WO2012081665A1 - Substance capable of inhibiting glycine transporter - Google Patents

Substance capable of inhibiting glycine transporter Download PDF

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WO2012081665A1
WO2012081665A1 PCT/JP2011/079043 JP2011079043W WO2012081665A1 WO 2012081665 A1 WO2012081665 A1 WO 2012081665A1 JP 2011079043 W JP2011079043 W JP 2011079043W WO 2012081665 A1 WO2012081665 A1 WO 2012081665A1
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group
substituted
substituents selected
substituent
compound
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修資 山本
裕之 太田
公美 阿部
裕子 荒木
実 守谷
相敏 孫
明登 安原
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大正製薬株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—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
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—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
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a compound having a glycine transporter inhibitory action.
  • NMDA receptor which is one of glutamate receptors, exists on nerve cell membranes in the brain and is involved in various neurophysiological phenomena such as nerve plasticity, cognition, attention, and memory.
  • the NMDA receptor has a plurality of allosteric binding sites, one of which is the glycine binding site (NMDA receptor complex glycine binding site). It has been reported that the NMDA receptor complex glycine binding site is involved in the activation of the NMDA receptor (Non-patent Document 1).
  • Glycine transporter is a protein involved in the reuptake of extracellular glycine into cells, and the existence of two subtypes, GlyT1 and GlyT2, has been clarified so far.
  • GlyT1 is mainly expressed in cerebral cortex, hippocampus and thalamus, etc., and is schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder (generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, Post-traumatic stress disorder, specific phobia, acute stress disorder, etc.), depression, drug dependence, convulsions, tremor, pain, Parkinson's disease, attention deficit / hyperactivity disorder, bipolar disorder, eating disorder, and sleep A relationship with a disease such as a disorder has been reported (Non-Patent Documents 2 to 4).
  • Patent Documents 1 and 2 Compounds having GlyT1 inhibitory activity and having an imidazolidin-2-one structure have been reported in the following documents (Patent Documents 1 and 2). These compounds described in Patent Documents 1 and 2 are compounds in which an aryl group is bonded to one ring nitrogen atom of imidazolidine via an amide or carbonyl.
  • the present invention relates to schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder (general anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post-traumatic stress disorder, specific Prevention, depression, drug dependence, convulsions, tremors, pain, Parkinson's disease, attention deficit / hyperactivity disorder, bipolar disorder, eating disorders, or sleep disorders Alternatively, it is an object to provide a novel compound useful for treatment or a pharmaceutically acceptable salt thereof.
  • anxiety disorder general anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post-traumatic stress disorder, specific Prevention, depression, drug dependence, convulsions, tremors, pain, Parkinson's disease, attention deficit / hyperactivity disorder, bipolar disorder, eating disorders, or sleep disorders
  • the present inventors have found that the compound is represented by the following formula, and is an amide or carbonyl group with respect to the nitrogen atom in the ring of imidazolidine.
  • the present inventors have found that a compound characterized in that an aryl group is bonded without intervening is an excellent GlyT1 inhibitor and completed the present invention.
  • R 1 represents a phenyl group, a pyridyl group, a pyridazyl group, a pyrimidyl group, a pyrazyl group, or a pyridonyl group;
  • the phenyl group, pyridyl group, pyridazyl group, pyrimidyl group, pyrazyl group, and pyridonyl group may be substituted with 1 to 3 substituents selected from the substituent group 1.
  • Substituent group 1 is a C 1-6 alkyl group (the C 1-6 alkyl group is selected from the group consisting of a hydroxy group, a C 1-6 alkanoyloxy group, and a group represented by the formula —NR 7 R 8.
  • R 7 and R 8 may be the same or different and each represents a hydrogen atom or a C 1-6 alkyl group), a halo C 1-6 alkyl group, C 1 -6 alkoxy group, halo C 1-6 alkoxy group, C 2-7 alkoxycarbonyl group, cyano group, halogen atom, 5-membered or 6-membered heteroaryl group (the 5-membered or 6-membered heteroaryl group is 1 And may be substituted with two C 1-6 alkyl groups), a C 1-6 alkanoyl group, and a formula —NR 9 R 10 (R 9 and R 10 may be the same or different and represent a hydrogen atom or C 1-6 represents an alkyl group, or a saturated double of R 9, and together with the nitrogen atom to which R 10 is attached 4-6 membered Forms a ring, saturated heterocyclic ring of the 4-6 membered are the group consisting of groups represented by oxo may be
  • the C 1-6 alkyl group is a C 1-6 alkoxy group, a phenyl group, a C 3-6 cycloalkyl group, a halo C 1-6 alkoxy group, a halo C 3-6 A cycloalkyl group, and 1 to 3 substituents selected from the group consisting of a 3-methyloxetane-3-yl group), a halo C 1-6 alkyl group, a C 1-6 alkoxy group (
  • the C 1-6 alkoxy group includes 1 to 3 substituents selected from the group consisting of a C 1-6 alkoxy group, a hydroxy group, a C 3-6 cycloalkyl group, and a 3-methyloxetane-3-yl group.
  • R 11 and R 12 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group, or R 11 , And a nitrogen atom to which R 12 is bonded to form a 4- to 6-membered saturated heterocyclic ring, and the 4- to 6-membered saturated heterocyclic ring may be substituted with an oxo group, and formula -CONR 13 R 14 ( 13, and R 14 are the same or different, and represent a hydrogen atom or a C 1-6 alkyl group, or, R 13, and R 14 together with the nitrogen atom bonded 4-6 membered saturated heterocyclic Forming a ring, and the 4- to 6-membered saturated heterocyclic ring may be substituted with an oxo group).
  • R 3 and R 4 are the same or different and each represents a hydrogen atom, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a phenyl group, or a benzyl group, or R 3 and R 4 are Combined with the carbon atom to form a C 3-7 cycloalkane ring, tetrahydrofuran ring, or tetrahydropyran ring (except when R 3 and R 4 are both hydrogen atoms) R 5 and R 6 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group) or a pharmaceutically acceptable salt thereof (provided that R 1 is selected from substituent group 1)
  • R 2 is a monocyclic or bicyclic hetero ring which may be substituted with 1 to 3 substituents selected from Substituent Group 2; An aryl group).
  • R 5 and R 6 are both hydrogen atoms.
  • R 3 and R 4 together with the carbon atom to which R 4 is bonded form a C 3-7 cycloalkane ring.
  • R 2 may be substituted with a phenyl group which may be substituted with 1 to 3 substituents selected from Substituent Group 2 or with 1 to 3 substituents selected from Substituent Group 2
  • R 2 may be substituted with a phenyl group which may be substituted with 1 to 3 substituents selected from Substituent Group 3 or with 1 to 3 substituents selected from Substituent Group 4 A monocyclic heteroaryl group
  • Substituent group 3 is a group consisting of a C 1-6 alkoxy group, a halo C 1-6 alkoxy group, and a 5-membered heteroaryl group
  • Substituent group 4 is a phenyl group (the phenyl group may be substituted with 1 to 3 substituents selected from the group consisting of a C 1-6 alkyl group, a C 1-6 alkoxy group, and a halogen atom.
  • R 2 is a phenyl group which may be substituted with 1 to 3 substituents selected from Substituent Group 3; an iso group which may be substituted with 1 to 2 substituents selected from Substituent Group 4; An oxazole group, an oxadiazole group which may be substituted with one substituent selected from substituent group 4, a triazole group which may be substituted with one or two substituents selected from substituent group 4, A pyrazole group which may be substituted with 1 to 3 substituents selected from group 4 or a pyridyl group which may be substituted with 1 to 3 substituents selected from substituent group 4 (1) A compound or a pharmaceutically acceptable salt thereof according to any one of (3) to (3).
  • R 2 is a phenyl group which may be substituted with one 5-membered heteroaryl group, an isoxazole group which may be substituted with 1 to 2 substituents selected from Substituent Group 4 and a substituent A pyrazole group which may be substituted with 1 to 3 substituents selected from group 4 or a pyridyl group which may be substituted with 1 to 3 substituents selected from substituent group 4 (1) to The compound according to any one of (3) or a pharmaceutically acceptable salt thereof.
  • R 1 is a pyridyl group, a pyridazyl group, a pyrimidyl group, a pyrazyl group, or a pyridonyl group
  • the pyridyl group, pyridazyl group, pyrimidyl group, pyrazyl group, and pyridonyl group may be substituted with any one of 1 to 3 substituents selected from Substituent Group 1 (1) to (7) Or a pharmaceutically acceptable salt thereof.
  • R 1 is a phenyl group, a pyridyl group, a pyrimidyl group, or a pyrazyl group
  • the phenyl group, pyridyl group, pyrimidyl group, and pyrazyl group may be substituted with 1 to 3 substituents selected from the substituent group 5.
  • Substituent group 5 is a group consisting of a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 1-6 alkoxy group, a halo C 1-6 alkoxy group, a cyano group, and a halogen atom (1).
  • the compound or a pharmaceutically acceptable salt thereof according to any one of (7) to (7).
  • R 1 is a pyridyl group substituted with 1 to 3 substituents selected from substituent group 5 or a pyrimidyl group substituted with 1 to 3 substituents selected from substituent group 5
  • a pharmaceutical composition comprising as an active ingredient the compound according to any one of (1) to (10) or a pharmaceutically acceptable salt thereof.
  • Schizophrenia Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, comprising as an active ingredient the compound according to any one of (1) to (10) or a pharmaceutically acceptable salt thereof,
  • the compound of the present invention has glycine transporter (GlyT1) inhibitory activity.
  • C xy (x and y are natural numbers) indicates that the number of carbon atoms is from x to y.
  • C 1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl Group, isobutyl group, tert-butyl group, pentyl group, isopentyl group and hexyl group.
  • C 3-6 cycloalkyl group means a cycloalkyl group having 3 to 6 carbon atoms, and is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.
  • C 3-7 cycloalkane ring means a cycloalkane ring having 3 to 7 carbon atoms, and is a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, or a cycloheptane ring.
  • C 1-6 alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, A butoxy group, an isobutoxy group, a pentyloxy group, an isopentyloxy group, and a hexyloxy group can be exemplified.
  • C 3-6 cycloalkoxy group means a cycloalkoxy group having 3 to 6 carbon atoms, and is a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, or a cyclohexyloxy group.
  • halogen is fluorine, chlorine, bromine or iodine.
  • C 1-6 alkanoyl group refers to a linear or branched alkanoyl group having 1 to 6 carbon atoms, such as formyl group, acetyl group, propanoyl group, butanoyl group, pivaloyl group. The group can be mentioned.
  • C 1-6 alkanoyloxy group refers to a linear or branched alkanoyloxy group having 1 to 6 carbon atoms, such as formyloxy group, acetyloxy group, propanoyloxy group. Group, butanoyloxy group and pivaloyloxy group.
  • halo C 1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms substituted with a halogen atom. There are 1 to 3, and examples thereof include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, and a trichloromethyl group.
  • halo C 1-6 alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms substituted with a halogen atom. 1 to 3, for example, a fluoromethoxy group, a difluoromethoxy group, and a trifluoromethoxy group.
  • halo C 3-6 cycloalkyl group means a cycloalkyl group having 3 to 6 carbon atoms substituted with a halogen atom, and the preferred number of substitution of halogen atoms is 1 to 3. Examples thereof include a fluorocyclopropyl group and a difluorocyclopropyl group.
  • R 9 , R 10 , R 11 , and R 12 , and R 13 and R 14 a “4- to 6-membered saturated heterocyclic ring together with the nitrogen atom to be bonded,” includes an azetidine ring. , A pyrrolidine ring and a piperidine ring. Furthermore, a ring structure containing a hetero atom in the ring such as a morpholine ring and a thiomorpholine ring is also included.
  • “monocyclic or bicyclic heteroaryl group” refers to a monocyclic or bicyclic heteroaryl having at least one atom selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom in the ring.
  • An aryl group is meant.
  • the nitrogen atom may be an N oxide.
  • the monocyclic heteroaryl group is preferably a 5- or 6-membered heteroaryl group, for example, pyridyl group, pyridazyl group, pyrimidyl group, pyrazyl group, pyrazolyl group, thiazolyl group, imidazolyl group, oxazolyl group, isoxazolyl group, thienyl Group, triazolyl group and oxadiazolyl group.
  • examples of the “divalent monocyclic heteroaryl group” used in the present specification include groups in which any hydrogen atom of each of the above groups is removed.
  • the bicyclic heteroaryl group is preferably a 9- or 10-membered heteroaryl group, and examples thereof include an indolyl group, a benzofuranyl group, a benzimidazolyl group, an imidazolidyl group, a quinolyl group, and an isoquinolyl group.
  • C 2-7 alkoxycarbonyl group refers to a group in which a C 1-6 alkoxy group is substituted via a carbonyl group, such as a methoxycarbonyl group, an ethoxycarbonyl group, or a propoxycarbonyl group. Can do.
  • the “pharmaceutically acceptable salt” means a pharmaceutically acceptable acid addition salt, and the acid used includes sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid and phosphoric acid.
  • Inorganic acids such as acetic acid, oxalic acid, lactic acid, citric acid, malic acid, gluconic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid Mention may be made of organic acids. Conversion from the educt to the salt can be performed by conventional methods.
  • R 1 is a phenyl group, a pyridyl group, a pyrimidyl group, or a pyrazyl group;
  • the phenyl group, pyridyl group, pyrimidyl group, and pyrazyl group are preferably compounds that may be substituted with 1 to 3 substituents selected from Substituent Group 5.
  • R 1 is selected from Substituent Group 5
  • a compound that is a pyridyl group substituted with 1 to 3 substituents or a pyrimidyl group substituted with 1 to 3 substituents selected from Substituent Group 5 is more preferable.
  • R 2 is a phenyl group which may be substituted with 1 to 3 substituents selected from substituent group 3, an isoxazole group which may be substituted with 1 to 2 substituents selected from substituent group 4, An oxadiazole group which may be substituted with one substituent selected from substituent group 4, a triazole group which may be substituted with one or two substituents selected from substituent group 4, substituent group 4 1-3 substituents optionally pyrazole group optionally substituted with, or compounds which may be substituted pyridyl group with 1 to 3 substituents selected from substituent group 4 is preferably selected from, R 2 Is selected from a phenyl group which may be substituted with one 5-membered heteroaryl group, an isoxazole group which may be substituted with 1 to 2 substituents selected from substituent group 4 and a substituent group 4 A pyrazole group optionally substituted by 1 to 3 substituents, Alternatively, a compound that is a pyridyl group that may be
  • a compound in which R 3 and R 4 together with the carbon atom to which R 4 is bonded forms a C 3-7 cycloalkane ring is preferred.
  • R 5 and R 6 are both hydrogen atoms are preferred.
  • the compound of the present invention can contain a plurality of asymmetric centers. Therefore, the compound can exist in an optically active form and also in a racemic form thereof, and a plurality of diastereomers can also exist. All of the above forms are included within the scope of the present invention.
  • the individual isomers are known methods, for example the use of optically active starting materials or intermediates, optically selective or diastereoselective reactions in the production of intermediates or final products, or intermediates or final products. It can be obtained by separation using chromatography in the production of Further, when the compounds of the present invention form hydrates or solvates, they are also included within the scope of the present invention. Similarly, pharmaceutically acceptable salts of hydrates or solvates of the compounds of the invention are also included within the scope of the invention.
  • the compound according to the present invention can be administered orally or parenterally.
  • the dosage forms are tablets, capsules, granules, powders, powders, troches, ointments, creams, emulsions, suspensions, suppositories, injections, etc., all of which are conventional formulation techniques (for example, Etc.) according to the 15th revision Japanese Pharmacopoeia. These dosage forms can be appropriately selected according to the patient's symptoms, age and purpose of treatment.
  • compositions containing the compounds of the invention are pharmaceutically acceptable carriers for the compositions containing the compounds of the invention, ie excipients (eg crystalline cellulose, starch, lactose, mannitol), binders (eg hydroxypropylcellulose). , Polyvinylpyrrolidone), lubricants (for example, magnesium stearate, talc), disintegrants (for example, carboxymethyl cellulose calcium), and other various pharmacologically acceptable additives.
  • the compounds of the present invention can be combined with one or more other therapeutic agents, various antipsychotics, antidepressants such as 5HT3 antagonists, 5HT2 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake Inhibitor (SSRI), serotonin noradrenaline reuptake inhibitor (SNRI), tricyclic antidepressant, dopaminergic antidepressant, H3 antagonist, 5HT1A antagonist, 5HT1B antagonist, 5HT1D antagonist, D1 agonist, M1 agonist, anti It may be used with anticonvulsants, cognitive enhancers, and other psychoactive drugs.
  • antidepressants such as 5HT3 antagonists, 5HT2 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake Inhibitor (SSRI), serotonin noradrenaline reuptake inhibitor (SNRI), tricyclic antidepressant, dopaminergic antidepressant, H3 antagonist, 5HT
  • Particularly advantageous points related to the use and treatment methods of the combination of compounds of the present invention may include the same or improved effect of individual components at doses less than those normally used. Furthermore, further enhancement of the therapeutic effect on positive and / or negative symptoms of mental disorders and / or cognitive dysfunction is also expected.
  • the use and method of treatment according to the combination of the present invention may also provide benefits in the treatment of patients who do not fully respond to or are resistant to treatment with certain neuroleptic drugs.
  • the dose of the compound according to the present invention is 1 to 2000 mg per day when treating an adult, and this is administered once or divided into several times a day. This dosage can be appropriately increased or decreased depending on the age, weight and symptoms of the patient.
  • the compound of the formula [I] can be produced by various synthetic methods.
  • the following method is an illustration of the production method of the compound of the present invention, and is not limited thereto.
  • inert solvent means, for example, alcohols such as methanol, ethanol, isopropanol, n-butanol, ethylene glycol, diethyl ether, t-butyl methyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane.
  • Ethers such as 1,2-dimethoxyethane, hydrocarbons such as pentane, hexane, heptane, toluene, benzene, xylene, esters such as ethyl acetate and ethyl formate, ketones such as acetone and methyl ethyl ketone, chloroform and dichloromethane
  • esters such as ethyl acetate and ethyl formate
  • ketones such as acetone and methyl ethyl ketone
  • amides such as dimethylformamide and N-methylpyrrolidone, acetonitrile, dimethyl sulfoxide, water or a mixed solvent thereof.
  • Base means, for example, hydrides of alkali metals or alkaline earth metals such as lithium hydride, sodium hydride, potassium hydride, calcium hydride; lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium Alkali metal or alkaline earth metal amides such as hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; alkali metals such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or alkaline earth Lower alkoxides of similar metals; alkyllithiums such as butyllithium, sec-butyllithium, tert-butyllithium, methyllithium; sodium hydroxide, potassium hydroxide, lithium hydroxide, water Alkali metal or alkaline earth metal hydroxides such as barium fluoride; Alkali metal or alkaline earth metal hydro
  • Examples of the “acid” include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, citric acid, oxalic acid, etc. Organic acid. These acids are appropriately selected according to various reaction conditions known to those skilled in the art.
  • X 1 and X 4 represent a halogen atom or a hydroxyl group
  • X 2 represents a chlorine atom, a bromine atom, an iodine atom, or a trifluoromethanesulfonyloxy group
  • X 3 represents a halogen atom or a trifluoromethanesulfonyloxy group
  • P 1 represents a protecting group for a nitrogen atom such as a tert-butoxycarbonyl group or a benzyloxycarbonyl group (Theodora W.
  • P 2 is a methyl group, a protecting group of the ester such as a benzyl group (see ibid article)
  • P 3 is benzyl group, such as p- methoxybenzyl group
  • P 4 represents a 2- (trimethylsilyl) protecting group for the nitrogen atom of the pyrazole, such as ethoxymethyl group (see ibid article)
  • the R a substituent group 2 A phenyl group which may be substituted with 1 to 2 substituents selected, or a monocyclic or bicyclic heteroaryl group which may be substituted with 1 to 2 substituents selected from Substituent Group 2
  • R b is a phenyl group (the phenyl group may be substituted with 1 to 3 substituents selected from the group consisting
  • R d and R e may be the same or different and represent a hydrogen atom or C 1- or it shows a 6 alkyl group, or, R d, and R e to bind Together with the nitrogen atom, forms a 4- to 6-membered saturated heterocyclic ring (the 4- to 6-membered saturated heterocyclic ring may be substituted with an oxo group) or a 5-membered heteroaryl ring; It is synonymous.
  • Step 1 Compound [I] of the present invention can be obtained by reacting compound (1) with compound (2) wherein X 1 is a halogen atom in an inert solvent in the presence or absence of a base.
  • the compound (1) and the compound (2) in which X 1 is a hydroxyl group in an inert solvent in the presence or absence of a base are subjected to Mitsunobu reaction using an organic phosphorus compound and an azo compound or a phosphorus ylide reagent.
  • Invention compound [I] can be obtained.
  • Step 2 Compound (3) and Compound (4) are reacted in an inert solvent in the presence or absence of a base by using a palladium catalyst or a copper catalyst and optionally a metal catalyst ligand.
  • the compound [I] of the present invention can be obtained.
  • the palladium catalyst include Pd (OAc) 2 , Pd 2 (dba) 3 , and Pd (PPh 3 ) 4
  • examples of the copper catalyst include CuI and CuBr.
  • Examples of the ligand for the palladium catalyst include triphenylphosphine, Xantphos, BINAP (registered trademark), and the like, and examples of the ligand for the copper catalyst include N, N′-dimethylethylenediamine, 1,2-cyclohexanediamine, Examples include phenanthroline and proline.
  • Step 3 Compound (I) of the present invention can be obtained by cyclization of compound (5) in an inert solvent in the presence or absence of a base using a reagent such as triphosgene, phosgene, or carbonyldiimidazole.
  • a reagent such as triphosgene, phosgene, or carbonyldiimidazole.
  • the aforementioned compound (1) can be produced according to the following method.
  • General manufacturing method 4
  • Step 4 Compound (7) can be obtained by a general oxidation reaction from an alcohol to an aldehyde using an oxidizing agent in an inert solvent.
  • the oxidation reaction include a method using an oxidizing agent such as IBX, TEMPO, PCC, and PDC, and swallowing.
  • Step 5 Compound (9) can be obtained by subjecting compound (7) and compound (8) to a reductive amination reaction using an reducing agent in an inert solvent in the presence or absence of an acid.
  • the reducing agent include sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride and the like.
  • Step 6 Theodora W. Green, Peter G. et al. M.M.
  • Compound (10) can be obtained by the deprotection reaction described in Wuts, “Protecting Group in Organic Synthesis (Green's Protective Groups in Organic Synthesis, Forth Edition)”.
  • Step 7 Compound (10) can be converted to compound (1) by the same method as in Step 3 in General Production Method 3.
  • the aforementioned compound (1) can also be produced according to the following method.
  • General manufacturing method 5
  • Step 8 A urea structure is formed by reacting, for example, an isocyanate such as compound (12) with compound (11) in an inert solvent in the presence or absence of a base to obtain compound (13). it can.
  • Step 9 Compound (14) can be obtained by heating and stirring compound (13) in an inert solvent in the presence or absence of a base.
  • Step 10 Compound (1) can be obtained by reacting Compound (14) with a reducing agent in an inert solvent. Examples of the reducing agent include lithium aluminum hydride and sodium bis (2-methoxyethoxy) aluminum hydride, and heating and stirring and use of aluminum trichloride are preferable if necessary.
  • the aforementioned compound (1) can also be produced according to the following method. General manufacturing method 6
  • Step 11 Compound (15) can be converted to compound (16) by the same method as in Step 8 in General Production Method 5.
  • Step 12 Compound (1) can be obtained from compound (16) according to the method described in Journal of Organic Chemistry (1999, 64, 2941-2943). The aforementioned compound (1) can also be produced according to the following method.
  • General manufacturing method 7
  • Step 13 Compound by reacting compound (17) with a cyanating reagent such as ammonium carbonate, potassium cyanide or trimethylsilicon cyanide in an inert solvent in the presence or absence of a base, if necessary, by heating. (18) can be obtained.
  • Step 14 Compound (18) can be converted to compound (19) by the same method as in Step 10 in General Production Method 5.
  • Step 15 Compound (19) can be converted to compound (1) by the same method as in Step 2 in General Production Method 2.
  • the aforementioned compound (10) can also be produced according to the following method.
  • General manufacturing method 8 General manufacturing method 8
  • Step 16 Compound (21) can be obtained by subjecting Compound (20) to an amidation reaction using Compound (8) in an inert solvent in the presence or absence of a base.
  • the amidation reaction here can be carried out by a number of standard procedures known to those skilled in the art, for example amides via mixed acid anhydrides using ethyl chlorocarbonate, isobutyl chlorocarbonate, pivaloyl chloride, etc.
  • Step 17 Compound (21) can be converted to compound (22) by the same method as in Step 6 in General Production Method 4.
  • Step 18 Compound (10) can be obtained by reacting compound (22) with a reducing agent in an inert solvent.
  • the reducing agent is a reagent capable of reducing an amide to convert it to an amine, and examples thereof include lithium aluminum hydride, borane, sodium bis (2-methoxyethoxy) aluminum hydride, diisobutylaluminum hydride and the like. Can do.
  • the aforementioned compound (3) can be produced according to the following method.
  • Step 19 Compound (24) is reacted with an inorganic cyanide reagent or an organic cyanation reagent in the presence of compound (23) with compound (17) in the presence or absence of an acid in an inert solvent.
  • an inorganic cyanating reagent include potassium cyanide and sodium cyanide
  • examples of the organic cyanating reagent include trimethylsilyl cyanide.
  • a compound (25) can be obtained by performing a reductive reaction with respect to a compound (24) in an inert solvent.
  • the reduction reaction refers to a method of reducing a cyano group to a primary amine, for example, a method using a reducing agent such as lithium aluminum hydride in an inert solvent, or catalytic hydrogen using a catalyst such as palladium carbon in a hydrogen atmosphere. And the like.
  • Step 21 Theodora W. Green, Peter G. et al. M.M.
  • the compound (26) can be obtained from the compound (25) by the protection reaction of the amine described in Wuts, “Protecting Group in Organic Synthesis (Green's Protective Groups in Organic Synthesis, Forth Edition)”.
  • Step 22 Compound (26) can be converted to compound (27) by the same method as in Step 6 in General Production Method 4.
  • Step 23 Compound (30) can be obtained by reacting compound (27) with compound (27) in an inert solvent in the presence or absence of a base.
  • R 5 can be obtained by performing reductive amination reaction of Compound (27) and Compound (29) in the same manner as in Step 5 of General Production Method 4 in the presence or absence of an acid in an inert solvent.
  • Step 24 Compound (30) can be converted to compound (31) by the same method as in Step 6 in General Production Method 4.
  • Step 25 Compound (31) can be converted to compound (3) by the same method as in Step 3 in General Production Method 3.
  • the aforementioned compound (5) can be produced according to the following method.
  • General manufacturing method 10 General manufacturing method 10
  • Step 26 Compound (5) can be obtained by reacting compound (32) with compound (32) in the presence or absence of a base in an inert solvent.
  • X 3 is a chlorine atom, a bromine atom, an iodine atom, or a trifluoromethanesulfonyloxy group
  • the compound (31) can be converted to the compound (5) by using a ligand as necessary.
  • Step 27 Compound (10) can be converted to compound (5) by the same method as in Step 23 in General Production Method 9. However, when the compound (29) is used, R 5 and R 6 are both hydrogen atoms.
  • Step 28 Compound (34) can be obtained from compound (1) and compound (33) by the same method as in Step 1 in General Production Method 1.
  • the present compound [I2] can be obtained by reacting.
  • the palladium catalyst include Pd (OAc) 2 , Pd 2 (dba) 3 , and Pd (PPh 3 ) 4
  • examples of the ligand include triphenylphosphine, Xantphos, BINAP (registered trademark), and the like. It is done.
  • Compound (35) represents an organometallic reagent, for example, a Grignard reactant such as R b MgCl, a zinc reactant such as R b ZnCl, a boron reactant in which R b and boric acid or borate ester are bonded, or R b SnBu.
  • a Grignard reactant such as R b MgCl
  • a zinc reactant such as R b ZnCl
  • a boron reactant in which R b and boric acid or borate ester are bonded or R b SnBu.
  • the compound [I3] of the present invention can be obtained.
  • the palladium catalyst, the copper catalyst, and the respective ligands mentioned in Step 2 in General Production Method 2 may be used
  • Step 31 Compound of the present invention by reacting compound (37) wherein X 4 is a halogen atom with compound (37) wherein X 1 is a hydroxyl group in an inert solvent in the presence or absence of a base [I4] can be obtained.
  • the compound of the present invention can also be obtained by reacting the compound (34) in which X 4 is a hydroxyl group with a compound (37) in which X 1 is a halogen atom in an inert solvent in the presence or absence of a base. I4] can be obtained.
  • General manufacturing method 12
  • Step 32 Compound (39) can be obtained from compound (1) and compound (38) by the same method as in Step 1 in General Production Method 1.
  • Step 33 Compound (39) can be converted to compound (40) by the same method as in Step 6 in General Production Method 4.
  • Step 34 Compound (41) of the present invention can be obtained by reacting compound (41) with compound (40) in the presence or absence of a base in an inert solvent.
  • R b is a phenyl group which may be substituted or a heteroaryl group which may be substituted
  • the compound of the present invention can be obtained by reacting compound (41) with a copper catalyst and, if necessary, a ligand [ I5] can be obtained.
  • the copper catalyst include CuI and CuBr
  • examples of the ligand include N, N′-dimethylethylenediamine, 1,2-cyclohexanediamine, phenanthroline, proline and the like.
  • microwave reactor used was Biotage Initiator.
  • Biotage (registered trademark) SNAP Cartridge KP-NH is used for the “NH silica gel cartridge” when purified using column chromatography
  • Biotage (registered trademark) SNAP Cartridge KP is used for the “silica gel cartridge”.
  • -Sil or HP-Sil was used.
  • MORITEX (registered trademark) Purif-Pack ODS was used for the “reverse phase silica gel cartridge”.
  • NH silica gel when purified using preparative thin layer chromatography (PTLC) is Wako, NH 2 silica gel 60F254 plate-Wako 20 cm ⁇ 20 cm, “silica gel” is Merck Silica gel 60F254, 20 cm ⁇ 20 cm was used.
  • PTLC preparative thin layer chromatography
  • N-bromosuccinimide (774 mg) and 2,2′-azobis (2-methylpropionitrile) (48 mg) were added to a carbon tetrachloride (15 mL) solution of 2-bromo-5-methylpyrazine (500 mg) at 80 ° C. Stir overnight. After filtration through celite, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate) to give the title compound (253 mg).
  • reaction solution was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate) to give 3- [6- (trifluoromethyl) pyridin-3-yl] -1-[(1- ⁇ [2- (trimethylsilyl) ethoxy ] Methyl ⁇ -1H-pyrazol-4-yl) methyl] -1,3-diazaspiro [4.5] decan-2-one (820 mg) was obtained.
  • Example 11 1- ⁇ [6- (propan-2-ylamino) pyridin-3-yl] methyl ⁇ -3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4. 5] Decan-2-one
  • the filtrate was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform (2 mL), and bis (2-methoxyethyl) aminosulfur trifluoride (0.25 mL) was added under ice cooling. After stirring at room temperature for 2 hours, water was added and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate, and then washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate) to give a yellow oil. This was dissolved in 1,4-dioxane (2 mL), 1M hydrochloric acid (2 mL) was added, and the mixture was stirred overnight. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform and dried over anhydrous magnesium sulfate.
  • Example 16 3- [6- (Difluoromethoxy) pyridin-3-yl] -1- ⁇ [6- (propan-2-yloxy) pyridin-3-yl] methyl ⁇ -1,3-diazaspiro [4.5 ]
  • Example 19 1-[(1-Methyl-2-phenyl-1H-imidazol-4-yl) methyl] -3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4 .5] Decan-2-one
  • Table 1-1, Table 1-2, and Tables 2-1 to 2-24 show the structural formulas of the compounds shown in Examples 1 to 26 and the compounds synthesized by the same method and their instrument data.
  • the numbers described in the column of the examples in the table indicate which of the above Examples 1 to 26 was synthesized by the same method as in the above Examples.
  • a compound in which the salt column is blank indicates a free form.
  • Compounds 14 to 302 are compounds having a structure represented by the following formula [II].
  • Test Example 1 Glycine uptake inhibition experiment. Glycine uptake experiments were performed according to the method described in Neuron, 8, 927-935, 1992. T98G cells that are gliomas expressing human type 1 glycine transporter (GlyT1) were used. T98G cells were seeded in a 96-well plate at 2.0 ⁇ 10 4 cells / well and cultured overnight in a carbon dioxide incubator. A test substance is dissolved in a 100% DMSO solution, and then dissolved in 10 mM HEPES buffer (pH 7.4) containing 150 mM sodium chloride, 1 mM calcium chloride, 5 mM potassium chloride, 1 mM magnesium chloride, 10 mM glucose, and 0.2% bovine serum albumin. Dissolved.
  • the test substance was pretreated for 10 minutes. Thereafter, a test substance and [ 3 H] glycine (final concentration 250 nM) were added to the cells and allowed to react at room temperature for 15 minutes. After completion of the reaction, the extracellular fluid was aspirated with a manifold, the excess labeled glycine present outside the cells was removed, and then the cells were lysed with a 0.5 M aqueous sodium hydroxide solution. The amount of glycine present in the cells was determined by measuring the radioactivity in the cell lysate with a liquid scintillation counter.
  • the glycine uptake in the presence of 10 ⁇ M ALX5407 was defined as nonspecific uptake, and the total uptake in the absence of 10 ⁇ M ALX5407 minus the nonspecific uptake was defined as the specific uptake. Further, the glycine uptake inhibitory activity (IC 50 value) was calculated from the suppression curve of the test substance at 10 ⁇ 9 to 10 ⁇ 5 M concentration.
  • ALX5407 is N-[(3R) -3-([1,1'-biphenyl] -4-yloxy) -3- (4-fluorophenyl) propyl] -N-methylglycine HCl salt.
  • the IC 50 values of the example compounds in the present invention were all less than 10 ⁇ M. Specific examples, an IC 50 value of Compound 3 0.23MyuM, an IC 50 value of Compound 18 2.3MyuM, an IC 50 value is 0.087 ⁇ M of compound 29, the IC 50 values for compounds 100 0.062MyuM, Compound 134 has an IC 50 value of 0.43 ⁇ M, Compound 194 has an IC 50 value of 1.8 ⁇ M, Compound 240 has an IC 50 value of 0.091 ⁇ M, Compound 248 has an IC 50 value of 0.13 ⁇ M, and Compound 253 has an IC 50 value of 0.065 ⁇ M, Compound 257 had an IC 50 value of 0.057 ⁇ M, and Compound 297 had an IC 50 value of 0.038 ⁇ M.
  • the compound of the present invention has glycine transporter (GlyT1) inhibitory activity, and therefore, diseases related to the glycine transporter, specifically, schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder (generality) Anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post-traumatic stress disorder, specific phobia, acute stress disorder, etc.), depression, drug dependence, convulsions, tremor, pain, Parkinson's disease, attention deficit / many It is effective for the prevention or treatment of dyskinesia, bipolar disorder, eating disorder, or sleep disorder.
  • GlyT1 glycine transporter

Abstract

The present invention relates to a novel compound represented by formula [I] or a pharmaceutically acceptable salt thereof. This compound is useful for the prevention or treatment of diseases such as schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorders (generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, social anxiety disorder, post-traumatic stress disorder, a specific phobia, acute stress disorder, and the like), depression, drug dependence, convulsion, tremor, pain, Parkinson's disease, attention deficit/hyperactivity disorder, bipolar disorder, eating disorder, sleep disorder and the like, of which the action relies on an inhibitory activity on the intake of glycine.

Description

グリシントランスポーター阻害物質Glycine transporter inhibitor
　本発明は、グリシントランスポーター阻害作用を有する化合物に関する。 The present invention relates to a compound having a glycine transporter inhibitory action.
　グルタミン酸受容体の一つであるＮＭＤＡ受容体は脳内の神経細胞膜上に存在しており、神経の可塑性、認知、注意、記憶など様々な神経生理学的な現象に関わっている。ＮＭＤＡ受容体には複数のアロステリック結合部位が存在し、グリシン結合部位もその一つである（ＮＭＤＡ受容体複合体グリシン結合部位）。ＮＭＤＡ受容体複合体グリシン結合部位はＮＭＤＡ受容体の活性化に関与していることが報告されている（非特許文献１）。 NMDA receptor, which is one of glutamate receptors, exists on nerve cell membranes in the brain and is involved in various neurophysiological phenomena such as nerve plasticity, cognition, attention, and memory. The NMDA receptor has a plurality of allosteric binding sites, one of which is the glycine binding site (NMDA receptor complex glycine binding site). It has been reported that the NMDA receptor complex glycine binding site is involved in the activation of the NMDA receptor (Non-patent Document 1).
　グリシン作動性神経のシナプス前終末に活動電位が到達するとシナプス間隙へのグリシンの放出が開始される。放出されたグリシンはシナプス後部の受容体等と結合した後、トランスポーターによりシナプス間隙から取り除かれる。このことよりグリシンのトランスポーターは細胞外液にあるグリシン量を調節することでＮＭＤＡ受容体の機能を調節していると考えられている。 When the action potential reaches the presynaptic end of the glycinergic nerve, release of glycine into the synaptic cleft starts. The released glycine is removed from the synaptic cleft by the transporter after binding to a receptor or the like at the postsynaptic part. This suggests that the glycine transporter regulates the function of the NMDA receptor by regulating the amount of glycine in the extracellular fluid.
