (2,4,6 -Trifluorophenyl) isoquinoline-7-carboxamide hydrochloride (42 mg) was obtained.
Example 11
4-Chloro-N- (piperidin-4-yl) -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide dihydrochloride (60 mg), TEA (49 mg) and DMF (3 mL Bromoacetonitrile (32 mg) was added to the mixture and the mixture was stirred overnight at room temperature. A 1M aqueous sodium hydroxide solution and ethyl acetate were added to the reaction solution, and a liquid separation operation was performed. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 100: 0-85: 15). Ethyl acetate and 4M hydrogen chloride / ethyl acetate were added to the purified product, concentrated under reduced pressure, and 4-chloro-N- [1- (cyanomethyl) piperidin-4-yl] -1- (2,4,6-trifluoro Phenyl) isoquinoline-7-carboxamide hydrochloride (51 mg) was obtained.
Example 12
4-chloro-N- (piperidin-4-yl) -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide dihydrochloride (60 mg) and TEA (0.05 mL) in ethanol ( (S)-(-)-propylene oxide (0.09 mL) was added to 4.8 mL), and the mixture was stirred at room temperature for 18 hours. A saturated aqueous sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and a liquid separation operation was performed. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 100: 0-85: 15). Ethyl acetate and 4M hydrogen chloride / ethyl acetate were added to the purified product, and the resulting solid was collected by filtration, and 4-chloro-N- {1-[(2S) -2-hydroxypropyl] piperidin-4-yl} -1 -(2,4,6-trifluorophenyl) isoquinoline-7-carboxamide hydrochloride (14 mg) was obtained.
実施例１３
　4-クロロ-N-(ピペリジン-4-イル)-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド 二塩酸塩(80 mg)、TEA(82 mg)及びジクロロメタン(4 mL)の混合物に塩化アセチル(28 mg)を加え室温で一終夜攪拌した。反応液に1M水酸化ナトリウム水溶液及び酢酸エチルを加え、分液操作を行った。有機層を減圧下濃縮して、残渣をシリカゲルカラムクロマトグラフィー(クロロホルム/メタノール=100:0-85:15)で精製し、N-(1-アセチルピペリジン-4-イル)-4-クロロ-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド(50 mg)を得た。
実施例１４
　tert-ブチル4-({[4-クロロ-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-イル]カルボニル}アミノ)ピペリジン-1-カルボキシラート(169 mg)及び酢酸エチル(10 mL)の混合物に、4M 塩化水素/酢酸エチル(10 mL)を加え、室温で1日間攪拌後、反応液を減圧下濃縮した。残渣を酢酸エチルで洗浄し、4-クロロ-N-(ピペリジン-4-イル)-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド 二塩酸塩(161 mg)を得た。
実施例１５
　4-クロロ-N-(ピペリジン-4-イル)-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド 二塩酸塩(164 mg)、2-ブロモアセトアミド(61 mg)、DIPEA(129 mg)及びアセトニトリル(47 mL)の混合物を、室温で1日間攪拌した。反応液に1M水酸化ナトリウム水溶液(10 mL)及び酢酸エチルを加え分液操作を行った。有機層を飽和食塩水で洗浄後、乾燥して減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール=10:0-85:15）で精製した。精製物に酢酸エチル及び4M塩化水素/酢酸エチルを加え、反応液を減圧下濃縮し、N-[1-(2-アミノ-2-オキソエチル)ピペリジン-4-イル]-4-クロロ-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド 塩酸塩(13 mg)を得た。 Example 13
4-Chloro-N- (piperidin-4-yl) -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide dihydrochloride (80 mg), TEA (82 mg) and dichloromethane (4 mL ) Was added to the mixture and stirred at room temperature overnight. A 1M aqueous sodium hydroxide solution and ethyl acetate were added to the reaction solution, and a liquid separation operation was performed. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 100: 0-85: 15), and N- (1-acetylpiperidin-4-yl) -4-chloro-1 -(2,4,6-trifluorophenyl) isoquinoline-7-carboxamide (50 mg) was obtained.
Example 14
tert-butyl 4-({[4-chloro-1- (2,4,6-trifluorophenyl) isoquinolin-7-yl] carbonyl} amino) piperidine-1-carboxylate (169 mg) and ethyl acetate (10 4M hydrogen chloride / ethyl acetate (10 mL) was added to the mixture, and the mixture was stirred at room temperature for 1 day, and then the reaction mixture was concentrated under reduced pressure. The residue was washed with ethyl acetate to obtain 4-chloro-N- (piperidin-4-yl) -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide dihydrochloride (161 mg) .
Example 15
4-chloro-N- (piperidin-4-yl) -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide dihydrochloride (164 mg), 2-bromoacetamide (61 mg), DIPEA A mixture of (129 mg) and acetonitrile (47 mL) was stirred at room temperature for 1 day. A 1M aqueous sodium hydroxide solution (10 mL) and ethyl acetate were added to the reaction solution to carry out a liquid separation operation. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 10: 0-85: 15). Ethyl acetate and 4M hydrogen chloride / ethyl acetate were added to the purified product, and the reaction mixture was concentrated under reduced pressure to give N- [1- (2-amino-2-oxoethyl) piperidin-4-yl] -4-chloro-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide hydrochloride (13 mg) was obtained.
実施例１６
　6-[({[4-クロロ-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-イル]カルボニル}アミノ)メチル]ニコチン酸(50 mg)及びDMF(10 mL)の混合物に、CDI(25 mg)を加えて室温で1時間攪拌後、28%アンモニア水(5 mL)を加え、油温60℃で16時間攪拌した。反応液を室温に冷却し、減圧下濃縮した。残渣に水を加え、不溶物をろ取し、N-[(5-カルバモイルピリジン-2-イル)メチル]-4-クロロ-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド(14 mg)を得た。
実施例１７
　4-クロロ-N-[(2S)-ピペリジン-2-イルメチル]-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド 塩酸塩(70 mg)、DIPEA(57 mg)、ヨウ化メチル(28 mg)及びエタノール(1 mL)の混合物をマイクロウェーブ照射下、120℃で30分間攪拌した。反応液に1M水酸化ナトリウム水溶液(10 mL)及び酢酸エチルを加え分液操作を行った。有機層を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー(クロロホルム/メタノール=100:0-85:15)で精製した。精製物にエタノール及び4M塩化水素/ジオキサンを加え、減圧下濃縮し、4-クロロ-N-{[(2S)-1-メチルピペリジン-2-イル]メチル}-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド 塩酸塩(6 mg)を得た。
実施例１８
　4-クロロ-N-[(3S,4S)-4-メトキシピロリジン-3-イル]-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド 塩酸塩(60 mg)及びジクロロエタン(5 mL)の混合物に、DIPEA(49 mg)を加え室温で30分間攪拌後、37%ホルムアルデヒド水溶液(100 mg)、酢酸(38 mg)及びトリアセトキシ水素化ホウ素ナトリウム(40 mg)を加え、室温で18時間攪拌した。反応液に1M水酸化ナトリウム水溶液(10 mL)及びクロロホルムを加え分液操作を行った。有機層を減圧下濃縮し、残渣をシリカゲルクロマトグラフィー(クロロホルム/メタノール=100:0-85:15)で精製した。精製物にエタノール及びフマル酸を加え、生じた固体をろ取し、4-クロロ-N-[(3S,4S)-4-メトキシ-1-メチルピロリジン-3-イル]-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド フマル酸塩(24 mg)を得た。 Example 16
To a mixture of 6-[({[4-chloro-1- (2,4,6-trifluorophenyl) isoquinolin-7-yl] carbonyl} amino) methyl] nicotinic acid (50 mg) and DMF (10 mL) , CDI (25 mg) was added, and the mixture was stirred at room temperature for 1 hr, 28% aqueous ammonia (5 mL) was added, and the mixture was stirred at an oil temperature of 60 ° C. for 16 hr. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Water was added to the residue, the insoluble material was collected by filtration, and N-[(5-carbamoylpyridin-2-yl) methyl] -4-chloro-1- (2,4,6-trifluorophenyl) isoquinoline-7- Carboxamide (14 mg) was obtained.
Example 17
4-Chloro-N-[(2S) -piperidin-2-ylmethyl] -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide hydrochloride (70 mg), DIPEA (57 mg), iodine A mixture of methyl chloride (28 mg) and ethanol (1 mL) was stirred at 120 ° C. for 30 minutes under microwave irradiation. A 1M aqueous sodium hydroxide solution (10 mL) and ethyl acetate were added to the reaction solution to carry out a liquid separation operation. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 100: 0-85: 15). Ethanol and 4M hydrogen chloride / dioxane were added to the purified product, concentrated under reduced pressure, and 4-chloro-N-{[(2S) -1-methylpiperidin-2-yl] methyl} -1- (2,4,6 -Trifluorophenyl) isoquinoline-7-carboxamide hydrochloride (6 mg) was obtained.
Example 18
4-chloro-N-[(3S, 4S) -4-methoxypyrrolidin-3-yl] -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide hydrochloride (60 mg) and dichloroethane ( 5 mL), add DIPEA (49 mg) and stir at room temperature for 30 minutes. For 18 hours. A 1M aqueous sodium hydroxide solution (10 mL) and chloroform were added to the reaction solution to carry out a liquid separation operation. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform / methanol = 100: 0-85: 15). Ethanol and fumaric acid were added to the purified product, and the resulting solid was collected by filtration, and 4-chloro-N-[(3S, 4S) -4-methoxy-1-methylpyrrolidin-3-yl] -1- (2, 4,6-Trifluorophenyl) isoquinoline-7-carboxamide fumarate (24 mg) was obtained.