　グリシントランスポーター（ＧｌｙＴ）は細胞外グリシンの細胞内への再取り込みに関わっているタンパクであり、現在までにＧｌｙＴ１及びＧｌｙＴ２の二つのサブタイプの存在が明らかとなっている。ＧｌｙＴ１は主に大脳皮質、海馬及び視床等に発現しており、統合失調症、アルツハイマー病、認知機能障害、認知症、不安障害（全般性不安障害、パニック障害、強迫性障害、社会不安障害、外傷後ストレス障害、特定の恐怖症、急性ストレス障害等）、うつ病、薬物依存、痙攣、振戦、疼痛、パーキンソン病、注意欠陥・多動性障害、双極性障害、摂食障害、及び睡眠障害等の疾患との関連が報告されている（非特許文献２～４）。 Glycine transporter (GlyT) is a protein involved in the reuptake of extracellular glycine into cells, and the existence of two subtypes, GlyT1 and GlyT2, has been clarified so far. GlyT1 is mainly expressed in cerebral cortex, hippocampus and thalamus, etc., and is schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder (generalized anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, Post-traumatic stress disorder, specific phobia, acute stress disorder, etc.), depression, drug dependence, convulsions, tremor, pain, Parkinson's disease, attention deficit / hyperactivity disorder, bipolar disorder, eating disorder, and sleep A relationship with a disease such as a disorder has been reported (Non-Patent Documents 2 to 4).
　ＧｌｙＴ１阻害作用を有し、イミダゾリジン－２－オン構造をもつ化合物は以下の文献において報告がされている（特許文献１，２）。これらの特許文献１及び２に記載された化合物は、イミダゾリジンの一方の環内窒素原子に、アミド若しくはカルボニルを介してアリール基が結合していることを特徴とする化合物である。 Compounds having GlyT1 inhibitory activity and having an imidazolidin-2-one structure have been reported in the following documents (Patent Documents 1 and 2). These compounds described in Patent Documents 1 and 2 are compounds in which an aryl group is bonded to one ring nitrogen atom of imidazolidine via an amide or carbonyl.
WO2008092878WO2008092878 WO2009034062WO2009034062
　本発明は、グリシン取り込み阻害作用に基づいた統合失調症、アルツハイマー病、認知機能障害、認知症、不安障害（全般性不安障害、パニック障害、強迫性障害、社会不安障害、外傷後ストレス障害、特定の恐怖症、急性ストレス障害等）、うつ病、薬物依存、痙攣、振戦、疼痛、パーキンソン病、注意欠陥・多動性障害、双極性障害、摂食障害、又は睡眠障害等の疾患の予防又は治療に有用な新規な化合物又はその医薬上許容される塩を提供することを目的とする。 The present invention relates to schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder (general anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post-traumatic stress disorder, specific Prevention, depression, drug dependence, convulsions, tremors, pain, Parkinson's disease, attention deficit / hyperactivity disorder, bipolar disorder, eating disorders, or sleep disorders Alternatively, it is an object to provide a novel compound useful for treatment or a pharmaceutically acceptable salt thereof.
　本発明者らはＧｌｙＴ１に対し阻害作用を有する新規な骨格の化合物につき鋭意検討した結果、下記に示す式で表される化合物であって、イミダゾリジンの環内窒素原子に対して、アミド若しくはカルボニルを介さずにアリール基が結合していることを特徴とする化合物が優れたＧｌｙＴ１阻害物質であることを見出し、本発明を完成するに至った。 As a result of intensive studies on a novel skeletal compound having an inhibitory effect on GlyT1, the present inventors have found that the compound is represented by the following formula, and is an amide or carbonyl group with respect to the nitrogen atom in the ring of imidazolidine. The present inventors have found that a compound characterized in that an aryl group is bonded without intervening is an excellent GlyT1 inhibitor and completed the present invention.
　以下、本発明を詳細に説明する。本発明の態様（以下、「本発明化合物」という）は以下に示すものである。
（１）式［Ｉ］ Hereinafter, the present invention will be described in detail. The embodiment of the present invention (hereinafter referred to as “the compound of the present invention”) is shown below.
(1) Formula [I]
Figure JPOXMLDOC01-appb-C000002
　 
Figure JPOXMLDOC01-appb-C000002
　 
（式中、
Ｒ1は、フェニル基、ピリジル基、ピリダジル基、ピリミジル基、ピラジル基、又はピリドニル基を示し、
該フェニル基、ピリジル基、ピリダジル基、ピリミジル基、ピラジル基、及びピリドニル基は、置換基群１から選ばれる１～３個の置換基で置換されてもよく、
置換基群１は、Ｃ1-6アルキル基(該Ｃ1-6アルキル基は、ヒドロキシ基、Ｃ1-6アルカノイルオキシ基、及び式－ＮＲ7Ｒ8で示される基からなる群から選ばれる１～３個の置換基で置換されてもよく、Ｒ7、及びＲ8は、同一又は異なって、水素原子又はＣ1-6アルキル基を示す)、ハロＣ1-6アルキル基、Ｃ1-6アルコキシ基、ハロＣ1-6アルコキシ基、Ｃ2-7アルコキシカルボニル基、シアノ基、ハロゲン原子、５員若しくは６員のヘテロアリール基(該５員若しくは６員のヘテロアリール基は、１又２個のＣ1-6アルキル基で置換されてもよい)、Ｃ1-6アルカノイル基、及び式－ＮＲ9Ｒ10(Ｒ9、及びＲ10は、同一又は異なって、水素原子又はＣ1-6アルキル基を示すか、或いは、Ｒ9、及びＲ10が結合する窒素原子と一緒になって４～６員の飽和複素環を形成し、該４～６員の飽和複素環はオキソ基で置換されてもよい)で示される基からなる群であり、
Ｒ2は、置換基群２から選ばれる１～３個の置換基で置換されてもよいフェニル基、又は置換基群２から選ばれる１～３個の置換基で置換されてもよい単環若しくは二環のヘテロアリール基を示し、
該置換基群２は、フェニル基（該フェニル基は、Ｃ1-6アルキル基、Ｃ1-6アルコキシ基、及びハロゲン原子からなる群から選ばれる１～３個の置換基で置換されてもよい）、Ｃ1-6アルキル基(該Ｃ1-6アルキル基は、Ｃ1-6アルコキシ基、フェニル基、Ｃ3-6シクロアルキル基、ハロＣ1-6アルコキシ基、ハロＣ3-6シクロアルキル基、及び３－メチルオキセタン－３－イル基からなる群から選ばれる１～３個の置換基で置換されてもよい)、ハロＣ1-6アルキル基、Ｃ1-6アルコキシ基(該Ｃ1-6アルコキシ基は、Ｃ1-6アルコキシ基、ヒドロキシ基、Ｃ3-6シクロアルキル基、及び３－メチルオキセタン－３－イル基からなる群から選ばれる１～３個の置換基で置換されてもよい)、ヒドロキシ基、ベンジルオキシ基、ハロＣ1-6アルコキシ基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルコキシ基、テトラヒドロフラニル基、テトラヒドロフラニルオキシ基、テトラヒドロピラニル基、テトラヒドロピラニルオキシ基、Ｃ2-7アルコキシカルボニル基、シアノ基、ハロゲン原子、５員若しくは６員のヘテロアリール基(該５員若しくは６員のヘテロアリール基は、Ｃ1-6アルキル基、ハロゲン原子、及びＣ1-6アルコキシ基からなる群から選ばれる１又は２個の置換基で置換されてもよい)、Ｃ1-6アルカノイル基、式－ＮＲ11Ｒ12(Ｒ11、及びＲ12は、同一又は異なって、水素原子又はＣ1-6アルキル基を示すか、或いは、Ｒ11、及びＲ12が結合する窒素原子と一緒になって４～６員の飽和複素環を形成し、該４～６員の飽和複素環はオキソ基で置換されてもよい)で示される基、及び式－ＣＯＮＲ13Ｒ14(Ｒ13、及びＲ14は、同一又は異なって、水素原子又はＣ1-6アルキル基を示すか、或いは、Ｒ13、及びＲ14が結合する窒素原子と一緒になって４～６員の飽和複素環を形成し、該４～６員の飽和複素環はオキソ基で置換されてもよい)で示される基からなる群であり、
Ｒ3、及びＲ4は、同一又は異なって、水素原子、Ｃ1-6アルキル基、Ｃ3-6シクロアルキル基、フェニル基、又はベンジル基を示すか、或いは、Ｒ3、及びＲ4が結合する炭素原子と一緒になってＣ3-7シクロアルカン環、テトラヒドロフラン環、又はテトラヒドロピラン環を形成し（但し、Ｒ3、及びＲ4が共に水素原子である場合を除く）、
Ｒ5、及びＲ6は、同一又は異なって、水素原子、Ｃ1-6アルキル基を示す）で表される化合物又はその医薬上許容される塩(但し、Ｒ1が置換基群１から選ばれる１～３個の置換基で置換されてもよいフェニル基である場合、Ｒ2は置換基群２から選ばれる１～３個の置換基で置換されてもよい単環若しくは二環のヘテロアリール基である)。
（２）Ｒ5、及びＲ6が共に水素原子である（１）に記載の化合物又はその医薬上許容される塩。
（３）Ｒ3、及びＲ4が結合する炭素原子と一緒になってＣ3-7シクロアルカン環を形成する（１）又は（２）に記載の化合物又はその医薬上許容される塩。
（４）Ｒ2が置換基群２から選ばれる１～３個の置換基で置換されてもよいフェニル基、又は置換基群２から選ばれる１～３個の置換基で置換されてもよい単環のヘテロアリール基である（１）～（３）のいずれか１つに記載の化合物又はその医薬上許容される塩。
（５）Ｒ2が置換基群３から選ばれる１～３個の置換基で置換されてもよいフェニル基、又は置換基群４から選ばれる１～３個の置換基で置換されてもよい単環のヘテロアリール基であり、
置換基群３が、Ｃ1-6アルコキシ基、ハロＣ1-6アルコキシ基、及び５員のヘテロアリール基からなる群であり、
置換基群４が、フェニル基（該フェニル基は、Ｃ1-6アルキル基、Ｃ1-6アルコキシ基、及びハロゲン原子からなる群から選ばれる１～３個の置換基で置換されてもよい）、Ｃ1-6アルコキシ基、ハロＣ1-6アルコキシ基、及び５員若しくは６員のヘテロアリール基からなる群である（１）～（３）のいずれか１つに記載の化合物又はその医薬上許容される塩。
（６）Ｒ2が置換基群３から選ばれる１～３個の置換基で置換されてもよいフェニル基、置換基群４から選ばれる１～２個の置換基で置換されてもよいイソオキサゾール基、置換基群４から選ばれる１個の置換基で置換されてもよいオキサジアゾール基、置換基群４から選ばれる１～２個の置換基で置換されてもよいトリアゾール基、置換基群４から選ばれる１～３個の置換基で置換されてもよいピラゾール基、又は置換基群４から選ばれる１～３個の置換基で置換されてもよいピリジル基である（１）～（３）のいずれか１つに記載の化合物又はその医薬上許容される塩。
（７）Ｒ2が１個の５員のヘテロアリール基で置換されてもよいフェニル基、置換基群４から選ばれる１～２個の置換基で置換されてもよいイソオキサゾール基、置換基群４から選ばれる１～３個の置換基で置換されてもよいピラゾール基、又は置換基群４から選ばれる１～３個の置換基で置換されてもよいピリジル基である（１）～（３）のいずれか１つに記載の化合物又はその医薬上許容される塩。
（８）Ｒ1がピリジル基、ピリダジル基、ピリミジル基、ピラジル基、又はピリドニル基であり、
該ピリジル基、ピリダジル基、ピリミジル基、ピラジル基、及びピリドニル基は、置換基群１から選ばれる１～３個の置換基で置換されてもよい（１）～（７）のいずれか１つに記載の化合物又はその医薬上許容される塩。
（９）Ｒ1がフェニル基、ピリジル基、ピリミジル基、又はピラジル基であり、
該フェニル基、ピリジル基、ピリミジル基、及びピラジル基は、置換基群５から選ばれる１～３個の置換基で置換されてもよく、
置換基群５は、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ1-6アルコキシ基、ハロＣ1-6アルコキシ基、シアノ基、及びハロゲン原子からなる群である（１）～（７）のいずれか１つに記載の化合物又はその医薬上許容される塩。
（１０）Ｒ1が置換基群５から選ばれる１～３個の置換基で置換されたピリジル基、又は置換基群５から選ばれる１～３個の置換基で置換されたピリミジル基である（１）～（７）のいずれか１つに記載の化合物又はその医薬上許容される塩。
（１１）（１）～（１０）のいずれか１つに記載の化合物又はその医薬上許容される塩を有効成分として含む医薬組成物。
（１２）（１）～（１０）のいずれか１つに記載の化合物又はその医薬上許容される塩を有効成分として含む、統合失調症、アルツハイマー病、認知機能障害、認知症、不安障害、うつ病、薬物依存、痙攣、振戦、疼痛、パーキンソン病、注意欠陥・多動性障害、双極性障害、摂食障害、又は睡眠障害の疾患の予防剤又は治療剤。 (Where
R 1 represents a phenyl group, a pyridyl group, a pyridazyl group, a pyrimidyl group, a pyrazyl group, or a pyridonyl group;
The phenyl group, pyridyl group, pyridazyl group, pyrimidyl group, pyrazyl group, and pyridonyl group may be substituted with 1 to 3 substituents selected from the substituent group 1.
Substituent group 1 is a C 1-6 alkyl group (the C 1-6 alkyl group is selected from the group consisting of a hydroxy group, a C 1-6 alkanoyloxy group, and a group represented by the formula —NR 7 R 8. 1 to 3 substituents may be substituted, and R 7 and R 8 may be the same or different and each represents a hydrogen atom or a C 1-6 alkyl group), a halo C 1-6 alkyl group, C 1 -6 alkoxy group, halo C 1-6 alkoxy group, C 2-7 alkoxycarbonyl group, cyano group, halogen atom, 5-membered or 6-membered heteroaryl group (the 5-membered or 6-membered heteroaryl group is 1 And may be substituted with two C 1-6 alkyl groups), a C 1-6 alkanoyl group, and a formula —NR 9 R 10 (R 9 and R 10 may be the same or different and represent a hydrogen atom or C 1-6 represents an alkyl group, or a saturated double of R 9, and together with the nitrogen atom to which R 10 is attached 4-6 membered Forms a ring, saturated heterocyclic ring of the 4-6 membered are the group consisting of groups represented by oxo may be substituted with a group),
R 2 represents a phenyl group which may be substituted with 1 to 3 substituents selected from Substituent Group 2 or a monocycle which may be substituted with 1 to 3 substituents selected from Substituent Group 2 Or a bicyclic heteroaryl group,
The substituent group 2 is a phenyl group (the phenyl group may be substituted with 1 to 3 substituents selected from the group consisting of a C 1-6 alkyl group, a C 1-6 alkoxy group, and a halogen atom. C 1-6 alkyl group (the C 1-6 alkyl group is a C 1-6 alkoxy group, a phenyl group, a C 3-6 cycloalkyl group, a halo C 1-6 alkoxy group, a halo C 3-6 A cycloalkyl group, and 1 to 3 substituents selected from the group consisting of a 3-methyloxetane-3-yl group), a halo C 1-6 alkyl group, a C 1-6 alkoxy group ( The C 1-6 alkoxy group includes 1 to 3 substituents selected from the group consisting of a C 1-6 alkoxy group, a hydroxy group, a C 3-6 cycloalkyl group, and a 3-methyloxetane-3-yl group. A hydroxy group, a benzyloxy group, a halo C 1-6 alkoxy group, a C 3-6 cycloa Alkyl group, C 3-6 cycloalkoxy group, tetrahydrofuranyl group, tetrahydrofuranyloxy group, tetrahydropyranyl group, tetrahydropyranyloxy group, C 2-7 alkoxycarbonyl group, cyano group, halogen atom, 5 or 6 member (The 5- or 6-membered heteroaryl group is substituted with 1 or 2 substituents selected from the group consisting of a C 1-6 alkyl group, a halogen atom, and a C 1-6 alkoxy group. Or a C 1-6 alkanoyl group, the formula —NR 11 R 12 (R 11 and R 12 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group, or R 11 , And a nitrogen atom to which R 12 is bonded to form a 4- to 6-membered saturated heterocyclic ring, and the 4- to 6-membered saturated heterocyclic ring may be substituted with an oxo group, and formula -CONR 13 R 14 ( 13, and R 14 are the same or different, and represent a hydrogen atom or a C 1-6 alkyl group, or, R 13, and R 14 together with the nitrogen atom bonded 4-6 membered saturated heterocyclic Forming a ring, and the 4- to 6-membered saturated heterocyclic ring may be substituted with an oxo group).
R 3 and R 4 are the same or different and each represents a hydrogen atom, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a phenyl group, or a benzyl group, or R 3 and R 4 are Combined with the carbon atom to form a C 3-7 cycloalkane ring, tetrahydrofuran ring, or tetrahydropyran ring (except when R 3 and R 4 are both hydrogen atoms)
R 5 and R 6 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group) or a pharmaceutically acceptable salt thereof (provided that R 1 is selected from substituent group 1) R 2 is a monocyclic or bicyclic hetero ring which may be substituted with 1 to 3 substituents selected from Substituent Group 2; An aryl group).
(2) The compound or a pharmaceutically acceptable salt thereof according to (1), wherein R 5 and R 6 are both hydrogen atoms.
(3) The compound or pharmaceutically acceptable salt thereof according to (1) or (2), wherein R 3 and R 4 together with the carbon atom to which R 4 is bonded form a C 3-7 cycloalkane ring.
(4) R 2 may be substituted with a phenyl group which may be substituted with 1 to 3 substituents selected from Substituent Group 2 or with 1 to 3 substituents selected from Substituent Group 2 The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (3), which is a monocyclic heteroaryl group.
(5) R 2 may be substituted with a phenyl group which may be substituted with 1 to 3 substituents selected from Substituent Group 3 or with 1 to 3 substituents selected from Substituent Group 4 A monocyclic heteroaryl group,
Substituent group 3 is a group consisting of a C 1-6 alkoxy group, a halo C 1-6 alkoxy group, and a 5-membered heteroaryl group,
Substituent group 4 is a phenyl group (the phenyl group may be substituted with 1 to 3 substituents selected from the group consisting of a C 1-6 alkyl group, a C 1-6 alkoxy group, and a halogen atom. ), A C 1-6 alkoxy group, a halo C 1-6 alkoxy group, and a 5-membered or 6-membered heteroaryl group, or a compound thereof Pharmaceutically acceptable salt.
(6) R 2 is a phenyl group which may be substituted with 1 to 3 substituents selected from Substituent Group 3; an iso group which may be substituted with 1 to 2 substituents selected from Substituent Group 4; An oxazole group, an oxadiazole group which may be substituted with one substituent selected from substituent group 4, a triazole group which may be substituted with one or two substituents selected from substituent group 4, A pyrazole group which may be substituted with 1 to 3 substituents selected from group 4 or a pyridyl group which may be substituted with 1 to 3 substituents selected from substituent group 4 (1) A compound or a pharmaceutically acceptable salt thereof according to any one of (3) to (3).
(7) R 2 is a phenyl group which may be substituted with one 5-membered heteroaryl group, an isoxazole group which may be substituted with 1 to 2 substituents selected from Substituent Group 4 and a substituent A pyrazole group which may be substituted with 1 to 3 substituents selected from group 4 or a pyridyl group which may be substituted with 1 to 3 substituents selected from substituent group 4 (1) to The compound according to any one of (3) or a pharmaceutically acceptable salt thereof.
(8) R 1 is a pyridyl group, a pyridazyl group, a pyrimidyl group, a pyrazyl group, or a pyridonyl group,
The pyridyl group, pyridazyl group, pyrimidyl group, pyrazyl group, and pyridonyl group may be substituted with any one of 1 to 3 substituents selected from Substituent Group 1 (1) to (7) Or a pharmaceutically acceptable salt thereof.
(9) R 1 is a phenyl group, a pyridyl group, a pyrimidyl group, or a pyrazyl group,
The phenyl group, pyridyl group, pyrimidyl group, and pyrazyl group may be substituted with 1 to 3 substituents selected from the substituent group 5.
Substituent group 5 is a group consisting of a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 1-6 alkoxy group, a halo C 1-6 alkoxy group, a cyano group, and a halogen atom (1). The compound or a pharmaceutically acceptable salt thereof according to any one of (7) to (7).
(10) R 1 is a pyridyl group substituted with 1 to 3 substituents selected from substituent group 5 or a pyrimidyl group substituted with 1 to 3 substituents selected from substituent group 5 (1) A compound or a pharmaceutically acceptable salt thereof according to any one of (7) to (7).
(11) A pharmaceutical composition comprising as an active ingredient the compound according to any one of (1) to (10) or a pharmaceutically acceptable salt thereof.
(12) Schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, comprising as an active ingredient the compound according to any one of (1) to (10) or a pharmaceutically acceptable salt thereof, A preventive or therapeutic agent for diseases of depression, drug dependence, convulsions, tremors, pain, Parkinson's disease, attention deficit / hyperactivity disorder, bipolar disorder, eating disorder, or sleep disorder.
　本発明化合物はグリシントランスポーター（ＧｌｙＴ１）阻害活性を有する。 The compound of the present invention has glycine transporter (GlyT1) inhibitory activity.
　本明細書において用いる「Ｃx-y（ｘ、及びｙは自然数を示す）」とは、炭素原子の数が、ｘ個からｙ個であることを示す。 As used herein, “C xy (x and y are natural numbers)” indicates that the number of carbon atoms is from x to y.
　本明細書において用いる「Ｃ1-6アルキル基」とは直鎖状又は分岐鎖状の炭素数１～６個のアルキル基を意味し、例えばメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｔｅｒｔ－ブチル基、ペンチル基、イソペンチル基、ヘキシル基を挙げることができる。 As used herein, “C 1-6 alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl Group, isobutyl group, tert-butyl group, pentyl group, isopentyl group and hexyl group.
　本明細書において用いる「Ｃ3-6シクロアルキル基」とは炭素数３～６個のシクロアルキル基を意味し、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基である。 As used herein, “C 3-6 cycloalkyl group” means a cycloalkyl group having 3 to 6 carbon atoms, and is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.
　本明細書において用いる「Ｃ3-7シクロアルカン環」とは炭素数３～７個のシクロアルカン環を意味し、シクロプロパン環、シクロブタン環、シクロペンタン環、シクロヘキサン環、シクロヘプタン環である。 As used herein, “C 3-7 cycloalkane ring” means a cycloalkane ring having 3 to 7 carbon atoms, and is a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, or a cycloheptane ring.
　本明細書において用いる「Ｃ1-6アルコキシ基」とは直鎖状又は分岐鎖状の炭素数１～６個のアルコキシ基を意味し、例えばメトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブトキシ基、イソブトキシ基、ペンチルオキシ基、イソペンチルオキシ基、ヘキシルオキシ基を挙げることができる。 As used herein, “C 1-6 alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, A butoxy group, an isobutoxy group, a pentyloxy group, an isopentyloxy group, and a hexyloxy group can be exemplified.
　本明細書において用いる「Ｃ3-6シクロアルコキシ基」とは炭素数３～６個のシクロアルコキシ基を意味し、シクロプロポキシ基、シクロブトキシ基、シクロペンチルオキシ基、シクロヘキシルオキシ基である。 As used herein, the “C 3-6 cycloalkoxy group” means a cycloalkoxy group having 3 to 6 carbon atoms, and is a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, or a cyclohexyloxy group.
　本明細書において用いる「ハロゲン（ハロ）」とは、フッ素、塩素、臭素、ヨウ素である。 As used herein, “halogen” is fluorine, chlorine, bromine or iodine.
　本明細書において用いる「Ｃ1-6アルカノイル基」とは、鎖状又は分岐鎖状の炭素数１～６個のアルカノイル基を示し、例えば、ホルミル基、アセチル基、プロパノイル基、ブタノイル基、ピバロイル基を挙げることができる。 As used herein, the “C 1-6 alkanoyl group” refers to a linear or branched alkanoyl group having 1 to 6 carbon atoms, such as formyl group, acetyl group, propanoyl group, butanoyl group, pivaloyl group. The group can be mentioned.
　本明細書において用いる「Ｃ1-6アルカノイルオキシ基」とは、鎖状又は分岐鎖状の炭素数１～６個のアルカノイルオキシ基を示し、例えば、ホルミルオキシ基、アセチルオキシ基、プロパノイルオキシ基、ブタノイルオキシ基、ピバロイルオキシ基を挙げることができる。 As used herein, “C 1-6 alkanoyloxy group” refers to a linear or branched alkanoyloxy group having 1 to 6 carbon atoms, such as formyloxy group, acetyloxy group, propanoyloxy group. Group, butanoyloxy group and pivaloyloxy group.
　本明細書において用いる「ハロＣ1-6アルキル基」とはハロゲン原子で置換された直鎖状又は分岐鎖状の炭素数１～６個のアルキル基を意味し、ハロゲン原子の好ましい置換数は１～３個であり、例えばフルオロメチル基、ジフルオロメチル基、トリフルオロメチル基、トリクロロメチル基を挙げることができる。 As used herein, the term “halo C 1-6 alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms substituted with a halogen atom. There are 1 to 3, and examples thereof include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, and a trichloromethyl group.
　本明細書において用いる「ハロＣ1-6アルコキシ基」とはハロゲン原子で置換された直鎖状又は分岐鎖状の炭素数１～６個のアルコキシ基を意味し、ハロゲン原子の好ましい置換数は１～３個であり、例えばフルオロメトキシ基、ジフルオロメトキシ基、トリフルオロメトキシ基を挙げることができる。 As used herein, the term “halo C 1-6 alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms substituted with a halogen atom. 1 to 3, for example, a fluoromethoxy group, a difluoromethoxy group, and a trifluoromethoxy group.
　本明細書において用いる「ハロＣ3-6シクロアルキル基」とはハロゲン原子で置換された炭素数３～６個のシクロアルキル基を意味し、ハロゲン原子の好ましい置換数は１～３個であり、例えばフルオロシクロプロピル基、ジフルオロシクロプロピル基を挙げることができる。 As used herein, “halo C 3-6 cycloalkyl group” means a cycloalkyl group having 3 to 6 carbon atoms substituted with a halogen atom, and the preferred number of substitution of halogen atoms is 1 to 3. Examples thereof include a fluorocyclopropyl group and a difluorocyclopropyl group.
　本明細書のＲ9、及びＲ10、Ｒ11、及びＲ12、並びにＲ13、及びＲ14における「結合する窒素原子と一緒になって４～６員の飽和複素環」としては、アゼチジン環、ピロリジン環、ピペリジン環が挙げられる。さらに、モルホリン環、チオモルホリン環のように環内にヘテロ原子を含む環構造も含まれる。 In the present specification, R 9 , R 10 , R 11 , and R 12 , and R 13 and R 14 , a “4- to 6-membered saturated heterocyclic ring together with the nitrogen atom to be bonded,” includes an azetidine ring. , A pyrrolidine ring and a piperidine ring. Furthermore, a ring structure containing a hetero atom in the ring such as a morpholine ring and a thiomorpholine ring is also included.
　本明細書において用いる「単環若しくは二環のヘテロアリール基」とは窒素原子、酸素原子、及び硫黄原子からなる群から選ばれる少なくとも１個の原子を環内に有する単環若しくは二環のヘテロアリール基を意味する。窒素原子を環内に有する場合、その窒素原子はＮオキシドであってもよい。 As used herein, “monocyclic or bicyclic heteroaryl group” refers to a monocyclic or bicyclic heteroaryl having at least one atom selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom in the ring. An aryl group is meant. When a nitrogen atom is contained in the ring, the nitrogen atom may be an N oxide.
　単環ヘテロアリール基は、好ましくは５，又は６員のヘテロアリール基であり、例えばピリジル基、ピリダジル基、ピリミジル基、ピラジル基、ピラゾリル基、チアゾリル基、イミダゾリル基、オキサゾリル基、イソオキサゾリル基、チエニル基、トリアゾリル基、オキサジアゾリル基を挙げることができる。なお、本明細書において用いる「二価の単環ヘテロアリール基」としては、例えば上記各基の任意の水素原子を除いた基を挙げることができる。 The monocyclic heteroaryl group is preferably a 5- or 6-membered heteroaryl group, for example, pyridyl group, pyridazyl group, pyrimidyl group, pyrazyl group, pyrazolyl group, thiazolyl group, imidazolyl group, oxazolyl group, isoxazolyl group, thienyl Group, triazolyl group and oxadiazolyl group. In addition, examples of the “divalent monocyclic heteroaryl group” used in the present specification include groups in which any hydrogen atom of each of the above groups is removed.
　二環ヘテロアリール基は、好ましくは９，又は１０員のヘテロアリール基であり、例えばインドリル基、ベンゾフラニル基、ベンズイミダゾリル基、イミダゾピリジル基、キノリル基、イソキノリル基を挙げることができる。 The bicyclic heteroaryl group is preferably a 9- or 10-membered heteroaryl group, and examples thereof include an indolyl group, a benzofuranyl group, a benzimidazolyl group, an imidazolidyl group, a quinolyl group, and an isoquinolyl group.
　本明細書において用いる「Ｃ2-7アルコキシカルボニル基」とはＣ1-6アルコキシ基がカルボニル基を介して置換した基を示し、例えば、メトキシカルボニル基、エトキシカルボニル基、プロポキシカルボニル基を挙げることができる。 As used herein, “C 2-7 alkoxycarbonyl group” refers to a group in which a C 1-6 alkoxy group is substituted via a carbonyl group, such as a methoxycarbonyl group, an ethoxycarbonyl group, or a propoxycarbonyl group. Can do.
　本明細書中における「医薬上許容される塩」とは、薬剤的に許容することのできる酸付加塩を意味し、用いられる酸としては、硫酸、塩酸、臭化水素酸、硝酸及びリン酸等の無機酸、或いは、酢酸、シュウ酸、乳酸、クエン酸、リンゴ酸、グルコン酸、酒石酸、フマール酸、マレイン酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸及びｐ－トルエンスルホン酸等の有機酸を挙げることができる。遊離体から当該塩への変換は従来の方法で行うことができる。 In the present specification, the “pharmaceutically acceptable salt” means a pharmaceutically acceptable acid addition salt, and the acid used includes sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid and phosphoric acid. Inorganic acids such as acetic acid, oxalic acid, lactic acid, citric acid, malic acid, gluconic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid Mention may be made of organic acids. Conversion from the educt to the salt can be performed by conventional methods.
　本発明化合物において、好ましい態様を以下にあげる。
Ｒ1がフェニル基、ピリジル基、ピリミジル基、又はピラジル基であり、
該フェニル基、ピリジル基、ピリミジル基、及びピラジル基は、置換基群５から選ばれる１～３個の置換基で置換されてもよい化合物が好ましく、Ｒ1が置換基群５から選ばれる１～３個の置換基で置換されたピリジル基、又は置換基群５から選ばれる１～３個の置換基で置換されたピリミジル基である化合物がより好ましい。 Preferred embodiments of the compound of the present invention are listed below.
R 1 is a phenyl group, a pyridyl group, a pyrimidyl group, or a pyrazyl group;
The phenyl group, pyridyl group, pyrimidyl group, and pyrazyl group are preferably compounds that may be substituted with 1 to 3 substituents selected from Substituent Group 5. R 1 is selected from Substituent Group 5 A compound that is a pyridyl group substituted with 1 to 3 substituents or a pyrimidyl group substituted with 1 to 3 substituents selected from Substituent Group 5 is more preferable.
　Ｒ2が置換基群３から選ばれる１～３個の置換基で置換されてもよいフェニル基、置換基群４から選ばれる１～２個の置換基で置換されてもよいイソオキサゾール基、置換基群４から選ばれる１個の置換基で置換されてもよいオキサジアゾール基、置換基群４から選ばれる１～２個の置換基で置換されてもよいトリアゾール基、置換基群４から選ばれる１～３個の置換基で置換されてもよいピラゾール基、又は置換基群４から選ばれる１～３個の置換基で置換されてもよいピリジル基である化合物が好ましく、Ｒ2が１個の５員のヘテロアリール基で置換されてもよいフェニル基、置換基群４から選ばれる１～２個の置換基で置換されてもよいイソオキサゾール基、置換基群４から選ばれる１～３個の置換基で置換されてもよいピラゾール基、又は置換基群４から選ばれる１～３個の置換基で置換されてもよいピリジル基である化合物がより好ましい。 R 2 is a phenyl group which may be substituted with 1 to 3 substituents selected from substituent group 3, an isoxazole group which may be substituted with 1 to 2 substituents selected from substituent group 4, An oxadiazole group which may be substituted with one substituent selected from substituent group 4, a triazole group which may be substituted with one or two substituents selected from substituent group 4, substituent group 4 1-3 substituents optionally pyrazole group optionally substituted with, or compounds which may be substituted pyridyl group with 1 to 3 substituents selected from substituent group 4 is preferably selected from, R 2 Is selected from a phenyl group which may be substituted with one 5-membered heteroaryl group, an isoxazole group which may be substituted with 1 to 2 substituents selected from substituent group 4 and a substituent group 4 A pyrazole group optionally substituted by 1 to 3 substituents, Alternatively, a compound that is a pyridyl group that may be substituted with 1 to 3 substituents selected from Substituent Group 4 is more preferable.
　Ｒ3、及びＲ4が結合する炭素原子と一緒になってＣ3-7シクロアルカン環を形成する化合物が好ましい。 A compound in which R 3 and R 4 together with the carbon atom to which R 4 is bonded forms a C 3-7 cycloalkane ring is preferred.
　Ｒ5、及びＲ6が共に水素原子である化合物が好ましい。 A compound in which R 5 and R 6 are both hydrogen atoms is preferred.
　本発明化合物は複数の不斉中心を含むことができる。従って前記化合物は光学活性体で存在するとともにそのラセミ体でも存在することができ、さらに複数のジアステレオマーも存在することができる。前記の全ての形態は本発明の範囲内に含まれる。個々の異性体は公知の方法、例えば光学活性な出発物質若しくは中間体の使用、中間体若しくは最終生成物の製造における光学選択的な反応又はジアステレオ選択的な反応、或いは中間体又は最終生成物の製造におけるクロマトグラフィーを用いた分離等により得ることが可能である。さらに、本発明化合物が水和物又は溶媒和物を形成する場合、それらも本発明の範囲内に含まれる。同様に、本発明化合物の水和物又は溶媒和物の医薬上許容される塩も本発明の範囲内に含まれる。 The compound of the present invention can contain a plurality of asymmetric centers. Therefore, the compound can exist in an optically active form and also in a racemic form thereof, and a plurality of diastereomers can also exist. All of the above forms are included within the scope of the present invention. The individual isomers are known methods, for example the use of optically active starting materials or intermediates, optically selective or diastereoselective reactions in the production of intermediates or final products, or intermediates or final products. It can be obtained by separation using chromatography in the production of Further, when the compounds of the present invention form hydrates or solvates, they are also included within the scope of the present invention. Similarly, pharmaceutically acceptable salts of hydrates or solvates of the compounds of the invention are also included within the scope of the invention.
　本発明に係る化合物は、経口又は非経口的に投与することができる。その投与剤型は錠剤、カプセル剤、顆粒剤、散剤、粉剤、トローチ剤、軟膏剤、クリーム剤、乳剤、懸濁剤、坐剤、注射剤等であり、いずれも慣用の製剤技術（例えば、第１５改正日本薬局方に規定する方法等）によって製造することができる。これらの投与剤型は、患者の症状、年齢及び治療の目的に応じて適宜選択することができる。 The compound according to the present invention can be administered orally or parenterally. The dosage forms are tablets, capsules, granules, powders, powders, troches, ointments, creams, emulsions, suspensions, suppositories, injections, etc., all of which are conventional formulation techniques (for example, Etc.) according to the 15th revision Japanese Pharmacopoeia. These dosage forms can be appropriately selected according to the patient's symptoms, age and purpose of treatment.
　これらの製剤は、本発明の化合物を含有する組成物に薬理学的に許容されるキャリヤー、すなわち、賦形剤（例えば、結晶セルロース、デンプン、乳糖、マンニトール）、結合剤（例えば、ヒドロキシプロピルセルロース、ポリビニルピロリドン）、滑沢剤（例えば、ステアリン酸マグネシウム、タルク）、崩壊剤（例えば、カルボキシメチルセルロースカルシウム）、その他薬理学的に許容される各種添加剤を配合し、製造することができる。 These formulations are pharmaceutically acceptable carriers for the compositions containing the compounds of the invention, ie excipients (eg crystalline cellulose, starch, lactose, mannitol), binders (eg hydroxypropylcellulose). , Polyvinylpyrrolidone), lubricants (for example, magnesium stearate, talc), disintegrants (for example, carboxymethyl cellulose calcium), and other various pharmacologically acceptable additives.
　また、本発明の化合物を１以上の他の治療薬、種々の抗精神病薬（antipsychotics）、抗うつ薬、例えば、５ＨＴ３アンタゴニスト、５ＨＴ２アンタゴニスト、セロトニンアゴニスト、ＮＫ－１アンタゴニスト、選択的セロトニン再取込阻害薬（ＳＳＲＩ）、セロトニンノルアドレナリン再取込阻害薬（ＳＮＲＩ）、三環系抗うつ薬、ドーパミン作動性抗うつ薬、Ｈ３アンタゴニスト、５ＨＴ１Ａアンタゴニスト、５ＨＴ１Ｂアンタゴニスト、５ＨＴ１Ｄアンタゴニスト、Ｄ１アゴニスト、Ｍ１アゴニスト、抗けいれん薬、認知機能増強薬、および、その他向精神薬（psychoactive drug）と共に使用してもよい。 In addition, the compounds of the present invention can be combined with one or more other therapeutic agents, various antipsychotics, antidepressants such as 5HT3 antagonists, 5HT2 antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake Inhibitor (SSRI), serotonin noradrenaline reuptake inhibitor (SNRI), tricyclic antidepressant, dopaminergic antidepressant, H3 antagonist, 5HT1A antagonist, 5HT1B antagonist, 5HT1D antagonist, D1 agonist, M1 agonist, anti It may be used with anticonvulsants, cognitive enhancers, and other psychoactive drugs.