実施例１９
　6-ニトロイミダゾ[1,2-a]ピリジン(584 mg)、メタノール(41 mg)及び10%パラジウム/炭素(905 mg)の混合物を水素ガス雰囲気下、室温で3時間攪拌した。反応液をセライトろ過し、ろ液を減圧下濃縮した。得られた残渣に、4-クロロ-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボン酸(300 mg)、DIPEA(115 mg)、DMF(10 mL)及びO-(7-アザベンゾトリアゾール-1-イル)-N,N,N',N',-テトラメチルウロニウムヘキサフルオロりん酸塩(507 mg)を加え、室温で20時間攪拌した。反応液に1M水酸化ナトリウム水溶液及び酢酸エチルを加え、分液操作を行った。有機層を水で洗浄後、乾燥して減圧下濃縮し、残渣をシリカゲルクロマトグラフィー(クロロホルム/メタノール=100:0-85:15)で精製し、4-クロロ-N-(イミダゾ[1,2-a]ピリジン-6-イル)-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド(106 mg)を得た。また、別の分画より得た精製物に、エタノール及びフマル酸を加え、生じた固体をろ取し、4-クロロ-N-(5,6,7,8-テトラヒドロイミダゾ[1,2-a]ピリジン-6-イル)-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド フマル酸塩(43 mg)（後記表中、実施例番号１２２の化合物）を得た。
実施例２０
　4-クロロ-1-(2-フルオロフェニル)-N-(1H-イミダゾール-2-イルメチル)イソキノリン-7-カルボキサミド(88 mg)及びDMF(20 mL)の混合物に、1-クロロピロリジン-2,5-ジオン(34 mg)を加え、室温で1日攪拌した。反応液に水及び酢酸エチルを加え、分液操作を行った。有機層を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー(クロロホルム/メタノール=100:0-85:15)で精製し、4-クロロ-N-[(4-クロロ-1H-イミダゾール-2-イル)メチル]-1-(2-フルオロフェニルイソキノリン-7-カルボキサミド(6 mg)を得た。また、別の分画より、4-クロロ-N-[(4,5-ジクロロ-1H-イミダゾール-2-イル)メチル]-1-(2-フルオロフェニル)イソキノリン-7-カルボキサミド(17 mg)（後記表中、実施例１２５の化合物）を得た。
実施例２１
　アルゴンガス雰囲気下、N-[(6-クロロピリジン-3-イル)メチル]-1-(2-フルオロフェニルl)-4-メチルイソキノリン-7-カルボキサミド(269 mg)、トリメチルボロキシン(210 mg)、リン酸カリウム(422 mg)、トルエン(6 mL)及び水(0.4 mL)の混合物に、酢酸パラジウム(15 mg)、及びトリシクロヘキシルホスフィン(37 mg)を加え、油温100℃で1日間攪拌した。反応液を室温に冷却後、酢酸エチル及び水を加え、セライトろ過した。ろ液に酢酸エチル及び水を加え分液操作を行い、有機層を飽和食塩水で洗浄後、乾燥して減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール=100:0-85:15)で精製し、1-(2-フルオロフェニル)-4-メチル-N-[(6-メチルピリジン-3-イル)メチル]イソキノリン-7-カルボキサミド(39 mg)を得た。 Example 19
A mixture of 6-nitroimidazo [1,2-a] pyridine (584 mg), methanol (41 mg) and 10% palladium / carbon (905 mg) was stirred at room temperature for 3 hours in a hydrogen gas atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. To the resulting residue, 4-chloro-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxylic acid (300 mg), DIPEA (115 mg), DMF (10 mL) and O- (7 -Azabenzotriazol-1-yl) -N, N, N ′, N ′,-tetramethyluronium hexafluorophosphate (507 mg) was added, and the mixture was stirred at room temperature for 20 hours. A 1M aqueous sodium hydroxide solution and ethyl acetate were added to the reaction solution, and a liquid separation operation was performed. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform / methanol = 100: 0-85: 15), and 4-chloro-N- (imidazo [1,2 -a] pyridin-6-yl) -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide (106 mg) was obtained. Further, ethanol and fumaric acid were added to the purified product obtained from another fraction, and the resulting solid was collected by filtration, and 4-chloro-N- (5,6,7,8-tetrahydroimidazo [1,2- a] pyridin-6-yl) -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide fumarate (43 mg) (the compound of Example No. 122 in the table below) was obtained.
Example 20
To a mixture of 4-chloro-1- (2-fluorophenyl) -N- (1H-imidazol-2-ylmethyl) isoquinoline-7-carboxamide (88 mg) and DMF (20 mL) was added 1-chloropyrrolidine-2, 5-dione (34 mg) was added, and the mixture was stirred at room temperature for 1 day. Water and ethyl acetate were added to the reaction liquid, and liquid separation operation was performed. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 100: 0-85: 15) to give 4-chloro-N-[(4-chloro-1H-imidazol-2-yl ) Methyl] -1- (2-fluorophenylisoquinoline-7-carboxamide (6 mg) was obtained, and 4-chloro-N-[(4,5-dichloro-1H-imidazole- 2-yl) methyl] -1- (2-fluorophenyl) isoquinoline-7-carboxamide (17 mg) (the compound of Example 125 in the table below) was obtained.
Example 21
Under an argon gas atmosphere, N-[(6-chloropyridin-3-yl) methyl] -1- (2-fluorophenyl-l) -4-methylisoquinoline-7-carboxamide (269 mg), trimethylboroxine (210 mg ), Potassium phosphate (422 mg), toluene (6 mL) and water (0.4 mL), palladium acetate (15 mg) and tricyclohexylphosphine (37 mg) are added, and the oil temperature is 100 ° C. for 1 day. Stir. The reaction mixture was cooled to room temperature, ethyl acetate and water were added, and the mixture was filtered through Celite. Ethyl acetate and water were added to the filtrate for liquid separation, and the organic layer was washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 100: 0-85: 15), and 1- (2-fluorophenyl) -4-methyl-N-[(6-methylpyridin-3-yl) methyl Isoquinoline-7-carboxamide (39 mg) was obtained.
実施例２２
　4-クロロ-1-(2-フルオロフェニル)-N-(1H-イミダゾール-2-イルメチル)イソキノリン-7-カルボキサミド(60 mg)、2-ブロモエチルメチルエーテル(24 mg)、炭酸セシウム(128 mg)及びN-メチルピロリドン(1 mL)の混合物をマイクロウェーブ照射下、120℃で15分間攪拌した。反応溶液を氷冷し、水及び酢酸エチルを加えて分液操作を行った。有機層を減圧下濃縮して、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール=100:0-85:15）で精製し、4-クロロ-1-(2-フルオロフェニル)-N-{[1-(2-メトキシエチル)-1H-イミダゾール-2-イル]メチル}イソキノリン-7-カルボキサミド(48 mg)を得た。
実施例２３
　4-クロロ-1-(2-フルオロフェニル)-N-(1H-イミダゾール-2-イルメチル)イソキノリン-7-カルボキサミド(60 mg)、2-ブロモアセトアミド(24 mg)、炭酸セシウム(128 mg)及びDMF(10 mL)の混合物を、油温60℃で15時間攪拌した。反応液を室温に冷却後、酢酸エチル及び水を加えて分液操作を行った。有機層を水及び飽和食塩水で順次洗浄し、乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール = 100/0-85:15）で精製後、ジイソプロピルエーテルで洗浄し、N-{[1-(2-アミノ-2-オキソエチル)-1H-イミダゾール-2-イル]メチル}-4-クロロ-1-(2-フルオロフェニル)イソキノリン-7-カルボキサミド(24 mg)を得た。
実施例２４
　4-クロロ-1-(2-フルオロフェニル)-N-(1H-イミダゾール-2-イルメチル)イソキノリン-7-カルボキサミド(52 mg)、DIPEA(35 mg)、1M オキシラン/THF溶液(1.4 mL)、メタノール(1 mL)及びN-メチルピロリドン(1 mL)の混合物を、マイクロウェーブ照射下60℃で30分間攪拌し、更に150℃で15分間攪拌した。室温まで放冷後、反応液に酢酸エチル及び水を加え分液操作を行った。有機層を水及び飽和食塩水で順次洗浄し、乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール=100/0-85:15）で精製して、ジイソプロピルエーテルで洗浄し、4-クロロ-1-(2-フルオロフェニル)-N-{[1-(2-ヒドロキシエチル)-1H-イミダゾール-2-イル]メチル}イソキノリン-7-カルボキサミド(24 mg)を得た。 Example 22
4-Chloro-1- (2-fluorophenyl) -N- (1H-imidazol-2-ylmethyl) isoquinoline-7-carboxamide (60 mg), 2-bromoethyl methyl ether (24 mg), cesium carbonate (128 mg ) And N-methylpyrrolidone (1 mL) were stirred at 120 ° C. for 15 minutes under microwave irradiation. The reaction solution was ice-cooled, and water and ethyl acetate were added to carry out a liquid separation operation. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 100: 0-85: 15) to give 4-chloro-1- (2-fluorophenyl) -N-{[1 -(2-Methoxyethyl) -1H-imidazol-2-yl] methyl} isoquinoline-7-carboxamide (48 mg) was obtained.
Example 23
4-chloro-1- (2-fluorophenyl) -N- (1H-imidazol-2-ylmethyl) isoquinoline-7-carboxamide (60 mg), 2-bromoacetamide (24 mg), cesium carbonate (128 mg) and A mixture of DMF (10 mL) was stirred at an oil temperature of 60 ° C. for 15 hours. After the reaction solution was cooled to room temperature, ethyl acetate and water were added to carry out a liquid separation operation. The organic layer was washed successively with water and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 100 / 0-85: 15), washed with diisopropyl ether, and N-{[1- (2-amino-2-oxoethyl) -1H-imidazole-2 -Il] methyl} -4-chloro-1- (2-fluorophenyl) isoquinoline-7-carboxamide (24 mg) was obtained.
Example 24
4-chloro-1- (2-fluorophenyl) -N- (1H-imidazol-2-ylmethyl) isoquinoline-7-carboxamide (52 mg), DIPEA (35 mg), 1M oxirane / THF solution (1.4 mL), A mixture of methanol (1 mL) and N-methylpyrrolidone (1 mL) was stirred at 60 ° C. for 30 minutes under microwave irradiation, and further stirred at 150 ° C. for 15 minutes. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction solution to carry out a liquid separation operation. The organic layer was washed successively with water and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 100 / 0-85: 15), washed with diisopropyl ether, and 4-chloro-1- (2-fluorophenyl) -N-{[1- ( 2-Hydroxyethyl) -1H-imidazol-2-yl] methyl} isoquinoline-7-carboxamide (24 mg) was obtained.