　本発明の化合物と組み合わせて共に使用してもよい他の治療薬とは、例えばオンダンセトロン（ｏｎｄａｎｓｅｔｒｏｎ）、グラニセトロン（ｇｒａｎｉｓｅｔｒｏｎ）、メトクロプラミド（ｍｅｔｏｃｌｏｐｒａｍｉｄｅ）、スマトリプタン（ｓｕｍａｔｒｉｐｔａｎ）、ラウオルシン（ｒａｕｗｏｌｓｃｉｎｅ）、ヨヒムビン（ｙｏｈｉｍｂｉｎｅ）、メトクロプラミド（ｍｅｔｏｃｌｏｐｒａｍｉｄｅ）、フルオキセチン（ｆｌｕｏｘｅｔｉｎｅ）、シタロプラム（ｃｉｔａｌｏｐｒａｍ）、エスシタロプラム（ｅｓｃｉｔａｌｏｐｒａｍ）、フェモキセチン（ｆｅｍｏｘｅｔｉｎｅ）、フルボキサミン（ｆｌｕｖｏｘａｍｉｎｅ）、パロキセチン（ｐａｒｏｘｅｔｉｎｅ）、インダルピン（ｉｎｄａｌｐｉｎｅ）、サートラリン（ｓｅｒｔｒａｌｉｎｅ）、ジメルジン（ｚｉｍｅｌｄｉｎｅ）、ベンラファキシン（ｖｅｎｌａｆａｘｉｎｅ）、レボキセチン（ｒｅｂｏｘｅｔｉｎｅ）、ミルナシプラン（Ｍｉｌｎａｃｉｐｒａｎ）、デュロキセチン（ｄｕｌｏｘｅｔｉｎｅ）、イミプラミン（ｉｍｉｐｒａｍｉｎｅ）、アミトリプチリン（ａｍｉｔｒｉｐｔｉｌｉｎｅ）、クロミプラミン（ｃｈｌｏｍｉｐｒａｍｉｎｅ）、ノルトリプチリン（ｎｏｒｔｒｉｐｔｉｌｉｎｅ）、ブプロピオン（ｂｕｐｒｏｐｉｏｎ）、アミネプチン（ａｍｉｎｅｐｔｉｎｅ）、ジバルプロエクス（ｄｉｖａｌｐｒｏｅｘ）、カルバマゼピン（ｃａｒｂａｍａｚｅｐｉｎｅ）、ジアゼパム（ｄｉａｚｅｐａｍ）、リスペリドン（ｒｉｓｐｅｒｉｄｏｎｅ）、オランザピン（ｏｌａｎｚａｐｉｎｅ）、ジプラシドン（ｚｉｐｒａｓｉｄｏｎｅ）、アリピプラゾール（ａｒｉｐｉｐｒａｚｏｌｅ）、クエチアピン（ｑｕｅｔｉａｐｉｎｅ）、ペロスピロン（ｐｅｒｏｓｐｉｒｏｎｅ）、クロザピン（ｃｌｏｚａｐｉｎｅ）ハロペリドール（ｈａｌｏｐｅｒｉｄｏｌ）、ピモジド（ｐｉｍｏｚｉｄｅ）、ドロペリドール（ｄｒｏｐｅｒｉｄｏｌ）、クロルプロマジン（ｃｈｌｏｒｐｒｏｍａｚｉｎｅ）、チオリダジン（ｔｈｉｏｒｉｄａｚｉｎｅ）、メソリダジン（ｍｅｓｏｒｉｄａｚｉｎｅ）、トリフルオペラジン（ｔｒｉｆｌｕｏｐｅｒａｚｉｎｅ）、ペルフェナジン（ｐｅｒｐｈｅｎａｚｉｎｅ）、フルフェナジン（ｆｌｕｐｈｅｎａｚｉｎｅ）、チフルプロマジン（ｔｈｉｆｌｕｐｒｏｍａｚｉｎｅ）、プロクロルペラジン（ｐｒｏｃｈｌｏｒｐｅｒａｚｉｎｅ）、アセトフェナジン（ａｃｅｔｏｐｈｅｎａｚｉｎｅ）、チオチキセン（ｔｈｉｏｔｈｉｘｅｎｅ）、クロルプロチキセン（ｃｈｌｏｒｐｒｏｔｈｉｘｅｎｅ）、ラモトリジン（ｌａｍｏｔｒｉｇｉｎｅ）、ロキサピン（ｌｏｘａｐｉｎｅ）、モリンドン（ｍｏｌｉｎｄｏｎｅ）等を挙げることができる。これら組み合わせは、同時に（同一の医薬処方において、または異なる医薬処方において）、別々に、または連続的に投与されればよい。 Other therapeutic agents that may be used in combination with the compounds of the present invention include, for example, ondansetron, granisetron, metoclopramide, sumatriptan, lauolsine, yohimbine (Yohimbine), metoclopramide (metoclopramide), fluoxetine (fluxetine), citalopram (citalopram), escitalopram (dal), feloxetine (fluxetine) ertraline, zimeldine, venlafaxine, reboxetine, milnacipran, duloxetine, imipramine, imitriprine, imipramine ), Bupropion, amineeptine, divalproex, carbamazepine, diazepam, risperidone, olanzapine e), ziprasidone, aripiprazole, quetiapine, perispirone, clozapine, cloperpine, haloperidol, pimozide, ), Mesoridazine, trifluoperazine, perphenazine, fluphenazine, tiflupromazine, prochlorperazine (pr) ochlorperazine, acetophenazine, thiothixene, chlorprothixene, lamotrigine, loxapine, molindon, etc. These combinations may be administered simultaneously (in the same pharmaceutical formulation or in different pharmaceutical formulations), separately or sequentially.
　本発明の化合物の組み合わせによる使用および治療方法に関連する特に有利な点には、個々の成分の通常使用される投与量よりも少ない投与量での同等または改善された効果を挙げることができる。また、精神障害の陽性症状および／または陰性症状および／または認知機能障害に対する治療効果のさらなる増強も期待される。本発明の組み合わせによる使用および治療方法は、ある種の神経弛緩薬での治療に十分に応答しない、または該治療に耐性のある患者の治療においても利益を提供しうる。 Particularly advantageous points related to the use and treatment methods of the combination of compounds of the present invention may include the same or improved effect of individual components at doses less than those normally used. Furthermore, further enhancement of the therapeutic effect on positive and / or negative symptoms of mental disorders and / or cognitive dysfunction is also expected. The use and method of treatment according to the combination of the present invention may also provide benefits in the treatment of patients who do not fully respond to or are resistant to treatment with certain neuroleptic drugs.
　本発明に係る化合物の投与量は、成人を治療する場合で１日１～２０００ｍｇであり、これを１日１回又は数回に分けて投与する。この投与量は、患者の年齢、体重及び症状によって適宜増減することができる。 The dose of the compound according to the present invention is 1 to 2000 mg per day when treating an adult, and this is administered once or divided into several times a day. This dosage can be appropriately increased or decreased depending on the age, weight and symptoms of the patient.
　式[Ｉ]の化合物は種々の合成方法によって製造することができる。以下の方法は、本発明化合物の製造法の例示であり、これに限定されるものではない。 The compound of the formula [I] can be produced by various synthetic methods. The following method is an illustration of the production method of the compound of the present invention, and is not limited thereto.
　一般的製造法中、「不活性溶媒」とは例えばメタノール、エタノール、イソプロパノール、ｎ－ブタノール、エチレングリコール等のアルコール類、ジエチルエーテル、ｔ－ブチルメチルエーテル、ジイソプロピルエーテル、テトラヒドロフラン、１，４－ジオキサン、１，２－ジメトキシエタン等のエーテル類、ペンタン、ヘキサン、ヘプタン、トルエン、ベンゼン、キシレン等の炭化水素類、酢酸エチル、ギ酸エチル等のエステル類、アセトン、メチルエチルケトン等のケトン類、クロロホルム、ジクロロメタン等のハロゲン化炭素系溶媒、ジメチルホルムアミド、N-メチルピロリドン等のアミド類、アセトニトリル、ジメチルスルホキシド、水又はこれらの混合溶媒等である。 In general production methods, “inert solvent” means, for example, alcohols such as methanol, ethanol, isopropanol, n-butanol, ethylene glycol, diethyl ether, t-butyl methyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane. Ethers such as 1,2-dimethoxyethane, hydrocarbons such as pentane, hexane, heptane, toluene, benzene, xylene, esters such as ethyl acetate and ethyl formate, ketones such as acetone and methyl ethyl ketone, chloroform and dichloromethane And amides such as dimethylformamide and N-methylpyrrolidone, acetonitrile, dimethyl sulfoxide, water or a mixed solvent thereof.
　「塩基」とは例えば、水素化リチウム、水素化ナトリウム、水素化カリウム、水素化カルシウムなどのアルカリ金属又はアルカリ土類金属の水素化物；リチウムアミド、ナトリウムアミド、リチウムジイソプロピルアミド、リチウムジシクロヘキシルアミド、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、カリウムヘキサメチルジシラジドなどのアルカリ金属又はアルカリ土類金属のアミド；ナトリウムメトキシド、ナトリウムエトキシド、カリウム　ｔｅｒｔ－ブトキシドなどのアルカリ金属又はアルカリ土類金属の低級アルコキシド；ブチルリチウム、ｓｅｃ－ブチルリチウム、ｔｅｒｔ－ブチルリチウム、メチルリチウムなどのアルキルリチウム；水酸化ナトリウム、水酸化カリウム、水酸化リチウム、水酸化バリウムなどのアルカリ金属又はアルカリ土類金属の水酸化物；炭酸ナトリウム、炭酸カリウム、炭酸セシウムなどのアルカリ金属又はアルカリ土類金属の炭酸塩；炭酸水素ナトリウム、炭酸水素カリウムなどのアルカリ金属又はアルカリ土類金属の炭酸水素塩；トリエチルアミン、Ｎ－メチルモルホリン、Ｎ，Ｎ－ジイソプロピルエチルアミン、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン（ＤＢＵ）、１，５－ジアザビシクロ［４．３．０］ノン－５－エン（ＤＢＮ）、Ｎ，Ｎ－ジメチルアニリンなどのアミン；ピリジン、イミダゾール、２，６－ルチジンなどの塩基性ヘテロ環化合物などである。これらの塩基は当業者に公知である種々の反応条件に応じて適宜選択される。 “Base” means, for example, hydrides of alkali metals or alkaline earth metals such as lithium hydride, sodium hydride, potassium hydride, calcium hydride; lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium Alkali metal or alkaline earth metal amides such as hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide; alkali metals such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or alkaline earth Lower alkoxides of similar metals; alkyllithiums such as butyllithium, sec-butyllithium, tert-butyllithium, methyllithium; sodium hydroxide, potassium hydroxide, lithium hydroxide, water Alkali metal or alkaline earth metal hydroxides such as barium fluoride; Alkali metal or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate; Alkali metals or alkalis such as sodium hydrogen carbonate and potassium hydrogen carbonate Earth metal bicarbonates; triethylamine, N-methylmorpholine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4 .3.0] amines such as non-5-ene (DBN) and N, N-dimethylaniline; basic heterocyclic compounds such as pyridine, imidazole and 2,6-lutidine. These bases are appropriately selected according to various reaction conditions known to those skilled in the art.
　「酸」とは例えば、塩酸、臭化水素酸、硫酸、硝酸、リン酸などの無機酸及びｐ－トルエンスルホン酸、メタンスルホン酸、トリフルオロ酢酸、ギ酸、酢酸、クエン酸、シュウ酸などの有機酸である。これらの酸は当業者に公知である種々の反応条件に応じて適宜選択される。 Examples of the “acid” include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, citric acid, oxalic acid, etc. Organic acid. These acids are appropriately selected according to various reaction conditions known to those skilled in the art.
　一般的製造法中、Ｘ1およびＸ4はハロゲン原子又は水酸基を示し、Ｘ2は塩素原子、臭素原子、ヨウ素原子、又はトリフルオロメタンスルホニルオキシ基を示し、Ｘ3はハロゲン原子又はトリフルオロメタンスルホニルオキシ基を示し、Ｐ1はｔｅｒｔ－ブトキシカルボニル基、ベンジルオキシカルボニル基などの窒素原子の保護基（Ｔｈｅｏｄｏｒａ　Ｗ．Ｇｒｅｅｎ，Ｐｅｔｅｒ　Ｇ．Ｍ．Ｗｕｔｓ、「有機合成における保護基（Ｇｒｅｅｎ’ｓ　Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ，Ｆｏｒｔｈ　Ｅｄｉｔｉｏｎ）」；Ｗｉｌｅｙ　Ｉｎｔｅｒｓｃｉｅｎｃｅ参照）を示し、Ｐ2はメチル基、ベンジル基などのエステルの保護基（同上資料参照）を示し、Ｐ3はベンジル基、ｐ－メトキシベンジル基等の１級アミノ基を形成するアミノ基の保護基を示し、Ｐ4は２－（トリメチルシリル）エトキシメチル基等のピラゾールの窒素原子の保護基（同上資料参照）を示し、Ｒaは置換基群２から選ばれる１～２個の置換基で置換されてもよいフェニル基、又は置換基群２から選ばれる１～２個の置換基で置換されてもよい単環若しくは二環のヘテロアリール基を示し、Ｒbはフェニル基（該フェニル基はＣ1-6アルキル基、Ｃ1-6アルコキシ基、およびハロゲン原子からなる群から選ばれる１～３個の置換基で置換されても良い）、Ｃ1-6アルキル基（該アルキル基は、Ｃ1-6アルコキシ基、フェニル基、Ｃ3-6シクロアルキル基、ハロＣ1-6アルコキシ基、ハロＣ3-6シクロアルキル基、及び３－メチルオキセタン－３－イル基からなる群から選ばれる１～３個の置換基で置換されてもよい)、ハロＣ1-6アルキル基、Ｃ3-6シクロアルキル基、テトラヒドロフラニル基、テトラヒドロピラニル基、又は５員若しくは６員のヘテロアリール基(該５員若しくは６員のヘテロアリール基は、Ｃ1-6アルキル基、ハロゲン原子、及びＣ1-6アルコキシ基からなる群から選ばれる１又２個の置換基で置換されてもよい)を示し、ＲcはＣ1-6アルキル基（該Ｃ1-6アルキル基はＣ1-6アルコキシ基、ヒドロキシ基、Ｃ3-6シクロアルキル基、３－メチルオキセタン－３－イル基、ハロゲン原子、及びフェニル基からなる群から選ばれる１～３個の置換基で置換されても良い）、又はＣ3-6シクロアルキル基を示し、ＲdおよびＲeは同一又は異なって、水素原子又はＣ1-6アルキル基を示すか、或いは、Ｒd、及びＲeが結合する窒素原子と一緒になって４～６員の飽和複素環（該４～６員の飽和複素環はオキソ基で置換されてもよい）又は5員のへテロアリール環を形成し、その他は前記と同義である。
一般的製造法１ In general production methods, X 1 and X 4 represent a halogen atom or a hydroxyl group, X 2 represents a chlorine atom, a bromine atom, an iodine atom, or a trifluoromethanesulfonyloxy group, and X 3 represents a halogen atom or a trifluoromethanesulfonyloxy group. P 1 represents a protecting group for a nitrogen atom such as a tert-butoxycarbonyl group or a benzyloxycarbonyl group (Theodora W. Green, Peter GM Wuts, “Protecting group in organic synthesis (Green's Protective Groups in Organic Synthesis, Forth Edition) "; see Wiley Interscience) indicates, P 2 is a methyl group, a protecting group of the ester such as a benzyl group (see ibid article), P 3 is benzyl group, such as p- methoxybenzyl group An amino-protecting group to form a grade amino group, P 4 represents a 2- (trimethylsilyl) protecting group for the nitrogen atom of the pyrazole, such as ethoxymethyl group (see ibid article), the R a substituent group 2 A phenyl group which may be substituted with 1 to 2 substituents selected, or a monocyclic or bicyclic heteroaryl group which may be substituted with 1 to 2 substituents selected from Substituent Group 2 , R b is a phenyl group (the phenyl group may be substituted with 1 to 3 substituents selected from the group consisting of a C 1-6 alkyl group, a C 1-6 alkoxy group, and a halogen atom), C 1-6 alkyl group (the alkyl group includes a C 1-6 alkoxy group, a phenyl group, a C 3-6 cycloalkyl group, a halo C 1-6 alkoxy group, a halo C 3-6 cycloalkyl group, and 3-methyl 1-3 selected from the group consisting of oxetane-3-yl groups Substituted with substituents may be), halo C 1-6 alkyl group, C 3-6 cycloalkyl group, tetrahydrofuranyl group, tetrahydropyranyl group, or a 5- or 6-membered heteroaryl group (said 5-membered Or a 6-membered heteroaryl group may be substituted with one or two substituents selected from the group consisting of a C 1-6 alkyl group, a halogen atom, and a C 1-6 alkoxy group), and R c is a C 1-6 alkyl group (the C 1-6 alkyl group is a C 1-6 alkoxy group, a hydroxy group, a C 3-6 cycloalkyl group, a 3-methyloxetane-3-yl group, a halogen atom, and a phenyl group). Or a C 3-6 cycloalkyl group, and R d and R e may be the same or different and represent a hydrogen atom or C 1- or it shows a 6 alkyl group, or, R d, and R e to bind Together with the nitrogen atom, forms a 4- to 6-membered saturated heterocyclic ring (the 4- to 6-membered saturated heterocyclic ring may be substituted with an oxo group) or a 5-membered heteroaryl ring; It is synonymous.
General manufacturing method 1
Figure JPOXMLDOC01-appb-C000003
  　 
Figure JPOXMLDOC01-appb-C000003
  　 
工程１：不活性溶媒中、塩基の存在下又は非存在下、化合物（１）とX1がハロゲン原子である化合物（２）を反応させることで本発明化合物［Ｉ］を得ることができる。又は、不活性溶媒中、塩基の存在下又は非存在下、化合物（１）とX1が水酸基である化合物（２）を、有機リン化合物とアゾ化合物もしくはリンイリド試薬を用いた光延反応により、本発明化合物［Ｉ］を得ることができる。ここで有機リン化合物としてはトリフェニルホスフィン、トリブチルホスフィン等が、アゾ化合物としてはアゾジカルボン酸ジエチル、アゾジカルボン酸ジイソプロピル、アゾジカルボン酸ジｔｅｒｔブチル等が、リンイリド試薬としてはシアノメチレントリブチルホスホラン等が挙げられる。
一般的製造法２ Step 1: Compound [I] of the present invention can be obtained by reacting compound (1) with compound (2) wherein X 1 is a halogen atom in an inert solvent in the presence or absence of a base. Alternatively, the compound (1) and the compound (2) in which X 1 is a hydroxyl group in an inert solvent in the presence or absence of a base are subjected to Mitsunobu reaction using an organic phosphorus compound and an azo compound or a phosphorus ylide reagent. Invention compound [I] can be obtained. Here, triphenylphosphine, tributylphosphine, etc. are used as the organic phosphorus compound, diethyl azodicarboxylate, diisopropyl azodicarboxylate, ditertbutyl azodicarboxylate, etc. as the azo compound, and cyanomethylene tributylphosphorane, etc. as the phosphorus ylide reagent. Can be mentioned.
General manufacturing method 2
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
工程２：不活性溶媒中、塩基の存在下又は非存在下、パラジウム触媒もしくは銅触媒および必要に応じて金属触媒の配位子を使用することで、化合物（３）と化合物（４）を反応させ、本発明化合物［Ｉ］を得ることができる。
ここでパラジウム触媒としてはＰｄ（ＯＡｃ）2、Ｐｄ2（ｄｂａ）3、Ｐｄ（ＰＰｈ3）4等が挙げられ、銅触媒としてはＣｕＩ、ＣｕＢｒ等が挙げられる。パラジウム触媒の配位子としては、トリフェニルホスフィン、Ｘａｎｔｐｈｏｓ、ＢＩＮＡＰ（登録商標）等が挙げられ、また銅触媒の配位子としては、Ｎ，Ｎ’－ジメチルエチレンジアミン、１，２－シクロヘキサンジアミン、フェナントロリン、プロリン等が挙げられる。
一般的製造法３ Step 2: Compound (3) and Compound (4) are reacted in an inert solvent in the presence or absence of a base by using a palladium catalyst or a copper catalyst and optionally a metal catalyst ligand. The compound [I] of the present invention can be obtained.
Here, examples of the palladium catalyst include Pd (OAc) 2 , Pd 2 (dba) 3 , and Pd (PPh 3 ) 4 , and examples of the copper catalyst include CuI and CuBr. Examples of the ligand for the palladium catalyst include triphenylphosphine, Xantphos, BINAP (registered trademark), and the like, and examples of the ligand for the copper catalyst include N, N′-dimethylethylenediamine, 1,2-cyclohexanediamine, Examples include phenanthroline and proline.
General manufacturing method 3
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
工程３：不活性溶媒中、塩基の存在下又は非存在下、化合物（５）をトリホスゲン、ホスゲン、カルボニルジイミダゾール等の試薬を用いて環化し、本発明化合物［Ｉ］を得ることができる。
前述の化合物（１）は以下の方法に従って製造することができる。
一般的製造法４ Step 3: Compound (I) of the present invention can be obtained by cyclization of compound (5) in an inert solvent in the presence or absence of a base using a reagent such as triphosgene, phosgene, or carbonyldiimidazole.
The aforementioned compound (1) can be produced according to the following method.
General manufacturing method 4
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
工程４：不活性溶媒中、酸化剤を用いたアルコールからアルデヒドへの一般的な酸化反応により、化合物（７）を得ることができる。ここで酸化反応とはＩＢＸ、ＴＥＭＰＯ、ＰＣＣ、ＰＤＣなどの酸化剤を用いた方法やスワーン酸化などが挙げられる。
工程５：不活性溶媒中、酸存在下又は非存在下、還元剤を用いて化合物（７）と化合物（８）を還元的アミノ化反応に供することで、化合物（９）を得ることができる。ここで還元剤として水素化トリアセトキシホウ素ナトリウム、水素化シアノホウ素ナトリウム、水素化ホウ素ナトリウムなどが挙げられる。
工程６：Ｔｈｅｏｄｏｒａ　Ｗ．Ｇｒｅｅｎ，Ｐｅｔｅｒ　Ｇ．Ｍ．Ｗｕｔｓ、「有機合成における保護基（Ｇｒｅｅｎ’ｓ　Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ，Ｆｏｒｔｈ　Ｅｄｉｔｉｏｎ）」に記載の脱保護反応により、化合物（１０）を得ることができる。
工程７：一般的製造法３中の工程３と同様の方法により、化合物（１０）を化合物（１）に変換することができる。
前述の化合物（１）は以下の方法に従っても製造することができる。
一般的製造法５ Step 4: Compound (7) can be obtained by a general oxidation reaction from an alcohol to an aldehyde using an oxidizing agent in an inert solvent. Here, examples of the oxidation reaction include a method using an oxidizing agent such as IBX, TEMPO, PCC, and PDC, and swallowing.
Step 5: Compound (9) can be obtained by subjecting compound (7) and compound (8) to a reductive amination reaction using an reducing agent in an inert solvent in the presence or absence of an acid. . Examples of the reducing agent include sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride and the like.
Step 6: Theodora W. Green, Peter G. et al. M.M. Compound (10) can be obtained by the deprotection reaction described in Wuts, “Protecting Group in Organic Synthesis (Green's Protective Groups in Organic Synthesis, Forth Edition)”.
Step 7: Compound (10) can be converted to compound (1) by the same method as in Step 3 in General Production Method 3.
The aforementioned compound (1) can also be produced according to the following method.
General manufacturing method 5
Figure JPOXMLDOC01-appb-C000007
  　 
Figure JPOXMLDOC01-appb-C000007
  　 
工程８：不活性溶媒中、塩基の存在下又は非存在下、例えば化合物（１２）のようなイソシアネートを化合物（１１）に反応させることでウレア構造を形成し、化合物（１３）を得ることができる。
工程９：不活性溶媒中、塩基の存在下又は非存在下、化合物（１３）を加熱撹拌することで、化合物（１４）を得ることができる。
工程１０：不活性溶媒中、化合物（１４）を還元剤と反応させることで化合物（１）を得ることができる。ここで還元剤とは水素化アルミニウムリチウムや水素化ビス（２－メトキシエトキシ）アルミニウムナトリウムなどが挙げられ、また必要に応じて加熱撹拌や三塩化アルミニウムの使用が好ましい。
前述の化合物（１）は以下の方法に従っても製造することができる。
一般的製造法６ Step 8: A urea structure is formed by reacting, for example, an isocyanate such as compound (12) with compound (11) in an inert solvent in the presence or absence of a base to obtain compound (13). it can.
Step 9: Compound (14) can be obtained by heating and stirring compound (13) in an inert solvent in the presence or absence of a base.
Step 10: Compound (1) can be obtained by reacting Compound (14) with a reducing agent in an inert solvent. Examples of the reducing agent include lithium aluminum hydride and sodium bis (2-methoxyethoxy) aluminum hydride, and heating and stirring and use of aluminum trichloride are preferable if necessary.
The aforementioned compound (1) can also be produced according to the following method.
General manufacturing method 6
Figure JPOXMLDOC01-appb-C000008
　 
Figure JPOXMLDOC01-appb-C000008
　 
工程１１：一般的製造法５中の工程８と同様の方法により、化合物（１５）を化合物（１６）に変換することができる。
工程１２：Ｊｏｕｒｎａｌ　ｏｆ　Ｏｒｇａｎｉｃ　Ｃｈｅｍｉｓｔｒｙ（１９９９，６４，２９４１－２９４３）に記載の方法に従い、化合物（１６）から化合物（１）を得ることができる。
前述の化合物（１）は以下の方法に従っても製造することができる。
一般的製造法７ Step 11: Compound (15) can be converted to compound (16) by the same method as in Step 8 in General Production Method 5.
Step 12: Compound (1) can be obtained from compound (16) according to the method described in Journal of Organic Chemistry (1999, 64, 2941-2943).
The aforementioned compound (1) can also be produced according to the following method.
General manufacturing method 7
Figure JPOXMLDOC01-appb-C000009
　 
Figure JPOXMLDOC01-appb-C000009
　 
工程１３：不活性溶媒中、塩基の存在下又は非存在下、化合物（１７）とアンモニウムカーボネート、シアン化カリウムやシアン化トリメチルケイ素などシアノ化試薬を、必要に応じて加熱して、反応させることで化合物（１８）を得ることができる。
工程１４：一般的製造法５中の工程１０と同様の方法により、化合物（１８）を化合物（１９）に変換することができる。
工程１５：一般的製造法２中の工程２と同様の方法により、化合物（１９）を化合物（１）に変換することができる。
前述の化合物（１０）は以下の方法に従っても製造することもできる。
一般的製造法８ Step 13: Compound by reacting compound (17) with a cyanating reagent such as ammonium carbonate, potassium cyanide or trimethylsilicon cyanide in an inert solvent in the presence or absence of a base, if necessary, by heating. (18) can be obtained.
Step 14: Compound (18) can be converted to compound (19) by the same method as in Step 10 in General Production Method 5.
Step 15: Compound (19) can be converted to compound (1) by the same method as in Step 2 in General Production Method 2.
The aforementioned compound (10) can also be produced according to the following method.
General manufacturing method 8
Figure JPOXMLDOC01-appb-C000010
  
Figure JPOXMLDOC01-appb-C000010
  
工程１６：不活性溶媒中、塩基の存在下又は非存在下、化合物（２０）に対して化合物（８）を用いてアミド化反応を行うことにより化合物（２１）を得ることができる。ここでアミド化反応とは当業者に公知である多くの標準的な手順により実施することができ、例えばクロロ炭酸エチル、クロロ炭酸イソブチル、ピバロイルクロリド等を用いた混合酸無水物経由のアミド化、或いは１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（ＥＤＣ・ＨＣｌ）、1，3－ジシクロヘキシルカルボジイミド（ＤＣＣ）、ジフェニルホスホリルアジド（ＤＰＰＡ）、シアノリン酸ジエチル、カルボニルジイミダゾール（ＣＤＩ）、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　ヘキサフルオロリン酸（ＨＡＴＵ）、又はベンゾトリアゾール－1－イルオキシトリス（ジメチルアミノ）ホスホニウム　ヘキサフルオロホスフェート（ＢＯＰ試薬）等の縮合剤を用いたアミド化を挙げることができる。ここで縮合剤を用いたアミド化反応の際、必要に応じて１－ヒドロキシベンゾトリアゾール（ＨＯＢｔ）、ヒドロキシスクシンイミド（ＨＯＳｕ）などの添加剤を使用することができる。
工程１７：一般的製造法４中の工程６と同様の方法により、化合物（２１）を化合物（２２）に変換することができる。
工程１８：不活性溶媒中、化合物（２２）に対して還元剤を反応させることにより、化合物（１０）を得ることができる。ここで還元剤とはアミドを還元してアミンに変換することができる試薬であり、例えば水素化アルミニウムリチウム、ボラン、水素化ビス（２－メトキシエトキシ）アルミニウムナトリウム、水素化ジイソブチルアルミニウム等を挙げることができる。
前述の化合物（３）は以下の方法に従って製造することができる。
一般的製造法９ Step 16: Compound (21) can be obtained by subjecting Compound (20) to an amidation reaction using Compound (8) in an inert solvent in the presence or absence of a base. The amidation reaction here can be carried out by a number of standard procedures known to those skilled in the art, for example amides via mixed acid anhydrides using ethyl chlorocarbonate, isobutyl chlorocarbonate, pivaloyl chloride, etc. Or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC · HCl), 1,3-dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide (DPPA), diethyl cyanophosphate, carbonyldiimidazole ( CDI), O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU), or benzotriazol-1-yloxytris (dimethyl) Condensing agents such as amino) phosphonium hexafluorophosphate (BOP reagent) Amidation using can be mentioned. Here, in the amidation reaction using the condensing agent, additives such as 1-hydroxybenzotriazole (HOBt) and hydroxysuccinimide (HOSu) can be used as necessary.
Step 17: Compound (21) can be converted to compound (22) by the same method as in Step 6 in General Production Method 4.
Step 18: Compound (10) can be obtained by reacting compound (22) with a reducing agent in an inert solvent. Here, the reducing agent is a reagent capable of reducing an amide to convert it to an amine, and examples thereof include lithium aluminum hydride, borane, sodium bis (2-methoxyethoxy) aluminum hydride, diisobutylaluminum hydride and the like. Can do.
The aforementioned compound (3) can be produced according to the following method.
General manufacturing method 9
Figure JPOXMLDOC01-appb-C000011
　 
Figure JPOXMLDOC01-appb-C000011
　 
工程１９：不活性溶媒中、酸存在下又は非存在下、化合物（１７）に対して化合物（２３）の存在下無機シアノ化試薬若しくは有機シアノ化試薬を反応させることで、化合物（２４）を得ることができる。ここで無機シアノ化試薬とは例えばシアン化カリウム、シアン化ナトリウム等を、また有機シアノ化試薬とは例えばトリメチルシリルシアニド等を挙げることができる。
工程２０： 不活性溶媒中、化合物（２４）に対して還元反応を行うことで化合物（２５）を得ることができる。ここで還元反応とはシアノ基を１級アミンに還元する方法を指し、例えば不活性溶媒中水素化アルミニウムリチウムなどの還元剤を用いる方法や、水素雰囲気下パラジウム炭素などの触媒を用いた接触水素化反応などが挙げられる。
工程２１：Ｔｈｅｏｄｏｒａ　Ｗ．Ｇｒｅｅｎ，Ｐｅｔｅｒ　Ｇ．Ｍ．Ｗｕｔｓ、「有機合成における保護基（Ｇｒｅｅｎ’ｓ　Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ，Ｆｏｒｔｈ　Ｅｄｉｔｉｏｎ）」に記載のアミンの保護反応により、化合物（２５）より化合物（２６）を得ることができる。
工程２２：一般的製造法４中の工程６と同様の方法により、化合物（２６）を化合物（２７）に変換することができる。
工程２３：不活性溶媒中、塩基の存在下又は非存在下、化合物（２７）に対して化合物（２８）を反応させることにより、化合物（３０）を得ることができる。また不活性溶媒中、酸存在下又は非存在下、化合物（２７）と化合物（２９）を一般的製造法４中の工程５と同様の方法により還元的アミノ化反応を行うことで、Ｒ5、及びＲ6が共に水素原子である化合物（３０）を得ることができる。
工程２４：一般的製造法４中の工程６と同様の方法により、化合物（３０）を化合物（３１）に変換することができる。
工程２５：一般的製造法３中の工程３と同様の方法により、化合物（３１）を化合物（３）に変換することができる。
前述の化合物（５）は以下の方法に従って製造することができる。
一般的製造法１０ Step 19: Compound (24) is reacted with an inorganic cyanide reagent or an organic cyanation reagent in the presence of compound (23) with compound (17) in the presence or absence of an acid in an inert solvent. Obtainable. Examples of the inorganic cyanating reagent include potassium cyanide and sodium cyanide, and examples of the organic cyanating reagent include trimethylsilyl cyanide.
Process 20: A compound (25) can be obtained by performing a reductive reaction with respect to a compound (24) in an inert solvent. Here, the reduction reaction refers to a method of reducing a cyano group to a primary amine, for example, a method using a reducing agent such as lithium aluminum hydride in an inert solvent, or catalytic hydrogen using a catalyst such as palladium carbon in a hydrogen atmosphere. And the like.
Step 21: Theodora W. Green, Peter G. et al. M.M. The compound (26) can be obtained from the compound (25) by the protection reaction of the amine described in Wuts, “Protecting Group in Organic Synthesis (Green's Protective Groups in Organic Synthesis, Forth Edition)”.
Step 22: Compound (26) can be converted to compound (27) by the same method as in Step 6 in General Production Method 4.
Step 23: Compound (30) can be obtained by reacting compound (27) with compound (27) in an inert solvent in the presence or absence of a base. In addition, R 5 can be obtained by performing reductive amination reaction of Compound (27) and Compound (29) in the same manner as in Step 5 of General Production Method 4 in the presence or absence of an acid in an inert solvent. And a compound (30) in which R 6 are both hydrogen atoms.
Step 24: Compound (30) can be converted to compound (31) by the same method as in Step 6 in General Production Method 4.
Step 25: Compound (31) can be converted to compound (3) by the same method as in Step 3 in General Production Method 3.
The aforementioned compound (5) can be produced according to the following method.
General manufacturing method 10
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
工程２６：不活性溶媒中、塩基の存在下又は非存在下、化合物（３２）に対して化合物（３１）を反応させることで化合物（５）を得ることができる。またＸ3が塩素原子、臭素原子、ヨウ素原子、又はトリフルオロメタンスルホニルオキシ基の場合、不活性溶媒中、塩基の存在下又は非存在下、一般的製造法２中の工程２に記載のパラジウム触媒および必要に応じて配位子を用いることでも化合物（３１）を化合物（５）に変換することができる。
工程２７：一般的製造法９中の工程２３と同様の方法により、化合物（１０）を化合物（５）に変換することができる。但し、化合物（２９）を用いた場合、Ｒ5、及びＲ6は共に水素原子である。
一般的製造法１１ Step 26: Compound (5) can be obtained by reacting compound (32) with compound (32) in the presence or absence of a base in an inert solvent. When X 3 is a chlorine atom, a bromine atom, an iodine atom, or a trifluoromethanesulfonyloxy group, the palladium catalyst according to Step 2 in General Production Method 2 in an inert solvent, in the presence or absence of a base Also, the compound (31) can be converted to the compound (5) by using a ligand as necessary.
Step 27: Compound (10) can be converted to compound (5) by the same method as in Step 23 in General Production Method 9. However, when the compound (29) is used, R 5 and R 6 are both hydrogen atoms.
General manufacturing method 11
Figure JPOXMLDOC01-appb-C000013
 　 
Figure JPOXMLDOC01-appb-C000013
 　 
工程２８：一般的製造法１中の工程１と同様の方法により、化合物（１）と化合物（３３）より化合物（３４）を得ることができる。
工程２９：Ｘ4がハロゲン原子である化合物（３４）に対して、不活性溶媒中、塩基の存在下又は非存在下、パラジウム触媒および必要に応じて配位子を使用して化合物（３５）を反応させることにより、本発明化合物［Ｉ２］を得ることができる。
ここでパラジウム触媒としてはＰｄ（ＯＡｃ）2、Ｐｄ2（ｄｂａ）3、Ｐｄ（ＰＰｈ3）4等が挙げられ、配位子としては、トリフェニルホスフィン、Ｘａｎｔｐｈｏｓ、ＢＩＮＡＰ（登録商標）等が挙げられる。また化合物（３５）は有機金属試薬を示し、例えばＲbＭｇＣｌなどのＧｒｉｇｎａｒｄ反応剤、ＲbＺｎＣｌなどの亜鉛反応剤、Ｒbとホウ酸又はホウ酸エステルが結合したホウ素反応剤やＲbＳｎＢｕ3などのスズ反応剤等が挙げられる
工程３０：Ｘ4がハロゲン原子である化合物（３４）に対して、不活性溶媒中、塩基の存在下又は非存在下、化合物（３６）を反応させることにより、本発明化合物［Ｉ３］を得ることができる。この工程において、必要に応じて一般的製造法２中の工程２で挙げたパラジウム触媒、銅触媒、および各々の配位子を用いることもある。
工程３１：Ｘ4がハロゲン原子である化合物（３４）に対して、不活性溶媒中、塩基の存在下又は非存在下、Ｘ1が水酸基である化合物（３７）を反応させることにより本発明化合物［Ｉ４］を得ることができる。またＸ4が水酸基である化合物（３４）に対して、不活性溶媒中、塩基の存在下又は非存在下、Ｘ1がハロゲン原子である化合物（３７）を反応させることによっても本発明化合物［Ｉ４］を得ることができる。
一般的製造法１２ Step 28: Compound (34) can be obtained from compound (1) and compound (33) by the same method as in Step 1 in General Production Method 1.
Step 29: For compound (34) wherein X 4 is a halogen atom, compound (35) using a palladium catalyst and optionally a ligand in an inert solvent in the presence or absence of a base The present compound [I2] can be obtained by reacting.
Here, examples of the palladium catalyst include Pd (OAc) 2 , Pd 2 (dba) 3 , and Pd (PPh 3 ) 4 , and examples of the ligand include triphenylphosphine, Xantphos, BINAP (registered trademark), and the like. It is done. Compound (35) represents an organometallic reagent, for example, a Grignard reactant such as R b MgCl, a zinc reactant such as R b ZnCl, a boron reactant in which R b and boric acid or borate ester are bonded, or R b SnBu. Process 30 in which tin reactants such as 3 are mentioned: Compound (36) is reacted with compound (34) in which X 4 is a halogen atom in an inert solvent in the presence or absence of a base. The compound [I3] of the present invention can be obtained. In this step, the palladium catalyst, the copper catalyst, and the respective ligands mentioned in Step 2 in General Production Method 2 may be used as necessary.
Step 31: Compound of the present invention by reacting compound (37) wherein X 4 is a halogen atom with compound (37) wherein X 1 is a hydroxyl group in an inert solvent in the presence or absence of a base [I4] can be obtained. The compound of the present invention can also be obtained by reacting the compound (34) in which X 4 is a hydroxyl group with a compound (37) in which X 1 is a halogen atom in an inert solvent in the presence or absence of a base. I4] can be obtained.
General manufacturing method 12
Figure JPOXMLDOC01-appb-C000014
  　 
Figure JPOXMLDOC01-appb-C000014
  　 
工程３２：一般的製造法１中の工程1と同様の方法により、化合物（１）と化合物（３８）より化合物（３９）を得ることができる。
工程３３：一般的製造法４中の工程６と同様の方法により、化合物（３９）を化合物（４０）に変換することができる。
工程３４：不活性溶媒中、塩基の存在下又は非存在下、化合物（４０）に対して化合物（４１）を反応させることにより、本発明化合物［Ｉ５］を得ることができる。またＲbが置換されてもよいフェニル基、又は置換されてもよいヘテロアリール基の場合、銅触媒および必要に応じて配位子を用いて化合物（４１）を反応させることで本発明化合物［Ｉ５］を得ることができる。ここで銅触媒としてはＣｕＩ、ＣｕＢｒ等が挙げられ、配位子としては、Ｎ，Ｎ’－ジメチルエチレンジアミン、１，２－シクロヘキサンジアミン、フェナントロリン、プロリン等が挙げられる。 Step 32: Compound (39) can be obtained from compound (1) and compound (38) by the same method as in Step 1 in General Production Method 1.
Step 33: Compound (39) can be converted to compound (40) by the same method as in Step 6 in General Production Method 4.
Step 34: Compound (41) of the present invention can be obtained by reacting compound (41) with compound (40) in the presence or absence of a base in an inert solvent. In the case where R b is a phenyl group which may be substituted or a heteroaryl group which may be substituted, the compound of the present invention can be obtained by reacting compound (41) with a copper catalyst and, if necessary, a ligand [ I5] can be obtained. Here, examples of the copper catalyst include CuI and CuBr, and examples of the ligand include N, N′-dimethylethylenediamine, 1,2-cyclohexanediamine, phenanthroline, proline and the like.
　次に、製造例、実施例及び試験例により本発明をさらに詳細に説明するが、本発明はこれらの実施例に限定されるものではない。 Next, the present invention will be described in more detail with reference to production examples, examples and test examples, but the present invention is not limited to these examples.
　以下の製造例および実施例において、使用したマイクロウエーブ反応装置はＢｉｏｔａｇｅ社Ｉｎｉｔｉａｔｏｒである。 In the following production examples and examples, the microwave reactor used was Biotage Initiator.
　以下の製造例および実施例において、カラムクロマトグラフィーを使用して精製した際の「ＮＨシリカゲルカートリッジ」にはＢｉｏｔａｇｅ（登録商標）ＳＮＡＰＣａｒｔｒｉｄｇｅ　ＫＰ－ＮＨ、「シリカゲルカートリッジ」にはＢｉｏｔａｇｅ（登録商標）ＳＮＡＰＣａｒｔｒｉｄｇｅ　ＫＰ－ＳｉｌもしくはＨＰ－Ｓｉｌを使用した。「逆相シリカゲルカートリッジ」にはＭＯＲＩＴＥＸ（登録商標）Ｐｕｒｉｆ－Ｐａｃｋ　ＯＤＳを使用した。 In the following production examples and examples, Biotage (registered trademark) SNAP Cartridge KP-NH is used for the “NH silica gel cartridge” when purified using column chromatography, and Biotage (registered trademark) SNAP Cartridge KP is used for the “silica gel cartridge”. -Sil or HP-Sil was used. For the “reverse phase silica gel cartridge”, MORITEX (registered trademark) Purif-Pack ODS was used.
　以下の製造例および実施例において、分取薄層クロマトグラフィー（ＰＴＬＣ）を使用して精製した際の「ＮＨシリカゲル」には和光、ＮＨ２シリカゲル６０Ｆ２５４プレート－ワコー　２０ｃｍ×２０ｃｍ、「シリカゲル」にはメルク、シリカゲル６０Ｆ２５４、２０ｃｍ×２０ｃｍを使用した。 In the following production examples and examples, “NH silica gel” when purified using preparative thin layer chromatography (PTLC) is Wako, NH 2 silica gel 60F254 plate-Wako 20 cm × 20 cm, “silica gel” is Merck Silica gel 60F254, 20 cm × 20 cm was used.
　以下の製造例および実施例において、分取高速液体クロマトグラフィー（ＨＰＬＣ）による精製は以下の条件により行った。ただし、塩基性官能基を有する化合物の場合、本操作でトリフルオロ酢酸を用いたときには、フリー体を得るための中和操作等を行う場合がある。
機械：Ｇｉｌｓｏｎ社　ｐｒｅｐａｒａｔｉｖｅ　ＨＰＬＣ　ｓｙｓｔｅｍ
カラム：資生堂　Ｃａｐｃｅｌｐａｋ　Ｃ１８　ＭＧII　５μｍ　２０×１５０ｍｍ
溶媒：Ａ液；０．１％トリフルオロ酢酸含有水、Ｂ液；０．１％トリフルオロ酢酸含有アセトニトリル
グラジエント条件１：０分（Ａ液／Ｂ液＝９０／１０）、２２分（Ａ液／Ｂ液＝２０／８０）、２５分（Ａ液／Ｂ液＝１０／９０）
グラジエント条件２：０分（Ａ液／Ｂ液＝８０／２０）、２０分（Ａ液／Ｂ液＝５／９５）、２５分（Ａ液／Ｂ液＝１／９９）
流速：２０ｍＬ／ｍｉｎ、検出法：ＵＶ　２５４ｎｍ
　以下の製造例および実施例において、マススペクトル（ＭＳ）は、以下の条件により測定した。
ＭＳスペクトル：島津ＬＣＭＳ－２０１０ＥＶ又はｍｉｃｒｏｍａｓｓ　Ｐｌａｔｆｏｒｍ　ＬＣ
　以下の製造例および実施例の構造確認には、核磁気共鳴スペクトル（ＮＭＲ）を用いた。核磁気共鳴スペクトル（ＮＭＲ）は以下の条件により測定した。
ＮＭＲスペクトル：［１Ｈ－ＮＭＲ］６００ＭＨｚ：ＪＮＭ－ＥＣＡ６００（日本電子）、５００ＭＨｚ：ＪＮＭ－ＥＣＡ５００（日本電子）、３００ＭＨｚ：ＵＮＩＴＹＮＯＶＡ３００（Ｖａｒｉａｎ　Ｉｎｃ．）、２００ＭＨｚ：ＧＥＭＩＮＩ２０００／２００（Ｖａｒｉａｎ　Ｉｎｃ．）
　以下の製造例および実施例において、化合物名はＡＣＤ／Ｎａｍｅ　（ＡＣＤ／Ｌａｂｓ　１２．０１，　Ａｄｖａｎｃｅｄ　Ｃｈｅｍｉｓｔｒｙ　Ｄｅｖｅｌｏｐｍｅｎｔ　Ｉｎｃ．）により命名した。
製造例１　３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン In the following production examples and examples, purification by preparative high performance liquid chromatography (HPLC) was performed under the following conditions. However, in the case of a compound having a basic functional group, when trifluoroacetic acid is used in this operation, a neutralization operation for obtaining a free form may be performed.
Machine: Gilson preparative HPLC system
Column: Shiseido Capcelpak C18 MGII 5 μm 20 × 150 mm
Solvent: Solution A; 0.1% trifluoroacetic acid-containing water, Solution B; 0.1% trifluoroacetic acid-containing acetonitrile gradient Conditions 1: 0 minutes (A solution / B solution = 90/10), 22 minutes (A solution / B liquid = 20/80), 25 minutes (A liquid / B liquid = 10/90)
Gradient condition 2: 0 minutes (A liquid / B liquid = 80/20), 20 minutes (A liquid / B liquid = 5/95), 25 minutes (A liquid / B liquid = 1/99)
Flow rate: 20 mL / min, detection method: UV 254 nm
In the following production examples and examples, mass spectra (MS) were measured under the following conditions.
MS spectrum: Shimadzu LCMS-2010EV or micromass Platform LC
Nuclear magnetic resonance spectra (NMR) were used to confirm the structures of the following production examples and examples. Nuclear magnetic resonance spectrum (NMR) was measured under the following conditions.
NMR spectrum: [1H-NMR] 600 MHz: JNM-ECA600 (JEOL), 500 MHz: JNM-ECA500 (JEOL), 300 MHz: UNITYNOVA300 (Varian Inc.), 200 MHz: GEMINI 2000/200 (Varian Inc.)
In the following production examples and examples, the compound names were named by ACD / Name (ACD / Labs 12.01, Advanced Chemistry Development Inc.).
Production Example 1 3- [6- (Trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] decan-2-one
Figure JPOXMLDOC01-appb-C000015
  　 
Figure JPOXMLDOC01-appb-C000015
  　 
（１）［１－（ヒドロキシメチル）シクロヘキシル］カルバミン酸　ｔｅｒｔ－ブチル（０．８２ｇ）のＤＭＳＯ（１０ｍＬ）溶液に２－ヨードキシ安息香酸（１．２ｇ）を加え、室温で一晩撹拌した。水、酢酸エチルを加え、不溶物をセライトでろ去し、ろ液を酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した後、乾燥剤をろ去した。ろ液を減圧下濃縮した後、残渣をクロロホルム（１０ｍＬ）に溶かし、２－トリフルオロメチル－５－アミノピリジン（０．７ｇ）および水素化トリアセトキシホウ素ナトリウム（１．１ｇ）を加え、室温で一晩撹拌した。飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出の後、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別後、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル）で精製し、［１－（｛［６－（トリフルオロメチル）ピリジン－３－イル］アミノ｝メチル）シクロヘキシル］カルバミン酸　ｔｅｒｔ－ブチル（０．６３ｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.17 - 2.11 (m, 19 H), 3.66 (s, 1 H), 4.28 - 4.64 (m, 2 H), 6.86 - 6.95 (m, 1 H), 7.41 (d, J=8.3 Hz, 1 H), 8.04 (d, J=3.2 Hz, 1 H)
(ESI pos.) m/z : 396（［Ｍ+Na］+）
（２）［１－（｛［６－（トリフルオロメチル）ピリジン－３－イル］アミノ｝メチル）シクロヘキシル］カルバミン酸　ｔｅｒｔ－ブチル（６００ｍｇ）のエタノール（８ｍＬ）溶液に４Ｍ塩酸／酢酸エチル（４ｍＬ）を加え、一晩撹拌した。反応液を減圧下濃縮し、飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥し、乾燥剤をろ別後、ろ液を減圧下濃縮した。Ｎ－［（１－アミノシクロヘキシル）メチル］－６－（トリフルオロメチル）ピリジン－３－アミン（３００ｍｇ）を得た。
(ESI pos.) m/z : 274（［Ｍ+H］+）
（３）Ｎ－［（１－アミノシクロヘキシル）メチル］－６－（トリフルオロメチル）ピリジン－３－アミン（３００ｍｇ）のＴＨＦ（１０ｍＬ）溶液に、トリエチルアミン（０．７ｍＬ）を加え、氷冷し、トリホスゲン（１３０ｍｇ）を加えた。室温で２時間撹拌した後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。無水硫酸ナトリウムで乾燥した後、乾燥剤をろ別し、ろ液を減圧下濃縮した。残渣をイソプロピルエーテルで洗浄し、標題化合物（２３０ｍｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.50 (d, J=5.0 Hz, 2 H), 1.57 - 1.67 (m, 3 H), 1.67 - 1.79 (m, 5 H), 3.69 (s, 2 H), 5.52 (br. s., 1 H), 7.64 (d, J=8.7 Hz, 1 H), 8.36 (s, 1 H), 8.69 (d, J=2.8 Hz, 1 H)
(ESI pos.) m/z : 300（［Ｍ+H］+）
(ESI neg.) m/z : 298（［Ｍ-H］-）
同様の方法により、以下の化合物を合成した。
３－（５－メトキシピリジン－２－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン
(ESI pos.) m/z : 262（［Ｍ+H］+）
４－（２－オキソ－１，３－ジアザスピロ［４．５］デカ－３－イル）安息香酸メチル
(ESI pos.) m/z : 289（［Ｍ+H］+）
３－（６－メトキシピリジン－３－イル）－１，３－ジアザスピロ［４．４］ノナン－２－オン
(ESI pos.) m/z : 248（［Ｍ+H］+）
３－（６－クロロピリジン－３－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン
(ESI pos.) m/z : 266（［Ｍ+H］+）
３－（６－メトキシピリジン－３－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン
(ESI pos.) m/z : 262（［Ｍ+H］+）
３－（ピリジン－３－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン
(ESI pos.) m/z : 232（［Ｍ+H］+）
３－（２，４－ジフルオロフェニル）－１，３－ジアザスピロ［４．５］デカン－２－オン
(ESI pos.) m/z : 267（［Ｍ+H］+）
３－（４－フルオロ－３－メトキシフェニル）－１，３－ジアザスピロ［４．５］デカン－２－オン
(ESI pos.) m/z : 279（［Ｍ+H］+）
３－（５－クロロピリジン－２－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン
(ESI pos.) m/z : 266（［Ｍ+H］+）
３－（５－フルオロピリジン－２－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン
(ESI pos.) m/z : 250（［Ｍ+H］+）
３－（６－メチルピリジン－３－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン
(ESI pos.) m/z : 246（［Ｍ+H］+）
３－（２－メトキシピリジン－４－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン
(ESI pos.) m/z : 262（［Ｍ+H］+）
３－（４－メチルフェニル）－１，３－ジアザスピロ［４．５］デカン－２－オン
(ESI pos.) m/z : 245（［Ｍ+H］+）
３－（４－エチルフェニル）－１，３－ジアザスピロ［４．５］デカン－２－オン
(ESI pos.) m/z : 259（［Ｍ+H］+）
４－（２－メチルプロピル）－１－［６－（トリフルオロメチル）ピリジン－３－イル］イミダゾリジン－２－オン
(ESI pos.) m/z : 288（［Ｍ+H］+）
４－（プロパン－２－イル）－１－［６－（トリフルオロメチル）ピリジン－３－イル］イミダゾリジン－２－オン
(ESI pos.) m/z : 274（［Ｍ+H］+）
３－（６－ブロモピリジン－３－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン
(ESI pos.) m/z : 310（［Ｍ+H］+）
３－（５－メトキシピリジン－３－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン
(ESI pos.) m/z : 262（［Ｍ+H］+）
３－（５－フルオロピリジン－３－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン
(ESI pos.) m/z : 250（［Ｍ+H］+）
３－（５－メチルピリジン－３－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン
(ESI pos.) m/z : 246（［Ｍ+H］+）
３－（６－フルオロピリジン－３－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン
(ESI pos.) m/z : 250（［Ｍ+H］+）
４－（ブタン－２－イル）－１－［６－（トリフルオロメチル）ピリジン－３－イル］イミダゾリジン－２－オン
(ESI pos.) m/z : 288（［Ｍ+H］+）
３－（４－メトキシフェニル）－１，３－ジアザスピロ［４．５］デカン－２－オン
(ESI pos.) m/z : 261（［Ｍ+H］+）
３－（６－エトキシピリジン－３－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン
(ESI pos.) m/z : 276（［Ｍ+H］+）
１－（４－メトキシフェニル）－４－プロピルイミダゾリジン－２－オン
(ESI pos.) m/z : 257（［Ｍ+Na］+）
製造例２　３－（４－フルオロフェニル）－１，３－ジアザスピロ［４．５］デカン－２－オン (1) 2-iodoxybenzoic acid (1.2 g) was added to a solution of tert-butyl [1- (hydroxymethyl) cyclohexyl] carbamate in DMSO (10 mL) and stirred at room temperature overnight. Water and ethyl acetate were added, the insoluble material was filtered off through celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the desiccant was removed by filtration. After the filtrate was concentrated under reduced pressure, the residue was dissolved in chloroform (10 mL), 2-trifluoromethyl-5-aminopyridine (0.7 g) and sodium triacetoxyborohydride (1.1 g) were added, and Stir overnight. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate) and tert-butyl [1-({[6- (trifluoromethyl) pyridin-3-yl] amino} methyl) cyclohexyl] carbamate (0 0.63 g) was obtained.
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.17-2.11 (m, 19 H), 3.66 (s, 1 H), 4.28-4.64 (m, 2 H), 6.86-6.95 (m, 1 H), 7.41 (d, J = 8.3 Hz, 1 H), 8.04 (d, J = 3.2 Hz, 1 H)
(ESI pos.) M / z: 396 ([M + Na] +)
(2) [1-({[6- (Trifluoromethyl) pyridin-3-yl] amino} methyl) cyclohexyl] carbamate tert-butyl (600 mg) in ethanol (8 mL) solution in 4M hydrochloric acid / ethyl acetate (4 mL ) And stirred overnight. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. N-[(1-aminocyclohexyl) methyl] -6- (trifluoromethyl) pyridin-3-amine (300 mg) was obtained.
(ESI pos.) M / z: 274 ([M + H] +)
(3) To a solution of N-[(1-aminocyclohexyl) methyl] -6- (trifluoromethyl) pyridin-3-amine (300 mg) in THF (10 mL) was added triethylamine (0.7 mL), and the mixture was ice-cooled. , Triphosgene (130 mg) was added. After stirring at room temperature for 2 hours, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was washed with isopropyl ether to give the title compound (230 mg).
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.50 (d, J = 5.0 Hz, 2 H), 1.57-1.67 (m, 3 H), 1.67-1.79 (m, 5 H), 3.69 (s, 2 H), 5.52 (br. S., 1 H), 7.64 (d, J = 8.7 Hz, 1 H), 8.36 (s, 1 H), 8.69 (d, J = 2.8 Hz, 1 H)
(ESI pos.) M / z: 300 ([M + H] +)
(ESI neg.) M / z: 298 ([M-H]-)
The following compounds were synthesized by the same method.
3- (5-Methoxypyridin-2-yl) -1,3-diazaspiro [4.5] decan-2-one
(ESI pos.) M / z: 262 ([M + H] +)
Methyl 4- (2-oxo-1,3-diazaspiro [4.5] dec-3-yl) benzoate
(ESI pos.) M / z: 289 ([M + H] +)
3- (6-Methoxypyridin-3-yl) -1,3-diazaspiro [4.4] nonan-2-one
(ESI pos.) M / z: 248 ([M + H] +)
3- (6-Chloropyridin-3-yl) -1,3-diazaspiro [4.5] decan-2-one
(ESI pos.) M / z: 266 ([M + H] +)
3- (6-Methoxypyridin-3-yl) -1,3-diazaspiro [4.5] decan-2-one
(ESI pos.) M / z: 262 ([M + H] +)
3- (Pyridin-3-yl) -1,3-diazaspiro [4.5] decan-2-one
(ESI pos.) M / z: 232 ([M + H] +)
3- (2,4-Difluorophenyl) -1,3-diazaspiro [4.5] decan-2-one
(ESI pos.) M / z: 267 ([M + H] +)
3- (4-Fluoro-3-methoxyphenyl) -1,3-diazaspiro [4.5] decan-2-one
(ESI pos.) M / z: 279 ([M + H] +)
3- (5-Chloropyridin-2-yl) -1,3-diazaspiro [4.5] decan-2-one
(ESI pos.) M / z: 266 ([M + H] +)
3- (5-Fluoropyridin-2-yl) -1,3-diazaspiro [4.5] decan-2-one
(ESI pos.) M / z: 250 ([M + H] +)
3- (6-Methylpyridin-3-yl) -1,3-diazaspiro [4.5] decan-2-one
(ESI pos.) M / z: 246 ([M + H] +)
3- (2-Methoxypyridin-4-yl) -1,3-diazaspiro [4.5] decan-2-one
(ESI pos.) M / z: 262 ([M + H] +)
3- (4-Methylphenyl) -1,3-diazaspiro [4.5] decan-2-one
(ESI pos.) M / z: 245 ([M + H] +)
3- (4-Ethylphenyl) -1,3-diazaspiro [4.5] decan-2-one
(ESI pos.) M / z: 259 ([M + H] +)
4- (2-Methylpropyl) -1- [6- (trifluoromethyl) pyridin-3-yl] imidazolidin-2-one
(ESI pos.) M / z: 288 ([M + H] +)
4- (propan-2-yl) -1- [6- (trifluoromethyl) pyridin-3-yl] imidazolidin-2-one
(ESI pos.) M / z: 274 ([M + H] +)
3- (6-Bromopyridin-3-yl) -1,3-diazaspiro [4.5] decan-2-one
(ESI pos.) M / z: 310 ([M + H] +)
3- (5-Methoxypyridin-3-yl) -1,3-diazaspiro [4.5] decan-2-one
(ESI pos.) M / z: 262 ([M + H] +)
3- (5-Fluoropyridin-3-yl) -1,3-diazaspiro [4.5] decan-2-one
(ESI pos.) M / z: 250 ([M + H] +)
3- (5-Methylpyridin-3-yl) -1,3-diazaspiro [4.5] decan-2-one
(ESI pos.) M / z: 246 ([M + H] +)
3- (6-Fluoropyridin-3-yl) -1,3-diazaspiro [4.5] decan-2-one
(ESI pos.) M / z: 250 ([M + H] +)
4- (Butan-2-yl) -1- [6- (trifluoromethyl) pyridin-3-yl] imidazolidin-2-one
(ESI pos.) M / z: 288 ([M + H] +)
3- (4-Methoxyphenyl) -1,3-diazaspiro [4.5] decan-2-one
(ESI pos.) M / z: 261 ([M + H] +)
3- (6-Ethoxypyridin-3-yl) -1,3-diazaspiro [4.5] decan-2-one
(ESI pos.) M / z: 276 ([M + H] +)
1- (4-Methoxyphenyl) -4-propylimidazolidin-2-one
(ESI pos.) M / z: 257 ([M + Na] +)
Production Example 2 3- (4-Fluorophenyl) -1,3-diazaspiro [4.5] decan-2-one
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
（１）１－アミノシクロヘキサンカルボン酸メチル塩酸塩（１．２３ｇ）のエタノール（１３ｍＬ）溶液にトリエチルアミン（２．７ｍＬ）、４－フルオロフェニルイソシアネート（０．８７ｍＬ）を加え、マイクロ波照射下、１５０℃で１５分撹拌した。同様の操作を計３セット行い、すべてを合わせ、減圧下濃縮した。水（１０ｍＬ）を加え、室温で１０分撹拌した後、ろ過した。固体を水、酢酸エチルで洗浄し、３－（４－フルオロフェニル）－１，３－ジアザスピロ［４．５］デカン－２，４－ジオン（３．７７ｇ）を得た。
(ESI pos.) m/z : 263（［Ｍ+H］+）
（２）窒素雰囲気下、３－（４－フルオロフェニル）－１，３－ジアザスピロ［４．５］デカン－２，４－ジオン（３．６ｇ）のＴＨＦ（７０ｍＬ）溶液に水素化ビス（２－メトキシエトキシ）アルミニウムナトリウム（７０％／トルエン溶液、１９．７ｇ）を加え、４時間加熱還流した。氷冷した後、２Ｍ水酸化カリウム水溶液（１００ｍＬ）を加え、酢酸エチルで抽出した。無水硫酸ナトリウムで乾燥した後、乾燥剤をろ別し、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲル、ヘキサン／酢酸エチル＝７０：３０～６０：４０）で精製し、標題化合物（２．５ｇ）を得た。
(ESI pos.) m/z : 249（［Ｍ+H］+）
製造例３　酢酸　４－（２－オキソ－１，３－ジアザスピロ［４．５］デカ－３－イル）ベンジル (1) To a solution of methyl 1-aminocyclohexanecarboxylate hydrochloride (1.23 g) in ethanol (13 mL), triethylamine (2.7 mL) and 4-fluorophenyl isocyanate (0.87 mL) were added. Stir at 15 ° C. for 15 minutes. A total of 3 sets of the same operations were performed, all were combined and concentrated under reduced pressure. Water (10 mL) was added, and the mixture was stirred at room temperature for 10 minutes and filtered. The solid was washed with water and ethyl acetate to obtain 3- (4-fluorophenyl) -1,3-diazaspiro [4.5] decane-2,4-dione (3.77 g).
(ESI pos.) M / z: 263 ([M + H] +)
(2) Under a nitrogen atmosphere, 3- (4-fluorophenyl) -1,3-diazaspiro [4.5] decane-2,4-dione (3.6 g) in a THF (70 mL) solution in bis (2 -Methoxyethoxy) aluminum sodium (70% / toluene solution, 19.7 g) was added and heated to reflux for 4 hours. After cooling with ice, 2M aqueous potassium hydroxide solution (100 mL) was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane / ethyl acetate = 70: 30-60: 40) to obtain the title compound (2.5 g).
(ESI pos.) M / z: 249 ([M + H] +)
Production Example 3 4- (2-Oxo-1,3-diazaspiro [4.5] dec-3-yl) benzyl acetate
Figure JPOXMLDOC01-appb-C000017
 　 
Figure JPOXMLDOC01-appb-C000017
 　 
（１）４－（２－オキソ－１，３－ジアザスピロ［４．５］デカ－３－イル）安息香酸メチル（２５０ｍｇ）のＴＨＦ（５ｍＬ）溶液を氷冷し、水素化アルミニウムリチウム（６６ｍｇ）を加え、２時間撹拌した。１０％水酸化ナトリウム水溶液（１ｍＬ）を滴下し、室温で３０分撹拌した後、無水硫酸マグネシウムを加えた。乾燥剤をろ別し、ろ液を減圧下乾燥し、３－［４－（ヒドロキシメチル）フェニル］－１，３－ジアザスピロ［４．５］デカン－２－オン（０．２ｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.40 - 1.78 (m, 10 H), 3.65 (s, 2 H), 4.65 (s, 2 H), 4.84 - 4.93 (m, 1 H), 7.31 - 7.39 (m, 2 H), 7.52 - 7.57 (m, 2 H)
(ESI pos.) m/z : 261（［Ｍ+H］+）
（２）３－［４－（ヒドロキシメチル）フェニル］－１，３－ジアザスピロ［４．５］デカン－２－オン（０．２ｇ）をクロロホルム（５ｍＬ）に溶かし、トリエチルアミン（０．２２ｍＬ）および無水酢酸（０．１１ｍＬ）を加え、室温で３０分撹拌した。飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別後、ろ液を減圧下濃縮し、標題化合物（２３４ｍｇ）を得た。
1H NMR (200 MHz, CHLOROFORM-d) d ppm 1.25 - 1.78 (m, 10 H), 2.06 (s, 3 H), 3.62 (s, 2 H), 4.95 - 5.11 (m, 3 H), 7.26 - 7.39 (m, 2 H), 7.47 - 7.61 (m, 2 H)
(ESI pos.) m/z : 325（［Ｍ+Na］+）
製造例４　３－（６－メトキシピリジン－３－イル）－８－オキサ－１，３－ジアザスピロ［４．５］デカン－２－オン (1) A solution of methyl 4- (2-oxo-1,3-diazaspiro [4.5] dec-3-yl) benzoate (250 mg) in THF (5 mL) was ice-cooled and lithium aluminum hydride (66 mg) Was added and stirred for 2 hours. A 10% aqueous sodium hydroxide solution (1 mL) was added dropwise, and the mixture was stirred at room temperature for 30 minutes, and then anhydrous magnesium sulfate was added. The desiccant was filtered off, and the filtrate was dried under reduced pressure to give 3- [4- (hydroxymethyl) phenyl] -1,3-diazaspiro [4.5] decan-2-one (0.2 g). .
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.40-1.78 (m, 10 H), 3.65 (s, 2 H), 4.65 (s, 2 H), 4.84-4.93 (m, 1 H), 7.31- 7.39 (m, 2 H), 7.52-7.57 (m, 2 H)
(ESI pos.) M / z: 261 ([M + H] +)
(2) 3- [4- (hydroxymethyl) phenyl] -1,3-diazaspiro [4.5] decan-2-one (0.2 g) was dissolved in chloroform (5 mL), triethylamine (0.22 mL) and Acetic anhydride (0.11 mL) was added, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution was added, extracted with chloroform, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (234 mg).
1H NMR (200 MHz, CHLOROFORM-d) d ppm 1.25-1.78 (m, 10 H), 2.06 (s, 3 H), 3.62 (s, 2 H), 4.95-5.11 (m, 3 H), 7.26- 7.39 (m, 2 H), 7.47-7.61 (m, 2 H)
(ESI pos.) M / z: 325 ([M + Na] +)
Production Example 4 3- (6-Methoxypyridin-3-yl) -8-oxa-1,3-diazaspiro [4.5] decan-2-one
Figure JPOXMLDOC01-appb-C000018
　 
Figure JPOXMLDOC01-appb-C000018
　 
（１）４－｛［（ベンジルオキシ）カルボニル］アミノ｝テトラヒドロ－２Ｈ－ピラン－４－カルボン酸（０．８５ｇ）のクロロホルム（１５ｍＬ）溶液にジイソプロピルエチルアミン（０．５７ｍＬ）、ＨＡＴＵ（１．２５ｇ）、および５－アミノ－２－メトキシピリジン（０．４１ｇ）を加え、室温で一晩撹拌した。飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別の後、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、クロロホルム／メタノール）で精製し、｛４－［（６－メトキシピリジン－３－イル）カルバモイル］テトラヒドロ－２Ｈ－ピラン－４－イル｝カルバミン酸ベンジル（４６５ｍｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.98 - 2.08 (m, 2 H), 2.28 - 2.39 (m, 2 H), 3.61 - 3.73 (m, 2 H), 3.82 - 3.88 (m, 2 H), 3.91 (s, 3 H), 5.03 (s, 1 H), 5.13 (s, 2 H), 6.70 (d, J=9.2 Hz, 1 H), 7.28 - 7.43 (m, 5 H), 7.66 - 7.88 (m, 1 H), 8.13 (br. s., 1 H), 8.88 (br. s., 1 H)
(ESI pos.) m/z : 386（［Ｍ+H］+）
（２）｛４－［（６－メトキシピリジン－３－イル）カルバモイル］テトラヒドロ－２Ｈ－ピラン－４－イル｝カルバミン酸ベンジル（３００ｍｇ）のエタノール（５ｍＬ）溶液に５％パラジウム炭素（３０ｍｇ）を加え、系内を水素ガスで置換した後、一晩撹拌した。パラジウム炭素をろ別し、ろ液を減圧濃縮し、４－アミノ－Ｎ－（６－メトキシピリジン－３－イル）テトラヒドロ－２Ｈ－ピラン－４－カルボキサミド（１９０ｍｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.31 - 1.41 (m, 2 H), 1.65 (br. s., 2 H), 2.36 - 2.47 (m, 2 H), 3.60 - 3.70 (m, 2 H), 3.91 (s, 3 H), 3.94 - 4.01 (m, 2 H), 6.73 (d, J=8.7 Hz, 1 H), 8.00 - 8.07 (m, 1 H), 8.20 (d, J=2.3 Hz, 1 H), 9.80 (br. s., 1 H)
(ESI pos.) m/z : 252（［Ｍ+H］+）
（３）４－アミノ－Ｎ－（６－メトキシピリジン－３－イル）テトラヒドロ－２Ｈ－ピラン－４－カルボキサミド（１８０ｍｇ）のＴＨＦ（６ｍＬ）溶液を氷冷し、水素化アルミニウムリチウム（１３７ｍｇ）を加え、室温で３時間撹拌した。氷冷した後、１０％水酸化ナトリウム水溶液（１ｍＬ）を滴下し、室温で１時間撹拌した。無水硫酸マグネシウムで乾燥し、乾燥剤をろ別の後、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、クロロホルム／メタノール）で精製し、Ｎ－［（４－アミノテトラヒドロ－２Ｈ－ピラン－４－イル）メチル］－６－メトキシピリジン－３－アミン（１６５ｍｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.43 - 1.49 (m, 2 H), 1.70 - 1.80 (m, 2 H), 2.97 (s, 2 H), 3.71 - 3.78 (m, 4 H), 3.86 (s, 3 H), 6.61 (d, J=9.2 Hz, 1 H), 6.99 - 7.06 (m, 1 H), 7.60 (d, J=3.2 Hz, 1 H)
(ESI pos.) m/z : 238（［Ｍ+H］+）
（４）製造例１（３）と同様の方法により、Ｎ－［（４－アミノテトラヒドロ－２Ｈ－ピラン－４－イル）メチル］－６－メトキシピリジン－３－アミン（１５０ｍｇ）から標題化合物（７３ｍｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.79 - 1.91 (m, 4 H), 3.70 (s, 2 H), 3.71 - 3.80 (m, 4 H), 3.91 (s, 3 H), 5.25 (br. s., 1 H), 6.75 (d, J=9.6 Hz, 1 H), 8.03 (d, J=2.3 Hz, 1 H), 8.06 - 8.14 (m, 1 H)
(ESI pos.) m/z : 264（［Ｍ+H］+）
実施例５　４－シクロヘキシル－１－（４－メトキシフェニル）イミダゾリジン－２－オン (1) 4-{[(Benzyloxy) carbonyl] amino} tetrahydro-2H-pyran-4-carboxylic acid (0.85 g) in chloroform (15 mL) in diisopropylethylamine (0.57 mL), HATU (1.25 g) And 5-amino-2-methoxypyridine (0.41 g) were added, and the mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added, extracted with chloroform, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, chloroform / methanol) to give benzyl {4-[(6-methoxypyridin-3-yl) carbamoyl] tetrahydro-2H-pyran-4-yl} carbamate (465 mg). Obtained.
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.98-2.08 (m, 2 H), 2.28-2.39 (m, 2 H), 3.61-3.73 (m, 2 H), 3.82-3.88 (m, 2 H ), 3.91 (s, 3 H), 5.03 (s, 1 H), 5.13 (s, 2 H), 6.70 (d, J = 9.2 Hz, 1 H), 7.28-7.43 (m, 5 H), 7.66 -7.88 (m, 1 H), 8.13 (br. S., 1 H), 8.88 (br. S., 1 H)
(ESI pos.) M / z: 386 ([M + H] +)
(2) {4-[(6-Methoxypyridin-3-yl) carbamoyl] tetrahydro-2H-pyran-4-yl} benzyl carbamate (300 mg) in ethanol (5 mL) was charged with 5% palladium carbon (30 mg). In addition, the system was replaced with hydrogen gas and stirred overnight. Palladium on carbon was filtered off and the filtrate was concentrated under reduced pressure to give 4-amino-N- (6-methoxypyridin-3-yl) tetrahydro-2H-pyran-4-carboxamide (190 mg).
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.31-1.41 (m, 2 H), 1.65 (br. S., 2 H), 2.36-2.47 (m, 2 H), 3.60-3.70 (m, 2 H), 3.91 (s, 3 H), 3.94-4.01 (m, 2 H), 6.73 (d, J = 8.7 Hz, 1 H), 8.00-8.07 (m, 1 H), 8.20 (d, J = 2.3 Hz, 1 H), 9.80 (br. S., 1 H)
(ESI pos.) M / z: 252 ([M + H] +)
(3) A solution of 4-amino-N- (6-methoxypyridin-3-yl) tetrahydro-2H-pyran-4-carboxamide (180 mg) in THF (6 mL) was ice-cooled, and lithium aluminum hydride (137 mg) was added. The mixture was further stirred at room temperature for 3 hours. After ice cooling, 10% aqueous sodium hydroxide solution (1 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After drying over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, chloroform / methanol) to obtain N-[(4-aminotetrahydro-2H-pyran-4-yl) methyl] -6-methoxypyridin-3-amine (165 mg). It was.