実施例２５
　アルゴンガス雰囲気下、4-クロロ-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボン酸(60 mg)及びジクロロメタン(1 mL)の混合物に、氷冷下、塩化オキサリル(25 mg)、及びDMF(0.01 mL)を順次加え、室温で1.5時間攪拌した溶液を、別容器のピリミジン-2-アミン(20 mg)、TEA(18 mg)及びジクロロメタン(1 mL)の混合物に氷冷下滴下し、室温で2時間撹拌した。反応液にメタノールを加えて減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール=10:0-9:1）で精製し、4-クロロ-N-(ピリミジン-2-イル)-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド(5 mg)を得た。
実施例２６
　エチル-2-[({[4-クロロ-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-イル]カルボニル}アミノ)メチル]-1,3-チアゾール-4-カルボキシラート(50 mg)、エタノール(0.5 mL)及びTHF(0.5 mL)の混合物に、1M水酸化ナトリウム水溶液(0.5 mL)を加え、油温50℃で0.5時間攪拌した。反応液を減圧下濃縮し、水、及びジエチルエーテルを加え分液操作を行った。水層を1M塩酸で弱酸性とし、クロロホルムを加えて分液操作を行った。有機層を飽和食塩水で洗浄後、乾燥して、減圧下濃縮し、2-[({[4-クロロ-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-イル]カルボニル}アミノ)メチル]-1,3-チアゾール-4-カルボン酸(38 mg)を得た。
実施例２７
　2-[({[4-クロロ-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-イル]カルボニル}アミノ)メチル]-1,3-チアゾール-4-カルボン酸(30 mg)、HOBt(13 mg)、WSC塩酸塩(18 mg)、及びDMF(1.2 mL)の混合物を、室温で1時間攪拌後、28%アンモニア水(0.04 mL)を加え、室温で更に16時間攪拌した。反応液に水及び酢酸エチルを加え、分液操作を行った。有機層を飽和食塩水で洗浄後、乾燥して減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール=10:0-9:1）で精製し、N-[(4-カルバモイル-1,3-チアゾール-2-イル)メチル]-4-クロロ-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド(16 mg)を得た。 Example 25
Under an argon gas atmosphere, a mixture of 4-chloro-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxylic acid (60 mg) and dichloromethane (1 mL) was added to oxalyl chloride (25 mg) and DMF (0.01 mL) were added sequentially, and the solution stirred at room temperature for 1.5 hours was added to a mixture of pyrimidine-2-amine (20 mg), TEA (18 mg) and dichloromethane (1 mL) in a separate container with ice. The solution was added dropwise under cooling and stirred at room temperature for 2 hours. Methanol was added to the reaction mixture and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 10: 0-9: 1) to give 4-chloro-N- (pyrimidin-2-yl) -1 -(2,4,6-trifluorophenyl) isoquinoline-7-carboxamide (5 mg) was obtained.
Example 26
Ethyl-2-[({[4-chloro-1- (2,4,6-trifluorophenyl) isoquinolin-7-yl] carbonyl} amino) methyl] -1,3-thiazole-4-carboxylate (50 mg), ethanol (0.5 mL) and THF (0.5 mL) were added 1M aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at an oil temperature of 50 ° C. for 0.5 hr. The reaction solution was concentrated under reduced pressure, and water and diethyl ether were added to carry out a liquid separation operation. The aqueous layer was weakly acidified with 1M hydrochloric acid, and chloroform was added to carry out a liquid separation operation. The organic layer was washed with saturated brine, dried, concentrated under reduced pressure, and 2-[({[4-chloro-1- (2,4,6-trifluorophenyl) isoquinolin-7-yl] carbonyl}. Amino) methyl] -1,3-thiazole-4-carboxylic acid (38 mg) was obtained.
Example 27
2-[({[4-Chloro-1- (2,4,6-trifluorophenyl) isoquinolin-7-yl] carbonyl} amino) methyl] -1,3-thiazole-4-carboxylic acid (30 mg) , HOBt (13 mg), WSC hydrochloride (18 mg), and DMF (1.2 mL) were stirred at room temperature for 1 hour, 28% aqueous ammonia (0.04 mL) was added, and the mixture was further stirred at room temperature for 16 hours. . Water and ethyl acetate were added to the reaction liquid, and liquid separation operation was performed. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 10: 0-9: 1), and N-[(4-carbamoyl-1,3-thiazol-2-yl) methyl] -4-chloro-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide (16 mg) was obtained.
実施例２８
　アルゴンガス雰囲気下、N-[(4-カルバモイル-1,3-チアゾール-2-イル)メチル]-4-クロロ-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド(10 mg)及びピリジン(0.13 mL)の混合物に、氷冷下、塩化ホスホリル(2.5 μL)を加え、室温で1時間攪拌した。反応液に水及び酢酸エチルを加え、分液操作を行った。有機層を飽和食塩水で洗浄後、乾燥して、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール=100:0-95:5）で精製し、4-クロロ-N-[(4-シアノ-1,3-チアゾール-2-イル)メチル]-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド(3 mg)を得た。
実施例２９
　4-クロロ-N-{[4-(ヒドロキシメチル)-1,3-チアゾール-2-イル]メチル}-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド(14 mg)及びメタノール(720 mL)の混合物に、オルトギ酸トリメチル(640 mg)及び硫酸(31 mg)を加え、加熱還流下3時間攪拌した。室温に冷却後、反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール=100:0-92:8）で精製し、4-クロロ-N-{[4-(メトキシメチルl)-1,3-チアゾール-2-イル]メチル}-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド(4 mg)を得た。
実施例３０
　4-クロロ-N-[2-ヒドロキシ-2-(1-トリチル-1H-イミダゾール-2-イル)エチル]-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド(120 mg)とジオキサン(3.5 mL)の混合物に、1M塩酸(2 mL)を加え、油温60℃で2時間加熱攪拌し、室温に冷却した。反応液に1M水酸化ナトリウム水溶液を加え中和した後、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄後、乾燥、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール=10:0-9:1）で精製し、4-クロロ-N-[2-ヒドロキシ-2-(1-トリチル-1H-イミダゾール-2-イル)エチル]-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド(57 mg)を得た。
実施例３１
　1,2,2,6,6-ペンタメチルピペリジン-4-アミン(4.3 mg)に、4-クロロ-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボン酸(8.4 mg)、DIPEA(19.2 μl)のDMF溶液(400 μl)、及びN-[(ジメチルアミノ)(3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-3-イルオキシ)メチレン]-N-メチルメタナミニウム ヘキサフルオロリン酸(11.4mg)のDMF溶液(100μl)を加え、室温で一終夜攪拌した。反応液に水及びクロロホルムを加えて分液操作を行い、有機層を減圧下濃縮した。HPLC（高速液相カラムクロマトグラフィー）で分取精製を行い、4-クロロ-N-(1,2,2,6,6-ペンタメチルピぺリジン-4-イル)-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド(10.1 mg)を得た。 Example 28
Under an argon gas atmosphere, N-[(4-carbamoyl-1,3-thiazol-2-yl) methyl] -4-chloro-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide (10 mg) and pyridine (0.13 mL) were added phosphoryl chloride (2.5 μL) under ice-cooling and stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction liquid, and liquid separation operation was performed. The organic layer was washed with saturated brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 100: 0-95: 5) to give 4-chloro-N-[(4-cyano-1,3-thiazol-2-yl) methyl] -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide (3 mg) was obtained.
Example 29
4-Chloro-N-{[4- (hydroxymethyl) -1,3-thiazol-2-yl] methyl} -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide (14 mg) And methanol (720 mL) were added trimethyl orthoformate (640 mg) and sulfuric acid (31 mg), and the mixture was stirred with heating under reflux for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 100: 0-92: 8) to give 4-chloro-N-{[4- (methoxymethyl-l ) -1,3-thiazol-2-yl] methyl} -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide (4 mg) was obtained.
Example 30
4-Chloro-N- [2-hydroxy-2- (1-trityl-1H-imidazol-2-yl) ethyl] -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide (120 mg ) And dioxane (3.5 mL), 1M hydrochloric acid (2 mL) was added, and the mixture was stirred with heating at an oil temperature of 60 ° C. for 2 hours and cooled to room temperature. The reaction mixture was neutralized with 1M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 10: 0-9: 1) and 4-chloro-N- [2-hydroxy-2- (1-trityl-1H-imidazol-2-yl) ethyl ] -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide (57 mg) was obtained.
Example 31
1,2,2,6,6-pentamethylpiperidin-4-amine (4.3 mg) and 4-chloro-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxylic acid (8.4 mg) , DIPEA (19.2 μl) in DMF (400 μl), and N-[(dimethylamino) (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methylene] -N -Methylmethananium Hexafluorophosphoric acid (11.4 mg) in DMF (100 μl) was added and stirred at room temperature overnight. Water and chloroform were added to the reaction solution to carry out a liquid separation operation, and the organic layer was concentrated under reduced pressure. Preparative purification is performed by HPLC (high performance liquid phase column chromatography), and 4-chloro-N- (1,2,2,6,6-pentamethylpiperidin-4-yl) -1- (2,4,6 -Trifluorophenyl) isoquinoline-7-carboxamide (10.1 mg) was obtained.
実施例３５９
tert-ブチル(2S)-2-[({[4-クロロ-1-(2-フルオロフェニル)イソキノリン-7-イル]カルボニル}アミノ)メチル]ピペリジン-1-カルボキシラート(157 mg)のジオキサン(1 mL)溶液に、室温で塩化水素 (約4 mol/L ジオキサン溶液 1 mL)を加え、室温で2時間撹拌した。反応液を減圧下濃縮し、乾燥することで4-クロロ-1-(2-フルオロフェニル)-N-[(2S)-ピペリジン-2-イルメチル]イソキノリン-7-カルボキサミド一塩酸塩(136 mg)を得た。
実施例３６０
4-クロロ-1-(2-フルオロフェニル)-N-[(2S)-ピペリジン-2-イルメチル]イソキノリン-7-カルボキサミド一塩酸塩（63 mg）のDMF(2 mL)溶液に、炭酸カリウム(mg)、よう化メチル(11μL)を順次加え、室温にて5時間攪拌した。反応液に水を加え、酢酸エチルで抽出、飽和食塩水で順次洗浄し、乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール=100:0-95:5）にて精製し、4-クロロ-1-(2-フルオロフェニル)-N-{[(2S)-1-メチルピペリジン-2-イル]メチル}イソキノリン-7-カルボキサミド(18 mg)を得た。 Example 359
tert-butyl (2S) -2-[({[4-chloro-1- (2-fluorophenyl) isoquinolin-7-yl] carbonyl} amino) methyl] piperidine-1-carboxylate (157 mg) in dioxane ( 1 mL) solution was added with hydrogen chloride (approximately 4 mol / L dioxane solution 1 mL) at room temperature and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and dried to give 4-chloro-1- (2-fluorophenyl) -N-[(2S) -piperidin-2-ylmethyl] isoquinoline-7-carboxamide monohydrochloride (136 mg) Got.
Example 360
4-Chloro-1- (2-fluorophenyl) -N-[(2S) -piperidin-2-ylmethyl] isoquinoline-7-carboxamide monohydrochloride (63 mg) in DMF (2 mL) was added to potassium carbonate ( mg) and methyl iodide (11 μL) were sequentially added, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed successively with saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 100: 0-95: 5) to give 4-chloro-1- (2-fluorophenyl) -N-{[(2S) -1-methylpiperidine- 2-Iyl] methyl} isoquinoline-7-carboxamide (18 mg) was obtained.
　上記実施例の方法と同様にして後記表に示す実施例化合物をそれぞれ対応する原料を使用して製造した。また、実施例化合物の構造式、物理化学的データ及び製造法を後記表に示す。 Example compounds shown in the table below were produced using the corresponding raw materials in the same manner as in the above examples. The structural formulas, physicochemical data and production methods of the example compounds are shown in the table below.
　後記表中以下の略号を用いる。
PEx：製造例番号、Ex：実施例番号、Str：構造式、Dat：物理化学的データ（ESI+： ESI-MS[M+H]+又はESI-MS[M]+；APCI/ESI+：APCI/ESI-MS[M+H]+又はAPCI/ESI-MS[M]+（APCI/ESIはAPCIとESIの同時測定を意味する）； NMR：CDCl3又はDMSO-d6中の1HNMRにおけるピークのδ(ppm)）「-」：未測定、Me：メチル、Et：エチル、nPr：ノルマルプロピル、iPr：イソプロピル、cPr：シクロプロピル、iBu：イソブチル、cBu：シクロブチル、cPen：シクロペンチル、cHex：シクロへキシル、tBu：tert-ブチル、Ph：フェニル、Tf：トリフルオロメタンスルホニル、Boc：tert-ブトキシカルボニル、Ac：アセチル、Bn:ベンジル、Trt:トリチル、TMS:トリメチルシリル、Fum：フマル酸(0.5 Fumはヘミフマル酸塩を意味する)、TFA:トリフルオロ酢酸、DMSO：ジメチルスルホキシド、Syn：製造方法（数字は、当該化合物が、その番号を製造例番号又は実施例番号として有する化合物と同様の方法により、対応する原料を用いて製造したことを示す。例えば「P2」は製造例２の化合物と同様の方法で製造し、「2」は実施例２の化合物と同様に製造したことを示す。）。 The following abbreviations are used in the tables below.
PEx: Production example number, Ex: Example number, Str: Structural formula, Dat: Physicochemical data (ESI +: ESI-MS [M + H] + or ESI-MS [M] + ; APCI / ESI +: APCI / ESI-MS [M + H] + or APCI / ESI-MS [M] + (APCI / ESI means simultaneous measurement of APCI and ESI); NMR: peak in 1 HNMR in CDCl 3 or DMSO-d 6 Δ (ppm)) “-”: not measured, Me: methyl, Et: ethyl, nPr: normal propyl, iPr: isopropyl, cPr: cyclopropyl, iBu: isobutyl, cBu: cyclobutyl, cPen: cyclopentyl, cHex: cyclo Hexyl, tBu: tert-butyl, Ph: phenyl, Tf: trifluoromethanesulfonyl, Boc: tert-butoxycarbonyl, Ac: acetyl, Bn: benzyl, Trt: trityl, TMS: trimethylsilyl, Fum: fumaric acid (0.5 Fum Hemifumarate), TFA: trifluoroacetic acid, DMSO: dimethyl sulfoxide, Syn: production method This indicates that the compound was produced using the corresponding raw material by the same method as the compound having the production number or the example number, for example, “P2” was produced by the same method as the compound of Production Example 2. 2 "indicates that it was prepared in the same manner as the compound of Example 2.)
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000017
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000018
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000019
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000020
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000021
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000022
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000026
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000032
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000033
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000034
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000035
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000036
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000037
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000038
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000039
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000040
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000041
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000043
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000044
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000046
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000047
Figure JPOXMLDOC01-appb-T000048
Figure JPOXMLDOC01-appb-T000048
Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000050
Figure JPOXMLDOC01-appb-T000050
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000053
Figure JPOXMLDOC01-appb-T000053
Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000056
Figure JPOXMLDOC01-appb-T000056
Figure JPOXMLDOC01-appb-T000057
Figure JPOXMLDOC01-appb-T000057
Figure JPOXMLDOC01-appb-T000058
Figure JPOXMLDOC01-appb-T000058
Figure JPOXMLDOC01-appb-T000059
Figure JPOXMLDOC01-appb-T000059
Figure JPOXMLDOC01-appb-T000060
Figure JPOXMLDOC01-appb-T000060
Figure JPOXMLDOC01-appb-T000061
Figure JPOXMLDOC01-appb-T000061
Figure JPOXMLDOC01-appb-T000062
Figure JPOXMLDOC01-appb-T000062
Figure JPOXMLDOC01-appb-T000063
Figure JPOXMLDOC01-appb-T000063
Figure JPOXMLDOC01-appb-T000064
Figure JPOXMLDOC01-appb-T000064
Figure JPOXMLDOC01-appb-T000065
Figure JPOXMLDOC01-appb-T000065
Figure JPOXMLDOC01-appb-T000066
Figure JPOXMLDOC01-appb-T000066
Figure JPOXMLDOC01-appb-T000067
Figure JPOXMLDOC01-appb-T000067
Figure JPOXMLDOC01-appb-T000068
Figure JPOXMLDOC01-appb-T000068
Figure JPOXMLDOC01-appb-T000069
Figure JPOXMLDOC01-appb-T000069
Figure JPOXMLDOC01-appb-T000070
Figure JPOXMLDOC01-appb-T000070
（試験例）
　式（I）の化合物の薬理活性は、以下の試験により確認した。 (Test example)
The pharmacological activity of the compound of formula (I) was confirmed by the following test.
試験例１　ヒト5-HT5A受容体強制発現HEK293細胞の取得
　ヒト5-HT5A受容体（Genbank AF498985）のORF（open reading frame；蛋白質コード領域）をヒト海馬cDNAライブラリーよりクローニングしたのちpCR2.1ベクター（Invitrogen）に挿入し、そのプラスミドを持った大腸菌を大量培養した。次に、ヒト5-HT5A受容体全長cDNA配列解析し、発現ベクターであるpCDNA3.1ベクター（Invitrogen）に組み替え大量培養した。ヒト胎児腎由来株化細胞HEK293細胞（ATCC）を播種し、上記で得られた発現プラスミド（1μg）をLIPOFECTAMINE 2000（Invitrogen; 2μl）とともに加え、HEK293細胞に遺伝子を導入した後、薬剤耐性マーカーであるGeneticin（G418 sulfate 500μg/ml; 関東化学）で発現細胞の選別をした。この様にして作製された当該遺伝子を発現する組換え細胞をD-MEM（ダルベッコ改変イーグル培地、シグマ）、10% FCS（Fetal calf serum：牛胎児血清）、1% Pc./Sm（ペニシリン/ストレプトマイシン、Invitrogen社）、500μg/ml G418 培地により3日間培養を行った。以上の実験操作は、公知の方法（Sambrook, J. et al, "Molecular Cloning-A Laboratory Manual", Cold Spring Harabor laboratory, NY, 1989）等の遺伝子操作実験マニュアルや試薬等に添付の指示書に従った。 PCR2 After the; (protein coding region open reading frame) was cloned from human hippocampus cDNA library acquired human 5-HT 5A receptors in Test Example 1 Human 5-HT 5A receptor forced expression HEK293 cells ORF of (Genbank AF498985). Inserted into 1 vector (Invitrogen), E. coli with the plasmid was cultured in large quantities. Next, the human 5-HT 5A receptor full-length cDNA sequence was analyzed and recombinantly cultured in the expression vector pCDNA3.1 vector (Invitrogen). Human embryonic kidney-derived cell line HEK293 cells (ATCC) are seeded, and the expression plasmid (1 μg) obtained above is added together with LIPOFECTAMINE 2000 (Invitrogen; 2 μl). After introducing the gene into HEK293 cells, An expression cell was selected with a certain geneticin (G418 sulfate 500 μg / ml; Kanto Chemical). Recombinant cells expressing the gene thus produced were D-MEM (Dulbecco's Modified Eagle Medium, Sigma), 10% FCS (Fetal calf serum), 1% Pc./Sm (penicillin / Culturing was performed with streptomycin (Invitrogen) and 500 μg / ml G418 medium for 3 days. The above experimental procedures are described in the instruction manual attached to the genetic manipulation experiment manuals and reagents such as known methods (Sambrook, J. et al, “Molecular Cloning-A Laboratory Manual”, Cold Spring Harabor laboratory, NY, 1989). I followed.
試験例２　ヒト5-HT5A受容体結合阻害試験
（１）ヒト5-HT5A受容体強制発現HEK293細胞からの膜調製
　ヒト5-HT5A受容体強制発現HEK293細胞をF500プレートで培養し、スクレイパーでかきとった。遠心後、沈殿物を集め、インキュベーションバッファー（50mM トリス (HCl) PH7.4、10mM MgSO4、0.5mM EDTA（エチレンジアミン四酢酸））を加えた。ホモジナイズ後、さらに遠心し、沈殿物にインキュベーションバッファーを加えよく懸濁させた。この操作を繰り返した後、タンパク濃度を測定し、膜調製完了とした。
（２）ヒト5-HT5A受容体結合阻害実験
　被検化合物および150μMの5-CT（5-カルボキサミドトリプタミン）のDMSO溶液を2μl/ウェルで96ウェルプレートに加え、インキュベーションバッファーに懸濁し、200μg/mlに調製したヒト5-HT5A受容体強制発現HEK293細胞膜を100μl/ウェルで加えた。室温で15分インキュベーション後、[3H]5-CT溶液(3nM [3H]5-CT、インキュベーションバッファー)を100μl/ウェルで加えた。
　別途、100μlを液体シンチレーションバイアルに分注し、アクアゾールII（Aquasol II：登録商標）を2ml加え攪拌した後、液体シンチレーションカウンターで放射活性を測定した。37℃で60分インキュベーションを行った。反応混合物を0.2% ポリエチレンイミンで前処理した96 ウェル GF/C フィルタープレートに吸引し、氷冷50mMトリス(pH7.5)バッファーで6回洗浄した。GF/Cフィルタープレートを乾燥させた。
　マイクロシンチPS（MicroscintTMPS：登録商標）を40μl/ウェルで添加した。トップカウントにてGF/Cフィルタープレート上に残存する放射活性を測定した。
　各実験における被検化合物による[3H]5-CT結合阻害活性は、DMSOのみを加えた時の放射活性を0%、1μM 5-CTを加えた時の放射活性を100%阻害として、IC50値を算出した。別途、スキャッチャード解析より求めた[3H]5-CTのKd値より、Ki値を以下の式より算出した。
　Ki=IC50(1+添加したリガンド濃度/Kd (4.95nM)) Test Example 2 Human 5-HT 5A receptor binding inhibition test (1) were cultured in F500 plates membrane preparation Human 5-HT 5A receptor forced expression HEK293 cells from human 5-HT 5A receptor forced expression HEK293 cells, scraper I've written it. After centrifugation, the precipitate was collected, and incubation buffer (50 mM Tris (HCl) PH7.4, 10 mM MgSO 4 , 0.5 mM EDTA (ethylenediaminetetraacetic acid)) was added. After homogenization, the mixture was further centrifuged, and an incubation buffer was added to the precipitate to suspend well. After repeating this operation, the protein concentration was measured and the membrane preparation was completed.
(2) Human 5-HT 5A receptor binding inhibition test A test compound and 150 μM of 5-CT (5-carboxamide tryptamine) in DMSO at 2 μl / well are added to a 96-well plate, suspended in an incubation buffer, and 200 μg / Human 5-HT 5A receptor forced expression HEK293 cell membrane prepared in ml was added at 100 μl / well. After 15 minutes incubation at room temperature, [ 3 H] 5-CT solution (3 nM [ 3 H] 5-CT, incubation buffer) was added at 100 μl / well.