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.43-1.49 (m, 2 H), 1.70-1.80 (m, 2 H), 2.97 (s, 2 H), 3.71-3.78 (m, 4 H), 3.86 (s, 3 H), 6.61 (d, J = 9.2 Hz, 1 H), 6.99-7.06 (m, 1 H), 7.60 (d, J = 3.2 Hz, 1 H)
(ESI pos.) M / z: 238 ([M + H] +)
(4) In the same manner as in Production Example 1 (3), the title compound (150 mg) was obtained from N-[(4-aminotetrahydro-2H-pyran-4-yl) methyl] -6-methoxypyridin-3-amine (150 mg). 73 mg) was obtained.
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.79-1.91 (m, 4 H), 3.70 (s, 2 H), 3.71-3.80 (m, 4 H), 3.91 (s, 3 H), 5.25 ( br. s., 1 H), 6.75 (d, J = 9.6 Hz, 1 H), 8.03 (d, J = 2.3 Hz, 1 H), 8.06-8.14 (m, 1 H)
(ESI pos.) M / z: 264 ([M + H] +)
Example 5 4-Cyclohexyl-1- (4-methoxyphenyl) imidazolidin-2-one
Figure JPOXMLDOC01-appb-C000019
　 
Figure JPOXMLDOC01-appb-C000019
　 
（１）２－アミノ－２－シクロヘキシルエタノール（３００ｍｇ）のＴＨＦ（１０ｍＬ）溶液に４－メトキシフェニルイソシアネート（０．２５ｍＬ）を滴下し、室温で一晩撹拌した。反応液を減圧下濃縮した後、固体をジエチルエーテルで洗浄し、１－（１－シクロヘキシル－２－ヒドロキシエチル）－３－（４－メトキシフェニル）尿素（０．５６ｇ）を得た。
1H NMR (200 MHz, CHLOROFORM-d) d ppm 0.85 - 1.87 (m, 11 H), 2.93 - 3.11 (m, 1 H), 3.56 - 3.70 (m, 2 H), 3.81 (s, 3 H), 4.82 - 4.96 (m, 1 H), 6.48 (br. s, 1 H), 6.81 - 6.96 (m, 2 H), 7.16 - 7.31 (m, 2 H)
(ESI pos.) m/z : 293（［Ｍ+H］+）
（２）氷冷下、１－（１－シクロヘキシル－２－ヒドロキシエチル）－３－（４－メトキシフェニル）尿素（０．３０ｇ）のＴＨＦ（１０ｍＬ）溶液にｔｅｒｔ－ブトキシカリウム（２６９ｍｇ）を加え、懸濁状態にし、塩化ｐ－トルエンスルホン酸（２２９ｍｇ）のＴＨＦ（３ｍＬ）溶液を滴下した。氷冷下３０分撹拌し、水を加えた後、酢酸エチルで抽出し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別後、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル）で精製し、標題化合物（４３ｍｇ）を得た。
1H NMR (200 MHz, CHLOROFORM-d) d ppm 0.83 - 1.91 (m, 11 H), 3.40 - 3.65 (m, 2 H), 3.77 (s, 3 H), 3.82 - 3.96 (m, 1 H), 4.73 (br. s., 1 H), 6.71 - 6.93 (m, 2 H), 7.35 - 7.48 (m, 2 H)
(ESI pos.) m/z : 275（［Ｍ+H］+）
同様の方法により、以下の化合物を合成した。
４－ベンジル－１－（４－メトキシフェニル）イミダゾリジン－２－オン
(ESI pos.) m/z : 283（［Ｍ+H］+）
４－（２，２－ジメチルプロピル）－１－（４－メトキシフェニル）イミダゾリジン－２－オン
(ESI pos.) m/z : 263（［Ｍ+H］+）
１－（４－メトキシフェニル）－４－フェニルイミダゾリジン－２－オン
(ESI pos.) m/z : 269（［Ｍ+H］+）
製造例６　３－（５－クロロピリミジン－２－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン (1) 4-Methoxyphenyl isocyanate (0.25 mL) was added dropwise to a THF (10 mL) solution of 2-amino-2-cyclohexylethanol (300 mg), and the mixture was stirred overnight at room temperature. After the reaction solution was concentrated under reduced pressure, the solid was washed with diethyl ether to obtain 1- (1-cyclohexyl-2-hydroxyethyl) -3- (4-methoxyphenyl) urea (0.56 g).
1H NMR (200 MHz, CHLOROFORM-d) d ppm 0.85-1.87 (m, 11 H), 2.93-3.11 (m, 1 H), 3.56-3.70 (m, 2 H), 3.81 (s, 3 H), 4.82-4.96 (m, 1 H), 6.48 (br. S, 1 H), 6.81-6.96 (m, 2 H), 7.16-7.31 (m, 2 H)
(ESI pos.) M / z: 293 ([M + H] +)
(2) Under ice cooling, tert-butoxypotassium (269 mg) was added to a solution of 1- (1-cyclohexyl-2-hydroxyethyl) -3- (4-methoxyphenyl) urea (0.30 g) in THF (10 mL). In suspension, a solution of p-toluenesulfonic acid chloride (229 mg) in THF (3 mL) was added dropwise. The mixture was stirred for 30 minutes under ice-cooling, water was added, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate) to give the title compound (43 mg).
1H NMR (200 MHz, CHLOROFORM-d) d ppm 0.83-1.91 (m, 11 H), 3.40-3.65 (m, 2 H), 3.77 (s, 3 H), 3.82-3.96 (m, 1 H), 4.73 (br. S., 1 H), 6.71-6.93 (m, 2 H), 7.35-7.48 (m, 2 H)
(ESI pos.) M / z: 275 ([M + H] +)
The following compounds were synthesized by the same method.
4-Benzyl-1- (4-methoxyphenyl) imidazolidin-2-one
(ESI pos.) M / z: 283 ([M + H] +)
4- (2,2-Dimethylpropyl) -1- (4-methoxyphenyl) imidazolidin-2-one
(ESI pos.) M / z: 263 ([M + H] +)
1- (4-Methoxyphenyl) -4-phenylimidazolidin-2-one
(ESI pos.) M / z: 269 ([M + H] +)
Production Example 6 3- (5-Chloropyrimidin-2-yl) -1,3-diazaspiro [4.5] decan-2-one
Figure JPOXMLDOC01-appb-C000020
  　 
Figure JPOXMLDOC01-appb-C000020
  　 
窒素雰囲気下、１，３－ジアザスピロ［４．５］デカン－２－オン（１００ｍｇ）、５－クロロ－２－ヨードピリミジン、Ｐｄ2（ｄｂａ）3（３４ｍｇ）、Ｘａｎｔｐｈｏｓ（３８ｍｇ）、およびｔｅｒｔ－ブトキシナトリウム（９４ｍｇ）のトルエン（４ｍＬ）溶液を１００℃で２時間撹拌した。反応液をクロロホルムで希釈し、ＮＨシリカゲルを加え、減圧下濃縮した。これをカラムクロマトグラフィー（シリカゲルカートリッジ、クロロホルム／メタノール）で精製し、標題化合物（１２３ｍｇ）を得た。
(ESI pos.) m/z : 267（［Ｍ+H］+）
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.37 - 1.76 (m, 10 H), 3.85 (s, 2 H), 5.13 (br. s., 1 H), 8.55 (s, 2 H)
同様の方法により、以下の化合物を合成した。
３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．６］ウンデカン－２－オン
(ESI pos.) m/z : 314（［Ｍ+H］+）
４－メチル－４－（プロパン－２－イル）－１－［６－（トリフルオロメチル）ピリジン－３－イル］イミダゾリジン－２－オン
(ESI pos.) m/z : 288（［Ｍ+H］+）
３－［３－フルオロ－５－（トリフルオロメチル）ピリジン－２－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン
(ESI pos.) m/z : 318（［Ｍ+H］+）
３－［５－（トリフルオロメチル）ピリミジン－２－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン
(ESI pos.) m/z : 301（［Ｍ+H］+）
製造例７　３－［６－（ジフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン Under a nitrogen atmosphere, 1,3-diazaspiro [4.5] decan-2-one (100 mg), 5-chloro-2-iodopyrimidine, Pd 2 (dba) 3 (34 mg), Xantphos (38 mg), and tert- A solution of butoxy sodium (94 mg) in toluene (4 mL) was stirred at 100 ° C. for 2 hours. The reaction mixture was diluted with chloroform, NH silica gel was added, and the mixture was concentrated under reduced pressure. This was purified by column chromatography (silica gel cartridge, chloroform / methanol) to obtain the title compound (123 mg).
(ESI pos.) M / z: 267 ([M + H] +)
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.37-1.76 (m, 10 H), 3.85 (s, 2 H), 5.13 (br. S., 1 H), 8.55 (s, 2 H)
The following compounds were synthesized by the same method.
3- [6- (Trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.6] undecan-2-one
(ESI pos.) M / z: 314 ([M + H] +)
4-Methyl-4- (propan-2-yl) -1- [6- (trifluoromethyl) pyridin-3-yl] imidazolidin-2-one
(ESI pos.) M / z: 288 ([M + H] +)
3- [3-Fluoro-5- (trifluoromethyl) pyridin-2-yl] -1,3-diazaspiro [4.5] decan-2-one
(ESI pos.) M / z: 318 ([M + H] +)
3- [5- (Trifluoromethyl) pyrimidin-2-yl] -1,3-diazaspiro [4.5] decan-2-one
(ESI pos.) M / z: 301 ([M + H] +)
Production Example 7 3- [6- (Difluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] decan-2-one
Figure JPOXMLDOC01-appb-C000021
 
Figure JPOXMLDOC01-appb-C000021
 
（１）３－（６－ブロモピリジン－３－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン（５２０ｍｇ）のＤＭＦ－メタノール（２：１、８ｍＬ）溶液に炭酸カリウム（３４８ｍｇ）およびＰｄ（ＰＰｈ3）4（１９４ｍｇ）を加え、系内を一酸化炭素ガスで置換した後、８０℃で２時間撹拌した。飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した後、有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥し、乾燥剤をろ別の後、ろ液を減圧下濃縮した。残渣をヘキサンおよび酢酸エチルの混合溶媒（５：１）で洗浄し、５－（２－オキソ－１，３－ジアザスピロ［４．５］デカ－３－イル）ピリジン－２－カルボン酸メチル（３８９ｍｇ）を得た。
1H NMR (200 MHz, CHLOROFORM-d) d ppm 1.40 - 1.90 (m, 10 H), 3.71 (s, 2 H), 4.01 (s, 3 H), 5.65 (br. s, 1 H), 8.06 - 8.19 (m, 1 H), 8.26 - 8.38 (m, 1 H), 8.74 (d, J=2.2 Hz, 1 H)
（２）５－（２－オキソ－１，３－ジアザスピロ［４．５］デカ－３－イル）ピリジン－２－カルボン酸メチル（３８０ｍｇ）のＴＨＦ（１５ｍＬ）溶液に水素化ホウ素リチウム（１４０ｍｇ）を加え、一晩撹拌した。飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した後、有機層を水および飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥した後、乾燥剤をろ別し、ろ液を減圧下濃縮した。残渣をＤＭＳＯ（１０ｍＬ）に溶解し、２－ヨードキシ安息香酸（０．７４ｇ）を加え、２時間撹拌した。反応液に水および酢酸エチルを加え、不溶物をろ去した後、ろ液を酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別後、ろ液を減圧濃縮し、５－（２－オキソ－１，３－ジアザスピロ［４．５］デカ－３－イル）ピリジン－２－カルバルデヒド（３６２ｍｇ）を得た。
1H NMR (200 MHz, CHLOROFORM-d) d ppm 1.42 - 1.84 (m, 10 H), 3.71 (s, 2 H), 5.63 (br. s., 1 H), 7.94 (d, J=7.9 Hz, 1 H), 8.20 - 8.36 (m, 1 H), 8.77 - 8.87 (m, 1 H), 9.99 (s, 1 H)
（３）５－（２－オキソ－１，３－ジアザスピロ［４．５］デカ－３－イル）ピリジン－２－カルバルデヒド（３６２ｍｇ）をクロロホルムに溶解し、氷冷した後、ビス（２－メトキシエチル）アミノ硫黄　三フッ化物（０．９６ｍＬ）を加え、室温で３０分撹拌した。飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した後、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別後、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、クロロホルム／メタノール）で精製し、標題化合物（１９５ｍｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.43 - 1.79 (m, 10 H), 3.67 (s, 3 H), 5.42 (br. s., 1 H), 6.46 - 6.78 (m, 1 H), 7.59 (d, J=8.7 Hz, 1 H), 8.21 - 8.35 (m, 1 H), 8.65 (d, J=2.3 Hz, 1 H)
(ESI pos.) m/z : 280（［Ｍ-H］-）
製造例８　［３－（６－メトキシピリジン－３－イル）－２－オキソ－１，３－ジアザスピロ［４．５］デカ－１－イル］酢酸 (1) 3- (6-Bromopyridin-3-yl) -1,3-diazaspiro [4.5] decan-2-one (520 mg) in DMF-methanol (2: 1, 8 mL) in potassium carbonate (2: 1, 8 mL) 348 mg) and Pd (PPh 3 ) 4 (194 mg) were added, and the system was replaced with carbon monoxide gas, followed by stirring at 80 ° C. for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was washed with a mixed solvent of hexane and ethyl acetate (5: 1), and methyl 5- (2-oxo-1,3-diazaspiro [4.5] dec-3-yl) pyridine-2-carboxylate (389 mg). )
1H NMR (200 MHz, CHLOROFORM-d) d ppm 1.40-1.90 (m, 10 H), 3.71 (s, 2 H), 4.01 (s, 3 H), 5.65 (br. S, 1 H), 8.06- 8.19 (m, 1 H), 8.26-8.38 (m, 1 H), 8.74 (d, J = 2.2 Hz, 1 H)
(2) Lithium borohydride (140 mg) in a THF (15 mL) solution of methyl 5- (2-oxo-1,3-diazaspiro [4.5] dec-3-yl) pyridine-2-carboxylate (380 mg) And stirred overnight. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in DMSO (10 mL), 2-iodoxybenzoic acid (0.74 g) was added, and the mixture was stirred for 2 hr. Water and ethyl acetate were added to the reaction solution, the insoluble material was removed by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure to give 5- (2-oxo-1,3-diazaspiro [4.5] dec-3-yl) pyridine-2-carbaldehyde (362 mg).
1H NMR (200 MHz, CHLOROFORM-d) d ppm 1.42-1.84 (m, 10 H), 3.71 (s, 2 H), 5.63 (br. S., 1 H), 7.94 (d, J = 7.9 Hz, 1 H), 8.20-8.36 (m, 1 H), 8.77-8.87 (m, 1 H), 9.99 (s, 1 H)
(3) 5- (2-oxo-1,3-diazaspiro [4.5] dec-3-yl) pyridine-2-carbaldehyde (362 mg) was dissolved in chloroform, cooled on ice, and bis (2- Methoxyethyl) aminosulfur trifluoride (0.96 mL) was added and stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added, extracted with chloroform, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, chloroform / methanol) to obtain the title compound (195 mg).
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.43-1.79 (m, 10 H), 3.67 (s, 3 H), 5.42 (br. S., 1 H), 6.46-6.78 (m, 1 H) , 7.59 (d, J = 8.7 Hz, 1 H), 8.21-8.35 (m, 1 H), 8.65 (d, J = 2.3 Hz, 1 H)
(ESI pos.) M / z: 280 ([M-H]-)
Production Example 8 [3- (6-Methoxypyridin-3-yl) -2-oxo-1,3-diazaspiro [4.5] dec-1-yl] acetic acid
Figure JPOXMLDOC01-appb-C000022
  　 
Figure JPOXMLDOC01-appb-C000022
  　 
（１）３－（６－メトキシピリジン－３－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン（１．４５ｇ）のＤＭＦ（２０ｍＬ）溶液を氷冷し、水素化ナトリウム（２６６ｍｇ）を加え、３０分撹拌した。ブロモ酢酸エチル（０．７４ｍＬ）を加え、室温で一晩撹拌した。飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した後、有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥し、乾燥剤をろ別の後、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル＝７５：２５～６０：４０）で精製し、［３－（６－メトキシピリジン－３－イル）－２－オキソ－１，３－ジアザスピロ［４．５］デカ－１－イル］酢酸エチル（１．０５ｇ）を得た。
1H NMR (200 MHz, CHLOROFORM-d) d ppm 1.01 - 1.92 (m, 10 H), 1.24 - 1.37 (m, 3 H), 3.68 (s, 2 H), 3.93 (s, 3 H), 3.97 (s, 2 H), 4.22 (q, J=7.0 Hz, 2 H), 6.64 - 6.82 (m, 1 H), 8.06 (d, J=3.1 Hz, 1 H), 8.15 - 8.26 (m, 1 H)
(ESI pos.) m/z : 348（［Ｍ+H］+）
（２）［３－（６－メトキシピリジン－３－イル）－２－オキソ－１，３－ジアザスピロ［４．５］デカ－１－イル］酢酸エチル（１．００ｇ）のメタノール（１０ｍＬ）溶液に水（５ｍＬ）、水酸化ナトリウム（１４０ｍｇ）を加え、室温で一晩撹拌した。減圧下溶媒を留去した後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで洗浄した。水層を１Ｍ塩酸で中性にした後、クロロホルムで抽出し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別の後、ろ液を減圧下濃縮し、標題化合物（０．９９ｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.09 - 1.20 (m, 1 H), 1.30 - 1.41 (m, 2 H), 1.47 - 1.60 (m, 2 H), 1.66 - 1.90 (m, 5 H), 3.68 (s, 2 H), 3.91 (s, 3 H), 3.97 (s, 2 H), 6.74 (d, J=9.6 Hz, 1 H), 8.02 - 8.17 (m, 2 H)
(ESI pos.) m/z : 320（［Ｍ+H］+）
同様の方法により、以下の化合物を合成した。
｛２－オキソ－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカ－１－イル｝酢酸
(ESI pos.) m/z : 358（［Ｍ+H］+）
［３－（６－クロロピリジン－３－イル）－２－オキソ－１，３－ジアザスピロ［４．５］デカ－１－イル］酢酸
(ESI pos.) m/z : 324（［Ｍ+H］+）
製造例９　１－［（３－プロポキシ－１，２－オキサゾール－５－イル）メチル］－１，３－ジアザスピロ［４．５］デカン－２－オン (1) A solution of 3- (6-methoxypyridin-3-yl) -1,3-diazaspiro [4.5] decan-2-one (1.45 g) in DMF (20 mL) was ice-cooled and sodium hydride was added. (266 mg) was added and stirred for 30 minutes. Ethyl bromoacetate (0.74 mL) was added and stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate = 75: 25 to 60:40), and [3- (6-methoxypyridin-3-yl) -2-oxo-1,3-diazaspiro [ 4.5] Dec-1-yl] ethyl acetate (1.05 g) was obtained.
1H NMR (200 MHz, CHLOROFORM-d) d ppm 1.01-1.92 (m, 10 H), 1.24-1.37 (m, 3 H), 3.68 (s, 2 H), 3.93 (s, 3 H), 3.97 ( s, 2 H), 4.22 (q, J = 7.0 Hz, 2 H), 6.64-6.82 (m, 1 H), 8.06 (d, J = 3.1 Hz, 1 H), 8.15-8.26 (m, 1 H )
(ESI pos.) M / z: 348 ([M + H] +)
(2) A solution of [3- (6-methoxypyridin-3-yl) -2-oxo-1,3-diazaspiro [4.5] dec-1-yl] ethyl acetate (1.00 g) in methanol (10 mL) To the mixture were added water (5 mL) and sodium hydroxide (140 mg), and the mixture was stirred overnight at room temperature. After evaporating the solvent under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was washed with ethyl acetate. The aqueous layer was neutralized with 1M hydrochloric acid, extracted with chloroform, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (0.99 g).
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.09-1.20 (m, 1 H), 1.30-1.41 (m, 2 H), 1.47-1.60 (m, 2 H), 1.66-1.90 (m, 5 H ), 3.68 (s, 2 H), 3.91 (s, 3 H), 3.97 (s, 2 H), 6.74 (d, J = 9.6 Hz, 1 H), 8.02-8.17 (m, 2 H)
(ESI pos.) M / z: 320 ([M + H] +)
The following compounds were synthesized by the same method.
{2-Oxo-3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] dec-1-yl} acetic acid
(ESI pos.) M / z: 358 ([M + H] +)
[3- (6-Chloropyridin-3-yl) -2-oxo-1,3-diazaspiro [4.5] dec-1-yl] acetic acid
(ESI pos.) M / z: 324 ([M + H] +)
Production Example 9 1-[(3-propoxy-1,2-oxazol-5-yl) methyl] -1,3-diazaspiro [4.5] decan-2-one
Figure JPOXMLDOC01-appb-C000023
 　 
Figure JPOXMLDOC01-appb-C000023
 　 
（１）シクロヘキサノン（５．０ｇ）、ベンジルアミン（５．４５ｇ）、およびシアン化トリメチルシリル（７．５７ｇ）のアセトニトリル（２００ｍＬ）溶液にヨウ素（１．２９ｇ）を加え、一晩撹拌した。減圧下溶媒を留去した後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。無水硫酸マグネシウムで乾燥した後、乾燥剤をろ別し、ろ液を減圧下濃縮した。１－（ベンジルアミノ）シクロヘキサンカルボニトリル（１２．５ｇ）を得た。
(ESI pos.) m/z : 215（［Ｍ+H］+）
（２）窒素雰囲気下１－（ベンジルアミノ）シクロヘキサンカルボニトリル（１２．４ｇ）のＴＨＦ（２００ｍＬ）溶液を氷冷し、水素化アルミニウムリチウム（５．６ｇ）を加え、室温で４時間撹拌した。氷冷した後、１０％水酸化ナトリウム水溶液（２５ｍＬ）を滴下し、室温で１時間撹拌した。無水硫酸マグネシウムで乾燥した後、乾燥剤をろ別し、ろ液を減圧下濃縮した。１－（アミノメチル）－Ｎ－ベンジルシクロヘキサンアミン（１０．７ｇ）を得た。
(ESI pos.) m/z : 219（［Ｍ+H］+）
（３）１－（アミノメチル）－Ｎ－ベンジルシクロヘキサンアミン（１０．７ｇ）をＴＨＦ（１５０ｍＬ）に溶かし、二炭酸ジ－ｔｅｒｔ－ブチル（１０．９ｇ）のＴＨＦ（５０ｍＬ）溶液を滴下した。２時間撹拌した後、ジメチルアミン（１Ｍ／ＴＨＦ溶液、２０ｍＬ）を加え、１０分撹拌した。反応液を減圧下濃縮した後、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル）で精製を行い、｛［１－（ベンジルアミノ）シクロヘキシル］メチル｝カルバミン酸　ｔｅｒｔ－ブチル（１１．６ｇ）を得た。
(ESI pos.) m/z : 319（［Ｍ+H］+）
（４）｛［１－（ベンジルアミノ）シクロヘキシル］メチル｝カルバミン酸　ｔｅｒｔ－ブチル（６．６ｇ）のメタノール（１００ｍＬ）溶液に１０％パラジウム炭素（１．５ｇ）を加え、系内を水素ガスで置換した後、３日間撹拌した。パラジウム炭素をろ去した後、ろ液を減圧下濃縮し、［（１－アミノシクロヘキシル）メチル］カルバミン酸　ｔｅｒｔ－ブチル（４．８ｇ）を得た。
(ESI pos.) m/z : 229（［Ｍ+H］+）
（５）［（１－アミノシクロヘキシル）メチル］カルバミン酸　ｔｅｒｔ－ブチル（０．５５ｇ）のＤＭＦ（１０ｍＬ）溶液に炭酸カリウム（０．４ｇ）および３－プロピルオキシ－５－ブロモメチルイソオキサゾール（０．５５ｇ）のＤＭＦ（２ｍＬ）溶液を加え、一晩撹拌した。飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した後、有機層を水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥した後、乾燥剤をろ別し、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル）で精製し、［（１－｛［（３－プロポキシ－１，２－オキサゾール－５－イル）メチル］アミノ｝シクロヘキシル）メチル］カルバミン酸　ｔｅｒｔ－ブチル（０．６２ｇ）を得た。
(ESI pos.) m/z : 368（［Ｍ+H］+）
（６）製造例１（２）と同様の方法により、［（１－｛［（３－プロポキシ－１，２－オキサゾール－５－イル）メチル］アミノ｝シクロヘキシル）メチル］カルバミン酸　ｔｅｒｔ－ブチル（０．５５ｇ）から１－（アミノメチル）－Ｎ－［（３－プロポキシ－１，２－オキサゾール－５－イル）メチル］シクロヘキサンアミンの粗体（０．４２ｇ）を得た。
(ESI pos.) m/z : 268（［Ｍ+H］+）
（７）製造例１（３）と同様の方法により、１－（アミノメチル）－Ｎ－［（３－プロポキシ－１，２－オキサゾール－５－イル）メチル］シクロヘキサンアミン（０．４２ｇ、粗体）から標題化合物（０．５２ｇ）を得た。
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.00 (t, J=7.6 Hz, 3 H), 1.07 - 1.84 (m, 12 H), 3.27 - 3.31 (m, 2 H), 4.16 (t, J=6.6 Hz, 2 H), 4.30 (s, 2 H), 5.86 (s, 1 H)
(ESI pos.) m/z : 316（［Ｍ+Na］+）
同様の方法により、以下の化合物を合成した。
１－［（６－プロポキシピリジン－３－イル）メチル］－１，３－ジアザスピロ［４．５］デカン－２－オン
(ESI pos.) m/z : 304（［Ｍ+H］+）
製造例１０　［３－（プロパン－２－イルオキシ）－１，２－オキサゾール－５－イル］メタノール (1) Iodine (1.29 g) was added to a solution of cyclohexanone (5.0 g), benzylamine (5.45 g), and trimethylsilyl cyanide (7.57 g) in acetonitrile (200 mL) and stirred overnight. After evaporating the solvent under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the desiccant was filtered off and the filtrate was concentrated under reduced pressure. 1- (Benzylamino) cyclohexanecarbonitrile (12.5 g) was obtained.
(ESI pos.) M / z: 215 ([M + H] +)
(2) A solution of 1- (benzylamino) cyclohexanecarbonitrile (12.4 g) in THF (200 mL) was cooled with ice in a nitrogen atmosphere, lithium aluminum hydride (5.6 g) was added, and the mixture was stirred at room temperature for 4 hours. After cooling with ice, 10% aqueous sodium hydroxide solution (25 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hr. After drying over anhydrous magnesium sulfate, the desiccant was filtered off and the filtrate was concentrated under reduced pressure. 1- (Aminomethyl) -N-benzylcyclohexaneamine (10.7 g) was obtained.
(ESI pos.) M / z: 219 ([M + H] +)
(3) 1- (Aminomethyl) -N-benzylcyclohexaneamine (10.7 g) was dissolved in THF (150 mL), and a solution of di-tert-butyl dicarbonate (10.9 g) in THF (50 mL) was added dropwise. After stirring for 2 hours, dimethylamine (1M / THF solution, 20 mL) was added and stirred for 10 minutes. After the reaction solution was concentrated under reduced pressure, the residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate), and tert-butyl {[1- (benzylamino) cyclohexyl] methyl} carbamate (11.6 g) Got.
(ESI pos.) M / z: 319 ([M + H] +)
(4) {[1- (benzylamino) cyclohexyl] methyl} carbamate 10% palladium on carbon (1.5 g) was added to a solution of tert-butyl (6.6 g) in methanol (100 mL), and the system was filled with hydrogen gas. After the replacement, the mixture was stirred for 3 days. After removing palladium on carbon, the filtrate was concentrated under reduced pressure to obtain tert-butyl [(1-aminocyclohexyl) methyl] carbamate (4.8 g).
(ESI pos.) M / z: 229 ([M + H] +)
(5) To a solution of tert-butyl [(1-aminocyclohexyl) methyl] carbamate (0.55 g) in DMF (10 mL), potassium carbonate (0.4 g) and 3-propyloxy-5-bromomethylisoxazole (0 .55 g) in DMF (2 mL) was added and stirred overnight. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate) to give [(1-{[(3-propoxy-1,2-oxazol-5-yl) methyl] amino} cyclohexyl) methyl] carbamic acid tert -Butyl (0.62 g) was obtained.
(ESI pos.) M / z: 368 ([M + H] +)
(6) In the same manner as in Production Example 1 (2), [(1-{[(3-propoxy-1,2-oxazol-5-yl) methyl] amino} cyclohexyl) methyl] carbamate tert-butyl ( 0.55 g) gave a crude product (0.42 g) of 1- (aminomethyl) -N-[(3-propoxy-1,2-oxazol-5-yl) methyl] cyclohexaneamine.
(ESI pos.) M / z: 268 ([M + H] +)
(7) In the same manner as in Production Example 1 (3), 1- (aminomethyl) -N-[(3-propoxy-1,2-oxazol-5-yl) methyl] cyclohexaneamine (0.42 g, crude To give the title compound (0.52 g).
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.00 (t, J = 7.6 Hz, 3 H), 1.07-1.84 (m, 12 H), 3.27-3.31 (m, 2 H), 4.16 (t, J = 6.6 Hz, 2 H), 4.30 (s, 2 H), 5.86 (s, 1 H)
(ESI pos.) M / z: 316 ([M + Na] +)
The following compounds were synthesized by the same method.
1-[(6-Propoxypyridin-3-yl) methyl] -1,3-diazaspiro [4.5] decan-2-one
(ESI pos.) M / z: 304 ([M + H] +)
Production Example 10 [3- (propan-2-yloxy) -1,2-oxazol-5-yl] methanol
Figure JPOXMLDOC01-appb-C000024
  　 
Figure JPOXMLDOC01-appb-C000024
  　 
（１）３－ヒドロキシ－１，２－オキサゾール－５－カルボン酸メチル（３．０ｇ）のＤＭＦ（８０ｍＬ）溶液に炭酸カリウム（５．８ｇ）および２－ヨードプロパン（３．２ｍＬ）を加え、７０℃で３時間撹拌した。飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を水および飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥した後、乾燥剤をろ別し、ろ液を減圧下濃縮した。３－（プロパン－２－イルオキシ）－１，２－オキサゾール－５－カルボン酸メチル（３．３５ｇ）を得た。
1H NMR (200 MHz, CHLOROFORM-d) d ppm 1.40 (d, J=6.2 Hz, 6 H), 3.95 (s, 3 H), 4.96 (spt, J=6.2 Hz, 1 H), 6.50 (s, 1 H)
（２）３－（プロパン－２－イルオキシ）－１，２－オキサゾール－５－カルボン酸メチル（３．３５ｇ）のＴＨＦ（８０ｍＬ）溶液を氷冷し、水素化アルミニウムリチウム（０．６８ｇ）を加え、３０分撹拌した。１０％水酸化ナトリウム水溶液（４ｍＬ）を滴下し、室温で１時間撹拌した。無水硫酸マグネシウムで乾燥した後、乾燥剤をろ別し、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル）で精製し、標題化合物（１．３３ｇ）を得た。
(ESI pos.) m/z : 158（［Ｍ+H］+）
同様の方法により、以下の化合物を合成した。
（３－エトキシ－１，２－オキサゾール－５－イル）メタノール
(ESI pos.) m/z : 166（［Ｍ+Na］+）
（３－プロポキシ－１，２－オキサゾール－５－イル）メタノール
(ESI pos.) m/z : 158（［Ｍ+H］+）
（３－ブトキシ－１，２－オキサゾール－５－イル）メタノール
(ESI pos.) m/z : 194（［Ｍ+Na］+）
［３－（シクロプロピルメトキシ）－１，２－オキサゾール－５－イル］メタノール
(ESI pos.) m/z : 170（［Ｍ+H］+）
［３－（２，２，２－トリフルオロエトキシ）－１，２－オキサゾール－５－イル］メタノール
(ESI pos.) m/z : 198（［Ｍ+H］+）
［３－（３，３，３－トリフルオロプロポキシ）－１，２－オキサゾール－５－イル］メタノール
(ESI pos.) m/z : 212（［Ｍ+H］+）
［３－（３－フルオロプロポキシ）－１，２－オキサゾール－５－イル］メタノール
(ESI pos.) m/z : 176（［Ｍ+H］+）
［３－（ブタン－２－イルオキシ）－１，２－オキサゾール－５－イル］メタノール
(ESI pos.) m/z : 172（［Ｍ+H］+）
｛３－［（２Ｒ）－ブタン－２－イルオキシ］－１，２－オキサゾール－５－イル｝メタノール
(ESI pos.) m/z : 172（［Ｍ+H］+）
｛３－［（２Ｓ）－ブタン－２－イルオキシ］－１，２－オキサゾール－５－イル｝メタノール
(ESI pos.) m/z : 172（［Ｍ+H］+）
［３－（２－メトキシエトキシ）－１，２－オキサゾール－５－イル］メタノール
(ESI pos.) m/z : 174（［Ｍ+H］+）
［３－（２－｛［ｔｅｒｔ－ブチル（ジメチル）シリル］オキシ｝エトキシ）－１，２－オキサゾール－５－イル］メタノール
(ESI pos.) m/z : 274（［Ｍ+H］+）
（３－｛［（２Ｓ）－１，１，１－トリフルオロプロパン－２－イル］オキシ｝－１，２－オキサゾール－５－イル）メタノール
(ESI pos.) m/z : 212（［Ｍ+H］+）
［３－（２－メチルプロポキシ）－１，２－オキサゾール－５－イル］メタノール
(ESI pos.) m/z : 172（［Ｍ+H］+）
（５－プロポキシピリジン－３－イル）メタノール
(ESI pos.) m/z : 168（［Ｍ+H］+）
［３－（３－｛［ｔｅｒｔ－ブチル（ジメチル）シリル］オキシ｝プロポキシ）－１，２－オキサゾール－５－イル］メタノール
(ESI pos.) m/z : 288（［Ｍ+H］+）
［３－（２－フルオロエトキシ）－１，２－オキサゾール－５－イル］メタノール
(ESI pos.) m/z : 162（［Ｍ+H］+）
［３－（２，２－ジフルオロエトキシ）－１，２－オキサゾール－５－イル］メタノール
(ESI pos.) m/z : 180（［Ｍ+H］+）
［３－（シクロブチルメトキシ）－１，２－オキサゾール－５－イル］メタノール
(ESI pos.) m/z : 184（［Ｍ+H］+）
［３－（２－フルオロプロポキシ）－１，２－オキサゾール－５－イル］メタノール
(ESI pos.) m/z : 176（［Ｍ+H］+）
製造例１１　５－（ブロモメチル）－３－プロポキシ－１，２－オキサゾール (1) To a solution of methyl 3-hydroxy-1,2-oxazole-5-carboxylate (3.0 g) in DMF (80 mL) was added potassium carbonate (5.8 g) and 2-iodopropane (3.2 mL), Stir at 70 ° C. for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was added, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off and the filtrate was concentrated under reduced pressure. Methyl 3- (propan-2-yloxy) -1,2-oxazole-5-carboxylate (3.35 g) was obtained.
1H NMR (200 MHz, CHLOROFORM-d) d ppm 1.40 (d, J = 6.2 Hz, 6 H), 3.95 (s, 3 H), 4.96 (spt, J = 6.2 Hz, 1 H), 6.50 (s, 1 H)
(2) A solution of methyl 3- (propan-2-yloxy) -1,2-oxazole-5-carboxylate (3.35 g) in THF (80 mL) was ice-cooled, and lithium aluminum hydride (0.68 g) was added. Added and stirred for 30 minutes. A 10% aqueous sodium hydroxide solution (4 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After drying over anhydrous magnesium sulfate, the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate) to give the title compound (1.33 g).
(ESI pos.) M / z: 158 ([M + H] +)
The following compounds were synthesized by the same method.