Separately, 100 μl was dispensed into a liquid scintillation vial, 2 ml of Aquasol II (registered trademark) was added and stirred, and then the radioactivity was measured with a liquid scintillation counter. Incubation was performed at 37 ° C for 60 minutes. The reaction mixture was aspirated into a 96-well GF / C filter plate pretreated with 0.2% polyethyleneimine and washed 6 times with ice-cold 50 mM Tris (pH 7.5) buffer. The GF / C filter plate was dried.
Microscint PS (Microscint ™ PS) was added at 40 μl / well. The radioactivity remaining on the GF / C filter plate was measured using a top count.
The [ 3 H] 5-CT binding inhibitory activity by the test compound in each experiment is defined as IC with 0% of the radioactivity when DMSO alone is added, and 100% of the radioactivity when 1 μM 5-CT is added. 50 values were calculated. Separately, the Ki value was calculated from the following formula from the Kd value of [ 3 H] 5-CT determined by Scatchard analysis.
Ki = IC 50 (1+ added ligand concentration / Kd (4.95 nM))
　後記表にいくつかの実施例化合物のKi値を示す。表中Exは実施例番号を示し、「―」は未評価を示す。 The following table shows the Ki values of some example compounds. In the table, Ex indicates an example number, and “-” indicates not evaluated.
Figure JPOXMLDOC01-appb-T000071
 　以上のことから、式(I)の化合物が5-HT5A受容体親和性を有し、他の5-HTサブタイプ受容体である5-HT7受容体よりも、5-HT5A受容体に対する優れたサブタイプ選択性を有することが確認できた。
Figure JPOXMLDOC01-appb-T000071
 From the above, the compound of formula (I) has 5-HT 5A receptor affinity, and 5-HT 5A receptor than 5-HT 7 receptor which is another 5-HT subtype receptor It has been confirmed that it has excellent subtype selectivity for.
試験例３　マウスの運動量を増加させる薬物（MK-801）に対する各種薬剤の評価　(放出赤外線運動量測定法)
　式（Ｉ）の化合物の統合失調症に対する改善効果を、MK-801により症状を惹起したモデルにおいて、化合物投与下で抑制された運動量を測定することにより評価した。
（１）動物
　種：雄ICRマウス
（２）操作手順
　飼育ケージから動物を取り出し被験化合物を経口投与したのち飼育用ケージに入れた。30分後に、測定用ケージに入れて、被験化合物単独の運動量を測定した。さらに30～90分後、動物を取り出し運動量を増加させる薬物（MK-801;0.3mg/kgを、生理食塩水に溶解）をそれぞれ皮下投与または腹腔内投与し、赤外線センサーによる運動量測定装置（CompACT　AMS　室町機械）を用いて一定時間（60分間）の運動量を測定した。
（３）解析
　ノーマルマウス（生理食塩水投与マウス）と運動量を増加させる薬剤を投与したマウスにおいては、それぞれの間隔においてスチューデントT検定（Student's T test）で判定した。被験化合物を投与した群においては、溶媒（vehicle）群とダネット検定（Dunnett's T test）をおこない、検定した。判定は、有意に（P<0.05）差があったときに効果があるとした。
　被験化合物として、式（I）で示される幾つかの化合物を用いた結果、マウスの運動量増加の抑制が確認できた。例えば、実施例32、39、42、62、63、85、106及び158の化合物は、MK-801により誘発された過活動を、各々1.0mg/kg、0.1mg/kg、0.3mg/kg、0.3mg/kg、0.3mg/kg、0.3mg/kg、0.03mg/kg及び0.3mg/kgの投与量で有意に抑制した。このことから、式（Ｉ）の化合物は、統合失調症の症状である運動量増加（過活動）に対して改善効果を有することが確認された。 Test Example 3 Evaluation of various drugs against a drug that increases mouse momentum (MK-801) (Measurement method of infrared radiation momentum)
The improvement effect of the compound of formula (I) on schizophrenia was evaluated by measuring the amount of exercise suppressed under the administration of the compound in a model in which symptoms were induced by MK-801.
(1) Animal species: Male ICR mouse (2) Operating procedure The animal was removed from the breeding cage, and the test compound was orally administered and placed in the breeding cage. After 30 minutes, the test compound alone was measured for momentum in a measurement cage. After another 30-90 minutes, the animal is removed and a drug (MK-801; 0.3 mg / kg dissolved in physiological saline) that increases exercise is administered subcutaneously or intraperitoneally, respectively, and an exercise sensor (CompACT AMS (Muromachi Machine) was used to measure the momentum for a certain period of time (60 minutes).
(3) Analysis In normal mice (saline-administered mice) and mice administered with a drug that increases momentum, determination was made by Student's T test at each interval. In the group to which the test compound was administered, a Dunnett's test (Dunnett's T test) was performed with the vehicle group. Judgment was effective when there was a significant (P <0.05) difference.
As a result of using some compounds represented by the formula (I) as test compounds, it was confirmed that the increase in the momentum of the mice was suppressed. For example, the compounds of Examples 32, 39, 42, 62, 63, 85, 106 and 158 caused MK-801-induced overactivity by 1.0 mg / kg, 0.1 mg / kg, 0.3 mg / kg, respectively. The dose was significantly suppressed at 0.3 mg / kg, 0.3 mg / kg, 0.3 mg / kg, 0.03 mg / kg and 0.3 mg / kg. From this, it was confirmed that the compound of Formula (I) has an improvement effect with respect to the increase in exercise amount (overactivity) which is a symptom of schizophrenia.
試験例４　マウスでのスコポラミン誘発自発交替行動に対する改善効果
　式（Ｉ）の化合物の認知症及び統合失調症の認知障害に対する改善効果を、短期学習障害のモデルとして周知の首記の試験法により評価した。
（１）動物
　種：雄ddYマウス
（２）測定方法
　被験化合物の経口投与後10～30分後に、0.5mg/kgスコポラミン (ノーマル群においては生理食塩水)を腹腔内投与し、その20分後に試験を行った。なお、ノーマル群（生理食塩水を投与した群）と対照群（0.5 mg/kgスコポラミンを投与した群）においては、被験化合物投与時に溶媒（vehicle）を経口投与した。
　3方向に同じ長さのアームをもつ迷路（Y-maze）のアームの一端にマウスを入れて8分間自由に探索させ、この間のアームへのエントリー数をカウントした。また、連続して3つの異なるアームにエントリーした場合を自発交替行動(Spontaneous alternation behavior)とし、この行動数の総エントリー数に対する割合を自発交替率(Alternation rate)として、以下の式により算出した。
　自発交替率(%) =自発交替行動数/ (総エントリー数-2)×100
（３）データ解析
　自発交替率(%)においてノーマル群と対照群の間に有意な差(スチューデントT検定)が認められた場合、スコポラミン投与による学習障害成立と判断した。対照群に対する被験化合物投与群のダネット検定を行うことで、被験化合物の学習障害作用の有無を判定した。各検定においてp<0.10で傾向、p<0.05で有意な差とした。
　被験化合物として、式（I）で示される幾つかの化合物を用いた本試験の結果、式（I）の化合物はスコポラミンにより誘発されたマウスの自発交替行動を抑制した。例えば、実施例39、62、63、85及び106の化合物は、スコポラミンにより誘発された自発交替行動を、各々0.03mg/kg、0.03mg/kg、0.3mg/kg、1.0mg/kg及び0.01mg/kgの投与量で有意に抑制した。よって、式（Ｉ）の化合物が認知症及び統合失調症の認知障害に効果を有することが確認された。 Test Example 4 Improvement Effect on Scopolamine-Induced Spontaneous Alternating Behavior in Mice Evaluation of the improvement effect of the compound of formula (I) on dementia and schizophrenia cognitive impairment by the well-known test method as a model of short-term learning disorder did.
(1) Animal species: Male ddY mouse (2) Measurement method 10-30 minutes after oral administration of the test compound, 0.5 mg / kg scopolamine (saline in normal group) was administered intraperitoneally, and 20 minutes later A test was conducted. In the normal group (group to which physiological saline was administered) and the control group (group to which 0.5 mg / kg scopolamine was administered), the vehicle was orally administered at the time of test compound administration.
A mouse was placed in one end of a maze (Y-maze) arm with the same length of arm in three directions, and allowed to explore freely for 8 minutes, and the number of entries into the arm during this period was counted. Moreover, the case where it entered into three different arms continuously was made into the spontaneous alternation behavior (Spontaneous alternation behavior), and the ratio with respect to the total number of entries of this behavior number was computed as the spontaneous alternation rate (Alternation rate) by the following formula | equation.
Spontaneous turnover rate (%) = number of spontaneous turnover actions / (total number of entries -2) x 100
(3) Data analysis When a significant difference (Student T test) was found between the normal group and the control group in the spontaneous alternation rate (%), it was judged that learning disability was established by scopolamine administration. The presence or absence of the learning disorder effect of the test compound was determined by conducting a Dunnett test of the test compound administration group with respect to the control group. In each test, p <0.10 was a trend, and p <0.05 was a significant difference.
As a result of this test using several compounds represented by the formula (I) as test compounds, the compound of the formula (I) suppressed spontaneous alternation behavior of mice induced by scopolamine. For example, the compounds of Examples 39, 62, 63, 85 and 106 show that scopolamine-induced spontaneous alternation behavior was 0.03 mg / kg, 0.03 mg / kg, 0.3 mg / kg, 1.0 mg / kg and 0.01 mg, respectively. It was significantly suppressed at a dose of / kg. Thus, it was confirmed that the compound of formula (I) has an effect on cognitive impairment in dementia and schizophrenia.
試験例５　ラットでのPCP誘発プレパルス抑制（Prepulse inhibition：PPI）の障害に対する改善効果
　式（Ｉ）の化合物の統合失調症に対する改善効果を、病態モデルとして公知のPCP誘発プレパルス抑制障害モデルにより評価することができる。具体的には、「ニューロサイコファーマコロジー（Neuropsychopharmacology, 1989;2:61-66, Mansbach, R.S. and Geyer, M.A.）及びブレインリサーチ（Brain Research, 1998;781:227-235）」記載の方法に従う。 Test Example 5 Improving effect on disorder of PCP-induced prepulse inhibition (PPI) in rats The ameliorating effect of the compound of formula (I) on schizophrenia is evaluated by a known PCP-induced prepulse inhibition disorder model as a disease state model. be able to. Specifically, the method described in “Neuropsychopharmacology, 1989; 2: 61-66, Mansbach, RS and Geyer, MA” and Brain Research (1998; 781: 227-235) is followed.
試験例６　老齢ラットの水迷路学習障害における薬剤の評価
　式（Ｉ）の化合物の認知症に対する改善効果を、病態モデルとして公知の水迷路学習障害モデルにより評価することができる。具体的には、「ジャーナル　オブ　ファーマコロジー　アンド　エクスペリメンタル　セラピューティックス（J Pharmacol Exp Ther, 1996;279:1157-73, Yamazaki M. et al.」記載の方法に従う。 Test Example 6 Evaluation of Drugs in Water Maze Learning Disorders of Aged Rats The improvement effect of the compound of formula (I) on dementia can be evaluated by a known water maze learning disorder model as a disease state model. Specifically, the method described in “J Pharmacol Exp Ther, 1996; 279: 1157-73, Yamazaki M. et al.” Is followed.
試験例７　DBA/２マウスの強制水泳試験における薬剤の評価
　式（Ｉ）化合物のうつに対する改善効果を、評価モデルとして公知の強制水泳試験により評価することができる。具体的には、「ビヘイビオーラル　ブレイン　リサーチ（Behav Brain Res. 2005;156(1):153-162, Ducottet C. et al.）」記載方法に従う。 Test Example 7 Evaluation of Drug in Forced Swimming Test of DBA / 2 Mice The improvement effect of the compound of formula (I) on depression can be evaluated by a known forced swimming test as an evaluation model. Specifically, the method described in “Behav Brain Res. 2005; 156 (1): 153-162, Ducottet C. et al.)” Is followed.
　また、いくつかの式（I）の化合物について、以下の試験例８に従って光毒性作用を評価した。
試験例８：光毒性作用評価試験
[1日目]：細胞培養(96穴プレート)
1)　BALB/3T3を培養フラスコから剥離し，細胞数を計測する。
2)　細胞濃度を0.7×105cells/mlに調整し，96穴プレートに100μl/wellまく。細胞をまかない両端1列づつの穴にはPBS 100μl添加する。
3)　2日間，CO2インキュベーターで培養する。
[２日目]：化合物の添加およびUV照射(非照射)
1)　試験化合物の秤量は最低0.8 mg。
2)　化合物溶解濃度と同じDMSO含有EBSSを必要量調製する。
3)　チューブ(1化合物につき7本)にDMSO含有EBSS 600μl入れ希釈の準備をする。
4)　最高濃度の化合物にDMSOを加え，さらにEBSSを加え溶解する。超音波。加温。
5)　最高濃度の化合物溶液から隣のチューブに300μl移すことを繰り返し，各段階希釈濃度の溶液を調製する。
6)　ペーパータオルに96穴プレートを逆さにして伏せ，培養液を捨てる。
7)　マルチピペットマンで細胞を傷つけないように吸引する。
8)　同じ化合物を加えるもう1対のプレートの培養液も同様に捨てる。
9)　両端各2列(計4列)にDMSO含有EBSS 100μl/well分注する。
10) 各化合物毎に8段階希釈の化合物溶液を100μl/well分注する。
11) 60分間，暗所に静置する(実験台引き出しの中)。
12) 次に，70分間，UV照射を行う（1200μW/cm2）。非照射のプレートは空き箱を伏せた中へ入れる。
13) ペーパータオルに伏せて化合物溶液を捨てる。残ってしまった液をピペットマンで吸引する。
14)培養用培養液DMEMを100μl/well加える。
15)CO2インキュベーターで培養する。
[3日目]：ニュートラルレッド取り込み試験
1)ニュートラルレッド（NR）50μg/mlを調製する。
2)プレートをペーパータオルに伏せ，培養液を取り除く。残った培養液はピペットマンで吸引しない。
3)NR液を100μl/wellづつ分注する。
4)CO2インキュベーターで3時間培養する。
5)プレートをペーパータオルに伏せ，NR液を捨てる。残った液をピペットマンで吸引しない。
6)EBSS　150μl/well分注する。
7)プレートをペーパータオルに再び伏せてEBSSを捨てる。ピペットマンで残っているEBSSを吸引する。
8)NR溶出液を150μl/well分注する。
9)振とう機で約10分間プレートを振とうさせる。
10)microplate readerを用いて540nmの吸光度を測定する。 Further, several compounds of formula (I) were evaluated for their phototoxic effects according to Test Example 8 below.
Test Example 8: Phototoxic effect evaluation test
[Day 1]: Cell culture (96-well plate)
1) Remove BALB / 3T3 from the culture flask and count the number of cells.
2) Adjust the cell concentration to 0.7 × 10 5 cells / ml and spread 100 μl / well in a 96-well plate. Add 100 μl of PBS to each side of the hole that does not cover cells.
3) Incubate in a CO2 incubator for 2 days.
[Day 2]: Addition of compound and UV irradiation (non-irradiation)
1) The minimum weight of the test compound is 0.8 mg.
2) Prepare the required amount of DMSO-containing EBSS equal to the compound concentration.
3) Prepare 600 μl of DMSO-containing EBSS in a tube (7 per compound) for dilution.
4) Add DMSO to the highest concentration of compound, and add EBSS to dissolve. Ultrasound. Warming.
5) Repeat the transfer of 300 μl from the highest concentration compound solution to the next tube to prepare solutions at each dilution level.
6) Turn the 96-well plate upside down on a paper towel and discard the culture medium.
7) Aspirate with a multipipetteman so as not to damage the cells.
8) Discard the other pair of plates containing the same compound.
9) Dispense 100 μl / well of DMSO-containing EBSS into 2 rows at each end (4 rows in total).
10) Dispense 100 µl / well of compound solution of 8 serial dilutions for each compound.
11) Leave in the dark for 60 minutes (in the laboratory drawer).
12) Next, UV irradiation is performed for 70 minutes (1200μW / cm2). Put the non-irradiated plate inside the empty box.
13) Lay down on a paper towel and discard the compound solution. Aspirate the remaining liquid with a Pipetman.
14) Add 100 μl / well of culture medium DMEM for culture.
15) Culture in a CO2 incubator.
[Day 3]: Neutral red uptake test
1) Prepare neutral red (NR) 50μg / ml.
2) Place the plate on a paper towel and remove the culture medium. Do not aspirate remaining culture with Pipetman.
3) Dispense NR solution at 100μl / well.
4) Incubate for 3 hours in a CO2 incubator.
5) Place the plate on a paper towel and discard the NR solution. Do not aspirate remaining liquid with Pipetman.
6) Dispense EBSS 150μl / well.
7) Reposition the plate on a paper towel and discard the EBSS. Aspirate remaining EBSS with Pipetman.
8) Dispense 150μl / well of NR eluate.
9) Shake the plate for about 10 minutes with a shaker.
10) Measure absorbance at 540 nm using a microplate reader.
上記試験例８に従い、幾つかの式(I)の化合物を評価した。その結果、実施例32、39、63及び158の化合物のMPEは、それぞれ0.01、0.05、0.01、及び-0.00であり、光毒性を有さない化合物であることが確認された。ここで、MPEとは、Mean Photo Effect、すなわち平均光作用を示す値である。MPEの算出は、例えば下記文献のEquation 2に従って算出することができる。
ATLA (2002), 30, 415-432 According to Test Example 8 above, several compounds of formula (I) were evaluated. As a result, the MPEs of the compounds of Examples 32, 39, 63, and 158 were 0.01, 0.05, 0.01, and −0.00, respectively, and it was confirmed that the compounds did not have phototoxicity. Here, MPE is a value indicating a mean photo effect, that is, an average light effect. For example, MPE can be calculated according to Equation 2 in the following document.
ATLA (2002), 30, 415-432
　また、幾つかの式（I）の化合物について、以下の試験例に従って溶解性を評価した。
試験例９：溶解性試験
　予め調製した被験物質の10 mM DMSO溶液13 μLに日本薬局方崩壊試験第２液1 mLを正確に加え、25℃で20時間振とうさせ、試料原液とした。次に、予め試料原液200 μLをろ過して湿したフィルターを用い、新たに試料原液200 μ\ochLを加えてろ過し、得られた液を試料溶液とした。別に被験物質の10 mM DMSO溶液10 μLにメタノール1 mLを正確に加えて撹拌し、標準溶液とした。試料溶液及び標準溶液10 μLにつき、液体クロマトグラフにより試験を行い、標準溶液のピーク面積に対する試料溶液のピーク面積の比を求め、溶解度を計算した。
その結果、実施例６３の化合物の溶解度は、98 μmol/Lであり、実施例15、32、39、42、51、58、62、85、90、91及び158の化合物の溶解度は何れも100μmol/L以上であった。 Further, the solubility of some compounds of the formula (I) was evaluated according to the following test examples.
Test Example 9: Solubility test 1 mL of Japanese Pharmacopoeia disintegration test solution 2 was accurately added to 13 μL of a 10 mM DMSO solution of a test substance prepared in advance, and shaken at 25 ° C. for 20 hours to obtain a sample stock solution. Next, a sample stock solution of 200 μL was filtered and moistened in advance, a sample stock solution of 200 μ \ ochL was newly added and filtered, and the resulting solution was used as a sample solution. Separately, 1 mL of methanol was accurately added to 10 μL of a 10 mM DMSO solution of the test substance and stirred to obtain a standard solution. The sample solution and 10 μL of the standard solution were tested by liquid chromatography, the ratio of the peak area of the sample solution to the peak area of the standard solution was determined, and the solubility was calculated.
As a result, the solubility of the compound of Example 63 was 98 μmol / L, and the solubility of the compounds of Examples 15, 32, 39, 42, 51, 58, 62, 85, 90, 91 and 158 were all 100 μmol. It was more than / L.
　また、幾つかの式（I）の化合物について、CYP1A2代謝酵素に対する阻害活性を評価した。その結果、実施例15、32、39、42、58、62、63、91、106及び158の化合物のCYP1A2代謝酵素阻害活性は何れもIC50値が20μM以上であり、当該代謝酵素を阻害しない化合物であることを確認した。 Moreover, the inhibitory activity with respect to the CYP1A2 metabolic enzyme was evaluated about some compounds of Formula (I). As a result, the CYP1A2 metabolic enzyme inhibitory activities of the compounds of Examples 15, 32, 39, 42, 58, 62, 63, 91, 106 and 158 all have an IC 50 value of 20 μM or more and do not inhibit the metabolic enzyme. It was confirmed to be a compound.
　上記薬理試験例の試験結果から、本発明の式（I）の化合物が、5-HT5Aの関与する疾患の治療又は予防、特に、認知症、統合失調症（陽性症状、陰性症状、認知障害、気分障害等の症状を含む）、双極性障害、注意欠陥多動性障害、及び気分障害（不安障害、うつ病性障害）、の治療又は予防剤として有用であることが確認できた。 From the test results of the above pharmacological test examples, the compound of formula (I) of the present invention is used for the treatment or prevention of diseases involving 5-HT 5A , particularly dementia, schizophrenia (positive symptoms, negative symptoms, cognitive impairment). , Including symptoms such as mood disorder), bipolar disorder, attention deficit / hyperactivity disorder, and mood disorder (anxiety disorder, depressive disorder).