(3-Ethoxy-1,2-oxazol-5-yl) methanol
(ESI pos.) M / z: 166 ([M + Na] +)
(3-propoxy-1,2-oxazol-5-yl) methanol
(ESI pos.) M / z: 158 ([M + H] +)
(3-Butoxy-1,2-oxazol-5-yl) methanol
(ESI pos.) M / z: 194 ([M + Na] +)
[3- (Cyclopropylmethoxy) -1,2-oxazol-5-yl] methanol
(ESI pos.) M / z: 170 ([M + H] +)
[3- (2,2,2-trifluoroethoxy) -1,2-oxazol-5-yl] methanol
(ESI pos.) M / z: 198 ([M + H] +)
[3- (3,3,3-trifluoropropoxy) -1,2-oxazol-5-yl] methanol
(ESI pos.) M / z: 212 ([M + H] +)
[3- (3-Fluoropropoxy) -1,2-oxazol-5-yl] methanol
(ESI pos.) M / z: 176 ([M + H] +)
[3- (Butan-2-yloxy) -1,2-oxazol-5-yl] methanol
(ESI pos.) M / z: 172 ([M + H] +)
{3-[(2R) -butan-2-yloxy] -1,2-oxazol-5-yl} methanol
(ESI pos.) M / z: 172 ([M + H] +)
{3-[(2S) -Butan-2-yloxy] -1,2-oxazol-5-yl} methanol
(ESI pos.) M / z: 172 ([M + H] +)
[3- (2-methoxyethoxy) -1,2-oxazol-5-yl] methanol
(ESI pos.) M / z: 174 ([M + H] +)
[3- (2-{[tert-Butyl (dimethyl) silyl] oxy} ethoxy) -1,2-oxazol-5-yl] methanol
(ESI pos.) M / z: 274 ([M + H] +)
(3-{[(2S) -1,1,1-trifluoropropan-2-yl] oxy} -1,2-oxazol-5-yl) methanol
(ESI pos.) M / z: 212 ([M + H] +)
[3- (2-Methylpropoxy) -1,2-oxazol-5-yl] methanol
(ESI pos.) M / z: 172 ([M + H] +)
(5-propoxypyridin-3-yl) methanol
(ESI pos.) M / z: 168 ([M + H] +)
[3- (3-{[tert-Butyl (dimethyl) silyl] oxy} propoxy) -1,2-oxazol-5-yl] methanol
(ESI pos.) M / z: 288 ([M + H] +)
[3- (2-Fluoroethoxy) -1,2-oxazol-5-yl] methanol
(ESI pos.) M / z: 162 ([M + H] +)
[3- (2,2-difluoroethoxy) -1,2-oxazol-5-yl] methanol
(ESI pos.) M / z: 180 ([M + H] +)
[3- (Cyclobutylmethoxy) -1,2-oxazol-5-yl] methanol
(ESI pos.) M / z: 184 ([M + H] +)
[3- (2-Fluoropropoxy) -1,2-oxazol-5-yl] methanol
(ESI pos.) M / z: 176 ([M + H] +)
Production Example 11 5- (Bromomethyl) -3-propoxy-1,2-oxazole
Figure JPOXMLDOC01-appb-C000025
  　 
Figure JPOXMLDOC01-appb-C000025
  　 
（３－プロポキシ－１，２－オキサゾール－５－イル）メタノール（４５０ｍｇ）のＴＨＦ（５ｍＬ）溶液にトリフェニルホスフィン（８５２ｍｇ）および四臭化炭素（１．０４ｇ）を加え、室温で２時間撹拌した。クロロホルムおよびシリカゲルを加えた後、溶媒を減圧下留去した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル＝９８／２～８０／２０）で精製し、標題化合物（４９６ｍｇ）を得た。
(ESI pos.) m/z : 220（［Ｍ+H］+）
同様の方法により、以下の化合物を合成した。
５－（ブロモメチル）－３－エトキシ－１，２－オキサゾール
(ESI pos.) m/z : 206（［Ｍ+H］+）
５－（ブロモメチル）－３－（プロパン－２－イルオキシ）－１，２－オキサゾール
(ESI pos.) m/z : 220（［Ｍ+H］+）
５－（ブロモメチル）－３－ブトキシ－１，２－オキサゾール
(ESI pos.) m/z : 234（［Ｍ+H］+）
５－（ブロモメチル）－３－（シクロプロピルメトキシ）－１，２－オキサゾール
(ESI pos.) m/z : 232（［Ｍ+H］+）
５－（ブロモメチル）－３－（２，２，２－トリフルオロエトキシ）－１，２－オキサゾール
1H NMR (600 MHz, CHLOROFORM-d) d ppm 4.36 (s, 2 H), 4.64 (q, J=8.3 Hz, 2 H), 6.08 (s, 1 H)
５－（ブロモメチル）－３－（３，３，３－トリフルオロプロポキシ）－１，２－オキサゾール
(ESI pos.) m/z : 274（［Ｍ+H］+）
５－（ブロモメチル）－３－（３－フルオロプロポキシ）－１，２－オキサゾール
(ESI pos.) m/z : 238（［Ｍ+H］+）
５－（ブロモメチル）－３－（ブタン－２－イルオキシ）－１，２－オキサゾール
(ESI pos.) m/z : 234（［Ｍ+H］+）
５－（ブロモメチル）－３－［（２Ｒ）－ブタン－２－イルオキシ］－１，２－オキサゾール
(ESI pos.) m/z : 234（［Ｍ+H］+）
５－（ブロモメチル）－３－［（２Ｓ）－ブタン－２－イルオキシ］－１，２－オキサゾール
(ESI pos.) m/z : 234（［Ｍ+H］+）
５－（ブロモメチル）－３－（２－メトキシエトキシ）－１，２－オキサゾール
(ESI pos.) m/z : 236（［Ｍ+H］+）
５－（ブロモメチル）－３－（２－｛［ｔｅｒｔ－ブチル（ジメチル）シリル］オキシ｝エトキシ）－１，２－オキサゾール
(ESI pos.) m/z : 336（［Ｍ+H］+）
５－（ブロモメチル）－３－｛［（２Ｓ）－１，１，１－トリフルオロプロパン－２－イル］オキシ｝－１，２－オキサゾール
(ESI pos.) m/z : 274（［Ｍ+H］+）
５－（ブロモメチル）－３－（２－メチルプロポキシ）－１，２－オキサゾール
(ESI pos.) m/z : 234（［Ｍ+H］+）
５－（ブロモメチル）－２－エトキシピリジン
(ESI pos.) m/z : 216（［Ｍ+H］+）
５－（ブロモメチル）－２－プロポキシピリジン
(ESI pos.) m/z : 230（［Ｍ+H］+）
３－（ブロモメチル）－１－メチル－５－プロポキシ－１Ｈ－ピラゾール
(ESI pos.) m/z : 233（［Ｍ+H］+）
２－（ブロモメチル）－５－（プロパン－２－イルオキシ）ピリジン
1H NMR (200 MHz, CHLOROFORM-d) d ppm 1.36 (d, J=6.2 Hz, 6 H), 4.47 (s, 2 H), 5.31 (spt, J=6.2 Hz, 1 H), 6.68 (d, J=8.8 Hz, 1 H), 7.49 - 7.69 (m, 1 H), 8.15 (d, J=2.2 Hz, 1 H)
２－（ブロモメチル）－５－プロポキシピリジン
1H NMR (200 MHz, CHLOROFORM-d) d ppm 1.06 (t, J=7.3 Hz, 3 H), 1.85 (sxt, J=7.0 Hz, 2 H), 3.99 (t, J=6.6 Hz, 2 H), 4.56 (s, 2 H), 7.09 - 7.25 (m, 1 H), 7.30 - 7.41 (m, 1 H), 8.27 (d, J=2.6 Hz, 1 H)
４－（ブロモメチル）－５－メチル－１－フェニル－１Ｈ－１，２，３－トリアゾール
(ESI pos.) m/z : 252（［Ｍ+H］+）
５－（ブロモメチル）－２－（プロパン－２－イルオキシ）ピリジン
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.33 (d, J=6.4 Hz, 6 H), 4.45 (s, 2 H), 5.19 - 5.34 (m, 1 H), 6.66 (d, J=8.7 Hz, 1 H), 7.59 (dd, J=8.7, 2.8 Hz, 1 H), 8.13 (d, J=2.8 Hz, 1 H)
５－（ブロモメチル）－３－（３－｛［ｔｅｒｔ－ブチル（ジメチル）シリル］オキシ｝プロポキシ）－１，２－オキサゾール
(ESI pos.) m/z : 350（［Ｍ+H］+）
５－（ブロモメチル）－３－（２－フルオロエトキシ）－１，２－オキサゾール
(ESI pos.) m/z : 224（［Ｍ+H］+）
５－（ブロモメチル）－３－（２，２－ジフルオロエトキシ）－１，２－オキサゾール
(ESI pos.) m/z : 242（［Ｍ+H］+）
５－（ブロモメチル）－３－（シクロブチルメトキシ）－１，２－オキサゾール
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.77 - 2.01 (m, 4 H), 2.07 - 2.17 (m, 2 H), 2.76 (spt, J=7.4 Hz, 1 H), 4.20 (d, J=6.6 Hz, 2 H), 4.33 (s, 2 H), 5.94 (s, 1 H)
５－（ブロモメチル）－３－（２－フルオロプロポキシ）－１，２－オキサゾール
(ESI pos.) m/z : 238（［Ｍ+H］+）
製造例１２　２－ブロモ－５－（ブロモメチル）ピラジン Triphenylphosphine (852 mg) and carbon tetrabromide (1.04 g) were added to a solution of (3-propoxy-1,2-oxazol-5-yl) methanol (450 mg) in THF (5 mL), and the mixture was stirred at room temperature for 2 hours. did. After adding chloroform and silica gel, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate = 98 / 2-80 / 20) to give the title compound (496 mg).
(ESI pos.) M / z: 220 ([M + H] +)
The following compounds were synthesized by the same method.
5- (Bromomethyl) -3-ethoxy-1,2-oxazole
(ESI pos.) M / z: 206 ([M + H] +)
5- (Bromomethyl) -3- (propan-2-yloxy) -1,2-oxazole
(ESI pos.) M / z: 220 ([M + H] +)
5- (Bromomethyl) -3-butoxy-1,2-oxazole
(ESI pos.) M / z: 234 ([M + H] +)
5- (Bromomethyl) -3- (cyclopropylmethoxy) -1,2-oxazole
(ESI pos.) M / z: 232 ([M + H] +)
5- (Bromomethyl) -3- (2,2,2-trifluoroethoxy) -1,2-oxazole
1H NMR (600 MHz, CHLOROFORM-d) d ppm 4.36 (s, 2 H), 4.64 (q, J = 8.3 Hz, 2 H), 6.08 (s, 1 H)
5- (Bromomethyl) -3- (3,3,3-trifluoropropoxy) -1,2-oxazole
(ESI pos.) M / z: 274 ([M + H] +)
5- (Bromomethyl) -3- (3-fluoropropoxy) -1,2-oxazole
(ESI pos.) M / z: 238 ([M + H] +)
5- (Bromomethyl) -3- (butan-2-yloxy) -1,2-oxazole
(ESI pos.) M / z: 234 ([M + H] +)
5- (Bromomethyl) -3-[(2R) -butan-2-yloxy] -1,2-oxazole
(ESI pos.) M / z: 234 ([M + H] +)
5- (Bromomethyl) -3-[(2S) -butan-2-yloxy] -1,2-oxazole
(ESI pos.) M / z: 234 ([M + H] +)
5- (Bromomethyl) -3- (2-methoxyethoxy) -1,2-oxazole
(ESI pos.) M / z: 236 ([M + H] +)
5- (Bromomethyl) -3- (2-{[tert-butyl (dimethyl) silyl] oxy} ethoxy) -1,2-oxazole
(ESI pos.) M / z: 336 ([M + H] +)
5- (Bromomethyl) -3-{[(2S) -1,1,1-trifluoropropan-2-yl] oxy} -1,2-oxazole
(ESI pos.) M / z: 274 ([M + H] +)
5- (Bromomethyl) -3- (2-methylpropoxy) -1,2-oxazole
(ESI pos.) M / z: 234 ([M + H] +)
5- (Bromomethyl) -2-ethoxypyridine
(ESI pos.) M / z: 216 ([M + H] +)
5- (Bromomethyl) -2-propoxypyridine
(ESI pos.) M / z: 230 ([M + H] +)
3- (Bromomethyl) -1-methyl-5-propoxy-1H-pyrazole
(ESI pos.) M / z: 233 ([M + H] +)
2- (Bromomethyl) -5- (propan-2-yloxy) pyridine
1H NMR (200 MHz, CHLOROFORM-d) d ppm 1.36 (d, J = 6.2 Hz, 6 H), 4.47 (s, 2 H), 5.31 (spt, J = 6.2 Hz, 1 H), 6.68 (d, J = 8.8 Hz, 1 H), 7.49-7.69 (m, 1 H), 8.15 (d, J = 2.2 Hz, 1 H)
2- (Bromomethyl) -5-propoxypyridine
1H NMR (200 MHz, CHLOROFORM-d) d ppm 1.06 (t, J = 7.3 Hz, 3 H), 1.85 (sxt, J = 7.0 Hz, 2 H), 3.99 (t, J = 6.6 Hz, 2 H) , 4.56 (s, 2 H), 7.09-7.25 (m, 1 H), 7.30-7.41 (m, 1 H), 8.27 (d, J = 2.6 Hz, 1 H)
4- (Bromomethyl) -5-methyl-1-phenyl-1H-1,2,3-triazole
(ESI pos.) M / z: 252 ([M + H] +)
5- (Bromomethyl) -2- (propan-2-yloxy) pyridine
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.33 (d, J = 6.4 Hz, 6 H), 4.45 (s, 2 H), 5.19-5.34 (m, 1 H), 6.66 (d, J = 8.7 Hz, 1 H), 7.59 (dd, J = 8.7, 2.8 Hz, 1 H), 8.13 (d, J = 2.8 Hz, 1 H)
5- (Bromomethyl) -3- (3-{[tert-butyl (dimethyl) silyl] oxy} propoxy) -1,2-oxazole
(ESI pos.) M / z: 350 ([M + H] +)
5- (Bromomethyl) -3- (2-fluoroethoxy) -1,2-oxazole
(ESI pos.) M / z: 224 ([M + H] +)
5- (Bromomethyl) -3- (2,2-difluoroethoxy) -1,2-oxazole
(ESI pos.) M / z: 242 ([M + H] +)
5- (Bromomethyl) -3- (cyclobutylmethoxy) -1,2-oxazole
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.77-2.01 (m, 4 H), 2.07-2.17 (m, 2 H), 2.76 (spt, J = 7.4 Hz, 1 H), 4.20 (d, J = 6.6 Hz, 2 H), 4.33 (s, 2 H), 5.94 (s, 1 H)
5- (Bromomethyl) -3- (2-fluoropropoxy) -1,2-oxazole
(ESI pos.) M / z: 238 ([M + H] +)
Production Example 12 2-Bromo-5- (bromomethyl) pyrazine
Figure JPOXMLDOC01-appb-C000026
  　 
Figure JPOXMLDOC01-appb-C000026
  　 
２－ブロモ－５－メチルピラジン（５００ｍｇ）の四塩化炭素（１５ｍＬ）溶液にＮ－ブロモスクシンイミド（７７４ｍｇ）および２，２’－アゾビス（２－メチルプロピオニトリル）（４８ｍｇ）を加え、８０℃で一晩撹拌した。セライトろ過の後、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル）で精製し、標題化合物（２５３ｍｇ）を得た。
1H NMR (200 MHz, CHLOROFORM-d) d ppm 4.52 (s, 2 H), 8.48 (d, J=1.3 Hz, 1 H), 8.65 (d, J=1.3 Hz, 1 H)
同様の方法により、以下の化合物を合成した。
５－（ブロモメチル）－４－メチル－３－プロポキシ－１，２－オキサゾール
４－（ブロモメチル）－５－メチル－３－プロポキシ－１，２－オキサゾール
上記２化合物は、混合物として得た。
５－（ブロモメチル）－４－フルオロ－３－プロポキシ－１，２－オキサゾール
(ESI pos.) m/z : 238（［Ｍ+H］+）
５－（ブロモメチル）－１，２－オキサゾール－３－カルボン酸エチル
1H NMR (200 MHz, CHLOROFORM-d) d ppm 1.36 - 1.48 (m, 3 H), 4.34 - 4.55 (m, 4 H), 6.74 (s, 1 H)
製造例１３　（１－｛［２－（トリメチルシリル）エトキシ］メチル｝－１Ｈ－ピラゾール－４－イル）メタノール N-bromosuccinimide (774 mg) and 2,2′-azobis (2-methylpropionitrile) (48 mg) were added to a carbon tetrachloride (15 mL) solution of 2-bromo-5-methylpyrazine (500 mg) at 80 ° C. Stir overnight. After filtration through celite, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate) to give the title compound (253 mg).
1H NMR (200 MHz, CHLOROFORM-d) d ppm 4.52 (s, 2 H), 8.48 (d, J = 1.3 Hz, 1 H), 8.65 (d, J = 1.3 Hz, 1 H)
The following compounds were synthesized by the same method.
5- (Bromomethyl) -4-methyl-3-propoxy-1,2-oxazole 4- (Bromomethyl) -5-methyl-3-propoxy-1,2-oxazole The above two compounds were obtained as a mixture.
5- (Bromomethyl) -4-fluoro-3-propoxy-1,2-oxazole
(ESI pos.) M / z: 238 ([M + H] +)
Ethyl 5- (bromomethyl) -1,2-oxazole-3-carboxylate
1H NMR (200 MHz, CHLOROFORM-d) d ppm 1.36-1.48 (m, 3 H), 4.34-4.55 (m, 4 H), 6.74 (s, 1 H)
Production Example 13 (1-{[2- (Trimethylsilyl) ethoxy] methyl} -1H-pyrazol-4-yl) methanol
Figure JPOXMLDOC01-appb-C000027
  　 
Figure JPOXMLDOC01-appb-C000027
  　 
（１）４－ピラゾールカルボン酸　エチル（９．０ｇ）のＤＭＦ（１００ｍＬ）溶液に炭酸カリウム（１７．８ｇ）および塩化　２－（トリメチルシリル）エトキシメチル（１３．６ｍＬ）を加え、室温で一晩撹拌した。ジエチルエーテルで希釈した後、水を加えた。有機層を減圧下濃縮した後、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル）で精製し、１－｛［２－（トリメチルシリル）エトキシ］メチル｝－１Ｈ－ピラゾール－４－カルボン酸　エチル（１２．４ｇ）を得た。
1H NMR (200 MHz, CHLOROFORM-d) d ppm -0.01 (s, 9 H), 0.86 - 0.98 (m, 2 H), 1.36 (t, J=7.3 Hz, 3 H), 3.51 - 3.65 (m, 2 H), 4.32 (q, J=7.0 Hz, 2 H), 5.44 (s, 2 H), 7.95 (s, 1 H), 8.06 (s, 1 H)
（２）１－｛［２－（トリメチルシリル）エトキシ］メチル｝－１Ｈ－ピラゾール－４－カルボン酸　エチル（１２．４ｇ）のＴＨＦ（２５０ｍＬ）溶液を氷冷し、水素化ジイソブチルアルミニウム（１．０Ｍトルエン溶液、１３６ｍＬ）を滴下した。室温で２時間撹拌した後、反応液に酒石酸カリウムナトリウム水溶液を加え、室温で１時間撹拌した。クロロホルムで抽出した後、有機層を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル）で精製し、標題化合物（６．０ｇ）を得た。
(ESI pos.) m/z : 229（［Ｍ+H］+）
1H NMR (200 MHz, CHLOROFORM-d) d ppm -0.01 (s, 9 H), 0.82 - 0.99 (m, 2 H), 3.48 - 3.68 (m, 2 H), 4.62 (s, 2 H), 5.41 (s, 2 H), 7.53 - 7.62 (m, 2 H)
製造例１４　１－（１Ｈ－ピラゾール－４－イルメチル）－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン (1) Potassium carbonate (17.8 g) and 2- (trimethylsilyl) ethoxymethyl chloride (13.6 mL) were added to a solution of ethyl 4-pyrazolecarboxylate (9.0 g) in DMF (100 mL) and stirred overnight at room temperature. did. After dilution with diethyl ether, water was added. After the organic layer was concentrated under reduced pressure, the residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate), and ethyl 1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrazole-4-carboxylate (12.4 g) was obtained.
1H NMR (200 MHz, CHLOROFORM-d) d ppm -0.01 (s, 9 H), 0.86-0.98 (m, 2 H), 1.36 (t, J = 7.3 Hz, 3 H), 3.51-3.65 (m, 2 H), 4.32 (q, J = 7.0 Hz, 2 H), 5.44 (s, 2 H), 7.95 (s, 1 H), 8.06 (s, 1 H)
(2) A solution of ethyl 1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrazole-4-carboxylate (12.4 g) in THF (250 mL) was ice-cooled and diisobutylaluminum hydride (1.0 M Toluene solution (136 mL) was added dropwise. After stirring at room temperature for 2 hours, an aqueous potassium sodium tartrate solution was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After extraction with chloroform, the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate) to give the title compound (6.0 g).
(ESI pos.) M / z: 229 ([M + H] +)
1H NMR (200 MHz, CHLOROFORM-d) d ppm -0.01 (s, 9 H), 0.82-0.99 (m, 2 H), 3.48-3.68 (m, 2 H), 4.62 (s, 2 H), 5.41 (s, 2 H), 7.53-7.62 (m, 2 H)
Production Example 14 1- (1H-pyrazol-4-ylmethyl) -3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] decan-2-one
Figure JPOXMLDOC01-appb-C000028
  　 
Figure JPOXMLDOC01-appb-C000028
  　 
（１）３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン（５２０ｍｇ）、（１－｛［２－（トリメチルシリル）エトキシ］メチル｝－１Ｈ－ピラゾール－４－イル）メタノール（５９０ｍｇ）、およびシアノメチレントリ－ｎ－ブチルホスホラン（８３０ｍｇ）のトルエン（５ｍＬ）溶液を１５０℃で４時間撹拌した。反応液をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル）で精製し、３－［６－（トリフルオロメチル）ピリジン－３－イル］－１－［（１－｛［２－（トリメチルシリル）エトキシ］メチル｝－１Ｈ－ピラゾール－４－イル）メチル］－１，３－ジアザスピロ［４．５］デカン－２－オン（８２０ｍｇ）を得た。
(ESI pos.) m/z : 510（［Ｍ+H］+）
（２）３－［６－（トリフルオロメチル）ピリジン－３－イル］－１－［（１－｛［２－（トリメチルシリル）エトキシ］メチル｝－１Ｈ－ピラゾール－４－イル）メチル］－１，３－ジアザスピロ［４．５］デカン－２－オン（８２０ｍｇ）のエタノール（２０ｍＬ）溶液に２Ｍ塩酸（４０ｍＬ）を加え、室温で１時間撹拌した後、４時間加熱還流した。反応液を減圧下濃縮した後、残渣をカラムクロマトグラフィー（ＮＨカートリッジ、ヘキサン／酢酸エチル～クロロホルム／メタノール）で精製を行い、標題化合物（５３０ｍｇ）を得た。
(ESI pos.) m/z : 380（［Ｍ+H］+）
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.12 - 1.23 (m, 1 H), 1.33 - 1.44 (m, 2 H), 1.58 - 1.90 (m, 7 H), 3.66 (s, 2 H), 4.36 (s, 2 H), 7.57 - 7.69 (m, 4 H), 8.34 - 8.43 (m, 1 H), 8.67 - 8.75 (m, 1 H)
製造例１５　２－（クロロメチル）－１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－ベンゾイミダゾール (1) 3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] decan-2-one (520 mg), (1-{[2- (trimethylsilyl) ethoxy ] A solution of methyl} -1H-pyrazol-4-yl) methanol (590 mg) and cyanomethylenetri-n-butylphosphorane (830 mg) in toluene (5 mL) was stirred at 150 ° C. for 4 hours. The reaction solution was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate) to give 3- [6- (trifluoromethyl) pyridin-3-yl] -1-[(1-{[2- (trimethylsilyl) ethoxy ] Methyl} -1H-pyrazol-4-yl) methyl] -1,3-diazaspiro [4.5] decan-2-one (820 mg) was obtained.
(ESI pos.) M / z: 510 ([M + H] +)
(2) 3- [6- (Trifluoromethyl) pyridin-3-yl] -1-[(1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrazol-4-yl) methyl] -1 2,3-diazaspiro [4.5] decan-2-one (820 mg) in ethanol (20 mL) was added with 2M hydrochloric acid (40 mL), stirred at room temperature for 1 hour, and then heated to reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (NH cartridge, hexane / ethyl acetate to chloroform / methanol) to give the title compound (530 mg).
(ESI pos.) M / z: 380 ([M + H] +)
1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.12-1.23 (m, 1 H), 1.33-1.44 (m, 2 H), 1.58-1.90 (m, 7 H), 3.66 (s, 2 H), 4.36 (s, 2 H), 7.57-7.69 (m, 4 H), 8.34-8.43 (m, 1 H), 8.67-8.75 (m, 1 H)
Production Example 15 2- (Chloromethyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-benzimidazole
Figure JPOXMLDOC01-appb-C000029
  　 
Figure JPOXMLDOC01-appb-C000029
  　 
２－クロロメチルベンズイミダゾール（１．０ｇ）のＴＨＦ（１０ｍＬ）溶液に３，４－ジヒドロ－２Ｈ－ピラン（０．８２ｍＬ）および１０－カンファースルホン酸（４１８ｍｇ）を加え、１６時間撹拌した。水酸化ナトリウム水溶液を加え、クロロホルムで抽出し、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、乾燥剤をろ別し、ろ液を減圧下濃縮した。残渣を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、標題化合物（３００ｍｇ）を得た。
(ESI pos.) m/z : 251（［Ｍ+H］+）
実施例１　３－（６－メトキシピリジン－３－イル）－１－［（３－フェニル－１，２－オキサゾール－５－イル）メチル］－１，３－ジアザスピロ［４．５］デカン－２－オン 3,4-Dihydro-2H-pyran (0.82 mL) and 10-camphorsulfonic acid (418 mg) were added to a solution of 2-chloromethylbenzimidazole (1.0 g) in THF (10 mL), and the mixture was stirred for 16 hours. Aqueous sodium hydroxide was added, extracted with chloroform, and the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate) to give the title compound (300 mg).
(ESI pos.) M / z: 251 ([M + H] +)
Example 1 3- (6-Methoxypyridin-3-yl) -1-[(3-phenyl-1,2-oxazol-5-yl) methyl] -1,3-diazaspiro [4.5] decane-2 -on
Figure JPOXMLDOC01-appb-C000030
  　 
Figure JPOXMLDOC01-appb-C000030
  　 
窒素雰囲気下、３－（６－メトキシピリジン－３－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン（１００ｍｇ）のDMF（２ｍL）溶液を氷冷し、水素化ナトリウム（２３ｍｇ）を加えた。３０分撹拌した後、５－（クロロメチル）－３－フェニル－１，２－オキサゾール（１１０ｍｇ）を加え、室温で一晩撹拌した。飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した後、有機層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別し、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル＝８０：２０～７０：３０）で精製し、標題化合物（１０９ｍｇ）を得た。
実施例２　１－｛［３－（３－メトキシフェニル）－１，２，４－オキサジアゾール－５－イル］メチル｝－３－（６－メトキシピリジン－３－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン　塩酸塩 Under a nitrogen atmosphere, a solution of 3- (6-methoxypyridin-3-yl) -1,3-diazaspiro [4.5] decan-2-one (100 mg) in DMF (2 mL) was ice-cooled and sodium hydride ( 23 mg) was added. After stirring for 30 minutes, 5- (chloromethyl) -3-phenyl-1,2-oxazole (110 mg) was added, and the mixture was stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate = 80: 20-70: 30) to give the title compound (109 mg).
Example 2 1-{[3- (3-Methoxyphenyl) -1,2,4-oxadiazol-5-yl] methyl} -3- (6-methoxypyridin-3-yl) -1,3- Diazaspiro [4.5] decan-2-one hydrochloride
Figure JPOXMLDOC01-appb-C000031
 　 
Figure JPOXMLDOC01-appb-C000031
 　 
［３－（６－メトキシピリジン－３－イル）－２－オキソ－１，３－ジアザスピロ［４．５］デカ－１－イル］酢酸（５０ｍｇ）のＤＭＡ溶液にＥＤＣ・ＨＣｌ（４６ｍｇ）、ＨＯＢＴ・Ｈ2Ｏ（３７ｍｇ）、Ｎ’－ヒドロキシ－３－メトキシベンゼンカルボキシミドアミド（４０ｍｇ）を加え、室温で一晩撹拌した。これを１１０℃に加熱し、５時間撹拌した。飽和炭酸水素ナトリウム水溶液を加え酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別後、ろ液を減圧下濃縮した。残渣をＰＴＬＣ（ヘキサン／酢酸エチル＝１：１）で精製を行い、無色油状物をえた。これを酢酸エチル／イソプロパノールに溶解し、４Ｍ塩酸／酢酸エチル溶液を加えた。生じた固体をろ取し、標題化合物（３４ｍｇ）を得た。
実施例３　３－（６－メトキシピリジン－３－イル）－１－［（５－フェニル－１，３，４－オキサジアゾール－２－イル）メチル］－１，３－ジアザスピロ［４．５］デカン－２－オン [3- (6-Methoxypyridin-3-yl) -2-oxo-1,3-diazaspiro [4.5] dec-1-yl] acetic acid (50 mg) in DMA solution was added to EDC · HCl (46 mg), HOBT H 2 O (37 mg) and N′-hydroxy-3-methoxybenzenecarboximidamide (40 mg) were added and stirred overnight at room temperature. This was heated to 110 ° C. and stirred for 5 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by PTLC (hexane / ethyl acetate = 1: 1) to give a colorless oil. This was dissolved in ethyl acetate / isopropanol, and 4M hydrochloric acid / ethyl acetate solution was added. The resulting solid was collected by filtration to give the title compound (34 mg).
Example 3 3- (6-Methoxypyridin-3-yl) -1-[(5-phenyl-1,3,4-oxadiazol-2-yl) methyl] -1,3-diazaspiro [4.5 ] Decan-2-on
Figure JPOXMLDOC01-appb-C000032
 　 
Figure JPOXMLDOC01-appb-C000032
 　 
［３－（６－メトキシピリジン－３－イル）－２－オキソ－１，３－ジアザスピロ［４．５］デカ－１－イル］酢酸（１００ｍｇ）のクロロホルム（３ｍＬ）溶液を氷冷し、ＣＤＩ（５３ｍｇ）を加え、３０分撹拌した。ベンゾヒドラジド（４４ｍｇ）を加え、さらに１時間撹拌した後、トリフェニルホスフィン（１６３ｍｇ）、四臭化炭素（２０６ｍｇ）を加え、室温で一晩撹拌した。反応液をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル＝７５：２５～５０：５０）で精製を行い、標題化合物（５０ｍｇ）を得た。
実施例４　３－｛４－［（ジメチルアミノ）メチル］フェニル｝－１－［（３－フェニル－１，２－オキサゾール－５－イル）メチル］－１，３－ジアザスピロ［４．５］デカン－２－オン A solution of [3- (6-methoxypyridin-3-yl) -2-oxo-1,3-diazaspiro [4.5] dec-1-yl] acetic acid (100 mg) in chloroform (3 mL) was ice-cooled and subjected to CDI. (53 mg) was added and stirred for 30 minutes. Benzohydrazide (44 mg) was added, and the mixture was further stirred for 1 hr. Triphenylphosphine (163 mg) and carbon tetrabromide (206 mg) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate = 75: 25-50: 50) to give the title compound (50 mg).
Example 4 3- {4-[(Dimethylamino) methyl] phenyl} -1-[(3-phenyl-1,2-oxazol-5-yl) methyl] -1,3-diazaspiro [4.5] decane -2-On
Figure JPOXMLDOC01-appb-C000033
  　 
Figure JPOXMLDOC01-appb-C000033
  　 
（１）酢酸　４－｛２－オキソ－１－［（３－フェニル－１，２－オキサゾール－５－イル）メチル］－１，３－ジアザスピロ［４．５］デカ－３－イル｝ベンジル（０．１２ｇ）のＴＨＦ（２ｍＬ）溶液に水（１ｍＬ）、水酸化ナトリウム（２０ｍｇ）を加え、室温で３０分撹拌した。メタノール（２ｍＬ）を加え、さらに２時間撹拌した。反応液を減圧下濃縮し、飽和炭酸水素ナトリウム水溶液を加え酢酸エチルで抽出し、有機層を無水硫酸マグネシウムで乾燥した。乾燥剤をろ別の後、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル＝７５：２５～５０：５０）で精製を行い、３－［４－（ヒドロキシメチル）フェニル］－１－［（３－フェニル－１，２－オキサゾール－５－イル）メチル］－１，３－ジアザスピロ［４．５］デカン－２－オン（９１ｍｇ）を得た。
（２）３－［４－（ヒドロキシメチル）フェニル］－１－［（３－フェニル－１，２－オキサゾール－５－イル）メチル］－１，３－ジアザスピロ［４．５］デカン－２－オン（１００ｍｇ）のクロロホルム（２ｍＬ）溶液にトリエチルアミン（０．０４ｍＬ）、メタンスルホニルクロリド（０．０２ｍＬ）を加え、室温で３０分撹拌した。飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別後、ろ液を減圧下濃縮した。残渣をＤＭＦ（２ｍＬ）に溶かし、ジメチルアミン塩酸塩（３９ｍｇ）、トリエチルアミン（０．０７ｍＬ）を加え、マイクロ波照射下、１５０℃で１０分撹拌した。飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した後、有機層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別後、ろ液を減圧濃縮した。残渣をカラムクロマトグラフィー（ＮＨカートリッジ、ヘキサン／酢酸エチル＝７５：２５～５０：５０）で精製し、標題化合物（４４ｍｇ）を得た。
実施例５　４－｛［３－（６－メトキシピリジン－３－イル）－２－オキソ－１，３－ジアザスピロ［４．５］デカ－１－イル］メチル｝－Ｎ，Ｎ－ジメチルベンズアミド　塩酸塩 (1) Acetic acid 4- {2-oxo-1-[(3-phenyl-1,2-oxazol-5-yl) methyl] -1,3-diazaspiro [4.5] dec-3-yl} benzyl ( Water (1 mL) and sodium hydroxide (20 mg) were added to a THF (2 mL) solution of 0.12 g), and the mixture was stirred at room temperature for 30 minutes. Methanol (2 mL) was added and stirred for another 2 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate = 75: 25 to 50:50), and 3- [4- (hydroxymethyl) phenyl] -1-[(3-phenyl-1,2 -Oxazol-5-yl) methyl] -1,3-diazaspiro [4.5] decan-2-one (91 mg) was obtained.
(2) 3- [4- (hydroxymethyl) phenyl] -1-[(3-phenyl-1,2-oxazol-5-yl) methyl] -1,3-diazaspiro [4.5] decane-2- Triethylamine (0.04 mL) and methanesulfonyl chloride (0.02 mL) were added to a solution of ON (100 mg) in chloroform (2 mL), and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution was added, extracted with chloroform, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (2 mL), dimethylamine hydrochloride (39 mg) and triethylamine (0.07 mL) were added, and the mixture was stirred at 150 ° C. for 10 minutes under microwave irradiation. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH cartridge, hexane / ethyl acetate = 75: 25 to 50:50) to obtain the title compound (44 mg).
Example 5 4-{[3- (6-Methoxypyridin-3-yl) -2-oxo-1,3-diazaspiro [4.5] dec-1-yl] methyl} -N, N-dimethylbenzamide Hydrochloride salt
Figure JPOXMLDOC01-appb-C000034
  　 
Figure JPOXMLDOC01-appb-C000034
  　 
（１）４－｛［３－（６－メトキシピリジン－３－イル）－２－オキソ－１，３－ジアザスピロ［４．５］デカ－１－イル］メチル｝安息香酸メチル（３４０ｍｇ）のメタノール（４ｍＬ）溶液に水（２ｍＬ）と水酸化ナトリウム（９２ｍｇ）を加え、室温で一晩撹拌した。１Ｍ塩酸で反応液を中性にした後、クロロホルムで抽出し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別後、ろ液を減圧下濃縮し、４－｛［３－（６－メトキシピリジン－３－イル）－２－オキソ－１，３－ジアザスピロ［４．５］デカ－１－イル］メチル｝安息香酸（３３１ｍｇ）を得た。
(ESI pos.) m/z : 396（［Ｍ+H］+）
（２）４－｛［３－（６－メトキシピリジン－３－イル）－２－オキソ－１，３－ジアザスピロ［４．５］デカ－１－イル］メチル｝安息香酸（５０ｍｇ）のＤＭＦ（１ｍＬ）溶液にＥＤＣ・ＨＣｌ（３０ｍｇ）、ＨＯＢＴ・Ｈ2Ｏ（２４ｍｇ）、５０％ジメチルアミン水溶液（０．０３ｍＬ）を順次加え、室温で一晩撹拌した。飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した後、有機層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別後、ろ液を減圧下濃縮した。残渣をＰＴＬＣ（酢酸エチルのみ）にて精製を行い、無色油状物を得た。これを酢酸エチルに溶解し、４Ｍ塩酸／酢酸エチル溶液を加えた後、減圧濃縮し、標題化合物（１９ｍｇ）を得た。
実施例６　１－（４－エトキシベンジル）－３－（６－メトキシピリジン－３－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン　塩酸塩 (1) Methanol of methyl 4-{[3- (6-methoxypyridin-3-yl) -2-oxo-1,3-diazaspiro [4.5] dec-1-yl] methyl} benzoate (340 mg) Water (2 mL) and sodium hydroxide (92 mg) were added to the (4 mL) solution, and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized with 1M hydrochloric acid, extracted with chloroform, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure to give 4-{[3- (6-methoxypyridin-3-yl) -2-oxo-1,3-diazaspiro [4.5] dec-1- Yl] methyl} benzoic acid (331 mg) was obtained.
(ESI pos.) M / z: 396 ([M + H] +)
(2) 4-{[3- (6-Methoxypyridin-3-yl) -2-oxo-1,3-diazaspiro [4.5] dec-1-yl] methyl} benzoic acid (50 mg) in DMF ( 1 mL) solution was added sequentially with EDC.HCl (30 mg), HOBT.H 2 O (24 mg), and 50% aqueous dimethylamine (0.03 mL), and the mixture was stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by PTLC (ethyl acetate only) to obtain a colorless oil. This was dissolved in ethyl acetate, 4M hydrochloric acid / ethyl acetate solution was added, and the mixture was concentrated under reduced pressure to give the title compound (19 mg).
Example 6 1- (4-Ethoxybenzyl) -3- (6-methoxypyridin-3-yl) -1,3-diazaspiro [4.5] decan-2-one hydrochloride
Figure JPOXMLDOC01-appb-C000035
  　 
Figure JPOXMLDOC01-appb-C000035
  　 
（１）１－［４－（ベンジルオキシ）ベンジル］－３－（６－メトキシピリジン－３－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン（１．２３ｇ）のメタノール（１５ｍＬ）溶液に１０％パラジウム炭素（０．１２ｇ）を加え、反応系内を水素ガスで置換した。室温で６時間撹拌した後、パラジウム炭素をろ去し、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル＝７０：３０～５０：５０）で精製し、１－（４－ヒドロキシベンジル）－３－（６－メトキシピリジン－３－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン（０．９３ｇ）を得た。
（２）１－（４－ヒドロキシベンジル）－３－（６－メトキシピリジン－３－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン（５０ｍｇ）のＤＭＦ溶液に炭酸セシウム（８８ｍｇ）、ブロモエタン（０．０２ｍＬ）、ヨウ化ナトリウム（２ｍｇ）を加え、マイクロ波照射下、１６０℃で２５分撹拌した。さらに１８０℃で１０分撹拌した後、不溶物をろ去し、ろ液を分取ＨＰＬＣにて精製を行った。得られた無色油状物をイソプロパノール（１ｍＬ）に溶解し、４Ｍ塩酸／酢酸エチル溶液（０．２ｍＬ）を加えた後、減圧下濃縮し、標題化合物（３２ｍｇ）を得た。
実施例７　５－｛２－オキソ－１－［（３－フェニル－１，２－オキサゾール－５－イル）メチル］－１，３－ジアザスピロ［４．５］デカ－３－イル｝ピリジン－２－カルボニトリル (1) 1- [4- (Benzyloxy) benzyl] -3- (6-methoxypyridin-3-yl) -1,3-diazaspiro [4.5] decan-2-one (1.23 g) of methanol (15 mL) To the solution was added 10% palladium carbon (0.12 g), and the reaction system was replaced with hydrogen gas. After stirring at room temperature for 6 hours, palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate = 70: 30-50: 50) to give 1- (4-hydroxybenzyl) -3- (6-methoxypyridin-3-yl) -1, 3-Diazaspiro [4.5] decan-2-one (0.93 g) was obtained.
(2) 1- (4-Hydroxybenzyl) -3- (6-methoxypyridin-3-yl) -1,3-diazaspiro [4.5] decan-2-one (50 mg) in a DMF solution with cesium carbonate ( 88 mg), bromoethane (0.02 mL), and sodium iodide (2 mg) were added, and the mixture was stirred at 160 ° C. for 25 minutes under microwave irradiation. After further stirring at 180 ° C. for 10 minutes, insolubles were removed by filtration, and the filtrate was purified by preparative HPLC. The obtained colorless oil was dissolved in isopropanol (1 mL), 4M hydrochloric acid / ethyl acetate solution (0.2 mL) was added, and the mixture was concentrated under reduced pressure to give the title compound (32 mg).
Example 7 5- {2-oxo-1-[(3-phenyl-1,2-oxazol-5-yl) methyl] -1,3-diazaspiro [4.5] dec-3-yl} pyridine-2 -Carbonitrile
Figure JPOXMLDOC01-appb-C000036
  　 
Figure JPOXMLDOC01-appb-C000036
  　 
３－（６－クロロピリジン－３－イル）－１－［（３－フェニル－１，２－オキサゾール－５－イル）メチル］－１，３－ジアザスピロ［４．５］デカン－２－オン（１００ｍｇ）のＤＭＦ（１．５ｍＬ）溶液にシアン化亜鉛（１７ｍｇ）、Ｐｄ2（ｄｂａ）3（７．５ｍｇ）、Ｘａｎｔｐｈｏｓ（８．３ｍｇ）、Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルエチレンジアミン（０．０１ｍＬ）を加え、マイクロウェーブ照射下、１８０℃で３０分撹拌した。飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した後、有機層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別後、ろ液を減圧下濃縮した。残渣を分取ＨＰＬＣで精製し、標題化合物（１９ｍｇ）を得た。
実施例８　１－［４－（１Ｈ－イミダゾール－１－イル）ベンジル］－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン 3- (6-Chloropyridin-3-yl) -1-[(3-phenyl-1,2-oxazol-5-yl) methyl] -1,3-diazaspiro [4.5] decan-2-one ( 100 mg) in DMF (1.5 mL) solution of zinc cyanide (17 mg), Pd 2 (dba) 3 (7.5 mg), Xantphos (8.3 mg), N, N, N ′, N′-tetramethylethylenediamine (0.01 mL) was added, and the mixture was stirred at 180 ° C. for 30 minutes under microwave irradiation. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (19 mg).
Example 8 1- [4- (1H-imidazol-1-yl) benzyl] -3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] decane-2 -on
Figure JPOXMLDOC01-appb-C000037
 　 
Figure JPOXMLDOC01-appb-C000037
 　 
１－（４－ヨードベンジル）－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン（７０ｍｇ）、イミダゾール（１４ｍｇ）、３，４，７，８－テトラメチル－１，１０－フェナントロリン（１３ｍｇ）、ヨウ化銅（Ｉ）（５ｍｇ）、および炭酸カリウム（５６ｍｇ）のＤＭＳＯ（１ｍＬ）溶液を１００℃で３時間撹拌した。飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した後、有機層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別の後、ろ液を減圧下濃縮した。残渣を分取ＨＰＬＣで精製し、標題化合物（２３ｍｇ）を得た。
実施例９　１－｛［６－（１－メチル－１Ｈ－ピラゾール－５－イル）ピリジン－３－イル］メチル｝－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン 1- (4-iodobenzyl) -3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] decan-2-one (70 mg), imidazole (14 mg), A solution of 3,4,7,8-tetramethyl-1,10-phenanthroline (13 mg), copper (I) iodide (5 mg), and potassium carbonate (56 mg) in DMSO (1 mL) was stirred at 100 ° C. for 3 hours. . A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (23 mg).
Example 9 1-{[6- (1-Methyl-1H-pyrazol-5-yl) pyridin-3-yl] methyl} -3- [6- (trifluoromethyl) pyridin-3-yl] -1, 3-Diazaspiro [4.5] decan-2-one
Figure JPOXMLDOC01-appb-C000038
  　 
Figure JPOXMLDOC01-appb-C000038
  　 
１－［（６－ブロモピリジン－３－イル）メチル］－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン（７０ｍｇ）、１－メチル－５－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）－１Ｈ－ピラゾール（３７ｍｇ）、Ｐｄ（ＰＰｈ3）4（１７ｍｇ）、炭酸カリウム（３１ｍｇ）のＤＭＦ／エタノール（２：１、１ｍＬ）溶液をマイクロ波照射下、１５０℃で１５分撹拌した。酢酸エチルで希釈し、ＮＨシリカゲルを加えて撹拌した。セライトろ過の後、ろ液を減圧下濃縮し、残渣を分取ＨＰＬＣで精製した。標題化合物（４２ｍｇ）を得た。
実施例１０　１－｛［６－（シクロヘキシルオキシ）ピリジン－３－イル］メチル｝－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン 1-[(6-Bromopyridin-3-yl) methyl] -3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] decan-2-one (70 mg ), 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (37 mg), Pd (PPh 3 ) 4 (17 mg), A solution of potassium carbonate (31 mg) in DMF / ethanol (2: 1, 1 mL) was stirred at 150 ° C. for 15 minutes under microwave irradiation. Diluted with ethyl acetate, added NH silica gel and stirred. After filtration through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC. The title compound (42 mg) was obtained.
Example 10 1-{[6- (Cyclohexyloxy) pyridin-3-yl] methyl} -3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] decane -2-On
Figure JPOXMLDOC01-appb-C000039
  　 
Figure JPOXMLDOC01-appb-C000039
  　 
シクロヘキサノール（２６ｍｇ）のＮＭＰ（１ｍＬ）溶液に水素化ナトリウム（１０ｍｇ）を加え、室温で１０分撹拌した。１－［（６－ブロモピリジン－３－イル）メチル］－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン（６０ｍｇ）を加え、マイクロウェーブ照射下、２００℃で２０分撹拌した。飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した後、有機層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別の後、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル）で精製を行い、標題化合物（４０ｍｇ）を得た。
実施例１１　１－｛［６－（プロパン－２－イルアミノ）ピリジン－３－イル］メチル｝－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン Sodium hydride (10 mg) was added to a solution of cyclohexanol (26 mg) in NMP (1 mL), and the mixture was stirred at room temperature for 10 minutes. 1-[(6-Bromopyridin-3-yl) methyl] -3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] decan-2-one (60 mg ) And stirred at 200 ° C. for 20 minutes under microwave irradiation. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate) to obtain the title compound (40 mg).
Example 11 1-{[6- (propan-2-ylamino) pyridin-3-yl] methyl} -3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4. 5] Decan-2-one
Figure JPOXMLDOC01-appb-C000040
 　 
Figure JPOXMLDOC01-appb-C000040
 　 
１－［（６－ブロモピリジン－３－イル）メチル］－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン（１００ｍｇ）、イソプロピルアミン（１９ｍｇ）、Ｐｄ2（ｄｂａ）3（１１ｍｇ）、Ｘａｎｔｐｈｏｓ（１９ｍｇ）、およびナトリウムｔｅｒｔ－ブトキシド（３１ｍｇ）のトルエン（２ｍＬ）溶液を、マイクロ波照射下、１７０℃で２０分撹拌した。クロロホルムで希釈後、飽和炭酸水素ナトリウム水溶液で洗浄した。水層をクロロホルムで抽出し、有機層を水で洗浄した。有機層を減圧下濃縮した後、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル）およびＰＴＬＣ（ＮＨプレート、ヘキサン／酢酸エチル＝２：１）で精製し、標題化合物（３２ｍｇ）を得た。
実施例１２　３－［６－（モルホリン－４－イル）ピリジン－３－イル］－１－｛［６－（プロパン－２－イルオキシ）ピリジン－３－イル］メチル｝－１，３－ジアザスピロ［４．５］デカン－２－オン 1-[(6-Bromopyridin-3-yl) methyl] -3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] decan-2-one (100 mg ), Isopropylamine (19 mg), Pd 2 (dba) 3 (11 mg), Xantphos (19 mg), and sodium tert-butoxide (31 mg) in toluene (2 mL) were stirred at 170 ° C. for 20 minutes under microwave irradiation. did. After dilution with chloroform, the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted with chloroform, and the organic layer was washed with water. The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate) and PTLC (NH plate, hexane / ethyl acetate = 2: 1) to give the title compound (32 mg). .
Example 12 3- [6- (morpholin-4-yl) pyridin-3-yl] -1-{[6- (propan-2-yloxy) pyridin-3-yl] methyl} -1,3-diazaspiro [ 4.5] Decan-2-one
Figure JPOXMLDOC01-appb-C000041
  　 
Figure JPOXMLDOC01-appb-C000041
  　 
３－（６－フルオロピリジン－３－イル）－１－｛［６－（プロパン－２－イルオキシ）ピリジン－３－イル］メチル｝－１，３－ジアザスピロ［４．５］デカン－２－オン（４６ｍｇ）のＤＭＳＯ（０．５ｍＬ）溶液にモルホリン（１００ｍｇ）を加え、マイクロウェーブ照射下、２００℃で２０分撹拌した。モルホリン（１００ｍｇ）を追加し、さらに２００℃で３０分撹拌した。反応液をＤＭＳＯで希釈し、分取ＨＰＬＣで精製を行い、標題化合物（３０ｍｇ）を得た。
実施例１３　３－［６－（ジフルオロメチル）ピリジン－３－イル］－１－｛［６－（プロパン－２－イルオキシ）ピリジン－３－イル］メチル｝－１，３－ジアザスピロ［４．５］デカン－２－オン 3- (6-Fluoropyridin-3-yl) -1-{[6- (propan-2-yloxy) pyridin-3-yl] methyl} -1,3-diazaspiro [4.5] decan-2-one Morpholine (100 mg) was added to a solution of (46 mg) in DMSO (0.5 mL), and the mixture was stirred at 200 ° C. for 20 minutes under microwave irradiation. Morpholine (100 mg) was added, and the mixture was further stirred at 200 ° C. for 30 minutes. The reaction mixture was diluted with DMSO and purified by preparative HPLC to give the title compound (30 mg).
Example 13 3- [6- (Difluoromethyl) pyridin-3-yl] -1-{[6- (propan-2-yloxy) pyridin-3-yl] methyl} -1,3-diazaspiro [4.5 ] Decan-2-on
Figure JPOXMLDOC01-appb-C000042
 　 
Figure JPOXMLDOC01-appb-C000042
 　 
（１）３－（６－ブロモピリジン－３－イル）－１－｛［６－（プロパン－２－イルオキシ）ピリジン－３－イル］メチル｝－１，３－ジアザスピロ［４．５］デカン－２－オン（４００ｍｇ）のＤＭＦ－エタノール（２：１、５ｍＬ）溶液にＰｄ（ＰＰｈ3）4（１００ｍｇ）、および炭酸カリウム（１８０ｍｇ）を加え、系内を一酸化炭素ガスで置換し、１００℃で３時間撹拌した。水を加え、酢酸エチルで抽出した後、有機層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別の後、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル）で精製を行い、５－（２－オキソ－１－｛［６－（プロパン－２－イルオキシ）ピリジン－３－イル］メチル｝－１，３－ジアザスピロ［４．５］デカ－３－イル）ピリジン－２－カルボン酸メチル（３７５ｍｇ）を得た。
（２）５－（２－オキソ－１－｛［６－（プロパン－２－イルオキシ）ピリジン－３－イル］メチル｝－１，３－ジアザスピロ［４．５］デカ－３－イル）ピリジン－２－カルボン酸メチル（８９ｍｇ）のＴＨＦ（２ｍＬ）溶液を氷冷し、水素化アルミニウムリチウム（８ｍｇ）を加え、１時間撹拌した。１０％水酸化ナトリウム水溶液（０．５ｍＬ）を加え、室温で１時間撹拌した。無水硫酸マグネシウムで乾燥した後、乾燥剤をろ別し、ろ液を減圧下濃縮した。残渣を分取ＨＰＬＣで精製し、３－［６－（ヒドロキシメチル）ピリジン－３－イル］－１－｛［６－（プロパン－２－イルオキシ）ピリジン－３－イル］メチル｝－１，３－ジアザスピロ［４．５］デカン－２－オン（２４ｍｇ）を得た。
(ESI pos.) m/z : 411（［Ｍ+H］+）
（３）３－［６－（ヒドロキシメチル）ピリジン－３－イル］－１－｛［６－（プロパン－２－イルオキシ）ピリジン－３－イル］メチル｝－１，３－ジアザスピロ［４．５］デカン－２－オン（１３０ｍｇ）のＤＭＳＯ（２ｍＬ）溶液に２－ヨードキシ安息香酸（１０８ｍｇ）を加え、室温で２時間撹拌した。２－ヨードキシ安息香酸（８０ｍｇ）を追加し、さらに２時間撹拌した。水、酢酸エチルを加え、不溶物をセライトでろ去した。ろ液を酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別後、ろ液を減圧濃縮した。残渣をクロロホルム（２ｍＬ）に溶かし、氷冷下ビス（２－メトキシエチル）アミノ硫黄　三フッ化物（０．２５ｍＬ）を加えた。室温で２時間撹拌した後、水を加え、クロロホルムで抽出した。有機層を水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別の後、ろ液を減圧下濃縮し、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル）で精製した。標題化合物（６２ｍｇ）を得た。
実施例１４　３－［６－（フルオロメチル）ピリジン－３－イル］－１－｛［６－（プロパン－２－イルオキシ）ピリジン－３－イル］メチル｝－１，３－ジアザスピロ［４．５］デカン－２－オン (1) 3- (6-Bromopyridin-3-yl) -1-{[6- (propan-2-yloxy) pyridin-3-yl] methyl} -1,3-diazaspiro [4.5] decane- Pd (PPh 3 ) 4 (100 mg) and potassium carbonate (180 mg) were added to a solution of 2-one (400 mg) in DMF-ethanol (2: 1, 5 mL), and the system was replaced with carbon monoxide gas. Stir at 0 ° C. for 3 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate) to give 5- (2-oxo-1-{[6- (propan-2-yloxy) pyridin-3-yl] methyl} -1, Methyl 3-diazaspiro [4.5] dec-3-yl) pyridine-2-carboxylate (375 mg) was obtained.
(2) 5- (2-oxo-1-{[6- (propan-2-yloxy) pyridin-3-yl] methyl} -1,3-diazaspiro [4.5] dec-3-yl) pyridine- A solution of methyl 2-carboxylate (89 mg) in THF (2 mL) was ice-cooled, lithium aluminum hydride (8 mg) was added, and the mixture was stirred for 1 hr. 10% Aqueous sodium hydroxide solution (0.5 mL) was added, and the mixture was stirred at room temperature for 1 hr. After drying over anhydrous magnesium sulfate, the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 3- [6- (hydroxymethyl) pyridin-3-yl] -1-{[6- (propan-2-yloxy) pyridin-3-yl] methyl} -1,3 -Diazaspiro [4.5] decan-2-one (24 mg) was obtained.
(ESI pos.) M / z: 411 ([M + H] +)
(3) 3- [6- (Hydroxymethyl) pyridin-3-yl] -1-{[6- (propan-2-yloxy) pyridin-3-yl] methyl} -1,3-diazaspiro [4.5 2-iodoxybenzoic acid (108 mg) was added to a solution of decan-2-one (130 mg) in DMSO (2 mL), and the mixture was stirred at room temperature for 2 hours. 2-iodoxybenzoic acid (80 mg) was added, and the mixture was further stirred for 2 hours. Water and ethyl acetate were added, and the insoluble material was filtered off through celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform (2 mL), and bis (2-methoxyethyl) aminosulfur trifluoride (0.25 mL) was added under ice cooling. After stirring at room temperature for 2 hours, water was added and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate). The title compound (62 mg) was obtained.
Example 14 3- [6- (Fluoromethyl) pyridin-3-yl] -1-{[6- (propan-2-yloxy) pyridin-3-yl] methyl} -1,3-diazaspiro [4.5 ] Decan-2-on
Figure JPOXMLDOC01-appb-C000043
  　 
Figure JPOXMLDOC01-appb-C000043
  　 
５－（２－オキソ－１－｛［６－（プロパン－２－イルオキシ）ピリジン－３－イル］メチル｝－１，３－ジアザスピロ［４．５］デカ－３－イル）ピリジン－２－カルボン酸メチル（１５０ｍｇ）のＴＨＦ（２ｍＬ）溶液に水素化ホウ素リチウム（３０ｍｇ）を加え、室温で２時間撹拌した。飽和塩化アンモニウム水溶液を加え、室温で１時間撹拌した。酢酸エチルで抽出した後、飽和炭酸水素ナトリウム水溶液、および飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別後、ろ液を減圧下濃縮した。残渣をクロロホルム（３ｍＬ）に溶解し、氷冷下ビス（２－メトキシエチル）アミノ硫黄　三フッ化物（０．２５ｍＬ）を加え、室温で１時間撹拌した。飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別の後、ろ液を減圧下濃縮した。残渣を分取ＨＰＬＣおよびカラムクロマトグラフィー（ＮＨカートリッジ、ヘキサン／酢酸エチル）で精製し、標題化合物（２５ｍｇ）を得た。
実施例１５　３－［６－（１，１－ジフルオロエチル）ピリジン－３－イル］－１－｛［６－（プロパン－２－イルオキシ）ピリジン－３－イル］メチル｝－１，３－ジアザスピロ［４．５］デカン－２－オン 5- (2-oxo-1-{[6- (propan-2-yloxy) pyridin-3-yl] methyl} -1,3-diazaspiro [4.5] dec-3-yl) pyridine-2-carvone To a solution of methyl acid (150 mg) in THF (2 mL) was added lithium borohydride (30 mg), and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added and stirred at room temperature for 1 hour. After extraction with ethyl acetate, the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform (3 mL), bis (2-methoxyethyl) aminosulfur trifluoride (0.25 mL) was added under ice cooling, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added, extracted with chloroform, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC and column chromatography (NH cartridge, hexane / ethyl acetate) to give the title compound (25 mg).
Example 15 3- [6- (1,1-Difluoroethyl) pyridin-3-yl] -1-{[6- (propan-2-yloxy) pyridin-3-yl] methyl} -1,3-diazaspiro [4.5] Decan-2-one
Figure JPOXMLDOC01-appb-C000044
  　 
Figure JPOXMLDOC01-appb-C000044
  　 
（１）３－（６－ブロモピリジン－３－イル）－１－｛［６－（プロパン－２－イルオキシ）ピリジン－３－イル］メチル｝－１，３－ジアザスピロ［４．５］デカン－２－オン（２００ｍｇ）、トリブチル（１－エトキシビニル）スズ（１８６ｍｇ）、ＰｄＣｌ2（ＰＰｈ3）2（３０ｍｇ）、およびヨウ化銅（Ｉ）（８ｍｇ）のアセトニトリル（２ｍＬ）溶液を、マイクロ波照射下、１５０℃で２０分撹拌した。飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した後、水、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥し、乾燥剤をろ別後、ろ液を減圧濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル）にて精製を行い、黄色油状物を得た。これを１，４－ジオキサン（２ｍＬ）に溶かし、１Ｍ塩酸（２ｍＬ）を加え一晩撹拌した。飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出し無水硫酸マグネシウムで乾燥した。乾燥剤をろ別の後、ろ液を減圧下濃縮した。残渣を分取ＨＰＬＣで精製し、３－（６－アセチルピリジン－３－イル）－１－｛［６－（プロパン－２－イルオキシ）ピリジン－３－イル］メチル｝－１，３－ジアザスピロ［４．５］デカン－２－オン（１０１ｍｇ）を得た。
（２）３－（６－アセチルピリジン－３－イル）－１－｛［６－（プロパン－２－イルオキシ）ピリジン－３－イル］メチル｝－１，３－ジアザスピロ［４．５］デカン－２－オン（９０ｍｇ）のクロロホルム（２ｍＬ）溶液を氷冷し、ビス（２－メトキシエチル）アミノ硫黄　三フッ化物（０．１５ｍＬ）を加え、室温で２時間撹拌した。ジエチルアミノ硫黄三フッ化物（０．１１ｍＬ）を加え、１時間撹拌した。６０℃に加熱し、さらに４時間撹拌した。水を加え、クロロホルムで抽出し、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別後、ろ液を減圧下濃縮した。残渣を分取ＨＰＬＣおよびＰＴＬＣ（ＮＨプレート、ヘキサン／酢酸エチル＝２：１）で精製し、標題化合物（２７ｍｇ）を得た。
実施例１６　３－［６－（ジフルオロメトキシ）ピリジン－３－イル］－１－｛［６－（プロパン－２－イルオキシ）ピリジン－３－イル］メチル｝－１，３－ジアザスピロ［４．５］デカン－２－オンおよび３－［１－（ジフルオロメチル）－６－オキソ－１，６－ジヒドロピリジン－３－イル］－１－｛［６－（プロパン－２－イルオキシ）ピリジン－３－イル］メチル｝－１，３－ジアザスピロ［４．５］デカン－２－オン (1) 3- (6-Bromopyridin-3-yl) -1-{[6- (propan-2-yloxy) pyridin-3-yl] methyl} -1,3-diazaspiro [4.5] decane- A solution of 2-one (200 mg), tributyl (1-ethoxyvinyl) tin (186 mg), PdCl 2 (PPh 3 ) 2 (30 mg), and copper (I) iodide (8 mg) in acetonitrile (2 mL) was microwaved. The mixture was stirred at 150 ° C. for 20 minutes under irradiation. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate, and then washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate) to give a yellow oil. This was dissolved in 1,4-dioxane (2 mL), 1M hydrochloric acid (2 mL) was added, and the mixture was stirred overnight. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 3- (6-acetylpyridin-3-yl) -1-{[6- (propan-2-yloxy) pyridin-3-yl] methyl} -1,3-diazaspiro [ 4.5] Decan-2-one (101 mg) was obtained.
(2) 3- (6-Acetylpyridin-3-yl) -1-{[6- (propan-2-yloxy) pyridin-3-yl] methyl} -1,3-diazaspiro [4.5] decane- A solution of 2-one (90 mg) in chloroform (2 mL) was ice-cooled, bis (2-methoxyethyl) aminosulfur trifluoride (0.15 mL) was added, and the mixture was stirred at room temperature for 2 hr. Diethylamino sulfur trifluoride (0.11 mL) was added and stirred for 1 hour. The mixture was heated to 60 ° C. and further stirred for 4 hours. Water was added, extracted with chloroform, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC and PTLC (NH plate, hexane / ethyl acetate = 2: 1) to give the title compound (27 mg).
Example 16 3- [6- (Difluoromethoxy) pyridin-3-yl] -1-{[6- (propan-2-yloxy) pyridin-3-yl] methyl} -1,3-diazaspiro [4.5 ] Decan-2-one and 3- [1- (difluoromethyl) -6-oxo-1,6-dihydropyridin-3-yl] -1-{[6- (propan-2-yloxy) pyridin-3-yl ] Methyl} -1,3-diazaspiro [4.5] decan-2-one
Figure JPOXMLDOC01-appb-C000045
  　 
Figure JPOXMLDOC01-appb-C000045
  　 
（１）３－（６－メトキシピリジン－３－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン（１．２５ｇ）の酢酸（５ｍＬ）溶液に３０％臭化水素／酢酸溶液（１０ｍＬ）を加え、１００℃で２時間撹拌した。臭化水素／酢酸溶液（１０ｍＬ）を追加し、さらに１００℃で１時間撹拌した。飽和炭酸水素ナトリウム水溶液で中和し、酢酸エチルで抽出の後、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別後、ろ液を減圧濃縮し、トルエンで共沸した。３－（６－オキソ－１，６－ジヒドロピリジン－３－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン（１，０９ｇ）を得た。
(ESI pos.) m/z : 248（［Ｍ+H］+）
（２）３－（６－オキソ－１，６－ジヒドロピリジン－３－イル）－１，３－ジアザスピロ［４．５］デカン－２－オン（２００ｍｇ）のＤＭＦ／水混合溶液（１０：１、５ｍＬ）に炭酸カリウム、クロロジフルオロ酢酸ナトリウム（０．２４ｇ）を加え、室温で撹拌した。水を加え、クロロホルムで抽出した後、減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、クロロホルム／メタノール）で精製を行い、無色固体（４９ｍｇ）を得た。これは２種類の化合物の混合物であった。
（３）上記（２）で得られた混合物をＤＭＦ（２ｍＬ）に溶かし、水素化ナトリウム（１０ｍｇ）を加え、室温で撹拌した。５－（ブロモメチル）－２－（プロパン－２－イルオキシ）ピリジン（７０ｍｇ）を加え、室温で２日間撹拌した。飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出の後、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別後、ろ液を減圧下乾燥した。残渣を分取ＨＰＬＣで精製し、３－［６－（ジフルオロメトキシ）ピリジン－３－イル］－１－｛［６－（プロパン－２－イルオキシ）ピリジン－３－イル］メチル｝－１，３－ジアザスピロ［４．５］デカン－２－オン（３８ｍｇ）および３－［１－（ジフルオロメチル）－６－オキソ－１，６－ジヒドロピリジン－３－イル］－１－｛［６－（プロパン－２－イルオキシ）ピリジン－３－イル］メチル｝－１，３－ジアザスピロ［４．５］デカン－２－オン（２．３ｍｇ）を得た。
実施例１７　１－［（５－プロポキシピリジン－３－イル）メチル］－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン　塩酸塩 (1) 30% Hydrogen bromide / acetic acid in a solution of 3- (6-methoxypyridin-3-yl) -1,3-diazaspiro [4.5] decan-2-one (1.25 g) in acetic acid (5 mL) The solution (10 mL) was added and stirred at 100 ° C. for 2 hours. A hydrogen bromide / acetic acid solution (10 mL) was added, and the mixture was further stirred at 100 ° C. for 1 hr. The mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure and azeotroped with toluene. 3- (6-Oxo-1,6-dihydropyridin-3-yl) -1,3-diazaspiro [4.5] decan-2-one (1,09 g) was obtained.
(ESI pos.) M / z: 248 ([M + H] +)
(2) DMF / water mixed solution (10: 1, 3- (6-oxo-1,6-dihydropyridin-3-yl) -1,3-diazaspiro [4.5] decan-2-one (200 mg) 5 mL) was added potassium carbonate and sodium chlorodifluoroacetate (0.24 g), and the mixture was stirred at room temperature. Water was added, the mixture was extracted with chloroform, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, chloroform / methanol) to obtain a colorless solid (49 mg). This was a mixture of two compounds.
(3) The mixture obtained in (2) above was dissolved in DMF (2 mL), sodium hydride (10 mg) was added, and the mixture was stirred at room temperature. 5- (Bromomethyl) -2- (propan-2-yloxy) pyridine (70 mg) was added, and the mixture was stirred at room temperature for 2 days. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was dried under reduced pressure. The residue was purified by preparative HPLC to give 3- [6- (difluoromethoxy) pyridin-3-yl] -1-{[6- (propan-2-yloxy) pyridin-3-yl] methyl} -1,3 -Diazaspiro [4.5] decan-2-one (38 mg) and 3- [1- (difluoromethyl) -6-oxo-1,6-dihydropyridin-3-yl] -1-{[6- (propane- 2-yloxy) pyridin-3-yl] methyl} -1,3-diazaspiro [4.5] decan-2-one (2.3 mg) was obtained.
Example 17 1-[(5-propoxypyridin-3-yl) methyl] -3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] decane-2- On hydrochloride
Figure JPOXMLDOC01-appb-C000046
  　 
Figure JPOXMLDOC01-appb-C000046
  　 
（１）（５－プロポキシピリジン－３－イル）メタノール（１３０ｍｇ）のＤＭＳＯ（５ｍＬ）溶液に２－ヨードキシ安息香酸（２６０ｍｇ）を加え、３時間撹拌した。水、酢酸エチルを加え撹拌し、不溶物をろ去した。ろ液を酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤をろ別後、ろ液を減圧下濃縮した。残渣をクロロホルム（３ｍＬ）に溶かし、Ｎ－［（１－アミノシクロヘキシル）メチル］－６－（トリフルオロメチル）ピリジン－３－アミン（２００ｍｇ）、水素化トリアセトキシホウ素ナトリウム（１６５ｍｇ）を加え、室温で１時間撹拌した。水素化トリアセトキシホウ素ナトリウム（２００ｍｇ）を追加し、さらに一晩撹拌した。飽和炭酸水素ナトリウム水溶液を加え、有機層を無水硫酸マグネシウムで乾燥した。乾燥剤をろ別し、ろ液を減圧下濃縮した後、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル）で精製し、Ｎ－［（１－｛［（５－プロポキシピリジン－３－イル）メチル］アミノ｝シクロヘキシル）メチル］－６－（トリフルオロメチル）ピリジン－３－アミン（１８５ｍｇ）を得た。
(ESI pos.) m/z : 423（［Ｍ+H］+）
（２）Ｎ－［（１－｛［（５－プロポキシピリジン－３－イル）メチル］アミノ｝シクロヘキシル）メチル］－６－（トリフルオロメチル）ピリジン－３－アミン（１５０ｍｇ）のＴＨＦ（３ｍＬ）溶液にトリエチルアミン（０．２ｍＬ）を加え、氷冷し、トリホスゲン（４３ｍｇ）を加えた。室温で１時間撹拌した後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。無水硫酸マグネシウムで乾燥した後、乾燥剤をろ別し、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル）で精製し、油状物を得た。これを酢酸エチルに溶かし、４Ｍ塩酸／酢酸エチルを加え、溶媒を減圧下濃縮し、標題化合物（１００ｍｇ）を得た。
実施例１８　３－（５－クロロピリミジン－２－イル）－１－［（３－プロポキシ－１，２－オキサゾール－５－イル）メチル］－１，３－ジアザスピロ［４．５］デカン－２－オン (1) To a solution of (5-propoxypyridin-3-yl) methanol (130 mg) in DMSO (5 mL) was added 2-iodoxybenzoic acid (260 mg), and the mixture was stirred for 3 hours. Water and ethyl acetate were added and stirred, and the insoluble material was removed by filtration. The filtrate was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform (3 mL), N-[(1-aminocyclohexyl) methyl] -6- (trifluoromethyl) pyridin-3-amine (200 mg), sodium triacetoxyborohydride (165 mg) were added, and room temperature was added. For 1 hour. Sodium triacetoxyborohydride (200 mg) was added, and the mixture was further stirred overnight. A saturated aqueous sodium hydrogen carbonate solution was added, and the organic layer was dried over anhydrous magnesium sulfate. After the desiccant was filtered off and the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate), and N-[(1-{[(5-propoxypyridine-3- Yl) methyl] amino} cyclohexyl) methyl] -6- (trifluoromethyl) pyridin-3-amine (185 mg).
(ESI pos.) M / z: 423 ([M + H] +)
(2) N-[(1-{[(5-propoxypyridin-3-yl) methyl] amino} cyclohexyl) methyl] -6- (trifluoromethyl) pyridin-3-amine (150 mg) in THF (3 mL) Triethylamine (0.2 mL) was added to the solution, ice-cooled, and triphosgene (43 mg) was added. After stirring at room temperature for 1 hour, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate) to give an oil. This was dissolved in ethyl acetate, 4M hydrochloric acid / ethyl acetate was added, and the solvent was concentrated under reduced pressure to obtain the title compound (100 mg).
Example 18 3- (5-Chloropyrimidin-2-yl) -1-[(3-propoxy-1,2-oxazol-5-yl) methyl] -1,3-diazaspiro [4.5] decane-2 -on
Figure JPOXMLDOC01-appb-C000047
  　 
Figure JPOXMLDOC01-appb-C000047
  　 
１－［（３－プロポキシ－１，２－オキサゾール－５－イル）メチル］－１，３－ジアザスピロ［４．５］デカン－２－オン（５０ｍｇ）および２－ヨード－５－クロロピリミジン（６１ｍｇ）、Ｐｄ2（ｄｂａ）3（１６ｍｇ）、Ｘａｎｔｐｈｏｓ（１７ｍｇ）、ナトリウムｔｅｒｔ－ブトキシド（５ｍｇ）のトルエン（１ｍＬ）溶液を、マイクロ波照射下、１８０℃で１０分撹拌した。ＮＨカートリッジを通した後、カラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル）および分取ＨＰＬＣで精製を行い、標題化合物（１０ｍｇ）を得た。
実施例１９　１－［（１－メチル－２－フェニル－１Ｈ－イミダゾール－４－イル）メチル］－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン 1-[(3-propoxy-1,2-oxazol-5-yl) methyl] -1,3-diazaspiro [4.5] decan-2-one (50 mg) and 2-iodo-5-chloropyrimidine (61 mg ), Pd 2 (dba) 3 (16 mg), Xantphos (17 mg), sodium tert-butoxide (5 mg) in toluene (1 mL) was stirred at 180 ° C. for 10 minutes under microwave irradiation. After passing through an NH cartridge, purification was performed by column chromatography (silica gel cartridge, hexane / ethyl acetate) and preparative HPLC to obtain the title compound (10 mg).
Example 19 1-[(1-Methyl-2-phenyl-1H-imidazol-4-yl) methyl] -3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4 .5] Decan-2-one
Figure JPOXMLDOC01-appb-C000048
  　 
Figure JPOXMLDOC01-appb-C000048
  　 
３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン（１００ｍｇ）、（１－メチル－２－フェニル－１Ｈ－イミダゾール－４－イル）メタノール（１７０ｍｇ）、およびシアノメチレントリ－Ｎ－ブチルホスホラン（１３０ｍｇ）のトルエン（２ｍＬ）溶液を、封管中、１５０℃で４時間撹拌した。反応液をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル）およびＰＴＬＣ（ヘキサン／酢酸エチル＝３：１）で精製を行い、標題化合物（９２ｍｇ）を得た。
実施例２０　１－｛［１－（ピリジン－２－イル）－１Ｈ－ピラゾール－４－イル］メチル｝－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン 3- [6- (Trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] decan-2-one (100 mg), (1-methyl-2-phenyl-1H-imidazole-4 A solution of -yl) methanol (170 mg) and cyanomethylenetri-N-butylphosphorane (130 mg) in toluene (2 mL) was stirred at 150 ° C. for 4 hours in a sealed tube. The reaction solution was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate) and PTLC (hexane / ethyl acetate = 3: 1) to obtain the title compound (92 mg).
Example 20 1-{[1- (Pyridin-2-yl) -1H-pyrazol-4-yl] methyl} -3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] Decan-2-one
Figure JPOXMLDOC01-appb-C000049
  　 
Figure JPOXMLDOC01-appb-C000049
  　 
１－（１Ｈ－ピラゾール－４－イルメチル）－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン（５０ｍｇ）、２－ブロモピリジン（３１ｍｇ）、トランス－１，２－ビス（メチルアミノ）シクロヘキサン（３ｍｇ）、ヨウ化銅（Ｉ）（３ｍｇ）、および炭酸セシウム（６５ｍｇ）の１，４－ジオキサン（１ｍＬ）溶液を、封管中、１２０℃で１時間撹拌した。反応液をＰＴＬＣ（ヘキサン／酢酸エチル＝３：１）で精製し、標題化合物（４２ｍｇ）を得た。
実施例２１　１－｛［１－（プロパン－２－イル）－１Ｈ－ピラゾール－４－イル］メチル｝－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン 1- (1H-pyrazol-4-ylmethyl) -3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] decan-2-one (50 mg), 2- A solution of bromopyridine (31 mg), trans-1,2-bis (methylamino) cyclohexane (3 mg), copper (I) iodide (3 mg), and cesium carbonate (65 mg) in 1,4-dioxane (1 mL) was added. It stirred at 120 degreeC in the sealed tube for 1 hour. The reaction solution was purified by PTLC (hexane / ethyl acetate = 3: 1) to obtain the title compound (42 mg).