　式（Ｉ）の化合物又はその塩の１種又は２種以上を有効成分として含有する製剤は、当分野において通常用いられている薬剤用担体、賦形剤等を用いて通常使用されている方法によって調製することができる。
　投与は錠剤、丸剤、カプセル剤、顆粒剤、散剤、液剤等による経口投与、又は、関節内、静脈内、筋肉内等の注射剤、坐剤、点眼剤、眼軟膏、経皮用液剤、軟膏剤、経皮用貼付剤、経粘膜液剤、経粘膜貼付剤、吸入剤等による非経口投与のいずれの形態であってもよい。
　本発明による経口投与のための固体組成物としては、錠剤、散剤、顆粒剤等が用いられる。このような固体組成物においては、1種又は2種以上の有効成分を、少なくとも1種の不活性な賦形剤、例えば乳糖、マンニトール、ブドウ糖、ヒドロキシプロピルセルロース、微結晶セルロース、デンプン、ポリビニルピロリドン、及び/又はメタケイ酸アルミン酸マグネシウム等と混合される。組成物は、常法に従って、不活性な添加剤、例えばステアリン酸マグネシウムのような滑沢剤やカルボキシメチルスターチナトリウム等のような崩壊剤、安定化剤、溶解補助剤を含有していてもよい。錠剤または丸剤は必要により糖衣または胃溶性若しくは腸溶性物質のフィルムで被膜してもよい。
　経口投与のための液体組成物は、薬剤的に許容される乳濁剤、溶液剤、懸濁剤、シロップ剤またはエリキシル剤等を含み、一般的に用いられる不活性な希釈剤、例えば精製水またはエタノールを含む。当該液体組成物は不活性な希釈剤以外に可溶化剤、湿潤剤、懸濁剤のような補助剤、甘味剤、風味剤、芳香剤、防腐剤を含有していてもよい。
　非経口投与のための注射剤は、無菌の水性又は非水性の溶液剤、懸濁剤又は乳濁剤を含有する。水性の溶剤としては、例えば注射用蒸留水又は生理食塩液が含まれる。非水溶性の溶剤としては、例えばプロピレングリコール、ポリエチレングリコール又はオリーブ油のような植物油、エタノールのようなアルコール類、又はポリソルベート８０（局方名）等がある。このような組成物は、更に等張化剤、防腐剤、湿潤剤、乳化剤、分散剤、安定化剤、又は溶解補助剤を含んでもよい。これらは例えばバクテリア保留フィルターを通す濾過、殺菌剤の配合又は照射によって無菌化される。また、これらは無菌の固体組成物を製造し、使用前に無菌水または無菌の注射用溶媒に溶解または懸濁して使用することもできる。
　外用剤としては、軟膏剤、硬膏剤、クリーム剤、ゼリー剤、パップ剤、噴霧剤、ローション剤、点眼剤、眼軟膏等を包含する。一般に用いられる軟膏基剤、ローション基剤、水性または非水性の液剤、懸濁剤、乳剤等を含有する。例えば、軟膏またはローション基剤としては、ポリエチレングリコール、プロピレングリコール、白色ワセリン、サラシミツロウ、ポリオキシエチレン硬化ヒマシ油、モノステアリン酸グリセリン、ステアリルアルコール、セチルアルコール、ラウロマクロゴール、セスキオレイン酸ソルビタン等が挙げられる。
　吸入剤や経鼻剤等の経粘膜剤は、固体、液体又は半固体状のものが用いられ、従来公知の方法に従って製造することができる。例えば公知の賦形剤や、更に、pH調整剤、防腐剤、界面活性剤、滑沢剤、安定剤や増粘剤等が適宜添加されていてもよい。投与は、適当な吸入又は吹送のためのデバイスを使用することができる。例えば、計量投与吸入デバイス等の公知のデバイスや噴霧器を使用して、化合物を単独で又は処方された混合物の粉末として、若しくは医薬的に許容し得る担体と組み合わせて溶液又は懸濁液として投与することができる。乾燥粉末吸入器等は、単回又は多数回の投与用のものであってもよく、乾燥粉末又は粉末含有カプセルを利用することができる。或いは、適当な駆出剤、例えば、クロロフルオロアルカン、ヒドロフルオロアルカン又は二酸化炭素等の好適な気体を使用した加圧エアゾールスプレー等の形態であってもよい。
　通常経口投与の場合、1日の投与量は、体重当たり約0.0001～100mg/kg、好ましくは0.0001～10mg/kg、更に好ましくは0.0001～1mg/kgが適当であり、これを1回であるいは2乃至4回に分けて投与する。静脈内投与される場合は、1日の投与量は、体重当たり約0.00001～1mg/kgが適当で、1日1回乃至複数回に分けて投与する。また、外用剤や経粘膜剤としては、体重当たり約0.0001～10mg/kgを1日1回乃至複数回に分けて投与する。投与量は症状、年令、性別等を考慮して個々の場合に応じて適宜決定される。製剤中の有効成分の含有量としては、0.0001～50%、より好ましくは0.001～50%である。
　式（Ｉ）の化合物は、前述の式（Ｉ）の化合物が有効性を示すと考えられる疾患の種々の治療剤又は予防剤と併用することができる。当該併用は、同時投与、或いは別個に連続して、若しくは所望の時間間隔をおいて投与してもよい。同時投与製剤は、配合剤であっても別個に製剤化されていてもよい。 Formulations containing one or more of the compounds of formula (I) or salts thereof as active ingredients are generally used methods using pharmaceutical carriers, excipients and the like that are usually used in the art Can be prepared.
Administration is orally by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intra-articular, intravenous, intramuscular, suppositories, eye drops, ophthalmic ointments, transdermal solutions, Any form of parenteral administration such as an ointment, a transdermal patch, a transmucosal liquid, a transmucosal patch, and an inhalant may be used.
As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, one or more active ingredients are combined with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone. And / or mixed with magnesium aluminate metasilicate. The composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, a stabilizer, and a solubilizing agent according to a conventional method. . If necessary, tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, and commonly used inert diluents such as purified water. Or contains ethanol. The liquid composition may contain solubilizers, wetting agents, auxiliaries such as suspending agents, sweeteners, flavors, fragrances and preservatives in addition to the inert diluent.
Injections for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of the aqueous solvent include distilled water for injection or physiological saline. Examples of water-insoluble solvents include propylene glycol, polyethylene glycol or vegetable oils such as olive oil, alcohols such as ethanol, or polysorbate 80 (a pharmacopeia name). Such compositions may further contain isotonic agents, preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents, or solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like. Contains commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like. For example, ointments or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, etc. Can be mentioned.
Transmucosal agents such as inhalants and nasal agents are used in solid, liquid or semi-solid form and can be produced according to conventionally known methods. For example, known excipients, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added. For administration, an appropriate device for inhalation or insufflation can be used. For example, using a known device such as a metered dose inhalation device or a nebulizer, the compound is administered alone or as a powder in a formulated mixture or as a solution or suspension in combination with a pharmaceutically acceptable carrier. be able to. The dry powder inhaler or the like may be for single or multiple administration, and a dry powder or a powder-containing capsule can be used. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable gas such as a suitable propellant such as chlorofluoroalkane, hydrofluoroalkane or carbon dioxide.
In general, in the case of oral administration, the appropriate daily dose is about 0.0001 to 100 mg / kg, preferably 0.0001 to 10 mg / kg, more preferably 0.0001 to 1 mg / kg per body weight. Administer in 4 to 4 divided doses. When administered intravenously, the appropriate daily dosage is about 0.00001 to 1 mg / kg per body weight, and is administered once a day or divided into multiple times. As an external preparation or transmucosal agent, about 0.0001 to 10 mg / kg per body weight is administered once to several times a day. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like. The content of the active ingredient in the preparation is 0.0001 to 50%, more preferably 0.001 to 50%.
The compound of the formula (I) can be used in combination with various therapeutic agents or preventive agents for diseases for which the compound of the formula (I) is considered to be effective. The combination may be administered simultaneously, separately separately, or at desired time intervals. The simultaneous administration preparation may be a combination drug or may be separately formulated.
　式（Ｉ）の化合物は、強力な5-HT5A受容体調節作用と、これに基づく良好な薬理作用を有するという利点がある。本発明の医薬組成物は、5-HT5A受容体の関与する疾患の治療又は予防、特に、認知症、統合失調症、双極性障害、注意欠陥多動性障害及び気分障害の治療又は予防に有用である。 The compound of the formula (I) has an advantage of having a potent 5-HT 5A receptor modulating action and a good pharmacological action based thereon. The pharmaceutical composition of the present invention is used for the treatment or prevention of diseases involving 5-HT 5A receptor, particularly for the treatment or prevention of dementia, schizophrenia, bipolar disorder, attention deficit hyperactivity disorder and mood disorder. Useful.

Claims (15)

  1. 式（Ｉ）の化合物又はその製薬学的に許容される塩。
    Figure JPOXMLDOC01-appb-C000001
     （式中の記号は以下の意味を示す。
    A：アリール、ヘテロアリール又はシクロアルキル、
    R1～R3：それぞれ同一又は互いに異なって、H、ハロゲン、ハロゲノ低級アルキル、-CN、-OH、-OR0、-O-(ハロゲノ低級アルキル)、-R00-OH、-R00-OR0、シクロアルキル又は低級アルキル、
    R4：H、ハロゲン、ハロゲノ低級アルキル、R0、-CN、-OH、-OR0、-O-(ハロゲノ低級アルキル)、-R00-OH、-R00-OR0、又はシクロアルキル、
    R5：H又はR0、
    L：単結合、-R00-O-、-R00-S-、-R00-SO2-、-R00-NH-、-R00-NR0-、シクロアルキレン、又は置換されていてもよい低級アルキレン、
    B：-OH、-OR0、-SR0、-N(R0)2、-R00-OR0、-CONH2、又は-CO2R0、或いはそれぞれ置換されていてもよい、ヘテロシクロアルキル、ヘテロアリール、シクロアルキル、又はアリール、
    R0：低級アルキル、
    R00：低級アルキレン。）     A compound of formula (I) or a pharmaceutically acceptable salt thereof.
    Figure JPOXMLDOC01-appb-C000001
     (The symbols in the formula have the following meanings.