Example 21 1-{[1- (propan-2-yl) -1H-pyrazol-4-yl] methyl} -3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] Decan-2-one
Figure JPOXMLDOC01-appb-C000050
  　 
Figure JPOXMLDOC01-appb-C000050
  　 
１－（１Ｈ－ピラゾール－４－イルメチル）－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン（５０ｍｇ）のＤＭＦ（１ｍＬ）溶液に水素化ナトリウム（７ｍｇ）を加え、室温で５分撹拌した。２－ヨードプロパン（３５ｍｇ）を加え、室温で１時間撹拌した。減圧下溶媒を留去し、ＰＴＬＣ（シリカゲル、ヘキサン／酢酸エチル＝３：１）で精製し、標題化合物（３２ｍｇ）を得た。
実施例２２　１－｛［６－（エトキシメチル）ピリジン－３－イル］メチル｝－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン 1- (1H-pyrazol-4-ylmethyl) -3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] decan-2-one (50 mg) in DMF ( To the solution was added sodium hydride (7 mg), and the mixture was stirred at room temperature for 5 minutes. 2-Iodopropane (35 mg) was added and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by PTLC (silica gel, hexane / ethyl acetate = 3: 1) to obtain the title compound (32 mg).
Example 22 1-{[6- (Ethoxymethyl) pyridin-3-yl] methyl} -3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] decane -2-On
Figure JPOXMLDOC01-appb-C000051
  　 
Figure JPOXMLDOC01-appb-C000051
  　 
（１）５－（｛２－オキソ－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカ－１－イル｝メチル）ピリジン－２－カルボン酸メチル（１７０ｍｇ）のＴＨＦ（３ｍＬ）溶液に水素化ホウ素リチウム（２５ｍｇ）を加え、室温で一晩撹拌した。飽和塩化アンモニウムを加え、酢酸エチルで抽出した後、有機層を水および飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥した後、乾燥剤をろ別し、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル～クロロホルム／メタノールで精製し、１－｛［６－（ヒドロキシメチル）ピリジン－３－イル］メチル｝－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン（８８ｍｇ）を得た。
(ESI pos.) m/z : 443（［Ｍ+Na］+）
（２）１－｛［６－（ヒドロキシメチル）ピリジン－３－イル］メチル｝－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン（８０ｍｇ）のＤＭＦ（２ｍＬ）溶液に水素化ナトリウム（１２ｍｇ）を加え、室温で１０分撹拌した。ヨウ化エチル（０．０３ｍＬ）を加え、室温で２時間撹拌した。酢酸エチルで希釈し、飽和炭酸水素ナトリウム水溶液、水、および飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥した後、乾燥剤をろ別し、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル）で精製し、標題化合物（４７ｍｇ）を得た。
実施例２３　１－（１Ｈ－ベンゾイミダゾール－２－イルメチル）－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン (1) 5-({2-oxo-3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] dec-1-yl} methyl) pyridine-2- To a solution of methyl carboxylate (170 mg) in THF (3 mL) was added lithium borohydride (25 mg), and the mixture was stirred overnight at room temperature. After adding saturated ammonium chloride and extracting with ethyl acetate, the organic layer was washed with water and saturated brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate to chloroform / methanol, 1-{[6- (hydroxymethyl) pyridin-3-yl] methyl} -3- [6- (trifluoromethyl) Pyridin-3-yl] -1,3-diazaspiro [4.5] decan-2-one (88 mg) was obtained.
(ESI pos.) M / z: 443 ([M + Na] +)
(2) 1-{[6- (hydroxymethyl) pyridin-3-yl] methyl} -3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] decane Sodium hydride (12 mg) was added to a solution of -2-one (80 mg) in DMF (2 mL), and the mixture was stirred at room temperature for 10 minutes. Ethyl iodide (0.03 mL) was added and stirred at room temperature for 2 hours. Dilute with ethyl acetate and wash with saturated aqueous sodium bicarbonate, water, and saturated brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate) to give the title compound (47 mg).
Example 23 1- (1H-Benzimidazol-2-ylmethyl) -3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] decan-2-one
Figure JPOXMLDOC01-appb-C000052
  　 
Figure JPOXMLDOC01-appb-C000052
  　 
３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン（１００ｍｇ）のＤＭＦ（５ｍＬ）溶液に水素化ナトリウム（６０％、４０ｍｇ）を加え、３０分撹拌した。２－（クロロメチル）－１－（テトラヒドロ－２Ｈ－ピラン－２－イル）－１Ｈ－ベンゾイミダゾール（１２６ｍｇ）を加え、２時間撹拌した。水を加え、クロロホルムで抽出した後、有機層を飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、乾燥剤をろ別し、ろ液を減圧下濃縮した。残渣をメタノール（５ｍＬ）に溶解し、ｐ－トルエンスルホン酸一水和物（１００ｍｇ）を加え、１１０℃で一晩撹拌した。水を加え、クロロホルムで抽出した後、有機層を飽和食塩水で洗浄した。
無水硫酸ナトリウムで乾燥した後、乾燥剤をろ別し、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル）で精製し、標題化合物（３７ｍｇ）を得た。
実施例２４　１－［（１－オキシド－５－プロポキシピリジン－２－イル）メチル］－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン To a solution of 3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] decan-2-one (100 mg) in DMF (5 mL) was added sodium hydride (60%, 40 mg). ) Was added and stirred for 30 minutes. 2- (Chloromethyl) -1- (tetrahydro-2H-pyran-2-yl) -1H-benzimidazole (126 mg) was added and stirred for 2 hours. After adding water and extracting with chloroform, the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (5 mL), p-toluenesulfonic acid monohydrate (100 mg) was added, and the mixture was stirred at 110 ° C. overnight. After adding water and extracting with chloroform, the organic layer was washed with saturated brine.
After drying over anhydrous sodium sulfate, the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate) to give the title compound (37 mg).
Example 24 1-[(1-Oxido-5-propoxypyridin-2-yl) methyl] -3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] Decan-2-on
Figure JPOXMLDOC01-appb-C000053
  　 
Figure JPOXMLDOC01-appb-C000053
  　 
１－［（５－プロポキシピリジン－２－イル）メチル］－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン（５０ｍｇ）のクロロホルム（２ｍＬ）溶液にメタクロロ過安息香酸（７０％、３６ｍｇ）を加え、室温で１６時間撹拌した。水酸化ナトリウム水溶液を加え、クロロホルムで抽出し、有機層を水および飽和食塩水で洗浄した。無水硫酸ナトリウムで乾燥した後、乾燥剤をろ別し、ろ液を減圧下濃縮した。残渣をカラムクロマトグラフィー（ヘキサン／酢酸エチル～酢酸エチル／メタノール）で精製し、標題化合物（４０ｍｇ）を得た。
実施例２５　１－｛［３－（２－ヒドロキシエトキシ）－１，２－オキサゾール－５－イル］メチル｝－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン 1-[(5-propoxypyridin-2-yl) methyl] -3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] decan-2-one (50 mg ) In chloroform (2 mL) was added metachloroperbenzoic acid (70%, 36 mg) and stirred at room temperature for 16 hours. Aqueous sodium hydroxide was added, extracted with chloroform, and the organic layer was washed with water and saturated brine. After drying over anhydrous sodium sulfate, the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (hexane / ethyl acetate to ethyl acetate / methanol) to give the title compound (40 mg).
Example 25 1-{[3- (2-Hydroxyethoxy) -1,2-oxazol-5-yl] methyl} -3- [6- (trifluoromethyl) pyridin-3-yl] -1,3- Diazaspiro [4.5] decan-2-one
Figure JPOXMLDOC01-appb-C000054
  　 
Figure JPOXMLDOC01-appb-C000054
  　 
１－｛［３－（２－｛［ｔｅｒｔ－ブチル（ジメチル）シリル］オキシ｝エトキシ）－１，２－オキサゾール－５－イル］メチル｝－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン（３９ｍｇ）のＴＨＦ（１ｍＬ）溶液にフッ化テトラブチルアンモニウム（１．０Ｍ／ＴＨＦ溶液、０．０８ｍＬ）を加え、室温でおよそ３日間撹拌した。溶媒を減圧下留去した後、残渣をカラムクロマトグラフィー（シリカゲルカートリッジ、ヘキサン／酢酸エチル）で精製し、標題化合物（３０ｍｇ）を得た。
実施例２６　１－｛［３－（３，３－ジフルオロプロポキシ）－１，２－オキサゾール－５－イル］メチル｝－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン 1-{[3- (2-{[tert-Butyl (dimethyl) silyl] oxy} ethoxy) -1,2-oxazol-5-yl] methyl} -3- [6- (trifluoromethyl) pyridine-3 -Il] -1,3-diazaspiro [4.5] decan-2-one (39 mg) in THF (1 mL) was added tetrabutylammonium fluoride (1.0 M / THF solution, 0.08 mL) at room temperature. For about 3 days. After the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (silica gel cartridge, hexane / ethyl acetate) to obtain the title compound (30 mg).
Example 26 1-{[3- (3,3-Difluoropropoxy) -1,2-oxazol-5-yl] methyl} -3- [6- (trifluoromethyl) pyridin-3-yl] -1, 3-Diazaspiro [4.5] decan-2-one
Figure JPOXMLDOC01-appb-C000055
  　 
Figure JPOXMLDOC01-appb-C000055
  　 
（１）実施例２５と同様の操作により、１－｛［３－（３－｛［ｔｅｒｔ－ブチル（ジメチル）シリル］オキシ｝プロポキシ）－１，２－オキサゾール－５－イル］メチル｝－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン（１１２ｍｇ）から、１－｛［３－（３－ヒドロキシプロポキシ）－１，２－オキサゾール－５－イル］メチル｝－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン（８７ｍｇ）を得た。
(ESI pos.) m/z : 455（［Ｍ+Ｈ］+）
1H NMR (500 MHz, CHLOROFORM-d) d ppm 1.10 - 1.24 (m, 1 H), 1.32 - 1.47 (m, 2 H), 1.61 - 1.92 (m, 7 H), 1.97 - 2.04 (m, 2 H), 3.71 (s, 2 H), 3.74 - 3.81 (m, 2 H), 4.38 (t, J=6.1 Hz, 2 H), 4.42 (s, 2 H), 5.91 (s, 1 H), 7.64 (d, J=8.8 Hz, 1 H), 8.30 - 8.41 (m, 1 H), 8.65 - 8.75 (m, 1 H)
（２）実施例１３の工程（３）と同様の操作により、１－｛［３－（３－ヒドロキシプロポキシ）－１，２－オキサゾール－５－イル］メチル｝－３－［６－（トリフルオロメチル）ピリジン－３－イル］－１，３－ジアザスピロ［４．５］デカン－２－オン（４３ｍｇ）から、標題化合物（３．７ｍｇ）を得た。 (1) In the same manner as in Example 25, 1-{[3- (3-{[tert-butyl (dimethyl) silyl] oxy} propoxy) -1,2-oxazol-5-yl] methyl} -3 From [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] decan-2-one (112 mg) to 1-{[3- (3-hydroxypropoxy) -1 , 2-Oxazol-5-yl] methyl} -3- [6- (trifluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] decan-2-one (87 mg) was obtained. .
(ESI pos.) M / z: 455 ([M + H] +)
1H NMR (500 MHz, CHLOROFORM-d) d ppm 1.10-1.24 (m, 1 H), 1.32-1.47 (m, 2 H), 1.61-1.92 (m, 7 H), 1.97-2.04 (m, 2 H ), 3.71 (s, 2 H), 3.74-3.81 (m, 2 H), 4.38 (t, J = 6.1 Hz, 2 H), 4.42 (s, 2 H), 5.91 (s, 1 H), 7.64 (d, J = 8.8 Hz, 1 H), 8.30-8.41 (m, 1 H), 8.65-8.75 (m, 1 H)
(2) 1-{[3- (3-Hydroxypropoxy) -1,2-oxazol-5-yl] methyl} -3- [6- (tri The title compound (3.7 mg) was obtained from (fluoromethyl) pyridin-3-yl] -1,3-diazaspiro [4.5] decan-2-one (43 mg).
　実施例１から２６で示した化合物と、同様の方法で合成した化合物の構造式とそれらの機器データを表１－１、表１－２、及び表２－１から２－２４に示した。表中の実施例の欄に記載された数字は、その化合物が上記実施例１から２６の内、どの実施例と同様な方法で合成されたかを示したものである。また、塩の欄が空欄になっている化合物はフリー体であることを示す。 Table 1-1, Table 1-2, and Tables 2-1 to 2-24 show the structural formulas of the compounds shown in Examples 1 to 26 and the compounds synthesized by the same method and their instrument data. The numbers described in the column of the examples in the table indicate which of the above Examples 1 to 26 was synthesized by the same method as in the above Examples. A compound in which the salt column is blank indicates a free form.
Figure JPOXMLDOC01-appb-T000056
  　 
Figure JPOXMLDOC01-appb-T000056
  　 
Figure JPOXMLDOC01-appb-T000057
  　 
Figure JPOXMLDOC01-appb-T000057
  　 
　化合物１４～３０２は、下記式［ＩＩ］で表される構造を有する化合物である。 Compounds 14 to 302 are compounds having a structure represented by the following formula [II].
Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000058
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
   　 
Figure JPOXMLDOC01-appb-T000071
   　 
Figure JPOXMLDOC01-appb-T000071
   　 
Figure JPOXMLDOC01-appb-T000072
   　 
Figure JPOXMLDOC01-appb-T000072
   　 
Figure JPOXMLDOC01-appb-T000073
   　 
Figure JPOXMLDOC01-appb-T000073
   　 
Figure JPOXMLDOC01-appb-T000074
   　 
Figure JPOXMLDOC01-appb-T000074
   　 
Figure JPOXMLDOC01-appb-T000075
   　 
Figure JPOXMLDOC01-appb-T000075
   　 
Figure JPOXMLDOC01-appb-T000076
   　 
Figure JPOXMLDOC01-appb-T000076
   　 
Figure JPOXMLDOC01-appb-T000077
   　 
Figure JPOXMLDOC01-appb-T000077
   　 
Figure JPOXMLDOC01-appb-T000078
   　 
Figure JPOXMLDOC01-appb-T000078
   　 
Figure JPOXMLDOC01-appb-T000079
   　 
Figure JPOXMLDOC01-appb-T000079
   　 
Figure JPOXMLDOC01-appb-T000080
   　 
Figure JPOXMLDOC01-appb-T000080
   　 
Figure JPOXMLDOC01-appb-T000081
   　 
Figure JPOXMLDOC01-appb-T000081
   　 
Figure JPOXMLDOC01-appb-T000082
   　 
Figure JPOXMLDOC01-appb-T000082
   　 
試験例１　[グリシン取り込み阻害実験]
　グリシン取り込み実験はＮｅｕｒｏｎ，８，９２７－９３５，１９９２に掲載された方法に従って行った。ヒト１型グリシントランスポーター（ＧｌｙＴ１）を発現した神経膠腫であるＴ９８Ｇ細胞を用いた。Ｔ９８Ｇ細胞を９６ウェルプレートに２．０×１０4個／ウェルにて播種し、炭酸ガスインキュベーター内にて一晩培養した。被検物質は１００％ＤＭＳＯ溶液に溶解したのち、１５０ｍＭ塩化ナトリウム、１ｍＭ塩化カルシウム、５ｍＭ塩化カリウム、１ｍＭ塩化マグネシウム、１０ｍＭグルコースおよび０．２％ウシ血清アルブミンを含む１０ｍＭＨＥＰＥＳ緩衝液（ｐＨ７．４）に溶解させた。細胞培養用培地を除去した後、被検物質を１０分間前処置した。その後、被検物質および［3Ｈ］グリシン（最終濃度　２５０ｎＭ）を細胞に添加し、室温にて１５分間反応させた。反応終了後、マニーホールドにて細胞外液を吸引し、細胞外に存在する余分な標識グリシンを除去したのち、０．５Ｍの水酸化ナトリウム水溶液にて細胞を溶解した。細胞内に存在するグリシン量は、細胞溶解液中の放射活性を液体シンチレーションカウンターで測定することにより求めた。１０μＭのＡＬＸ５４０７存在下におけるグリシン取り込み量を非特異的取り込みとし、１０μＭのＡＬＸ５４０７非存在下の総取り込み量から非特異的取り込み量を差し引いたものを特異的取り込み量とした。また、被検物質の１０-9～１０-5Ｍ濃度での抑制曲線からグリシン取り込み阻害活性（ＩＣ50値）を算出した。 Test Example 1 [Glycine uptake inhibition experiment]
Glycine uptake experiments were performed according to the method described in Neuron, 8, 927-935, 1992. T98G cells that are gliomas expressing human type 1 glycine transporter (GlyT1) were used. T98G cells were seeded in a 96-well plate at 2.0 × 10 4 cells / well and cultured overnight in a carbon dioxide incubator. A test substance is dissolved in a 100% DMSO solution, and then dissolved in 10 mM HEPES buffer (pH 7.4) containing 150 mM sodium chloride, 1 mM calcium chloride, 5 mM potassium chloride, 1 mM magnesium chloride, 10 mM glucose, and 0.2% bovine serum albumin. Dissolved. After removing the cell culture medium, the test substance was pretreated for 10 minutes. Thereafter, a test substance and [ 3 H] glycine (final concentration 250 nM) were added to the cells and allowed to react at room temperature for 15 minutes. After completion of the reaction, the extracellular fluid was aspirated with a manifold, the excess labeled glycine present outside the cells was removed, and then the cells were lysed with a 0.5 M aqueous sodium hydroxide solution. The amount of glycine present in the cells was determined by measuring the radioactivity in the cell lysate with a liquid scintillation counter. The glycine uptake in the presence of 10 μM ALX5407 was defined as nonspecific uptake, and the total uptake in the absence of 10 μM ALX5407 minus the nonspecific uptake was defined as the specific uptake. Further, the glycine uptake inhibitory activity (IC 50 value) was calculated from the suppression curve of the test substance at 10 −9 to 10 −5 M concentration.
　なおＡＬＸ５４０７はＮ－［（３Ｒ）－３－（［１，１’－ビフェニル］－４－イルオキシ）－３－（４－フルオロフェニル）プロピル］－Ｎ－メチルグリシンＨＣｌ塩である。 ALX5407 is N-[(3R) -3-([1,1'-biphenyl] -4-yloxy) -3- (4-fluorophenyl) propyl] -N-methylglycine HCl salt.
　本発明における実施例化合物のＩＣ50値はすべて１０μＭ未満であった。具体的に例示すると、化合物３のＩＣ50値は０．２３μＭ、化合物１８のＩＣ50値は２．３μＭ、化合物２９のＩＣ50値は０．０８７μＭ、化合物１００のＩＣ50値は０．０６２μＭ、化合物１３４のＩＣ50値は０．４３μＭ、化合物１９４のＩＣ50値は１．８μＭ、化合物２４０のＩＣ50値は０．０９１μＭ、化合物２４８のＩＣ50値は０．１３μＭ、化合物２５３のＩＣ50値は０．０６５μＭ、化合物２５７のＩＣ50値は０．０５７μＭ、また化合物２９７のＩＣ50値は０．０３８μＭであった。 The IC 50 values of the example compounds in the present invention were all less than 10 μM. Specific examples, an IC 50 value of Compound 3 0.23MyuM, an IC 50 value of Compound 18 2.3MyuM, an IC 50 value is 0.087μM of compound 29, the IC 50 values for compounds 100 0.062MyuM, Compound 134 has an IC 50 value of 0.43 μM, Compound 194 has an IC 50 value of 1.8 μM, Compound 240 has an IC 50 value of 0.091 μM, Compound 248 has an IC 50 value of 0.13 μM, and Compound 253 has an IC 50 value of 0.065 μM, Compound 257 had an IC 50 value of 0.057 μM, and Compound 297 had an IC 50 value of 0.038 μM.
　本発明化合物はグリシントランスポーター（ＧｌｙＴ１）阻害活性を有し、従って、グリシントランスポーターに関連する疾患、具体的には、統合失調症、アルツハイマー病、認知機能障害、認知症、不安障害（全般性不安障害、パニック障害、強迫性障害、社会不安障害、外傷後ストレス障害、特定の恐怖症、急性ストレス障害等）、うつ病、薬物依存、痙攣、振戦、疼痛、パーキンソン病、注意欠陥・多動性障害、双極性障害、摂食障害、又は睡眠障害等の予防又は治療に有効である。 The compound of the present invention has glycine transporter (GlyT1) inhibitory activity, and therefore, diseases related to the glycine transporter, specifically, schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder (generality) Anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, post-traumatic stress disorder, specific phobia, acute stress disorder, etc.), depression, drug dependence, convulsions, tremor, pain, Parkinson's disease, attention deficit / many It is effective for the prevention or treatment of dyskinesia, bipolar disorder, eating disorder, or sleep disorder.

Claims (12)

  1. 式［Ｉ］
    Figure JPOXMLDOC01-appb-C000001
      　 
    （式中、
    Ｒ1は、フェニル基、ピリジル基、ピリダジル基、ピリミジル基、ピラジル基、又はピリドニル基を示し、
    該フェニル基、ピリジル基、ピリダジル基、ピリミジル基、ピラジル基、及びピリドニル基は、置換基群１から選ばれる１～３個の置換基で置換されてもよく、
    置換基群１は、Ｃ1-6アルキル基(該Ｃ1-6アルキル基は、ヒドロキシ基、Ｃ1-6アルカノイルオキシ基、及び式－ＮＲ7Ｒ8で示される基からなる群から選ばれる１～３個の置換基で置換されてもよく、Ｒ7、及びＲ8は、同一又は異なって、水素原子又はＣ1-6アルキル基を示す)、ハロＣ1-6アルキル基、Ｃ1-6アルコキシ基、ハロＣ1-6アルコキシ基、Ｃ2-7アルコキシカルボニル基、シアノ基、ハロゲン原子、５員若しくは６員のヘテロアリール基(該５員若しくは６員のヘテロアリール基は、１又２個のＣ1-6アルキル基で置換されてもよい)、Ｃ1-6アルカノイル基、及び式－ＮＲ9Ｒ10(Ｒ9、及びＲ10は、同一又は異なって、水素原子又はＣ1-6アルキル基を示すか、或いは、Ｒ9、及びＲ10が結合する窒素原子と一緒になって４～６員の飽和複素環を形成し、該４～６員の飽和複素環はオキソ基で置換されてもよい)で示される基からなる群であり、
    Ｒ2は、置換基群２から選ばれる１～３個の置換基で置換されてもよいフェニル基、又は置換基群２から選ばれる１～３個の置換基で置換されてもよい単環若しくは二環のヘテロアリール基を示し、
    該置換基群２は、フェニル基（該フェニル基は、Ｃ1-6アルキル基、Ｃ1-6アルコキシ基、及びハロゲン原子からなる群から選ばれる１～３個の置換基で置換されてもよい）、Ｃ1-6アルキル基(該Ｃ1-6アルキル基は、Ｃ1-6アルコキシ基、フェニル基、Ｃ3-6シクロアルキル基、ハロＣ1-6アルコキシ基、ハロＣ3-6シクロアルキル基、及び３－メチルオキセタン－３－イル基からなる群から選ばれる１～３個の置換基で置換されてもよい)、ハロＣ1-6アルキル基、Ｃ1-6アルコキシ基(該Ｃ1-6アルコキシ基は、Ｃ1-6アルコキシ基、ヒドロキシ基、Ｃ3-6シクロアルキル基、及び３－メチルオキセタン－３－イル基からなる群から選ばれる１～３個の置換基で置換されてもよい)、ヒドロキシ基、ベンジルオキシ基、ハロＣ1-6アルコキシ基、Ｃ3-6シクロアルキル基、Ｃ3-6シクロアルコキシ基、テトラヒドロフラニル基、テトラヒドロフラニルオキシ基、テトラヒドロピラニル基、テトラヒドロピラニルオキシ基、Ｃ2-7アルコキシカルボニル基、シアノ基、ハロゲン原子、５員若しくは６員のヘテロアリール基(該５員若しくは６員のヘテロアリール基は、Ｃ1-6アルキル基、ハロゲン原子、及びＣ1-6アルコキシ基からなる群から選ばれる１又は２個の置換基で置換されてもよい)、Ｃ1-6アルカノイル基、式－ＮＲ11Ｒ12(Ｒ11、及びＲ12は、同一又は異なって、水素原子又はＣ1-6アルキル基を示すか、或いは、Ｒ11、及びＲ12が結合する窒素原子と一緒になって４～６員の飽和複素環を形成し、該４～６員の飽和複素環はオキソ基で置換されてもよい)で示される基、及び式－ＣＯＮＲ13Ｒ14(Ｒ13、及びＲ14は、同一又は異なって、水素原子又はＣ1-6アルキル基を示すか、或いは、Ｒ13、及びＲ14が結合する窒素原子と一緒になって４～６員の飽和複素環を形成し、該４～６員の飽和複素環はオキソ基で置換されてもよい)で示される基からなる群であり、
    Ｒ3、及びＲ4は、同一又は異なって、水素原子、Ｃ1-6アルキル基、Ｃ3-6シクロアルキル基、フェニル基、又はベンジル基を示すか、或いは、Ｒ3、及びＲ4が結合する炭素原子と一緒になってＣ3-7シクロアルカン環、テトラヒドロフラン環、又はテトラヒドロピラン環を形成し（但し、Ｒ3、及びＲ4が共に水素原子である場合を除く）、
    Ｒ5、及びＲ6は、同一又は異なって、水素原子、Ｃ1-6アルキル基を示す）で表される化合物又はその医薬上許容される塩(但し、Ｒ1が置換基群１から選ばれる１～３個の置換基で置換されてもよいフェニル基である場合、Ｒ2は置換基群２から選ばれる１～３個の置換基で置換されてもよい単環若しくは二環のヘテロアリール基である)。     Formula [I]
    Figure JPOXMLDOC01-appb-C000001

    (Where
    R 1 represents a phenyl group, a pyridyl group, a pyridazyl group, a pyrimidyl group, a pyrazyl group, or a pyridonyl group;
    The phenyl group, pyridyl group, pyridazyl group, pyrimidyl group, pyrazyl group, and pyridonyl group may be substituted with 1 to 3 substituents selected from the substituent group 1.
    Substituent group 1 is a C 1-6 alkyl group (the C 1-6 alkyl group is selected from the group consisting of a hydroxy group, a C 1-6 alkanoyloxy group, and a group represented by the formula —NR 7 R 8. 1 to 3 substituents may be substituted, and R 7 and R 8 may be the same or different and each represents a hydrogen atom or a C 1-6 alkyl group), a halo C 1-6 alkyl group, C 1 -6 alkoxy group, halo C 1-6 alkoxy group, C 2-7 alkoxycarbonyl group, cyano group, halogen atom, 5-membered or 6-membered heteroaryl group (the 5-membered or 6-membered heteroaryl group is 1 And may be substituted with two C 1-6 alkyl groups), a C 1-6 alkanoyl group, and a formula —NR 9 R 10 (R 9 and R 10 may be the same or different and represent a hydrogen atom or C 1-6 represents an alkyl group, or a saturated double of R 9, and together with the nitrogen atom to which R 10 is attached 4-6 membered Forms a ring, saturated heterocyclic ring of the 4-6 membered are the group consisting of groups represented by oxo may be substituted with a group),
    R 2 represents a phenyl group which may be substituted with 1 to 3 substituents selected from Substituent Group 2 or a monocycle which may be substituted with 1 to 3 substituents selected from Substituent Group 2 Or a bicyclic heteroaryl group,
    The substituent group 2 is a phenyl group (the phenyl group may be substituted with 1 to 3 substituents selected from the group consisting of a C 1-6 alkyl group, a C 1-6 alkoxy group, and a halogen atom. C 1-6 alkyl group (the C 1-6 alkyl group is a C 1-6 alkoxy group, a phenyl group, a C 3-6 cycloalkyl group, a halo C 1-6 alkoxy group, a halo C 3-6 A cycloalkyl group, and 1 to 3 substituents selected from the group consisting of a 3-methyloxetane-3-yl group), a halo C 1-6 alkyl group, a C 1-6 alkoxy group ( The C 1-6 alkoxy group includes 1 to 3 substituents selected from the group consisting of a C 1-6 alkoxy group, a hydroxy group, a C 3-6 cycloalkyl group, and a 3-methyloxetane-3-yl group. A hydroxy group, a benzyloxy group, a halo C 1-6 alkoxy group, a C 3-6 cycloa Alkyl group, C 3-6 cycloalkoxy group, tetrahydrofuranyl group, tetrahydrofuranyloxy group, tetrahydropyranyl group, tetrahydropyranyloxy group, C 2-7 alkoxycarbonyl group, cyano group, halogen atom, 5 or 6 member (The 5- or 6-membered heteroaryl group is substituted with 1 or 2 substituents selected from the group consisting of a C 1-6 alkyl group, a halogen atom, and a C 1-6 alkoxy group. Or a C 1-6 alkanoyl group, the formula —NR 11 R 12 (R 11 and R 12 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group, or R 11 , And a nitrogen atom to which R 12 is bonded to form a 4- to 6-membered saturated heterocyclic ring, and the 4- to 6-membered saturated heterocyclic ring may be substituted with an oxo group, and formula -CONR 13 R 14 ( 13, and R 14 are the same or different, and represent a hydrogen atom or a C 1-6 alkyl group, or, R 13, and R 14 together with the nitrogen atom bonded 4-6 membered saturated heterocyclic Forming a ring, and the 4- to 6-membered saturated heterocyclic ring may be substituted with an oxo group).
    R 3 and R 4 are the same or different and each represents a hydrogen atom, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a phenyl group, or a benzyl group, or R 3 and R 4 are Combined with the carbon atom to form a C 3-7 cycloalkane ring, tetrahydrofuran ring, or tetrahydropyran ring (except when R 3 and R 4 are both hydrogen atoms)
    R 5 and R 6 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group) or a pharmaceutically acceptable salt thereof (provided that R 1 is selected from substituent group 1) R 2 is a monocyclic or bicyclic hetero ring which may be substituted with 1 to 3 substituents selected from Substituent Group 2; An aryl group).
  2. Ｒ5、及びＲ6が共に水素原子である請求項１に記載の化合物又はその医薬上許容される塩。 The compound according to claim 1, wherein R 5 and R 6 are both hydrogen atoms, or a pharmaceutically acceptable salt thereof.
  3. Ｒ3、及びＲ4が結合する炭素原子と一緒になってＣ3-7シクロアルカン環を形成する請求項１又は２に記載の化合物又はその医薬上許容される塩。 The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R 3 and R 4 together with the carbon atom to which R 4 is bonded form a C 3-7 cycloalkane ring.
  4. Ｒ2が置換基群２から選ばれる１～３個の置換基で置換されてもよいフェニル基、又は置換基群２から選ばれる１～３個の置換基で置換されてもよい単環のヘテロアリール基である請求項１～３のいずれか１項に記載の化合物又はその医薬上許容される塩。 R 2 represents a phenyl group which may be substituted with 1 to 3 substituents selected from Substituent Group 2 or a monocyclic ring which may be substituted with 1 to 3 substituents selected from Substituent Group 2 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, which is a heteroaryl group.
  5. Ｒ2が置換基群３から選ばれる１～３個の置換基で置換されてもよいフェニル基、又は置換基群４から選ばれる１～３個の置換基で置換されてもよい単環のヘテロアリール基であり、
    置換基群３が、Ｃ1-6アルコキシ基、ハロＣ1-6アルコキシ基、及び５員のヘテロアリール基からなる群であり、
    置換基群４が、フェニル基（該フェニル基は、Ｃ1-6アルキル基、Ｃ1-6アルコキシ基、及びハロゲン原子からなる群から選ばれる１～３個の置換基で置換されてもよい）、Ｃ1-6アルコキシ基、ハロＣ1-6アルコキシ基、及び５員若しくは６員のヘテロアリール基からなる群である請求項１～３のいずれか１項に記載の化合物又はその医薬上許容される塩。     R 2 is a phenyl group which may be substituted with 1 to 3 substituents selected from substituent group 3 or a monocyclic ring which may be substituted with 1 to 3 substituents selected from substituent group 4 A heteroaryl group,
    Substituent group 3 is a group consisting of a C 1-6 alkoxy group, a halo C 1-6 alkoxy group, and a 5-membered heteroaryl group,
    Substituent group 4 is a phenyl group (the phenyl group may be substituted with 1 to 3 substituents selected from the group consisting of a C 1-6 alkyl group, a C 1-6 alkoxy group, and a halogen atom). ), A C 1-6 alkoxy group, a halo C 1-6 alkoxy group, and a 5-membered or 6-membered heteroaryl group, or a compound thereof according to any one of claims 1 to 3 Acceptable salt.
  6. Ｒ2が置換基群３から選ばれる１～３個の置換基で置換されてもよいフェニル基、置換基群４から選ばれる１～２個の置換基で置換されてもよいイソオキサゾール基、置換基群４から選ばれる１個の置換基で置換されてもよいオキサジアゾール基、置換基群４から選ばれる１～２個の置換基で置換されてもよいトリアゾール基、置換基群４から選ばれる１～３個の置換基で置換されてもよいピラゾール基、又は置換基群４から選ばれる１～３個の置換基で置換されてもよいピリジル基である請求項１～３のいずれか１項に記載の化合物又はその医薬上許容される塩。 R 2 is a phenyl group which may be substituted with 1 to 3 substituents selected from substituent group 3, an isoxazole group which may be substituted with 1 to 2 substituents selected from substituent group 4, An oxadiazole group which may be substituted with one substituent selected from substituent group 4, a triazole group which may be substituted with one or two substituents selected from substituent group 4, substituent group 4 4. The pyrazole group which may be substituted with 1 to 3 substituents selected from: or a pyridyl group which may be substituted with 1 to 3 substituents selected from substituent group 4. The compound according to any one of the above or a pharmaceutically acceptable salt thereof.
  7. Ｒ2が１個の５員のヘテロアリール基で置換されてもよいフェニル基、置換基群４から選ばれる１～２個の置換基で置換されてもよいイソオキサゾール基、置換基群４から選ばれる１～３個の置換基で置換されてもよいピラゾール基、又は置換基群４から選ばれる１～３個の置換基で置換されてもよいピリジル基である請求項１～３のいずれか１項に記載の化合物又はその医薬上許容される塩。 R 2 represents a phenyl group which may be substituted with one 5-membered heteroaryl group, an isoxazole group which may be substituted with 1 to 2 substituents selected from Substituent Group 4, and Substituent Group 4 4. The pyrazole group which may be substituted with 1 to 3 substituents selected, or the pyridyl group which may be substituted with 1 to 3 substituents selected from Substituent Group 4. Or a pharmaceutically acceptable salt thereof.
  8. Ｒ1がピリジル基、ピリダジル基、ピリミジル基、ピラジル基、又はピリドニル基であり、
    該ピリジル基、ピリダジル基、ピリミジル基、ピラジル基、及びピリドニル基は、置換基群１から選ばれる１～３個の置換基で置換されてもよい請求項１～７のいずれか１項に記載の化合物又はその医薬上許容される塩。     R 1 is a pyridyl group, pyridazyl group, pyrimidyl group, pyrazyl group, or pyridonyl group;
    8. The pyridyl group, pyridazyl group, pyrimidyl group, pyrazyl group, and pyridonyl group may be substituted with 1 to 3 substituents selected from the substituent group 1. Or a pharmaceutically acceptable salt thereof.
  9. Ｒ1がフェニル基、ピリジル基、ピリミジル基、又はピラジル基であり、
    該フェニル基、ピリジル基、ピリミジル基、及びピラジル基は、置換基群５から選ばれる１～３個の置換基で置換されてもよく、
    置換基群５は、Ｃ1-6アルキル基、ハロＣ1-6アルキル基、Ｃ1-6アルコキシ基、ハロＣ1-6アルコキシ基、シアノ基、及びハロゲン原子からなる群である請求項１～７のいずれか１項に記載の化合物又はその医薬上許容される塩。     R 1 is a phenyl group, a pyridyl group, a pyrimidyl group, or a pyrazyl group;
    The phenyl group, pyridyl group, pyrimidyl group, and pyrazyl group may be substituted with 1 to 3 substituents selected from the substituent group 5.
    The substituent group 5 is a group consisting of a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 1-6 alkoxy group, a halo C 1-6 alkoxy group, a cyano group, and a halogen atom. 8. The compound according to any one of 1 to 7 or a pharmaceutically acceptable salt thereof.
  10. Ｒ1が置換基群５から選ばれる１～３個の置換基で置換されたピリジル基、又は置換基群５から選ばれる１～３個の置換基で置換されたピリミジル基である請求項１～７のいずれか１項に記載の化合物又はその医薬上許容される塩。 2. R 1 is a pyridyl group substituted with 1 to 3 substituents selected from substituent group 5 or a pyrimidyl group substituted with 1 to 3 substituents selected from substituent group 5 8. The compound according to any one of 1 to 7 or a pharmaceutically acceptable salt thereof.
  11. 請求項１～１０のいずれか１項に記載の化合物又はその医薬上許容される塩を有効成分として含む医薬組成物。 A pharmaceutical composition comprising as an active ingredient the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.
  12. 請求項１～１０のいずれか１項に記載の化合物又はその医薬上許容される塩を有効成分として含む、統合失調症、アルツハイマー病、認知機能障害、認知症、不安障害、うつ病、薬物依存、痙攣、振戦、疼痛、パーキンソン病、注意欠陥・多動性障害、双極性障害、摂食障害、又は睡眠障害の疾患の予防剤又は治療剤。 A schizophrenia, Alzheimer's disease, cognitive dysfunction, dementia, anxiety disorder, depression, drug dependence, comprising the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof as an active ingredient , Convulsions, tremors, pain, Parkinson's disease, attention deficit / hyperactivity disorder, bipolar disorder, eating disorder, or sleep disorder preventive or therapeutic agent.
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