    A: aryl, heteroaryl or cycloalkyl,
    R 1 ~ R 3: different same or mutually, H, halogen, halogeno lower alkyl, -CN, -OH, -OR 0, -O- ( halogeno-lower alkyl), - R 00 -OH, -R 00 - OR 0 , cycloalkyl or lower alkyl,
    R 4: H, halogen, halogeno-lower alkyl, R 0, -CN, -OH, -OR 0, -O- ( halogeno-lower alkyl), - R 00 -OH, -R 00 -OR 0, or cycloalkyl,
    R 5 : H or R 0 ,
    L: a single bond, -R 00 -O -, - R 00 -S -, - R 00 -SO 2 -, - R 00 -NH -, - R 00 -NR 0 -, cycloalkylene, or substituted May be lower alkylene,
    B: -OH, -OR 0 , -SR 0 , -N (R 0 ) 2 , -R 00 -OR 0 , -CONH 2 , or -CO 2 R 0 , or heterocyclo, each of which may be substituted, Alkyl, heteroaryl, cycloalkyl, or aryl,
    R 0 : lower alkyl,
    R 00 : lower alkylene. )
  2. Lが、単結合、シクロアルキレン又は置換されていてもよい低級アルキレンである、請求項１の化合物又はその製薬学的に許容される塩。 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is a single bond, cycloalkylene or optionally substituted lower alkylene.
  3. Lが、-R00-O-、-R00-S-、-R00-NH-、-R00-NR0-又は-R00-SO2-であり、Bが、-R00-OR0、-CONH2又は-CO2R0、或いはそれぞれ置換されていてもよい、ヘテロシクロアルキル、ヘテロアリール、シクロアルキル又はアリールである、請求項１の化合物又はその製薬学的に許容される塩。 L is, -R 00 -O -, - R 00 -S -, - R 00 -NH -, - R 00 -NR 0 - or -R 00 -SO 2 - and is, B is, -R 00 -OR 0, -CONH 2 or -CO 2 R 0, or may be each substituted, heterocycloalkyl, heteroaryl, cycloalkyl or aryl, the compound of claim 1 or a pharmaceutically acceptable salt thereof .
  4. Aがフェニル、ピリジル又はC3-7シクロアルキルであり、R1～R3が、それぞれ同一又は互いに異なってF、Cl及びHから選択される基であり、R4がハロゲン、C1-3アルキル、-O-(C1-3アルキル)又はシクロプロピルであり、R5がHであり、Lが単結合又は低級アルキレンであり、Bが-R0、-R00-OH、-R00-OR0、-R00-CN、-R00-N(R0)2、-COR0、-CO2R0、-CONH2、-CN、-OH、-OR0、-NH2、-SR0、ハロゲン、-R00-(フェニル)、ハロゲノ低級アルキル、シクロアルキル、-R00-(シクロプロピル)、-R00-(シクロヘキシル)、-CO-(シクロプロピル)、-R00-(モルホリル)、-R00-(ピペリジル)、ピロリジル、ピペリジル、-R00-(ピリジル)、及びピリミジニルから選択される基でそれぞれ置換されていてもよい、単環式含窒素ヘテロシクロアルキル又は単環式含窒素ヘテロアリールである、請求項１の化合物又はその製薬学的に許容される塩。 A is phenyl, pyridyl or C 3-7 cycloalkyl, R 1 to R 3 are the same or different from each other and are selected from F, Cl and H, R 4 is halogen, C 1-3 Alkyl, —O— (C 1-3 alkyl) or cyclopropyl, R 5 is H, L is a single bond or lower alkylene, and B is —R 0 , —R 00 —OH, —R 00 -OR 0 , -R 00 -CN, -R 00 -N (R 0 ) 2 , -COR 0 , -CO 2 R 0 , -CONH 2 , -CN, -OH, -OR 0 , -NH 2 ,- SR 0, halogen, -R 00 - (phenyl), halogeno-lower alkyl, cycloalkyl, -R 00 - (cyclopropyl), - R 00 - (cyclohexyl), - CO- (cyclopropyl), - R 00 - ( morpholyl), - R 00 - (piperidyl), pyrrolidyl, piperidyl, -R 00 - (pyridyl), and a group selected from pyrimidinyl may each be substituted, monocyclic nitrogen-containing heterocycloalkyl or monocyclic In the formula nitrogen-containing heteroaryl A compound of claim 1 or a pharmaceutically acceptable salt thereof.
  5. Aがフェニルであり、R1～R3がF又はHであり、R4がF又はClであり、R5がHであり、Lが単結合、メチレン、エチレン又はトリメチレンであり、Bが低級アルキル、-R00-NH2、-R00-OH及び-R00-OR0から選択される基でそれぞれ置換されていてもよい、フェニル、ピペリジル、キヌクリジル、イミダゾリル、又はピリジルである、請求項１の化合物又はその製薬学的に許容される塩。 A is phenyl, R 1 to R 3 are F or H, R 4 is F or Cl, R 5 is H, L is a single bond, methylene, ethylene or trimethylene, and B is lower The phenyl, piperidyl, quinuclidyl, imidazolyl, or pyridyl, each optionally substituted with a group selected from alkyl, -R 00 -NH 2, -R 00 -OH, and -R 00 -OR 0. 1 compound or a pharmaceutically acceptable salt thereof.
  6. Aがフェニルであり、R1～R3がF又はHであり、R4がCl又はメチルであり、R5がHであり、Lが単結合であり、Bが低級アルキル、-R00-CO-NH2及び-R00-OR0から選択される基でそれぞれ置換されていてもよいピペリジルである、請求項１の化合物又はその製薬学的に許容される塩。 A is phenyl, R 1 to R 3 are F or H, R 4 is Cl or methyl, R 5 is H, L is a single bond, B is lower alkyl, -R 00- The compound of claim 1 or a pharmaceutically acceptable salt thereof, which is piperidyl optionally substituted with a group selected from CO-NH 2 and -R 00 -OR 0 .
  7. Aがフェニルであり、R1～R3がF又はHであり、R4がClであり、R5がHであり、Lが-OHで置換されていてもよいエチレンであり、Bがイミダゾリルである、請求項１の化合物又はその製薬学的に許容される塩。 A is phenyl, R 1 to R 3 are F or H, R 4 is Cl, R 5 is H, L is ethylene optionally substituted with —OH, and B is imidazolyl. Or a pharmaceutically acceptable salt thereof.
  8. 下記化合物群から選択される化合物、又はその製薬学的に許容される塩。
    4-クロロ-N-(1-メチルピペリジン-4-イル)-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド、
    N-[1-(2-アミノ-2-オキソエチル)ピペリジン-4-イル]-4-クロロ-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド、
    4-クロロ-N-(1-プロピルピペリジン-4-イル)-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド、
    4-メチル-N-(1-メチルピペリジン-4-イル)-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド、
    4-クロロ-1-(2,6-ジフルオロフェニル)-N-(1-イソプロピルピペリジン-4-イル)イソキノリン-7-カルボキサミド、
    4-クロロ-N-(1-エチルピペリジン-4-イル)-1-(2-フルオロフェニル)イソキノリン-7-カルボキサミド、
    4-クロロ-1-(2-フルオロフェニル)-N-(1-メチルピペリジン-4-イル)イソキノリン-7-カルボキサミド、
    4-メチル-N-(1-プロピルピペリジン-4-イル)-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド、
    4-クロロ-N-(1-メチルピペリジン-4-イル)-1-フェニルイソキノリン-7-カルボキサミド、
    N-[1-(2-アミノ-2-オキソエチル)ピペリジン-4-イル]-4-メチル-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド、
    4-クロロ-1-(2,4-ジフルオロフェニル)-N-(1-メチルピペリジン-4-イル)-イソキノリン-7-カルボキサミド、
    4-クロロ-N-[1-(2-メトキシエチル)ピペリジン-4-イル]-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド、
    4-クロロ-N-[2-(1H-イミダゾール-2-イル)エチル]-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド、及び
    4-クロロ-N-[2-ヒドロキシ-2-(1H-イミダゾール-2-イル)エチル]-1-(2,4,6-トリフルオロフェニル)イソキノリン-7-カルボキサミド。     The compound selected from the following compound group, or its pharmaceutically acceptable salt.
    4-chloro-N- (1-methylpiperidin-4-yl) -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide,
    N- [1- (2-amino-2-oxoethyl) piperidin-4-yl] -4-chloro-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide,
    4-chloro-N- (1-propylpiperidin-4-yl) -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide,
    4-methyl-N- (1-methylpiperidin-4-yl) -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide,
    4-chloro-1- (2,6-difluorophenyl) -N- (1-isopropylpiperidin-4-yl) isoquinoline-7-carboxamide,
    4-chloro-N- (1-ethylpiperidin-4-yl) -1- (2-fluorophenyl) isoquinoline-7-carboxamide,
    4-chloro-1- (2-fluorophenyl) -N- (1-methylpiperidin-4-yl) isoquinoline-7-carboxamide,
    4-methyl-N- (1-propylpiperidin-4-yl) -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide,
    4-chloro-N- (1-methylpiperidin-4-yl) -1-phenylisoquinoline-7-carboxamide,
    N- [1- (2-amino-2-oxoethyl) piperidin-4-yl] -4-methyl-1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide,
    4-chloro-1- (2,4-difluorophenyl) -N- (1-methylpiperidin-4-yl) -isoquinoline-7-carboxamide,
    4-chloro-N- [1- (2-methoxyethyl) piperidin-4-yl] -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide,
    4-chloro-N- [2- (1H-imidazol-2-yl) ethyl] -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide, and
    4-Chloro-N- [2-hydroxy-2- (1H-imidazol-2-yl) ethyl] -1- (2,4,6-trifluorophenyl) isoquinoline-7-carboxamide.
  9. 請求項１に記載の化合物又はその塩、及び製薬学的に許容される賦形剤を含有する医薬組成物。 A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof, and a pharmaceutically acceptable excipient.
  10. 5-HT5A受容体調節剤である、請求項７の医薬組成物。 The pharmaceutical composition of claim 7, which is a 5-HT 5A receptor modulator.
  11. 認知症又は統合失調症の予防用若しくは治療用医薬組成物である請求項１に記載の医薬組成物。 The pharmaceutical composition according to claim 1, which is a pharmaceutical composition for preventing or treating dementia or schizophrenia.
  12. 認知症又は統合失調症の予防若しくは治療用医薬組成物の製造のための請求項１に記載の化合物又はその塩の使用。 Use of the compound according to claim 1 or a salt thereof for the manufacture of a pharmaceutical composition for preventing or treating dementia or schizophrenia.
  13. 認知症又は統合失調症の予防若しくは治療のための請求項１に記載の化合物又はその塩の使用。 Use of the compound according to claim 1 or a salt thereof for the prevention or treatment of dementia or schizophrenia.
  14. 認知症又は統合失調症の予防若しくは治療のための請求項１に記載の化合物又はその塩。 The compound or a salt thereof according to claim 1 for the prevention or treatment of dementia or schizophrenia.
  15. 請求項１に記載の化合物又はその塩の有効量を対象に投与することからなる認知症又は統合失調症の予防若しくは治療方法。 A method for preventing or treating dementia or schizophrenia, comprising administering an effective amount of the compound according to claim 1 or a salt thereof to a subject.
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